AbstractMetabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds; 4-hydroxybenzaldehyde (1), 4-hydroxybenzoic acid (2), tyrosol (3), azelaic acid (4), malic acid (5), and fusaric acid (6). Fungal extract as well as its metabolites were evaluated for their anti-inflammatory and anti-hyperpigmentation potential via in vitro cyclooxygenases and tyrosinase inhibition assays, respectively.

摘要代谢物探索从地锦草根中分离出的茄镰刀菌培养液的乙酸乙酯提取物，得到五种化合物；4-羟基苯甲醛（1），4-羟基苯甲酸（2），酪醇（3），壬二酸（4），苹果酸（5）和镰刀菌酸（6）。分别通过体外环加氧酶和酪氨酸酶抑制试验评估真菌提取物及其代谢物的抗炎和抗色素沉着潜力。

Azelaic acid (4) exhibited powerful and selective COX-2 inhibition followed by fusaric acid (6) with IC50 values (2.21 ± 0.06 and 4.81 ± 0.14 μM, respectively). As well, azelaic acid (4) had the most impressive tyrosinase inhibitory effect with IC50 value of 8.75 ± 0.18 μM compared to kojic acid (IC50 = 9.27 ± 0.19 μM).

壬二酸（4）表现出强大的选择性COX-2抑制作用，其次是镰刀菌酸（6），IC50值分别为2.21±0.06和4.81±0.14μM。同样，壬二酸（4）具有最令人印象深刻的酪氨酸酶抑制作用，与曲酸相比，IC50值为8.75±0.18μM（IC50=9.27±0.19μM）。

Exclusive computational studies of azelaic acid and fusaric acid with COX-2 were in good accord with the in vitro results. Interestingly, this is the first time to investigate and report the potential of compounds 3–6 to inhibit cyclooxygenase enzymes. One of the most invasive forms of skin cancer is melanoma, a molecular docking study using a set of enzymes related to melanoma suggested pirin to be therapeutic target for azelaic acid and fusaric acid as a plausible mechanism for their anti-melanoma activity..

壬二酸和镰刀菌酸与COX-2的独家计算研究与体外结果非常一致。有趣的是，这是首次研究和报道化合物3-6抑制环氧合酶的潜力。黑色素瘤是最具侵袭性的皮肤癌之一，一项使用一组与黑色素瘤相关的酶进行的分子对接研究表明，吡啶是壬二酸和镰刀菌酸的治疗靶点，是其抗黑色素瘤活性的合理机制。。

IntroductionNatural products are usually a promising source for active drugs. One of the recently promising sources of natural products is endophytes. Endophytes are microorganisms that can survive inter- or intracellularly in plants for at least a portion of their lives without inflecting outward signs of infection.

引言天然产物通常是活性药物的有前途的来源。最近有希望的天然产物来源之一是内生菌。内生菌是能够在植物体内或细胞内存活至少一段时间而不影响外部感染迹象的微生物。

In many cases, endophytes afford new active natural products, while in some cases they have the potential to synthesize similar products to those yielded by the host plants1. Although Fusarium species have been considered for many years as significant plant pathogens and as one of the main manufacturers of mycotoxins, such as fumonisin, zearalenone, and trichothecene, that can lead to diseases in humans, plants and animals2,3, Fusarium species have been identified as a significant source of various constituents with diverse therapeutic values such as pyranones, alkaloids, amides, quinones, peptides, and terpenoids4.

在许多情况下，内生菌提供了新的活性天然产物，而在某些情况下，它们有可能合成与宿主植物产生的相似的产物1。虽然镰刀菌物种多年来一直被认为是重要的植物病原体，并且是真菌毒素（如伏马菌素，玉米赤霉烯酮和曲霉菌烯）的主要制造商之一，可导致人类，植物和动物的疾病2,3，但镰刀菌物种已被确定为具有不同治疗价值的各种成分的重要来源，如吡喃酮，生物碱，酰胺，醌，肽和萜类化合物4。

Herein, we investigated the endophytic fungus Fusarium solani, which was cultured from the roots of Euphorbia tirucalli. Euphorbia tirucalli is a subtropical and tropical ornamental succulent cactus-like plant that is often known as aveloz or pencil tree and is used in folk medicine to treat many types of cancer, such as prostate cancer, basal cell carcinoma, breast cancer, and leukemia5, it has been reported to have antibacterial6, analgesic, anti-inflammatory7, hepato-protective, antioxidant8, cytotoxic9 and antimicrobial activities10.

在此，我们研究了内生真菌Fusarium solani，它是从地锦草的根中培养出来的。大戟（Euphorbia tirucalli）是一种亚热带和热带观赏性多汁仙人掌状植物，常被称为aveloz或铅笔树，用于民间医学治疗多种癌症，如前列腺癌、基底细胞癌、乳腺癌和白血病。据报道，它具有抗菌、镇痛、抗炎、保肝、抗氧化、细胞毒性和抗菌活性。

Our previous exploration of the phytoconstituents of the aerial parts of Euphorbia pseudocactus led to the isolation and identification of astragalin, kaempferol, nicotiflorin, astragalin-6′′-gallate, gallic acid, ethyl gallate, 1,2,3,4,6-pentagalloylglucose, and ellagic acid, further biological investigation un.

我们之前对大戟属假仙人掌地上部分植物成分的探索导致了黄芪素，山奈酚，烟碱，黄芪-6''-没食子酸，没食子酸，没食子酸乙酯，1,2,3,4,6-五没食子酸葡萄糖和鞣花酸的分离和鉴定，进一步的生物学研究联合国。

Table 1 IC50 and selectivity index of the total extract and the isolated metabolites from the endophytic fungus Fusarium solani against COX-1 and COX-2 enzymes.Full size tableTyrosinase inhibitory assayThe effectiveness of the total extract and the isolated compounds (1–6) to inhibit tyrosinase enzyme was detemined, compared to kojic acid as a reference drug.

表1来自内生真菌Fusarium solani的总提取物和分离的代谢物对COX-1和COX-2酶的IC50和选择性指数。全尺寸表酪氨酸酶抑制试验与曲酸作为参考药物相比，测定了总提取物和分离的化合物（1-6）抑制酪氨酸酶的有效性。

The results demonstrated in (Table 2) showed that azelaic acid had considerable tyrosinase inhibitory effect with IC50 value of 8.75 ± 0.18 μM which was comparable with that of kojic acid (IC50 = 9.27 ± 0.19 μM). Tyrosol showed inhibitory activity with IC50 of 11.35 ± 0.24 μM, followed by fusaric acid with IC50 of 13.42 ± 0.26 μM.

（表2）显示，壬二酸具有相当大的酪氨酸酶抑制作用，IC50值为8.75±0.18μM，与曲酸相当（IC50=9.27±0.19μM）。酪醇显示出抑制活性，IC50为11.35±0.24μM，其次是镰刀菌酸，IC50为13.42±0.26μM。

The total extract of the endophytic fungus and 4-hydroxybenzoic acid showed moderate inhibitory effect with IC50 of 21.79 ± 0.44 and 25.45 ± 0.54 μM, respectively in comparison with the previous compounds. On the other hand, 4-hydroxybenzaldehyde and malic acid showed IC50 > 50 μM indicating very little inhibitory effect.

与以前的化合物相比，内生真菌和4-羟基苯甲酸的总提取物显示出中等的抑制作用，IC50分别为21.79±0.44和25.45±0.54μM。另一方面，4-羟基苯甲醛和苹果酸显示IC50>50μM，表明抑制作用很小。

All mammalian melanocytes contain the tyrosinase enzyme, which limits the rate at which melanin is produced42. Tyrosinase is over expressed by aggressive tumors such as melanoma, so, it is necessary to control tyrosinase activity in order to avoid the excess production of melanin43..

所有哺乳动物黑素细胞都含有酪氨酸酶，这限制了黑色素的产生速率42。酪氨酸酶被黑色素瘤等侵袭性肿瘤过度表达，因此，有必要控制酪氨酸酶活性，以避免黑色素43的过量产生。。

Table 2 IC50 of tyrosinase inhibitory activity of the total extract and the isolated metabolites from the endophytic fungus Fusarium solani.Full size tableMolecular docking studyFor more understanding of the COX inhibition activity at the molecular level, a computational study has been conducted to investigate binding of the metabolites into the active sites of COX enzymes.

表2来自内生真菌Fusarium solani的总提取物和分离的代谢物的酪氨酸酶抑制活性的IC50。全尺寸表分子对接研究为了在分子水平上更好地了解COX抑制活性，已经进行了一项计算研究，以研究代谢物与COX酶活性位点的结合。

Cyclooxygenases are oxidoreductase enzymes of two isoforms COX-1 and COX-2. Both isoforms are homodimer enzymes of three domains, where they are similar to a great extent in their amino acids sequence44,45. The entrance to the active site cavity of COX-2 is surrounded by three amino acids Arg120, Tyr355, and Glu524 and afterwards, the binding site is located near the catalytically significant Tyr385 and comprised the amino acids Val523, Val434, Arg513, and Leu50346.

环加氧酶是两种同工型COX-1和COX-2的氧化还原酶。两种同工型都是三个结构域的同型二聚体酶，它们的氨基酸序列在很大程度上相似44,45。COX-2活性位点腔的入口被三个氨基酸Arg120，Tyr355和Glu524包围，然后，结合位点位于催化显着的Tyr385附近，并由氨基酸Val523，Val434，Arg513和Leu50346组成。

In COX-1, substitution of Val523 with the sterically hindered Ile523 causes the presence of an additional side pocket in COX-2 allowing larger active site47. The docking study was conducted exclusively on the COX enzymes for azelaic and fusaric acids since these two compounds have not been docked into the active site of COXs previously.

在COX-1中，用空间位阻的Ile523取代Val523导致COX-2中存在额外的侧袋，从而允许更大的活性位点47。对接研究仅针对壬二酸和镰刀菌酸的COX酶进行，因为这两种化合物以前没有对接到COX的活性位点。

Binding affinities and intermolecular interactions are summarized in (Table 3). Docking of azelaic acid into binding site of COX-2 revealed hydrogen bond with Ser530 located between Arg120 at the entrance of the enzyme channel and the buried Tyr385 in the hydrophobic pocket. This orientation of azelaic carboxylic oxygen to be in proximity to Ser530 hydroxyl group was supported by hydrogen bonding between the same carboxylic group and hydroxyl group of Tyr385.

结合亲和力和分子间相互作用总结在（表3）中。壬二酸与COX-2结合位点的对接揭示了与Ser530的氢键，Ser530位于酶通道入口处的Arg120和疏水口袋中埋藏的Tyr385之间。氮杂环羧酸氧接近Ser530羟基的这种取向由Tyr385的相同羧基和羟基之间的氢键支持。

Moreover, the amino acids Leu352, Val523, and Ala527 showed alkyl-hydrophobic interactions with azelaic acid, while it exhibited van der Waals intera.

此外，氨基酸Leu352，Val523和Ala527显示出与壬二酸的烷基疏水相互作用，而它表现出范德华相互作用。

Table 3 Binding scores and comprehensive intermolecular interactions of the isolated metabolites from the endophytic fungus Fusarium solani and the targeted enzymes COX-2 and COX-1.Full size tableFigure 4Binding modes of azelaic acid (A), (B) and fusaric acid (C), (D) into COX-2 (5IKV) and COX-1 (6Y3C) binding sites, respectively.

表3内生真菌镰刀菌（Fusarium solani）分离的代谢物与靶向酶COX-2和COX-1的结合评分和综合分子间相互作用。全尺寸表4壬二酸（A），（B）和镰刀菌酸（C），（D）分别与COX-2（5IKV）和COX-1（6Y3C）结合位点的结合模式。

Ligands are depicted in green tube models. The amino acids are shown in labelled line models. Hydrogen bonds are represented by yellow and green dashed lines, while hydrophobic interactions by pink and magenta dashed lines.Full size imageFigure 5Superposition of arachidonic acid (green) and azelaic acid (blue) bound in the active site of COX-2 indicating similar conformation.Full size imagePrevious reports indicated that some of the isolated compounds have cytotoxic activity against melanoma cell lines, azelaic acid was reported to be active against murine B16 and human SK23 and HMB2 melanoma cell lines49, while 4-hydroxybenzoic acid showed cytotoxic activity aganist human SK-MEL-28 and murine B16-F0 cell lines21.

配体在绿管模型中描述。氨基酸显示在标记线模型中。氢键由黄色和绿色虚线表示，而疏水相互作用由粉红色和品红色虚线表示。全尺寸图像图5结合在COX-2活性位点的花生四烯酸（绿色）和壬二酸（蓝色）的叠加，表明相似的构象。全尺寸图像先前的报道表明，一些分离的化合物对黑色素瘤细胞系具有细胞毒活性，据报道壬二酸对鼠B16和人SK23和HMB2黑色素瘤细胞系49具有活性，而4-羟基苯甲酸对人SK-MEL-28和鼠B16-F0细胞系21具有细胞毒活性。

Fusaric acid inhibited the melanoma tyrosinase as previously reported22. Further previous data concluded that the anticancer activity of azelaic acid could be attributed to its interference with synthesis of cellular DNA and/or oxidative phosphorylation, instead of tyrosinase inhibitory activity25. Another study on hydroxytyrosol indicated its effectiveness against A375, HT-144, and M74 melanoma cells50.Since molecular docking is a beneficial approach for in silico determination of mechanism of action and biomolecular target, the current effort included docking studies to evaluate the potential binding of the isolated metabolites against a set of enzymes related to melanoma to discern which of them may be targeted by the metabolites..

如先前报道的，镰刀菌酸抑制黑色素瘤酪氨酸酶22。进一步的先前数据得出结论，壬二酸的抗癌活性可归因于其干扰细胞DNA的合成和/或氧化磷酸化，而不是酪氨酸酶抑制活性25。另一项关于羟基酪醇的研究表明其对A375，HT-144和M74黑色素瘤细胞的有效性50。由于分子对接是计算机测定作用机制和生物分子靶标的有益方法，因此目前的工作包括对接研究，以评估分离的代谢物与一组与黑色素瘤相关的酶的潜在结合，以辨别其中哪些可能是代谢物的靶标。。

tirucalli

昨天

E. tirucalli was collected and uprooted. The plant roots were rinsed in streaming tap water to clear out the dust particles, soil sand, and other external microorganisms61. The separated plant roots were cut into 2 mm segments and the surface was sterilized for 1 min by submerging in ethyl alcohol 70% then for 2 min in 5% sodium hypochlorite and finally washed with sterilized demineralized water for 1 min.

E、 Tirucali被收集并连根拔起。用流动的自来水冲洗植物根部，以清除灰尘颗粒，土壤沙子和其他外部微生物61。将分离的植物根切成2毫米的片段，通过将表面浸入70%的乙醇中灭菌1分钟，然后在5%的次氯酸钠中灭菌2分钟，最后用灭菌的软化水洗涤1分钟。

To remove the moisture, the explant parts were pressed in the sterilized tissue paper. The separated explant parts were transferred and cultivated on the Petri dishes containing SDA (Sabouraud Dextrose Agar) provided with 150 mg/L chloramphenicol. The Petri dishes containing the explants were incubated at 27 °C for 14 days and fungus growth was daily monitored.

为了除去水分，将外植体部分压在无菌纸巾中。将分离的外植体部分转移并在含有SDA（Sabouraud葡萄糖琼脂）的培养皿上培养，SDA含有150 mg/L氯霉素。将含有外植体的培养皿在27℃下孵育14天，每天监测真菌生长。

New petri dishes with SDA devoid of antibiotics were used to carefully transfer the developing fungus from the explant samples62.Morphological features of the recovered isolateSuccessive subcultures on SDA (Sabouraud dextrose agar) were done to purify pure fungal isolate. The fungal colony was grown on SDA for 10 days, then the cultural appearances (colony color and pigmentations) were observed.

使用不含抗生素的SDA的新培养皿小心地从外植体样品中转移发育中的真菌62。回收的分离物的形态特征在SDA（Sabouraud葡萄糖琼脂）上进行连续传代培养以纯化纯真菌分离物。将真菌菌落在SDA上生长10天，然后观察培养外观（菌落颜色和色素沉着）。

For microscopic analysis of microconidia and conidiospore staining of fungal component was done with lactophenol cotton blue stain.Molecular identification of the endophytic fungusHundred milligrams of fungal mycelium was transferred to a sterile mortar previously cooled with liquid nitrogen. The mycelium was solidified by addition of 1 ml of liquid nitrogen.

对于微孢子虫和分生孢子的显微镜分析，用乳酚棉蓝染色剂对真菌成分进行染色。内生真菌的分子鉴定将数百毫克真菌菌丝体转移到预先用液氮冷却的无菌研钵中。通过加入1毫升液氮使菌丝体固化。

Using a sterile pestle, the mycelium was finely ground for 10 min. The ground mycelium was recovered using 2 ml of lysis solution (20 mM EDTA, 10 mM Tris (pH 8.0), 1% Triton X100 (v/v)) then incubated at 37 °C for 60 min. Subsequently, 2 ml of 5 M NaCl and 1 ml of .

使用无菌研杵，将菌丝体细磨10分钟。使用2 ml裂解液（20 mM EDTA，10 mM Tris（pH 8.0），1%Triton X100（v/v））回收研磨的菌丝体，然后在37°C下孵育60分钟。随后，加入2 ml 5 M NaCl和1 ml。

Data availability

数据可用性

The corresponding author can provide the data supporting the study's findings upon reasonable request.

通讯作者可以根据合理的要求提供支持研究结果的数据。

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Download referencesAcknowledgementsThe authors would like to thank Mr. Tharout Badawy, the proprietor of Cactus Farm in Tahanop, Shebin El-Qanater, Qalubiya, Egypt for providing us with the plant and Dr. Abdel Haleem Mohammed for his help in identifying it. As well we would like to appreciate Dr.

下载参考文献致谢作者要感谢埃及Qalubiya Shebin El Qanater Tahanop仙人掌农场的所有者Tharout Badawy先生为我们提供了这种植物，并感谢Abdel Haleem Mohammed博士帮助我们鉴定了它。我们也要感谢Dr。

Wafaa R. Mohamed, Associate professor of pharmacology and toxicology, Faculty of Pharmacy, Beni-Suef University, for her kind help in accomplishing the statistical analysis.FundingOpen access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

WafaaR.Mohamed，Beni Suef大学药学院药理学和毒理学副教授，感谢她在完成统计分析方面的善意帮助。基金科学、技术与创新基金管理局（STDF）与埃及知识银行（EKB）合作提供的开放获取资金。

The authors are gratefully acknowledging the financial support from Beni-Suef University, university performance development center, projects support and finance office, project ID (YR4-BSU2110).Author informationAuthor notesThese authors contributed equally: Mona Ismail and Marwa H. A. Hassan.Authors and AffiliationsDepartment of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, EgyptMona Ismail, Marwa H.

作者非常感谢Beni Suef大学，大学绩效发展中心，项目支持和财务办公室，项目ID（YR4-BSU2110）的财务支持。作者信息作者注意到这些作者做出了同样的贡献：Mona Ismail和Marwa H.A.Hassan。作者和附属机构贝尼苏夫大学药学院生药学系，贝尼苏夫，62514，埃及莫纳伊斯梅尔，马尔瓦H。

A. Hassan, Enas I. A. Mohamed, Abeer Moawad, Rabab Mohammed & Mohamed A. ZakiDepartment of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, EgyptAhmed F. AzmyAuthorsMona IsmailView author publicationsYou can also search for this author in.

A、 哈桑（Hassan），埃纳斯·穆罕默德（Enas I.A.Mohamed），阿贝尔·莫瓦德（Abeer Moawad），拉巴布·穆罕默德（Rabab Mohammed）和穆罕默德·扎基德（Mohammed A.ZakiDepartment of Microbiology and Immunology），贝尼苏夫大学药学院，贝尼苏夫（Beni Suef），62514，埃及艾哈迈德·阿兹米（Ahmed F.AzmyAuthorsMona IsmailView）作者出版物您也可以。

PubMed Google ScholarMarwa H. A. HassanView author publicationsYou can also search for this author in

PubMed Google ScholarMarwa H.A.HassanView作者出版物您也可以在

PubMed Google ScholarEnas I. A. MohamedView author publicationsYou can also search for this author in

PubMed Google ScholarEnas I.A.MohamedView作者出版物您也可以在

PubMed Google ScholarAhmed F. AzmyView author publicationsYou can also search for this author in

PubMed Google ScholarAhmed F.AzmyView作者出版物您也可以在

PubMed Google ScholarAbeer MoawadView author publicationsYou can also search for this author in

PubMed Google ScholarAbeer MoawadView作者出版物您也可以在

PubMed Google ScholarRabab MohammedView author publicationsYou can also search for this author in

PubMed Google Scholararabab MohammedView作者出版物您也可以在

PubMed Google ScholarMohamed A. ZakiView author publicationsYou can also search for this author in

PubMed Google ScholarMohamed A.ZakiView作者出版物您也可以在

PubMed Google ScholarContributionsConcept and design, data acquisition, data analysis, interpretation, and final approval were created by all of the authors. The original article draft was cowritten by M.I., M.H.A.H. and M.A.Z. Endophyte isolation and identification were done by A.F.A and M.I.

PubMed谷歌学术贡献概念和设计，数据采集，数据分析，解释和最终批准由所有作者创建。原始条款草案由M.I.，M.H.A.H.和M.A.Z.共同撰写。内生菌的分离和鉴定由A.F.A和M.I.完成。

Molecular docking study was performed and written by E.I.A.M. Finally, R.M., A.M., M.A.Z. and M.H.A.H. contributed to supervision, technical material support, and critical revision of the manuscript. All authors agree to publication.Corresponding authorsCorrespondence to.

分子对接研究由E.I.A.M.进行并撰写。最后，R.M.，A.M.，M.A.Z.和M.H.A.H.为监督，技术材料支持和稿件的批判性修订做出了贡献。所有作者都同意发表。通讯作者通讯。

Abeer Moawad or Rabab Mohammed.Ethics declarations

Abeer Moawad或Rabab Mohammed。道德宣言

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Reprints and permissionsAbout this articleCite this articleIsmail, M., Hassan, M.H.A., Mohamed, E.I.A. et al. New insights into the anti-inflammatory and anti-melanoma mechanisms of action of azelaic acid and other Fusarium solani metabolites via in vitro and in silico studies.

转载和许可本文引用本文Ismail，M.，Hassan，M.H.A.，Mohamed，E.I.A.等人通过体外和计算机研究对壬二酸和其他茄病镰刀菌代谢物的抗炎和抗黑色素瘤作用机制的新见解。

Sci Rep 14, 14370 (2024). https://doi.org/10.1038/s41598-024-63958-0Download citationReceived: 22 December 2023Accepted: 04 June 2024Published: 22 June 2024DOI: https://doi.org/10.1038/s41598-024-63958-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1414370（2024）。https://doi.org/10.1038/s41598-024-63958-0Download引文收到日期：2023年12月22日接受日期：2024年6月4日发布日期：2024年6月22日OI：https://doi.org/10.1038/s41598-024-63958-0Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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Keywords

关键词

Fusarium solani

茄病镰刀菌

Euphorbia tirucalli

大戟

Cyclooxygenase (COX-1 and COX-2)DockingMelanomaPirinAzelaic

环氧合酶（COX-1和COX-2）对接黑色素瘤

Subjects

主题

Computational biology and bioinformaticsDrug discovery

计算生物学和生物信息学药物发现

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