查找使用阿拉丁产品的科研文献

Structural Optimization of Berberine as a Synergist to Restore Antifungal Activity of Fluconazole against Drug-Resistant Candida albicans

Hong Liu,Liang Wang,Yan Li,Jiang Liu,Maomao An,Shaolong Zhu,Yongbing Cao,Zhihui Jiang,Mingzhu Zhao,Zhan Cai,Li Dai,Tingjunhong Ni,Wei Liu,Simin Chen,Changqing Wei,Chengxu Zang,Shujuan Tian,Jingyu Yang,Chunfu Wu,Dazhi Zhang,Hua Liu,Yuanying Jiang

Graphical Build it better: Structural optimization of berberine led to the identification of the novel scaffold of N -(2-(benzo[ d ][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acetamides 7 a – l , which exhibited remarkable in vitro synergistic antifungal activity against fluconazole-resistant Candida albicans in combination with fluconazole. Compound 7 d exhibited much lower cytotoxicity than berberine toward human umbilical vein endothelial cells. We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. A structure–activity relationship study of 95 analogues led us to identify the novel scaffold of N -(2-(benzo[ d ][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acetamides 7 a – l , which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d ( N -(2-(benzo[ d ][1,3]dioxol-5-yl)ethyl)-2-(2-fluorophenyl)acetamide) significantly decreased the MIC 80 values of fluconazole from 128.0 μg mL −1 to 0.5 μg mL −1 against fluconazole-resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells.

Synergistic effect of caffeic acid phenethyl ester with caspofungin against Candida albicans is mediated by disrupting iron homeostasis

Lingmei Sun,Chengcheng Hang,Kai Liao

Effect of metal ions on the enzymatic hydrolysis of hemp seed oil by lipase Candida sp. 99–125

Jike Lu,Pei Wang,Zhaodi Ke,Xin Liu,Qiaozhen Kang,Limin Hao

In order to study the effect of metal ions on the enzymatic hydrolysis of hemp seed oil by Candida sp. 99–125, the spectroscopy, stability and hydrolytic activity of the biocatalyst were investigated in presence of Ca 2+ , Mg 2+ , Fe 2+ , Fe 3+ , Cu 2+ , Sn 2+ , Pb 2+ , Zn 2+ and Ba 2+ metal ions, respectively. The UV spectroscopy showed that all the metal ions enhanced the absorbance but the decrease of fluorescence intensity was observed. All the metal ions could improve the lipase thermal stability except Cu 2+ and Ba 2+ . Hydrolysis of hemp seed oil proved that Ca 2+ , Fe 3+ , Pb 2+ and Ba 2+ could significantly improve the hydrolytic rate, and metal ions could influence lipase selectivity. The study revealed that metal ions could improve lipase stability, hydrolysis activity in the hydrolytic process of hemp seed oil by Candida sp. 99–125.

Ethyl caffeate reprograms macrophage immunometabolism via the SIRT3–FOXO3A–AKT axis to enhance host defense against Candida auris

Xiaohui Yang,Jie Li,Yilang Zhong,Yuanjiayi Shen,Chenqin Xu,Zhouyu Nie,He Wang,Rui Cao,Miaomiao Wang,Jinyu Zhang,Chao Ma,Tongkai Cai,Chenglin Jia,Ruilian Wang,Hao Yin,Jian Chen,Yongbing Cao

Background Candida auris ( C. auris ) is an emerging multidrug-resistant fungal pathogen. Current antifungals are often insufficient, creating a need for host-directed strategies. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that regulates redox homeostasis, but its role in antifungal macrophage defense is not well defined. We examined how SIRT3 shapes macrophage responses to C. auris . We also evaluated ethyl caffeate (EC) as a host-directed modulator. Methods We used murine macrophages with Sirt3 knockdown or overexpression. We quantified phagocytosis, intracellular fungal survival, mitochondrial ROS dynamics, and macrophage cell integrity using imaging, flow cytometry, CFU assays, and LDH release. We profiled infection-induced transcriptional programs by RNA-seq and performed pathway analyses. We tested EC both in vitro and in systemic infection models in Drosophila and mice. We assessed pathway markers by immunoblotting and immunofluorescence. We used the SIRT3 inhibitor 3-TYP to test inhibition sensitivity. Results SIRT3 deficiency impaired macrophage antifungal function and was accompanied by redox imbalance. mtROS regulation was disrupted in a biphasic pattern, with an early spike followed by late depletion. Transcriptomics linked SIRT3-dependent programs to FOXO and PI3K–AKT signaling. In macrophages, SIRT3 status tracked with FOXO3A acetylation and AKT phosphorylation. EC showed weak direct antifungal activity in vitro but improved outcomes in systemic infection models. EC treatment increased SIRT3 abundance and was associated with reduced FOXO3A acetylation and restrained infection-associated AKT activation. These functional and signaling effects were largely sensitive to SIRT3 inhibition by 3-TYP. Conclusion This study connects SIRT3-dependent redox control to FOXO3A–AKT signaling during C. auris infection. It also supports EC as a host-directed candidate that improves antifungal defense in vivo while limiting inflammatory injury.

Discovery and Structural Optimization of Spirodioxynaphthalene-Based Mdr1 Efflux Pump Inhibitor to Combat Azole Resistance in Candida albicans

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.

Glutaraldehyde cross-linked Candida antarctica lipase B on NH₂-UiO-66: A high-efficiency biocatalyst for diacylglycerol synthesis

Jiawei Zheng,Xuan Hu,Jiufang Chen,Fengxia Lan,Li Xu,Zeping Lu,Binbin Nian,Nanjing Zhong

CALB@GA-NH 2 -UiO-66 exhibited 97.31% oleic acid conversion and 77.60% DAG content. • CALB@GA-NH 2 -UiO-66 retained full initial activity after 11 reuse cycles. • The immobilized CALB exhibited a single conformational basin. • Covalent enzyme–carrier conjugates were formed via Schiff base linkages. • The immobilization moderately restrained the flexibility of α-helix 5 of CALB. This study aimed to develop a robust biocatalyst for diacylglycerol (DAG) synthesis. Candida antarctica lipase B (CALB) was immobilized on NH₂-UiO-66 via glutaraldehyde (GA) cross-linking. The cross-linked CALB exhibited significantly better performance than the adsorbed counterpart. Oleic acid conversion reached 97.31% with DAG content up to 77.60%. Moreover, the immobilized CALB retained its full initial activity after 11 reuse cycles. The temperature dependence of oleic acid conversion followed the equation ln V₀  = 8.86–4.67 × 10 3 / T , with an activation energy of 38.83 kJ·Mol −1 . Molecular dynamics simulations revealed that the flexibility of α-helix 5 in CALB@GA-NH₂-UiO-66 is moderately restrained, and the immobilized CALB exhibits a single conformational basin. Additionally, immobilization induces slight contraction of the CALB active site pocket, and reduced length and increased bottleneck radius of the tunnel. This study provides molecular insights into the structure–stability relationship of immobilized enzymes, guiding the rational design of robust biocomposites We develop a robust biocatalyst via glutaraldehyde cross-linking of CALB onto NH₂-UiO-66 for DAG production by esterification. Download: Download high-res image (210KB) Download: Download full-size image

Effects of β-cyclodextrin on the enzymatic hydrolysis of hemp seed oil by lipase Candida sp.99–125

Pei Wang,Zhaodi Ke,Juanjuan Yi,Xin Liu,Limin Hao,Qiaozhen Kang,Jike Lu

To enhance the stability of lipases, the additive method is attractive because of its high efficiency and simplicity, of which β-cyclodextrin (β-CD), as an additive has attracted attention. In the present study, the effects of β-CD on enzymatic hydrolysis of hemp seed oil by lipases were investigated. The stability, spectroscopy, and reusability of C andida sp.99–125 were compared by the addition of β-CD, respectively. The results showed that Candida sp.99–125 could produce the highest yield of α-linolenic acid (ALA, 18.27%, w/w) in the presence of β-CD after 24h, and the thermal stability of lipase was also improved. The UV spectroscopy showed that the absorbance of lipase decreased with increasing concentrations of β-CD and the fluorescence result was similar. Moreover, the reusability of lipase with β-CD was better than free lipase. This study revealed that β-CD could increase hydrolysis activity and stability of the lipase, thereby improving the hydrolytic process of hemp seed oil by Candida sp.99–125.

Chemical modification for improving activity and stability of lipase B from Candida antarctica with imidazolium-functional ionic liquids

Ru Jia,Yi Hu,Luo Liu,Ling Jiang,He Huang

Various imidazolium-functional ionic liquids (ILs) composed of different cations and anions were grafted onto Candida antarctica lipase B (CALB) through lysine coupling, and 4–6 of the 9 primary amino groups of the lysine residues were modified. The catalytic activity and stability were investigated in a p-nitrophenyl palmitate hydrolysis reaction. After modification, CALB was activated and achieved a high catalytic efficiency in the aqueous phase (e.g., [HOOCMMIm][Cl] modification showed a 1.5-fold increase in the catalytic efficiency). The thermostability and organic solvent tolerance were significantly increased with the ILs modification (e.g., [HOOCBMIm][Cl] owned kosmotropic cation and chaotropic anion modification showed a 7-fold thermostability increase at 70 °C, 1-fold increase in 50% aqueous dimethylformamide and 5-fold increase in 50% aqueous methanol). Conformation changes were confirmed by fluorescence spectroscopy, circular dichroism spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy.

Unusual Flavones from Primula macrocalyx as Inhibitors of OAT1 and OAT3 and as Antifungal Agents against Candida rugosa

Li Xue,Wang Xue,Li Caiyu,Khutsishvili Manana,Fayvush George,Atha Daniel,Zhang Youcai,Borris Robert P.

A bioactivity guided program exploring the interaction of phytochemicals in the entire plant Primula macrocalyx with the organic anion transporters (OAT1 and OAT3) and microorganisms led to the elucidation of ten known flavones ( 1 – 4 , 6 – 10 , 12 ) and two previously undescribed flavones ( 5 , 11 ). The structures of the compounds were determined by extensive analysis of spectroscopic data, as well as by comparison with data from previous reports. Two known flavones ( 9 , 12 ) are reported for the first time from the family Primulaceae. All compounds were evaluated for inhibition of OAT1 and OAT3. Six flavones ( 2 , 3 , 6 – 8 , 12 ) showed potent inhibitory activity on OAT1, while seven flavones ( 2 , 3 , 6 – 9 , 12 ) showed marked inhibitory activity on OAT3, with IC 50  ≤ 10.0  µ M. Antimicrobial activities of crude fractions against sixteen microorganisms were tested to give a target yeast strain Candida rugosa for further evaluation of MICs on the isolates. Three flavones ( 7 , 8 , 12 ) showed marked antifungal activity with MIC < 2.0  µ M. To our knowledge, this study is the first to evaluate these flavones as inhibitors of the OAT1 and OAT3, and as antifungal agents.

Chelerythrine, a major ingredient isolated from Macleaya cordata (Willd.) R. Br. (Papaveraceae), inhibits fluconazole-resistant Candida albicans biofilms

Ying Liu,Xia Zhang,Huaiyu Cheng,Yifang Li,Guangxiong Zhou

ABSTRACT Introduction It has a long history to employ Macleaya cordata (Willd.) R. Br. (Papaveraceae) for the treatment of a variety of diseases in China. Chelerythrine, one of the major of M. cordata with detoxifying and anti-inflammatory effect, is reported to combat bacteria and fungus. This work aims to explore the effect of chelerythrine against fluconazole-resistant C. albicans and also illustrate its potential mechanism. Methods The microdilution method, following CLSI-M27-A3 was used to evaluate the effect of chelerythrine against fluconazole-resistant C. albicans. Meanwhile, biofilm viability was assessed by XTT assay and cell morphology was observed by inverted microscope. RT-qPCR and confocal laser scanning microscope were employed to detect the mRNA expression and DCFH-DA staining, respectively. Fluorescence intensity was quantified by flow cytometry. Results The total alkaloids extract of M. cordata significantly inhibited the viability of C. albicans, concentration of which in 64 μg/mL presented to 40% inhibitory effect . In addition, the MIC 80 for chelerythrine was 8 μM, whereas chelerythrine in 4 μM inhibited biofilm formation by 47.7%. Further studies revealed that chelerythrine reduced the hydrophobicity of cellular surface, inhibited hyphal growth, downregulated the expression of genes related to cAMP pathway, increased cellular permeability and promoted the production of reactive oxygen species (ROS). Conclusion Chelerythrine inhibited biofilm formation by decreasing CSH and inhibiting the cAMP pathway. Chelerythrine increased cellular permeability and promoted the production of reactive oxygen species, which leads to the cell death of fluconazole-resistant C. albicans .

Transesterification of phosphatidylcholine with DHA-rich algal oil using immobilized Candida antarctica lipase B to produce DHA-phosphatidylcholine

Liwen Shu,Xin Zheng,Shuhua Qi,Shuizhi Lin,Yinghua Lu,Chuanyi Yao,Xueping Ling

Docosahexaenoic acid (DHA) enriched with phospholipids (PLs) (DHA-PLs) is a type of structured PL with good physicochemical and nutritional properties. Compared to PLs and DHA, DHA-PLs has higher bioavailability and structural stability and many nutritional benefits. To improve the enzymatic synthesis of DHA-PLs, this study investigated the preparation of phosphatidylcholine (PC) enriched with DHA (DHA-PC) via enzymatic transesterification of algal oil, which is rich in DHA-triglycerides, using immobilized Candida antarctica lipase B (CALB). The optimized reaction system incorporated 31.2% DHA into the acyl chain of PC and converted 43.6% PC to DHA-PC within 72 h at 50 °C, 1:8 PC: algal oil mass ratio, 25% enzyme load (based on total substrate mass), and 0.02 g/mL molecular sieve concentration. Consequently, the side reactions of PC hydrolysis were effectively suppressed and products with high PC content (74.8%) were produced. Molecular structure analysis showed that exogenous DHA was specifically incorporated into the sn-1 site of the PC by immobilized CALB. Furthermore, the evaluation of reusability with eight cycles showed that the immobilized CALB had good operational stability in the present reaction system. Collectively, this study demonstrated the applicability of immobilized CALB as a biocatalyst for synthesizing DHA-PC and provided an improved enzyme-catalyzed method for future DHA-PL synthesis.

Tannic acid-modified ZIF-67 immobilized CRL for screening CRL inhibitors from traditional Chinese medicines

Hong-Hong Wang,Jia Liu,Juan Chen

With the increasing demand for lipase inhibitors and novel anti-obesity therapies, it is of paramount importance to screen Candida rugosa lipase (CRL) inhibitors from traditional Chinese medicines (TCMs) as anti-obesity drugs. Immobilized enzyme screening technology combined with capillary electrophoresis has become a powerful tool for the exploration of CRL inhibitors due to its easy separation characteristics and high separation efficiency. In this work, tannic acid (TA)-modified ZIF-67 was adopted as a readily available carrier for CRL immobilization. ZIF-67 was fabricated by mixing Co(NO 3 ) 2 ·6 H 2 O with 2-methylimidazole under ambient conditions. TA was subsequently introduced to chelate the surface metal ions of ZIF-67, yielding a ZIF-67/TA hybrid carrier. CRL was then immobilized onto the ZIF-67/TA via physical adsorption. The immobilization of CRL on TA-modified ZIF-67 minimally alters its conformation, enabling 98.7 % recovery of enzymatic activity. Additionally, it exhibits a high CRL loading capacity of 36.5 mg·g⁻¹ determined by the Bradford protein assay. The ZIF˗67/TA/CRL demonstrated notable improvements in thermal resistance, operational durability, recyclability, and storage performance. Its calculated Michaelis constant ( K m ) was determined to be 1.41 mM, while the half-maximal inhibitory concentration (IC 50 ) of orlistat against the system was measured to be 19.74 µM. Finally, capillary electrophoresis was employed to evaluate CRL inhibitions across 18 TCMs, identifying Schisandrae Chinensis Fructus as the most potent CRL inhibitor. This investigation not only presents an innovative strategy for discovering lipase inhibitors and prospective anti-obesity agents, but also underscores the therapeutic potential of TCMs in metabolic disorder intervention.