Frontiers in Microbiology
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2023
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IF 5.2
Wang Junqi,Liu Meijie,Mao Chengzhi,Li Sizhu,Zhou Jiabao,Fan Yaqin,Guo Lizhong,Yu Hao,Yang Xiuqing
Cyclosporine A (CsA) is a secondary cyclopeptide metabolite produced by Tolypocladium inflatum that is widely used clinically as an immunosuppressant. CsA production and mycelial growth differed when T. inflatum was cultured in different carbon source media. During early fermentation, CsA was preferred to be produced in fructose medium, while the mycelium preferred to accumulate in sucrose medium. On the sixth day, the difference was most pronounced. In this study, high-throughput comparative proteomics methods were applied to analyze differences in protein expression of mycelial samples on day 6, revealing the proteins and mechanisms that positively regulate CsA production related to carbon metabolism. The differences included small molecule acid metabolism, lipid metabolism, organic catabolism, exocrine secretion, CsA substrate Bmt synthesis, and transcriptional regulation processes. The proteins involved in the regulation of mycelial growth related to carbon metabolism were also revealed and were associated with waste reoxidation processes or coenzyme metabolism, small molecule synthesis or metabolism, the stress response, genetic information or epigenetic changes, cell component assembly, cell wall integrity, membrane metabolism, vesicle transport, intramembrane localization, and the regulation of filamentous growth. This study provides a reliable reference for CsA production from high-efficiency fermentation. This study provides key information for obtaining more CsA high-yielding strains through metabolic engineering strategies.
研究领域:
微生物学
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药理学
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生物化学
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DOI
PubMed
高影响因子
PHARMAZIE
·
2020
·Vol. 75
·期 9
·424-429
·
IF 1.198
Chen Jiangfei,Guo Suhang,Yu Xianzhu,Lei Jinxiu,Xu Tao,Zhu Suyan,Chen Lu,Xu Ping,Zhou Xuan,Yu Lushan
Flumatinib, indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, is a structural analog of imatinib and has shown higher potency than imatinib as a BCR-ABL inhibitor. In this paper, the metabolic profile of flumatinib was studied. It was found that
CYP3A4 and CYP2C8 were the main cytochrome P450 enzyme substyles catalyzing the metabolism of flumatinib, and CYP3A4 has a stronger metabolic ability for flumatinib than CYP2C8. Erythromycin, cyclosporine, and voriconazole can inhibit the metabolism of flumatinib in vitro. Accordingly,
co-administration of erythromycin and cyclosporine with flumatinib increased the plasma concentration and the systemic exposure of flumatinib in rats, which indicated that lower doses should be considered in clinical practice.
研究领域:
药理学
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肿瘤学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Xiaopei Ma,Yaodong Liu,Jun Wang,Hui Liu,Gang Wei,Weiyue Lu,Yu Liu
Strong precorneal clearance mechanisms including reflex blink, constant tear drainage, and rapid mucus turnover constitute great challenges for eye drops for effective drug delivery to the ocular epithelium. In this study, cyclosporine A (CsA) for the treatment of dry eye disease (DED) was selected as the model drug. Two strategies, PEGylation for mucus penetration and cationization for potent cellular uptake, were combined to construct a novel CsA nanosuspension (NS@lipid-PEG/CKC) by coating nanoscale drug particles with a mixture of lipids, DSPE-PEG2000, and a cationic surfactant, cetalkonium chloride (CKC). NS@lipid-PEG/CKC with the mean size ∼173 nm and positive zeta potential ∼+40 mV showed promoted mucus penetration, good cytocompatibility, more cellular uptake, and prolonged precorneal retention without obvious ocular irritation. More importantly, NS@lipid-PEG/CKC recovered tear production and goblet cell density more efficiently than the commercial cationic nanoemulsion on a dry eye disease rat model. All results indicated that a combination of PEGylation and cationization might provide a promising strategy to coordinate mucus penetration and cellular uptake for enhanced drug delivery to the ocular epithelium for nanomedicine-based eye drops.
研究领域:
药剂学
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眼科医学
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DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2023
·Vol. 37
·期 12
·e5751
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IF 1.8
Feng Chen,Xiaoxia Yang,Huanhuan Li,Xiaodan Zeng,Ziwei Deng,Hongqiang Wang,Yuanxiang Jin,Chengfeng Qiu,Zhihua Shi
In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC–MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 μl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy.
研究领域:
临床药理学
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分析化学
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医学检验
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DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHIC SCIENCE
·
2014
·Vol. 53
·期 4
·548-553
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IF 1.026
Liu Wen-na,Fan Jun,Lin Chun,Zheng Sheng-run,Zhang Wei-guang
A new cyclosporine-bonded stationary phase has been synthesized through the Staudinger reaction between azido cyclosporine A (CsA) and aminopropyl silica gel and applied in separations of six disubstituted aromatic analytes by high-performance liquid chromatography. For dimethyl phthalate, nitroaniline and chloronitrobenzene, their positional isomers were well-separated on this CsA stationary phase, in which the separation factor for m-/o-dimethyl phthalates was the biggest. For nitrotoluene, dichlorobenzene and benzenediol, the m-/o-isomers were co-eluted. Then, effects of chromatographic conditions (such as types and content of alcoholic modifiers) on separation of nitroaniline positional isomers have been investigated. Retention behaviors of nitroaniline isomers on the column exhibited the strengthening trend along with increasing carbon number of alcohols, from ethanol to 1-propanol, and to 1-butanol. A similar phenomenon was observed by lowering the content of alcohol.
研究领域:
分析化学
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药物化学
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DOI
PubMed
高影响因子
Polymers
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2022
·Vol. 14
·期 10
·1975
·
IF 4.967
Wenjun Sun,Yang Tian,Zengming Wang,Hui Zhang,Aiping Zheng
Cyclosporin A nanocrystals (CsA-NCs) interaction with Caco-2 cells were investigated in this study, including cellular uptake and transport across Caco-2 cell monolayers. CsA-NCs of 165 nm, 240 nm and 450 nm were formulated. The dissolution of CsA-NCs was investigated by paddle method. The effect of size, concentration and incubation time on cellular uptake and dissolution kinetics of CsA-NCs in cells were studied. Uptake mechanisms were also evaluated using endocytotic inhibitors and low temperature (4 °C). The cell monolayers were incubated with each diameter CsA-NCs to evaluate the effect of size on the permeation characteristics of CsA across the intestinal mucosa. The results of dissolution study showed that 165 nm CsA-NC had the highest dissolution rate followed by 240 CsA-NC and finally 450 nm CsA-NC. The saturation of cell uptake of CsA-NCs was observed with the increase of incubation concentration and time. 240 nm and 450 nm CsA-NCs had the lowest and highest uptake efficiency at different time and drug concentration, respectively. The uptake of all three-sized CsA-NCs declined significantly in some different degree after the pre-treatment with different endocytosis inhibitors. 165 nm CsA-NC showed a highest transport capacity across monolayers at the same concentration and time. The results suggest that the size of CsA-NCs can not only affect the efficiency of cellular uptake, but also the type of endocytosis. Decreasing particle size of CsA-NCs can improve transport capacity of CsA through cell monolayer.Keywords:cyclosporin A nanocrystals;endocytosis inhibitor;cellular uptake;Caco-2 cell monolayer
研究领域:
药理学
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生物医学工程
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PubMed
高影响因子
Revista Brasileira de Farmacognosia-Brazilian Journal of Pharmacognosy
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2024
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IF 1.4
Xie Huilong,Fu Yunrong,Lin Zhisheng,Wang Jiayi,Wu Jingyu,You Xiuhua,Xie Jieming
This study explores the synergistic effect of T-CUS 245C combined with cyclosporin A, and its possible mechanism. T-CUS 245C is an immunotoxin conjugated with tastuzumab and recombinant cucurmosin 245C (CUS 245C ). Cyclosporin A is a calcium antagonist mainly used as an immune-suppressive agent, which enhances the cytotoxicity of immunotoxins through an unknown mechanism. The sulforhodamine B assay, flow cytometry, DNA fragmentation apoptosis assay, and western blot analysis were used to evaluate the synergistic effects of cyclosporin A combined with T-CUS 245C on proliferation inhibition and apoptosis induction in SK-OV-3 ovarian cancer cells with HER-2-overexpressing. Meanwhile, using confocal microscopy and flow cytometry, the effect of cyclosporin A on the intracellular distribution of T-CUS 245C was observed and quantified. The results of this study showed that the combination index of cyclosporin A combined with T-CUS 245C is less than 0.7, indicating that cyclosporin A significantly enhances the proliferation inhibition and apoptosis induction induced by T-CUS 245C in SK-OV-3 cells. The confocal microscopy and flow cytometry results show that cyclosporin A effectively increases the dispersion of T-CUS 245C in the cytoplasm by promoting the endolysosomal escape. This study demonstrates that cyclosporin A combined with T-CUS 245C has a synergistic anticancer effect, by facilitating the release of T-CUS 245C in the intracellular space. Graphical Abstract
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
高影响因子
TALANTA
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2019
·
IF 4.916
Xing Huang,Dan Xiao,Yanli Tong,Zuanguang Chen
High performance liquid chromatography (HPLC) post-column photochemical reaction (PR) coupled capacitively coupled contactless conductivity detector (C 4 D) was used for the first time in analysis of weak ultraviolet (UV)-absorbing, non-fluorescence and nonpolar compound. A series of conditions including the radiation power of light source, the length of the reaction tube and the thickness of detection tube were investigated. HPLC-PR-C 4 D system was successfully applied to the determination of Cyclosporin A (CsA). Consequently, under optimal conditions, the detection system exhibited a detection limit of 0.04 μg/mL and wide linear range from 0.5 μg/mL to 100 μg/mL for CsA detection. Application of the HPLC-PR- C 4 D system to pharmaceutical formulation and biological samples revealed the system developed maybe reliably applied to clinical studies.
研究领域:
分析化学
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药学
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DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2022
·Vol. 8
·期 2
·e10405
·
IF 10.684
Kaiheng Liu,Wenjuan Liu,Zirong Dong,Luyu Zhang,Qiuyu Li,Renjie Zhang,Haisheng He,Yi Lu,Wei Wu,Jianping Qi
Ionic liquids (ILs) attract more and more interests in improving drug transport across membrane, including transdermal, nasal, and oral delivery. However, some drawbacks of ILs impede the application in oral drug delivery, such as rapid precipitation of poorly soluble drugs in stomach. This study aimed to employ enteric mesoporous silica nanoparticles (MSNs) to load ILs to overcome the shortcomings faced in oral administration. The choline sorbate ILs (SCILs) were synthesized by choline bicarbonate and sorbic acid and then adsorbed in mesopores of MSNs after dissolving cyclosporin A (CyA). MSNs loading SCILs and CyA were coated by Eudragit® L100 to form enteric nanoparticles. The in vitro release study showed that the CyA and SCILs released only 10% for 2 h in simulated gastric fluids but more than 90% in simulated intestinal fluid. In addition, SCILs and CyA were able to release from MSNs synchronously. After oral administration, enteric MSNs loading SCILs were capable of improving oral absorption of CyA significantly and the oral bioavailability of CyA was similar with that of oral Neoral®. In addition, the oral absorption of enteric MSNs was higher than that of nonenteric MSNs, which showed that enteric coating was necessary to ILs in oral delivery. These findings revealed great potential of translation of ILs to be enteric nanoparticles for facilitating oral absorption of CyA. It is predictable this delivery system is promising to be a platform for delivering poorly water-soluble drugs and even biologics orally.
研究领域:
药剂学
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生物医学工程
·
药物传输系统
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2025
·
IF 5.2
Wenjun Sun,Dehao He,Xueru Ren,Jiayin Li,Linghui Meng,Fang liu,Aiping Zheng
Understanding cellular uptake and intracellular dissolution of drug nanocrystals is necessary. Due to their superior sensitivity, luminescent materials with aggregation-induced emission (AIE) are embedded into drug nanocrystals (hybrid nanocrystals) as a good strategy for tracking intact nanocrystals in cells. However, AIE materials are strongly hydrophobic and tend to self-aggregate, generating fluorescent interference. To exclusively mark nanocrystals, AIE materials must be embedded in nanocrystals and remain soluble when released from dissolved nanocrystals. In this study, cyclosporin A (CsA) nanocrystals (CsA/THPE NCs) embedded with tetrakis(4-hydroxyphenyl)ethylene (THPE) possessing AIE properties were prepared. The self-fluorescence of CsA/THPE NCs was collectively corroborated by scanning electron microscopy, powder X-ray diffraction, fluorescence microscopy, and dissolution experiments. During the dissolution test, CsA/THPE NCs showed a certain degree of slow-release property. Cellular uptake studies were conducted with Caco-2 cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The intact nanocrystals could be directly taken up by cells. The cellular uptake was found to be concentration- and time-dependent. Based on the above experimental results, hybrid nanocrystals integrated with AIE materials were verified to have specific self-fluorescence. Additionally, the dissolution rate of nanocrystals can be adjusted by physically embedding them with other materials.
研究领域:
药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2020
·Vol. 75
·期 5
·186-190
·
IF 1.198
Qin Yanjie,Wang Nanxi,Chen Fen,Han Xuemei,Zhu Ying,Rang Ying,Zhai Xuejia,Lu Yongning
Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It
was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and
MDR1 and its effect the irinotecan treatment in vivo. However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused
on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions in vitro and in vivo. After treatment with 10 mg·kg-1 CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC0-∞
increased significantly. The AUC0-∞ (SN-38G)/AUC0-∞ (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC50 of CsA for UGT1A1 enzyme was 9.4 μM. Furthermore, the UGT1A1
mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving
irinotecan's treatment index.
研究领域:
药理学
·
肿瘤学
·
毒理学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2022
·
IF 7.033
Wenjun Sun,Jing Gao,Ranran Fan,Ting Zhang,Yang Tian,Zengming Wang,Hui Zhang,Aiping Zheng
Background Cyclosporin A (CsA) is a hydrophobic drug widely used as an immunosuppressant and anti-rejection drug in solid organ transplantation. On the market, there are two oral CsA formulations available containing polyoxyethylene castor oil, which can cause serious allergic reactions and nephrotoxicity. In order to eliminate polyoxyethylene castor oil, CsA was formulated into a nanosuspension. This study aimed to design an oral cyclosporin A nanosuspensions (CsA-NSs) and investigate the effect of particle size on absorption of CsA-NSs. Methods CsA-NSs were prepared using a wet bead milling method. Particle size, morphology and crystallinity state of CsA-NSs were characterized. The in vitro dissolution, the intestinal absorption properties and pharmacokinetic study of CsA-NSs were investigated. Results CsA-NSs with sizes of 280 nm, 522 nm and 2967 nm were prepared. The shape of CsA-NSs with smaller size was similar to that of spheres. The crystallinity of CsA in nanocrystals was reduced. The dissolution rate of CsA-NSs (280 nm) was greater than that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). CsA-NSs (280 nm) showed higher absorption rate constants ( K α ) and effective permeability coefficients ( P eff ) of different intestinal segments compared with that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). AUC 0-48h of 280 nm CsA-NSs was about 1.12-fold of that of 522 nm CsA-NSs, and about 1.51-fold of that of 2967 nm CsA-NSs. In particular, the particle size of CsA-NSs was nanoscale, and their bioavailability was bioequivalent with marked self-microemulsion (Sandimmun Neoral ® ). Conclusion It is feasible to prepare CsA-NSs. The dissolution rate, gastrointestinal transport properties and the oral absorption of CsA-NSs were promoted by reducing size. Considering the cost, efficiency and energy consumption, there should be an optimal particle size range in industrial production.
研究领域:
药剂学
·
药物科学
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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
危险品化学品经营许可证（带存储）