PHYTOMEDICINE
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2024
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IF 6.7
Heung Lam MOK,Ka Wing CHENG,Yiqi XU,Chunhua HUANG,Cheng LYU,Jiaruo XU,Die HU,Lin ZHU,Chengyuan LIN,Hor-Yue TAN,Zhaoxiang BIAN
Background Ulcerative colitis (UC) is associated with intestinal macrophage infiltration due to disruption of the mucosal barrier and bacterial invasion. Therefore, it is crucial to identify therapeutic agents capable of attenuating the macrophage-induced inflammatory response to preserve mucosal homeostasis and immune tolerance. The modified Zhenwu decoction (CDD-2103) is a novel herbal formulation developed based on the principles of Traditional Chinese medicine. To date, there are no clinically approved herbal formulations for UC with a well-known mechanism of action on macrophages. Purpose The objective of this study was to systematically investigate the inhibitory effect of the active fraction of CDD-2103 in a mouse model of chronic colitis and delineate the mechanisms underlying its inhibitory action. Methods CDD-2103 was extracted into four fractions using organic solvents with increasing polarity. A chronic 49-day dextran sulfate sodium (DSS)-induced colitis mice model, closely resembling human clinical conditions, was used to examine the effect of CDD-2103 on chronic colitis. To confirm the effect of CDD-2103 on macrophages in this chronic colitis model, adoptive macrophage transfer and CCL2 supplementation were conducted. The mechanisms of action of CDD-2103 were further elucidated utilizing bone marrow-derived macrophages (BMDMs). Transcriptome analysis was conducted to gain insights into the underlying mechanism of action of CDD-2103 in BMDMs. Results Our in vitro and in vivo findings demonstrated that the ethanol-enriched fraction of CDD-2103 exhibited significant anti-inflammatory effects, leading to the suppression of colitis severity. This effect was associated with diminished accumulation of colonic macrophages in the lamina propria of CDD-2103-intervened colitis mice. Specifically, CDD-2103 inhibited CCR2/L2-mediated proinflammatory macrophage infiltration into the colon without affecting macrophage proliferation. Mechanistically, CDD-2103 inhibited Fyn expression-mediated p38 MAPK activation and subsequently suppressed CCR2 expression in BMDMs. Conclusions Collectively, our study supports the potential use of CDD-2103 to limit macrophage infiltration, thereby reducing inflammation during UC treatment. CDD-2103 and the components in the ethanolic fraction are promising candidates for the development of novel drugs for UC management. Additionally, our study underscores Fyn-mediated CCR2 expression as a potential therapeutic target for the management of UC.
研究领域:
药理学
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免疫学
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中医药
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炎症性肠病
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Anquan Ma,Ziqing Yang,Qixuan He,Wenhao Wang,Huiping Ren,Chuanyao Zhai,Jing Lan
Environmental glyphosate exposure has been linked to glioblastoma (GBM), yet its molecular basis remains unclear. Integrating network-toxicology and druggable Mendelian randomization screens, we identified the Src-family kinase FYN as the principal glyphosate target. Molecular-dynamics simulations, surface-plasmon resonance (KD = 1.54 μM) and pull-down assays confirmed high-affinity binding and highlighted ASP353 as a dominant contact residue. Multi-omics profiling showed FYN over-expression and promoter hypomethylation in GBM, correlating with diminished immune infiltration. In U87 cells, sub-toxic glyphosate (0.1 mg/L, 12 h) up-regulated FYN, activated PI3K–AKT–mTOR signaling, increased GLUT1, LDHA and PKM2, and accelerated proliferation, migration and invasion; lentiviral sh-FYN reversed these effects and curtailed glycolytic flux. Orthotopic mouse studies mirrored the in-vitro findings, with FYN knock-down suppressing glyphosate-driven tumor growth. Exosomes derived from sh-FYN glioma cells weakened macrophage M2 polarization and reduced CXCL1, IL-10 and TGF-β secretion, revealing an immunometabolism axis. Collectively, these results establish FYN as the mechanistic conduit between glyphosate and GBM and demonstrate that targeting FYN—directly or via exosome delivery—reprograms tumor glycolysis and immunity, offering a tractable strategy against glyphosate-associated malignancy.
研究领域:
毒理学
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肿瘤学
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分子生物学
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生物信息学
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神经肿瘤学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2021
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IF 5.275
Lanmei Chen,Jie Wang,Xianhong Cai,Suxiang Chen,Jingjing Zhang,Baojun Li,Weigang Chen,Xinhua Guo,Hui Luo,Jincan Chen
Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3 , RuIQ-4 , and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5 , were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo . Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.
研究领域:
药理学
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肿瘤学
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细胞生物学
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化疗
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Kunmei Xie,Feibiao Wang,Yue Yang,Shoujie Pan,Junyao Wang,Nan Xiao,Xinyan Wang,Zhihao Ma,Xiaolong Xu,Zibo Dong
Sepsis-associated acute liver injury (ALI) is a deadly condition resulting from a systemic inflammatory response to liver cell damage and malfunction. Monotropein (MON) belongs to the iris group of compounds extracted from the natural product Mollen dae officinalis radix, which has strong anti-inflammatory and antioxidant pharmacological effects. The purpose of this study was to elucidate the underlying mechanism of MON in the treatment of sepsis ALI. In this study, an in vivo caecal ligation puncture (CLP)-induced ALI model and in vitro LPS-stimulated AML12 cells and RAW264.7 cells model were established. Additionally, a variety of experimental techniques, including CCK8, H&E staining, DHE probe labelling, biochemical, QPCR, and Western blotting and blocking tests, were used to explore the role of MON in ALI. The results showed that MON improved liver morphological abnormalities, oedema, histopathological injury, and elevated ALT and AST, providing a protective effect against ALI. MON reduced CYP2E1 expression, alleviated oxidative stress (downregulation of MDA levels and upregulation of GSH, CAT, and T-AOC levels) and ROS accumulation with the involvement of the NRF2-Keap-1 pathway. MON inhibited inflammation via the TLR4/NF-κB/NLRP3 inflammasome pathway. In addition, it activated the Akt (Ser473)/GSK3β (Ser9)/Fyn pathway and accelerated NRF2 nuclear accumulation; MK-2206 blockade reversed the NRF2 nuclear accumulation and anti-inflammatory function of MON. MON also restricted the mitochondrial apoptosis pathway, a process specifically blocked by MK-2206. In summary, we concluded that MON alleviated septic ALI by restricting oxidative stress, inflammation, and apoptosis via the AKT (Ser473)/GSK3β (Ser9)/Fyn/NRF2 pathway.
研究领域:
药理学
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免疫学
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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
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产品关联
DOI
PubMed
高影响因子
Cancer Cell International
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2020
·Vol. 20
·期 1
·1-16
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IF 4.175
Tang Ling,Long Jing,Li Keke,Zhang Xu,Chen Xiang,Peng Cong
Background Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111,277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What’s more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.
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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癌症研究
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Kaixin Ping,Panpan Zhao,Jingyuan Zhou,Yue Xin,Boran Hu,Baihao Zhang,Dong Xu,Aimin Li,Yong Sun
Background Subarachnoid hemorrhage (SAH) is a lethal stroke subtype with high mortality. Microglia-driven neuroinflammation plays a pivotal role in early brain injury (EBI) after SAH. Xanthotoxol (Xol), a natural furanocoumarin, exhibits anti-inflammatory properties and neuroprotective potential, yet its role in SAH remains unclear. This study investigates whether Xol alleviates SAH-induced neuroinflammation and its underlying mechanisms. Methods SAH was induced in male SD rats and Balb/c mice via endovascular perforation. Three weeks prior to the SAH surgery, AAV2/9-CX3CR1-ZsGreen-miR30-Fyn virus was injected into the medial prefrontal cortex for in vivo mechanistic investigations. In vitro SAH models were established using oxyhemoglobin-stimulated microglia and microglia-neuron co-cultures. Finally, the efficacy of Xol was investigated both in vivo and in vitro following SAH. Assessments included neurological and cognitive function evaluation, brain water content measurement, detection of apoptosis, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, immunohistochemistry, and Nissl staining. Results Fyn was upregulated in microglia post-SAH and associated with neuroinflammatory and apoptotic pathways via proteomics. Its knockdown ameliorated neurological deficits, edema, neuronal injury, and NLRP3 activation. Mechanistically, Fyn promoted K48-linked ubiquitination and degradation of Sirt1 via E3 ligase C-cbl. Xol directly bound Fyn, inhibiting its kinase activity and NLRP3 activation, thereby mitigating brain injury. Conclusion This study revealed Fyn recruits E3 ligase C-cbl to mediate Sirt1-K48 ubiquitination/degradation, activating NLRP3 inflammasome to drive SAH-induced neuroinflammation and brain injury. Xol inhibits Fyn activation, thereby attenuating inflammatory injury. The Fyn/Sirt1 axis represents a novel therapeutic target, and Xol offers a promising natural strategy for SAH treatment.
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DOI
PubMed
高影响因子
PROTEIN SCIENCE
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2020
·Vol. 30
·期 3
·558-570
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IF 3.876
Shuhao Li,Yang Zou,Dongping Zhao,Yuqing Yin,Jingyi Song,Ningning He,Huadong Liu,Dongmeng Qian,Lei Li,Haiming Huang
Protein engineering through directed evolution is an effective way to obtain proteins with novel functions with the potential applications as tools for diagnosis or therapeutics. Many natural proteins have undergone directed evolution in vitro in the test tubes in the laboratories worldwide, resulting in the numerous protein variants with novel or enhanced functions. we constructed here an SH2 variant library by randomizing 8 variable residues in its phosphotyrosine (pTyr) binding pocket. Selection of this library by a pTyr peptide led to the identification of SH2 variants with enhanced affinities measured by EC50. Fluorescent polarization was then applied to quantify the binding affinities of the newly identified SH2 variants. As a result, three SH2 variants, named V3, V13 and V24, have comparable binding affinities with the previously identified SH2 triple-mutant superbinder. Biolayer Interferometry assay was employed to disclose the kinetics of the binding of these SH2 superbinders to the phosphotyrosine peptide. The results indicated that all the SH2 superbinders have two-orders increase of the dissociation rate when binding the pTyr peptide while there was no significant change in their associate rates. Intriguingly, though binding the pTyr peptide with comparable affinity with other SH2 superbinders, the V3 does not bind to the sTyr peptide. However, variant V13 and V24 have cross-reactivity with both pTyr and sTyr peptides. The newly identified superbinders could be utilized as tools for the identification of pTyr-containing proteins from tissues under different physiological or pathophysiological conditions and may have the potential in the therapeutics.
研究领域:
分子生物学
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蛋白质工程
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生物化学
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DOI
PubMed
高影响因子
SURGICAL ONCOLOGY-OXFORD
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2020
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IF 2.521
Feng Xue,Yong Jia,Jian Zhao
Background Tyrosine-protein kinase Fyn (FYN) plays a crucial role in Src family, which participates in the signal transduction of brain nerves and the development and activation of T lymphocytes in physiological conditions. We probed into the roles and mechanisms of FYN in lung adenocarcinoma (LUAD). Methods Cell activity, apoptosis , invasion, and migration were detected by CCK-8, FCM , transwell, and wound-healing assays, respectively. The angiogenesis capacity was evaluated by in vitro angiogenesis test. Relative mRNA and protein expressions were determined by qRT-PCR, Western blot , and immunohistochemistry assays, respectively. Insulin-like growth factors-I (IGF-I) was used as an agonist of PI3K/AKT pathway. Results We demonstrated that FYN expression correlated with LUAD prognosis and was down-regulated in LUAD tissues and LUAD cells. Overexpression of FYN suppressed the cell viability , together with invasion and migration abilities of A549 cells. FYN overexpression accelerated the cell apoptosis and reduced the angiogenesis capacity of A549 cells. Overexpression of FYN suppressed E-cadherin, Vimentin , Snail , and PI3K/AKT expressions in A549 cells. High expression level of FYN reduced the migration and invasion capacities of A549 cells via down-regulating the PI3K/AKT pathway. Conclusion Collectively, our findings reveal that overexpression of FYN inhibits the epithelial-to-mesenchymal transition (EMT) through down-regulating the PI3K/AKT pathway in A549 cells.
研究领域:
肿瘤学
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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
Asian Pacific Journal of Cancer Prevention
·
2021
·
IF 0
Yanjun An,Jiandong Zhao,Yourui Zhang,Wen Wu,Jiangtao Hu,Haosen Hao,Yu Qiao,Ying Tao,Liping An
Background: Rosmarinic acid (RA) is a natural phenolic compound that acts as a Fyn inhibitor by 53 homology modeling of the human Fyn structure. Therefore, the apoptosis mechanism related to NF-κB signaling pathway induced by RA in HepG2 was investigated. Methods: The cell growth, apoptosis, and proliferation of HepG2 regulated by various concentrations of RA were studied. The proteins expression of MMP-2, MMP-9, PI3K, AKT, NF-κB, and apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 were detected. Results: RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expressions of invasion-related factors, such as matrix metalloproteinase (MMP)-2 and MMP-9. TUNEL staining revealed that RA resulted in a dose-dependent increase of HepG2 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl-2 was downregulated and that of the pro-apoptotic proteins Bax and cleaved caspase-3 was increased. In addition, we found that the phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor kappa B (NF-κB) signaling pathway was involved in RA-mediated inhibition of HepG2 cell metastasis. Conclusion: Our study identified that RA as a drug candidate for the treatment of HCC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2021
·Vol. 47
·期 5
·1-11
·
IF 4.101
Yunsheng Liu,Xiangping Xu,Han Tang,Yuchen Pan,Bing Hu,Guodong Huang
There is a growing evidence that Fyn kinase is upregulated in glioblastoma multiforme (GBM), where it plays a key role in tumor proliferation and invasion. In the present study, the antitumor effects of rosmarinic acid (RA), a Fyn inhibitor, were explored in human‑derived U251 and U343 glioma cell lines. These cells were treated with various concentrations of RA to determine its effects on proliferation, migration, invasion, apoptosis, and gene and protein expression levels. The CCK‑8 assay revealed that RA significantly suppressed cell viability of U251 and U343 cells. Furthermore, RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expression levels of invasion‑related factors, such as matrix metalloproteinase (MMP)‑2 and MMP‑9. TUNEL staining revealed that RA resulted in a dose‑dependent increase of U251 and U343 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl‑2 was downregulated and that of the pro‑apoptotic proteins Bax and cleaved caspase‑3 was increased. In addition, it was revealed that the phosphatidylinositol 3‑kinase (PI3K)/Akt/nuclear factor‑κB (NF‑κB) signaling pathway was involved in RA‑induced cytotoxicity in U251 and U343 cells. Collectively, the present study suggested RA as a drug candidate for the treatment of GBM.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2021
·
IF 5.858
Mingming Sun,Hao Sheng,Tingfeng Wu,Jiaqi Song,Huanran Sun,Yingzhi Wang,Jiyan Wang,Zhen Li,Huifang Zhao,Junzhen Tan,Yanping Li,Guo Chen,Qingrong Huang,Yuan Zhang,Bei Lan,Shuangping Liu,Changliang Shan,Shuai Zhang
Reprogramming of energy metabolism is a hallmark of cancer, and the pentose phosphate pathway (PPP) is a major glucose metabolic pathway important for meeting the cellular demands of biosynthesis and anti-oxidant defense. Our previous study showed that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) plays an important role in glioblastoma cell survival and growth under cellular energy stress condition. However, the crucial functions of PIKE-A in cancer energy metabolism are poorly understood. In the present study, we show that PIKE-A promotes DNA biosynthesis, NADPH production and inhibits reactive oxygen species (ROS) production, leading to increasing proliferation and growth of glioblastoma cell and suppressing cellular senescence. Mechanistically, PIKE-A binds to STAT3 and stimulates its phosphorylation mediated by tyrosine kinase Fyn , which enhances transcription of the rate-limitting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the PPP. Finally, targeting PIKE-A-G6PD axis sensitizes glioblastoma to temozolomide (TMZ) treatment. This study reveals that STAT3 is a novel binding partner of PIKE-A which recruits Fyn to phosphorylate STAT3, contributing to the expression of G6PD, leading to promoting tumor growth and suppressing cellular senescence. Thus, the PIKE-A/STAT3/G6PD axis strongly links the PPP to carcinogenesis and may become a promising cancer therapeutic target.
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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药理学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2026
·
IF 16.2
Jiani Gao,Ke Zhou,Yijiu Ren,Fengjing Yang,Minjue Shan,Yubing Fang,Changbo Sun,Weili Han,Chang Chen,Xuefei Hu
Transfusion-related acute lung injury (TRALI) remains a life-threatening complication of blood transfusion, yet the macrophage-neutrophil-NETosis inflammatory amplification mechanism and effective interventions are still incompletely defined. Here, we examined a CD36/Fyn-CXCL-related axis in TRALI and evaluated a ROS-responsive platelet extracellular vesicle biomimetic nanosystem (PEV@SP@EG) as a targeted delivery strategy. In a murine TRALI model, exploratory single-cell transcriptomic analysis showed immune-cell remodeling and linked CD36 expression to M1-like macrophage features. CD36 knockdown or pharmacological inhibition of Fyn/NF-kappaB reduced M1 polarization markers, CXCL production, and ROS generation. Conditioned medium from CD36-overexpressing BMDMs promoted neutrophil migration and NETosis, whereas CXCL-CXCR2 blockade or CD36/Fyn inhibition weakened these responses. PEV@SP@EG showed ROS-triggered drug release and preferential lung enrichment. In vivo , PEV@SP@EG attenuated CD36/Fyn-NF-kappaB-CXCL-related inflammatory signaling, NET formation, and oxidative stress in TRALI lung tissue, with concomitant improvement in lung architecture and gas exchange. These findings support a role for macrophage CD36/Fyn signaling in TRALI-associated macrophage-neutrophil inflammatory crosstalk and suggest that PEV@SP@EG may provide a targeted nanotherapeutic delivery platform for TRALI intervention.
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高影响因子
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