PHARMACEUTICAL RESEARCH
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2019
·Vol. 36
·期 12
·1-10
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IF 3.896
Li Songtao,Zhao Hongling,Mao Xiaoxia,Fan Yanfang,Liang Xiujun,Wang Ruxing,Xiao Lijun,Wang Jianping,Liu Qi,Zhao Guiqin
Purpose Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. Methods Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. Results Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC 50 6.21 ± 1.12 μM) was approximately one-sixth of that of free DOX (IC 50 1.03 ± 0.13 μM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. Conclusions The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.
研究领域:
药理学
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肿瘤学
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分子生物学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Ze-Rui Sun,Hua-Rong Liu,Di Hu,Mao-Si Fan,Ming-Yue Wang,Meng-Fei An,Yun-Li Zhao,Ze-Min Xiang,Jun Sheng
Hyperuricemia is a metabolic disease caused by impaired uric acid (UA) metabolism. Ellagic acid (EA) is a natural small-molecule polyphenolic compound with known antioxidative and anti-inflammatory properties. Here, we evaluated the regulatory effects of EA on hyperuricemia and explored the underlying mechanisms. We found that EA is an effective xanthine oxidase (XOD) inhibitor (IC50 = 165.6 μmol/L) and superoxide anion scavenger (IC50 = 27.66 μmol/L). EA (5 and 10 μmol/L) treatment significantly and dose-dependently reduced UA levels in L-O2 cells; meanwhile, intraperitoneal EA administration (50 and 100 mg/kg) also significantly reduced serum XOD activity and UA levels in hyperuricemic mice and markedly improved their liver and kidney histopathology. EA treatment significantly reduced the degree of foot edema and inhibited the expression of NLPR3 pathway-related proteins in foot tissue of monosodium urate (MSU)-treated mice. The anti-inflammatory effect was also observed in lipopolysaccharide-stimulated RAW-264.7 cells. Furthermore, EA significantly inhibited the expressions of XOD and NLRP3 pathway-related proteins (TLR4, p-p65, caspase-1, TNF-α, and IL-18) in vitro and in vivo. Our results indicated that EA exerts ameliorative effects in experimental hyperuricemia and foot edema via regulating the NLRP3 signaling pathway and represents a promising therapeutic option for the management of hyperuricemia.
研究领域:
药理学
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代谢疾病
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炎症
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生物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Natural Medicines
·
2020
·Vol. 75
·期 1
·129-141
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IF 2.055
An Meng-Fei,Wang Ming-Yue,Shen Chang,Sun Ze-Rui,Zhao Yun-Li,Wang Xuan-Jun,Sheng Jun
Abstract Isoorientin (ISO), a natural flavonoid compound, has been identified in several plants and its biological activity is determined and the study on lowering uric acid has not been reported. In view of the current status of treatment of hyperuricemia, we evaluated the hypouricemic effects of ISO in vivo and in vitro, and explored the underlying mechanisms. Yeast extract-induced hyperuricemia animal model as well as hypoxanthine and xanthine oxidase (XOD) co-induced high uric acid L-O2 cell model and enzymatic experiments in vitro were selected. The XOD activity and uric acid (UA) level were inhibited after the treatment of ISO in vitro and in vivo. Furthermore, serum creatinine (CRE) and blood urea nitrogen (BUN) levels were also significantly reduced and liver damage was recovered in pathological histology after the ISO administration in hyperuricemia animal model. The results of mechanism illustrated that protein expressions such as XOD, toll-like receptor 4 (TLR4), cathepsin B (CTSB), NLRP3, and its downstream caspase-1 as well as interleukin-18 (IL-18) were markedly downregulated by ISO intervention in vitro and in vivo. Our results suggest that ISO exerts a urate-lowering effect through inhibiting XOD activity and regulating TLR4-NLRP3 inflammasome signal pathway, thus representing a promising candidate therapeutic agent for hyperuricemia. Graphic abstract Both animal models and in vitro experiments suggested that ISO may effectively lower uric acid produce. The mechanism might be the inhibition of XOD activity and NLRP3 inflammasome of upregulation.
研究领域:
药理学
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生物化学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
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2024
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IF 2.5
Ling Jiang,Cai-Bo Tian,Rui-Han Ye,Nian Shi,Xing-Chao He,Yun-Li Zhao,Xiao-Dong Luo
Drug-induced liver injury caused acute hepatic failure and hepatitis frequently. In this investigation, kakuol and asarinin reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST) and malondialdehyde (MDA) dramatically, and ameliorated the pathological damage of liver tissues in APAP-induced mice. Furthermore, both compounds increased the viabilities of APAP-induced L-O2 cells and extracellular glutathione (GSH) levels accompanied significantly by reducing the level of intracellular ROS in vitro . In addition, HSP90AA1/CDK2/mTOR signaling pathway and five target proteins (CDK2, HSP90AA1, HRAS, MMP1, mTOR) were proposed from network pharmacology and molecular docking prediction, and then the up-regulation of protein expression of CDK2, mTOR and down-regulation of HSP90AA1, HRAS, MMP1 by kakuol and asarinin in western blotting supported their mechanism.
研究领域:
药理学
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分子生物学
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毒理学
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肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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