口服纳米抗氧化剂用于肠道炎症的治疗作用

口服纳米抗氧化剂用于肠道炎症的治疗作用摘要炎症性肠病（IBD）是一种由免疫介导的慢性复发性肠道疾病，全球患病人数超过500万，已成为世界上第3大常见疾病。当前治疗药物（小分子药物、抗生素和抗体）取得了一定疗效，然而，长期使用可能导致严重的并发症、抗生素耐药性和不良的免疫反应。基于纳米颗粒的靶向给药系统近年取得显著进展，有望提升疗效，改善肠道炎症，并降低副作用风险。本研究设计开发了一种口服纳米氧化剂Cur-Ce@FTA，利用单宁酸（TA）与聚醚F127自组装行为形成姜黄素（Cur）与氧化铈包埋的纳米组装体，以提高其溶解度并可能增强其生物活性，使其更有效地到达肠道病变部位发挥作用。Cur-Ce@FTA能保持对炎症结肠的良好靶向能力，这主要归因于带负电荷的单宁酸和带正电荷的炎症上皮细胞之间的静电相互作用。CeO2纳米材料的生物医学应用潜力主要源于其模拟天然酶的抗氧化特性，包括过氧化氢酶（CAT）、过氧化物酶（POD）和超氧化物歧化酶（SOD）样活性。这种多酶仿生特性使其能够高效清除自由基及活性氧（ROS），从而有效保护生物系统免受氧化损伤，在IBD的抗氧化及抗炎治疗中潜力显著，同时利用姜黄素强大的抗氧化特性，协同发挥治疗作用，达到长期治疗IBD的目的。关键词：炎症性肠病纳米抗氧化剂姜黄素氧化铈单宁酸第一章绪论1.1肠道炎症的研究背景1.1.1肠道炎症的简介炎症性肠病（Inflammatoryboweldisease，IBD）是免疫反应介导的慢性缓解和复发性肠病的总称，是一种慢性复发性和缓解性疾病，全球患病人数超过500万，已成为世界上第3大常见疾病ADDINEN.CITEADDINEN.CITE.DATA[1]。IBD分为克罗恩病（CD）和溃疡性结肠炎（UC）ADDINEN.CITEADDINEN.CITE.DATA[2,3]。CD病变范围广泛，可累及整个消化道，表现为肠道炎症和溃疡，并伴有肉芽肿形成ADDINEN.CITE<EndNote><Cite><Author>Zhou</Author><Year>2023</Year><RecNum>144</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>144</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1715246051">144</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhou,Feini</author><author>Mai,Ting</author><author>Wang,Ziren</author><author>Zeng,Zhaolong</author><author>Shi,Jingjing</author><author>Zhang,Fan</author><author>Kong,Ning</author><author>Jiang,Hao</author><author>Guo,Lingnan</author><author>Xu,Maosheng</author><author>Lin,Jiangnan</author></authors></contributors><auth-address>ZhejiangChineseMedUniv,SchClinMed1,Hangzhou,PeoplesRChina ZhejiangChineseMedUniv,AffiliatedHosp1,ZhejiangProvHospChineseMed,DeptRadiol,54YoudianRd,Hangzhou,PeoplesRChina ZhejiangChineseMedUniv,SchClinMed3,Hangzhou,PeoplesRChina</auth-address><titles><title>Theimprovementofintestinaldysbiosisandhepaticmetabolicdysfunctionindextransulfatesodium-inducedcolitismice:effectsofcurcumin</title><secondary-title>JOURNALOFGASTROENTEROLOGYANDHEPATOLOGY</secondary-title></titles><periodical><full-title>JOURNALOFGASTROENTEROLOGYANDHEPATOLOGY</full-title></periodical><pages>1333-1345</pages><volume>38</volume><number>8</number><dates><year>2023</year><pub-dates><date>2023AUG</date></pub-dates></dates><isbn>0815-9319 1440-1746</isbn><accession-num>WOS:000990196800001</accession-num><work-type>Article</work-type><urls></urls><custom6>MAY2023</custom6><electronic-resource-num>10.1111/jgh.16205</electronic-resource-num><access-date>2023-05-28</access-date></record></Cite></EndNote>[4]，UC可使结肠肠道菌群紊乱和肠道屏障功能严重破坏，一般只发生在结肠部位，只涉及黏膜和黏膜下层，其结肠镜检查结果是假性息肉和连续的炎症区域。虽然CD和UC在多种方面有较大差异，但它们在症状上表现出类似性，包括腹痛、腹泻、肠外表现和营养不良等，部分患者还会伴有关节炎、口腔溃疡及皮炎等症状ADDINEN.CITE<EndNote><Cite><Author>王佳俊</Author><Year>2021</Year><RecNum>148</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>148</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1716035020">148</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author><styleface="normal"font="default"charset="134"size="100%">王佳俊</style><styleface="normal"font="default"size="100%">,</style><styleface="normal"font="default"charset="134"size="100%">陈青垚</style><styleface="normal"font="default"size="100%">,</style><styleface="normal"font="default"charset="134"size="100%">王建</style><styleface="normal"font="default"size="100%">,</style><styleface="normal"font="default"charset="134"size="100%">等</style></author></authors></contributors><titles><title><styleface="normal"font="default"charset="134"size="100%">基于数据挖掘和网络药理</style><styleface="normal"font="default"size="100%"></style><styleface="normal"font="default"charset="134"size="100%">学探究含黄连方剂治疗溃疡性结肠炎的配伍规律及作</style><styleface="normal"font="default"size="100%"></style><styleface="normal"font="default"charset="134"size="100%">用机制</style><styleface="normal"font="default"size="100%">[J]</style></title><secondary-title><styleface="normal"font="default"charset="134"size="100%">中草药</style><styleface="normal"font="default"size="100%">,2021,52(19):5984-5995.</style></secondary-title></titles><periodical><full-title>中草药,2021,52(19):5984-5995.</full-title></periodical><dates><year>2021</year></dates><urls></urls></record></Cite></EndNote>[5]。IBD的确切病因尚不清楚，但目前认为IBD的发病机制与氧化应激、炎症介质增多、破坏黏膜屏障、肠道微生物菌群以及免疫反应有关ADDINEN.CITEADDINEN.CITE.DATA[6,7]。IBD病程的延长与结直肠癌的发生和发展密切相关，并且对患者的身体、心理和社会的某些方面都造成很大的影响，通常会导致患者的抑郁和焦虑情绪ADDINEN.CITEADDINEN.CITE.DATA[8]。因此，研究IBD的治疗方法对于保障患者的生活质量至关重要。目前，氨基水杨酸盐、皮质类固醇、免疫抑制剂、生物制剂和抗生素等药物已被广泛用于治疗IBD，然而，此类治疗方法存在生物利用度低和系统副作用大的问题，如长期摄入这些药物会对患者产生严重的不良反应ADDINEN.CITE<EndNote><Cite><Author>Pithadia</Author><Year>2011</Year><RecNum>123</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>123</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1714560255">123</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Pithadia,A.B.</author><author>Jain,S.</author></authors></contributors><auth-address>DepartmentofPharmacology,L.M.CollegeofPharmacy,Navrangpura,Ahmedabad-380009Gujarat,India.abpithadia@</auth-address><titles><title>Treatmentofinflammatoryboweldisease(IBD)</title><secondary-title>PharmacolRep</secondary-title></titles><periodical><full-title>PharmacolRep</full-title></periodical><pages>629-42</pages><volume>63</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Anti-InflammatoryAgents/adverseeffects/therapeuticuse</keyword><keyword>Colitis,Ulcerative/*drugtherapy/physiopathology</keyword><keyword>CrohnDisease/*drugtherapy/physiopathology</keyword><keyword>*DrugDeliverySystems</keyword><keyword>Glucocorticoids/adverseeffects/therapeuticuse</keyword><keyword>Humans</keyword><keyword>ImmunologicFactors/adverseeffects/pharmacology/therapeuticuse</keyword><keyword>ImmunosuppressiveAgents/adverseeffects/therapeuticuse</keyword></keywords><dates><year>2011</year></dates><isbn>1734-1140</isbn><accession-num>21857074</accession-num><urls></urls><electronic-resource-num>10.1016/s1734-1140(11)70575-8</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[9]：急性胰腺炎、肠道菌群失衡、肝功能损伤和骨质疏松症等。所以迫切需要开发有较好疗效且不良反应较小的靶向治疗药物和方法ADDINEN.CITE<EndNote><Cite><Author>GodatS</Author><Year>2018</Year><RecNum>149</RecNum><DisplayText><styleface="superscript">[10,11]</style></DisplayText><record><rec-number>149</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1716035343">149</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>GodatS,FournierN,SafroneevaE,etal.</author></authors></contributors><titles><title>Frequencyandtypeofdrug-relatedsideeffectsnecessitatingtreatmentdiscontinuationintheswissinflammatoryboweldiseasecohort.</title><secondary-title>EurJGastroenterolHepatol,2018,30(6):612-620.</secondary-title></titles><periodical><full-title>EurJGastroenterolHepatol,2018,30(6):612-620.</full-title></periodical><dates><year>2018</year></dates><urls></urls></record></Cite><Cite><Author>MaXW</Author><Year>2018</Year><RecNum>150</RecNum><record><rec-number>150</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1716035625">150</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>MaXW,HuYC,LiX,etal.</author></authors></contributors><titles><title>Periplanetaamericanaamelioratesdextransulfatesodium-inducedulcerativecolitisinratsbyKeap1/Nrf-2activation,intestinalbarrierfunction,andgutmicrobiotaregulation.</title><secondary-title>FrontPharmacol,2018,9:944.</secondary-title></titles><periodical><full-title>FrontPharmacol,2018,9:944.</full-title></periodical><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>[10,11]。近年来，基于纳米颗粒的靶向给药系统在IBD治疗方面取得了显著进展，有望提高治疗效果，减少副作用。1.1.2ROS与氧化应激氧气代谢是哺乳动物细胞生存所不可或缺的环节，该过程会产生活性氧（ROS）。ROS包含自由基类物质（如超氧阴离子•O2-、羟自由基•OH）和非自由基类物质（如过氧化氢H2O2、单线态氧1O2）。此外，次氯酸HOCl、氯胺RNHCl及臭氧O3等也属于ROS范畴。另一类重要活性分子是活性氮族（RNS），其代表物有一氧化氮•NO、二氧化氮•NO2，以及过氧亚硝酸盐ONOO-、三氧化二氮N2O3等非自由基化合物。ROS和RNS都是负责细胞内碳水化合物、蛋白质、脂质和核酸损伤的主要媒介，并且它们都具有不配对电子的不稳定性，因此具有高度的反应性和活性。据报道，ROS和RNS可上调参与消化道先天和适应性免疫反应的基因的表达ADDINEN.CITEADDINEN.CITE.DATA[12]。当ROS和自由基的细胞毒性作用超过了抗氧化剂对其细胞毒性作用的消除，就会产生氧化应激进而导致组织损伤ADDINEN.CITEADDINEN.CITE.DATA[13,14]。在生理状态下，细胞内ROS水平通过严格的动态平衡机制维持于极低浓度范围，这对保障细胞正常功能至关重要。然而，当ROS过量累积时，会打破氧化还原稳态，引发氧化应激反应。过量的ROS会攻击和损伤几乎所有的细胞成分，包括细胞膜、脂质、蛋白质、酶和DNA，并因此导致细胞凋亡ADDINEN.CITEADDINEN.CITE.DATA[15]。ROS对细胞膜的影响主要表现为由于细胞膜脂质双分子层中的多不饱和脂肪酸具有两个或多个碳双键的结构，这种结构易受到氧化攻击，导致过氧化脂质积累ADDINEN.CITE<EndNote><Cite><Author>曹䶮</Author><Year>2021</Year><RecNum>367</RecNum><DisplayText><styleface="superscript">[16]</style></DisplayText><record><rec-number>367</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1747660269">367</key></foreign-keys><ref-typename="Thesis">32</ref-type><contributors><authors><author>曹䶮</author></authors><tertiary-authors><author>焦拥政,</author></tertiary-authors></contributors><titles><title>基于ROS-MAPK-线粒体途径探讨补肾益精方治疗少弱精子症的作用机制</title></titles><keywords><keyword>少弱精子症</keyword><keyword>补肾益精方</keyword><keyword>氧化应激</keyword><keyword>p38MAPK信号通路</keyword><keyword>线粒体凋亡</keyword></keywords><dates><year>2021</year></dates><work-type>博士</work-type><urls><related-urls><url>/doi/10.27658/ki.gzzyy.2021.000038</url></related-urls></urls><electronic-resource-num>10.27658/ki.gzzyy.2021.000038</electronic-resource-num><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[16]。而过氧化脂质的积累加速了对细胞膜完整性的破坏，这种损伤和ROS增加导致跨膜酶、受体和其他膜蛋白失活，导致细胞膜破裂死亡。其次，作为细胞主要成分的蛋白质和酶也是ROS氧化的目标，例如•OH自由基攻击并破坏了许多蛋白质和酶。•OH的氧化作用包括诱导蛋白质构象发生变化，这是导致蛋白质功能部分或完全丧失的一个主要原因。ONOO-是一种由•O2-和•NO反应快速形成的强有力的氧化剂和硝化物，它可与多种生物大分子（如蛋白质）发生相互作用，诱导其发生氧化修饰或硝化反应，最终引发细胞结构损伤。此外，ROS会对DNA产生一定的影响，已知核DNA和线粒体DNA也是ROS氧化攻击的目标，特别是来自•OH和ONOO-的攻击，它们导致碱基甲基化、羟基化损伤以及双链断裂，从而导致三磷酸腺苷耗竭、基因突变和线粒体DNA缺失，这些变化最终诱发恶性转化和细胞死亡。因此，ROS通过氧化应激损伤了几乎所有的细胞成分ADDINEN.CITE<EndNote><Cite><Author>Mittal</Author><Year>2014</Year><RecNum>361</RecNum><DisplayText><styleface="superscript">[17]</style></DisplayText><record><rec-number>361</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1746699893">361</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mittal,M.</author><author>Siddiqui,M.R.</author><author>Tran,K.</author><author>Reddy,S.P.</author><author>Malik,A.B.</author></authors></contributors><auth-address>1DepartmentofPharmacology,CenterforLungandVascularBiology,UniversityofIllinoisCollegeofMedicine,Chicago,Illinois.</auth-address><titles><title>Reactiveoxygenspeciesininflammationandtissueinjury</title><secondary-title>AntioxidRedoxSignal</secondary-title></titles><periodical><full-title>AntioxidRedoxSignal</full-title></periodical><pages>1126-67</pages><volume>20</volume><number>7</number><edition>20131022</edition><keywords><keyword>Animals</keyword><keyword>Endothelium,Vascular/metabolism/*pathology</keyword><keyword>Humans</keyword><keyword>Inflammation/metabolism/*pathology</keyword><keyword>Neutrophils/metabolism/pathology</keyword><keyword>OxidativeStress/physiology</keyword><keyword>ReactiveOxygenSpecies/*metabolism</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar1</date></pub-dates></dates><isbn>1523-0864(Print) 1523-0864</isbn><accession-num>23991888</accession-num><urls></urls><custom2>PMC3929010</custom2><electronic-resource-num>10.1089/ars.2012.5149</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[17]。虽然不受控制的氧化应激会对机体造成损害，但内源性抗氧化防御系统能够有效调控ROS/RNS水平，确保其浓度得到控制，防止其积累至有害程度。这一保护体系主要包括：（1）胞内抗氧化酶，如超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPX）和过氧化氢酶（CAT）；（2）非酶类抗氧化分子（如还原型谷胱甘肽）；（3）胞外抗氧化物质，例如维生素、矿物质、磷脂及尿酸等ADDINEN.CITEADDINEN.CITE.DATA[18]。1.1.3ROS与IBD在IBD中，肠道黏膜活性氧（ROS）水平异常升高，其病理机制表现为多维度损伤：ROS通过直接破坏肠上皮细胞间紧密连接蛋白（如occludin）削弱肠道屏障完整性，导致病原体和抗原易位ADDINEN.CITEADDINEN.CITE.DATA[19]；同时激活NF-κB和NLRP3炎症小体信号通路，促进TNF-α、IL-1β等促炎因子过度表达，驱动慢性炎症恶化ADDINEN.CITE<EndNote><Cite><Author>Neurath</Author><Year>2014</Year><RecNum>236</RecNum><DisplayText><styleface="superscript">[20]</style></DisplayText><record><rec-number>236</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1746115552">236</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Neurath,M.F.</author></authors></contributors><auth-address>DepartmentofMedicine1,UniversityofErlangen-Nürnberg,KussmaulCampusforMedicalResearch,91054Erlangen,Germany.</auth-address><titles><title>Cytokinesininflammatoryboweldisease</title><secondary-title>NatRevImmunol</secondary-title></titles><periodical><full-title>NatRevImmunol</full-title></periodical><pages>329-42</pages><volume>14</volume><number>5</number><edition>20140422</edition><keywords><keyword>AdaptiveImmunity/immunology</keyword><keyword>Animals</keyword><keyword>Cytokines/*immunology</keyword><keyword>Humans</keyword><keyword>Immunity,Innate/immunology</keyword><keyword>InflammatoryBowelDiseases/*immunology</keyword></keywords><dates><year>2014</year><pub-dates><date>May</date></pub-dates></dates><isbn>1474-1733</isbn><accession-num>24751956</accession-num><urls></urls><electronic-resource-num>10.1038/nri3661</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[20]；此外，ROS的过度生成会选择性抑制肠道共生菌生长，引发菌群失调并加剧免疫微环境紊乱ADDINEN.CITE<EndNote><Cite><Author>Grisham</Author><Year>1994</Year><RecNum>235</RecNum><DisplayText><styleface="superscript">[21]</style></DisplayText><record><rec-number>235</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1746115219">235</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Grisham,M.B.</author></authors></contributors><auth-address>DepartmentofPhysiologyandBiophysics,LouisianaStateUniversityMedicalCenter,Shreveport71130.</auth-address><titles><title>Oxidantsandfreeradicalsininflammatoryboweldisease</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>859-61</pages><volume>344</volume><number>8926</number><keywords><keyword>AminosalicylicAcids/pharmacology/therapeuticuse</keyword><keyword>Animals</keyword><keyword>FreeRadicals</keyword><keyword>Humans</keyword><keyword>InflammatoryBowelDiseases/*metabolism/prevention&control</keyword><keyword>Mesalamine</keyword><keyword>Oxygen/*metabolism</keyword><keyword>ReactiveOxygenSpecies/*metabolism</keyword></keywords><dates><year>1994</year><pub-dates><date>Sep24</date></pub-dates></dates><isbn>0140-6736(Print) 0140-6736</isbn><accession-num>7916405</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(94)92831-2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[21]。研究表明，IBD患者结肠组织中超氧化物歧化酶（SOD）和过氧化氢酶（CAT）等抗氧化酶活性显著降低，提示抗氧化系统功能缺陷是疾病进展的关键病理环节ADDINEN.CITE<EndNote><Cite><Author>Kruidenier</Author><Year>2003</Year><RecNum>238</RecNum><DisplayText><styleface="superscript">[22]</style></DisplayText><record><rec-number>238</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1746116065">238</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Kruidenier,L.</author><author>Kuiper,I.</author><author>VanDuijn,W.</author><author>Mieremet-Ooms,M.A.</author><author>vanHogezand,R.A.</author><author>Lamers,C.B.</author><author>Verspaget,H.W.</author></authors></contributors><auth-address>DepartmentofGastroenterologyandHepatology,LeidenUniversityMedicalCenter,TheNetherlands.</auth-address><titles><title>Imbalancedsecondarymucosalantioxidantresponseininflammatoryboweldisease</title><secondary-title>JPathol</secondary-title></titles><periodical><full-title>JPathol</full-title></periodical><pages>17-27</pages><volume>201</volume><number>1</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged,80andover</keyword><keyword>Antioxidants/*metabolism</keyword><keyword>Catalase/metabolism</keyword><keyword>Female</keyword><keyword>Glutathione/metabolism</keyword><keyword>GlutathionePeroxidase/metabolism</keyword><keyword>Humans</keyword><keyword>ImmunoenzymeTechniques</keyword><keyword>InflammatoryBowelDiseases/enzymology/*metabolism</keyword><keyword>IntestinalMucosa/enzymology/*metabolism</keyword><keyword>Male</keyword><keyword>Metallothionein/metabolism</keyword><keyword>MiddleAged</keyword><keyword>OxidativeStress</keyword><keyword>Peroxidase/metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0022-3417(Print) 0022-3417</isbn><accession-num>12950013</accession-num><urls></urls><electronic-resource-num>10.1002/path.1408</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[22]。随着UC的发展，结肠内炎症细胞异常活化，触发促氧化剂分子生成增加。氧化应激归因于氧化还原失衡，而氧化还原失衡是ROS的过量生成和抗氧化系统清除能力不足引起的ADDINEN.CITEADDINEN.CITE.DATA[23,24]。过多的ROS产生导致细胞蛋白质、脂质和核酸的氧化损伤，从而导致一些细胞功能障碍，促使UC的发生发展。结肠上皮细胞虽含有多种抗氧化系统，如抗氧化酶，即谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GPX）和脂氧合酶（LOXs），但它们通常在UC病理条件下失调ADDINEN.CITEADDINEN.CITE.DATA[25,26]。因此，我们认为，通过消除ROS来改善促炎微环境这一方法在促进IBD黏膜愈合方面具有巨大潜力。1.2姜黄素1.2.1姜黄素的简介姜黄素（Curcumin）是一种黄色多酚类化合物，提取自传统中药材姜黄（Curcumalonga）的根茎组织。其化学结构特征为两个邻甲氧基苯酚单元通过α,β-不饱和二酮连接桥形成高度共轭的平面结构。这一特殊构型使其能够与多种生物分子（如蛋白质、DNA）相互作用，从而表现出显著的抗炎、抗氧化、抗菌及抑制肿瘤细胞生长的功能ADDINEN.CITEADDINEN.CITE.DATA[27]。然而，姜黄素在应用中面临三大瓶颈：水溶性极低（常温下约11ng/mL，难以被肠道吸收）、口服生物利用度低（<1%）及体内快速代谢（半衰期约0.8小时）ADDINEN.CITEADDINEN.CITE.DATA[28,29]。通过结构修饰（如环糊精包合、金属螯合）或纳米递送系统（脂质体、聚合物纳米粒），可显著提升其稳定性和靶向性。实验证明，经改良的姜黄素制剂生物利用度可提升至天然姜黄素的10倍以上ADDINEN.CITE<EndNote><Cite><Author>Yallapu</Author><Year>2013</Year><RecNum>240</RecNum><DisplayText><styleface="superscript">[29]</style></DisplayText><record><rec-number>240</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1746117222">240</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yallapu,M.M.</author><author>Jaggi,M.</author><author>Chauhan,S.C.</author></authors></contributors><auth-address>CancerBiologyResearchCenter,SanfordResearch/UniversityofSouthDakota,SiouxFalls,SD57104,USA.</auth-address><titles><title>Curcuminnanomedicine:aroadtocancertherapeutics</title><secondary-title>CurrPharmDes</secondary-title></titles><periodical><full-title>CurrPharmDes</full-title></periodical><pages>1994-2010</pages><volume>19</volume><number>11</number><keywords><keyword>Animals</keyword><keyword>AntineoplasticAgents,Phytogenic/administration&</keyword><keyword>dosage/chemistry/pharmacokinetics/*therapeuticuse</keyword><keyword>BiologicalAvailability</keyword><keyword>Chemistry,Pharmaceutical</keyword><keyword>Curcumin/administration&dosage/analogs&</keyword><keyword>derivatives/chemistry/pharmacokinetics/*therapeuticuse</keyword><keyword>*DrugCarriers</keyword><keyword>Humans</keyword><keyword>*Nanomedicine</keyword><keyword>Neoplasms/*drugtherapy/metabolism/pathology</keyword><keyword>Technology,Pharmaceutical/*methods</keyword></keywords><dates><year>2013</year></dates><isbn>1381-6128(Print) 1381-6128</isbn><accession-num>23116309</accession-num><urls></urls><custom1>CONFLICTOFINTERESTTheauthorsconfirmthatthisarticlecontenthasnoconflictsofinterest.</custom1><custom2>PMC3640558</custom2><custom6>NIHMS439708</custom6><electronic-resource-num>10.2174/138161213805289219</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[29]。1.2.2姜黄素在IBD中的作用姜黄素通过干预IBD的核心信号网络发挥治疗作用。抗炎机制方面，姜黄素可直接抑制IκB激酶（IKK）的磷酸化，阻断NF-κB通路向细胞核的转位，同时下调MAPK通路中ERK和JNK蛋白的活化，从而显著减少TNF-α、IL-1β和IL-6等促炎因子的转录与分泌ADDINEN.CITE<EndNote><Cite><Author>Jurenka</Author><Year>2009</Year><RecNum>241</RecNum><DisplayText><styleface="superscript">[30]</style></DisplayText><record><rec-number>241</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1746117753">241</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Jurenka,J.S.</author></authors></contributors><auth-address>ThorneResearch,Inc.jjurenka@</auth-address><titles><title>Anti-inflammatorypropertiesofcurcumin,amajorconstituentofCurcumalonga:areviewofpreclinicalandclinicalresearch</title><secondary-title>AlternMedRev</secondary-title></titles><periodical><full-title>AlternMedRev</full-title></periodical><pages>141-53</pages><volume>14</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Anti-InflammatoryAgents/*pharmacology/*therapeuticuse</keyword><keyword>AntineoplasticAgents/pharmacology/therapeuticuse</keyword><keyword>AutoimmuneDiseases/drugtherapy</keyword><keyword>CardiovascularDiseases/drugtherapy</keyword><keyword>ClinicalTrialsasTopic</keyword><keyword>Curcuma</keyword><keyword>Humans</keyword><keyword>Inflammation/drugtherapy</keyword><keyword>MetabolicDiseases/drugtherapy</keyword><keyword>Neoplasms/drugtherapy</keyword><keyword>NeurodegenerativeDiseases/drugtherapy</keyword><keyword>PlantExtracts/*pharmacology/*therapeuticuse</keyword></keywords><dates><year>2009</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1089-5159(Print) 1089-5159</isbn><accession-num>19594223</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[30]。此外，姜黄素促进Nrf2与抗氧化反应元件（ARE）结合，驱动超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）的基因表达，将肠道内ROS水平降低40%～60%ADDINEN.CITEADDINEN.CITE.DATA[31]。此外，姜黄素可上调肠上皮细胞中Occludin和ZO-1等紧密连接蛋白的合成，修复因炎症损伤而增大的细胞间隙，有效阻止细菌内毒素从肠腔向血液的易位ADDINEN.CITEADDINEN.CITE.DATA[32]。姜黄素对IBD的治疗作用还体现在肠道菌群重塑上。其通过抑制革兰氏阴性致病菌（如肠杆菌科）脂多糖（LPS）的生物合成，减少TLR4/MyD88通路介导的免疫激活，同时促进乳酸菌和双歧杆菌等益生菌的增殖，从而改善肠道菌群多样性并恢复微生态平衡ADDINEN.CITEADDINEN.CITE.DATA[33]。1.3氧化铈1.3.1氧化铈的简介氧化铈（CeO2）作为一种稀土氧化物，因其独特的萤石型立方晶系结构及可调控的表面特性，在纳米材料领域展现出重要应用价值。其晶体结构由Ce⁴⁺离子构成的八面体骨架与O²⁻离子共同构成，通过水热法、溶胶-凝胶法等合成策略可精准调控材料形貌，获得纳米颗粒、纳米线、纳米管及纳米片等不同维度结构ADDINEN.CITE<EndNote><Cite><Author>Ma</Author><Year>2022</Year><RecNum>162</RecNum><DisplayText><styleface="superscript">[34]</style></DisplayText><record><rec-number>162</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1716803446">162</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ma,Y.</author><author>Tian,Z.</author><author>Zhai,W.</author><author>Qu,Y.</author></authors></contributors><auth-address>KeyLaboratoryofSpecialFunctionalandSmartPolymerMaterialsofMinistryofIndustryandInformationTechnology,SchoolofChemistryandChemicalEngineering,NorthwesternPolytechnicalUniversity,Xi'an,710072China.GRID:grid.440588.5.ISNI:0000000103071240</auth-address><titles><title>InsightsoncatalyticmechanismofCeO(2)asmultiplenanozymes</title><secondary-title>NanoRes</secondary-title></titles><periodical><full-title>NanoRes</full-title></periodical><pages>10328-10342</pages><volume>15</volume><number>12</number><edition>20220711</edition><keywords><keyword>ceria</keyword><keyword>heterogeneouscatalysis</keyword><keyword>nanozyme</keyword><keyword>oxygenvacancy</keyword></keywords><dates><year>2022</year></dates><isbn>1998-0124(Print) 1998-0000</isbn><accession-num>35845145</accession-num><urls></urls><custom2>PMC9274632</custom2><electronic-resource-num>10.1007/s12274-022-4666-y</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[34]。值得注意的是，纳米CeO₂的物理化学性质（如比表面积、氧空位浓度）和催化活性高度依赖于其形貌特征，这为功能化设计提供了关键切入点。CeO2纳米材料的生物医学应用潜力主要归因于其类酶抗氧化活性，可模拟过氧化氢酶（CAT）、过氧化物酶（POD）及超氧化物歧化酶（SOD）的催化功能ADDINEN.CITE<EndNote><Cite><Author>李锋</Author><Year>2022</Year><RecNum>52</RecNum><DisplayText><styleface="superscript">[35]</style></DisplayText><record><rec-number>52</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1712477047">52</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>李锋</author><author>李雪</author><author>柏娜</author><author>李健</author></authors></contributors><auth-address>青岛大学口腔医学院;青岛大学附属医院口腔修复科;</auth-address><titles><title>氧化铈纳米颗粒促成骨分化及其对相关致病菌抗菌作用的研究进展</title><secondary-title>吉林大学学报(医学版)</secondary-title></titles><periodical><full-title>吉林大学学报(医学版)</full-title></periodical><pages>1348-1353</pages><volume>48</volume><number>05</number><keywords><keyword>氧化铈纳米颗粒</keyword><keyword>氧化还原反应</keyword><keyword>促成骨分化作用</keyword><keyword>抗菌作用</keyword></keywords><dates><year>2022</year></dates><isbn>1671-587X</isbn><urls><related-urls><url>/doi/10.13481/j.1671-587X.20220531</url></related-urls></urls><electronic-resource-num>10.13481/j.1671-587X.20220531</electronic-resource-num><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[35]。这种多酶仿生特性使其能够高效清除自由基及活性氧（ROS），从而有效保护生物系统免受氧化损伤。其抗氧化机制的核心在于Ce³⁺/Ce⁴⁺氧化还原对的动态循环：Ce⁴⁺的半充满4f轨道（电子构型[Xe]4f⁰）赋予其强氧化性，而Ce³⁺的未成对4f电子（[Xe]4f¹）则使其具备还原能力。这种独特的电子结构使CeO₂在反应中可逆地发生Ce⁴⁺↔Ce³⁺的价态转换，不仅驱动了ROS的歧化与分解，还为其催化氧化反应（如CO氧化）、还原反应（如NOx转化）及裂解反应（如水分解）提供了电子传递通道ADDINEN.CITE<EndNote><Cite><Author>Chen</Author><Year>2022</Year><RecNum>154</RecNum><DisplayText><styleface="superscript">[36]</style></DisplayText><record><rec-number>154</rec-number><foreign-keys><keyapp="EN"db-id="atzs09sav2att3edf5tv9vryrftrsvdx02s5"timestamp="1716799468">154</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chen,Xiwen</author><author>Cheng,Chaoqun</author><author>Cheng,Yuan</author><author>Zhao,Sheng</author><author>Wei,Hui</author></authors></contributors><auth-address>CollEngn&ApplSci,DeptBiomedEngn,NanjingNatlLabMicrostruct,JiangsuKeyLabArtificialFunctMat,Nanjing210023,PeoplesRChina NanjingUniv,Chem&BiomedInnovatCtrChemBIC,SchChem&ChemEngn,StateKeyLabAnalytChemLifeSci,Nanjing210023,PeoplesRChina NanjingUniv,Chem&BiomedInnovatCtrChemBIC,SchChem&ChemEngn,StateKeyLabCoordinatChem,Nanjing210023,PeoplesRChina</auth-address><titles><title>CeO2@montmorilloniteNanozymeforCrohn'sDiseaseTherapy</title><secondary-title>CHEMICALJOURNALOFCHINESEUNIVERSITIES-CHINESE</secondary-title></titles><periodical><full-title>CHEMICALJOURNALOFCHINESEUNIVERSITIES-CHINESE</full-title></periodical><volume>43</volume><number>12</number><section>CollEngn&ApplSci<