EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
·
IF 5.195
Xiao-guo Suo,Fang Wang,Chuan-hui Xu,Xiao-yan He,Jia-nan Wang,Yao Zhang,Wei-jian Ni,Hao Lu,Ming-lu Ji,Yuan He,Shuai-shuai Xie,Ya-ru Yang,Jia-gen Wen,Juan Jin,Qian Gong,Jun Li,Ming-ming Liu,Xiao-ming Meng
Renal fibrosis , a common feature of chronic kidney disease , causes the progressive loss of renal function, in which TGF-β 1 plays a critical role. In this study, we found that expression levels of TGF-β 1 and its receptor 1 (TGF-βR1) were both significantly increased in obstructive fibrosis kidneys. AZ12601011 is a small molecular inhibitor of TGF-βR1; however, its therapeutic potential for renal fibrosis remains unclear. During the experiments, AZ12601011 was applied to various models of renal fibrosis followed by unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) in vivo , in addition to renal tubular epithelial cells (TECs) challenged by hypoxia/reoxygenation (H/R) and TGF-β 1 in vitro. Our results revealed that AZ12601011 ameliorated renal injuries and fibrosis shown by PAS, HE , and Masson staining , which was consistent with the decrease in Col-1 and α-SMA expression in the kidneys from UUO and I/R mice. Similarly, in vitro data showed that AZ12601011 inhibited the induction of Col-1 and α-SMA in both TECs treated with TGF-β 1 and H/R. In addition, the results of cellular thermal shift assay (CETSA), molecular docking , and western bolt indicated that AZ12601011 could directly bind to TGF-βR1 and block activation of the downstream Smad3. Taken together, our findings suggest that AZ12601011 can attenuate renal fibrosis by blocking the TGF-β/Smad3 signaling pathway and it might serve as a promising clinical candidate in the fight against fibrotic kidney diseases.
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Yichao Du,Junjie Bai,Tingting Ma,Ziming Wu,Pengru Wang,Xiaolin Zhong,Wenguang Fu,Shuixiang He
Liver fibrosis, a pivotal pathological feature in the progression of chronic liver injury, currently lacks effective therapies. Sinomenine (SIN), a bioactive alkaloid derived from traditional Chinese medicine, demonstrates diverse pharmacological properties. However, its therapeutic potential and mechanisms in liver fibrosis remain inadequately characterized. This study investigates the anti-fibrotic effects of SIN and its underlying molecular mechanisms. The anti-fibrotic efficacy of SIN was evaluated in two murine models of liver fibrosis induced by carbon tetrachloride (CCl 4 ) or bile duct ligation (BDL), along with transforming growth factor-beta 1 (TGF-β1)-stimulated rat hepatic stellate cells (HSC-T6). Serum biochemical markers, histopathological analyses (Hematoxylin–Eosin, Sirius red, and Masson's trichrome staining), immunofluorescence, and immunohistochemistry were employed to assess hepatic injury and collagen deposition. Western blotting elucidated molecular mechanisms. SIN administration significantly attenuated hepatic injury in CCl 4 - or BDL-induced mice, as evidenced by reduced transaminase levels and improved histopathological features. In both in vivo and in vitro models, SIN suppressed fibrogenesis by decreasing collagen deposition and downregulating expression of α-smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP2), and collagen I. Mechanistically, SIN inhibited the TGF-β/SMAD pathway through reduced phosphorylation of SMAD2/3 and attenuated c-JUN signaling via diminished phosphorylated c-JUN levels. Pretreatment with TP0427736 (a SMAD2/3 inhibitor) or SP600125 (a c-JUN inhibitor) synergistically enhanced SIN-mediated α-SMA suppression in HSC-T6 cells. SIN ameliorates liver fibrosis through inhibition of TGF-β/SMAD and c-JUN signaling pathways. These findings position SIN as a promising therapeutic candidate for liver fibrotic disorders.
研究领域:
药理学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Xiaowei Zhang,Liang Zhao,Shixie Xiang,Yiran Sun,Pan Wang,Jenny Jie Chen,Brian Sheng-Xian Teo,Zhishen Xie,Zhenqiang Zhang,Jiangyan Xu
Ethnopharmacological relevance Yishen Tongluo formula (YSTLF) is formulated based on traditional Chinese medicine theory for the treatment of Diabetic kidney disease (DKD) and has been shown to be effective in improving the symptoms of DKD according to the clinical observation. Aim of the study To explore the effect of YSTLF on DKD and figure out whether its effects were due to the regulation Sirt6/TGF-β1/Smad2/3 pathway and promoting degradation of TGF-β1. Materials and methods The extract of YSTLF at 1, 2.5 and 5 g/kg was orally administered to C57BLKS/J ( db/db ) mice for 8 weeks and db/db mice were given valsartan as a positive control. The littermate db/m and db/db mice were given vehicle as the control and model group, respectively. Blood urea nitrogen and serum creatinine were detected and the urinary albumin excretion, urea albumin creatinine ratio was calculated. The histopathological change of renal tissues in each group was determined. Simultaneously, the levels of fibrosis-related proteins and messenger RNA (mRNA) in kidney and high glucose (HG)-induced SV40-MES-13 cells were detected. The roles of YSTLF in regulating of Sirt6/TGF-β1/Smad2/3 signaling pathway were investigated in HG-stimulated SV40-MES-13 cells and validated in db/db mice. Furthermore, the effect of YSTLF on TGF-β1 degradation was investigated in HG-stimulated SV40-MES-13 cells. Results YSTLF significantly improved the renal function in DKD mice. YSTLF dose-dependently attenuated pathological changes and suppressed the expression of type I collagen , alpha smooth muscle actin , type IV collagen , and fibronectin in vitro and in vivo , resulting in ameliorating of renal fibrosis . YSTLF positively regulated Sirt6 expression, while inhibited the activating of TGF-β1/Smad2/3 signaling pathway. TGF-β1 was steady expressed in HG-stimulated SV40-MES-13 cells, whereas was continuously degraded under YSTLF treatment. Conclusions YSTLF significantly ameliorates renal damages and fibrosis may via regulating Sirt6/TGF-β1/Smad2/3 signaling pathway as well as promoting the degradation of TGF-β1.
研究领域:
药理学
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内分泌学
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分子生物学
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中医
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DOI
PubMed
高影响因子
DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY
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2025
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IF 2.4
Hao Wang,Junfu Guo,Xuanyi Chen,Siqi Liu,Wenna Li,Lu Yang,Jianmiao Wang,Yinglun Han
The regulation of inflammatory balance is central to immune homeostasis, with disruptions contributing to autoimmune diseases. As representatives of early vertebrates, lampreys offer a valuable model for investigating the evolutionary foundations of immune regulation. This study examines the dual role of L-TGF-β2 in modulating inflammation in lampreys, providing insights into the evolutionary origins of immune homeostasis mechanisms. Using lipopolysaccharide (LPS)-induced inflammation models, recombinant L-TGF-β2 was found to enhance leukocyte chemotaxis in quiescent states while inhibiting excessive migration during activation. Quantitative PCR revealed that L-TGF-β2 stimulates pro-inflammatory cytokine expression during early inflammatory phases and attenuates it during resolution. Tissue-specific expression patterns of TGF-β receptors indicated their potential role in mediating the distinct regulatory effects of L-TGF-β2 across diverse immune environments. These findings align with the biphasic functions of TGF-β observed in higher vertebrates, underscoring the evolutionary conservation of this signaling pathway. This research enhances understanding the functional versatility of TGF-β signaling and its pivotal role in vertebrate immune evolution, providing insights into ancient mechanisms of immune homeostasis and their modern implications for inflammatory disease research.
研究领域:
免疫学
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进化生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nutrients
·
2022
·Vol. 14
·期 8
·1564
·
IF 6.706
Hongbo Jiang,Pei Ma,Zhiguang Duan,Yannan Liu,Shihong Shen,Yu Mi,Daidi Fan
Gastric cancer (GC) is the leading causes of cancer-related death worldwide. Surgery remains the cornerstone of gastric cancer treatment, and new strategies with adjuvant chemotherapy are currently gaining more and more acceptance. Ginsenoside Rh4 has excellent antitumor activity. Conversely, the mechanisms involved in treatment of GC are not completely understood. In this study, we certified that Rh4 showed strong anti-GC efficiency in vitro and in vivo. MTT and colony formation assays were performed to exhibit that Rh4 significantly inhibited cellular proliferation and colony formation. Results from the wound healing assay, transwell assays, and Western blotting indicated that Rh4 restrained GC cell migration and invasion by reversing epithelial–mesenchymal transition (EMT). Further validation by proteomic screening, co-treatment with disitertide, and SIX1 signal silencing revealed that SIX1, a target of Rh4, induced EMT by activating the TGF-β/Smad2/3 signaling pathway. In summary, our discoveries demonstrated the essential basis of the anti-GC metastatic effects of Rh4 via suppressing the SIX1–TGF-β/Smad2/3 signaling axis, which delivers a new idea for the clinical treatment of GC.Keywords:ginsenoside Rh4;SIX1;TGF-β/Smad2/3 pathway;gastric 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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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 8
·1-10
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IF 8.1
Zhu Chen,Weng Qingyu,Gao Shenwei,Li Fei,Li Zhouyang,Wu Yinfang,Wu Yanping,Li Miao,Zhao Yun,Han Yinling,Lu Weina,Qin Zhongnan,Yu Fangyi,Lou Jiafei,Ying Songmin,Shen Huahao,Chen Zhihua,Li Wen
Eosinophils, traditionally associated with allergic phenomena, play a pivotal role in inflammatory responses. Despite accumulating evidence suggesting their pro-inflammatory function upon activation, the underlying mechanisms governing eosinophil activation remain incompletely characterized. In this study, we investigate the local activation of pulmonary and colon eosinophils within the inflammatory microenvironment. Leveraging transcriptional sequencing, we identify TGF-β as a putative regulator of eosinophil activation, leading to the secretion of granule proteins, including peroxidase. Genetic deletion of TGF-β receptors on eosinophils resulted in the inhibition of peroxidase synthesis, affirming the significance of TGF-β signaling in eosinophil activation. Using models of HDM-induced asthma and DSS-induced colitis, we demonstrate the indispensability of TGF-β-driven eosinophil activation in both disease contexts. Notably, while TGF-β signaling did not significantly influence asthmatic inflammation, its knockout conferred protection against experimental colitis. This study delineates a distinct pattern of eosinophil activation within inflammatory responses, highlighting the pivotal role of TGF-β signaling in regulating eosinophil behavior. These findings deepen our comprehension of eosinophil-related pathophysiology and may pave the way for targeted therapeutic approaches in allergic and inflammatory diseases.
研究领域:
免疫学
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炎症
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过敏
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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 BIOMEDICAL MATERIALS RESEARCH PART A
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2013
·Vol. 102
·期 3
·801-807
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IF 2.834
Ke Jiang,Ziming Wang,Quanyin Du,Jiang Yu,Aimin Wang,Yan Xiong
The post-operative outcome of flexor tendon healing remains limited by flexor tendon adhesion that reduces joint range of motion. Despite improvement in different methods, peritendinous adhesion formation continues to present a formidable challenge. Recent studies showed that transforming growth factor-β3 (TGF-β3) may be the key factor to reducing adhesion formation in skin or tendon. In this study, we designed a novel type of tissue engineering synovial sheath containing TGF-β3, to prevent flexor tendon adhesion. First, to achieve a stable release of TGF-β3, chitosan microspheres, prepared by crosslinking-emulsion, were used for the delivery of TGF-β3. Second, a three-dimensional chitosan scaffold was prepared by lyophilization, and TGF-β3 microspheres were carefully introduced into the scaffold. Then, synovial cells were cultured and then seeded into the TGF-β3 loaded scaffold to produce TGF-β3 controlled-released tissue engineering synovial sheath. Tests clearly demonstrated that the scaffold has good structure and compatibility with cells. These results expand the feasibility of combinative strategies of controlled protein release and tissue-engineered synovial sheath formation. Application of this scaffold to tendon repair sites may help to prevent adhesion of tendon healing. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 801–807, 2014.
研究领域:
生物医学工程
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组织工程
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骨科手术
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
·
IF 4.8
Jianfa Wu,Lingli Jiang,Sihong Wang,Lei Peng,Rong Zhang,Zhou Liu
The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-β1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-β1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-β1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-β1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-β1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-β1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Journal of Functional Biomaterials
·
2025
·Vol. 16
·期 2
·52
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IF 5.2
He Bai,Wei Zhang,Xuanxuan Yan,Lin Qiu,Pengfei Cui,Weiyang Chen
In recent years, factors such as the postponement of childbearing and the relaxation of the childbearing policy have led to an increase in the proportion of cesarean sections and other intrauterine surgeries among pregnant women, further increasing the incidence of uterine scars. Currently, there is a lack of effective clinical treatment methods for uterine scars. In this study, a suture loaded with gene medicine was designed for the repair of uterine scars. Specifically, the non-viral vector Lipo8000 was first used to form a complex solution with the plasmid TGF-β3. Then, it was mixed and adsorbed with the surgical sutures pretreated with recombinant human type III collagen (RhCol III). In vitro experiments confirmed that RhCol III and the plasmid were successfully loaded onto the sutures and could be released and expressed. In vivo experiments were carried out using a rat model simulating uterine scars. The section results showed that compared with the scar model group, the expression level of TGF-β3 in the RhCol III+TGF-β3 group increased by 39%, the expression level of TGF-β1 decreased by 62.8%, and the fibrosis rate decreased by 16.8%, which has a positive effect on the prevention of uterine scars. This study integrates the therapeutic medicine into the sutures, ensuring that the medicine can come into contact with the wound site after suturing. Moreover, RhCol III and the gene medicine work synergistically to promote the repair of uterine wounds.
研究领域:
妇产科学
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分子生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Wenjuan Ning,Xiaoxiao Xu,Shican Zhou,Xiao Wu,Hang Wu,Yijie Zhang,Jichang Han,Junpeng Wang
This study explored the profibrotic impact of high glucose in the lung and potential mechanisms using latent TGF-β1-induced human epithelial cell pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrosis models. Results demonstrated that high glucose administration induced epithelial-mesenchymal transition (EMT) in human epithelial cells in a dose-dependent manner via activating latent TGF-β1, followed by increased expression of mesenchymal-related proteins and decreased expression of epithelial marker protein E-cadherin. Further mechanism analysis showed that administration of high glucose dose-dependently promoted total and mitochondrial reactive oxygen species (ROS) accumulation in human epithelial cells, which promoted latent TGF-β1 activation. However, N -acetyl-L-cysteine, a ROS eliminator, inhibited such effects. An in vivo feed study found that mice given a high-glucose diet had more seriously pathological characteristics of pulmonary fibrosis in BLM-treated mice, including increasing infiltrated inflammatory cells, collagen I deposition, and the expression of mesenchymal-related proteins while decreasing the expression of the epithelial marker E-cadherin. In addition, high glucose intake further increased TGF-β1 concentration and upregulated p-Smad2/3 and snail in lung tissues from BLM-treated mice when compared to BLM-treated mice. Finally, supplementation with high glucose further increased the production of lipid peroxidation metabolite malondialdehyde and decreased superoxide dismutase activity in BLM-treated mice. Collectively, these findings illustrate that high glucose supplementation activates a form of latent TGF-β1 by promoting ROS accumulation and ultimately exacerbates the development of pulmonary fibrosis.
研究领域:
肺科学
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细胞生物学
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药理学
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病理学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 12
·3369
·
IF 3.098
Li-Min Zhao,Zhen Guo,Yi-Jie Xue,Jun Zhe Min,Wen-Jing Zhu,Xiang-Yu Li,Hu-Ri Piao,Cheng Hua Jin
The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles14a–d,15a–d,16a–d,17a–d,18a–d,19a–d,25a,25b,25d,26a,26b,26d,27b, and27dwere synthesized and evaluated for their activin TGF-β type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound19binhibited TGF-β type I receptor kinase phosphorylation with an IC50value of 0.28 µM, with 98% inhibition at 10 µM. Compound19balso had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound3(LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.Keywords:TGF-β;ALK5 inhibitor;kinase assay;selectivity;docking
研究领域:
药理学
·
分子生物学
·
药物化学
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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
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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