BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Zhiwen Qi,Guliang Yang,Tao Deng,Jianmin Wang,Hao Zhou,Sergey A. Popov,Elvira E. Shults,Chengzhang Wang
Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A - 1F , in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B , connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC 50 value of 0.23 ~ 0.39 μM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.
研究领域:
药理学
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肿瘤学
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化学生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2015
·
IF 3.35
Yu Gao,Zhihong Li,Xiaodong Xie,Chaoqun Wang,Jiali You,Fan Mo,Biyu Jin,Jianzhong Chen,Jingwei Shao,Haijun Chen,Lee Jia
The anticancer efficacy of ursolic acid (UA) was limited by poor water solubility, non-specific tumor distribution, and low bioavailability. To overcome this problem, polyamidoamine (PAMAM) conjugated with UA and folic acid (FA) as novel dendrimeric prodrugs were designed and successfully synthesized by a concise one-pot synthetic approach. Both FA and UA were covalently conjugated to the surface of PAMAM through acid-labile ester bonds and the covalently linked UA could be hydrolysed either in acidic (pH 5.4) or in neutral (pH 7.4) PBS solution. The cellular uptake study indicated that the presence of FA enhanced uptake of the dendrimeric prodrugs in folate receptor (FR) over-expressing Hela cells. The enhanced cellular uptake could be due to the electrostatic absorptive endocytosis and FR-mediated endocytosis. In contrast, for HepG2 cells, a FR-negative cell line, FA conjugation on the surface of the dendrimer showed no effect on the cellular uptake. In MTT assay and cell cycle analysis, FA-modified dendrimeric prodrugs showed significantly enhanced toxicity than non-FA-modified ones in Hela cells. These results suggested that FA-modified dendrimeric UA prodrugs have the potential for targeted delivery of UA into cancer cells to improve its anti-tumor efficacy.
研究领域:
药理学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2023
·
IF 8.8
Ruiling Liu,Liping Zhang,Shangyue Xiao,Hangjun Chen,Yanchao Han,Ben Niu,Weijie Wu,Haiyan Gao
Cuticular wax has been reported to play an essential role in resisting pathogens in various fruits. This study investigated the antifungal ability of the components in blueberry cuticular wax. We showed that the cuticular wax of blueberry inhibited the growth of Botrytis cinerea and ursolic acid (UA) was the key antifungal compound. UA inhibited B. cinerea growth in vitro and in vivo . Furthermore, UA increased extracellular conductivity and cellular leakage in B. cinerea , deformed the mycelial morphology, and destroyed cell ultrastructure. We also demonstrated that UA stimulated the accumulation of reactive oxygen species (ROS) and inactivated ROS scavenging enzymes. These results indicate that UA may exert antifungal effects against B. cinerea by disrupting cell membrane integrity. Thus, UA has significant potential as an agent for the control of gray mold in blueberry.
研究领域:
植物病理学
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食品科学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
·
IF 5.3
Zhiwen Qi,Pujun Xie,Zhihong Wang,Hao Zhou,Ran Tao,Sergey A. Popov,Guliang Yang,Elvira E. Shults,Chengzhang Wang
Excessive oxidation can lead to inflammation and affect health. Studies have shown that ursolic acid (UA) and gallic acid are widely employed in medicine and cosmetics owing to their obvious antioxidant and anti-inflammatory properties. In this study, a series of 16 novel UA hybrids tethered via 1,2,3-triazole to the modified gallate moieties were synthesized via CuAAC 1,3-cycloaddition reactions. In vitro , all derivatives were proved to be effective in antioxidation and anti-inflammation activities. Interestingly, compound 20 significantly inhibited the expression of pro-inflammatory cytokines including mRNA of inducible nitric oxide synthase (iNOS) ( p < 0.05) and cyclooxygenase-2 (COX-2) ( p < 0.01) in lipopolysaccharide (LPS)-induced RAW264.7 cells in a dose-dependent manner. The inhibitory effect of compound 20 on pro-inflammatory cytokines was closely associated with suppression of the LPS-activated PI 3 K/Akt signal pathway. Compound 20 significantly alleviated inflammation in the gastrointestinal tract of zebrafish in vivo . In addition, compound 20 showed good biosafety in cytotoxicity evaluation. This study provides a novel reference for the development of treatments for health problems related to anti-oxidation and anti-inflammation properties.
研究领域:
药理学
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有机化学
·
炎症研究
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产品关联
DOI
高影响因子
Food Packaging and Shelf Life
·
2025
·
IF 10.6
Fengyan Liang,Jinwen Geng,Ziming Yang,Wanqi Cen,Miaoyu Zhao,Xunting Huang,Changbin Wei,Puwang Li,Kaidong Liu
Amphiphilic chitosan (DA-CS-AG) was synthesized and incorporated with ursolic acid (UA) to develop an active coating film. Characterization techniques confirmed the preparation of DA-CS-AG, and UA was successfully entrapped in the active coating films. With the weight ratios of UA to DA-CS-AG increasing from 1:20, 2:20–4:20, the coating films exhibited increased thickness, improved water resistance, higher tensile strength, and enhanced antioxidant and antibacterial properties. As the UA/DA-CS-AG weight ratio increased from 1:20–2:20, the films ’ UV-shielding capability, water vapor barrier properties, and elastic properties increased. However, these properties deteriorated when the weight ratio increased to 4:20. Preservation experiments of papaya fruits demonstrated that UA/DA-CS-AG-2 coating films delayed the ripening of papaya at 25 º C for 16 days based on appearance, color changes, quality indexes, and sensory evaluation. In conclusion, these active coating films can serve as packaging materials for fruits and vegetables.
研究领域:
食品科学
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材料科学
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植物学
✓ 已验证
产品关联
DOI
高影响因子
Parasites & Vectors
·
2018
·Vol. 11
·期 1
·1-9
·
IF 3.163
Yin Jianhai,Liu Congshan,Shen Yujuan,Zhang Haobing,Cao Jianping
Background Cystic echinococcosis is a global public health problem; however, the drugs (albendazole and mebendazole) currently recommended by WHO for its treatment, have limited efficacy. Therefore, novel drugs are required to provide more choices for the treatment of this disease. Methods The anthelmintic effects of ursolic acid (UA) were tested on Echinococcus granulosus protoscoleces, germinal cells and metacestodes in vitro. The in vivo efficacy of UA was investigated in mice following secondary infection with E. granulosus . Furthermore, the corresponding ultrastructural damage induced by UA was evaluated by electron microscopy. Results In vitro, 45.95 ± 5.30% of protoscoleces were killed by UA at 40 μg/ml, while the growth of more than 90% of germinal cells was inhibited by UA at 10 to 40 μg/ml. The same effect was observed in metacestodes 7 days after treatment with UA at 10, 20 and 40 μg/ml, and more than 50% of metacestodes showed loss of integrity at the end of the experiment. In vivo, metacestode weight was significantly reduced following oral administration of UA at 200 and 100 mg/kg (39.5 and 38.3%, respectively). Additionally, ultrastructural damage, such as alternations in germinal cell morphology and formation of vacuoles and lipid granules were observed in parasites treated with UA in vitro, while detachment of the germinal layer from the laminated layer was also seen in metacestodes in vivo. Conclusions UA was demonstrated to exert parasiticidal activity against E. granulosus in vitro and in vivo, thus implicating UA as a potential anti-echinococcosis agent.
研究领域:
寄生虫学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2019
·Vol. 100
·期 3
·986-994
·
IF 2.422
Jing Wang,Jiang Zhao,Yong Yan,Dong Liu,Chengtao Wang,Hao Wang
BACKGROUND Controlling the blood glucose level is an effective method to reduce type 2 diabetes and prevent diabetes-related complications. Ursolic acid is a plant extract that can reduce postprandial hyperglycemia effectively. This study aimed to explore the inhibitory effect and interaction mechanism of ursolic acid against α-amylase and α-glucosidase. RESULTS In this study, the effect of ursolic acid on glycosidase was studied in vitro , in vivo , and in silico . The half-maximal inhibitory concentration (IC 50 ) of ursolic acid on α-amylase and α-glucosidase was 0.482 ± 0.12 mg mL −1 and 0.213 ± 0.042 mg mL −1 , respectively. The results of enzymatic kinetics showed that ursolic acid inhibited α-amylase and α-glucosidase activity in a non-competitive manner. The fluorescence spectrum showed that the combination of ursolic acid and glycosidase caused the intrinsic fluorescence quenching of glycosidase. The observation of starch granules revealed that the activity of α-amylase was inhibited and the hydrolysis of starch granules was prevented in the presence of ursolic acid. Molecular docking results showed that ursolic acid bound to the inactive site of α-amylase and α-glucosidase through the formation of ursolic acid–glucosidase complex. Ursolic acid interacted with α-amylase and α-glucosidase mainly through hydrogen bonding. The postprandial hypoglycemic effect of ursolic acid in C57BL/6J mice showed that the high concentration of ursolic acid could quickly reduce postprandial blood glucose level. CONCLUSION Ursolic acid can be considered as a natural ingredient in functional foods to control postprandial blood glucose levels and prevent diabetes by delaying the digestion of starch in foods. © 2019 Society of Chemical Industry
研究领域:
药理学
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生物化学
·
计算生物学
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产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Ao Sun,Yu-fei Li,Yang Miao,Hong-xia Wang,Lin-lin Zhang
The objective of this study was to investigate the potential targets and mechanisms of UA in the treatment of PD. The efficacy of UA in PD was assessed through network pharmacology, molecular docking, and experimental methods. Common target protein-protein interaction (PPI) networks were constructed and visualized using Cytoscape. As a result, 9 key genes, namely CASP3, IL6, IL1B, PTGS2, CREB1, TNF, MAPK3, JUN, and CASP8, were selected. Molecular docking simulations were performed using Discovery Studio 2019 to validate the correlation between UA and the core targets. The results demonstrated a favorable binding affinity between UA and CASP8, IL1B, CASP3, TNF, MAPK3 and IL6. In vivo studies showed UA ameliorated motor dysfunction, and UA can significantly increase the protein expression of tyrosine hydroxylase (TH) in PD mice model. In addition, in vitro experiments confirmed that UA effectively reduced the protein expression of CASP8, CASP3 and MAPK3 in PD cell models and suppressed the gene expression of TNF-α, IL-6, and IL-1β. These findings indicate that the therapeutic effects of UA on PD could be due to its influence on various targets within both the apoptosis and neuroinflammatory signaling pathways. Consequently, this study provides a methodological and theoretical foundation for further elucidating the pharmacological mechanism of UA.
研究领域:
药理学
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神经科学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
·
IF 3.671
Huafang Ding,Xing Hu,Ximing Xu,Guowen Zhang,Deming Gong
Glycemic control which can be efficaciously regulated by inhibiting α-glucosidase activity is an effective therapy for diabetes mellitus. This work is to investigate the kinetics and inhibition mechanism of oleanolic acid and ursolic acid on α-glucosidase. Oleanolic acid and ursolic acid exhibited potent inhibitory activities with IC 50 values of (6.35 ± 0.02) × 10 −6 and (1.69 ± 0.03) × 10 −5 mol L −1 respectively in a reversible and non-competitive manner. Both of them binding to α-glucosidase induced the conformational change and intrinsic fluorescence quenching of α-glucosidase. The binding constants of oleanolic acid and ursolic acid with α-glucosidase at 298 K were (2.04 ± 0.02) × 10 3 and (1.87 ± 0.02) × 10 3 L mol −1 , respectively. Docking results showed that oleanolic acid and ursolic acid bound in different allosteric sites of cavity 2 and cavity 4 on α-glucosidase, respectively, which triggered allosteric regulation to perturb conformational dynamics of α-glucosidase, eventually leading to a decrease of catalytic activity of the enzyme. The substrate was not catalyzed by α-glucosidase to generate further products due to formation of a nonreactive ternary complex of oleanolic acid– or ursolic acid–α-glucosidase–substrate. The combination of oleanolic acid and ursolic acid displayed a significant synergistic inhibition on α-glucosidase.
研究领域:
生物化学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2023
·
IF 4.1
Ying Wang,Xiaodan Wu,Guansong Shao,Tao Wang,Zihan Wang,Bingyang Qin,Jingru Zhao,Zhiguo Liu,Yujie Fu
In this article, thermosensitive molecularly imprinted polymer and composite aerogel were combined for the first time to create an intelligent temperature-responsive aerogel reactor to effectively enrich ursolic acid (UA). Because aerogel carrier had a higher specific surface area and higher porosity compared to other carriers, the ursolic acid molecularly imprinted intelligent temperature responsive aerogel reactor (ITR&AR(G570)&UA-MIP) demonstrated a higher adsorption capacity for UA. More notably, ITR&AR(G570)&UA-MIP have the extraordinary capacity to spontaneously adsorb-desorb target molecule UA by regulating the reaction temperature. The ratio of the target molecule UA to the functional monomer and crosslinker in the grafting process and external influences had a major impact on how ITR&AR(G570)&UA-MIP were prepared overall. When the molar ratio of UA to 4-VP was 1:8, the weight ratio between ITR&AR(G570)&UA-MIP and EGDMA/DVB was 1:2:10, the reaction temperature was 60 °C, and the ambient pH = 6, the material showed the best adsorption capacity, reaching a peak of about 70 mg g −1 . After researching the appropriate synthesis conditions, ITR&AR(G570)&UA-MIP were applied to lingonberry (Vaccinium Vitis-Idaea L .) berry extracts in this work. The outcomes show that this technique provides a new, intelligent, temperature-controlled adsorption material for the solid-phase extraction of triterpenoid acids in natural products, with good specific adsorption performance for the target molecule UA.
研究领域:
材料科学
·
药物化学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 2
·426
·
IF 7.675
Tian Wei,Lei Wu,Xiaowen Ji,Yan Gao,Guiran Xiao
Ursolic acid (UA) is a bioactive molecule widely distributed in various fruits and vegetables, which was reported to play a therapeutic role in ulcerative colitis (UC) induced by toxic chemicals. However, the underlying mechanism has not been well clarified in vivo. Here, using aDrosophilaUC model induced by sodium dodecyl sulfate (SDS), we investigated the defensive effect of UA on intestinal damage. The results showed that UA could significantly protectDrosophilafrom the damage caused by SDS exposure. Further, UA alleviated the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by SDS and upregulated the activities of total superoxide dismutase (T-SOD) and catalase (CAT). Moreover, the proliferation and differentiation of intestine stem cells (ISCs) as well as the excessive activation of the c-Jun N-terminal kinase (JNK)-dependent JAK/STAT signaling pathway induced by SDS were restored by UA. In conclusion, UA prevents intestine injury from toxic compounds by reducing the JNK/JAK/STAT signaling pathway. UA may provide a theoretical basis for functional food or natural medicine development.Keywords:ursolic acid;ulcerative colitis;JNK;JAK/STAT;Drosophila
研究领域:
药理学
·
分子生物学
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
·
2023
·
IF 8.3
Zhichun Shi,Xiuqi Huang,Yingnan Zhao,Jun Li,Yan Qing Tian,Piao Piao Zhang,Min Zhu,Ming Zhao
Pentacyclic triterpenes is a natural amphipathic product which possess a rigid backbone and several polar functional groups such as hydroxyl, carbonyl and carboxyl groups . The amphipathic character makes it easy to realize self-assemble into complex nano structure and therefore attract extensive attention due to the simple synthetic processes and renewable raw materials . Hence, a novel Ursolic acid-based hydrogel was prepared successfully via a simple self-assembly of triterpenoid derivative in methanol by capture water molecule in air. The resulting hydrogel show a porous morphology and good elasticity including strong heat resistance . Based on the characteristic above, the hydrogel showed a good iodine adsorption capacity and can removal 75.0% of the iodine from cyclohexane solution and 66.3% from aqueous solution within 36 h. Data analysis indicate that all the iodine adsorption process are dominated by chemisorption and belongs to the multi-site adsorption on heterogenous surfaces. In addition, the obtained hydrogel also possesses a good recyclability which can maintain more than 82% of its capacity after 5 cycles. The simple preparation method and easily available raw materials endow it a great potential in future pollutant treatment.
研究领域:
材料科学
·
环境科学
·
有机化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）