MOLECULAR DIVERSITY
·
2024
·
IF 3.9
Ding Shu-Yan,Yang Yu-Xuan,Liu Chuang,Quan Xu-Yin,Zhao Zi-Han,Jin Cheng-Hua
Four series of sulfonamide derivatives ( 13a – b , 14a – d , 15a – b , and 16a – d ) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC 50 = 0.130 μM) and 15a (IC 50 = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY - 2157299 . Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.
研究领域:
药物化学
·
分子生物学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
·
2018
·Vol. 46
·期 3
·1078-1090
·
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
·
分子生物学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
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
·
分子生物学
·
肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2019
·
IF 3.046
Ling-Hui Zeng,Qing-Mei Wang,Lin-Yi Feng,Yu-Dun Ke,Qian-Zi Xu,An-Yi Wei,Chong Zhang,Rong-Biao Ying
Purpose Vitamin C (VC) is a kind of essential nutrient in the body regarded as a canonical antioxidant during the past hundred years. However, the anti-cancer effect of VC is controversial. Our study is trying to clarify the relationship between VC dosage and breast cancer metastasis. Methods Human breast cancer cell lines Bcap37 and MDA-MB-453 were treated with VC at three different concentrations (low-dose, 0.01 mM; medium-dose, 0.1 mM; high-dose, 2 mM). Wound healing assays were conducted for migration assay; transwell tests were performed to detect the ability of cell invasion. The protein levels were evaluated by Western blot analysis or immunohistochemistry. Tumor xenografts in nude mice were built to test the effects of VC on breast cancer cell proliferation and metastasis. Results 0.01 and 0.1 mM VC promoted cell migration and invasion when compared with the control group, but 2 mM VC significantly suppressed cell migration and invasion of breast cancer cell lines. High-dose VC increased E-cadherin and reduced Vimentin, indicating that high-dose VC suppressed epithelial-mesenchymal transition (EMT) in breast cancer cells. Besides, high-dose VC inhibited cell invasion promoted by TGF-β1 in breast cancer cells. Meanwhile, high-dose VC reversed the suppression of E-cadherin and enhancement of Vimentin induced by TGF-β1 in breast cancer cells. Furthermore, high-dose VC significantly inhibited breast cancer metastasis in vivo. Conclusion High-dose VC inhibits cell migration and invasion of breast cancer cell lines through suppressing EMT. Thus, it may be considered as an anticancer drug candidate for breast cancer patients.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Lili Niu,Yao Liu,Nannan Li,Yang Wang,Lin Kang,Xiaomin Su,Ce Xu,Zanya Sun,Weicong Sang,Jingyuan Xu,Huishu Guo,Shun Shen
Transforming growth factor β (TGF-β), a versatile immunosuppressive cytokine, has gained increasing attention as a potential target for cancer immunotherapy. However, current strategies are constrained by tumor heterogeneity and drug resistance. Therapeutic probiotics, such as Escherichia coli Nissle1917 ( EcN ), not only regulate the gut microbiota to increase beneficial bacteria with anti-tumor effects, but also modulate immune factors within the body, thereby enhancing immunity. In this study, we developed an oral microgel delivery system of EcN @(CS-SA) 2 by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN @(CS-SA) 2 microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-β inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8 + T cells into the tumor microenvironment (TME).
研究领域:
肿瘤学
·
免疫治疗
·
药学
·
微生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2020
·Vol. 22
·期 5
·3687-3694
·
IF 2.1
Yingli Ren,Xiangdong Jian,Zhongchen Zhang,Qiong Ning,Baotian Kan,Li Kong
Paraquat is a highly toxic pesticide, which often causes pulmonary interstitial fibrosis after poisoning, and there is no specific antidote. At present, limited studies have reported that tacrolimus, as an immunosuppressant, can inhibit pulmonary fibrosis, but the specific mechanism remains unknown. The aim of the present study was to demonstrate the effect of tacrolimus on the TGF‑β1 pathway associated with pulmonary fibrosis in paraquat exposed alveolar type II epithelial cells, and to identify the antipulmonary fibrosis mechanism of tacrolimus The rat alveolar epithelial type II RLE‑6TN cell line was exposed to paraquat and treated with or without tacrolimus for 24 h, or with a TGF‑β1 receptor type I/II inhibitor (LY2109761) for 1, 4, 8 or 16 h. MTT assays were used to detect the viability of rat alveolar type II epithelial cells under these different treatment conditions, while the concentrations of TGF‑β1, SMAD3, SMAD7 and connective tissue growth factor (CTGF) in the cell culture supernatant were determined using ELISAs. Additionally, reverse transcription‑quantitative PCR and immunofluorescence were used to analyze the mRNA and protein expression levels of TGF‑β1, SMAD3, CTGF and SMAD7. The results demonstrated that the inhibition of the proliferation of RLE‑6TN cells exposed to 200 nmol/l paraquat was 26.05±2.99%. The inhibition rate of 10 ng/ml tacrolimus on paraquat‑exposed alveolar type II epithelial cells was 18.40±3.49%. The inhibition rate caused by 5 µmol/l LY2109761 was 26.56±4.49%. The expression levels of TGF‑β1, SMAD3 and CTGF, as well as their concentrations in the culture supernatant, were significantly downregulated in the tacrolimus group compared with the paraquat group. However, both the concentration and expression levels of SMAD7 were significantly upregulated in the tacrolimus group compared with the paraquat group. In conclusion, tacrolimus can reduce the levels of TGF‑β1, SMAD3 and CTGF, increase the level of SMAD7 in TGF‑β1 signaling pathway and protect the development of pulmonary fibrosis in paraquat exposed alveolar epithelial cells.
研究领域:
药理学
·
肺病学
·
细胞生物学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 6
·
IF 7.7
Yifang Chen,Qian Zhang,Na Li,Zhaoqi Zhang,Tong Lei,Han Guo,Hezhe Lu,Yong Zhao
Dendritic cells (DCs) are professional antigen-presenting cells that exhibit significant heterogeneity in development and function. This study found that among 17 cytokines screened, only IL-33 could induce DCs to display a Th9-type cytokine profile, including IL-9, IL-4, and IL-13, in vitro . The response of DCs to IL-33 was synergistically enhanced by TGF-β and IL-4, defining a distinct subset termed DC9. Transcriptomic analysis revealed that DC9 possesses a unique gene expression signature, particularly in cytokine/chemokine clusters, compared to conventional DCs. Mechanistically, DC9 polarization depends on the JAK-STAT6-IRF4 signaling pathway. Functionally, DC9 preferentially drives naive CD4 + T cell differentiation toward Th9 cells in vitro . In an ovalbumin-induced allergic airway inflammatory mouse model, DC9 cells were detectable in lungs and adoptive transfer of DC9 exacerbated disease severity, and increased pulmonary Th9 cells. Collectively, we identify DC9 as a novel DC subset induced by IL-33/TGF-β/IL-4 through the JAK-STAT6-IRF4 axis, which promotes Th9 differentiation and aggravates allergic airway inflammation.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF THERMAL BIOLOGY
·
2026
·
IF 3.2
Yukun Cao,Xin Li,Wangang Gong,Jia Tan,Jing Shen,Xinli Zhou
Cryoablation remodels desmoplastic TME in pancreatic cancer. • Sub-lethal freezing inhibits TGF-β/Smad signaling pathway. • Cryoablation preceding chemotherapy yields superior efficacy. • Disruption of fibrotic barriers sensitizes PDAC to chemotherapy. Cryoablation is effective for solid tumors but is often constrained by limited thermal efficiency and incomplete ablation. Conventional strategies prioritize expanding lethal isotherms to minimize the sub-lethal zone, a practice that increases the risk of collateral injury to adjacent critical structures. This study proposes a novel strategy utilizing the sub-lethal zone to remodel the tumor microenvironment for enhanced therapeutic efficacy. Using pancreatic cancer and stellate cell co-cultured spheroids and subcutaneous tumor models, we investigated fibrotic tumor microenvironment changes induced by the cryoablation sub-lethal zone combined with gemcitabine plus nab-paclitaxel. Results demonstrated that cryoablation significantly disrupted collagen structures and downregulated TGF-β1, p-Smad3, α-SMA, and Collagen I expression. This modulation is associated with the mitigation of fibrotic barriers, thereby potentially improving the accessibility of chemotherapy drugs within the sub-lethal zone. In vivo, cryoablation followed by chemotherapy yielded optimal efficacy compared to reverse sequencing or monotherapy, significantly inhibiting angiogenesis and promoting mitochondrial apoptosis via upregulated Bax and Caspase-3 levels. In conclusion, cryoablation functions as a potent tumor microenvironment remodeler. By downregulating TGF-β/Smad signaling, it sensitizes pancreatic ductal adenocarcinoma to subsequent chemotherapy, offering a superior sequential strategy to effectively inhibit the growth of residual tumor cells, offering an approach to improve local tumor control in PDAC.
✓ 已验证
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
·
2026
·Vol. 17
·期 1
·200
·
IF 7.8
Chen Qi,Chen Xiaolong,Yang Qu,Miao Xinxin,Yuan Jinghong,Ding Shuihua,Ding Rui,Cai Shenghao,Li Bin,Cheng Xigao
Background Intervertebral disc degeneration (IVDD) is characterized by progressive nucleus pulposus cell loss and extracellular matrix degradation, in which persistent oxidative stress plays a critical pathogenic role. Transplantation of nucleus pulposus–derived stem cells (NPSCs) is a promising therapeutic strategy, yet the hostile oxidative microenvironment severely compromises cell survival. Although cellular quiescence has been suggested to enhance stress tolerance, its regulatory mechanisms and relevance in NPSCs remain largely unexplored. Methods Oxidative stress was evaluated in human degenerated disc tissues, a rat needle-puncture degeneration model, and tert-butyl hydroperoxide–treated NPSCs in vitro. Proliferating and quiescent NPSCs were compared for reactive oxygen species (ROS) levels, apoptosis, viability, and transcriptomic profiles. Pathway enrichment analyses were performed to identify critical signaling mechanisms. Recombinant transforming growth factor-beta 3 (rhTGF-β3) was used to activate the pathway, while small interfering RNA targeting the transforming growth factor-beta receptor type 2 ( Tgfbr2 ) and the pharmacological inhibitor SB431542 were applied for pathway suppression. Functional assays, organ culture, and in vivo transplantation were conducted to assess cell survival and regenerative effects. Results Elevated oxidative stress was consistently observed across clinical, animal, and cellular models of disc degeneration. Quiescent NPSCs demonstrated enhanced resistance to oxidative injury, with reduced ROS accumulation, decreased apoptosis, and improved survival. Transcriptomic analyses revealed suppression of metabolic and P53-mediated apoptotic pathways, alongside marked activation of TGF-β/SMAD signaling. Activation of this pathway induced quiescence, reduced ROS levels, inhibited mitochondrial apoptotic signaling, and protected NPSCs from oxidative injury, whereas pathway inhibition abolished these protective effects. In both organ culture and in vivo transplantation models, quiescent and TGF-β–activated NPSCs exhibited superior survival and significantly improved disc structural preservation compared with proliferating or pathway-blocked cells. Conclusion Activation of the TGF-β/SMAD pathway induces NPSC quiescence and enhances oxidative stress tolerance by suppressing P53-dependent mitochondrial apoptosis. Pharmacological induction of quiescence represents a potential strategy to improve stem cell–based therapies for intervertebral disc degeneration.
✓ 已验证
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2020
·Vol. 30
·期 43
·2004886
·
IF 16.836
Zilin Wang,Lili Liu,Wenhuan Bu,Mengdan Zheng,Nianqiang Jin,Kai Zhang,Xiaowei Xu,Ding Zhou,Bai Yang,Hongchen Sun
Skin lesions, as a relatively common clinical manifestation, not only damage the skin's barrier function, but also affect the skin's ability to feel temperature, pain and touch. However, a highly efficient method to restore the morphology and function of damaged skin remains an unmet goal. In this work, carbon dots (CDots) with excellent biocompatibility are synthesized via microwave-assisted heating ascorbic acid and polyethyleneimine. The synthesized CDots can induce the epithelial-mesenchymal transition (EMT) process by activating transforming growth factor-β/p-38 mitogen-activated kinase/Snail signaling pathway, leading to an increase of cell motility. Further, by assessing a series of in vivo wound healing assays and histological examinations, it is demonstrated that CDots can accelerate the migration of epithelial cells in the full-thickness cutaneous wounds through EMT. As a result, a rapid re-epithelialization covers the granulation tissue and epidermal barrier formed, leading to a block of the external stimuli, reduction of the inflammatory reaction and the granulation tissue area, and finally the promotion of the wound healing with fewer scars.
✓ 已验证
产品关联
DOI
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Ruiying Zhang,Hanfeng Li,Tong Zhang,Bing Zhang,Yihu Wang,Yanchuan Guo
Addressing the underappreciated critical role of angiogenesis and immune dysregulation in keloid formation, we developed a novel nanocarrier (PCS) based on a dual network of physical cross-linking for the efficient release of siTGF-β1 and chlorogenic acid. PCS was self-assembled from polyethylenimine/siTGF-β1 and chlorogenic acid-embedded polylysine/sodium alginate. The results demonstrated that PCS could inhibit the proliferation, induce apoptosis of human umbilical vein endothelial cells and human keloid fibroblasts by regulating their cell cycle, and improve the immune microenvironment at the lesion. By transcriptomics and network pharmacology analysis, PCS inhibited keloid development mainly through the TGF-β1/EGR1 signaling pathway. The final results of animal experiments also proved that the material exerted a favorable effect in keloid treatment. Overall, PCS, as a novel nanocarrier combining siRNA-based gene therapy with chlorogenic acid, was a promising approach for the treatment of keloids.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Chemical Biology
·
2024
·
IF 12.9
Gan Lu,Jiang Qiwei,Huang Dong,Wu Xueji,Zhu Xinying,Wang Lei,Xie Wei,Huang Jialuo,Fan Runzhu,Jing Yihang,Tang Guihua,Li Xiang David,Guo Jianping,Yin Sheng
Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)–hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2–SERCA2–PERK–HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.
研究领域:
药理学
·
分子生物学
·
肝病学
✓ 已验证
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）