PHARMACOLOGICAL RESEARCH
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2020
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IF 5.893
Yong Xia,Fuyan Xu,Meiping Xiong,Hao Yang,Wentao Lin,Yao Xie,Huizhi Xi,Qiang Xue,Tinghong Ye,Luoting Yu
Targeted therapies and immunotherapy have brought substantial benefits to patients with melanoma . However, brain metastases remain the biggest threat to the survival and quality of life of melanoma patients. One of the major challenges to an effective therapy is the inability of drugs to penetrate the blood-brain barrier (BBB). Anti-schizophrenic drugs can cross the BBB, and many of them have demonstrated anti-cancer effects. Repurposing existing drugs for new clinical indications is an alluring strategy for anticancer drug discovery . Herein, we applied this strategy and screened a small collection of existing anti-schizophrenic drugs to use as anti-melanoma agents. Among them, trifluoperazine dihydrochloride (TFP) exhibited promising potencies for suppressing the growth and metastasis of melanoma, both in vitro and in vivo . TFP obviously suppressed the viability of melanoma cells within the micromolar range and inhibited the growth of melanoma in the subcutaneous mice models. Notably, intraperitoneal (i.p.) administration of TFP (40 mg/kg/day) obviously inhibited the growth of intra-carotid-injection established melanoma brain metastasis and extended the survival of brain metastasis-bearing mice. Moreover, TFP significantly suppressed lung metastasis and bone metastasis of melanoma in preclinical metastasis models. Mechanistically, TFP caused G0/G1 cell cycle arrest and mitochondrial-dependent intrinsic apoptosis of melanoma cells. In addition, TFP treatment increased the expression of microtubule associated protein 1 light chain 3 beta-II (LC3B-II) and p62 in vitro , suggesting an inhibition of autophagic flux. TFP decreased LysoTracker Red uptake after treatment, indicating impaired acidification of lysosomes. Moreover, the colocalization of LC3 with lysosomal-associated membrane protein 1 (LAMP1), a lysosome marker, was also suppressed after TFP treatment, suggesting that TFP might block the fusion of autophagosomes with lysosomes, which led to autophagosome accumulation. Taken together, our data highlight the potential of repurposing TFP as a new adjuvant drug for treating melanoma patients with brain, lung, and bone metastases.
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
MOLECULES
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2023
·Vol. 28
·期 3
·1479
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IF 4.6
Shuai Liu,Keming Zheng,Yilin Jiang,Susu Gai,Bohan Li,Dehai Li,Shuang Yang,Zhihua Lv
Penindolone (PND) is a novel broad-spectrum anti-Influenza A Virus (IAV) agent blocking hemagglutinin-mediated adsorption and membrane fusion. The goal of this work was to reveal the metabolic route of PND in rats. Ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC–HRMS) was used for metabolite identification in rat bile, feces and urine after administration of PND. A total of 25 metabolites, including 9 phase I metabolites and 16 phase II metabolites, were characterized. The metabolic pathways were proposed, and metabolites were visualized via Global Natural Product Social Molecular Networking (GNPS). It was found that 65.24–80.44% of the PND presented in the formation of glucuronide conjugate products in bile, and more than 51% of prototype was excreted through feces. In in vitro metabolism of PND by rat, mouse and human liver microsomes (LMs) system, PND was discovered to be eliminated in LMs to different extents with significant species differences. The effects of chemical inhibitors of isozymes on the metabolism of PND in vitro indicated that CYP2E1/2C9/3A4 and UGT1A1/1A6/1A9 were the metabolic enzymes responsible for PND metabolism. PND metabolism in vivo could be blocked by UGTs inhibitor (ibrutinib) to a certain extent. These findings provided a basis for further research and development of PND.Keywords:penindolone;biotransformation;metabolite;liquid chromatography–mass spectrometry
研究领域:
药理学
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病毒学
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分析化学
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药物代谢
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DOI
PubMed
高影响因子
RSC Advances
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2017
·Vol. 7
·期 83
·52661-52671
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IF 3.108
Zhihong Yao,Shishi Li,Zifei Qin,Xiaodan Hong,Yi Dai,Baojian Wu,Wencai Ye,Frank J. Gonzalez,Xinsheng Yao
Norbakuchinic acid (NBKA) is the most abundant metabolite of bakuchiol (a hepatotoxicity and nephrotoxicity component in Psoralea corylifolia L.) in plasma and urine. The present study aimed to identify human UDP-glucuronosyltransferase (UGT) isoforms involved in NBKA glucuronidation, and to assess the inhibition potential of NBKA against recombinant UGTs. NBKA glucuronidation was determined using human liver microsomes (HLM) and human intestine microsomes (HIM) as well as expressed UGTs. The mechanisms of NBKA-UGT interactions were explored through kinetic characterization and modeling. As a result, two glucuronides (G1 and G2) were detected by HLM and HIM. G2 was dominantly produced with CLint values of 3.21 and 0.96 μL min−1 mg−1 in HLM and HIM, respectively. Furthermore, based on the relative activity factor (RAF) approach, UGT1A9 and 2B7 represented 5.98 and 46.16% of G2 in HLM, respectively. In addition, G2 was both significantly correlated with propofol-glucuronidation (r = 0.681, p = 0.015) and AZT-glucuronidation (r = 0.832, p = 0.0008). Also, NBKA glucuronidation showed marked species differences. Moreover, NBKA displayed broad-spectrum inhibition against human UGTs. Kinetic analyses showed that inhibition of these UGTs followed competitive (UGT1A1), mixed (UGT1A3, 1A6, 1A10, 2B7, 2B15 and 2B17) and non-competitive (UGT1A4, 1A7, 1A8 and 1A9) mechanisms, with Ki values ranging from 2.48 to 20.31 μM. Among them, NBKA exhibited moderate inhibitory effects against UGT1A1, 1A3, 1A4, 1A7, 1A8, 2B15 and 2B17 (both IC50 and Ki values lower than 8 μM). In contrast, the effect of NBKA was activating for UGT2B10. Taken altogether, these findings together demonstrate that NBKA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose BK is co-administered with UGT substrates.
研究领域:
药理学
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毒理学
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DOI
高影响因子
APPLIED SURFACE SCIENCE
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2023
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IF 6.7
Boxuan Yao,Ke Zhang,Xiaoyang Liu,Hua Wei,Zihan Li,Jiarui Zhou,Guangfei Yuan,Xin Wang,Shenghong Yang,Jian Liu
Pursuing special negatively charged adsorbents is critical to selectively removing cationic pollutants from effluent. Herein, we proposed a versatile preparation strategy of negatively charged saccharide-based polymers using easily available saccharides as building blocks and hexachlorocyclotriphosphazene as a linker in a facile “one-step” method. Because of the existence of numerous hydroxyl groups and phosphine nitrile units in the skeleton, these polymers show selective adsorption capacity towards cationic dyes and pharmaceuticals, but not for ionic dyes and uncharged bisphenol A. Notably, β-cyclodextrin-based polymers (β-CDPs) displayed remarkable adsorption towards methylene blue (Q m , 1563 mg g −1 ) and promethazine (Q m , 944 mg g −1 ). Systematic experiments revealed that the synergy of “host-guest” inclusion, electrostatic attraction, and π-π interaction promoted the selective and efficient adsorption of cationic pollutants. Given the efficiently selective adsorption of cationic dyes and pharmaceuticals, these negatively charged saccharide-based polymers should be candidates for the adsorption of other cationic pollutants, including heavy metal ions. This work expanded the scope of the special utilization of biomass-based adsorbents for water remediation.
研究领域:
环境科学
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材料科学
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化学工程
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DOI
高影响因子
INTERNATIONAL JOURNAL OF FOOD SCIENCE AND TECHNOLOGY
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2023
·Vol. 58
·期 5
·2599-2608
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IF 3.3
Cen Chen,Yuhang Zhang,Yulong Tang,Guangrong Huang,Han Jiang
Summary Magnetic molecularly imprinted polymers (MMIPs) were prepared by surface precipitation polymerisation, which used xylazine as its template molecule and Fe 3 O 4 as its support. The characterisation analysis and adsorption experiments of MMIPs were carried out. At the same time, promethazine, chlorpromazine, trifluoperazine, acepromazine and perphenazine were selected as structural analogues for selective experiments. The results showed MMIPs were successfully prepared with small particle size, excellent magnetic and thermal stability, high adsorption capacity and selectivity for xylazine. The maximum adsorption capacity of MMIPs for xylazine was 4.2017 mg g −1 , and the adsorption reached binding equilibrium within 30 min. The magnetic solid phase extraction (MSPE) based on MMIPs and traditional solid phase extraction (SPE) based on SPE column for xylazine in milk samples were compared and xylazine was analysed by HPLC. Although the difference between the two SPE methods was not significant, the MSPE method procedure took only about 35 min, which was faster than the traditional SPE method (>100 min), and the MSPE method had lower LOD (2.62 ng mL −1 ). MSPE has the advantages of simple operation, short extraction time, low cost and friendly to the environment, it has good application potential in the detection of xylazine in milk samples.
研究领域:
食品科学
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分析化学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）