CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Yue Gao,Shicheng Fan,Pengfei Zhao,Huilin Li,Chenghui Cai,Xuan Li,Yanying Zhou,Min Huang,Huichang Bi
Liver fibrosis can be characterized by the over-deposition of extracellular matrix (ECM). It has been reported that β-catenin/TCF4 interaction was enhanced in bile duct ligation (BDL) model, which implicated the critical role of β-catenin/TCF4 interaction during the progression of fibrosis . However, whether inhibiting β-catenin/TCF4 signaling attenuates liver fibrosis remains unknown. In the current study, we used ICG-001, an inhibitor that disrupts the interaction between CREB binding protein (CBP) and β-catenin, to inhibit β-catenin/TCF4 transcriptional activity. We also used LF3, a small molecule antagonist, to inhibit β-catenin/TCF4 interaction. The antifibrotic effect of ICG-001 and LF3 was assessed on BDL-induced liver fibrosis model. The results indicated both ICG-001 and LF3 significantly reduced the positive staining area of Sirius Red and α-SMA. The protein expression levels of α-SMA, Collagen Ⅰ and CD31 were also significantly downregulated in BDL + ICG-001 and BDL + LF3 groups. Besides, ICG-001 and LF3 promoted portal angiogenesis and inhibited sinusoids capillarization in fibrotic livers. For mechanistic study, we measured the level of leukocyte cell-derived chemotaxin 2 (LECT2), a direct target of β-catenin/TCF4, which was recently reported to participate in hepatic fibrosis by regulating angiogenesis. The results showed that both ICG-001 and LF3 reduced LECT2 expression in BDL mice. LF3 also downregulated pSer 675 β-catenin and nuclear β-catenin. In conclusion, this study demonstrated that inhibiting β-catenin/TCF4 signaling by ICG-001 or LF3 mitigated liver fibrosis by downregulating LECT2, promoting portal angiogenesis and inhibiting sinusoids capillarization, which provided new evidence that β-catenin/TCF4 signaling might be a target for the treatment of liver fibrosis.
研究领域:
肝病学
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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
Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Chao Chen,Hongxia Zhang,Lingling Qi,Haoqi Lei,Xuefei Feng,Yingjie Chen,Yuanyuan Cheng,Defeng Pang,Jufeng Wan,Haiying Xu,Shifeng Cao,Baofeng Yang,Yan Zhang,Xin Zhao
Obesity is a significant risk factor for cancer and is associated with breast cancer metastasis. Nevertheless, the mechanism by which alterations in systemic metabolism affect tumor microenvironment (TME) and consequently influence tumor metastasis remains inadequately understood. Herein, we found that perturbations in circulating metabolites induced by obesity promote metastasis-like phenotypes in breast cancer. Oleoylcarnitine (OLCarn) concentrations were elevated in the serum of obese mice and humans. Administration of exogenous OLCarn induces metastasis-like characteristics in breast cancer cells. Mechanistically, OLCarn directly interacts with the Arg176 site of adenylate cyclase 10 (ADCY10), leading to the activation of ADCY10 and enhancement of cAMP production. Mutations at Arg176 prevent OLCarn from binding to ADCY10, disrupting the ADCY10-mediated activation of cyclic adenosine monophosphate (cAMP) signaling pathway. This activation promotes transcription factor 4 (TCF4)-dependent kinesin family member C1 (KIFC1) transcription, thereby driving breast cancer metastasis. Conversely, the neutralization of both ADCY10 and KIFC1 through knockdown or pharmacological inhibition abrogates the oncogenic effects mediated by OLCarn. Hence, obesity-induced systemic environmental changes lead to the aberrant accumulation of OLCarn within the TME, making it a potential therapeutic target and biomarker for breast cancer.
研究领域:
肿瘤学
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代谢学
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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
MOLECULAR CANCER RESEARCH
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2026
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IF 5.8
Han Tianci,Xie Junwei,Tong Wei,Zhang Liang
The poor prognosis of esophageal carcinoma (ESCA) highlights the need to identify novel targets for ESCA treatment. We found that inhibitor of differentiation 4 (ID4) was decreased in ESCA tumor tissues and its expression was associated with the survival of ESCA patients. However, the role of ID4 in ESCA remains unclear. Here, in this study, we found that overexpression of ID4 suppressed the cell proliferation of ESCA in vitro as well as tumor growth in vivo, whereas knockdown of ID4 presented the opposite trend. On the other hand, ESCA cells with overexpression of ID4 reduced macrophage migration and M2 polarization. However, significant increases in macrophage migration and M2 polarization were observed in cultures with ID4 silence. Interestingly, CCL2 was found to mediate the function of ID4 on macrophage polarization. Mechanistically, we identified for the first time that ID4 interacted physically with TCF4 to inactivate TCF4 transcriptional activity, which led to a decrease in CCL2 expression. Moreover, RNA binding protein cell cycle associated protein 1 (CAPRIN1) bound to ID4 mRNA and downregulated its stability, which may contribute to its low expression in ESCA. Taken together, these results support a novel hypothesis that ID4 downregulation may contribute to the development of ESCA by interacting with TCF4, resulting in abnormal proliferation of ESCA cells and tumor-associated macrophage infiltration. ID4 may contribute to the innovation of ESCA biotherapy.
Implications: ID4 inhibits ESCA through suppresses cancer cell proliferation and macrophage M2 polarization, and ID4 could be a potential prognostic marker for patients with ESCA.
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Jiao Kong,Yujia Chen,Shuanghui Lu,Lvexiang Yuan,Tao He,Minlei Dong,Yingqiong Zhang,Xiaoyi Pan,Hui Zhou,Huidi Jiang
Ethnopharmacological relevance The pollen of Brassica campestris L. (BCP, syn. Brassica rapa L. subsp. oleifera (DC.) Metzg.), included in the Chinese Pharmacopoeia as a licensed patent medicine (Pule'an tablets), is used clinically for kidney-qi deficiency-related lower urinary tract symptoms in chronic prostatitis and benign prostatic hyperplasia. Prostatic obstruction is a common cause of obstructive uropathy that may progress to renal fibrosis. However, the renoprotective effects and the underlying mechanism remain to be fully elucidated. Aim of the study To study the renoprotective effects, the active fraction, the effective components of BCP and the underlying mechanisms. Materials and methods Mouse models of hyperuricemic nephropathy (HN) and unilateral ureteral obstruction (UUO) were established to evaluate the renoprotective effects of BCP. Transcriptomics and liquid chromatography-mass spectrometry were applied to explore potential mechanisms and intrarenal constituents. Erastin- and uric acid (UA)-induced HK-2 cells were employed to validate the cytoprotective effects of the potential active compounds, whose binding capability with direct target was confirmed by CETSA/SPR. Results BCP dose-dependently reduced UA levels and reversed the protein expression of UA-producing enzymes and renal transporters (for reabsorption and excretion) in HN mice. Additionally, BCP improved renal injury and fibrosis in HN mice and UUO mice by reducing UA and direct renoprotection, in which the flavonoids of BCP played a crucial role. Meanwhile, BCP alleviated renal fibrosis by inhibiting the β-catenin/TCF4-ferroptosis axis, which was achieved mainly by its bioactive components, kaempferol and kaempferol-3-glucuronide (K-3-G), in HK-2 cells. Furthermore, kaempferol and K-3-G were demonstrated to directly bind with β-catenin, block the transcriptional activation of β-catenin, and subsequently suppress ferroptosis. Conclusions BCP and its major bioactive compounds, kaempferol and K-3-G, exert nephroprotective effects by inhibiting the β-catenin/TCF4-ferroptosis axis.
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产品关联
DOI
PubMed
高影响因子
ARCHIV DER PHARMAZIE
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2025
·Vol. 358
·期 3
·e2400796
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IF 3.6
Yating Guo,Meng Cao,Zhaohui Li,Hongfei Zhou,Zhuo Chen,Qianbin Li
Hyperactivation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Based on a previously reported lead compound, iCRT14, a series of 2,4-thiazolidinedione derivatives were designed, synthesized, and evaluated in vitro for their antiproliferative activity against colon cancer cells. Compound 15k exhibited the most potent activity against the HCT116 and SW480 cell lines. Compound 15k inhibited Wnt/β-catenin signaling by disrupting the protein–protein interactions between β-catenin and TCF4. Compound 15k simultaneously inhibited tubulin polymerization, disorganized the microtubule network, and arrested the cell cycle at the G2/M phase, offering an additional mechanism of action and 15k induced cell apoptosis by activating caspase-3 and poly(ADP-ribose) polymerase. Additionally, compound 15k inhibited cell migration without affecting the levels of β-catenin protein. These results offer guidance for developing the current series as potential new anticancer therapeutics.
研究领域:
肿瘤学
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分子生物学
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药物化学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
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2024
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IF 4.5
Zhiguang Chen,Qi Zhao,Lianghong Chen,Songlan Gao,Lingshuai Meng,Yingjie Liu,Yu Wang,Tiegang Li,Jinqi Xue
Osteogenic differentiation is important for fracture healing. Microfibrial-associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical-sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3-E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating β-catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor-related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and β-catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, β-catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with β-catenin/TCF4 to enhance β-catenin/TCF4's function and activate LRP5-activated β-catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.
研究领域:
骨骼生物学
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骨科
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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
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