Advanced Healthcare Materials
·
2026
·
IF 11
Ling Wang,Haiping Zhong,Hui Zhang,Rongjie Wei,Maoyu Cai,Liangpin Li,Xueyan Zhou,Xia Hua,Shutao Guo,Xiaoyong Yuan
Fungal keratitis is a major cause of corneal blindness and remains difficult to treat due to poor drug retention, frequent dosing, and inadequate modulation of pathogenic mechanisms. Current therapies largely focus on antifungal efficacy while neglecting inflammation-, fibrosis-, and cell death–related pathways. Here, ferroptosis is identified as a critical pathogenic target, and a synergistic therapeutic strategy is developed using a thermosensitive in situ-forming hydrogel composed of poloxamer and hyaluronic acid, enabling the co-delivery of a ferroptosis inhibitor (ferrostatin-1, Fer-1) and the antifungal agent (voriconazole, VOR), termed PX/HA/Fer-1/VOR hydrogel. Upon administration, the hydrogel exhibits lens-like adhesion to corneal defects, forming a localized drug reservoir that significantly enhances corneal retention and prolongs drug residence time by at least 90 min. In vitro studies demonstrate enhanced antifungal activity, while in vivo fungal keratitis models show superior therapeutic efficacy compared with conventional voriconazole eye drops administered six times daily. Notably, a single daily application effectively suppresses inflammation, reduces corneal fibrosis and scarring, and promotes recovery of visual function. Mechanistically, the composite hydrogel exerts synergistic effects through zinc ion chelation–mediated antifungal activity, inhibition of ferroptosis, and attenuation of fibrosis. This multifunctional hydrogel platform offers a promising therapeutic strategy for fungal keratitis.
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Virulence
·
2026
·
IF 6.8
Ya-Hong Wang,Die Zhu,Dan Wang,Ruo-Cheng Sheng,Li-Chao Wang,Chen-Ning Zhang,Muhammad Faizan Latif,Huan Li,Feng-Mao Chen
The normal polar growth and morphogenesis represent fundamental factors in development, reproduction survival and host invasion of phytopathogenic fungi. The heterotetramerized AP-2 complex is widely present in eukaryotes and plays a specific role in clathrin-mediated vesicle formation and transport at the plasma membrane in mammals and plants. However, the functions of AP-2 complex in growth, metabolism and virulence of plant pathogenic fungi remain unclear. In this study, the conserved VdAP-2α subunit was identified in Verticillium dahliae by screening of a T-DNA insertion library. VdAP-2α was significantly induced during the developmental phases of V. dahliae, and its GFP-fused signals exhibited a punctate distribution in cytoplasm and on the plasma membrane. Like the insertional mutant, the deletion of VdAP-2α caused the suppression of radial growth, conidiation and virulence, as well as aggravated formation of melanized microsclerotia. Comparative transcriptomic analysis further elucidated the global regulation of VdAP-2α, including hyphal growth, vesicle transport, redox reactions and metabolic processes. Moreover, the impairment of hyphal polarity disordered chitin distribution, bidirectional conidia germination and hydrophobicity, which were associated with membrane defects caused by the decreasing of membrane-associated ergosterols and intermediates. These results contribute to the understanding of the functional characteristics of the AP-2 complex in filamentous fungi and suggest potential antifungal targets.
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PLoS Pathogens
·
2026
·Vol. 22
·期 3
·e1014021
·
IF 4.9
Dongmei Ma,Yanfang Yao,Chi Yang,Hong Lin,Minghui Sun,Yuanyuan Gao,Wenwen Xin,Dandan Wu,Kangfu Ye,Wenxin Luo,Zhenhong Zhuang,Shihua Wang
Aspergillus flavus is the second most prevalent species of Aspergillus causing invasive aspergillosis, but its treatment efforts had been hindered by the continuous emergence of drug-resistant fungal strains, while the underlying mechanisms remain largely unexplored. In this study, we investigated the role of the chromatin remodeling factor Arp9 in A. flavus drug-resistant. We show that Arp9 up-regulates the chromatin accessibility of the Erg3 and Erg6 promoters, thereby increasing their transcription levels and enhancing ergosterol synthesis. Therefore, the absence of Arp9 enhances A. flavus sensitivity to amphotericin B (AMB). Additionally, by down-regulating chromatin accessibility of Erg11A gene promoter, Arp9 leads to the decrease of its transcription level and subsequently reduces A. flavus resistance to voriconazole (VOR). Co-immunoprecipitation analysis revealed that Arp9 exists in both SWI/SNF and RSC complex. Drug susceptibility test results indicated that the drug sensitivity response induced by Arp9 may be unique to Arp9, as neither SWP82 of the SWI/SNF nor Sth1 of the RSC is required. The role of Arp9 in drug-resistance was also confirmed using the Galleria mellonella model. Furthermore, we found that VOR induces aflatoxin B1 (AFB1) biosynthesis in an Arp9-dependent manner at 35°C and 37°C, and the effect is dramatically magnified in the VOR-resistant A. flavus strain. This study demonstrates that Arp9 plays a critical role in regulating fungal drug-resistance in vitro and in vivo and revealed that Arp9 is an important factor in enhancing AFB1 biosynthesis under Mammalian physiological temperatures. This study provides potential new insights for the control of the infections caused by filamentous pathogenic fungi.
As the notorious aflatoxin producing pathogenic fungi in agriculture and medicine, Aspergillus flavus is widely distributed, contaminating various crops, and inducing invasive aspergillosis mainly to immunodeficiency-patients. Since the drug-resistant clinical A. flavus strains is continuously emergent, the underlying mechanisms urgently needs to be explored. This study demonstrates that chromatin remodeling factor Arp9 is a key switch in A. flavus drug-resistance. It reduces the resistance of A. flavus to VOR by down-regulating the expression of Erg11A . Additionally, Arp9 decreases the sensitivity of A. flavus to AMB by up-regulating ergosterol synthesis. And the role of Arp9 in drug-resistance in vivo was further verified by the G. mellonella model. More importantly, our study is the first to discover that Arp9 promotes AFB1 biosynthesis at mammalian physiological temperature (from 35°C to 37°C) under VOR stress, especially in VOR-resistant strain. This study reveals the important role of chromatin remodeling factor Arp9 in fungal drug-resistance, and provides a potential key target for the treatment of A. flavus infections.
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MICROCHEMICAL JOURNAL
·
2026
·
IF 5.1
Rongkun Zhu,Mengting Cai,Qiuyu Liao,Xiaobin Meng,Hong Yu,Huanghui Zeng,Zhuomiao Lin,Guicui Zhang
In this study, graphene quantum dots (GQDs) with a high density of carboxyl groups were synthesized via a thermal dissolution method. The surface carboxyl groups of the GQDs were then conjugated with the amino groups of dopamine (DA) through an amidation reaction, yielding a novel fluorescent prob.(GQDs@DA), which features catechol groups. Leveraging the distinctive catechol moiety of vancomycin (VAN) as a functional handle, we employed GQDs@DA and a sol-gel process to construct molecularly imprinted polymers (MIPs@GQDs@DA) on a SiO₂ matrix. This resulted in the formation of highly selective recognition cavities complementary to the VAN template molecule in the final MIPs@GQDs@DA probe.When we used excitation light with a wavelength of 360 nm to excite the composite material, MIPs@GQDs@DA emits a stable fluorescence peak at 460 nm. Vancomycin can sensitively and rapidly bind to MIPs@GQDs@DA, thereby quenching the fluorescence generated at 460 nm. Calculations revealed that the quenched fluorescence intensity at 460 nm exhibits a good linear relationship with the concentration of vancomycin, within a linear range of 0–80 μg/mL, and a detection limit of 0.83 μg/mL (S/N = 3). This probe was applied to detect vancomycin in real human serum samples, and the experimental results were consistent with the expected outcomes.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 6.8
Wenge Zhang,Jinyao Chen,Min Fang,Minghui Song,Zongxu Gao,Jingru Hao,Zejun Xu,Xiuyun Li,Shicun Zheng,Wenqiang Chang,Hongxiang Lou
Overexpression of efflux pump genes drives azole resistance in Candida albicans, highlighting the need for efflux pump inhibitors. We identified pleopcin A (PA), a novel spirodioxynaphthalene from Pleopunctum brunnescens, which reverses Mdr1-mediated azole resistance. To enhance potency, we achieved its first total synthesis and designed 82 derivatives via target–ligand analysis. Among them, PA36–2 emerged as the most potent lead compound, showing 64-fold greater activity than PA in combination with fluconazole against MDR1-overexpressing C. albicans strains. Mechanistic studies confirmed PA36–2 as a specific Mdr1 inhibitor. In addition, PA36–2 combined with fluconazole exhibited potent in vivo activity against Galleria mellonella and mice infected with MDR1-overexpressing C. albicans strain. These findings support further pharmaceutical investigation of the potential value of PA36–2 as an Mdr1 inhibitor for overcoming azole resistance in C. albicans infections.
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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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BIOMEDICAL CHROMATOGRAPHY
·
2022
·Vol. 37
·期 1
·e5525
·
IF 1.911
Yuhao Fu,Ying Li,Yinling Ma,Xueru He,Xuejiao Xun,Yanjun Cui,Liju Fan,Zhanjun Dong
Almonertinib was included in the first-line treatment of non-small cell lung cancer with EGFR T790M mutations by the Chinese Society of Clinical Oncology in 2021. Considering that immunocompromised lung cancer patients are prone to opportunistic fungal infections, and most triazole antifungal drugs are moderate or strong inhibitors of CYP3A4, this study was conducted to develop and validate an accurate and rapid ultra-performance liquid chromatography tandem mass spectrometry method for quantifying almonertinib in plasma and for investigating the pharmacokinetic changes of almonertinib caused by voriconazole and fluconazole in rats. After liquid–liquid extraction with tert -butyl methyl ether, an XSelect HSS T3 column (2.1 × 100 mm, 2.5 μm, Waters) was used for the chromatographic separation of almonertinib and sorafenib-D 3 (internal standard). The analytes were detected using an AB Sciex Triple Quad 5,500 mass spectrometer in the positive ionization mode. The method exhibited great linearity (0.5–200 ng/ml, r > 0.997) and stability under the established experimental conditions. All validation experiments were in accordance with the guidelines, and the results were all within the acceptable limits. This method was successfully applied to the researches of pharmacokinetics and drug interactions for almonertinib in rats. Voriconazole and fluconazole significantly altered the pharmacokinetic profiles of almonertinib and increased the systemic exposure of almonertinib in rats to different degrees, but further human trials should be conducted to validate the results.
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Cancers
·
2022
·Vol. 14
·期 10
·2551
·
IF 6.575
Qingwen Xu,Yuxi Liu,Wen Sun,Tiantian Song,Xintong Jiang,Kui Zeng,Su Zeng,Lu Chen,Lushan Yu
Simple SummaryThe transformation and mechanism of methionine metabolism of renal cell carcinoma (RCC) under a hypoxic microenvironment is not well understood as yet. This study illustrated that the reprogramming of methionine metabolism and the subsequent glutathione (GSH) synthesis were mediated by amino acid transporter 1 (LAT1). Correspondingly, we proposed a combination strategy of LAT1 inhibitor JPH203 and oxaliplatin, which presented an enhanced therapeutic efficacy for RCC both in vivo and in vitro.AbstractHypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatmentKeywords:renal cell carcinoma;hypoxia;methionine metabolism;LAT1;drug combination
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Frontiers in Microbiology
·
2022
·
IF 6.064
Guo Penghao,Chen Jianlong,Tan Yiwei,Xia Li,Zhang Weizheng,Li Xiaojie,Jiang Yujie,Li Ruiying,Chen Chunmei,Liao Kang,Peng Yaqin
Background: Fusarium species are opportunistic causative agents of superficial and disseminated human infections. Fast and accurate identification and targeted antifungal therapy give help to improve the patients’ prognosis.Objectives: This study aimed to evaluate the effectiveness of matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF MS) for Fusarium identification, and investigate the epidemiology and antifungal susceptibility profiles of clinical Fusarium isolates in Southern China.Methods: There were 95 clinical Fusarium isolates identified by DNA sequencing of translation elongation factor 1-alpha (TEF1α) and MALDI-TOF MS, respectively. Antifungal susceptibility testing of isolates was performed by broth microdilution according to the CLSI approved standard M38-A3 document.Results: Seven species complexes (SC) with 17 Fusarium species were identified. The most prevalent SC was the F. solani SC (70.5%, 67/95), followed by the F. fujikuroi SC (16.8%, 16/95). F. keratoplasticum within the F. solani SC was the most prevalent species (32.6%, 31/95). There were 91.6% (87/95) of isolates identified by MALDI-TOF MS at the SC level. In most of species, amphotericin B and voriconazole showed lower MICs compared to itraconazole and terbinafine. The F. solani SC showed higher MICs to these antifungal agents compared to the other SCs. There were 10.5% (10/95) of strains with high MICs for amphotericin B (≥8 μg/ml), terbinafine (≥32 μg/ml) and itraconazole (≥32 μg/ml) simultaneously, mostly focusing on F. keratoplasticum (9/10).Conclusion: MALDI-TOF MS exhibited good performance on the identification of Fusarium strains at the SC level. The F. solani SC was the most prevalent clinical SC in Southern China. The MICs varied significantly among different species or SCs to different antifungal agents.
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Thoracic Cancer
·
2023
·Vol. 14
·期 33
·3331-3341
·
IF 2.9
Mengming Xia,Xueyi Song,Zebei Lu,Yu Wang,Quan Zhou,Peiwu Geng,Shuanghu Wang,Yunfang Zhou,Qingjun Wu,Aixia Han
Background Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. Methods A total of 30 Sprague–Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC-Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC-MS–MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. Results AUC and C max of lenvatinib significantly increased with each of the azoles ( p < 0.05), whereas CLz/F decreased 0.83-flod, 0.41-fold ( p < 0.05) and 0.72-fold ( p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 μM in RLMs and 0.160, 1.933, 3.622 and 1.831 μM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes. Conclusion It is imperative to acknowledge the potential drug–drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2021
·Vol. 44
·期 3
·305-315
·
IF 2.233
Xin Yang,Zejun Pei,Renjing Hu,Zhehao Zhang,Zaixiang Lou,Xin Sun
In order to prevent and control the infection of Candida albicans, the antifungal activity, possible mechanism of myriocin against C. albicans and its biofilm were studied. The antifungal activity of myriocin was investigated by microdilution method. The effect of myriocin on fungal cell wall or membrane was evaluated by adding sorbitol, ergosterol or phytosphingosine (PHS). The damage to the cell membrane was investigated with propidium iodide (PI) staining and visualized by scanning electron microscope (SEM). The effects on biofilms and extracellular polysaccharides (EPS) were observed by crystal violet staining method and phenol-sulfuric acid method respectively. The adhesion of C. albicans cells to hydrocarbons was tested to evaluate cell surface hydrophobic (CSH). The combined effects of myriocin and antifungal drugs commonly used in clinical practice were investigated by using the checkerboard microdilution method. Minimal inhibitory concentrations (MICs) were found to be 0.125–4 µg/mL. Myriocin was found to affect both cell wall and cell membrane. After exposure to myriocin, biofilm and EPS were found to be inhibited and removed, and the CSH was decreased. The combined fungistasis of myriocin and voriconazole (VCZ) or amphotericin B (AMB) were additive. Myriocin had significant antifungal activity against C. albicans, and the antifungal mechanisms might be cell wall and membrane damage. Myriocin effectively inhibited and eliminated biofilms, and its mechanism may be related to the inhibition of EPS and CSH.
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International Journal of Environmental Research and Public Health
·
2019
·Vol. 17
·期 1
·134
·
IF 2.468
Kamran Bashir,Zhimin Luo,Guoning Chen,Hua Shu,Xia Cui,Wen Li,Wang Lu,Qiang Fu
Griseofulvin (GSF) is clinically employed to treat fungal infections in humans and animals. GSF was detected in surface waters as a pharmaceutical pollutant. GSF detection as an anthropogenic pollutant is considered as a possible source of drug resistance and risk factor in ecosystem. To address this concern, a new extraction and enrichment method was developed. GSF-surface molecularly imprinted polymers (GSF-SMIPs) were prepared and applied as solid phase extraction (SPE) sorbent. A dispersive solid phase extraction (DSPE) method was designed and combined with HPLC for the analysis of GSF in surface water samples. The performance of GSF-SMIPs was assessed for its potential to remove GSF from water samples. The factors affecting the removal efficiency such as sample pH and ionic strength were investigated and optimized. The DSPE conditions such as the amount of GSF-SMIPs, the extraction time, the type and volume of desorption solvents were also optimized. The established method is linear over the range of 0.1–100 µg/mL. The limits of detection and quantification were 0.01 and 0.03 µg/mL respectively. Good recoveries (91.6–98.8%) were achieved after DSPE. The intra-day and inter-day relative standard deviations were 0.8 and 4.3% respectively. The SMIPs demonstrated good removal efficiency (91.6%) as compared to powder activated carbon (67.7%). Moreover, the SMIPs can be reused 10 times for water samples. This is an additional advantage over single-use activated carbon and other commercial sorbents. This study provides a specific and sensitive method for the selective extraction and detection of GSF in surface water samples.Keywords:dispersive solid phase extraction;griseofulvin;HPLC;removal and analysis;pharmaceutical pollutants;surface water
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危险品化学品经营许可证（带存储）