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Bioresources and Bioprocessing · 2025 ·Vol. 12 ·期 1 ·1-16 · IF 5.1

Enzymatic synthesis of phosphatidyl-EPA/DHA using Candida antarctica lipase B immobilized on mesoporous MIL-88 A

Li Yuhan,Wu Guowei,Liu Zeqing,Dai Lingmei,Liu Dehua,Du Wei

Mesoporous MIL-88A (Meso-MIL-88A) shows significant potential as an effective carrier for immobilizing large molecules such as lipases. This study investigates Meso-MIL-88A immobilized lipase for the catalysis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) incorporation into soybean phosphatidylcholine. Phosphatidyl-EPA and phosphatidyl-DHA are known for their superior health benefits and have garnered significant global attention. Firstly, we developed a novel and green water-washing strategy to synthesize Meso-MIL-88A, demonstrating its significant potential as an effective carrier for immobilizing large molecules such as lipases. Nitrogen adsorption/desorption and XPS analyses revealed that water as the eluent yielded larger average pore diameters and lower sulfur residue content compared to ethanol. This optimized Meso-MIL-88A carrier was used to immobilize Candida antarctica lipase B (CalB@Meso-MIL-88A), which was applied to the production of phosphatidyl-EPA and phosphatidyl-DHA. The immobilized CalB@Meso-MIL-88A exhibited exceptional catalytic efficiency, achieving an unprecedented sn -1 positional incorporation rate of 86.8% (44.2% EPA, 42.7% DHA) with 90% EPA/DHA-ethyl ester (EE) donors, while 97% DHA-EE resulted in a record-high 90.1% DHA incorporation at the sn -1 position. Kinetic studies and molecular docking simulations indicated a higher substrate affinity for DHA-EE, attributed to enhanced transfer efficiency of EPA/DHA-EE in organic solvent system. This study presents the first demonstration of the potential of Meso-MIL-88A for industrial lipase immobilization via this optimized route, offering an eco-friendly and highly efficient catalytic application for nutraceutical synthesis. Graphical abstract

CAS / MDL: 70955-01-0
✓ 已验证 产品关联 DOI PubMed 高影响因子
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FOOD CHEMISTRY · 2026 · IF 10.4

Synergistic stabilization of DHA algal oil via amyloid fibril-anchored Haematococcus pluvialis protein/PVA core-shell nanofibers

Yangyang Guo,Xingru Yan,Yujuan Zhu,Bin Li,Yinxu Zhang,Wentao Su

Bio-based nanofibers use H. pluvialis protein and amyloid fibrils as emulsifiers. • Conductivity-viscosity balance induced hollow core-shell structures at 30% oil load. • Molecular-level hydrogen bonding between the lipid core and polymer shell underpins enhanced thermal stability. • Synergistic physical and chemical protection reduced DHA oxidation products effectively. The application of docosahexaenoic acid (DHA) in functional foods is severely restricted by its susceptibility to oxidative degradation. To overcome this, a novel bioactive delivery vehicle was engineered using Haematococcus pluvialis protein (HPP) and glycosylated soy protein amyloid fibrils (AFS) via emulsion electrospinning. This study investigated the physicochemical properties and oxidation stability of core-shell nanofibers fabricated from spinning solution with varying oil contents (0–4%). The spinning solutions exhibited shear-thinning non-Newtonian fluid behavior. The incorporation of oil increased the hydrophobicity of the nanofiber films, with the water contact angle rising from 46.8° (0% oil) to 86.4° (40% oil) due to physical cross-linking. Transmission electron microscopy (TEM) revealed that the 30% oil content group (E 3 ) formed a distinct, uniform hollow core-shell structure, driven by the optimal balance between conductivity and viscosity. Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA) suggested the presence of hydrogen bonding interactions between the lipid core and the polymer shell significantly enhanced thermal stability. Crucially, accelerated oxidation tests demonstrated a synergistic protective mechanism combining the physical barrier of the nanofiber shell with the chemical antioxidant activity of HPP. After 7 days, the E 3 nanofibers exhibited the lowest accumulation of primary and secondary oxidation products (POV: 238.66 ± 2.72 mmol/kg oil; TBARS: 49.26 ± 3.91 mg/kg oil), representing a 63.6% reduction in POV and 33.3% reduction in TBARs compared to the unencapsulated control (POV: 656.07 ± 2.14 mmol/kg oil; TBARS: 73.88 ± 0.27 mg/kg oil). This study supports the potential use of amyloid-fibril-stabilized natural interfaces for the efficient preservation of functional lipids, highlighting the superior synergistic protective effect of the HPP-AFS composite system. A PVA nanofiber membrane system was constructed by electrospinning to load the aqueous solution of proteins from Haematococcus pluvialis , algae oil, and chitosan soybean protein isolate, forming an AFS. This achieved the goal of protecting food from various forms of oxidation, including lipid oxidation, in practical applications. Download: Download high-res image (136KB) Download: Download full-size image

CAS / MDL: 9012-76-4
✓ 已验证 产品关联 DOI PubMed 高影响因子
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES · 2026 · IF 8.7

Sodium alginate-based composite gel beads encapsulation of algal oil emulsion: enhancing DHA bioaccessibility and reducing fishy odor

Ying Xu,Chengyu Zhang,Jialin Wang,Ruijie Liu,Ming Chang,Xingguo Wang

Algal oil, an eco-friendly and DHA-rich substance, is limited in market applications due to its fishy odor and low DHA bioaccessibility. This study investigated the effects of combining sodium alginate (SA) with carrageenan (C), Arabic gum (AG), or xanthan gum (XG) on the hardness, digestibility, and flavor controlling of gel beads encapsulating algal oil emulsion. The SA/other polysaccharides ratio of 0.8/0.2 was selected based on comprehensive evaluation of viscosity, hardness, and morphological uniformity. Under this ratio, SA-C, SA-AG and SA-XG exhibited distinct digestibility during in vitro digestion. SA-C gel beads showed the highest free fatty acids (FFA) release rate, with DHA bioaccessibility of 86.85%. Scanning electron microscopy (SEM), Fourier transform infrared (FTIR), and X-ray diffraction (XRD) analyses revealed that SA-C gel beads possessed a highly amorphous structure and relatively weak hydrogen bonds, consistent with the larger pore sizes after digestion and lower resistance to oil release observed compared to SA-AG and SA-XG gel beads. A 60-day storage experiment further demonstrated that gel bead encapsulation significantly ( P  < 0.05) reduced malodorous substances such as (E, E)-2,4-heptadienal by 76.26%, effectively alleviating the fishy odor.

✓ 已验证 DOI PubMed 高影响因子
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CHEMICAL ENGINEERING JOURNAL · 2025 · IF 13.2

DHA sustains frozen-cell-induced efferocytosis by mitigating endoplasmic reticulum stress to promote inflammation resolution and bone repair

Boya Zhang,Hanze Du,Lei Huang,Lijun Liu,Jing Cui,Linlin Wen,Junguang Liu,Wenhao Zhai,Rongrong Ye,Yuhuan Li,Kexuan Liu,Wangni Xie,Xue Zhang,Xinchen Liu,Huan Wang,Ying Xue,Shi Chen,Hui Pan,Daowei Li,Hongchen Sun

Osteoporosis, a prevalent age-related condition, is associated with chronic inflammation and impaired bone repair, exacerbated by defective efferocytosis—the clearance of apoptotic cells (ACs) by macrophages. Therefore, enhancing the efferocytosis by apoptotic cell injection to reduce inflammation is a potential strategy for the treatment of osteoporosis. However, phagocytes experience metabolic stress such as endoplasmic reticulum (ER) stress during continuous ACs uptake, reflecting requirement for safe and effective solutions. To address this, we develop a novel therapy utilizing liquid nitrogen-frozen cells loaded with docosahexaenoic acid (DHA, FrozCell-DHA). In an ovariectomy (OVX)-induced mouse model of postmenopausal osteoporosis, FrozCell-DHA significantly enhance macrophage efferocytosis, alleviate inflammation, and reduce bone loss. Mechanistically, DHA reduces ER stress by activating the PPARγ pathway, driving continuous efferocytosis. These findings highlight FrozCell-DHA as a safe therapeutic approach, capable of restoring efferocytosis and promoting bone regeneration. Our study indicates the potential of FrozCell-DHA as a transformative therapy for osteoporosis, providing a promising proposal for bone repair and healthy aging.

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Comparative Biochemistry and Physiology D-Genomics & Proteomics · 2025 · IF 2.4

Transcriptional responses to DHA-induced lipid droplet accumulation in primary adherent mantle cells of Sinonovacula constricta (Lamarck, 1818)

Bowen Yan,Zhaoshou Ran,Qiang Zhou,Jiaxin Zhu,Fei Kong,Jilin Xu

Docosahexaenoic acid (DHA), an essential omega-3 long-chain polyunsaturated fatty acid, is crucial for the development of marine mollusks. Despite its importance, the molecular mechanisms of DHA action in these organisms are poorly understood, primarily due to the lack of reliable in vitro models. This study utilizes the razor clam Sinonovacula constricta as a model organism, establishing a primary adherent cell culture from various tissues, with mantle tissue identified as the optimal source for its rapid migration and low contamination risk. Cells incubated with varying concentrations of DHA (0–400 μM) for 6 h exhibited a concentration-dependent accumulation of lipid droplets (LDs), highlighting the model's suitability for investigating lipid metabolism. Transcriptomic analysis of cells treated with 50 μM DHA identified 848 differentially expressed genes (DEGs), with 747 upregulated and 101 downregulated, indicating the complex effects of DHA. The top 20 significantly upregulated and downregulated DEGs revealed significant involvement in cell signaling transduction, extracellular matrix organization, and substance transport and metabolism. Particularly, lipid metabolism genes, including perilipin 2 and abhydrolase domain containing 2, as well as pathways such as the PPAR signaling pathway and sphingolipid metabolism, were significantly altered, suggesting a reprograming of fatty acid metabolism contributing to LD accumulation. Additionally, pathways related to immune response were notably affected, potentially enhancing cellular health. Collectively, this study provides the first comprehensive insights into the molecular mechanisms underlying DHA-induced LD accumulation in a marine mollusk model at the cellular level, laying a foundation for developing precise nutritional strategies involving DHA in S. constricta aquaculture.

CAS / MDL: 71939-50-9
✓ 已验证 产品关联 DOI PubMed 高影响因子
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Asian Journal of Pharmaceutical Sciences · 2022 · IF 9.273

pH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma

Yanjuan Huang,Hualu Lai,Jingwen Jiang,Xiaoyu Xu,Zishan Zeng,Lingling Ren,Qiuxing Liu,Meixu Chen,Tao Zhang,Xin Ding,Chunshun Zhao,Shengmiao Cui

Photodynamic therapy (PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation, but the strong hydrophobicity and poor tumor selectivity of photosensitizers, as well as the oxygen-consuming properties of PDT, leading to unsatisfactory therapeutic outcomes. Herein, a tumor acidic microenvironment activatable dissolving microneedle (DHA@HPFe-MN) was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification. The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin (PpIX)-ADH-hyaluronic acid (HA) conjugate HA-ADH-PpIX with “iron reservoir” PA-Fe 3+ complex in the needle tip via acylhydrazone bond formation, and dihydroartemisinin (DHA) was concurrently loaded in the hydrogel network. HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect. DHA@HPFe-MN with sharp needle tip, efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites, where the acidic pH triggered the degradation of microneedles, enabling Fe-activated and DHA-mediated oxidation treatment, as evidenced by abundant reactive oxygen species (ROS) generation. Moreover, under light irradiation, a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation. Importantly, the Fe-catalyzed ROS production of DHA was oxygen-independent, which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells. This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.

研究领域: 肿瘤学 · 药剂学 · 生物医学工程
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POULTRY SCIENCE · 2024 · IF 3.8

Effects of sodium dehydroacetate on broiler chicken bones

Meng Zhang,Pengfei Du,Jin Wan,Yimeng Chen,Xin Chen,Yumei Zhang

ABSTRACT Sodium dehydroacetate ( DHA-Na ) is a fungicidal preservative widely used in food and animal feed. DHA-Na can induce coagulation disorders in rats and poultry by inhibiting carboxylation of vitamin K-dependent proteins; it can also impair bone development in zebrafish. However, the effects of DHA-Na on broiler chicken bones remain unknown. Here, we assessed whether DHA-Na impairs bone development in broiler chickens. We administered Suji yellow chickens with 200 to 800 mg/kg DHA-Na, 2 mg/kg vitamin K, or both for 2 mo. Bone metabolite–related serum indicators, tissue micromorphology, and relevant protein expression were monitored during the treatment period. We also assessed primary chicken osteoblast activity, differentiation, and bone metabolite–related proteins after treatment with DHA-Na, vitamin K, or both. The results demonstrated that DHA-Na reduced bone index values and serum and bone osteoblast differentiation marker levels but blocked bone vitamin K cycle. DHA-Na also increased serum osteoclast differentiation marker levels, as well as the bone ratio of receptor activator of nuclear factor kappa-Β ligand to osteoprotegerin ratio. Moreover, DHA-Na reduced bone trabecular number, thickness, and area and increased trabecular separation considerably. In general, compared with the control group, the DHA-Na group demonstrated impairments in osteoblast activity and differentiation, as well as in the vitamin K cycle. By contrast, vitamin K supplementation led to considerable attenuation of the DHA-Na-induced decrease in osteogenic marker levels, along with a considerable increase in serum bone absorption marker levels and restoration of DHA-Na-induced bone microstructure damage. Vitamin K also attenuated DHA-Na-induced impairment in osteoclasts. In conclusion, the results indicated that in broiler chickens, DHA-Na supplementation can damage bones by inhibiting osteoblast function and increasing osteoclast activity; this damage can be prevented through vitamin K supplementation.

CAS / MDL: 84-80-0
研究领域: 动物科学 · 营养学 · 兽医学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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Antioxidants · 2026 ·Vol. 15 ·期 10 ·1303 · IF 8.2

Unusual Switch of Cell Death Mode by Docosahexaenoic Acid (DHA) via Enhancing Endoplasmic Reticulum Peroxidation Induced by Lipophilic Iron Complex

Bo Shao,Zhi-Guo Sheng,Huan Li,Shun-Li Jiang,Gui-Zhi Han,Chen-Jun Shao,Ben-Zhan Zhu

Although ferroptosis is a programmed iron-dependent cell death, many lipophilic iron complexes fail to induce ferroptosis through iron overload. The underlying mechanisms remain unclear. Here we found that a typical lipophilic iron complex 8-hydroxyquinoline (8HQ)-Fe(III) (1: 1, 10 μM), can efficiently induce cellular iron overload, lipid peroxidation, and finally cytotoxicity. However, the resulting cell death mode was not typical ferroptosis: it was not inhibited by the classic ferroptosis inhibitors and exhibited mitochondrial swelling rather than shrinkage. Mechanistic studies revealed that 8HQ-Fe(III) triggered both endoplasmic reticulum (ER) peroxidation and mitochondrial damage. The ER-targeted antioxidant (stobadine) inhibited lipid peroxidation but did not suppress cell death. In contrast, mitochondrial protectants effectively blocked 8HQ-Fe-induced cell death by mitigating mitochondrial damage. This indicates that mitochondrial damage plays an overwhelmingly dominant role in driving cell death. Strikingly, pre-incubation with docosahexaenoic acid (DHA) can strongly enrich the ER membrane and increase its peroxidation. As expected, both stobadine and the well-known ferroptosis inhibitor (Fer-1) suppressed 8HQ-Fe(III)-induced cell death via inhibition of ER peroxidation, while mitochondrial protectants failed to prevent cell death. Mitochondrial shrinkage was also observed. Thus, making ER peroxidation the dominant driver of cell death by DHA pretreatment will switch the cell death modality from non-ferroptosis to classical ferroptosis. This study revealed that the balance between ER peroxidation and mitochondrial damage dictated the type of iron-dependent cell death, and established DHA-primed 8HQ-Fe(III) as a novel, tunable strategy for efficiently inducing ferroptosis by deliberately shifting subcellular peroxidation dominance.

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INTERNATIONAL JOURNAL OF FOOD PROPERTIES · 2018 · IF 1.845

Chemical composition and thermal properties of Tilapia oil extracted by different methods

Xue Li,Jun Cao,Xinpeng Bai,Fangfang Zhang

Fish oil is beneficial to health and its quality is significantly impacted by the extraction method. To determine the effect of various methods used to extract the oil on its chemical composition and thermal properties, tilapia oil extracted by dilute alkali hydrolysis, enzymatic hydrolysis, and microwave-assisted methods were investigated in this study. Nutrient analyses showed that freeze-dried tilapia contained fat (36.69 g/100 g freeze-dried tilapia), protein (49.95 g/100 g freeze-dried tilapia), ash (12.04 g/100 g freeze-dried tilapia) and moisture (1.21 g/100 g freeze-dried tilapia). Chemical analysis showed that the fish oil extracted by dilute alkali hydrolysis had the lowest acid value (AV) and peroxide value (POV) (AV: 0.77 mg KOH/g oil and POV: 3.76 mmol/kg oil) compared to the oil extracted using the other methods. The main fatty acid components were palmitic acid (22.78–23.16%), oleic acid (25.73–26.19%), and linoleic acid (15.69–15.98%). Furthermore, the oil extracted by dilute alkali hydrolysis showed significantly higher content of DHA+ EPA (2.30%). The thermal behaviors indicated that the aforementioned oils had significantly different crystal structures. The main endothermic peaks of fish oil extracted by dilute alkali hydrolysis, enzymatic hydrolysis and microwave-assisted methods were located at −2.03℃, −3.20℃ and −4.37℃, respectively. However, infrared spectroscopic analyses indicated them had the same characteristic functional groups. Consequently, different extraction methods significantly affect the oil’s physical and chemical properties without affecting spectral characteristics. Furthermore, these results advocated the use of alkali hydrolysis for fish oil extraction.

CAS / MDL: 110-54-3 67-56-1
研究领域: 食品科学 · 化学 · 生物化学
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LWT-FOOD SCIENCE AND TECHNOLOGY · 2019 · IF 3.714

Purification and characterization of an extracellular lipase from Trichosporon sp. and its application in enrichment of omega-3 polyunsaturated fatty acids

Xi Cao,Linmeng Liao,Fengqin Feng

Lipase catalysis has become the most promising technique for enrichment of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) due to its mild and green conditions. In this study, Trichosporon sp. F1-2 was newly isolated from oil-contaminated sludge, and its extracellular lipase was purified using ammonium sulfate precipitation and DEAE-Sepharose chromatography. The molecular weight of the lipase was estimated to be 32.6 kDa. The optimal temperature and pH for lipase activity were 50 °C and 8.0, respectively, and the optimal storage conditions were found to be temperatures below 45 °C and pH 7.0–9.0. The lipase did not require metal ions as cofactors and was significantly inhibited by Zn 2+ . It was stable in various organic solvents with different log P values, and n-hexane, toluene, dichloromethane, diethyl ether and glycerol even enhanced its activity. It had sn -1,3 regioselectivity and the highest activity towards a medium-chain fatty acid (C8) ester. This study demonstrated the lipase has good potential as a catalyst in enrichment of EPA and DHA in fish oil. The content of EPA and DHA reached 22.9 and 25.4 mol%, respectively, using 100 U of the lipase within 24 h, and the enrichment efficiency of DHA was higher than that of EPA.

CAS / MDL: 9005-64-5 9005-65-6
研究领域: 生物技术 · 酶学 · 食品科学
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JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION · 2017 · IF 2.107

Microalgal Oil from Schizochytrium sp. Prevents HFD-Induced Abdominal Fat Accumulation in Mice

Jinhui Yu,Yong Ma,Jie Sun,Liyuan Ran,Youwei Li,Ning Wang,Tao Yu,Wenting Gao,Wenbin Jia,Rujiao Jiang,Meihua Guo,Yuping Bi,Yingjie Wu

Objective: Dietary n-3 polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acids (EPA) and docosahexaenoic acid (DHA), are proved to be effective in obesity reduction. Microalgal oil (MO) is an important alternative source of n-3 PUFAs that effectively alleviates obesity. The aim of the present study was to explore the anti-obesity effects of microalgal oil from Schizochytrium sp. (SMO) and to compare the effects of 2 SMOs (SMO1 and SMO2) with different levels of purity of n-3 PUFAs on high fat diet (HFD)-induced obesity in male C57BL/6J mice.Methods: Mice were randomly divided into 5 groups: (1) regular chow (RC); (2) HFD; (3) HFD + fish oil (FO); (4) HFD + SMO1; and (5) HFD + SMO2. Body weight and food intake were weekly monitored. After 16 weeks of treatment, a glucose tolerance test (GTT) and an insulin tolerance test (ITT) were performed. Serum lipid profile, morphological changes in the liver and epididymal white adipose tissue (eWAT), and the mRNA expression of lipid metabolism–related genes were also examined.Results: SMO treatment significantly decreased HFD-induced abdominal fat accumulation, lowered the levels of triglycerides, cholesterol, and low-density lipoprotein, as did the positive control treated with FO. Morphological examination revealed a remarkable reduction in lipid droplet formation in the liver tissue and the particle size of eWAT. An alleviation of inflammation infiltration in eWAT caused by a high-fat diet was also observed. Real-time reverse transcription–polymerase chain reaction analysis examination confirmed that microalgal oil inhibited the gene expression of fatty acid synthase, sterol responsive element-binding protein-1c, and acetyl-CoA carboxylase but promoted that of hormone-sensitive lipase and lipoprotein lipase, carnitine palmitoyltransferase-1, and uncoupling proteins in the liver and eWAT. Moreover, similar anti-obesity effects were obtained with the same dosage but different purity of n-3 PUFAs.Conclusions: As an alternative n-3 PUFAs resource, dietary intake of SMO might be beneficial to prevent HFD-induced abdominal fat accumulation.

CAS / MDL: 8001-30-7
研究领域: 营养学 · 肥胖研究 · 分子生物学 · 脂质代谢
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BIOPROCESS AND BIOSYSTEMS ENGINEERING · 2025 · IF 3.6

Synergistic enhancement of lipase catalysis via co-immobilization and chitosan-assisted crosslinking: a streamlined approach for EPA/DHA enrichment in fish oil

Yue Guoliang,Cai Zhenling,Meng Chun,Mao Yuhong

Efficient immobilized lipase systems are essential for industrial lipid modification, yet the combined effects of enzyme loading, support properties, and post-immobilization stabilization on catalytic performance remain underexplored. In this study, Thermomyces lanuginosus lipase (TLL), Candida antarctica lipase B (CalB), and their mixture (T + C) were respectively immobilized on two structurally distinct commercial supports (A & B)—differing in hydrophobicity, surface area, and pore size—at varied loading densities. Adsorption followed monolayer kinetics, with support B enabling higher enzyme up to 44.1 mg/g wet for T + C. Co-immobilized T + C systems exhibited enhanced catalytic activity compared to individual lipases, particularly in esterification and transesterification, benefiting from the complementary substrate specificities of TLL and CalB. Chemical crosslinking with chitosan and glutaraldehyde significantly reduced lipase desorption and improved thermal stability. The optimized system Cr-B-T + C-M (crosslinked support B-TLL + CalB with medium enzyme loading) efficiently catalyzed fish oil transesterification at 60 °C for 18 h, increasing the EPA + DHA content from 30.5% to 54.8%. All immobilized lipases retained over 80% of their initial catalytic activity after three reuses (60 °C and 18 h). These results highlight the synergistic benefits of co-immobilization and crosslinking on tailored supports, offering a versatile strategy for developing stable and efficient lipase biocatalysts for high-value lipid processing.

✓ 已验证 产品关联 DOI PubMed 高影响因子
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