Chemical Biology & Drug Design
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2025
·Vol. 105
·期 2
·e70067
·
IF 3.3
Jingting Zeng,Zhenshuo Luo,Tiansheng Zhao,Chunhua Xia,Fanglan Liu,Na Li,Lailiang Qu,Cheng Wang
Aberrant activation of the RAS/RAF/MEK/ERK pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1/2 has crucial roles in tumorigenesis, cell proliferation, and inhibition of apoptosis. At present, a number of MEK1/2 inhibitors are approved for the treatment of melanoma. However, MEK1/2 inhibitors have poor single-drug efficacy in the treatment of solid tumors and are prone to drug resistance. A series of compounds containing a diarylamine skeleton and phenylacrylamide (acrylamide) have been designed and synthesized in this paper. The most promising compound M15 showed good inhibitory activity of MEK1 (IC 50 = 10.29 nM) and good inhibitory effect on three types of solid tumor cells: MDA-MB-231(IC 50 = 2.76 μM), HepG2 (IC 50 = 2.57 μM) and A549 (IC 50 = 5.40 μM). At the same time, M15 was less toxic to human normal cells (MCF-10A IC 50 > 20 μM) and has certain stability of liver microsomes in vitro (human, t 1/2 = 27.9 min; rat, t 1/2 > 60 min). It can induce apoptosis of MDA-MB-231 cells and slow down their migration. Therefore, compound M15 acts as a novel MEK1/2 inhibitor and may be a promising candidate for solid tumor intervention.
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
Heliyon
·
2023
·
IF 4
Nanyu Cao,Heyang Wang
Regular insulin therapy is significantly related to worse cardiovascular outcomes in patients with type 2 diabetes and heart failure. However, the mechanisms of the causal relationship remain unclear. In this study, we observed the effect of insulin on cardiac structure and function and found that insulin dramatically augmented angiotensin II (Ang II)-induced cardiac dysfunction, as well as the proliferation and collagen production of primary cardiac fibroblasts. Total STAT3 expression, but not activation was stimulated by insulin; the effect of insulin on Ang II-induced fibrosis disappeared when STAT3 was blocked and could be entirely suppressed by the MEK inhibitor PD0325901. Our findings suggest a noninsulin-dependent glucose-lowering regimen for patients with type 2 diabetes (T2DM) and heart failure (HF).
研究领域:
心血管病学
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内分泌学
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分子生物学
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DOI
高影响因子
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
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 23
·2201878
·
IF 11.092
Ze Li,Jinjian Huang,Yungang Jiang,Ye Liu,Guiwen Qu,Kang Chen,Yun Zhao,Peige Wang,Xiuwen Wu,Jianan Ren
Wound healing is a significant problem in clinical management. Various functional dressings are studied to promote wound healing through biochemical factors. They are generally expensive, complex to fabricate, and may adversely affect the wound. Mechanical forces are the critical regulators of tissue repair. Although contraction is shown to promote wound healing, the underlying mechanisms are not fully understood. In this study, a novel adhesive temperature-sensitive mechanically active hydrogel with a simple and inexpensive preparation process is developed. The dressing is able to adhere to the wound surface and actively contract the wound in response to body temperature. This mechanical contraction enhances the proliferative activity of basal cells, reduces the inflammatory response of the wound, and promotes wound healing. Furthermore, RNA-seq clarifies how the gene regulatory network is regulated by contraction. Finally, using pharmacological inhibitors, YAP and MEK are identified as the key signaling molecules for contraction-mediated tissue healing in vivo.
研究领域:
生物医学工程
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组织工程
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分子生物学
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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
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癌症研究
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分子生物学
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药理学
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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
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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
JOURNAL OF NEUROSCIENCE
·
2023
·Vol. 43
·期 16
·2822-2836
·
IF 5.3
Jiao Ma,Zhechun Hu,Huimin Yue,Yujian Luo,Chao Wang,Xuan Wu,Yan Gu,Lang Wang
Metabotropic glutamate receptor 2 (GRM2) is highly expressed in hippocampal dentate granule cells (DGCs), regulating synaptic transmission and hippocampal functions. Newborn DGCs are continuously generated throughout life and express GRM2 when they are mature. However, it remained unclear whether and how GRM2 regulates the development and integration of these newborn neurons. We discovered that the expression of GRM2 in adult-born DGCs increased with neuronal development in mice of both sexes. Lack of GRM2 caused developmental defects of DGCs and impaired hippocampus-dependent cognitive functions. Intriguingly, our data showed that knockdown of Grm2 resulted in decreased b/c-Raf kinases and paradoxically led to an excessive activation of MEK/ERK1/2 pathway. Inhibition of MEK ameliorated the developmental defects caused by Grm2 knockdown. Together, our results indicate that GRM2 is necessary for the development and functional integration of newborn DGCs in the adult hippocampus through regulating the phosphorylation and activation state of MEK/ERK1/2 pathway.SIGNIFICANCE STATEMENT Metabotropic glutamate receptor 2 (GRM2) is highly expressed in mature dentate granule cells (DGCs) in the hippocampus. It remains unclear whether GRM2 is required for the development and integration of adult-born DGCs. We provided in vivo and in vitro evidence to show that GRM2 regulates the development of adult-born DGCs and their integration into existing hippocampal circuits. Lack of GRM2 in a cohort of newborn DGCs impaired object-to-location memory in mice. Moreover, we revealed that GRM2 knockdown paradoxically upregulated MEK/ERK1/2 pathway by suppressing b/c-Raf in developing neurons, which is likely a common mechanism underlying the regulation of the development of neurons expressing GRM2. Thus, Raf/MEK/ERK1/2 pathway could be a potential target for brain diseases related to GRM2 abnormality.
研究领域:
神经科学
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分子生物学
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发育生物学
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认知科学
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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
✓ 已验证
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
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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
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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
危险品化学品经营许可证（带存储）