PHYTOMEDICINE
·
2025
·
IF 8.3
Linhui Cheng,Tao Yu,Hanrong Xue,Shuangdi Xiang
Background Cardiovascular and cerebrovascular diseases are the leading causes of death worldwide. Pathological thrombosis is a major underlying mechanism, where excessive platelet activation triggered by vascular injury constitutes a key event. Liquiritigenin, a key flavonoid constituent of Glycyrrhiza glabra L., has been reported to possess diverse pharmacological properties, including anti-inflammatory, anti-tumor, neuroprotective, and cardiovascular protective effects. However, its specific role in platelet activation remains unclear. Purpose This study aimed to investigate the mechanism by which liquiritigenin inhibits platelet activation and attenuates thrombosis. Purpose This study aims to explore the mechanism through which liquiritigenin inhibits platelet activation to attenuate thrombosis. Methods The inhibitory effect of Liquiritigenin on platelet activation was evaluated using thrombin, ADP, and collagen as agonists. A co-culture system of platelets with human umbilical vein endothelial cells (HUVECs) on a collagen-coated surface was established to simulate platelet adhesion to vascular endothelia and subendothelial matrix under flow conditions. Flow cytometry, transmission electron microscopy, fluorescence labeling, and Western blotting were employed to assess P-selectin (CD62P) expression, dense granule secretion, and platelet adhesion following activation. The effects of Liquiritigenin on the Src/PLCγ2 signaling pathway, cytoplasmic Ca²⁺ mobilization, and the interaction between P2Y12R and the guanine nucleotide-binding protein Gi subunit alpha-1 (Gαi1) were further investigated. Additionally, integrated analysis of multiple single-cell transcriptome datasets was performed to identify cell types interacting with activated platelets in heart and lung tissues. The anti-thrombotic efficacy of liquiritigenin was evaluated in two in vivo models: acute pulmonary thromboembolism (APE) and coronary microvascular dysfunction (CMD). Results Liquiritigenin demonstrated a more potent inhibitory effect on ADP-activated platelets than on those activated by thrombin or collagen. It significantly suppressed ADP-induced P-selectin expression, dense granule secretion, and platelet adhesion to HUVECs. Furthermore, Liquiritigenin inhibited the ADP-triggered Src/PLCγ2 signaling pathway, reduced cytoplasmic Ca²⁺ mobilization, and attenuated the interaction between P2Y12R and Gαi1. Molecular modeling indicated that Liquiritigenin binds to key P2Y12R residues—LYS179, CYS97, and ASN191—which are also involved in ADP binding. In animal models, Liquiritigenin administration significantly reduced thrombus formation in the lung tissue of APE and within the coronary micro vessels of CMD model animals. Conclusion The findings indicate that Liquiritigenin inhibits platelet activation by targeting P2Y12R. This action disrupts the Src/PLCγ2 signaling pathway and subsequently reduces cytoplasmic calcium mobilization. These results suggest that Liquiritigenin may have therapeutic potential for the treatment of thrombotic diseases associated with platelet activation.
研究领域:
药理学
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心血管研究
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分子生物学
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血栓与止血
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信号转导
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DOI
PubMed
高影响因子
PeerJ
·
2021
·
IF 2.984
Yufan Zhu,Zhiqiang Yang,Yuanlong Xie,Min Yang,Yufeng Zhang,Zhouming Deng,Lin Cai
Objective This study aims to explore the effect of daidzein, which is a natural isoflavone compound mainly extracted from soybeans, on osteosarcoma and the potential molecular mechanism. Material and Methods 143B and U2OS osteosarcoma cells were treated with gradient concentrations of daidzein, and MTT assay was used to determine the cell proliferation capacity and IC 50 . Hoechst 33342 staining and Annexin V-FITC/PI detection were used to determine apoptosis. Cell cycle was analyzed by flow cytometry, and migration ability were detected by transwell assays and scratch wound assay. An osteosarcoma xenograft mice model was applied to investigate the effect of daidzein on osteosarcoma in vivo . Systematic pharmacology and molecular modeling analysis were applied to predict the target of daidzein to osteosarcoma, and the target Src was verified by western blotting. We also observed the effect of daidzein on cell proliferation and apoptosis of Src-overexpressing osteosarcoma cells. Results In vitro , daidzein significantly inhibited 143B and U2OS osteosarcoma cell proliferation and migration, and induced cell cycle arrest. In vivo , daidzein exerts antitumor effects in osteosarcoma xenograft mice. After systematic screening and analysis, Src-MAPK signaling pathway was predicted as the highest-ranked pathway. Western blot demonstrated that daidzein inhibited phosphorylation of the Src-ERK pathway in osteosarcoma cells. Also, overexpression of Src could partially reverse the inhibitory effects of daidzein on osteosarcoma cell proliferation. Conclusion Daidzein exerts an antitumor effect on osteosarcoma, and the mechanism may be through the Src-ERK pathway.
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
PLoS One
·
2026
·Vol. 21
·期 6
·e0351846
·
IF 2.8
Ming Liu,Xiaomei Liao,Fangchao Wang,Pengqing Jiao,Zhongkai Wang
Acquired drug resistance is a major cause of failure in gastric cancer treatment. The protein tyrosine phosphatase receptor type E (PTPRE) plays an oncogenic role in certain tumours; however, its function in chemotherapy-resistant gastric cancer remains unclear. Therefore, we analysed PTPRE expression in gastric cancer using The Cancer Genome Atlas. In vitro experiments were then conducted to investigate the effects of PTPRE on the resistance of cancer cells to 5-fluorouracil (5-FU) and its potential mechanisms. The results were further validated in vitro using xenograft studies. We found that PTPRE is upregulated in gastric cancer tissues and participates in the induction of 5-FU resistance. Mechanistic studies revealed that PTPRE suppressed ferroptosis in gastric cancer cells and promoted 5-FU resistance by activating the Src/FAK pathway to upregulate TRIB3 expression. In summary, PTPRE suppresses ferroptosis in gastric cancer cells via the Src/FAK/TRIB3 signalling pathway, thereby inducing 5-FU resistance. Intervention with PTPRE and its downstream targets may represent a potential approach for the clinical treatment of 5-FU-resistant gastric cancer.
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DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Zhang Wei,Zhu Xinghao,Shao Mingliang,Han Qi,Shen Hao,Zhang Kun,Chen Rui,Qi Dongmei,Xu Lijun,Wu Zongyao
The progression of hepatocellular carcinoma (HCC) was highly dependent on pathological angiogenesis, with tumor-associated macrophages (TAMs) serving as key mediators regulating angiogenesis within the tumor microenvironment. The role of protein tyrosine phosphatase 2 (SHP2), a multi-signaling pathway regulator containing an SH2 domain, in TAM-mediated angiogenesis remained unclear. This study aimed to elucidate the molecular mechanism by which SHP2 regulates HCC angiogenesis through the ROS/Src pathway in TAMs under hypoxic conditions. We employed a comprehensive approach. THP-1 macrophage cells were transfected with SHP2 shRNA lentivirus and co-cultured with HCC cell line Huh-7 cells. The co-cultured cells were then subcutaneously transplanted into nude mice. Tumor size was assessed via HE staining in nude mouse tumor formation assays. We engineered luciferase-transfected Huh-7 cells to establish an orthotopic HCC implantation model and measured tumor area via in vivo fluorescence imaging. THP-1 cells were respectively cultured in media supplemented with antioxidants, pro-oxidants, and Src inhibitors, followed by transfection with SHP2 shRNA lentivirus and SHP2 mock lentivirus. These cells were then co-cultured with Huh-7 cells and Hep3B cells, respectively. The proportion of CD68-positive cells detected by immunofluorescence staining was used to ensure that the observed effects in the study were primarily derived from tumor-associated macrophages. Western blot analysis was employed to detect expression levels of SHP2, ROS/Src pathway-related proteins, tumor migration-related proteins, and angiogenesis-related proteins in the cells. Relative fluorescence intensity of intracellular ROS in THP-1 cells was visualized using the fluorescent probe DCFH-DA combined with fluorescence microscopy. Cell migration and invasion capabilities were assessed via wound healing assays and transwell assays. Immunofluorescence staining further validated SHP2 expression levels in THP-1 cells. Additionally, we examined the effects of SHP2 on HCC angiogenesis using tube formation assays, Western Blot analysis, HE staining, and immunohistochemical staining for CD31. The impact of SHP2 on HCC cell proliferation was investigated through colony formation assays and cell cycle analysis by flow cytometry. Following co-culture of SHP2 shRNA-infected THP-1 cells with Huh-7 cells, nude mouse tumor formation assays and in vivo fluorescence imaging revealed significantly reduced tumor volume and area. Following antioxidant supplementation in THP-1 cell culture medium, western blot analysis revealed markedly reduced expression levels of ROS/Src pathway-associated proteins, tumor migration proteins, and angiogenesis-related proteins. Fluorescent probe-based fluorescence microscopy demonstrated decreased relative fluorescence intensity of ROS within tumor cells. Furthermore, Western blot and immunofluorescence staining experiments jointly demonstrated that SHP2 in TAMs can regulate the ROS/Src pathway. Wound healing assays, transwell assays, and tube formation assays demonstrated that SHP2 in TAMs enhanced HCC cell migration, invasion, and angiogenesis capabilities. Furthermore, HE staining and immunohistochemical staining for CD31 indicated that inhibiting ROS/Src pathway suppressed HCC angiogenesis. Colony formation assay and flow cytometry analysis revealed that SHP2 in TAMs promotes HCC proliferation and cell cycle progression via the ROS/Src pathway. Under hypoxic conditions, tyrosine phosphatase SHP2 in TAMs regulates angiogenesis in HCC through the modulation of the ROS/Src pathway.
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Nana Long,Youwei Zuo,Jian Li,Renxiu Yao,Xiao Zhang,Hongping Deng
Background Atopic dermatitis (AD) is characterized by epidermal barrier impairment and immune-driven inflammation. Strategies that restore barrier architecture while constraining inflammation are of therapeutic interest. Purpose To evaluate the barrier-reparative and anti-inflammatory effects of β-myrcene (MYR) in experimental atopic dermatitis and to investigate whether ECM–FAK/Src–YAP signaling is associated with these effects. Methods A 2,4-dinitrochlorobenzene (DNCB)-induced murine model of AD-like dermatitis was evaluated by transepidermal water loss (TEWL), histopathology, dermal collagen organization, filaggrin (FLG) immunofluorescence, and circulating inflammatory mediators. Integrated skin transcriptomic and proteomic analyses and public human AD transcriptomic datasets were used to identify MYR-associated pathways. In primary human keratinocytes stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), YAP localization, FAK Tyr397 and Src Tyr416 phosphorylation, YAP/TAZ target genes, barrier markers, and inflammatory outputs were assessed. Peptide 17 was used to examine the contribution of YAP-dependent transcription. Results MYR reduced dermatitis severity and epidermal hyperplasia, lowered TEWL, partially restored FLG immunofluorescence, and preserved dermal collagen organization in DNCB-challenged mice. Multi-omics profiling identified MYR-associated changes in extracellular matrix (ECM)–receptor interaction, focal adhesion, cytoskeletal remodeling, epidermal differentiation, and immune-related programs. In inflamed keratinocytes, MYR was associated with increased FAK and Src phosphorylation, YAP nuclear accumulation, CCN1/CCN2 expression, and barrier-marker expression, together with reduced inflammatory mediator production. Peptide 17 attenuated MYR-associated YAP nuclear accumulation and several downstream transcriptional responses. These findings support the participation of YAP-dependent signaling but do not establish MYR as a direct regulator of FAK, Src, or YAP or demonstrate a strictly linear signaling sequence. Conclusion MYR produced barrier-restorative and anti-inflammatory effects in experimental atopic dermatitis. The results identify ECM–FAK/Src–YAP signaling as a candidate pathway associated with the MYR response, with pharmacological inhibition providing partial functional evidence for a YAP-dependent component. Download: Download high-res image (265KB) Download: Download full-size image
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DOI
高影响因子
Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-21
·
IF 8.2
Wu Chengyan,Hu Li,Liu Bing,Zeng Xingyue,Ma Haixiang,Cao Yongkai,Li Huijun,Zhang Xiaohan
Background Desensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D 2 -like receptors (D 2 R, D 3 R, D 4 R), have suggested the existence of other desensitization mechanisms. The present study employed D 2 R/D 3 R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT. Results AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D 3 R, ubiquitination of AKT is also involved in the desensitization of β 2 adrenoceptors. Conclusion Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.
研究领域:
细胞生物学
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分子生物学
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药理学
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信号转导
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产品关联
DOI
PubMed
高影响因子
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
·
2022
·Vol. 119
·期 15
·e2117004119
·
IF 12.779
Wentao An,Hui Lin,Lijuan Ma,Chao Zhang,Yuan Zheng,Qiuxia Cheng,Chuanshun Ma,Xiang Wu,Zihao Zhang,Yani Zhong,Menghui Wang,Dongfang He,Zhao Yang,Lutao Du,Shiqing Feng,Chuanxin Wang,Fan Yang,Peng Xiao,Pengju Zhang,Xiao Yu,Jin-Peng Sun
GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.
研究领域:
癌症生物学
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分子生物学
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细胞信号传导
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Qian Wan,Jie Xu,Chengjing Zhu,Xingxing Liu,Yijun Tu,Jiachuan Lei,Jianqing Yu
Piper longum L. is widely cultivated for food, medicine, and other purposes in tropical and subtropical regions. Sixteen compounds including nine new amide alkaloids were isolated from the roots of P. longum. The structures of these compounds were determined by spectroscopic data. All compounds showed better anti-inflammatory activities (IC50 = 1.90 ± 0.68–40.22 ± 0.45 μM) compared to indomethacin (IC50 = 52.88 ± 3.56 μM). Among the isolated compounds, five dimeric amide alkaloids exhibited synergistic effects with three chemotherapeutic drugs (paclitaxel, adriamycin, or vincristine) against cervical cancer cells. Moreover, these dimeric amide alkaloids also enhanced the efficacy of paclitaxel in paclitaxel-resistant cervical cancer cells. The combination treatment of one of these dimeric amide alkaloids and paclitaxel promoted cancer cell apoptosis, which is related to the Src/ERK/STAT3 signaling pathway.
研究领域:
药理学
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肿瘤学
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化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
·
2024
·Vol. 28
·期 6
·3713-3737
·
IF 3.9
Zhang Minjie,Chen Guifen,Chen Yafang,Sui Yi,Zhang Yan,Yang Wude,Yu Xiang
In order to develop new natural product-based anticancer agents, a series of 1,3,4-oxadiazole analogues based on petiolide A were prepared and evaluated for their anticancer activities by MTT method. The structures of all analogues were characterized by various spectral analyses, and B9 was further confirmed by X-ray crystallography. Among all the synthesized compounds, B1 displayed the most promising growth inhibitory effect on colon cancer cells (HCT116) with the IC 50 value of 8.53 μM. Flow cytometric analysis exhibited that B1 arrested the cell cycle at G2 phase and induced apoptosis. Additionally, network pharmacology analysis calculated that B1 might target several key proteins, including AKT serine/threonine kinase 1 (AKT1), SRC proto-oncogene, non-receptor tyrosine kinase (SRC) and epidermal growth factor receptor (EGFR). Furthermore, molecular docking study indicated that B1 had potentially high binding affinity to these three target proteins. Given these results, analogue B1 could be deeply developed as potential anticancer agents.
研究领域:
药物化学
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药理学
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肿瘤学
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化学生物学
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结构生物学
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DOI
高影响因子
Cells
·
2024
·Vol. 13
·期 23
·2028
·
IF 5.1
Ying Wang,Xueru Wang,Kaijin Wang,Weiwei Qin,Ning Li
Postmenopausal osteoporosis (PMOP) is a bone disease characterized by bone thinning and an increased risk of fractures due to estrogen deficiency. Current PMOP therapies often result in adverse side effects. The traditional medicinal plantCurculigo capitulatais commonly used to strengthen bones and support kidney function, but its role in treating PMOP is not well understood. This study aims to investigate the therapeutic effects of the total extract ofCurculigo capitulata(Eocc) on PMOP and to explore the underlying mechanisms. The major components of the extract were identified using HPLC. Transcriptomics was employed to predict potential targets. An osteogenic differentiation model of MC3T3-E1 cells was used in vitro. The osteogenic potential of the Eocc was assessed through CCK-8 cell viability assays, alkaline phosphatase (ALP) staining, Alizarin Red staining, Western blotting, and qPCR. MCF-7 and HEK-293 cells were utilized to evaluate the estrogen-like activity of Eocc. Apoptosis rates were detected by flow cytometry. In vivo, a bilateral ovariectomized mouse model of PMOP was used to further validate the in vitro findings through histopathological analysis and WB results. The results demonstrated that the Eocc promoted the proliferation of MC3T3-E1 cells, increased ALP activity, and stimulated the formation of osteogenic mineralized nodules. It also upregulated the expression of osteogenic markers (Runx2, OCN, OPN, and BSP) at both the protein and mRNA levels. The Eocc induced the activation of ERα both in vitro and in vivo, initiating the Src/PI3K/AKT signaling pathway, leading to the phosphorylation of GSK3β and subsequent osteogenesis. The activation of this pathway also stimulated the phosphorylation of mTOR and p70S6K while downregulating cleaved caspase-3 and caspase-9. Additionally, the Eocc reduced apoptosis during osteogenic differentiation and promoted cell proliferation. These findings suggest that the Eocc facilitates osteoblast proliferation and differentiation, improving bone integrity in PMOP mice, and may represent a promising therapeutic candidate for managing PMOP.
研究领域:
药理学
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骨生物学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 9
·期 7
·2571-2583
·
IF 6.843
Qingqing Li,Xianwei Yang,Peipei Zhang,Fei Mo,Peiru Si,Ximeng Kang,Menghan Wang,Jiye Zhang
Corneal neovascularization (CNV) is one of the most important causes of visual impairment worldwide. Dasatinib, a poorly water-soluble tyrosine kinase inhibitor with dual Src family kinase and platelet derived growth factor receptor inhibiting capability, has great potential in the treatment of CNV. In this study, dasatinib was successfully encapsulated into a nanostructured lipid carrier (Dasa-NLC) and the size was approximately 78 nm with a small polydispersity index. The NLC increased the solubility of dasatinib by more than 1220 times, sustained the drug release, reduced the ocular toxicity and facilitated its penetration into the cornea. Dasa-NLC significantly inhibited the proliferation, migration and tube formation of HUVEC cells, the three most important angiogenesis-related cellular changes of the CNV. Next, the in vivo anti-CNV effect of Dasa-NLC was evaluated using an alkaline burned mice CNV model, in which the development of the CNV and pathological changes of the cornea were significantly inhibited. The immunohistochemistry analysis indicated that Dasa-NLC could inhibit both the expression and activation of Src family kinase, a key component in the angiogenesis cascade. Therefore, Dasa-NLC showed considerable promise in the treatment of CNV.
研究领域:
药理学
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眼科学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Zhixiang Mu,Tianxi Shen,Hui Deng,Bairui Zeng,Chen Huang,Zhengjin Mao,Yuyu Xie,Yu Pei,Liting Guo,Rongdang Hu,Limin Chen,Yunlong Zhou
Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.
研究领域:
生物材料
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免疫学
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组织工程
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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
危险品化学品经营许可证（带存储）