JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yuanbo Hu,Congke Zhao,Wenhua Tan,Mengqi Li,Yu Wang,Ruizhe Gao,Zhuo Chen,Zhenming Jin,Liqing Hu,Qianbin Li
Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.
研究领域:
药理学
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心血管疾病
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药物发现
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF GENE MEDICINE
·
2017
·Vol. 19
·期 12
·e2998
·
IF 2.524
Yunna Chen,Li Sun,Dongdong Guo,Ziteng Wu,Weidong Chen
Background Drug resistance cancer cells have become a major problem in chemotherapy. To solve this problem, the co-delivery of small interefering RNA (siRNA) and 5-fluorouracil chitosan nanoparticles was employed, aiming to reverse the multidrug resistance of gastric cancer SGC-7901 cells in vitro . Methods Chitosan nanoparticles were prepared using an ionic gel method. siRNA nanoparticles were characterized by gel retardation assays. Particle size and zeta potential were measured to confirm nanoparticle formation. The transfection efficiency of siRNA was determined by flow cytometry and high-content screening. Western blotting and a quantitative real-time-polymerase chain reaction were used to assess the silencing efficiency of siRNA. Accumulation and efflux experiments for rhodamine-123, cell migration experiments, cell sensitivity analyses and cell apoptosis assays were used to determine whether siRNA could reverse multidrug resistance. A systemic toxicity assay was used to evaluate the safety of nanoparticles. Results Compared to naked siRNA, the co-delivery system demonstrated a higher transfection efficiency and gene silencing efficiency by inhibiting the efflux of P-glycoprotein and cell migration. Moreover, the combination treatment with siRNA and 5-fluorouracil co-delivered by chitosan nanoparticles can increase the sensitivity of drug resistance cells and cell apoptosis. Finally, the safety of nanoparticles was evaluated in vivo and the results obtained suggested that nanoparticles did not have any obvious toxicity. Conclusions Co-delivery of siRNA and 5-fluorouracil chitosan nanoparticles is an attractive strategy for overcoming multidrug resistance.
研究领域:
肿瘤学
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药学
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分子生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2018
·
IF 3.115
Hongqing Xie,Xiaotong Li,Yajie Chen,Mingzi Lang,Zhangfei Shen,Liangen Shi
Ethnopharmacological relevance Cordyceps cicadae (Miq.) Massee is a traditional Chinese medicine that has been used for approximately 1600 years in China. C. cicadae , a member of the Cordyceps genus, exerts a therapeutic effect on many diseases, such as cancer. Objective This study aimed to evaluate the antineoplasmic activity of C. cicadae and to identify its molecular mechanism of cell death. Materials and methods The toxicity of the ethanolic extract of C. cicadae (EEC) against different cancer cell lines was determined through MTT assay. Human gastric cancer SGC-7901 cells were treated with EEC for 48 h. Cell morphology was examined by using an Olympus phase-contrast microscope. The cell apoptosis was quantified through Annexin V-FITC/PI staining. Cells were stained with PI and then subjected to flow cytometry for the investigation of cell cycle status. Cells were subjected to mitochondrial membrane potential (MMP) assay after incubation with JC-1 probes and to intracellular Ca 2+ measurement through flow cytometry after incubation with Fluo-3 AM fluorescent probes . Western blot analysis was conducted to quantify the expression of proteins related to apoptosis, cell cycle and endoplasmic reticulum stress. High-performance liquid chromatography (HPLC) analysis was performed to analyse the biological activity components of EEC. Results EEC suppressed the proliferation of SGC-7901 cells and induced the development of abnormal morphological features in a dose-dependent manner. Flow cytometry results indicated that EEC treatment caused cell apoptosis and arrested the cell cycle in the S phase. In addition, EEC treatment triggered MMP depolarization and Ca 2+ overloading in the cytosol of SGC-7901 cells. Western blot analysis demonstrated that EEC increased Bax, AIF, caspase-8, caspase-6 and caspase-3 activities and decreased Bcl-2 activity. The release of cytochrome c from mitochondria was associated with mitochondrial dysfunction, which was caused by the activation of the cell surface receptor Fas and the cleavage of PARP . EEC-induced S phase arrest was associated with the up-regulation of E2F1, cyclin A2 , cyclin E and p53 expression levels and the down-regulation of CDK2 expression. In addition, EEC increased the expression of endoplasmic reticulum stress-related proteins, such as calpain-1, caspase-12 and caspase-9. HPLC assay results suggested that EEC contained adenine , uridine , adenosine and N6-(2-Hydroxyethyl)-adenosine. Conclusion EEC inhibited the proliferation of SGC-7901 cells by inducing caspase-dependent apoptosis, arresting the cell cycle in the S phase and increasing endoplasmic reticulum stress. This study revealed that C. cicadae is a potential natural source of anticancer drugs .
研究领域:
药理学
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肿瘤学
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传统中药
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细胞生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Communications
·
2024
·
IF 3.7
Yao Yue,Peng Deng,Zhou Wang,Chen Ling,Ziye Zhu,Yongjin Li,Xiajun Zhang
Currently, ferrite magnetic nanoparticles are widely utilized in the biomedical domain, encompassing antibacterial, catalytic, imaging, and drug delivery among other fields. In this study, Cu 0.5 Zn 0.5 Fe 2 O 4 nanoparticles were synthesized via the rapid combustion-calcination process. By incorporating inorganic metal elements with specific functionalities, the limitations of iron oxide could be overcome, enabling targeted roles in various applications. The morphology, phase composition, and magnetic properties were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), and vibrating sample magnetometry (VSM). The impact of anhydrous ethanol quantity, calcination temperature, and duration on the magnetic properties and grain size of the nanomaterials was investigated. Cu 0.5 Zn 0.5 Fe 2 O 4 nanoparticles were evaluated for their inhibitory effects on human gastric cancer cells (SGC-7901 and HGC-27) under different preparation conditions. The results of the MTT assay revealed a concentration - and time-dependent inhibition of tumor cell proliferation by Cu 0.5 Zn 0.5 Fe 2 O 4 nanoparticles. Nanoparticles exhibiting a magnetic energy of 20.23 emu/g and an average particle size of 51.6 nm, synthesized using 20 mL of anhydrous ethanol, calcination temperature of 400 °C, and a calcination duration of 2.0 h, displayed significant inhibitory effects on tumor cells. Furthermore, The nanoparticles not only showed low toxicity to human normal stomach cells GES-1, but also enhanced the inhibitory effect on tumor cells under the action of an external magnetic field.
研究领域:
纳米技术
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生物医学工程
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材料科学
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肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Liqian Chen,Xinghong Zhou,Yijian Deng,Ying Yang,Xiaohu Chen,Qinghong Chen,Yanyan Liu,Xiuqiong Fu,Hiu Yee Kwan,Yanting You,Wen Jin,Xiaoshan Zhao
Ethnopharmacological relevance Zhenwu Decoction (ZWD) is a traditional Chinese medicine (TCM) formula which has wide scope of indications related to Yang deficiency and dampness retention in TCM syndrome. Cardiac hypertrophy can induce similar symptoms and signs to the clinical features of Yang deficiency and dampness retention syndrome. ZWD can increase the left ventricular ejection fraction, reduce cardiac hypertrophy of patients with chronic heart failure. However, its underlying pharmacological mechanism remains unclear. Aim of the study The study aimed to confirm the protective effects of ZWD on cardiac hypertrophy and explore the underlying mechanisms. Materials and methods The potential targets and pathways of ZWD in cardiac hypertrophy were highlighted by network pharmacology and validated by mechanistic and functional studies. Results Our network pharmacology analysis suggests that the protective effects of ZWD on cardiac hypertrophy are related to cyclic guanosine monophosphate (cGMP) - protein kinase G (PKG) pathway. Subsequent animal studies showed that ZWD significantly ameliorated cardiac function decline, cardiac hypertrophy, cardiac fibrosis and cardiomyocyte apoptosis. To explore the underlying mechanisms of action, we performed Western blotting, immunohistochemical analysis, and detection of inflammatory response and oxidative stress. Our results showed that ZWD activated the soluble guanylate cyclase (sGC) - cGMP - PKG signaling pathway. The sGC inhibitor ODQ that blocks the sGC-cGMP-PKG signaling pathway in zebrafish abolished the protective effects of ZWD, suggesting sGC-cGMP-PKG is the main signaling pathway mediates the protective effect of ZWD in cardiac hypertrophy. In addition, three major ingredients from ZWD, poricoic acid C, hederagenin and dehydrotumulosic acid, showed a high binding energy with prototype sGC. Conclusion ZWD reduces oxidative stress and inflammation and exerts cardioprotective effects by activating the sGC-cGMP-PKG signaling pathway.
研究领域:
药理学
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心脏病学
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中医药
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网络药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INVESTIGATIONAL NEW DRUGS
·
2020
·Vol. 39
·期 3
·627-635
·
IF 3.525
Chu Yafei,Xiao Zheng,Jing Nan,Yan Wenjuan,Wang Shanmei,Ma Bing,Zhang Jiangfeng,Li Yi
Arborinine is a natural product isolated from G. parva leaf extracts, which displays potentially antiproliferative activity against human cervical cancer cells. In contrast, its anticancer effects against gastric cancer cells and drug-resistant gastric cancer cells remain unknown. In this work, arborinine was evaluated as a broad-spectrum antiproliferative agent, and it exhibited potently inhibitory activity against NCI-N87 (IC 50 = 5.67 μM), BGC-823 (IC 50 = 7.26 μM), MGC803 (IC 50 = 4.75 μM), SGC-7901 (IC 50 = 1.96 μM), HGC-27 (IC 50 = 5.70 μM), SGC-7901/ADR (IC 50 = 0.24 μM), SGC-7901/VCR (IC 50 = 1.09 μM), and MGC803/PTX (IC 50 = 1.32 μM) cell lines. Subsequent target verification experiments demonstrated that arborinine selectively and reversibly inhibited LSD1 in a time-dependent manner. Furthermore, it was found that arborinine suppressed the epithelial-mesenchymal transition of gastric cancer cell line SGC-7901 and adriamycin-resistant gastric cancer cell line SGC-7901/ADR in a dose-dependent manner. The in vivo antitumor study further indicated that arborinine can significantly reduce the growth of tumors both in SGC-7901 and SGC-7901/ADR xenograft mouse models. Overall, we demonstrated the potential of arborinine as an effective treatment for gastric cancer and adriamycin-resistant gastric cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Yiqun Xia,Jundixia Chen,Yun Yu,Fengjiao Wu,Xin Shen,Chenyu Qiu,Tingting Zhang,Lin Hong,Peisen Zheng,Rongrong Shao,Chenxin Xu,Fang Wu,Wei Chen,Congying Xie,Ri Cui,Peng Zou
Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
研究领域:
肿瘤学
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药理学
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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 ASIAN NATURAL PRODUCTS RESEARCH
·
2014
·
IF 0.968
Ping Guo,Yue-Wu Wang,Bi-Xia Weng,Xiao-Kun Li,Shu-Lin Yang,Fa-Qing Ye
Using curcumol that was extracted from the volatile oil of Rhizoma Curcumae as the raw material, its derivatives were synthesized and purified. The structures of these compounds were confirmed by 1H, 13C NMR, and mass spectral data. The test compounds were evaluated for their in vitro anti-tumor activity against gastric cancer cell lines SGC-7901 and lung carcinoma cell line H460 by methyl thiazolyl tetrazolium chromatometry. Distinct structure–activity relationships of these curcumol derivatives were also revealed for inhibiting cell proliferation. Presence of electron-withdrawing groups or amino could increase the activity significantly, whereas esterification of 8-hydroxy diminished the anti-tumor activity. Many of the tested candidates exhibited higher inhibition efficiency than curcumol, suggesting that structural modifications could enhance its activity effectively.
研究领域:
药理学
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化学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2018
·Vol. 42
·期 3
·1473-1483
·
IF 2.784
Jun Fu,Luhua Yu,Jie Luo,Rui Huo,Bing Zhu
The purpose of the present study was to analyze the association between paeonol and the known genes related to gastric cancer (GC) using bioinformatics methods, and to investigate the role of paeonol in the potential impact on the nuclear factor‑κB (NF‑κB) signaling pathway, in order to provide a theoretical basis for further elucidating the effect of paeonol on cancer cells. Cell viability, morphology and apoptosis were detected using an MTT assay, an inverted microscope, and flow cytometry, respectively. The correlation between drugs and genes was analyzed using the Search Tool for Interactions of Chemicals (STITCH) gene‑drug interaction network. The expression levels of related mRNA and proteins were determined using reverse transcription‑quantitative polymerase chain reaction analysis and enzyme‑linked immunosorbent assay. The changes in protein expression were examined using western blot analysis. The correlation network between target genes directly affected by paeonol and known GC genes was determined by analyzing the association between the compounds and genes recorded in the STITCH database. The GC‑related epidermal growth factor receptor 2 (ERBB2) gene was at the core position of the paeonol interaction network and may be an important potential target gene for the effect of paeonol on cancer cells. The effect of paeonol on the viability of the SGC‑7901 GC cell line was detected using an MTT assay, which showed that the inhibitory effect occurred in a time‑ and dose‑dependent manner. The observations of cell morphology demonstrated that the cells were floating, abnormal in shape, had unclear boundaries and were sparse in arrangement following paeonol treatment. Flow cytometry indicated that paeonol significantly accelerated the apoptotic rate of the SGC‑7901 GC cells. The examination of clinical samples suggested that ERBB2 was expressed at a high level in GC samples, and was significantly downregulated following the addition of paeonol. The western blot analysis revealed that downregulating ERBB2 affected the activation of the NF‑κB signaling pathway, thereby upregulating the pro‑apoptotic factor B‑cell lymphoma‑associated X protein. Taken together, paeonol significantly downregulated ERBB2 and inhibited the activation of the NF‑κB signaling pathway, thereby inhibiting the proliferation of SGC‑7901 cells and inducing apoptosis.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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生物信息学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yuanbo Hu,Yu Wang,Wenhua Tan,Congke Zhao,Mengqi Li,Sufang Xiang,Xinru Liang,Ruizhe Gao,Bin Zeng,Zhuo Chen,Liqing Hu,Qianbin Li
Current vasodilator therapies for pulmonary arterial hypertension (PAH) improve outcomes but remain limited in halting disease progression. Emerging evidence suggests that dual-acting agents targeting both vasodilation and vascular remodeling demonstrate superior efficacy. Leveraging the distinct roles of LOXL2 in vascular remodeling and sGC in vasodilation, we designed and synthesized a series of 4-(aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine derivatives as dual LOXL2/sGC modulators via fragment fusion strategy. In vitro, compound 11k emerged as the most potent candidate, significantly suppressing pathological collagen cross-linking and malignant phenotypes while promoting vasodilation. In a hypoxia-induced PAH rat model, its esterified derivative 9k markedly alleviated vascular remodeling and reduced pulmonary artery pressure, showing efficacy comparable to the combination of riociguat and PAT-1251. Consequently, this study proposes a novel strategy for the development of bifunctional PAH drugs, with a focus on extracellular matrix dysfunction and vasoconstriction, and has identified a promising lead compound.
研究领域:
药物化学
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心血管药理学
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药物设计与开发
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2023
·
IF 6
Mingyi Ma,Zhixiang Lv,You Li,Ziye Zhu,Chen Ling,Dawei He,Ruijiang Liu
Problem Unhealthy dietary habits and inadequate existing treatment technologies have led to high morbidity and mortality rates in patients with gastric cancer, and the research shows that curcumin has excellent antitumor properties, however, the non-water-soluble characteristic of curcumin limits its applications. To break the limitation, the targeted drug carriers become the urgent need to treat gastric cancer. Method The heterogeneous magnetic α-Fe 2 O 3 /Fe 3 O 4 nanoparticles were obtained by rapid combustion method with citric acid (CA) and ferric nitrate as raw materials and anhydrous ethanol as solvent and fuel, and then modified with citric acid (CA) and chitosan (CTS), and loaded curcumin (Cur) to form α-Fe 2 O 3 /Fe 3 O 4 -CA-CTS-Cur nanosystem. Results The particle sizes of heterogeneous magnetic α-Fe 2 O 3 /Fe 3 O 4 nanoparticles and α-Fe 2 O 3 /Fe 3 O 4 -CA-CTS-Cur nanosystem were 24.9 nm and 35.6 nm, respectively, and their respective saturation magnetization were 70.9 emu/g and 30.3 emu/g. The magnetic α-Fe 2 O 3 /Fe 3 O 4 -CA-CTS-Cur nanosystem had good stability, excellent drug release rate, and enhanced apoptosis to gastric cancer cells (SGC-7901) through the caspase pathway and ferroptosis of cells. Conclusions The magnetic drug delivery nanosystem was successfully constructed, and revealed significant inhibitory and killing effects on SGC-7901 cells, and low toxic and side effects on normal cells.
研究领域:
肿瘤学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Yingying Jiang,Yu Cao,Yaoqi Li,Liuliu Bi,Lv Wang,Qianqian Chen,Yue Lin,Huanzhi Jin,Xiaoming Xu,Renyi Peng,Zheyan Chen
The incidence of diabetes is increasing annually, and the disease is uncurable due to its complex pathogenesis. Therefore, understanding diabetes pathogenesis and developing new treatments are crucial. This study showed that the NO donor SNP (8 µM) significantly alleviated high glucose-induced developmental toxicity in zebrafish larvae. High glucose levels caused hyperglycemia, leading to oxidative stress and mitochondrial damage from excessive ROS accumulation. This promoted mitochondrial-dependent apoptosis and lipid peroxidation (LPO)-induced ferroptosis, along with immune inflammatory reactions that decreased mitochondrial function and altered intracellular grid morphology, causing imbalanced kinetics and autophagy. After SNP treatment, zebrafish larvae showed improved developmental toxicity and glucose utilization, reduced ROS accumulation, and increased antioxidant activity. The NO-sGC-cGMP signaling pathway, inhibited by high glucose, was significantly activated by SNP, improving mitochondrial homeostasis, increasing mitochondrial count, and enhancing mitochondrial function. It's worth noting that apoptosis, ferroptosis and immune inflammation were effectively alleviated. In summary, SNP improved high glucose-induced developmental toxicity by activating the NO-sGC-cGMP signaling pathway to reduce toxic effects such as apoptosis, ferroptosis and inflammation resulting from mitochondrial homeostasis imbalance.
研究领域:
糖尿病
·
发育生物学
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毒理学
·
斑马鱼
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）