JOURNAL OF THE EUROPEAN CERAMIC SOCIETY
·
2025
·Vol. 45
·期 15
·117640
·
IF 6.2
Li Xu,Wei Liao,Xiaosong Zhou,Yongqiang Tan
The influences of Cr 3 C 2 addition on phase formation, microstructures and mechanical properties of (Zr,Ti,Nb,Ta,Hf)C prepared from binary carbides mixtures by spark plasma sintering were studied. The introduction of 4/3 mol.% Cr 3 C 2 significantly lowered the minimum temperature for uniform high-entropy phase (Zr,Ti,Nb,Ta,Hf)C from 2200 °C for to 1900 °C. The lower solubility limit of Cr in (Zr,Ti,Nb,Ta,Hf,Cr)C results in excessive Cr 3 C 2 -based carbides, which tends to segregate along grain boundaries at higher sintering temperatures while locate at triple junctions at lower sintering temperatures . High mechanical strength of 599 MPa were obtained when 4/3 mol.% Cr 2 C 3 was added and sintered at 1900 °C. The fine grain size and Cr 3 C 2 -based carbides are responsible for the high mechanical properties. More Cr 2 C 3 addition results in lower mechanical properties due to excessive Cr 3 C 2 -based carbides.
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JOURNAL OF THE AMERICAN CERAMIC SOCIETY
·
2025
·
IF 3.8
Qiqiang Zhang,Lei Cao,Bo Peng,Hui Zhang,Xingyuan San,Yanchun Zhou,Man Jiang,Qingguo Feng,Chunfeng Hu
MAX phase ceramics, as a family of ternary layered ceramics, have received a lot of attention in the past decade due to their potential as precursors for two-dimensional transition metal carbides. However, due to complex multi-component metallurgical reactions, multicomponent MAX phase ceramics have always faced difficulties in purification and homogenization. This paper identifies a new strategy for synthesizing multicomponent MAX phase ceramics that can eliminate these synthesis difficulties. This path utilizes low-temperature (below 1000°C) stable Ti 2 AlC and carbide powder as initial materials to simplify complex multi-component reactions into a one-step reaction, successfully achieving high purity and precise doping ratio. As an example, four novel doped MAX phase ceramics, Ti 2 MAlC 2 (M = Nb, Ta, W) and Ti 2 HEAlC 2 (HE = 1/7Ti, 1/7V, 1/7Zr, 1/7Nb, 1/7Hf, 1/7Ta, 1/7 W) were successfully synthesized using this method. This dynamic-based design, on one hand, simplifies the reaction mechanism to make purification easier, and on the other hand, the concentrated release of entropy during the reaction process promotes phase transition and related element homogenization.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
·
IF 3.8
Fei Gong,Huihui Hu,Ying Ouyang,Zheng-Zheng Liao,Ying Kong,Jin-Fang Hu,Hua He,Ying Zhou
The drug-drug interactions (DDIs) between tacrolimus and voriconazole are highly variable among individuals. We aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDIs in people with different CYP3A5 and CYP2C19 alleles. First, pharmacokinetic data of humans receiving tacrolimus with or without voriconazole from the literature were used to construct and validate the PBPK model. Thereafter, we developed a model incorporating the metabolism of voriconazole mediated by CYP2C19 and the inhibitory effect of voriconazole on CYP3A4/5. Finally, the model was used to evaluate the dose adjustment of tacrolimus in people with different CYP3A5 and CYP2C19 alleles. When tacrolimus was administered alone (3 mg PO, single dose), the predicted AUC 0-∞ of tacrolimus in CYP3A5 nonexpressers (19.22) was 3.5-fold higher than that in expressers (5.48). Following voriconazole (200 mg PO, bid) administration in human with different CYP2C19 genotypes, the AUC 0-∞ of tacrolimus increased by 5.1- to 8.3-fold in CYP3A5 expressers and by 5.3- to 10.2-fold in CYP3A5 nonexpressers. The lower the gene expression level of CYP2C19 in the population, the higher the exposure to tacrolimus. When tacrolimus was combined with voriconazole (200 mg, bid; 400 mg, bid, on Day 1), the final model simulations suggested that the dose regimen of tacrolimus should be regulated to 0.15 mg/kg/day (qd) in CYP3A5 expressers with different CYP2C19 genotypes. For CYP3A5 nonexpressers, the dosing schedule of tacrolimus should be modified to 0.05 mg/kg/24 h for patients with 2C19 EM, 0.05 mg/kg/48 h for 2C19 IM and 0.05 mg/kg/72 h for 2C19 PM. In conclusion, a PBPK model with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole to guide the clinical use of tacrolimus.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Wang Hongkang,Ji Zhe,Feng Yanru,Yan Tianhua,Cao Yongbing,Lu Hui,Jiang Yuanying
Introduction: Extrusion of azoles from the cell, mediated by an efflux pump Cdr1, is one of the most frequently used strategies for developing azole resistance in pathogenic fungi. The efflux pump Cdr1 is predominantly localized in lipid rafts within the plasma membrane, and its localization is sensitive to changes in the composition of lipid rafts. Our previous study found that the calcineurin signal pathway is important in transferring sphingolipids from the inner to the outer membrane.Methods: We investigated multiple factors that enhance the antifungal activity of fluconazole (FLC) using minimum inhibitory concentration (MIC) assays and disk diffusion assays. We studied the mechanism of action of myriocin through qRT-PCR analysis and confocal microscopy analysis. We tested whether myriocin enhanced the antifungal activity of FLC and held therapeutic potential using a mouse infection model.Results: We found that this signal pathway has no function in the activity of Cdr1. We found that inhibiting sphingolipid biosynthesis by myriocin remarkably increased the antifungal activity of FLC with a broad antifungal spectrum and held therapeutic potential. We further found that myriocin potently enhances the antifungal activity of FLC against C. albicans by blocking membrane localization of the Cdr1 rather than repressing the expression of Cdr1. In addition, we found that myriocin enhanced the antifungal activity of FLC and held therapeutic potential.Discussion: Our study demonstrated that blocking the membrane location and inactivating Cdr1 by inhibiting sphingolipids biogenesis is beneficial for enhancing the antifungal activity of azoles against azole-resistant C. albicans due to Cdr1 activation.
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Frontiers in Immunology
·
2023
·
IF 7.3
Xi Zhang,Tiaoxia Wang,Xiaona Zhu,Yong Lu,Mingpeng Li,Zhihong Huang,Deping Han,Longzhen Zhang,Yang Wu,Liantao Li,Frank Klawonn,Renata Stripecke
Introduction Epstein-Barr virus (EBV) is a widely spread pathogen associated with lymphoproliferative diseases, B/ T/ NK cell lymphomas, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). EBV lytic reactivations contribute to the genomic instability, inflammation and tumorigenesis of NPC, promoting cancer progression. Patients with NPC refractory to standard therapies show dismal survival. EBV gp350 is an envelope protein detectable in NPC specimens intracellularly and on the cell membrane of malignant cells, and is a potential viral antigen for T cell-directed immunotherapies. The potency of T cells engineered with a chimeric antigen receptor (CAR) targeting gp350 against EBV + lymphoproliferative disease was previously shown. Methods Here, we advanced towards preclinical and non-clinical developments of this virus-specific CAR-T cell immunotherapy against NPC. Different gp350CAR designs were inserted into a lentiviral vector (LV) backbone. Results A construct expressing the scFv 7A1-anti−gp350 incorporating the CD8 transmembrane and CD28.CD3ζ signaling domain (ZT002) was selected. High titer ZT002 (~1x10 8 TU/ml) was manufactured in HEK 293T/17 suspension cells in serum free media as large-scale production under good manufacturing practices (GMP). A LV multiplicity of infection (MOI) of 1 resulted in high frequencies of functional gp350CAR + T cells (>70%) at a low (<2) vector copy numbers in the genome. ZT002 was therefore used to establish gp350CAR-T batch run production methods. GMP upscaling and validation of T cell transduction and expansion in several runs resulted in average 3x10 9 gp350CAR-T cells per batch. >80% CD3 + gp350CAR-T cells bound to purified gp350 protein. In vitro cytotoxicity and cytokine secretion assays (IFN-γ and TNF-α) confirmed the specificity of gp350CAR-T cells against gp350 + NPC, GC and lymphoma cell targets. Immunocompromised B-NDG mice (NOD.CB17- PrkdcscidIl2rgtm1 /Bcgen) were challenged s.c. with a EBV + NPC C666.1 cell line expressing gp350 and then treated with escalating doses of gp350CAR-T cells or with non-transduced T cells. gp350CAR-T cells promoted antitumor responses, bio-distributed in several tissues, infiltrated in tumors and rejected gp350 + tumor cells. Discussion These results support the use of gp350CAR-T cells generated with ZT002 as an Innovative New Drug to treat patients with solid and liquid EBV-associated malignancies.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 9
·4485
·
IF 6.208
Qingfeng He,Fengjiao Bu,Qizhen Wang,Min Li,Jiaying Lin,Zhijia Tang,Wen Yao Mak,Xiaomei Zhuang,Xiao Zhu,Hai-Shu Lin,Xiaoqiang Xiang
Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug–drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes’ inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.Keywords:physiologically based pharmacokinetic (PBPK);Wuzhi capsule (WZC);tacrolimus (FK-506);CYP3A5 polymorphism;drug–drug interaction (DDI);schizandrol A (SZA);schizandrol B (SZB)
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Journal of Materials Chemistry B
·
2023
·Vol. 11
·期 20
·4464-4474
·
IF 7
Xiaoqian Jiang,Xinxin Xu,Hua Kuang,Liqiang Liu,Liguang Xu,Aihua Qu,Chuanlai Xu
Tacrolimus is a macrolide immunosuppressant widely used in organ transplantation. Due to the narrow treatment window, therapeutic drug monitoring of the clinical application of tacrolimus is necessary. In this study, a carboxyl group introduced at the hydroxyl or carbon positions of tacrolimus was used to couple with carrier protein to synthesize complete antigens. After screening different immunogens and coating antigens, a highly-sensitive and specific monoclonal antibody (mAb) 4C5 was obtained, with a half inhibitory concentration (IC50) value of 0.26 ng mL−1 determined by indirect competitive enzyme-linked immunosorbent assay (ic-ELISA). A colloidal gold-based immunochromatographic strip (CG-ICS) was established to monitor tacrolimus in human whole blood based on the mAb 4C5. Through visual observation, it was found that the visual limit of detection (vLOD) and cut-off value of qualitative detection were 1.0 and 20.0 ng mL−1, respectively. The calculated LOD (cLOD) value of quantitative detection was 0.16 ng mL−1, and the linear range was 0.48–7.57 ng mL−1. In addition, the results of the CG-ICS for analyzing real positive samples of human whole blood were basically consistent with those of LC-MS/MS. Therefore, the CG-ICS was suitable for rapid and accurate clinical monitoring of tacrolimus.
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BIOMEDICAL CHROMATOGRAPHY
·
2023
·Vol. 37
·期 12
·e5751
·
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.
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Frontiers in Pharmacology
·
2021
·
IF 5.811
Gao Ping,Du Xiaoyi,Liu Lili,Xu Hua,Liu Maochang,Guan Xinlei,Zhang Chengliang
Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-β1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.
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TRANSPLANT INTERNATIONAL
·
2020
·Vol. 33
·期 4
·450-461
·
IF 3.177
Shoubao Wang,Yao Xiong,Yinmin Wang,Jingting Chen,Jun Yang,Binbin Sun
Summary Systemic immunosuppression is indispensable for vascularized composite allotransplantation (VCA). Daily administration of standard triple therapy regimen of tacrolimus (FK506), mycophenolate mofetil (MMF), and steroid has severe side effects and reduces the compliance of VCA recipients. To overcome these hurdles, FK506/MMF/prednisolone (PDNN) was loaded into PLGA microspheres (PGLA MS). A single injection of FK506/MMF/PDNN-PLGA MS significantly prolonged the survival time of allograft in a rat hind limb transplantation model with a median survival time (MST) of more than 150 days compared to 34.5 days in the group treated orally with FK506/MMF/PDNN and 11 days in the nontreatment allograft and MS control groups. Analysis of showed that FK506/MMF/PDNN-PLGA MS could maintain relatively higher plasma and tissue drug concentrations for a long time. Moreover, histopathology and flow cytometry of circulating mononuclear cells revealed significantly prolonged immunosuppression by the FK506/MMF/PDNN-PLGA MS compared with the orally given FK506/MMF/PDNN. In conclusion, a single injection of FK506/MMF/PDNN-PLGA MS may provide a new approach for long-term prevention of immune rejection in VCA.
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POULTRY SCIENCE
·
2019
·
IF 2.027
Y. Chen,Y. Yang,F. Wang,X. Yang,F. Yao,K. Ming,W. Yuan,L. Zeng,J. Liu
ABSTRACT Duck hepatitis A virus type 1 ( DHAV-1 ) is one of the main pathogens of ducklings and causes a high mortality rate. Baicalin ( BA ) has potent antiviral effect, but the solubility is very poor. In order to increase the absorption, solubility, and pharmacological activity, the phospholipid complex was used to modify BA in present study. Therefore, BA phospholipid complex ( BAPC ) was prepared. The anti-DHAV-1 abilities of BA and BAPC in vitro was evaluated by cell counting kit-8 and reverse transcription quantitative PCR. The curative effects of BA and BAPC on ducklings which were infected by DHAV-1 in addition to the ALT and AST levels were also detected. The results indicated the anti-DHAV-1 ability of BAPC was stronger than that of BA both in vitro and in vivo . To explore the anti-DHAV-1 mechanism, the influence of BAPC on DHAV-1 adsorption, replication, and release was studied. Furthermore, the anti-oxidative and immuno-enhancing abilities of BAPC in the treatment of infected ducklings were also determined. The results showed BAPC inhibited DHAV-1 adsorption, replication and release. Furthermore, it played anti-oxidative and immno-enhancing roles in the treatment, and the immno-enhancing role was crucial to the treatment.
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BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2017
·Vol. 122
·期 3
·331-340
·
IF 3.176
Hongyan Zhang,Fengjiao Bu,Lei Li,Zheng Jiao,Guo Ma,Weimin Cai,Xiaomei Zhuang,Hai-Shu Lin,Jae-Gook Shin,Xiaoqiang Xiang
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug–drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.
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