INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Qiqi Yang,Yuan Yao,Junping Wang,Mengdi Pang,Jinyan Wu,Fusheng Yin,Jun He,Yanyan Wang,Weidong Chen
Non-small cell lung cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung cancer by injecting Lewis cells, and evaluated the therapeutic efficacy in vivo . The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting cancer cell apoptosis and reducing serum tumor marker levels. In vitro experiments revealed that this combination synergistically inhibited lung cancer cell proliferation and induced apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/AKT signaling, leading to enhanced apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP via PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/AKT pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.
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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DOI
PubMed
高影响因子
ONCOGENE
·
2025
·
IF 7.3
Li Honghao,Wu Junfeng,Dai Hua,Li Jiaming,Bai Xiaoyan,Sun Yueli,Lin Jiaxin,Li Yangsi,Li Peng,Shi Lingchao,Wang Zhen,Tu Haiyan,Ke Ee
Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4 , rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFR L858R -driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis. Graphical : Germline variation rs74955204 (p.G121E, c.362 G > A) in PDZRN4 significantly upregulated PDZRN4 expression and resulted in indolent growth of LUAD. Overexpressed PDZRN4 inhibits the ubiquitylation of HIF-1A by TRIM28, activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, thus restricting lung cancer cell growth.
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PubMed
高影响因子
EXPERIMENTAL DERMATOLOGY
·
2020
·Vol. 30
·期 7
·932-942
·
IF 3.368
Aimin Liu,Buxin Zhang,Wei Zhao,Yuanhui Tu,Qingxing Wang,Jing Li
Psoriasis is a chronic inflammatory disease characterized by abnormal hyperproliferation and differentiation. The object of this study is to explore the role of microRNA-215-5p in psoriasis-like inflammation. The expression of miR-215-5p was found to be down-regulated in pro-inflammatory factor-stimulated HaCaT cells and imiquimod (IMQ)-treated skin tissues. Overexpression of miR-215-5p suppressed the proliferation and cell cycle progression of HaCaT cells. Further, miR-215-5p agomir alleviated the disease severity, pathological features and Ki67 positive cells in IMQ-treated mice. Luciferase assay confirmed that miR-215-5p could bind to the 3′UTR of DYRK1A. The in vitro and in vivo results showed that miR-215-5p negatively regulates DYRK1A, which further inhibited EGFR and its downstream signalling pathways, AKT and ERK. Collectively, our results provide evidence that overexpression of miR-215-5p inhibits the proliferation of HaCaT cells and alleviates psoriasis-like inflammation partly by DYRK1A mediated inhibition of the EGFR signalling pathway. miR-215-5p may serve as a novel small molecule for therapeutic intervention in psoriasis.
研究领域:
分子生物学
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皮肤科
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炎症性疾病
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微小RNA研究
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DOI
PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2026
·
IF 4.9
Xinwen Li,Huiling Zhang,Chao Zhang,Xiaomin Zhang,Jiefeng He
Liver cirrhosis represents the irreversible end‐stage of various chronic liver diseases, whereas hepatic fibrosis, characterized by hepatic stellate cell (HSC) activation, constitutes the critical pathological intermediate in this progression. In this study, we investigated the antifibrotic effects of loganin, a natural iridoid glycoside, and elucidated its underlying mechanisms in bile duct ligation (BDL)–induced cholestatic liver injury and hepatic fibrosis and in TGF‐β1–stimulated HSCs. Sprague–Dawley rats subjected to BDL surgery received loganin for 14 days, resulting in marked amelioration of hepatomegaly, inflammatory infiltration, hepatocyte necrosis, and collagen deposition, alongside restoration of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (T‐BIL) levels and suppression of fibrogenic gene expression (collagen type I alpha 1 chain [COL1α1], alpha‐smooth muscle actin [α‐SMA], and fibronectin). Moreover, loganin attenuated hepatic autophagy, as evidenced by reduced Beclin‐1 expression and LC3B‐II/I ratio, with decreased colocalization of α‐SMA and LC3B. Bioinformatics analysis and molecular docking indicated that epidermal growth factor receptor (EGFR) may be the target protein through which loganin exerts its antifibrotic effect. Experimental validation demonstrated that loganin suppressed BDL‐induced EGFR phosphorylation in vivo. In TGF‐β1–activated HSC‐T6 cells, loganin inhibited cell activation, downregulated fibrosis markers, impaired autophagic flux, and suppressed TGF‐β1–induced upregulation of Beclin‐1 and LC3B‐II/I. Critically, cotreatment with the EGFR agonist EGF reversed the autophagy‐inhibitory and antifibrotic effects of loganin, whereas the EGFR inhibitor AG‐1478 mimicked loganin’s actions, confirming EGFR signaling as the functional mediator. Overall, these results indicated that loganin could alleviate liver injury and hepatic fibrosis in BDL rats by inhibiting autophagy and activation of HSCs, and this protective effect is mediated by the EGFR pathway.
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高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Zhitao Zhu,Zhengzhong Lv,Yurong Fan,Hongyuan Wen,Yuqi Zhang,Yirui Guo,Miao Li,Xingxiang Ren,Haibin Shi,Guohua Fan
Non-small cell lung cancer (NSCLC) is a cancer with high morbidity and mortality and faces multiple clinical challenges in early diagnosis, efficient treatment, targeted drug selection, and drug resistance. Herein, neovascularization and EGFR dual-targeting gold nanotheranostic system Bev-Au-CD(Osi) is designed and fabricated for epidermal growth factor receptror (EGFR)-mutated NSCLC treatment. This nanosystem consists of gold nanoparticle as drug nanocarrier and imaging contrast agent, Bevacizumab for targeting tumor neovascularization, and β-cyclodextrin (β-CD) as the cage for encapsulating EGFR mutant inhibitor Osimertinib. Taking advantage of the specific targeting ability of Bevacizumab to vascular endothelial growth factor (VEGF), Bev-Au-CD(Osi) nanoparticles target and accumulate at the tumor site for sensitive computed tomography (CT)/photoacoustic (PA) imaging of tumors. More notably, the sustained release of Osimertinib efficiently suppresses tumor growth through inhibiting angiogenesis and blocking the EGFR signaling pathway, significantly enhancing the therapeutic efficacy of NSCLC tumor in living mice. This work provides a powerful and universal nanotheranostic system for the precise treatment of EGFR-mutated NSCLC.
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Yuehua Yu,Zixuan Li,Yuan He,Ji Huang,Zhenxiao Sun
Lung adenocarcinoma is a highly fatal carcinoma worldwide with limited therapeutic options. We identified EGFR/ERBB2 as promising dual targets through integrative analysis of clinical data and TCGA database. Molecular docking and cytotoxicity screening of FDA-approved drugs identified Ebastine as a potent dual-targeting agent. Ebastine significantly inhibited NCI-H1975 cell viability (EGFR-mutant with high EGFR/ERBB2 expression), induced ROS elevation, decreased mitochondrial membrane integrity, and triggered apoptosis. Western blot revealed that Ebastine suppressed phosphorylation of EGFR, ERBB2, ERK1/2 and AKT. In xenograft models, Ebastine significantly inhibited NCI-H1975 tumor growth with no significant impact on body weight. Histopathological and immunohistochemical analyses showed reduced Ki67 expression and increased tumor cell apoptosis in Ebastine-treated tumors. Notably, Ebastine promoted macrophage infiltration and M1 polarization both in vivo and in vitro . Our findings establish Ebastine as a promising therapeutic candidate for EGFR/ERBB2-mutant lung adenocarcinoma through a unique dual-targeting approach that combines direct tumor cell inhibition with enhancement of anti-tumor immunity.
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Fangying Zheng,Yanyun Su,Xianbin Sun,Ding Tan,Ya Wang,Xiumei Li,Yu Gao
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are primary treatments for EGFR-mutated non-small cell lung cancer (NSCLC), but acquired resistance limits efficacy. To address this challenge, we developed CsO/IGA, a multifunctional nanoplatform combining osimertinib (AZD9291) with an indocyanine green-gadolinium (ICG-Gd) probe via oleanolic acid (OA)-modified chitosan encapsulation, integrating fluorescence/magnetic resonance imaging (FLI/MRI) with chemo-phototherapy and tumor microenvironment (TME) modulation. CsO/IGA (∼100 nm) demonstrated excellent stability and generated both singlet oxygen and hyperthermia under 808 nm irradiation. The nanoplatform exerted efficient anti-cancer effects to overcome resistance through reactive oxygen species induction, mitochondrial membrane potential reduction, and EGFR/phosphorylated EGFR downregulation in sensitive and resistant NSCLC cells. Notably, the OA component suppressed cancer-associated fibroblasts and α-smooth muscle actin expression, remodeling the TME to enhance tumor penetration. In vivo studies confirmed tumor-specific accumulation and deep penetration, FLI/MRI capability, and superior antitumor efficacy through chemo-phototherapy synergy. This work presents a promising OA-integrated theranostic strategy integrating targeted therapy, phototherapy, TME modulation, and diagnostic imaging for overcoming EGFR-TKI resistance in NSCLC.
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DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2018
·
IF 2.881
Ping Zhou,Gang Chen,Minqi Gao,Jiaquan Wu
Osimertinib has been approved as a first-line treatment for non-small-cell lung cancer (NSCLC) patients whose tumor carries EGFR activation and / or resistant mutations. To mitigate Osimertinib’s toxicity caused by AZ5104, the N-demethylation metabolite of Osimertinib, we designed and synthesized a series of Osimertinib analogs with different headpieces. In vitro and in vivo analysis rendered a potential clinical candidate C-005 which had pyrrolo-pyridine headpiece. Biochemically, C-005 and its main human hepatocyte metabolite showed over 30 fold selectivity of L858R/T790M mutant EGFR over WT EGFR. Such selectivity profile was retained at cellular level. In general, C-005 is 2-14 fold more selective than Osimertinib in a panel of WT EGFR cancer cell lines. Furthermore, C-005 demonstrated robust antitumor efficacy and good tolerability in NCI-H1975, PC-9 and HCC827 xenograft mouse models, making it a potential candidate for human test in clinical.
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 39
·期 2
·e6063
·
IF 1.7
Fan Tang,Xiaoli Hou,Jiajie Chen,Yasen Cao,Yixia Wang,Hong Cheng
Mobocertinib is a potent selective tyrosine kinase inhibitor approved for the treatment of non–small cell lung cancer with activating EGFR exon 20 insertions. The aim of this study was to develop a procedure for liquid chromatography tandem mass spectrometry (LC-MS/MS) for the determination of mobocertinib and its metabolite desmethyl-mobocertinib in human plasma. The human plasma samples were precipitated with acetonitrile and analyzed using a Waters ACQUITY BEH C 18 column coupled to a triple quadrupole mass spectrometer. Separation was executed using the acetonitrile–0.1% formic acid solution with gradient elution, at a flow rate of 0.4 mL/min. Mobocertinib and desmethyl-mobocertinib were monitored by multiple reaction monitoring (MRM) with m / z 586.5 > 72.2 and 572.4 > 473.2, respectively. The procedure demonstrated excellent linearity ( r > 0.997) within the concentration range of 0.1–200 ng/mL for both analytes. Precision in relative standard deviation was < 9.37% for mobocertinib and < 12.03% for desmethyl-mobocertinib. Accuracy in relative error was within −7.23% to 9.18% for mobocertinib and −2.78% to 9.87% for desmethyl-mobocertinib. Extraction recovery was > 80% for both analytes. The validated LC-MS/MS method was successfully applied to the pharmacokinetic study of mobocertinib and desmethyl-mobocertinib in healthy human volunteers with K 2 EDTA as anticoagulant after a single dose of mobocertinib (160 mg).
研究领域:
药理学
·
分析化学
·
肿瘤学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Bing Feng,Yanjing Lu,Bowen Zhang,Ying Zhu,Zuqing Su,Lipeng Tang,Laijun Yang,Tong Wang,Chunxia He,Chutian Li,Jie Zhao,Xirun Zheng,Guangjuan Zheng
Emerging evidence suggests that gut microbiota and its metabolites significantly influence the effectiveness of EGFR-TKIs (e.g., gefitinib, erlotinib) in lung cancer treatment. Plant polysaccharides can interact with gut microbiota, leading to changes in the host-microbe metabolome that may affect drug metabolism and therapeutic outcomes. Our previous research demonstrated the efficacy of basil polysaccharide (BPS) in treating various cancers by regulating hypoxic microenvironment and inhibiting epithelial-mesenchymal transition process. However, the potential impact of BPS on gut microbiota has not been thoroughly explored. In this study, we employed an immunodeficient gefitinib-resistant xenograft mouse model to explore whether BPS enhances the antitumor effects of gefitinib. A multi-omics approach, including 16S rDNA amplicon sequencing and LC-MS, was used to elucidate these synergistic effects. Our findings indicate that BPS can enhance tumor responsiveness to gefitinib by modulating the gut microbiota and its metabolites through multiple metabolic pathways. These changes in gut microbiota and metabolites could potentially affect cancer related signaling pathway and lung resistance-related protein, which are pivotal in determining the efficacy of EGFR-TKIs in cancer treatment.
研究领域:
肿瘤学
·
药理学
·
微生物学
·
代谢组学
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产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2021
·Vol. 13
·期 8
·1013-1018
·
IF 2.896
Ting Ju,Xingwei Zhai,Xinfeng Liu,Kun Han
Sensitive assay of EGFR T790M, a circulating tumor DNA marker in non-small-cell carcinoma, provides critical information for the decision of clinical treatments, evaluation of radiotherapy effect, and monitoring the progress of recurrence and metastasis. In this report, a novel flow cytometry-based sensing method is proposed for detecting T790M. The toehold-sequence hybridizes with the biotin-labeled initiator sequence and forms IT-dsDNA. The presence of a target induces the displacement of initiator-sequence from IT-dsDNA. The targets are continuously set free with the aid of a helper hairpin sequence for the next cycle. In tandem, the free initiator sequence starts the hybridization chain reaction, which binds the serial of fluorescence-labeled probe sequences. The products of the hybridization chain reaction are captured and separated by magnetic beads, which are finally assayed via flow cytometry. The capability to distinguish single-nucleotide polymorphism and the tolerance of complex matrix in blood serum indicate that this strategy has the promising potential to be applied in the liquid biopsy of clinical samples.
研究领域:
分子生物学
·
肿瘤学
·
临床诊断
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2019
·
IF 4.511
Wenjing Lu,Fangfang Du,Xuewei Zhao,Lihong Shi,Shaomin Shuang,Xinyan Tracy Cui,Chuan Dong
Because of the demand for precision medicine, the investigatation on the application of carbon-dots-based nanosystems in the field of biomedicine is attracting more and more attention. Therefore, we have built a multifunctional nanosystem based on sulforaphane-conjugated carbon dots (SFN-CDs) with thiourea skeleton and applied for EGFR-overexpressing cancer cells targeted imaging and inhibiting. The SFN-CDs are formed by grafting sulforaphane on the amino-rich yellow fluorescent carbon dots, which have excellent optical stability and can be distinguished from normal cells for targeted imaging of cancer cells. The vitro toxicity experiments demonstrated that the SFN-CDs can effectively inhibit EGFR-overexpressing cancer cell proliferation at concentrations below 100 μg mL–1. All these results validated that SFN-CDs nanoparticles with integration of diagnostic and therapeutic functions can be used as a potential nanodurg in early stage of cancer control. Moreover, this work provides useful insight into targeted nanoparticle design in the biological nanomedicine field.
研究领域:
纳米医学
·
癌症诊疗一体化
·
生物医学成像
·
分子靶向治疗
·
生物偶联化学
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DOI
高影响因子
危险品化学品经营许可证（带存储）