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
✓ 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
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分子生物学
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肾病学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Haibin Sun,Cheng Miao,Wei Liu,Xianghe Qiao,Wenbin Yang,Longjiang Li,Chunjie Li
Oral squamous cell carcinoma (OSCC) is the most common type of malignant cancer affecting the oral cavity. Tumor associated macrophages (TAMs) play a vital role in the initiation, progression and metastasis of OSCC. In this study, we investigated the correlation between macrophages and several clinical and pathological indicators, and we also explored how transforming growth factor-β1 (TGF-β1) effect on VEGF expression in TAMs. Seventy-two paraffin-embedded OSCC samples were collected. Association between macrophages density, micro vascular density (MVD) and clinical-pathological feature were explored by immunohistochemical staining. Western blot , ELISA and qRT-PCR were conducted to assess the VEGF expression in TAMs treated with or without neutralizing TGF-β1, TβRII and smad3 antibodies. Results showed that CD68 + macrophages were absent in normal tissues. Macrophages density was directly correlated to low pathological differentiation, late clinical staging and poor survival rate. MVD showed positive correlation with clinical staging and macrophages density. Furthermore, OSCC-associated macrophages expressed more VEGF than macrophages in healthy lymph nodes. However, when TGF-β1 or TβRII were neutralized or the Smad3 was inhibited, VEGF expression was down regulated as well. It is concluded that TGF-β1 could promote OSCC-associated macrophages to secrete more VEGF via TβRII/Smad3 signaling pathway . This result might explain the correlation between macrophages density and worse clinical-pathological condition.
研究领域:
肿瘤学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Cardiovascular Translational Research
·
2025
·
IF 2.5
Zhou Qiaofeng,Jiang Na,Li Shihuan,Li Suqin,Liu Jie,Yu Liangzhu,Liu Guoli,Xia Hongli,Li Mincai
Myocardial fibrosis (MF) severely impairs the heart structure and function post-myocardial infarction. The study investigated the effectiveness and mechanism of diammonium glycyrrhizinate (DG) on ISO-induced MF. ISO-stimulated mouse cardiac fibroblasts (CFs) were treated with DG to assess the proliferation, inflammation, and fibrosis markers (α-SMA, collagen, TGF-β1, Smad3). The MF model was induced in mice by administering ISO, followed by a 4-week treatment with DG (60 mg/kg/day). Cardiac function was measured using echocardiography, and histology and molecular analyses were performed. DG significantly suppressed the CF proliferation and reduced the expression of fibrotic markers. In ISO-treated mice, DG improved the cardiac function and attenuated the upregulated fibrosis markers. Molecular analysis revealed DG suppressed the TGF-β1/Smad3 pathway activation. The antifibrotic effect was enhanced when combined with STAT3 inhibition. DG effectively alleviates ISO-induced myocardial fibrosis dysfunction by inhibiting the STAT3/Smad3 signaling pathway, demonstrating its potential as a treatment for cardiac fibrosis. Graphical abstract
研究领域:
心脏病学
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药理学
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分子生物学
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细胞生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Yixiao Li,Yuhan Jiang,Haoyi Yan,Ziheng Qin,Yidi Peng,Danyu Lv,Hongquan Zhang
Histone lysine isonicotinylation (Kinic) induced by isoniazid (INH) was recently identified as a post-translational modification in cells. However, global cellular non-histone proteins Kinic remains unclear. Using proteomic technology, we identified 11,442 Kinic sites across 2,792 proteins and demonstrated that Kinic of non-histone proteins is involved in multiple function pathways. Non-histone proteins Kinic can be regulated by isonicotinyl-transferases, including CBP and Tip60, and deisonicotinylases, including HDAC8 and HDAC6. In particular, the Kinic of poly (ADP-ribose) (PAR) polymerase 1 (PARP1) can be catalyzed by CBP and deisonicotinylation can be catalyzed by HDAC8. Tip60 and HDAC6 are isonicotinyl-transferase and the deisonicotinylase of SMAD3, respectively. Importantly, we found the K378inic of SMAD3 increases its phosphorylation, activates TGFβ pathway, and promotes liver cancer cells migration and invasion. In conclusion, our study demonstrated non-histone proteins Kinic occur extensively in cells and plays an important role in regulation of various cellular functions, including cancer progression.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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蛋白质组学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Xu Dong,Jianyin Miao,Ling Wu,Ziyu Kong,Zenghui Liu,Diyi Jia,Qingqing Zhai,Dan Zhang,Yan Xu
Background Diabetes patients face an elevated wound infection susceptibility and delayed healing processes. Currently, no existing literature has reported on the effect and mechanism of theaflavin-3, 3’-digallate nanoparticles (TFDG NPS) and TFDG NPS@hydrogels on diabetic wounds. Purpose Given that the treatment options for diabetic wound are limited, the aim of this study is to develop an innovative therapeutic approach to address diabetic wounds. Methods The TFDG NPS were prepared using ionic cross-linking, and they were then characterized. The biocompatibility of the TFDG NPS and TFDG NPS@hydrogel was assessed using a Cell Counting Kit-8 (CCK-8) assay and live/dead staining on HK-2 cells in vitro . Diabetic ICR mice were induced through intraperitoneal injection of streptozocin (STZ). They were then subjected to the creation of two full-thickness wounds on their dorsal areas. The effect and mechanism of the TFDG NPS and TFDG NPS@hydrogel on wound healing in diabetic mice were evaluated using a histological analysis, a western blot analysis, and molecular docking. Results The optimal TFDG NPS proportion was found to be TFDG:Gelatin (Gel):Chitosan (CS) = 2:1:1. Images photographed using a transmission electron microscope (TEM) revealed that the TFDG NPS appeared spherical, with a diameter of approximately 140 ± 20 nm. The favorable bio-compatibility of the TFDG NPS and TFDG NPS@hydrogel was confirmed using cell experiments. Animal studies demonstrated that both the TFDG NPS and TFDG NPS@hydrogel enhanced collagen fiber accumulation and new blood vessel density, reduced F4/80 infiltration, and upregulated the expression levels of TGF-β1, SMAD3, Collagen I, and α-SMA. The potential mechanism may involve activation of the TGF-β1/SMAD3 pathway, stimulating the secretion of Collagen I and α-SMA, and thereby facilitating wound closure in diabetic mice. The molecular docking results confirmed a high affinity between TFDG and TGF-β1/SMAD3. Conclusion TFDG NPS and TFDG NPS@hydrogel promoted wound closure in diabetic mice through the TFG-β1/SMAD3 pathway, thus exhibiting promising therapeutic potential for diabetic wound treatment.
研究领域:
医学
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生物材料学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2017
·
IF 2.829
Chong Zhong,Yong-Fa Zhang,Jun-Hai Huang,Zi-Yu Wang,Qiu-Yuan Chen,Li-Tian Su,Zhen-Tao Liu,Cheng-Ming Xiong,Zhi Tao,Rong-Ping Guo
Background: Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors in the world. In China, traditional medicine is commonly used in the treatment of cancer. Among these medicines, Jianpi Huayu Decoction (JHD) is a typical clinical prescription against multiple tumors. However, the exact function and targets of JHD are currently unknown. The aim of this study is to assess the efficacy of JHD against HCC. Methods and results: Hepatic carcinoma SMMC7221 cells were treated with JHD drug-serum in a dose- and time-dependent manner. Real-time PCR (RT-PCR), western-blot (WB), and immunofluorescence microscopy revealed that JHD increased both the mRNA and protein levels of Smad7 and decreased the protein level of p-Smad3. It subsequently increased the E-cadherin expression level and decreased those of N-cadherin and Vimentin. Metastasis and invasion were eventually inhibited, as determined by the wound healing and transwell invasion assays. Treatment of Tanshinone IIA (Tan IIA) showed similar results as JHD, indicating that it is most likely the main functional drug monomer of JHD. The in vivo assay in nude mice also revealed the efficacy of JHD to inhibit epithelial mesenchymal transition (EMT). Conclusion: JHD was shown to be an effective therapeutic strategy against HCC.
研究领域:
肿瘤学
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分子生物学
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中医药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2024
·Vol. 72
·期 7
·669-675
·
IF 1.5
Xiongwei Deng,Qiang Li,Haitao Yuan,Hejun Hu,Shaoyong Fan
Tendon injury is a prevalent orthopedic disease that currently lacks effective treatment. Galangin (GLN) is a vital flavonoid found abundantly in galangal and is known for its natural activity. This study aimed to investigate the GLN-mediated molecular mechanism of tendon-derived stem cells (TDSCs) in tendon repair. The TDSCs were characterized using alkaline phosphatase staining, alizarin red S staining, oil red O staining, and flow cytometry. The effect of GLN treatment on collagen deposition was evaluated using Sirius red staining and quantitative (q)PCR, while a Western bot was used to assess protein levels and analyze pathways. Results showed that GLN treatment not only increased the collagen deposition but also elevated the mRNA expression and protein levels of multiple tendon markers like collagen type I alpha 1 (COL1A1), decorin (DCN) and tenomodulin (TNMD) in TDSCs. Moreover, GLN was also found to upregulate the protein levels of transforming growth factor β1 (TGF-β1) and p-Smad3 to activate the TGF-β1/Smad3 signaling pathway, while GLN mediated collagen deposition in TDSCs was reversed by LY3200882, a TGF-β receptor inhibitor. The study concluded that GLN-mediated TDSCs enhanced tendon repair by activating the TGF-β1/Smad3 signaling pathway, suggesting a novel therapeutic option in treating tendon repair.
研究领域:
骨科
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干细胞研究
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Hepatology International
·
2019
·Vol. 14
·期 1
·145-160
·
IF 5.49
Zhao Jing,Han Ming,Zhou Li,Liang Pu,Wang Yun,Feng Shenghu,Lu Hongping,Yuan Xiaoxue,Han Kai,Chen Xiaofan,Liu Shunai,Cheng Jun
Background This study aimed to investigate the roles and mechanisms of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in treating liver fibrosis. Methods The effects of TAF/TDF on carbon tetrachloride (CCl 4 )-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/Sekelsky mothers against decapentaplegic homolog 3 (Smad3) and NF-κB/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout. Results TAF/TDF significantly inhibited CCl 4 -induced liver fibrosis in mice, and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginal therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro. Conclusions TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 1
·215
·
IF 3.098
Xinyan Peng,Chongshan Dai,Quanwen Liu,Junke Li,Jingru Qiu
This study aimed to investigate the protective effect of curcumin against carbon tetrachloride (CCl4)-induced acute liver injury in a mouse model, and to explain the underlying mechanism. Curcumin at doses of 50, 100 and 200 mg/kg/day were administered orally once daily for seven days prior to CCl4exposure. At 24 h, curcumin-attenuated CCl4induced elevated serum transaminase activities and histopathological damage in the mouse’s liver. Curcumin pre-treatment at 50, 100 and 200 mg/kg significantly ameliorated CCl4-induced oxidative stress, characterized by decreased malondialdehyde (MDA) formations, and increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) content, followed by a decrease in caspase-9 and -3 activities. Curcumin pre-treatment significantly decreased CCl4-induced inflammation. Furthermore, curcumin pre-treatment significantly down-regulated the expression of TGF-β1 and Smad3 mRNAs (bothp< 0.01), and up-regulated the expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (bothp< 0.01) in the liver. Inhibition of HO-1 attenuated the protective effect of curcumin on CCl4-induced acute liver injury. Given these outcomes, curcumin could protect against CCl4-induced acute liver injury by inhibiting oxidative stress and inflammation, which may partly involve the activation of Nrf2/HO-1 and inhibition of TGF-β1/Smad3 pathways.Keywords:curcumin;acute liver injury;Nrf2/HO-1 pathway;oxidative stress;TGF-β1/Smad3 pathway
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Aging
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2025
·
IF 19.4
Liu Liu,Wang Qianyue,Chen Meng,Zhou Haifeng,Li Xu,Yuan Ziqi,Hu Yong,Wang Chaoqun,Zhang Xiaohui,Hu Sheng,Wu Xiaoting,Li Meixin,Li Juanjuan,Chen Aijun,Yan Wei
Lung aging is a multifactorial series of molecular alterations that leads to gradual deterioration of lung function and increased vulnerability to cancer. Tumor communicates with host organs partially through extracellular vesicles; however, the mechanistic drivers and consequences of lung aging in the context of cancer remain unclear. Here we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation and promotes lung fibrosis and aging. Mechanistically, our single-cell sequencing and genetic knockout mice evidence that citrulline availability elevation inhibits peptidyl arginine deiminase 4-mediated transforming growth factor-β1 (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting assists the packaging of DDAH1 into the late endosomes. The administration of DDAH1 inhibitor reduces fibrosis and alleviates lung aging. Conclusively, our findings reveal tumor-derived DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on the treatment and diagnosis of tumors by inhibiting senescent lung fibroblasts.
研究领域:
肿瘤学
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呼吸系统生物学
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分子生物学
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细胞衰老
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信号转导
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转化医学
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肿瘤微环境
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 7
·11440-11450
·
IF 3.923
Zheng-Yu Liu,Hong-Wei Pan,Yan Cao,Jiao Zheng,Yu Zhang,Yi Tang,Jin He,Yong-Jun Hu,Chang-Lu Wang,Qiong-Chao Zou,Qing-Hua Fu,Le Zhang,Jian-Qiang Peng,Jing Ling,Ning Peng,Jing-Jing Rong,Zhao-Fen Zheng
microRNAs (miRs) are essential in the development of heart failure. The aim of this study is to investigate the effect of microRNA-330 (miR-330) on left ventricular remodeling via the TGF-β1/Smad3 signaling pathway by targeting the sex-determining region Y (SRY) in mice with myocardial ischemia–reperfusion injury (MIRI). Differentially expressed gene (DEG) in myocardial ischemia–reperfusion (IR) was screened out and the miR that targeted the DEG was also predicted and verified. A model of MIRI was established to detect the expression of miR-330, SRY, transforming growth factor-β (TGF-β1), and Sekelsky mothers against dpp3 (Smad3). To further investigate the role of miR-330 in MIRI with the involvement of SRY and TGF-β1/Smad3 signaling pathway, the modeled mice were treated with different mimic, inhibitor, or small interfering RNA (siRNA) to observe the changes of the related gene expression, as well as the myocardial infarction size and volume of myocardial collagen. SRY was screened out and verified as a target gene of miR-330. The MIRI mice showed enlarged myocardial infarction size, increased volume of myocardial collagen, increased expression of miR-330, TGF-β1 and Smad3, while decreased the expression of SRY. The MIRI mice treated with miR-330 inhibitor showed decreased myocardial infarction size, the volume of myocardial collagen, and expression of TGF-β1 and Smad3 but promoted expression of SRY. Our findings demonstrated that downregulated miR-330 could suppress left ventricular remodeling to inhibit the activation of the TGF-β1/Smad3 signaling pathway via negatively targeting of SRY in mice with MIRI. This can be a potential target in the strategy to attenuate patient suffering.
研究领域:
心脏病学
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分子生物学
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遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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