Theranostics
·
2025
·Vol. 15
·期 9
·3877
·
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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PubMed
高影响因子
Food & Function
·
2020
·Vol. 11
·期 6
·5156-5165
·
IF 4.171
Yu-Sheng Shi,Xiao-Xing Li,Hao-Tian Li,Yan Zhang
Liver fibrosis is a histological change that often occurs due to hepatic stellate cell (HSC) activation and excessive formation of an extracellular matrix in the liver. Pelargonidin (PEL) is a natural anthocyanidin existing in blueberries, berries, strawberries, and red radishes and has been demonstrated to possess health beneficial effects. Herein, we investigated the effect of PEL on liver fibrosis induced by CCl4 and hepatic stellate cells induced by transforming growth factor-β (TGF-β). We found that PEL administration prevented liver injury and liver fibrosis induced by CCl4 in a dose-dependent manner. Further data revealed that PEL increased liver nuclear factor E2-related factor 2 (Nrf2) and reduced liver oxidative stress and the expression levels of NLRP3, caspase-1 and IL-1β. In TGF-β-challenged HSCs (LX-2 cells), PEL effectively inhibited the LX-2 cell activation. In addition, the anti-fibrosis effects of PEL in LX-2 cells were abolished by Nrf2 knockdown. In summary, our study demonstrated that PEL ameliorated CCl4-induced liver fibrosis and HSC activation induced by TGF-β. The possible molecular mechanisms of PEL in liver fibrosis may be attributed to its suppression of ROS-NLRP3-IL-1β signaling by Nrf2 activation.
研究领域:
药理学
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肝病学
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分子生物学
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PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·133-145
·
IF 6.15
Shen Dai-fei,Cheng He,Cai Bo-zhi,Cai Wen-feng,Wang Bin,Zhu Qing,Wu Yue-bin,Liu Man,Chen Run-ji,Gao Fen-fei,Zhang Yan-mei,Niu Yong-dong,Shi Gang-gang
N -n-Butyl haloperidol iodide (F 2 ) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F 2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl 4 ) or thioacetamide (TAA). The mice received F 2 (0.75, 1.5 or 3 mg·kg −1 ·d −1 , ip) for 4 weeks of fibrosis induction. We showed that F 2 administration dose-dependently ameliorated CCl 4 - or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-β receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F 2 (0.1, 1, 10 μM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F 2 inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-β signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-β1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-β signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F 2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-β signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F 2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1. F 2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.
研究领域:
药理学
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肝病学
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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
Frontiers in Marine Science
·
2025
·
IF 3
Fengxia Xu,Limin Dong,Chengxue Qin,Yanru Ren,Liang Kong,Mengru Zhang,Haitao Du,Qing Xia,Cheng Wang,Ping Wang
Introduction: Bone, as both a crucial organ with mechanical support and immune regulatory functions, profoundly influencing the growth and development of fish in aquaculture systems. Deer antler and its aqueous extract Cervi Cornus Colla (CCC), are natural medicinal substances known for their bone-protective properties.Methods: This study investigated the osteoprotective effects of CCC against lipopolysaccharide (LPS)-induced injury to fish bones. An LPS-mediated zebrafish skeletal injury model was established and evaluated using Alcian Blue/Alizarin Red staining, fluorescence tracing, ELISA, and qPCR.Results: The median lethal concentration (LC50) of CCC in zebrafish was 206.3 mg/mL, and staining revealed that CCC reversed LPS-induced reduction in cartilage and bone formation in a dose-dependent manner. In Tg (mpeg1: EGFP) zebrafish, CCC treatment significantly decreased macrophages-associated green fluorescence, suggesting that the extract suppressed the activation of macrophages caused by LPS. CCC also reduced the production of several inflammatory factors (IL-6, IL- 1β, and NO). Furthermore, qRT-PCR confirmed CCC restored COL2α1 and Sox9a mRNA levels. Additional studies revealed CCC inhibits LPS-induced activation of the TGF-β/Smad3 signaling pathway.Discussion: This study demonstrates that CCC can alleviate zebrafish bone injury, thereby providing an experimental basis for its application in the prevention and treatment of bone diseases in farmed fish.
研究领域:
水产养殖
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药理学
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免疫学
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分子生物学
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兽医学
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 9
·4061
·
IF 5.6
Yuelu Lan,Sijia Li,Shuangli Zhu,Can Pan,Kai Fu,Xueping Wang,Liwu Fu,Fang Wang
Chronic liver injury is characterized by sustained activation of transforming growth factor-β (TGF-β) signaling within the fibrotic microenvironment, yet the contribution of TGF-β-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-β signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-β1 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-β1/2 promoted HSC proliferation. In vitro, TGF-β1/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT/ERK/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-β-associated lipid accumulation in vitro, reduced SREBP1/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl 4 -induced liver fibrosis. Together, these findings support a model in which TGF-β-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone.
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PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2026
·
IF 19.9
Fengfeng Xiao,Shengni Hua,Fei Liu,Ziliang Yan,Zhengsheng Yi,Yanxia Xu,Haichuan Peng,Jing Xiao,Yongjun Peng,Liewei Wen,Yunlu Dai
Radiotherapy triggers an adaptive upregulation of transforming growth factor-β (TGF-β), which paradoxically promotes radioresistance by reinforcing the stromal barrier, suppressing immunity and accelerating DNA repair. To overcome these limitations, we engineered a multifunctional nanocoordinator (ASO TGF /MPN-aPD-L1) by leveraging the multimodal molecular interaction of bismuth-phenolic networks, creating an “all-in-one” platform that densely encapsulates TGF-β antisense oligonucleotides (ASO TGF ) via metal coordination and π–π stacking while adsorbing aPD-L1 on the surface for sensitizing radio-immunotherapy. Mechanistically, the bismuth component acts as a high-Z radiosensitizer to amplify initial DNA damage, while ASO TGF concurrently blocks TGF-β signaling by inhibiting its translation. This dual action not only abrogates DNA repair pathways but also suppresses cancer-associated fibroblasts (CAFs) activation and remodels the extracellular matrix (ECM) to facilitate cytotoxic T cell infiltration. Furthermore, surface-adsorbed aPD-L1 prevents T cell exhaustion, sustaining long-term antitumor immunity. Our results confirm that this strategy significantly alleviates tumor fibrosis, enhances CD8 + T cell infiltration, and potentiates radiotherapy efficacy in hepatocellular carcinoma models (HCC). Collectively, except for radiosensitization, by simultaneously targeting TGF-β signaling and PD-L1-mediated immune evasion, our nanocoordinator represents a promising strategy to potentiate radioimmunotherapy for HCC.
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DOI
高影响因子
Frontiers in Oncology
·
2020
·
IF 4.848
Chen Shuo,Shen Jiaqi,Zhao Jing,Wang Jiazhong,Shan Tao,Li Junhui,Xu Meng,Chen Xi,Liu Yang,Cao Gang
Magnolol, a hydroxylated biphenyl extracted from Magnolia officinalis, has recently drawn attention due to its anticancer potential. The present study was aimed to explore the effects of Magnolol on restraining the proliferation, migration and invasion of pancreatic cancer in vivo and in vitro. Magnolol showed significant anti-growth effect in an orthotopic xenograft nude mouse model, and immunohistochemical staining of the xenografts revealed that Magnolol suppressed vimentin expression and facilitated E-cadherin expression. The cytoactive detection using CCK-8 assay showed Magnolol inhibited PANC-1 and AsPC-1 concentration-dependently. Scratch healing assay and the Transwell invasion assay proved the inhibiting effects of Magnolol on cellular migration and invasion at a non-cytotoxic concentration. Western blot and rt-PCR showed that Magnolol suppressed epithelial-mesenchymal-transition by increasing the expression level of E-cadherin and decreasing those of N-cadherin and vimentin. Magnolol suppressed the TGF-β/Smad pathway by negatively regulating phosphorylation of Smad2/3. Moreover, TGF-β1 impaired the antitumor effects of Magnolol in vivo. These results demonstrated that Magnolol can inhibit proliferation, migration and invasion in vivo and in vitro by suppressing the TGF-β signal pathway and EMT. Magnolol could be a hopeful therapeutic drug for pancreatic malignancy.
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
ACS Biomaterials Science & Engineering
·
2018
·
IF 4.432
Hongjie Huang,Xiaoqing Hu,Xin Zhang,Xiaoning Duan,Jiying Zhang,Xin Fu,Linghui Dai,Lan Yuan,Chunyan Zhou,Yingfang Ao
Synovium-derived mesenchymal stem cells (SMSCs) are attractive tissue-specific cells for cartilage regeneration because of their easy availability, higher chondrogenic potential, and joint specificity. In the present study, we established a hybrid scaffold to codeliver SMSCs and transforming growth factor beta (TGF-β), which can integrate the scaffolds, the growth factor, and the autogenous cells within rabbit cartilage defects. A chitosan hydrogel and a decellularized bone matrix were used to fabricate the gel–solid duplex phase biomaterials, which were proven to retain more cells, promote tissue integration, and provide mechanical support. In vitro experiments demonstrated that this hybrid scaffold could release TGF-β in a controlled biphasic pattern, which can promote cell proliferation and chondrogenic differentiation of loaded rabbit SMSCs. For in vivo experiments, we filled cartilage defects with the hybrid materials, delivering autogenous SMSCs and TGF-β simultaneously via chitosan’s sol–gel transition. Histological analysis, magnetic resonance imaging, and nanoindentation assessment indicated superior cartilage regeneration using this codelivery system compared with that from routine microfracture or control delivery scaffolds. Beyond cartilage regeneration, the easy preparation, favorable biophysical properties, and controlled release ability make this codelivery system applicable to transport other tissue-specific cells or biofactors for tissue engineering.
研究领域:
生物医学工程
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再生医学
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组织工程
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DOI
PubMed
高影响因子
Scientific Reports
·
2025
·
IF 3.9
Xu Qiuling,Liu Zhuoxi,Wang Liyuan,Liu Guoyang,Zhao Long,Yue Hui,Liu Yong
Diabetic cardiomyopathy (DCM) requires a systematic approach for effective management. Focusing on key signaling pathways in myocardial fibrosis could offer novel therapeutic approaches for DCM. The objective of this research is to investigate new biomarker and the underlying mechanisms by which baicalin intervenes in the progression of DCM. Swiss Target Prediction databases and weighted correlation network analysis (WGCNA) were employed to collect and analyze targets of baicalin and DCM. Intersection targets were obtained through venn online website, network visualization was conducted through STRING database and Cytoscape 3.7.2 software. Molecular docking validation was completed via AutoDock Vina software. Western blotting, RT-qPCR and histology were carried out to validate the direct targets of baicalin and explore the molecular mechanism during DCM progression. In mice induced to DCM, we observed that disruptor of telomeric silencing 1-like (DOT1L) was upregulated. Baicalin (BC) reduced myocardial fibrosis in mice as indicated by the reduced expression levels of fibrosis markers COL-1 and TGF-β. The inhibitory effect of BC was reversed by overexpressed DOT1L and further enhanced by silenced DOT1L. Our results indicate that cardiomyocyte DOT1L exerts a pathogenic role in DCM and BC specifically targets DOT1L/COL-1 signaling to reduce myocardial fibrosis in DCM.
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PubMed
高影响因子
Molecular Medicine Reports
·
2016
·Vol. 13
·期 4
·3567-3573
·
IF 1.559
Ke Jiang,Guo Chun,Ziming Wang,Quanyin Du,Aimin Wang,Yan Xiong
Tendon adhesion is a common problem in the healing of injured tendons. The molecular mechanisms of the TGF-β/Smad signaling pathway have been determined, and the role of TGF-β has been well characterized in wound healing. However, the intracellular mechanism or downstream signals by which TGF-β3 modulates its effects on tendon healing have not been well elucidated. The aim of this study was to determine the effect of TGF‑β3 on the TGF-β/Smad signaling pathway in tenocytes. Quantitative polymerase chain reaction and western blot analysis were used to analyze the effect of TGF‑β3 on the regulation of the expression of Smad proteins in tenocytes. The results demonstrated that TGF‑β3 has no significant effect on the proliferation of tendon cells. The addition of TGF‑β3 to tenocytes can significantly downregulate the expression of Smad3 and upregulate the expression of Smad7 at the gene and protein levels. The results demonstrate that TGF‑β3 may regulate Smad3 and Smad7 proteins through the TGF-β/Smad signaling pathway to minimize extrinsic scarring. Thus, it may provide a novel approach to decrease tendon adhesion and promote tendon healing.
研究领域:
分子生物学
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细胞生物学
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骨科
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DOI
PubMed
高影响因子
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
·
2018
·Vol. 46
·期 3
·1078-1090
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IF 5.5
Zeng Xinliu,Yue Zhang,Gao Ying,Jiang Guosong,Zeng Fuqing,Shao Ying,Huang Jiayu,Yin Minuo,Li Yajie
Background/Aims: Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis. Methods: Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining. Results: The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers. Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo. Conclusion: NR4A1 can regulate fibrosis in endometriosis and may serve as a new target for the treatment of endometriosis
研究领域:
妇科学
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分子生物学
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病理生理学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·
IF 12.6
Shijin Xu,Naidi Yang,Fangning Du,Ziying Zhang,Yin Zhang,Yixuan Zhang,Jiawei Liang,Yihan Zhao,Jiajun Zhang,Ziwei Zhang,Xiaoxuan Han,Zena Chen,Zhiqiang Zhou,Shu Zhang,Lin Li,Ying Lv
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, marked by extensive stromal fibrosis and a profoundly immunosuppressive, immune-excluded tumor microenvironment (TME) that hampers the efficacy of immune checkpoint blockade. Although photodynamic therapy (PDT) can induce immunogenic cell death (ICD) and stimulate anti-tumor immunity, its effectiveness against PDAC is limited by insufficient immune activation and persistent stromal-mediated immunosuppression. To address these challenges, we develop a liposomal nanodrug that co-encapsulates a mitochondrial-targeted photosensitizer (MP) and a TGF-β receptor inhibitor (LY2109761) to synergize PDT with PD-1 checkpoint blockade. MP selectively accumulates in mitochondria and, upon light activation, amplifies mitochondrial reactive oxygen species production, inducing mitochondrial damage. This damage triggers the release of mitochondrial DNA and damage-associated molecular patterns, activating the STING pathway and eliciting potent ICD and anti-tumor immune responses. Simultaneously, liposome-mediated delivery of LY2109761 mitigates stromal desmoplasia and reverses TGF-β-driven immune suppression, enhancing effector T cell infiltration and activity. In murine PDAC models, this dual-action strategy transforms the immune-cold TME into an immune-inflamed phenotype, sensitizing tumors to PD-1 therapy and leading to pronounced tumor regression and prolonged survival. Our findings present a promising nanodrug-based approach to remodel the fibrotic and immunosuppressive TME of PDAC and enhance immunotherapeutic outcomes.
研究领域:
肿瘤学
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免疫治疗
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纳米医学
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光动力治疗
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肿瘤微环境
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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