JOURNAL OF FISH DISEASES
·
2025
·
IF 2.2
Jing Dong,Liwei Xia,Yongtao Liu,Qiuhong Yang,Ning Xu,Xiaohui Ai,Shun Zhou
Monogeneans are ectoparasitic flatworms causing significant economic losses in aquaculture. This study aimed to identify potential anthelmintic agents against these parasites by integrating computer-aided drug design (CADD) and in vivo evaluation. The β-tubulin gene, a well-established anthelmintic target, was cloned from Gyrodactylus kobayashii and its three-dimensional structure was generated using homology modelling. Virtual screening of 2319 FDA-approved drugs and nine common benzimidazoles against the modelled β-tubulin identified several promising compounds with low binding energy. Subsequent in vivo anthelmintic efficacy and acute toxicity assays in goldfish revealed etravirine as a potent candidate with an EC 50 value of 0.55 mg/L and a therapeutic index (TI) greater than 18.18. This favourable safety profile highlights etravirine's potential for controlling monogenean infections in aquaculture. Flubendazole and mebendazole also demonstrated potent anthelmintic activity, with EC 50 values of 0.022 and 0.023 mg/L and therapeutic indices exceeding 45.45 and 43.48, respectively. Molecular dynamics simulations confirmed stable binding modes for flubendazole and mebendazole with β-tubulin, providing mechanistic insights into their anthelmintic activity. Overall, this study demonstrated the utility of CADD in identifying potential therapeutic agents against monogenean and underscored the importance of β-tubulin as a key target for anthelmintic therapy, contributing to the development of sustainable aquaculture practices.
研究领域:
水产养殖
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药理学
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生物信息学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 18
·13812
·
IF 5.6
Miran Tang,Deyi Zhao,Sichen Liu,Xiaotuan Zhang,Zhuocheng Yao,Hule Chen,Cui Zhou,Tieli Zhou,Chunquan Xu
Combining pentamidine with Gram-positive-targeting antibiotics has been proven to be a promising strategy for treating infections from Gram-negative bacteria (GNB). However, which antibiotics pentamidine can and cannot synergize with and the reasons for the differences are unclear. This study aimed to identify the possible mechanisms for the differences in the synergy of pentamidine with rifampicin, linezolid, tetracycline, erythromycin, and vancomycin against GNB. Checkerboard assays were used to detect the synergy of pentamidine and the different antibiotics. To determine the mechanism of pentamidine, fluorescent labeling assays were used to measure membrane permeability, membrane potential, efflux pump activity, and reactive oxygen species (ROS); the LPS neutralization assay was used to evaluate the target site; and quantitative PCR was used to measure changes in efflux pump gene expression. Our results revealed that pentamidine strongly synergized with rifampicin, linezolid, and tetracycline and moderately synergized with erythromycin, but did not synergize with vancomycin againstE. coli,K. pneumoniae,E. cloacae, andA. baumannii. Pentamidine increased the outer membrane permeability but did not demolish the outer and inner membranes, which exclusively permits the passage of hydrophobic, small-molecule antibiotics while hindering the entry of hydrophilic, large-molecule vancomycin. It dissipated the membrane proton motive force and inactivated the efflux pump, allowing the intracellular accumulation of antimicrobials that function as substrates of the efflux pump, such as linezolid. These processes resulted in metabolic perturbation and ROS production which ultimately was able to destroy the bacteria. These mechanisms of action of pentamidine on GNB indicate that it is prone to potentiating hydrophobic, small-molecule antibiotics, such as rifampicin, linezolid, and tetracycline, but not hydrophilic, large-molecule antibiotics like vancomycin against GNB. Collectively, our results highlight the importance of the physicochemical properties of antibiotics and the specific mechanisms of action of pentamidine for the synergy of pentamidine–antibiotic combinations. Pentamidine engages in various pathways in its interactions with GNB, but these mechanisms determine its specific synergistic effects with certain antibiotics against GNB. Pentamidine is a promising adjuvant, and we can optimize drug compatibility by considering its functional mechanisms.Keywords:gram-negative bacteria;pentamidine;linezolid;synergy;adjuvant;efflux pump;outer membrane;vancomycin
研究领域:
微生物学
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药理学
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传染病学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Juan Sun,Han-Yu Liu,Yi-Heng Zhang,Ze-Yu Fang,Peng-Cheng Lv
Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPAR γ ) agonist with many side effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPAR γ . The study of anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g , which quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay confirmed direct binding of 4 g to the LBD of PPAR γ with IC 50 being 1790 nM, and dose-dependently increased the transcriptional activity of PPAR γ . Besides, through computer-aided drug design software simulation docking, it was found that compound 4 g showed the best binding ability to target protein PPAR γ . Furthermore, because of the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced and the stability of H3 and β -fold is increased, showing the characteristics of some PPAR γ agonists, based on the docking model analysis. Together, these results suggest that 4 g is a promising PPAR γ agonist that deserves further investigation.
研究领域:
药理学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2021
·Vol. 413
·期 28
·6951-6962
·
IF 4.157
Wang Huai-Song,Xia Xingya,Wang Yingming,Lyu Weiping,Sang Mangmang,Gu Congcong,Liu Wenyuan,Zheng Feng
Epithelial-mesenchymal transition (EMT) is implicated in the pathological processes of cancer metastasis and drug resistance. Anti-cancer drugs may also potentially lead to EMT, resulting in their reduced therapeutic effect. Therefore, the combination of these anti-cancer drugs with anti-EMT agents has been promoted in clinic. Screening anti-EMT drugs and evaluation of EMT process are highly dependent on EMT biomarkers on cell membrane. At present, the detection of EMT biomarker is mainly by Western blot method, which is time-consuming and complicated. In this work, for effectively screening anti-EMT drugs by evaluation of the EMT process, a type of aptamer probe based on aggregation-induced emission (AIE) was designed. The aptamer SYL3C was employed to target the EMT biomarker EpCAM on cell membrane. Two fluorophores, FAM and tetraphenylethene (TPE, an AIE dye), were modified at the two ends of SYL3C, respectively. This aptamer probe (TPE-SYL3C-FAM) can monitor the EpCAM expression, which can be recovered by anti-EMT drugs. By observation of the change in TPE emission intensity, the anti-EMT effect of drugs can be evaluated. The FAM emission was used as internal reference to reduce environmental interferences. This probe can be potentially used to screen anti-EMT agents as anti-cancer adjuvant drugs with high throughput. Graphical abstract
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL RESEARCH
·
2022
·
IF 1.097
Tiandi Ding,HaiJiao Chen,Yan Li,Ying Li,Ying Zhi,Zhiqiang Qu,Qiang Sun,Qingqiang Yao,Bo Liu
Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.
研究领域:
药理学
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癌症研究
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药物发现
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生物化学
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分子生物学
✓ 已验证
DOI
高影响因子
Cancer Nanotechnology
·
2024
·Vol. 15
·期 1
·1-36
·
IF 4.5
Abd El-Kaream Samir Ali,Zedan Doha Farhat Mohamed,Mohamed Hagar Mohamed,Soliman Amal Saleh Mohamed,El-Kholey Sohier Mahmoud,Nasra Mohammed Kamal El-Dein
Background Sono-photodynamic therapy (SPDT), which combines photodynamic (PDT) and sonodynamic (SDT) therapies with sensitizers, offers new avenues for cancer treatment. Even though new sensitizers for SPDT have been synthesized with great success, few of them are effectively used. The limited tumor-targeting specificity, inability to transport the sensitizers deeply intratumorally, and the deteriorating tumor microenvironment limit their anti-tumor effectiveness. The current study was carried out aiming at high-frequency ultrasound-assisted drug delivery of chia, cress and flax conjugated hematite iron oxide nanoparticles (CCF–HIONP) for photothermal–photodynamic lung cancer (LCA) treatment in vitro and in vivo as activated cancer treatment up-to-date modality. Materials and methods The study was conducted in vitro on human LCA cells (A-549) and the study protocol application groups in vivo on Swiss albino mice treated with benzo[a]pyrene only and were not received any treatment for inducing LCA, and only after LCA induction the study treatment protocol began, treatment was daily with CCF–HIONP as HIFU–SPDT sensitizer with or without exposure to laser (IRL) or high-frequency ultrasound (HIFU–US) or a combination of laser and/or high-frequency ultrasound for 3 min for 2 weeks. Results Revealed that HIONP can be employed as effective CCF delivery system that directly targets LCA cells. In addition, CCF–HIONP is a promising HIFU–SPS for HIFU–SPDT and when combined with HIFU–SPDT can be very effective in treatment of LCA–A549 in vitro (cell viability decreased in a dose-dependent basis, the cell cycle progression in G0/G1 was slowed down, and cell death was induced as evidenced by an increase in the population of Pre-G cells, an increase in early and late apoptosis and necrosis, and an increase in autophagic cell death) and benzo[a]pyrene LCA-induce mice in vivo (decreased oxidative stress (MDA), and ameliorated enzymatic and non-enzymatic antioxidants (SOD, GR, GPx, GST, CAT, GSH, and TAC) as well as renal (urea, creatinine) and hepatic (ALT, AST) functions, induced antiproliferative genes (caspase 3,9, p53, Bax, TNFalpha), suppressed antiapoptotic and antiangiogenic genes (Bcl2,VEGF respectively) and effectively reducing the growth of tumors and even leading to cancer cell death. This process could be attributed to photochemical and/or high-frequency sono-chemical activation mechanism HIFU–SPDT. Conclusions The results indicate that CCF–HIONP has great promise as an innovative, effective delivery system for selective localized treatment of lung cancer that is activated by HIFU–SPDT.
研究领域:
肿瘤学
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纳米医学
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生物化学
✓ 已验证
DOI
高影响因子
Future Medicinal Chemistry
·
2025
·
IF 3.4
Yan Li,Yajing Xing,Dongxia Huang,Jiuqing Xie,Yangrui Peng,Zhengfang Yi,Yihua Chen
Aim To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel N-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design.Methods Starting from the hit compound ZB979, we synthesized three series of pyrimidinediamine BCL6 inhibitors (13a-13e, 14a-14c and 15a-15g) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound 15d, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation.Results Compound 15d demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)).Conclusion These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.
✓ 已验证
DOI
PubMed
高影响因子
BMC CANCER
·
2025
·Vol. 25
·期 1
·1-25
·
IF 3.4
Abd El-Kaream Samir Ali,Hassan Nasser Ali Mohamed,Saleh Hassan Saleh Abdullatif,Albahloul Mohamed Albahloul Salem,Khedr Abdalla Mohamed,El-Kholey Sohier Mahmoud
Background Micro-photodynamic therapy (MWPDT) combines photo-dynamic (PDT) and microwave-dynamic (MWDT) therapies with sensitizers, offers new avenues for cancer treatment. Despite the fact that novel sensitizers for MWPDT have been successfully synthesized, only a few are being employed effectively. The low tumor-targeting specificity, inability to transport sensitizer's deeper intratumorally, and deteriorating tumor microenvironment all restrict their anti-tumor efficacy. The current work was done aiming at microwave assisted drug delivery of titanium dioxide / rose Bengal conjugated chitosan nanoparticles (TiO 2 /RB@CSNP) for micro- photo-dynamic skin cancer (SKCA) treatment in vitro and in vivo as activated cancer treatment up-to-date modality. Materials and methods The study was conducted in vitro on human SKCA cells (A-375) and the study protocol application groups in vivo on Swiss albino mice treated with 7,12-dimethylbenz[a]anthracene (DMBA)/croton oil only and were not received any treatment for inducing SKCA, and only after SKCA induction the study treatment protocol began, treatment was daily with TiO 2 /RB@CSNP as MWPDT sensitizer with or without exposure to laser (IRL) or microwave (MW) or a combination of them for 3 min for two weeks. Results Revealed that CSNP can be employed as effective TiO 2 /RB delivery system that directly targets SKCA cells. Additionally TiO 2 /RB@CSNP is a promising MWPS for and when combined with MWPDT can be very effective in treatment of SKCA-A-375 in vitro (cell viability decreased in a dose-dependent basis, the cell cycle progression in G0/G1 was slowed down, and cell death was induced as evidenced by an increase in the population of Pre-G cells, an increase in early and late apoptosis and necrosis, and an increase in autophagic cell death) and DMBA/croton oil SKCA-induce mice in vivo (induced antiproliferative genes (caspase 3,9, p53, Bax, TNFalpha), suppressed antiapoptotic and antiangiogenic genes (Bcl2,VEGF respectively) effectively reducing the tumors growth and leading to cancer cell death as well as decreased oxidative stress (MDA), and ameliorated enzymatic and non-enzymatic antioxidants (SOD, GR, GPx, GST, CAT, GSH, TAC) as well as renal (urea, creatinine) and hepatic (ALT, AST) functions. This process could be attributed to MWPDT; microwave and/or photo-chemical TiO 2 /RB activation mechanism and antioxidant potential of non activated TiO 2 /RB as well. Conclusion The results indicate that TiO 2 /RB@CSNP has great promise as an innovative, effective delivery system for selective localized treatment of skin cancer that is activated by MWPDT.
研究领域:
药理学
·
纳米技术
·
肿瘤学
·
皮肤病学
·
生物医学工程
·
光化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2015
·Vol. 5
·期 103
·84980-84987
·
IF 3.84
Hongda Chen,Fuyao Liu,Zhen Lei,Lina Ma,Zhenxin Wang
Herein, we present the synthesis and application of a new type of graphene-based magnetic and plasmonic nanocomposite for magnetic-field-assisted drug delivery and chemo-photothermal synergistic therapy. The nanocomposites were prepared via conjugation of the PEGylated Fe2O3@Au core/shell nanoparticles (Fe2O3@Au NPs) with reduced graphene oxide (rGO). The hybrid nanostructures (rGO–Fe2O3@Au NPs) are superparamagnetic and show great photothermal conversion efficiency under 808 nm near-infrared (NIR) laser irradiation and high drug loading ability (1.0 mg mg−1). MTT cell viability assay demonstrates that the chemotherapeutic drug, doxorubicin loaded rGO–Fe2O3@Au NPs (DOX–rGO–Fe2O3@Au NPs) have synergistic interaction between photothermal therapy (PTT) and chemotherapy. Furthermore, in vitro studies using HeLa cells show that the chemo-photothermal therapeutic efficacy of DOX–rGO–Fe2O3@Au NPs can be dramatically improved by the assistance of magnetic-field-guided drug delivery.
研究领域:
纳米技术
·
生物医学工程
·
癌症治疗
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）