Acta Biomaterialia
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2022
·
IF 10.633
Bin Liang,Dawei Jiang,Luqi Pan,Fang Xiong,Shuya Feng,Shenghao Wu,Haige Ye,Zhijie Yu,Changcan Shi,Shenmeng Gao
Selective BCL2 inhibitor ABT-199 has been approved to treat hematological malignancies including acute myeloid leukemia (AML). However, acquired drug resistance and severe side effects occur after extended treatment limiting the clinical usage of ABT-199. Here, we successfully encapsulated pure ABT-199 in amphiphilic mPEG- b -PTMC 169 block copolymer , forming mPEG-b-PTMC 169 @ABT-199 nanoparticles (abbreviated as PEG-ABT-199), which presented better aqueous dispersion and higher efficiency of loading and encapsulation than pure ABT-199. We then compared the anti-leukemic ability of pure ABT-199 and PEG-ABT-199 in vitro and in vivo . PEG-ABT-199 had a lower IC50 value compared with pure ABT-199 in MV4-11 and MOLM-13 cell lines. In addition, PEG-ABT-199 significantly induced apoptosis and decreased colony number than pure ABT-199. Most importantly, PEG-ABT-199 markedly reduced leukemic burden, inhibited the infiltration of leukemic blasts in the spleen, and extended the overall survival (OS) in MLL-AF9-transduced murine AML compared with free ABT-199. Meanwhile, the blank PEG169 NP was non-toxic to normal hematopoiesis in vitro and in vivo , suggesting that PEG169 NP is a safe carrier. Mechanistically, PEG-ABT-199 enhanced mitochondria-targeted delivery of ABT-199 to trigger the collapse of mitochondrial membrane potential (MMP), the release of cytochrome c (cyt-c), and mitochondria-based apoptosis. In conclusion, our results suggest that PEG-ABT-199 has more vital anti-leukemic ability than pure ABT-199. PEG-ABT-199 has potential application in clinical trials to alleviate side effects and improve anti-leukemia ability. Statement of significance ATB-199, an orally selective inhibitor for BCL2 protein, presents marked activity in relapsed or refractory AML, T-ALL, and CLL patients. However, ABT-199 resistance severely limits the further clinical usage because of off-target effects, non-specific toxicities, and low delivery of drugs. To reduce the side-effects and improve the solubility and bioavailability, ABT-199 was encapsulated into the amphiphilic mPEG- b -PTMC block copolymer by co-assembly method to obtain mPEG- b [email protected] nanoparticles (PEG-ABT-199). PEG-ABT-199 has several advantages compared with pure ABT-199. 1.PEG-ABT-199 presents better aqueous dispersion and higher efficiencies of loading and encapsulation than pure ABT-199. 2. PEG-ABT-199 substantially enhances the anti-leukemic ability in vitro and in vivo compared with pure ABT-199. 3. PEG-ABT-199 has little effects on normal cells. 4. PEG-ABT-199 can reduce treatment cost.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2020
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IF 5.162
Xin Huang,Junxiang Zhu,Li Wang,Huijuan Jing,Chaoyang Ma,Xingran Kou,Hongxin Wang
This study aimed to reveal the interaction and inhibitory mechanisms of tangeretin (TAN), nobiletin (NBT), and their acidic hydroxylated forms, 5-demethyltangeretin (5-DT) and 5-demethylnobiletin (5-DN) on porcine pancreatic lipase (PPL) using spectroscopic techniques and molecular dynamics (MD) simulation. PPL inhibition assay showed that the inhibitory activity of NBT (IC 50 value of 3.60 ± 0.19 μM) was superior to those of three polymethoxylated flavones (PMFs), indicating it may be related to the methoxy groups at the 3′-position in its molecular structure. Inhibition kinetic analyses demonstrated that the inhibition types of the 4 PMFs were consistent with the mixed inhibition model, which agreed well with the results from the ultraviolet-visible (UV–Vis) spectroscopy, Circular dichroism (CD), fluorescence spectroscopy, molecular docking , and MD simulation that PMFs could bind to the PPL catalytic site and non-catalytic site, affecting the normal spatial conformation of PPL and weakening its ability to decompose the substrate. All these findings suggest that PMFs are a kind of natural lipase inhibitors, and NBT has the potential as a lipase inhibition precursor because of its unique flavone skeleton structure.
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Molecular Catalysis
·
2021
·
IF 5.062
Chao Xu,Hongbo Suo,Yu Xue,Jing Qin,Hongyue Chen,Yi Hu
Four types of amino acid ionic liquids (AAILs) with chiral structure were used to modify Candida antarctica lipase B (CALB). The results showed that the catalytic activity at different temperatures and pH, thermostability, and tolerance to organic solvents of all modified lipases were improved. The composition and configuration of modifiers have great influence on the catalytic performance of the modified lipases. AAILs composed of l -proline exhibited better modification effect than those containing d -proline. The use of [N-AC- l -Pro] [Cl] led to the highest modification degree (47.92 %) of the lipase, which exhibited the highest hydrolytic activity (430.67 U/g), as well as enhanced thermal stability and tolerance to organic solvents. The structure of CALB was characterized by circular dichroism (CD) and fluorescence spectroscopy. It was found that the introduction of a modifier changes the secondary structure of CALB to a certain extent, and the microenvironment around the fluorescent group changed slightly. The structural stability of CALB modified with [N-AC- l -Pro] [Cl] and the mechanism of reaction were studied by molecular dynamics simulations. The molecular dynamics simulations of the native and modified CALB were performed for 20 ns at 300 and 328 K. The simulation results showed that the root mean square deviation (RMSD) and total energy of modified CALB were less than those of native CALB, indicating a more stable structure for the modified CALB. The root mean square fluctuation (RMSF) calculations showed that the rigidity of the modified CALB and the flexibility of the active center region were both enhanced. The solvent accessibility area (SASA) calculations showed that both hydrophilicity and hydrophobicity of the modified enzyme-protein were improved. The increase in radial distribution function (RDF) of water molecules confirmed that the number of water molecules around the active sites was also increased. Thus, the modified CALB has enhanced structural stability and higher hydrolytic activity towards the triglyceride substrates.
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JOURNAL OF CATALYSIS
·
2019
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IF 7.723
Meng Wang,Xiaoxu Wang,Bo Feng,Yuanhua Li,Xinchen Han,Zijie Lan,Huajun Gu,Huamin Sun,Meng Shi,Hexing Li,Hui Li
Acquisition of chiral amines is a very important item in scientific research. Chemoenzymatic catalyst combination of Pd nanoparticles supported on the external surface of the ethylenediamine-functionalized MIL-101 ( [email protected] ) with layered cross-linked enzyme aggregates of Candida antarctica lipase B (CALB-CLEAs) was established for the first time. This combination served as an ultra-efficient chemoenzymatic catalyst system for one-pot dynamic kinetic resolution (DKR) of rac -1-phenylethylamine leading to optically pure product (>99% ee value) with almost full conversion and excellent selectivity (>99%) without the aid of any additive. Significantly, aliphatic amines can be also efficiently converted to enantiomerically pure products, making this robust and heterogeneous combination one of the most powerful chemoenzymatic platforms for microwave-assisted one-pot DKR of amines available up to now.
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BIORESOURCE TECHNOLOGY
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2019
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IF 6.669
Konglong Feng,Zaocheng Huang,Bo Peng,Weijie Dai,Yunqi Li,Xiaoai Zhu,Yunjiao Chen,Xing Tong,Yaqi Lan,Yong Cao
Deacidification of high-acid soy sauce residue (SSR) oil is crucial to utilization of SSR oil. Aspergillus niger lipase (ANL) has been widely applied for such purpose while its immobilization still has large room for improvement. ANL was immobilized onto six different macroporous acrylic resins, accounting the effect of the different textural properties of resins on stability and their potential for application in enzymatic deacidification. The resin MARE with lower porosity, higher bulk density, and medium hydrophobicity, was chosen as the best carrier for the best thermostability and reusability. ANL-MARE is a promising catalyst than Novozym 40086, which not only exhibited higher deacidification activity and good thermostability, but also was continuously reused for 15 cycles and efficiently catalyzed from high-acid SSR oil into diacylglycerol-enriched oil. Therefore, immobilized ANL was a novel, low-cost and recyclable biocatalyst that could be used as a good alternative to higher-cost commercial lipases in industrial applications.
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Food Bioscience
·
2025
·
IF 5.9
Chunhao Qian,Yiren Zhang,Hui Li,Jun Jin,Hui Zhang,Qingzhe Jin,Xingguo Wang
Pinolenic acid (PLA) from pine nut oil was purified through a three-step process involving urea complexation (UC), lipase-catalyzed selective esterification, and rapid preparative reversed-phase liquid chromatography (RP-RPLC). UC was optimized with response surface methodology (RSM) under optimized conditions: fatty acid/urea (w/w) of 1:3.114, 95 % ethanol/urea (B, v/w) of 3.892:1, complexation time (h) of 12.303, and complexation temperature of −9.84 °C, achieving the optimal concentration of 62.19 ± 0.33 % and the yield of 46.55 ± 0.43 %. The one-step purified PLA was further purified through lipase-catalyzed selective esterification, resulting in purity and yield at 81.50 ± 0.32 % and 45.83 ± 0.2 % for the two-step purified PLA. The two-step purified PLA was then eluted from a C18 column to achieve the product with purity of 99.52 ± 0.08 % and yield of 71.93 ± 0.03 %. This study introduces an innovative PLA purification strategy for high-purity products suitable for nutritional and pharmaceutical uses.
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FOOD RESEARCH INTERNATIONAL
·
2024
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IF 7
Jun Dai,Zihan Liu,Lei Ma,Chunliu Yang,Ligai Bai,Dandan Han,Qi Song,Hongyuan Yan,Zhiqiang Wang
This study examined the suppressive effects of 16 selected plant-based foods on α-glucosidase and pancreatic lipase and their antioxidant properties. Among these, the bark of Cinnamomum cassia (Cinnamon, WLN-FM 15) showed the highest inhibitory activity against α-glucosidase and the highest antioxidant activity. Additionally, WLN-FM 15 showed promising results in the other tests. To further identify the bioactive constituents of WLN-FM 15, a multi-bioactivity-labeled molecular networking approach was used through a combination of GNPS-based molecular networking, DPPH-HPLC, and affinity-based ultrafiltration-HPLC. A total of nine procyanidins were identified as antioxidants and inhibitors of α-glucosidase and pancreatic lipase in WLN-FM 15. Subsequently, procyanidins A1, A2, B1, and C1 were isolated, and their efficacy was confirmed through functional assays. In summary, WLN-FM 15 has the potential to serve as a functional food ingredient with the procyanidins as its bioactive constituents. These results also suggest that the multi-bioactivity-labeled molecular networking approach is reliable for identifying bioactive constituents in plant-based foods.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Buqing Wang,Xiaoman Zhou,Yasen Wang,Yahui Gao,Hideki Nakanishi,Morihisa Fujita,Zijie Li
The acidic lipase from Rasamsonia emersonii named LIPR has great potential for biodiesel synthesis due to its strong methanol tolerance. Nonetheless, the limited thermostability of LIPR and low expression level in Escherichia coli remain major obstacles to its use in biodiesel synthesis. To enhance the thermostability, the mutant LIPR harboring mutations A126C-P238C for the formation of a new disulfide bond and amino acid substitution D214L was obtained through rational design. To our delight, the thermostability of LIPR mutant was greatly improved. Moreover, a comprehensive optimization strategy, such as employing the Mss signal peptide, co-expressing the molecular chaperone protein disulfide isomerase (PDI), knocking out the vacuolar sorting receptor gene VPS10-01 , and overexpressing the dihydroxyacetone synthase gene DAS2 , was adopted to obtain the combination-optimized mutant Pichia pastoris strain GS54. Furthermore, the biodiesel synthetic capability with the mutant GS54-LIPR was verified and the production yield was 52.2 % after 24 h in a shake flask. Subsequently, a continuous flow system was adopted to increase the biodiesel yield to 73.6 % within 3 h, demonstrating its efficacy in enhancing enzyme biocatalysis. The engineered GS54-LIPR mutant lipase is an efficient and reusable biocatalyst for the sustained production of biodiesel in a continuous flow reaction.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
·
IF 7.7
Jiachi Lei,Jun Zhang,Kuntai Li,Hongyu Qin,Hai Liu,Pei Li,Shucheng Liu,Jingliang Xu
Existing methods for chitin extraction usually produce substantial waste, which poses ecological hazards. Natural deep eutectic solvent (NADES) offers a promising one-step pretreatment alternative, replacing the resource-intensive demineralization (DM) and deproteinization (DP) process. Hence, in this study, the influence of various acidic NADES, on achieving a simplified one-step DM and DP in the chitin extraction process was investigated. The study yielded chitin with 87.73 % purity, and microstructural analysis showed that NADES pretreatment minimally affected chitin quality without deacetylation. In addition, chitin extracted using choline chloride-oxalic acid as a carrier displayed excellent performance in the immobilization of Geobacillus thermocatenulatus lipase 2 (GTL2) because of obvious Ca 2+ activation effect. This process contributed to enhancement of immobilized enzyme activity. The immobilized GTL2 showed excellent hydrolytic capabilities, with its highest activity reaching 547.80 ± 20.62 U/mg, significantly better than the five commercial lipases that exhibited <40 % of the enzyme activity. Furthermore, the hydrolytic capacity of immobilized GTL2 was notably high for 4-nitrophenyl butyrate, measuring 935.47 ± 51.60 U/mg. This study provided a constructive approach for the one-step pretreatment of shrimp shells with organic acid-based NADES to isolate and purify chitin and its potential application as an immobilized carrier to enhance enzyme activity.
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Food Bioscience
·
2026
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IF 6.2
Jiajuan Shang,Pengkai Xie,Xiaodong Xie,Yee-Ying Lee,Chin Ping Tan,Yong Wang,Zhen Zhang
Initial water additions, which serve as a critical variable for regulating the synthesis of diacylglycerol (DAG) from oleic acid esterification reaction, have not been sufficiently investigated regarding the molecular mechanism by which lipase is affected. This study elucidated that the initial water additions effectively modulated the conformational flexibility of the lipase at the interface, promoting the esterification process and enhancing the glycerol dioleate yield. Subsequently, a multi-scale research methodology was employed, gradually revealing the water-mediated catalytic mechanism. The results demonstrated that a 2 wt.% initial water addition significantly increased both esterification conversion rate and esterase activity. Moreover, secondary structure (α-helix increased) and tertiary structure (fluorescence intensity enhanced) indicated that an appropriate amount of water contributed to maintaining the conformational integrity of the enzyme molecules. Additionally, molecular dynamics (MD) simulations revealed that DAG synthesis was influenced by the initial water additions through the promotion of further opening of the lipase lid at the oil-water interface. This article systematically showed how water-regulated interfacial activation of lipase controlled the esterification process, thereby providing a theoretical foundation for the directed synthesis of structured acylglycerols.
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Biomass Conversion and Biorefinery
·
2022
·Vol. 14
·期 3
·3839-3851
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IF 4.05
Li Bowen,Sun Shangde,Chen Xiaowei,Zhang Hao
Polyglycerol fatty acid ester (PGFE) is one kind of non-ionic biosurfactant with excellent emulsifying property, physicochemical stability, and biodegradability. In this work, a low-cost liquid lipase Candida antarctica lipase B (CALB) was used as an eco-friendly biocatalyst to promote the esterification of polyglycerol-3 (PG3) and fatty acids (FA) from soybean oil waste soapstock for PGFE production. Effects of lipase load (0.1–0.6 wt%), reaction temperature (50–100 ℃), substrate ratio of PG3 to FA (1.0:1–2.0:1, mol/mol), and time (0.5–12 h) on the esterification were evaluated and optimized by central composite design. The high FA conversion (84.31%) was obtained under the optimal conditions: 0.54 wt% lipase load, 1.5:1 molar ratio of PG3 to FA, 84 °C, and 5.8 h. In PGFE products, the contents of mono-ester, di-ester, and tri-ester were 43.77%, 39.03%, and 17.20%, respectively. Additionally, PGFE showed excellent in vitro antioxidant efficiency and decreased 62% peroxide value in soybean oil system after 21 h of storage at 105 ℃. Graphical abstract
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CHEMICAL ENGINEERING JOURNAL
·
2021
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IF 13.273
Maohu Chen,Bo Qiu,Zhanlin Zhang,Shuang Xie,Yuan Liu,Tian Xia,Xiaohong Li
Major challenges remain in combat with the inevitable rise of intrinsic resistance to antibiotics and biofilm formation. Herein, we explore host–guest self-assembled micelles for light-triggered and stimuli-responsive release of antibiotics and β-lactamase inhibitors to combat biofilms derived from methicillin-resistant Staphylococcus aureus (MRSA). β-Cyclodextrin-capped phenylboronic acid-tetraphenylethylene (PBA-TPE) conjugates are coupled with ampicillin (Amp) via reactive oxygen species (ROS)-cleavable thioketal linkers to obtain cd-PTTA prodrug. Adamantane-capped poly(ethylene glycol)-poly(ε-caprolactone) (PECL-ad) amphiphilic copolymers are linked with cd-PTTA via host–guest complexation and simultaneously self-assembled into PECL@PTTA micelles. The digestion of poly(ε-caprolactone) segments by bacterial lipase destructs micelles and the aggregation-induced emission feature of cd-PTTA leads to ROS generation after light illumination. The produced ROS destroys biofilms and breaks thioketal linkers to release Amp antibiotics, while the pH-responsive removal of β-cyclodextrin activates the PBA β-lactamase inhibitors, affording synergistic actions on MRSA. The light illumination and intrinsic signals of acidic pH and lipase display interactive promotions of Amp release, micelle destabilization, and β-lactamase inhibition. Compared to those of cd-PTTA, the PECL@PTTA micelle treatment under light exposure shows sustained growth inhibition of planktonic MSRA, 2-fold higher elimination rate of biofilms, and 28-fold lower number of live MRSA embedded in biofilms. In an MRSA subcutaneous infection model, the micelle treatment with light exposure could eradicate bacteria and a complete wound closure was observed with normal re-epithelialization and skin morphology. Thus this strategy enables synchronous release of antibiotics and activation of β-lactamase inhibitors for photodynamic destruction of biofilms and restoration of the antibiotic activity to resistant bacteria embedded.
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危险品化学品经营许可证（带存储）