DOI:10.20047/j.issn1673-7210.26012333
中图分类号:R977
张建青, 牛钦, 陈莹, 欧阳杰, 思永玉
| 【作者机构】 | 昆明医科大学第二附属医院麻醉科 |
| 【分 类 号】 | R977 |
| 【基 金】 | 云南省科技厅基础研究计划项目(202401AT070024) 昆明医科大学硕士研究生创新基金项目(2025S097)。 |
虾青素是叶黄素家族天然类胡萝卜素,化学名称为3,3’-二羟基-4,4’-二酮基-β,β’-胡萝卜素(C40H52O4,相对分子质量596.86),其分子结构中的不对称碳原子与长链共轭双键,是其强抗氧化及抗炎活性的结构基础[1]。天然虾青素主要来源于雨生红球藻(含量达细胞干重2%~4%)、红发夫酵母等,也存在于鲑鱼、磷虾等水生动物中,全反式结构使其生物活性高、安全性佳;合成虾青素多为顺反异构体混合物,生物利用度低且长期大量摄入可能有潜在健康影响[2-3]。其抗氧化能力是维生素E的550倍、维生素C的1 000倍,可高效清除活性氧(reactive oxygen species,ROS)、抑制脂质过氧化,同时兼具抗凋亡、免疫调节等功能[4]。随着剂型优化技术发展,其生物利用度与靶向性显著提升,在炎症相关疾病防治中的潜力备受关注。
虾青素可穿透血-脑屏障,靶向调控脑内炎症,发挥神经保护作用。在阿尔茨海默病中,其可降低神经炎症介质如神经胶质细胞原纤维酸性蛋白和肿瘤坏死因子-α水平,减轻脂质过氧化,改善认知功能[5-6]。二十二碳六烯酸酰化修饰的虾青素-二十二碳六烯酸在抑制神经炎症、减少β-淀粉样蛋白及磷酸化tau蛋白沉积方面的疗效优于游离虾青素,提示分子(及剂型)修饰是提升其生物活性的重要方向[7]。此外,氧化应激平衡调控是虾青素抗炎的核心关联通路,该通路与其他抗氧化剂的联合应用,为优化阿尔茨海默病病理进程干预方案提供新思路[8]。
对帕金森病,虾青素-二十二碳六烯酸通过线粒体通路及JNK、p38 MAPK信号通路抑制多巴胺能神经元凋亡,改善小鼠行为缺陷[9];游离虾青素可调控miR-7/SNCA轴抑制内质网应激,阻断帕金森病进展[10];MAPK信号通路抑制是其应对百草枯诱导帕金森病模型的关键机制[11]。乳铁蛋白修饰脂质体可提升虾青素脑穿透性与细胞摄取效率,通过抑制胶质细胞活化、强化抗氧化及抗炎效应,为帕金森病靶向治疗提供新策略[12]。
针对缺血性脑损伤,其通过激活Nrf-2/HO-1信号通路、调节NF-κB平衡,下调促炎性细胞因子表达,抑制氧化应激与神经元凋亡,保护血-脑屏障完整性,且其抗炎作用呈现一定剂量相关性,中等剂量下对脑组织炎症损伤的抑制效果更显著[13-16]。
综上所述,虾青素在神经退行性疾病及脑损伤中的抗炎作用具有通路多样性,分子及剂型改良与剂量优化是提升其临床应用潜力的核心抓手,但其组织特异性调控机制仍需进一步明确。
虾青素可针对性干预胃肠道疾病炎症进程,核心通过调控NF-κB及下游通路实现抗炎护膜效应。对非甾体抗炎药诱导的胃溃疡、新生儿坏死性小肠结肠炎及葡聚糖硫酸钠诱导的结肠炎,虾青素分别通过下调NF-κB/Caspase-3表达、抑制TLR4/NF-κB信号通路、阻断NF-κB/AP-1/MAPK信号通路发挥作用,且对结肠炎的改善呈剂量依赖性,纳米载体修饰后可通过靶向线粒体进一步提升疗效[17-20]。调节肠道菌群及短链脂肪酸水平、维持胃肠道稳态则拓展其抗炎作用的多维机制[21]。虾青素对胃肠道炎症的干预兼具针对性与广谱性,剂型改良可突破其生物利用度瓶颈,但其在慢性胃肠道疾病中的长期干预效果及与临床常规药物的协同作用,仍需更多临床数据支撑。
虾青素通过抗炎-抗氧化交互调控,改善糖尿病及并发症损伤。可调节NOX4、Nrf2等信号通路,修复糖尿病心肌病和肾病的炎症与氧化应激损伤[22];针对糖尿病视网膜病变,激活Nrf2/Keap1信号通路并调控ROS-PI3K/Akt-NF-κB级联,抑制炎症与凋亡,同时可改善糖尿病相关牙周破坏、认知障碍及妊娠糖尿病症状[23-27]。对糖尿病肾病,虾青素不仅能减轻线粒体氧化应激,还可抑制非酶糖基化终末产物诱导的细胞紊乱[28]。体现其多维度抗炎护肾效能。虾青素的抗炎-抗氧化协同效应是其改善糖尿病并发症的核心优势,但其在不同并发症中的最优剂量、疗程差异尚未明确,联合抗氧化剂的抗炎干预方案值得进一步探索。
虾青素具有多途径、多靶点抗炎镇痛活性,可覆盖炎性疼痛、神经性疼痛等多种类型。炎性疼痛中,其通过抑制COX-2、p38 MAPK信号通路及调控Nrf2/HO-1信号通路发挥作用,与塞来昔布联用可产生协同效应[29-32]。神经性疼痛及慢性盆腔疼痛中,NF-κB、ERK1/2信号通路抑制与肠道菌群调节是关键机制[33-36]。此外,虾青素可通过抑制NLRP3炎症小体缓解纤维肌痛相关疼痛及抑郁症状,还能调控ERK、Akt信号通路减轻脊髓损伤后疼痛[37-39]。虾青素的镇痛作用与抗炎机制深度绑定,且适用疼痛类型广泛,为慢性疼痛的非甾体类药物替代干预提供新方向,但其在临床疼痛管理中的定位仍需大样本量研究验证。
虾青素在动脉粥样硬化、心肌损伤等心血管疾病中展现显著抗炎保护作用,核心依赖TLR4/NF-κB、氧化应激相关通路调控。其可减轻异丙肾上腺素诱导的心肌损伤,缓解慢性间歇性低压缺氧所致右心室肥厚,并通过抑制自噬、铁死亡及炎症反应,改善多柔比星、PM2.5诱导的心肌损伤[40-43]。在动脉粥样硬化模型中,虾青素通过circTPP2/miR-3073b-5p/ABCA1信号通路调节脂质代谢与炎症状态,保护心血管功能[44-45]。线粒体功能保护与炎症相关蛋白表达调控则进一步强化其效能,现有研究凸显虾青素在心血管炎症干预中的广谱性,但其在不同心血管疾病中的通路特异性差异,为精准干预方案的制订提供研究方向,剂量优化与联合用药是未来探索重点[46-47]。
针对药物性肝损伤,虾青素可下调肿瘤坏死因子-α等炎症因子,激活Nrf2/HO-1信号通路,缓解5-氟尿嘧啶、对乙酰氨基酚诱导的肝脏毒性[48-49]。对真菌毒素诱导损伤,可抑制白细胞介素-6、白细胞介素-1β释放,调节内质网应激与线粒体平衡[50]。对代谢性肝病,可通过调控AMPK/Nrf2轴、抑制miR-21等,减轻非酒精性脂肪肝及高脂饮食诱导的肝脏脂肪变性[51-52]。在酒精性肝损伤中,虾青素可通过修复线粒体中的氧化还原平衡与钙稳态,激活Nrf2/ARE信号通路减少脂质过氧化产物生成,发挥抗炎保护作用,纳米载体制剂能强化肝组织靶向抗炎与抗氧化效果[53-55]。此外,虾青素可通过调节p38 MAPK及PI3K/Akt信号通路,抑制高糖诱导的肝细胞炎症与凋亡,在自身免疫性肝炎中还能通过调控CD8+T淋巴细胞功能及炎症因子分泌,减轻肝组织免疫炎症损伤[56-57]。综上所述,虾青素对肝损伤的干预覆盖多类型诱因,通路调控具有针对性,剂型改良是提升其临床应用潜力的重要方向。
虾青素凭借显著的抗炎活性,对多种诱因引发的肾损伤发挥保护作用,其机制涉及多条信号通路的调控及炎症反应的多环节抑制。缺血再灌注性肾损伤中,可降低肾组织炎症水平,减少凋亡与组织损伤[58]。对造影剂诱导的急性肾损伤,通过SIRT1/p53信号通路及抑制ROS/NLRP3轴,减轻炎症与氧化应激[59-60]。对顺铂、锂中毒性肾损伤,分别调控MALAT-1/miR-146a/NF-κB信号通路及NF-κB/p65活性,改善肾功能,同时可缓解高糖饮食、阿特拉津及烧伤诱导的肾损伤,其多靶点抗炎特性为复杂诱因所致肾损伤的干预提供新思路,但不同肾损伤类型的最优干预剂量与疗程仍需进一步验证[61-65]。
急性皮肤创伤中,虾青素抑制炎症细胞浸润及肿瘤坏死因子-α、白细胞介素-6表达,促进M2型巨噬细胞极化,加速创面愈合[66]。对紫外线B诱导的皮肤损伤,可清除ROS、抑制角质形成细胞凋亡,离子液体脂质体修饰后,通过调控TGF-β1/smad信号通路增强抗炎效能[67-68]。此外,可促进Nrf2核转位,缓解高糖诱导的成纤维细胞衰老,同时改善皮肤屏障功能,发挥抗衰作用[69-70]。综上所述,虾青素对皮肤的保护作用兼具抗炎、抗氧化与修复特性,适配急性损伤、光老化等多种场景,局部靶向剂型的开发是其拓展皮肤护理与治疗应用的关键。
虾青素对干眼症具有显著抗炎护眼效果,可抑制高迁移率组蛋白B1、肿瘤坏死因子-α、白细胞介素-1β表达,调控PI3K/Akt信号通路以减轻眼表上皮炎症[71]。同时激活Keap1/Nrf2/HO-1信号通路,协同抑制炎症与氧化应激,保护角膜上皮细胞活力,还可通过强化SLC7A11/GPX4信号通路抑制角膜上皮细胞铁死亡[72];高亲和力脂质体剂型可提升角膜亲和力,进一步强化抗炎效果[73]。目前虾青素眼部应用研究集中于干眼症,其在结膜炎、角膜炎等其他眼部炎症疾病中的潜力仍需进一步探索。
多项随机对照试验研究证实虾青素的抗炎效能,如2型糖尿病患者每日补充10 mg虾青素,可下调炎症相关miRNA及白细胞介素-6、肿瘤坏死因子-α表达,改善代谢指标[74]。社区获得性肺炎患者每日12 mg虾青素联合抗生素治疗,可显著降低促炎性细胞因子水平,改善疾病严重程度评分[75]。心力衰竭患者每日20 mg虾青素干预8周,可抑制氧化应激与全身炎症,实现对心血管系统的保护作用[76]。针对职业消防员的研究显示,每日补充12 mg虾青素连续4周,能减轻增量最大运动测试中的炎症应答,抑制灭火作业时白细胞介素-1β、皮质醇及尿酸水平的升高,进而改善心血管健康,为高应激职业群体的炎症管理提供新思路[77]。在口腔领域,含虾青素牙科凝胶可缩短义齿适应时间,降低口腔炎风险[78];口腔黏膜下纤维化患者每日服用10 mg虾青素(分两次),可改善张口度及烧灼感[79]。在皮肤健康方面,每日4 mg虾青素补充4周可改善皮肤表面成分,实现年轻化效果[80]。Ng等[81]研究证实,现有临床数据支持每日3~6 mg虾青素补充对皮肤健康的益处,尤其适用于光老化皮肤的改善。此外,每日8 mg虾青素可缓解多囊卵巢综合征炎症状态[82]。
临床研究初步验证虾青素在多系统炎症干预中的安全性与有效性,但现有数据仍存在样本量小、场景局限等问题,难以形成统一临床应用指南。
尽管虾青素的抗炎作用在基础实验中得到充分验证,但其临床研究及转化仍存在以下局限性:①临床研究数量少、样本量小,多聚焦于健康群体或轻症患者,缺乏重症疾病大样本量长期随访数据,难以充分验证临床有效性与安全性;②研究设计异质性大,剂量、疗程、给药途径不一致,无法横向比较以确定最优方案;③作用机制尚未完全阐明,组织特异性调控、与其他物质协同效应及代谢产物活性仍不明确;④自身理化性质局限(水溶性差、稳定性低),改良剂型的临床研究及转化处于初级阶段;⑤文献检索存在遗漏,非英文及未公开发表的相关研究未纳入,影响结论全面性。
虾青素凭借多靶点、多通路协同抗炎特性,核心通过调控NF-κB、MAPK、Nrf2/HO-1等关键信号通路,在多系统炎症相关疾病中展现广泛保护潜力,天然虾青素及其分子修饰、改良剂型的生物利用度与效能更具优势。现有研究为临床转化奠定基础,但仍需突破临床研究规模、机制解析及产业化技术等瓶颈。
未来可聚焦于以下3个方面的研究:①开展大样本量、多中心长期临床试验,明确摄取方式、量-效关系及联合抗炎方案;②借助组学技术解析抗炎分子网络,挖掘虾青素对各类炎症相关疾病的特异性靶点;③优化提取与剂型技术,开发低成本靶向制剂,探索协同作用以拓展应用场景。虾青素凭借天然安全性与广谱抗炎活性,有望成为炎症相关疾病防治的新型候选物质和天然先导化合物,具有重要研究价值与广阔的应用前景。
利益冲突声明:所有作者均声明不存在利益冲突。
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Research progress on anti-inflammatory mechanism of astaxanthin and its preventive and therapeutic effects on various diseases
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