PLoS One
·
2025
·Vol. 20
·期 5
·e0322056
·
IF 2.6
Wenyue Hou,Ting Zou,Yichao Yan,Yaolong Zhuang,Shaomei Gao,Huijun Ju,Fei Yao,Qin Yuan,Liang Zhou,Guoqiang Liang,Xiudao Song,Lurong Zhang
5-O-Methylvisammioside (5OMV), a flavonol compound derived from the traditional Chinese medicine plant Saposhnikovia divaricat , has been shown to inhibit vasospasm induced by High Mobility Group Box 1 (HMGB1) protein. However, its therapeutic potential and molecular mechanisms in HMGB1-induced tumor angiogenesis remain unexplored. Through comprehensive in vitro assays, we demonstrated that 5OMV significantly attenuates HMGB1-induced proliferation, migration, tube formation, and angiogenic activity in human umbilical vein endothelial cells (HUVECs). Parallel in vivo studies using an orthotopic hepatocellular carcinoma model in C57BL/6 mice revealed that 5OMV treatment markedly reduced tumor progression and microvascular density. Mechanistic studies identified that 5OMV downregulates both total and phosphorylated forms of RAGE, MEK, and ERK in HUVECs and tumor tissues. These findings collectively establish that 5OMV exerts anti-tumor effects in hepatocellular carcinoma through targeted modulation of the HMGB1/RAGE/MEK/ERK signaling axis.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
·
2020
·
IF 2.886
Yanshi Wang,Shaojie Yang,Shanshan Zhang,Xin Wu
Purpose To evaluate the anti-tumor effects of oxymatrine in vulvar squamous cell carcinoma (VSCC) cells and to explore the underlying mechanisms. Methods We selected SW962 and A431 VSCC cell lines. Cell proliferation was examined using MTT assay. Cell cycle and apoptosis were detected using flow cytometry. Migration and invasion were evaluated using transwell and wound-healing assays. The relevant protein expression and signaling pathways were analyzed using Western blotting. Results Oxymatrine inhibited the proliferation of SW962 and A431 VSCC cells in a time- and dose-dependent manner. Oxymatrine induced cell cycle arrest in the G2/M phase by increasing the protein expression of P21 and decreasing levels of cyclin B1 and CDC2. Oxymatrine upregulated the expression of cleaved-caspase 3 and BAX and downregulated the expression of BCL2, which led to an increase in apoptosis. Oxymatrine also suppressed the migration and invasion of SW962 and A431 cells by reducing levels of MMP2 and MMP9. After treatment with oxymatrine or a RAS inhibitor (salirasib), expression levels of RAS, p-RAF, p-MEK, p-ERK, C-MYC, and MMP2 were reduced. When TGF-β1 was used to stimulate SW962 and A431 cells, the expression of the above proteins increased; this increase was reversed by using oxymatrine or salirasib again. Conclusion Oxymatrine inhibits proliferation and migration of VSCC cells by blocking the RAS/RAF/MEK/ERK pathway.
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
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Li-Ying Han,Hao Yu,Shuai Wang,Yong-Rui Bao,Tian-Jiao Li,Ying Zheng,Xi Luo,Meng-Nan Jia,Qiang Zhang,Xian-Sheng Meng
Ethnopharmacological relevance Colorectal cancer (CRC) belongs to the category of intestinal wind, anal ulcer, abdominal mass and other diseases in traditional Chinese medicine (TCM). Floris Sophorae Powder (F.S), is a classical prescription is recorded in Puji Benshi Fang for the treatment of intestinal carbuncle. It has been incorporated into the prescriptions for the treatment of intestinal diseases and achieved remarkable results in modern medicine. However, the mechanism of F.S in the treatment of colorectal cancer remains unclear and requires further study. Aim of the study To investigate F.S in treating CRC and clarify the underlying mechanism. Materials and methods This study was based on Dextran Sulfate Sodium Salt (DSS) combined with Azoxymethane (AOM) induced CRC mouse model to clarify the pharmacological effects of F.S. The serum metabolomics was used to study the mechanism of action, and the chemical composition of F.S was found by UPLC-Q-TOF-MS. The rationality of serm metabolomics results was verified through the clinical target database of network pharmacology, and the upstream and downstream targets of related pathways were found. The mechanism pathway was verified by Western blot to clarify its mechanism of action. Results In vivo pharmacological experiments showed that F.S inhibited tumor growth and improved hematochezia. The vital signs of mice in the high-dose F.S group approached to those in the control group. A total of 43 differential metabolites were found to be significantly changed by serum metabolomics. F.S could modulate and recover most of the differential metabolites, which proved to be closely related to the KRAS/MEK-ERK signaling pathway. A total of 46 compounds in F.S were identified, and the rationality of serm metabolic pathway was verified by network pharmacology. Western blot results also verified that the expression of KRAS, E2F1, p-MEK and p-ERK were significantly decreased after F.S treatment. Conclusion Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.
研究领域:
药理学
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肿瘤学
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中医
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代谢组学
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信号转导
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-15
·
IF 7
Ye Jianfeng,Liu Wangmin,Yu Xueyang,Wu Lina,Chen Zhengjie,Yu Yufei,Wang Jianfeng,Bai Song,Zhang Mo
Homeobox A5 (HOXA5), a homeodomain transcription factor, is considered a tumor suppressor in cancer progression; however, its function in prostate cancer (PCa) remains unclear. This study focused on the relevance of HOXA5 in PCa progression. We identified the downregulation of HOXA5 in PCa tissues based on the TCGA database and further verified in 30-paired PCa and adjacent normal tissues. Functional studies revealed that HOXA5 upregulation impaired the stem-like characteristics and malignant behaviors of PCa cells in vitro and in vivo. Mechanistically, HOXA5 was found to be regulated by tumor necrosis factor receptor-associated factor 7 (TRAF7), a putative E3-ubiquitin ligase. We observed that TRAF7 was overexpressed in PCa and subsequently enhanced the degradation of HOXA5 protein via its ubiquitin ligase activity, contributing to the acquisition of an aggressive PCa phenotype. For its downstream mechanism, we demonstrated that sprouty RTK signaling antagonist 2 (SPRY2) served as a downstream target of HOXA5. HOXA5 could directly bind to the SPRY2 promoter, thereby regulating the SPRY2-mediated MEK/ERK signaling pathway. Silencing SPRY2 largely compromised the tumor-suppressive effect of HOXA5 in PCa progression and cancer stemness. Our findings highlight the previously-underappreciated signaling axis of TRAF7–HOXA5–SPRY2, which provides a novel prognostic and therapeutic target for PCa treatment.
研究领域:
肿瘤学
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分子生物学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
ANTICANCER RESEARCH
·
2024
·Vol. 44
·期 7
·2861-2870
·
IF 1.6
YINA ZHANG,XIAOCEN NIU,YUANHE WANG,SHUTING BAO,PEIYUE JIANG,XIAORUI DONG
Background/Aim: Glutamine metabolism is crucial in cell proliferation, aging, and apoptosis across various cancer types. Existing research indicates that Sirtuin 4 (SIRT4), primarily located in mitochondria, modulates this process. This study aimed to clarify the regulatory relationship between SIRT4 and glutamine metabolism in cervical cancer. Materials and Methods: SIRT4 mRNA levels and their clinical correlation to cervical cancer were analyzed using the UALCAN database. Immunohistochemistry (IHC) was performed to assess SIRT4 protein expression in tissue samples from cervical cancer patients. Transient transfection was employed to create Hela and Siha cell lines with overexpressed SIRT4, mitogen-activated extracellular signal-regulated kinase (MEK), and glutaminase 1 (GLS1). The impact on cellular functions was studied using MTT, soft agar, transwell, and western blotting assays. Glutamate and ATP levels were also measured to evaluate metabolic changes. Results: Low levels of SIRT4 mRNA in cervical cancer tissues correlated with tumor metastasis and poor survival rates. Overexpression of SIRT4 led to suppressed cell proliferation, colony growth, and motility, along with significant down-regulation of GLS expression, a key contributor to glutamine metabolism. Additionally, SIRT4 overexpression resulted in the inactivation of the MEK/ERK/c-myc signaling pathway, while overexpression of MEK reversed these effects. Notably, the inhibitory effects of SIRT4 on cell proliferation, colony formation, migration, and invasion in Hela and Siha cells were significantly attenuated following GLS1 overexpression. Conclusion: SIRT4 acts as an anti-cancer agent in cervical cancer by inhibiting glutamine metabolism through the MEK/ERK/c-myc signaling pathway, providing a novel sight for cervical cancer therapy.
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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癌症代谢
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2024
·
IF 4.7
Lan Liang,Chenming He,Xue Han,Jia Liu,Liuhong Yang,Fengjiao Chang,Yami Zhang,Jie Lin
Background Precancerous lesions of gastric cancer (PLGC) represent critical stages in gastric cancer progression, with a high risk of malignancy. Current treatments, such as Helicobacter pylori eradication, show limited efficacy in reversing precancerous molecular changes. Zuojin Pill (ZJP), a traditional Chinese medicine, has demonstrated potential for treating digestive disorders and may offer a promising approach for PLGC intervention.Objective This study aims to investigate the therapeutic effects and mechanisms of ZJP in treating PLGC, focusing on its active components, target pathways, and molecular interactions. By using advanced analytical techniques, we provide a scientific foundation for ZJP’s potential application in early gastric cancer intervention.Methods Using ultra-high performance liquid chromatography-quadrupole orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS), we identified active components in ZJP. A network pharmacology approach was then applied to construct a “ZJP-compound-target-disease” network. Molecular docking and molecular dynamics simulations were conducted to analyze the stability and interactions of the main active components of ZJP with core protein targets in PLGC. Animal experiments were used to validate significant targets and pathways in vivo.Results Tangeritin, Isorhamnetin, Caffeic Acid, Azelaic Acid, and Adenosine were identified as the main active components of ZJP in the treatment of PLGC, with key targets including PIK3R1, MAPK3, SRC, JAK2, STAT3, and PIK3CA. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of ZJP predicted by network pharmacology analysis was confirmed in PLGC rats. ZJP downregulated IL-6, TNF-α, c-myc, p-MEK1 and p-ERK1/2, effectively reversing the progression of PLGC.Conclusion ZJP can reverse MNNG-induced PLGC, potentially through inhibition of the MEK/ERK/c-myc pathway and regulation of cellular proliferation and apoptosis.
研究领域:
中药学
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肿瘤学
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生物信息学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-18
·
IF 7.5
Tan Yanzhen,Li Hong,Cao Guojie,Xin Jialin,Yan Dongxu,Liu Yingying,Li Panpan,Zhang Yuxi,Shi Lei,Zhang Bing,Yi Wei,Sun Yang
Background In developed nations, myocardial infarction (MI) is one of the main causes of morbidity and mortality, resulting in a significant economic burden and becoming a global public health problem. C1q/tumor necrosis factor-related protein 9 (CTRP9) is a secreted protein comprising a variable domain, a collagenous region, and a C-terminal trimerizing globular C1q (gC1q) domain. In vivo, the full-length CTRP9 (fCTRP9) can be cleaved into the globular domain of CTRP9 (gCTRP9). Here, we tested the cardio-protective impacts of fCTRP9, gCTRP9, and N-terminal domain, including the variable and collagenous domain, of CTRP9 (nCTRP9) in the context of MI.Methods Studies comparing the protective properties of fCTRP9 and gCTRP9 against MI in mice hearts were performed both in vitro and in vivo. The role of matrix metalloproteinase-9 (MMP9) in CTRP9 cleavage was examined, and the effects of different CTRP9 domains on cardiac fibrosis and cardiac fibroblast (CF) activation were investigated.Results gCTRP9 exerted better protective effects than fCTRP9 against MI, demonstrating superior anti-apoptotic and anti-fibrotic properties. fCTRP9 was cleaved by MMP9, resulting in gCTRP9 and nCTRP9. MMP9 overexpression enhanced the cardioprotective effects of fCTRP9, while nCTRP9 supplementation aggravated cardiac fibrosis in MI mice. Mechanistically, nCTRP9 activated CFs via an increase in Rap1 expression and MEK 1/2 and ERK1/2 phosphorylation.Conclusion sDifferent domains of CTRP9 have distinct cardioprotective effects. gCTRP9 shows beneficial effects, while nCTRP9 promotes cardiac fibrosis. These findings highlight the importance of CTRP9 in cardiac function regulation and suggest prospective therapeutic options for MI treatment.
研究领域:
心脏病学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·
IF 4.3
Chen Xue,Zhou Xing-Yue,Lan Cai,Fu Hai-Jun,Li Zhi-Chao,Chen Meng-Yi,Wen Yong-Ping,Yu Lu,Qin Da-Lian,Wu An-Guo,Wu Jian-Ming,Zhou Xiao-Gang
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by pathological protein aggregation and oxidative stress, leading to progressive neurodegeneration. Enhancing autophagy, the primary intracellular pathway for clearing misfolded proteins, represents a promising therapeutic strategy. In this study, we identify Araloside A (ARA), a triterpenoid saponin derived from Aralia elata , as a potent autophagy inducer that alleviates AD- and PD-related pathology. In neuronal cell models, ARA promotes autophagosome formation, increases LC3-II and Beclin-1 levels, and decreases P62, indicating enhanced autophagic activity. Mechanistic investigations reveal that ARA directly binds to Raf, MEK, and ERK proteins and activates autophagy in a Raf/MEK/ERK-dependent manner. This activation facilitates the clearance of APP, total Tau, phosphorylated Tau, and α-synuclein, thereby reducing cytotoxicity. Furthermore, in transgenic Caenorhabditis elegans models of AD and PD, ARA treatment alleviates protein aggregation and behavioral deficits via ERK-dependent autophagy. Together, these findings identify ARA as a natural compound that enhances autophagic clearance of neurotoxic aggregates via Raf/MEK/ERK pathway activation, offering promising therapeutic insights for neurodegenerative proteinopathies.
研究领域:
神经科学
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药理学
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分子生物学
·
神经退行性疾病
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细胞生物学
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天然产物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2024
·
IF 3.2
Zhou Si Yun,Song Zhihua,Tian Xuelian,Xia Min,Hu Rongjing,Luo Mei
Chlamydia trachomatis (CT) is the leading cause of bacterial sexually transmitted diseases worldwide, which can cause diseases such as pelvic inflammatory disease, and cervical and fallopian tube inflammation, and poses a threat to human health. Rosmarinic acid (RosA) is an active ingredient of natural products with anti-inflammatory and immunomodulatory effects. This study aimed to investigate the role of RosA in inhibiting autophagy-regulated immune cells-CD8+ T cells via the Ras/Raf/MEK/ERK signaling pathway in a CT-infected mouse model. Mice were inoculated with CT infection solution vaginally, and the mechanistic basis of RosA treatment was established using H&E staining, flow cytometry, immunofluorescence, transmission electron microscopy, and western blot. The key factors involved in RosA treatment were further validated using the MEK inhibitor cobimetinib. Experimental results showed that both RosA and the reference drug azithromycin could attenuate the pathological damage to the endometrium caused by CT infection; flow cytometry showed that peripheral blood CD8+ T cells increased after CT infection and decreased after treatment with RosA and the positive drug azithromycin (positive control); immunofluorescence showed that endometrial CD8 and LC3 increased after CT infection and decreased after RosA and positive drug treatment; the results of transmission electron microscopy showed that RosA and the positive drug azithromycin inhibited the accumulation of autophagosomes; western bolt experiments confirmed the activation of autophagy proteins LC3Ⅱ/Ⅰ, ATG5, Beclin-1, and p62 after CT infection, as well as the inhibition of Ras/Raf/MEK/ERK signaling. RosA and azithromycin inhibition of autophagy proteins activates Ras/Raf/MEK/ERK signaling. In addition, the MEK inhibitor cobimetinib attenuated RosA's protective effect on endometrium by further activating CD8+ T cells on a CT-induced basis, while transmission electron microscopy, immunofluorescence, and western blots showed that cobimetinib blocked ERK signals activation and further induced phagocytosis on a CT-induced basis. These data indicated that RosA can activate the Ras/Raf/MEK/ERK signaling pathway to inhibit autophagy, and RosA could also regulate the activation of immune cells-CD8+T cells to protect the reproductive tract of CT-infected mice.
研究领域:
免疫学
·
微生物学
·
药理学
·
病理学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Hongwei Han,Minkai Yang,Zhongling Wen,Feng Mei,Qingqing Chen,Yudi Ma,Xiaohui Lai,Yahan Zhang,Rongjun Fang,Tongming Yin,Shucun Sun,Xiaoming Wang,Jinliang Qi,Hongyan Lin,Yonghua Yang
Triple negative breast cancer (TNBC) is associated with a poor prognosis and limited response to traditional chemotherapy, necessitating the exploration of novel treatment approaches. Recent researches have highlighted the interconnected roles of the PI3K/AKT pathway and MAPK pathway in TNBC cells, contributing to the efficacy of treatments. Therefore, the concurrent inhibition of both pathways presents a potential new therapeutic strategy for TNBC patients. This study aimed to evaluate the antitumor efficacy of M17, an AKT allosteric inhibitor and a new synthesized shikonin derivative, both alone and in combination with the MEK inhibitor trametinib. We applied various cellular assays and a subcutaneous 4T1 tumor bearing BALB/c mice model were utilized to assess the in vitro and in vivo antitumor effects. Computational docking and Bio-Layer Interferometry (BLI) were employed to investigate the binding of M17 with AKT. Additionally, flow cytometry, transwell assays, western blotting, and tumor xenograft assays were conducted to explore the potential synergistic mechanisms of the combined therapy. The results demonstrated that M17 exhibited moderate antitumor activity against TNBC cells, but significantly enhanced the apoptotic effects and inhibited proliferation and migration when combined with trametinib. Furthermore, the combination of M17 and trametinib showed even more pronounced antitumor activity in vivo . Mechanistically, the dual therapy synergistically suppressed TNBC by targeting the AKT/mTOR and MEK/ERK signaling pathways and inhibiting epithelial-mesenchymal transition. In conclusion, the findings suggested that the combination of M17 and trametinib holds promise as a synergistic treatment option for TNBC patients.
研究领域:
肿瘤学
·
癌症研究
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
INFLAMMATION
·
2025
·
IF 5
Li Ying,Wang Lei,Guan Tianyue,Chen Yaru,Zhu Wenting,Liu Xiao,Li Yusa,Huang Hongyu,Dong Zibo,Zhang Honggang
Diabetic cardiomyopathy (DCM) is a major complication of diabetes, characterized by myocardial inflammation, oxidative stress, fibrosis, apoptosis, and RhoA activation, ultimately leading to heart failure. This study aimed to evaluate whether higenamine hydrochloride (HGN), a natural alkaloid with anti-inflammatory and antioxidant properties, could alleviate DCM and elucidate its underlying mechanisms. A DCM model was established via streptozotocin injection in mice, followed by HGN administration. Fasudil, a RhoA inhibitor, was used to assess pathway involvement. Histology, biochemical assays, flow cytometry, immunoblotting, ELISA, and qPCR were employed for evaluation. Results showed that HGN effectively alleviated cardiac histological abnormalities and myocardial injury in DCM mice. Further analysis revealed that HGN attenuated DCM-induced cardiac inflammation, oxidative stress, fibrosis, and apoptosis ( p < 0.05). In vitro, HGN also reduced high glucose-induced inflammation, oxidative stress, fibrosis, and apoptosis in H9C2 cardiomyocytes ( p < 0.05). Mechanistically, these protective effects were mediated by inhibition of RhoA, through which HGN suppressed the MEK/ERK signalling pathway, thereby mitigating cardiomyocyte injury ( p < 0.05). However, the RhoA inhibitor fasudil hydrochloride abolished the cardioprotective effects of HGN in DCM mice, specifically, fasudil hydrochloride reversed the HGN-induced improvements in cTnT, CK, and LDH levels. Additionally, echocardiographic parameters (IVSD, LVPWd, LVPWs, LVIDd, LVIDs, IVSs, EF, and FS) were also reversed to levels seen in untreated DCM mice, further confirming that HGN exerts its therapeutic actions via the RhoA/MEK/ERK axis ( p < 0.05). Overall, HGN mitigates cardiac inflammation, oxidative stress, fibrosis, and apoptosis in DCM by inhibiting the MEK/ERK pathway through RhoA. This study provides a scientific basis for developing DCM treatments and highlights the therapeutic potential of HGN. Graphical
研究领域:
心血管研究
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分子生物学
·
药理学
·
内分泌学
·
糖尿病并发症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR MEDICINE-JMM
·
2025
·
IF 4.2
Wen Xin,Peng Yuefeng,Yang Wenqing,Zhu Yuzhong,Yu Fan,Geng Li,Wang Xianfeng,Wang Xiaoyan,Zhang Xiaodong,Tang Yi,Feng Lei,Zhou Tingting,Jia Hongliang,Yang Liu
Transient receptor potential canonical 1 (TRPC1) channel, a Ca 2+ -permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension. Key messages
AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice.
TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling.
Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.
研究领域:
心血管病学
·
分子生物学
·
药理学
✓ 已验证
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）