中国药学杂志

No.	黄酮类化合物	R3	R5	R6	R7	R8	R2'	R3'	R4'	R5'
1	Naringin	H	OH	ONG	H	H	H	OH	H	H
2	Baicalin	H	OH	OH	Ge	H	H	H	H	H
3	Quercetin	OH	OH	H	OH	H	H	H	OH	OH
4	Hyperoside	OGA	OH	H	OH	H	H	H	OH	OH
5	Isorhamnetin	OH	OH	H	OH	H	H	OCH₃	OH	H
6	Rutin	ORG	OH	H	OH	H	H	OH	OH	H
7	Luteolin	H	OH	H	OH	H	H	OH	OH	H
8	Myricetin	OH	OH	H	OH	H	H	OH	OH	OH
9	Kaempferol	OH	OH	H	OH	H	H	H	OH	H
10	Silibinin	OH	OH	H	OH	H
11	Fisetin	OH	H	H	OH	H	H	OH	OH	H
12	Taxifolin	OH	OH	H	OH	H	H	H	OH	OH
13	Farrerol	H	OH	CH₃	OH	CH₃	H	H	OH	H
14	Puerarin	-	H	H	OH	Cglc	H	H	OH	H
15	Daidzein	-	H	H	OH	H	H	H	OH	H
16	Hesperetin	-	H	OH	H	OH	H	OH	OH	H
17	Genistein	-	OH	H	OH	H	H	H	OH	H
18	Icariin	ORH	OH	H	OGL	-	H	H	OCH₃	H
19	Isoliquiritigenin	OH	H	-	-	-	H	H	OH	H
20	Mangiferin	-	H	OH	Cglc	OH	H	OH	OH	H

No.	黄酮类化合物	R3	R5	R6	R7	R8	R2'	R3'	R4'	R5'
1	Naringin	H	OH	ONG	H	H	H	OH	H	H
2	Baicalin	H	OH	OH	Ge	H	H	H	H	H
3	Quercetin	OH	OH	H	OH	H	H	H	OH	OH
4	Hyperoside	OGA	OH	H	OH	H	H	H	OH	OH
5	Isorhamnetin	OH	OH	H	OH	H	H	OCH₃	OH	H
6	Rutin	ORG	OH	H	OH	H	H	OH	OH	H
7	Luteolin	H	OH	H	OH	H	H	OH	OH	H
8	Myricetin	OH	OH	H	OH	H	H	OH	OH	OH
9	Kaempferol	OH	OH	H	OH	H	H	H	OH	H
10	Silibinin	OH	OH	H	OH	H
11	Fisetin	OH	H	H	OH	H	H	OH	OH	H
12	Taxifolin	OH	OH	H	OH	H	H	H	OH	OH
13	Farrerol	H	OH	CH₃	OH	CH₃	H	H	OH	H
14	Puerarin	-	H	H	OH	Cglc	H	H	OH	H
15	Daidzein	-	H	H	OH	H	H	H	OH	H
16	Hesperetin	-	H	OH	H	OH	H	OH	OH	H
17	Genistein	-	OH	H	OH	H	H	H	OH	H
18	Icariin	ORH	OH	H	OGL	-	H	H	OCH₃	H
19	Isoliquiritigenin	OH	H	-	-	-	H	H	OH	H
20	Mangiferin	-	H	OH	Cglc	OH	H	OH	OH	H

常见黄酮类天然产物对牙槽骨骨稳态的骨免疫调控研究

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黄越 ¹^,² , 柳芳洲 ¹ , 赵奕菲 ¹ , 李悦瑞 ¹ , 白国辉 ¹ , 胡欢 ¹^,²^,^*

中国药学杂志 | 综述 2025,60(2): 153-165

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中国药学杂志 | 综述 2025, 60(2): 153-165

常见黄酮类天然产物对牙槽骨骨稳态的骨免疫调控研究

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黄越¹^,², 柳芳洲¹, 赵奕菲¹, 李悦瑞¹, 白国辉¹, 胡欢¹^,²^,^*

作者信息

¹ 遵义医科大学口腔医学院, 贵州遵义 563000

² 贵州省普通高等学校微生物资源与药物开发特色重点实验室, 贵州遵义 563000

黄越,女,硕士研究生研究方向:口腔微生态及口腔感染性疾病的防治

通讯作者:

*胡欢,女,博士,副教授,硕士生导师研究方向:口腔微生态及口腔感染性疾病的防治,天然产物发现及生物合成 Tel:(0851)28609493

Advances in Osteoimmunological Modulation of Common Flavonoids in Alveolar Bone Homeostasis

Yue HUANG¹^,², Fangzhou LIU¹, Yifei ZHAO¹, Yuerui LI¹, Guohui BAI¹, Huan HU¹^,²^,^*

Affiliations

¹ School of Stomatology, Zunyi Medical University, Zunyi 563000, China

² Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Zunyi 563000, China

出版时间: 2025-01-22 doi: 10.11669/cpj.2025.02.007

文章导航

摘要

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“骨免疫”强调免疫系统与骨骼系统细胞间的相互作用,免疫失调会引起炎症刺激,释放出大量影响骨代谢的炎症因子。牙周炎是一种以牙菌斑为始动因子,宿主免疫炎症反应、遗传和环境等多种因素造成的牙周组织炎症性破坏的疾病。炎症反应和牙槽骨吸收是牙周炎的两大特征,免疫系统失调会引起骨稳态失衡(骨形成和吸收的平衡紊乱),导致牙槽骨丧失。黄酮类天然产物具有抗炎、抗氧化、促成骨及抗微生物等生物学活性,可有效改善过度炎症对牙周组织的损伤。本文概述了牙槽骨炎性吸收过程中可能涉及到的9条经典炎症信号通路,并从抑制炎症反应和调节炎症信号通路的方面梳理了近年来报道较多的20个黄酮类天然产物在抑制牙周炎相关牙周组织破坏方面的机制研究进展,以期为牙周炎的治疗策略提供理论基础和新的思路。

关键词

天然产物 / 炎症反应 / 信号通路 / 牙周炎 / 骨免疫学

Abstract

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"Osteoimmunology" is a field that emphasizes the interaction between the immune system and skeletal system cells. Specifically, it explores how dysregulation of the immune system can result in inflammatory stimulation and the release of inflammatory factors, which significantly impact bone metabolism. Periodontitis is an inflammatory destructive disease of periodontal tissue, triggered initially by dental plaque and influenced by host immune inflammatory responses, genetic factors, and environmental factors. Inflammatory response and alveolar bone resorption stand out as prominent features of periodontitis, with immune system imbalance disrupting bone homeostasis, resulting in alveolar bone loss due to the imbalance of bone formation and resorption. Flavonoid natural products exhibit biological activities such as anti-inflammatory, antioxidant, osteogenic promotion, and antimicrobial effects, effectively ameliorating inflammatory damage to periodontal tissues. This paper provides an overview of nine classical inflammatory signaling pathways potentially involved in alveolar bone inflammatory resorption and reviews advancements in the mechanisms of action of 20 flavonoids reported for inhibiting periodontal tissue destruction associated with periodontitis by suppressing inflammatory responses and modulating inflammatory signaling pathways. The aim is to offer theoretical foundations and novel insights to enhance the treatment strategy of periodontitis.

Key words

natural product / inflammatory response / signaling pathway / periodontitis / osteoimmunology

引用本文

黄越, 柳芳洲, 赵奕菲, 李悦瑞, 白国辉, 胡欢. 常见黄酮类天然产物对牙槽骨骨稳态的骨免疫调控研究. 中国药学杂志, 2025 , 60 (2) : 153 -165 . DOI: 10.11669/cpj.2025.02.007

Yue HUANG, Fangzhou LIU, Yifei ZHAO, Yuerui LI, Guohui BAI, Huan HU. Advances in Osteoimmunological Modulation of Common Flavonoids in Alveolar Bone Homeostasis[J]. Chinese Pharmaceutical Journal, 2025 , 60 (2) : 153 -165 . DOI: 10.11669/cpj.2025.02.007

正文

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牙周炎是发生在牙周支持组织的慢性感染性疾病,是一种多因素性疾病,菌斑微生物为发病的始动因子。微生物与宿主免疫系统之间的失衡,导致白细胞介素-1β(Interleukin-1β, IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)等多种促炎性细胞因子产生,刺激牙周硬组织破骨细胞增殖,诱导牙周软组织细胞外基质降解,限制骨形成并最终导致牙脱落^[1]。

近年来兴起的交叉学科—“骨免疫学”强调骨骼系统和免疫系统在生理和病理状态下,共享的信号转导通路、细胞因子、趋化因子、激素和转录因子等介导骨细胞与免疫细胞间的相互作用^[2-3]。Wnt、Toll样受体(toll-like receptor,TLR)、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK) 、NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)炎性小体和核因子-κB(nuclear factor-κB,NF-κB)等信号通路通过调控破骨细胞、成骨细胞、骨细胞、牙周韧带细胞、巨噬细胞和适应性免疫细胞的增殖、分化、凋亡和自噬等生命活动,调节炎症介质表达,影响核因子-κB受体活化因子配体(receptor activator for nuclear factor-κB ligand,RANKL)/ 核因子-κB受体活化因子(receptor activator for nuclear factor-κB,RANK)/ 骨保护素(osteoprotegerin,OPG)系统平衡,参与牙槽骨修复重建。此外,牙槽骨的骨改建也涉及磷脂酰肌醇3-激酶(phosphatidyl inositol 3-kinase,PI3K)/蛋白激酶B(protein kinase B,AKT)、Janus 激酶(Janus kinase,JAK)/转录激活因子(signal transducer and activator of transcription,STAT)和转化生长因子-β(transforming growth factor β,TGF-β)等信号通路。这些信号通路相互交织构成复杂的调控网络,介导牙槽骨骨稳态(图1)。

牙周炎的治疗主要包括基础治疗、药物治疗和手术治疗等。现有的牙周炎治疗药物主要以抗菌、消炎或促再生为目的,抑制已产生的炎症,并促进缺损组织的再生修复。黄酮类天然产物近年来在牙周炎治疗中显示出巨大的应用价值,它们主要通过调控炎症信号通路抑制炎症细胞因子、破骨细胞的生成,同时抑制氧化应激反应,达到抗炎、抗氧化、促成骨等作用。

1 骨免疫学与牙周炎

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骨骼和免疫系统之间存在双向动态作用关系,免疫调节失衡产生的大量炎症细胞和促炎细胞因子通过复杂的互作网络参与骨稳态的调节,导致不同程度的骨丢失^[4]。牙周炎是一种会引起炎症性骨流失的慢性病。患牙周炎时,微生物与宿主间异常的相互作用持续激活免疫系统,诱导炎性免疫反应,进而导致骨流失。生理条件下,B细胞可分泌OPG来抑制RANKL-RANKL受体相互作用,导致破骨细胞的分化成熟发生障碍,抑制破骨细胞的骨吸收功能;骨代谢紊乱时,炎症状态下活化的T细胞、B细胞和巨噬细胞分泌促破骨细胞生成因子,如IL-1β、TNF-α、RANKL等,通过MAPK、NF-κB和PI3K/ AKT、JAK/STAT等途径直接刺激破骨细胞分化,干扰成骨细胞功能,导致局部骨质破坏^[5-7]。此外,IL-1β、TNF-α、RANKL/OPG是评估牙周炎症和骨破坏的重要标志,还可以促进组织蛋白酶和胶原溶解酶(基质金属蛋白酶,matrix metalloproteinase,MMP)的表达,导致细胞外间质降解而限制骨形成并造成组织破坏^[8-10]。

1.1 关键免疫细胞和细胞因子在牙周炎骨吸收中的作用

牙周致病菌感染诱发的宿主过度免疫反应被认为是牙周炎发病的重要机制,涉及的主要免疫细胞包括单核/巨噬细胞、T细胞和B细胞等^[11]。

根据功能可将巨噬细胞分为2类,即M1、M2型巨噬细胞;M1型巨噬细胞在免疫反应中可促进机体炎症反应,M2型巨噬细胞可促进细胞增殖和组织修复^[12]。巨噬细胞在牙周致病菌及其代谢物刺激下,如牙龈卟啉单胞菌的产物脂多糖(Porphyromonas gingivalis lipopolysaccharide,P.g-LPS)与巨噬细胞受体TLR4结合后激活巨噬细胞向M1极化,分泌TNF-α、IL-1、IL-6、MMP等促炎因子,促进牙周组织局部炎症^[13-16]。

牙周致病菌及其毒素在入侵牙周组织时,可激活局部免疫环境中的固有免疫应答和特异性免疫应答,辅助性T(helper T,Th)细胞介导的细胞免疫应答是特异性免疫应答的重要组成部分。根据Th细胞在炎性疾病中的作用,可将其分为Th1、Th2、Th17及调节性T细胞(regulatory T cells,Treg)4种细胞亚型^[17]。这4种细胞分别通过分泌不同的细胞因子(IFN-γ、IL-4、IL-17A和IL-10)来介导牙周炎局部的组织损伤^[18-19]。慢性牙周炎患者外周血Treg降低,Th17升高,随着病情加重,Th17/Treg比率进一步上升^[20]。

B细胞在慢性牙周炎中具有双重作用,它是RANKL的重要来源,能诱导RANKL依赖性的牙槽骨破坏^[21]。此外,B细胞也可以在牙周炎时发挥保护作用,将B10细胞应用于全身治疗小鼠实验性牙周炎时,可以减少小鼠牙龈组织中RANKL /OPG、TNF-α和IL-1β的表达,促进抑炎因子IL-10的产生^[22]。

1.2 关键炎症信号通路在牙周炎骨吸收中的作用

1.2.1 RANKL/RANK/OPG信号通路

在牙槽骨重建过程中,RANKL/RANK/OPG信号通路主要参与破骨细胞的激活,导致骨吸收^[23]。RANKL多肽是发现于成骨细胞或基质细胞表面的Ⅱ型跨膜蛋白,它直接与破骨细胞表面的同源受体RANK相互作用。当RANKL与其受体RANK结合时,肿瘤坏死因子受体相关因子6(tumor necrosis factor receptor-associated factor,TRAF6)被召集,激活下游核因子NF-κB相关信号级联,引起NF-κB核易位,启动破骨细胞特异性基因转录,促进破骨细胞分化、融合、活化和存活^[24]。OPG是一种可溶性RANKL诱饵受体,主要由成骨细胞产生,可通过阻止RANKL与RANK结合来抑制破骨细胞骨吸收^[25]。生理状态下,RANKL的表达弱于OPG,破骨细胞生成较少,牙周内环境相对稳定;而牙周病活跃期可观察到RANKL/OPG系统失衡,表现为 RANKL表达增高,OPG降低,促进破骨细胞形成,引起牙槽骨骨质吸收,影响其骨密度和骨强度^[19,26]。

1.2.2 NF-κB信号通路

NF-κB 被称为炎症调控的开关,其转录入核活化可促进炎症因子转录释放^[27]。经典激活途径是由各种先天和后天的免疫介质诱导发生的,如促炎细胞因子(TNFα、IL-1β)、Toll样受体(TLRs)和T细胞抗原受体(TCR、BCR)结合体^[28-29],激活κB抑制因子激酶,促进NF-κB异二聚体RelA/p50瞬时核易位,调控促炎基因转录^[30]。大量研究表明,口腔致病菌及其毒性产物LPS可以通过经典的NF-κB信号通路诱导炎性巨噬细胞激活^[31],通过产生促炎因子,如TNF-α、IL-1β、活性氧(reactive oxygen species,ROS)等增强炎症反应并加重牙周骨组织破坏^[32]。例如,P.g-LPS可以促进NF-κB p65磷酸化,通过激活NF-κB信号通路增强IL-1β、IL-6等相关炎症因子的表达,进一步引发炎症反应,刺激破骨细胞中的RANKL表达使得破骨细胞活化,最终导致骨吸收^[33]。通过腹腔注射吡非尼酮抑制NF-κB信号通路,可导致LPS诱导的促炎细胞因子如IL-1β、IL-6、TNF-α等表达受到抑制,RANKL诱导的破骨细胞生成下降,明显减轻实验小鼠牙周炎的牙槽骨损失^[34]。

1.2.3 TLR信号通路

TLR4是连接固有免疫和适应性免疫的关键桥梁^[35]。据报道^[36],TLR4可介导革兰阴性菌LPS引起的人牙周膜成纤维细胞(human periodontal ligament fibroblast,hPDLF)的炎症反应以及牙槽骨的破坏。牙周致病菌通过LPS-TLR4 途径长期刺激机体,一方面促进牙周组织细胞与免疫细胞表面RANK的表达;同时介导细胞反应释放的促炎因子如IL-6、TNF-α,进一步促进T细胞与B细胞表达RANKL,显著增加局部RANKL的表达^[37]。TLR4还可通过靶向髓样分化因子88(myeloid differentiation factor 88,MyD88)激活 NF-κB 促炎信号通路,促使效应细胞分泌细胞因子,在炎症反应中发挥重要作用^[38]。在慢性牙周炎的牙周组织中TLR4及其下游MyD88、NF-κB的表达均明显增加,TLR4通过细胞内 MyD88 进行信号转导,激活NF-κB后使其入核并启动TNF-α、IL-6的表达^[39-41]。

1.2.4 Wnt/β-catenin信号通路

Wnt蛋白配体与细胞膜上的Frizzled受体、低密度脂蛋白受体相关蛋白5/6(low density lipoprotein receptor-related protein 5/6,LRP 5/6)等结合形成异源二聚体复合物,激活经典(依赖β-catenin)和非经典Wnt(不依赖β-catenin)信号通路介导细胞内信号的传递^[42]。Wnt/β-catenin通路在骨形成中起关键作用:当该通路被激活时,骨形成启动;当它被抑制时,骨形成则受阻^[43]。Wnt/β-catenin信号通路的激活还能够下调MMPs的表达,进而减轻牙周炎软组织破坏^[44]。

1.2.5 NLRP3炎症小体

NLRP3炎症小体由NLRP3蛋白、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing CARD,ASC)和半胱氨酸天冬蛋白酶1前体(procaspase-1)组成^[45]。NLRP3炎症小体被激活时,它与接头蛋白/结合蛋白结合,其中包括caspase募集域和pyrin域,然后NLRP3/ASC复合物募集并结合caspase-1,同时诱导其激活产生IL-1β^[46-47]。IL-1β由巨噬细胞、单核细胞等多种细胞分泌,参与机体炎症反应。因此,推测NLRP3炎症小体可能有助于炎症性牙周炎的发生。牙周炎患者龈沟液中,NLRP3、半胱氨酸天冬蛋白酶-1(caspase-1)和IL-18检出增多^[48],甚至唾液和血清NLRP3水平也有所提高^[49]。

1.2.6 MAPK信号通路

MAPK家族包括细胞外信号调节激酶(extracellular regulated protein kinases,ERK)、c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)和p38 MAPK等亚族。MAPK信号通路是成骨细胞分化和矿化的重要细胞信号通路^[50]。牙周炎会导致p38 MAPK磷酸化,RANKL和环氧化物酶-2(cyclooxygenase-2,COX-2)mRNA 表达上调,OPG 表达下调,表明p38 MAPK通路参与了RANKL、OPG在牙周炎中的表达^[51]。此外,p38MAPK通路可调控炎症免疫应答相关的巨噬细胞极化生物标示物的表达,如IL-6、TNF-α、IL-1β和IL-10等^[52]。

1.2.7 PI3K/AKT信号通路

PI3K/AKT信号通路是包括牙周炎在内的炎症发生发展中最常被激活的信号通路之一^[53]。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是AKT的重要底物,研究发现在牙龈卟啉单胞菌激活PI3K/AKT信号轴之后,mTOR磷酸化会抑制抗菌自噬,以逃避免疫监视并在树突状细胞中存活^[54]。在高糖和炎症环境下PI3K/AKT信号通路下调则会抑制人牙周膜干细胞(human periodontal ligament stem cells,hPDLSCs)的成骨分化和成骨细胞的增殖^[55-56],进一步探寻调控该信号通路的上游因子,或能为糖尿病牙周炎的治疗提供干预靶点。

1.2.8 JAK/STAT信号通路

JAK/STAT 通路参与多种免疫过程,包括细胞生长、增殖、分化、凋亡和炎症反应。它的基本功能为将信号从细胞膜受体传导至细胞核中^[57],接收到相应刺激后JAKs先出现磷酸化,随后STATs出现下一步的反应。与健康个体相比,牙周炎患者牙龈的内皮细胞中炎症相关JAK-STAT和NF-κB信号传导途径显著上调^[58]。在hPDLSCs炎症模型中,JAK/STAT通道相关蛋白磷酸化水平增加,也进一步表明JAK/STAT通路参与牙周炎的发生发展^[59]。

1.2.9 TGF-β

信号通路TGF-β的大部分生物学功能由Smad信号转导途径介导,并受到MAPK、Wnt等信号通路的影响^[60]。B细胞消耗疗法之所以能够减少牙周炎牙槽骨丢失是因为B细胞表达高水平的TGF-β1,并上调Smad 2/3表达和下调Runt-相关转录因子-2(runt-related transcription factor-2,RUNX2)表达来抑制成骨细胞分化^[61]。此外,牙周韧带相关蛋白-1(periodontal ligament-associated protein 1,PLAP-1)可以与TGF-β1结合后竞争性减弱与TGF-β1受体的结合,级联减弱下游通路的转导,导致Smad1磷酸化水平升高,从而促进破骨细胞分化。当PLAP-1靶向基因敲除则可抑制破骨细胞分化,减少牙槽骨吸收^[62-63]。

2 常见黄酮类天然产物对牙周炎的防治机制

收起

黄酮类化合物是植物中广泛分布的一大类次级代谢产物,已报道的化合物超过10 000个,结构多样且具有抗炎、抗氧化、促成骨等重要的药理活性。根据其结构不同可分为黄酮类、黄酮醇类、异黄酮类等亚型(结构见表1),其基本母核为2-苯基色原酮类化合物,目前泛指由2 个苯环(A环与B环)通过中间三碳原子相连而成的一系列化合物。不同分子结构的黄酮类化合物表现出不同程度的抗炎效果,与以下结构有密切关系:①C环中的2和3之间双键;②羟基的位置和数量;③羟基糖基化或甲氧基化等^[64]。影响抗氧化活性的结构因素包括:①B环3',4'-邻位羟基结构;②C环中的2和3之间双键和4位羰基;③3和5位的羟基等^[65]。黄酮类化合物在牙周炎的防治中具有抗炎、抗氧化、促成骨及抗微生物等重要的药理活性(图2)。

2.1 柚皮苷

柚皮苷(naringin,分子式:C₂₇H₃₂O₁₄,相对分子质量:580.535)又称柚苷、柑橘柑、异橙皮苷,为骨碎补、枳实、枳壳和化橘红等中药的主要药效成分^[66]。柚皮苷可以激活ERK1/2信号传导或者抑制Wnt/β-catenin信号通路,促进碱性磷酸酶(alkaline phosphatase,ALP)、RUNX2、骨钙素(osteocalcin,OCN)等成骨相关基因和β-catenin蛋白表达,以及矿化结节的形成,有效诱导牙周膜干细胞的成骨分化,促进牙周组织再生^[67-68]。柚皮苷水凝胶有利于药物在炎症组织中的递送和爆发释放,柚皮苷作为抗氧化剂,还可以抑制NF-κB信号通路的激活,下调TLR2和TNF-α的表达,有效抑制牙周炎症^[69]。

2.2 黄芩苷

黄芩苷(baicalin,分子式:C₂₁H₁₈O₁₁,相对分子质量:446.361)是从黄芩中分离得到的一种黄酮类化合物,具有强效抗炎活性。黄芩苷可以通过Wnt/β-catenin和RANKL/OPG信号通路,促进成骨标志物[如OCN、RUNX2、OPG、核心结合因子α1(core binding factor α1,Cbfα1) ]的表达,促进人成牙骨质细胞和人牙周膜细胞(human periodontal ligament cells, hPDLCs)向成骨分化^[70-72];负调控TLR信号转导,例如阻断TLR2和TLR4/ MyD88/p38MAPK/NF-κB信号通路,有效抑制炎症牙龈组织中TLR2、TLR4、MyD88、高迁移率族蛋白B1(HMGB1)、TNF-α、IL-1β、IL-6和IL-8的表达及 p38 MAPK、NF-κB和JNK的激活,减轻炎症反应和牙槽骨流失^[73-74];也可以抑制MMP-1金属蛋白酶组织抑制剂-1(tissue inhibitors of metalloproteinase-1,TIMP-1)的表达,刺激hPDLCs的I型胶原(type I collagen,COL-I)生成,促进胶原修复^[70]。而纳米胶束或水凝胶负载黄芩苷可控制药物缓释,提高生物利用度,对牙周炎的治疗效果优于游离黄芩苷^[75-77]。

2.3 槲皮素

槲皮素(quercetin,分子式:C₁₅H₁₀O₇,相对分子质量:302.236)广泛存在于蔬菜、水果和中草药中,具有抗炎、抗氧化、降糖等多种药理学活性^[78]。槲皮素一方面可通过抑制NF-κB/NLRP3炎性小体通路来减弱炎症条件对hPDLSCs中成骨相关基因和蛋白的抑制作用^[79],直接抑制人牙龈成纤维细胞中p65和IκB的磷酸化^[80],或调节巨噬细胞的NF-κB:A20轴来减少炎性细胞因子的产生^[81];也可以降低P.g-LPS诱导的炎症因子水平,抑制其激活的AKT/AMPK/mTOR信号转导,上调B淋巴细胞瘤基因-2蛋白(B-cell lymphoma-2 protein,Bcl-2,一种抗凋亡蛋白)和下调Bcl-2相关X蛋白(Bcl-2-associated X protein,Bax,一种促凋亡蛋白)的表达发挥抗细胞凋亡作用,发挥对牙周炎的保护作用^[82]。另一方面,槲皮素可以激活核因子E2相关因子2(nuclear factor E2 relater factor 2,Nrf2)信号传导,提高牙周膜细胞的抗氧化能力^[83];干扰活性氧-巨噬细胞极化级联反应,介导巨噬细胞M1型(促炎)向M2型(抗炎)极化,降低IL-6、TNF-α促炎因子的表达,重塑Th17/Treg稳态,消除炎症,促进牙槽骨再生^[84-86]。

2.4 金丝桃苷

金丝桃苷(hyperoside,分子式:C₂₁H₂₀O₁₂,相对分子质量:464.376)又名槲皮素-3-O-β-D-吡喃半乳糖苷,是一种主要存在于山楂、连翘和菟丝子中的黄酮醇苷^[87-88]。在体外实验中,金丝桃苷可以通过激活NF-κB信号通路促进骨髓间充质干细胞的增殖和成骨分化,减少破骨细胞形成和牙槽骨吸收^[89]。在体内实验中,金丝桃苷干预后实验性牙周炎大鼠牙周组织中TLR4、MyD88、NF-κB mRNA和蛋白水平显著降低,血清RANKL、TNF-α、IL-6水平显著升高,而金丝桃苷+TLR4激活剂组趋势相反,骨吸收增加,金丝桃苷可能通过抑制TLR4/MyD88/NF-κB炎症通路抑制炎症反应,缓解牙周组织损伤^[90]。

2.5 异鼠李素

异鼠李素(isorhamnetin,分子式:C₁₆H₁₂O₇,相对分子质量:316.262)主要从银杏、沙棘等药用植物中分离获得,具有抗炎、抗氧化等活性^[91]。异鼠李素可以显著抑制中间普雷沃菌脂多糖(Prevotella intermedia LPS)诱导的IL-6的产生,上调血红素氧合酶-1(heme oxygenase 1,HO-1)的表达量,通过抑制NF-κB p50亚基的核转位和DNA结合活性以及减弱信号转导子和转录激活子1(signal transducer and activator of transcription-1,STAT-1)信号传导来抑制NF-κB信号传导,阻断由IL-6介导的宿主破坏性过程^[92];也可以激活Nrf2信号通路抑制LPS诱导的人牙龈成纤维细胞中前列腺素E2(prostaglandin E2,PGE2)、一氧化氮(NO)、IL-6和IL-8的浓度,缓解牙周组织炎症反应^[93]。

2.6 芦丁

芦丁(rutin,分子式:C₂₇H₃₀O₁₆,相对分子质量:610.518)又名芸香苷,广泛存在于荞麦、茶叶、苹果等植物中,具有与内源性雌激素17-β-雌二醇(E2)相似的平面双苯环结构,发挥类雌激素作用,具有抗氧化、抗炎等药理活性^[94]。芦丁主要通过G蛋白偶联受体30(G protein-coupled receptor 30,GPR30,一种雌激素受体,可传导E2的快速效应,与骨骼形成密切相关)介导的PI3K/AKT/mTOR信号通路增强hPDLSCs的增殖和成骨分化(骨形成相关基因COL-1、OCN、RUNX2和ALP的转录水平升高)^[95];也通过该信号通路来抑制ROS,增加氧化应激因子[超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽(glutathione,GSH)]的分泌,促进hPDLSCs的抗氧化应激能力^[96-97]。芦丁也可以通过抑制mTOR磷酸化来抑制TNF-α激活的mTOR信号转导,逆转炎症环境对hPDLSCs成骨分化的损伤^[98]。另一方面,芦丁还可以显著降低骨形成部位的MMP1、MMP3、MMP9和MMP13的表达量,上调Ⅲ型胶原α1(collagen type Ⅲ alpha 1,COL-3A1)促进矿化,促进骨愈合^[99]。

2.7 木犀草素

木犀草素(luteolin,分子式:C₁₅H₁₀O₆,相对分子质量:286.236)广泛存在于水果和蔬菜中,如芹菜、甜椒、胡萝卜^[100]。木犀草素可以直接抑制牙龈卟啉单胞菌的主要毒力因子——牙龈蛋白酶的蛋白水解活性,限制其在口腔的生长和生物膜形成^[101]。在体外实验中,木犀草素一方面可以通过T细胞核因子1(nuclear factor of activated T cells 1,NFATc1)激活Oct-4/Sox2信号,有效维持hPDLCs的多能分化潜能^[102];也可以通过激活Wnt/β-catenin通路增加成骨分化相关基因,如骨形态发生蛋白2(bone morphogenetic protein 2,BMP-2)、OCN、RUNX2、cyclinD1和β-catenin的表达,加速hPDLCs的成骨分化^[103]。另一方面,木犀草素可以抑制LPS刺激下巨噬细胞的NF-κB和STAT1通路,降低促炎因子NO和IL-6介导的牙周组织破坏性进程^[104];也可以通过调控RANKL/OPG和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)/NO信号通路抑制单核巨噬细胞向破骨细胞分化,降低破骨细胞活性,减少牙槽骨吸收^[105]。在动物实验中,木犀草素干预可以抑制蛋白激酶R(protein kinase R,PKR)介导的炎症反应,发挥上级免疫调节作用^[106];同时,干预后牙周炎组的牙周组织切片中成骨细胞计数增多,BMP-2水平显著上调,明显改善了牙周炎引起的成骨抑制^[107]。

2.8 杨梅素

杨梅素(myricetin,分子式:C₁₅H₁₀O₈,相对分子质量:318.235)是一种从杨梅树的树皮中分离得到的多羟基黄酮醇化合物,具有抗炎、促成骨等作用^[108]。杨梅素首先可以下调牙龈卟啉单胞菌的重要毒力因子的表达,包括蛋白酶(rgpA、rgpB和kgp)和黏附素(fimA、hagA和hagB),降低致病菌的生长和毒力^[109]。其次,可以剂量依赖地调节BMP-2/Smad和ERK/JNK/p38MAPK信号传导途径,上调ALP活性及骨形成相关因子[如Runx2、骨桥蛋白(osteopontin,OPN)]的表达,显著促进hPDLSCs的成骨分化^[110],抑制RANKL刺激的单核巨噬细胞的破骨分化,下调c-Fos、NFATc1基因的表达^[111];同时,还阻断了IκB降解以及环氧合酶-2(COX-2)和PGE2的合成和表达,显著减少炎症细胞因子(TNF-α、IL-1β),有助于炎症控制^[112-114]。此外,杨梅素可以减少MMP-1,MMP-2和MMP-8的表达,缓解牙龈细胞外基质胶原蛋白的降解,阻止牙周组织的破坏性损伤^[111]。

2.9 山柰酚

山柰酚(kaempferol,分子式:C₁₅H₁₀O₆,相对分子质量:286.236)主要来源于山柰、高良姜、蜂胶等传统中药材,具有抗菌、抗氧化、抗炎等药理活性^[115]。山柰酚可激活Wnt/β-catenin信号通路,通过上调hPDLSCs中β-catenin、p-GSK3β (Ser9)以及下游信号因子淋巴增强结合因子(lymphoid enhancer binding factor,LEF)的表达,来显著增加ALP、RUNX2、Sp7转录因子(Sp7 transcription factor,SP7)、骨γ-羧谷氨酸蛋白(bone gamma-carboxyglutamate protein,BGLAP)的蛋白表达量,促进hPDLSCs的增殖、ALP活性和矿物沉积^[116]。山柰酚也可以通过上调HO-1减少牙周致病菌来源LPS诱导的ROS产生,在翻译水平上抑制iNOS蛋白表达和NO产生,防止过量NO导致MMP失活而引起的基质降解^[117]。在动物实验中,山柰酚也能显著降低牙周炎组牙龈组织MMP-1和MMP-8的表达,减少牙周炎软硬组织的破坏^[118]。

2.10 水飞蓟素

水飞蓟素(silibinin,分子式:C₂₅H₂₂O₁₀,相对分子质量:482.436)是从水飞蓟种子中提取的一类新型黄酮类化合物。水飞蓟素可通过阻断NF-κB/ NLRP3和MAPK信号通路以及NFATc1的表达和诱导,上调Nrf2的表达和抑制RANKL表达,降低 RANKL/OPG比值,减少破骨细胞前体分化;降低LPS刺激下人牙龈成纤维细胞的炎性细胞因子、趋化因子和氧化应激的产生,清除自由基、减少牙龈炎症^[119-120];也可以降低MMP-1和MMP-3水平,减少软组织的破坏^[121]。

2.11 漆黄素

漆黄素(fisetin,分子式:C₁₅H₁₀O₆,相对分子质量:286.236)存在于多种水果、蔬菜和中药黄栌、漆树等植物,具有抗炎、抗氧化等作用^[122]。研究发现:①漆黄素可通过成纤维细胞生长因子受体1(fibroblast growth factor receptor 1,FGFR1)/TLR4/NLRP3炎性小体通路抑制炎症反应、逆转组织病理学损伤、减少牙槽骨间隙,减轻牙周炎症状^[123];②漆黄素能阻断LPS介导的MAPK、AKT的活化和COX-2的表达,抑制骨吸收;同时减少促炎症因子(如TNF-α、IL-6)的表达,即漆黄素能减少炎症,抑制牙槽骨吸收^[124]。

2.12 花旗松素

花旗松素(taxifolin,分子式:C₁₅H₁₂O₇,相对分子质量:304.252)又名二氢槲皮素,广泛存在于落叶松、水飞蓟等多种松科与蔷薇科的植物中,具有抗氧化、抗炎、抗菌等作用^[125]。花旗松素一方面可以通过下调Bax和上调Bcl-2的蛋白表达来抑制牙周炎诱导的细胞凋亡,减少牙周组织损伤;另一方面,以剂量依赖方式通过NF-κB信号通路抑制RANKL诱导的破骨细胞生成,并增加了成骨细胞活性(BMP-2、OCN、COL-1和ALP表达增加)^[126-127]。

2.13 杜鹃素

杜鹃素(farrerol,分子式为C₁₇H₁₆O₅,相对分子质量为:300.306)是一种从杜鹃花中分离的二氢黄酮类化合物,具有抗炎、抗氧化、抗菌等活性。杜鹃素可以通过抑制PI3K/AKT和mTOR/STAT3信号通路来抑制炎性细胞因子如IL-6、TNF-α、IL-1β、IL-8等产生以及破骨细胞生成,减轻牙周组织炎症反应,有效减少牙槽骨吸收^[128-129]。

2.14 葛根素

葛根素(puerarin,分子式:C₂₁H₂₀O₉,相对分子质量:416.378)是一种从植物葛根中提取出来的异黄酮类化合物,发挥雌激素样作用,具有保骨、抗炎、抗氧化等活性^[130]。葛根素可以阻断MAPK、NF-κB和PI3K/AKT/mTOR信号通路的激活,抑制IL-1β、TNF-α、IL-23、IL-17等促炎因子的表达;减少引起牙龈和牙周膜胶原降解的MMP-2和MMP-9的产生;抑制RANKL表达量,降低RANKL/OPG比值,增加ALP活性、Runx2、OCN、COL-I表达,促进hPDLSCs成骨分化,有效抑制炎症、减少胶原破坏和破骨细胞形成,防止牙槽骨吸收^[131-136]。

2.15 大豆苷元

大豆苷元(daidzein,分子式:C₁₅H₁₀O₄,相对分子质量:254.238)是一种从大豆中提取的异黄酮,可作用于雌激素受体,又称为非甾体类植物雌激素化合物^[137]。大豆苷元可以显著逆转实验性牙周炎引起的牙槽骨高度丢失以及骨小梁微结构的恶化^[138]。这可能是因为大豆苷元可以通过调节NF-κB p50亚基的核转位和DNA结合活性来抑制NF-κB转录活性,并阻断STAT1磷酸化,从而显著抑制致病菌LPS介导的NO和IL-6的产生及其转录表达^[139]。此外,大豆苷元也可以促进hPDLSCs的增殖、细胞活力和ALP活性,并通过激活Wnt/β-catenin信号通路显著提高成骨分化相关蛋白,促进hPDLSCs的成骨分化^[140]。

2.16 橙皮素

橙皮素(hesperetin,分子式:C₁₆H₁₄O₆,相对分子质量:302.279)是一种主要存在于柠檬和橙子等柑橘类水果中的异黄酮类化合物,具有抗炎、抗氧化等多种药理活性。橙皮素可以通过激活Nrf2/HO-1信号通路,清除ROS;抑制NF-κB、MAPK信号通路,有效抑制破骨细胞特异性标志物(c-Fos、NFATc1)的表达,降低体内RANKL/OPG比值,抑制RANKL诱导的破骨细胞生成^[141];激活PI3K/AKT、Wnt/β-catenin信号通路,上调ALP、RUNX2、成骨细胞特异性转录因子(osterix,OSX)、Fos相关抗原1 IA型胶原(FRA1)、COL-IA和OPN的蛋白表达,增加hPDLSCs的成骨潜能,减少牙槽骨吸收^[55]。

2.17 染料木素

染料木素(genistein,分子式:C₁₅H₁₀O₅,相对分子质量:270.237)又称为染料木黄酮、金雀异黄酮,是广泛存在于染料木、槐角、山豆根等豆科植物中的一种异黄酮类化合物^[142]。染料木素一方面可通过抑制破骨细胞特异性分子的表达,显著阻止NF-κB配体受体激活剂或LPS刺激的巨噬细胞中破骨细胞的分化^[143];另一方面减弱了炎症相关因子的表达,如NOS2、COX-2、TNF-α、细胞间黏附分子1(intercellular adhesion molecule 1,ICAM-1)、MMP-2、MMP-9、NO和IL-6,改善牙周炎引起的骨小梁间隙增大、骨密度降低的症状,减少骨吸收^[143-144]。

2.18 淫羊藿苷

淫羊藿苷(icariin,分子式为:C₃₃H₄₀O₁₅,相对分子质量为:676.662)主要从淫羊藿茎叶或全草中分离获得,具有促进骨再生和骨修复、抗炎等作用^[145]。淫羊藿苷及其纳米改性水凝胶一方面可以下调促炎因子IL-1β、IFN-γ,上调抗炎因子IL-10,缓解牙周局部炎症,促进牙周组织中成骨相关蛋白(如Runx2、骨钙素、OPN)的表达和矿化水平,有效减少牙槽骨吸收面积和高度,诱导新骨形成^[146-149];另一方面,可以通过抑制TLR4和磷酸化p65的表达并阻断p65核易位来抑制TLR4/NF-κB信号通路,增加BMP-2、COL-I、OPG和ALP表达,促进hPDLCs的成骨分化和细胞外基质合成,促进牙周组织再生^[150]。

2.19 异甘草素

异甘草素(isoliquiritigenin,分子式:C₁₅H₁₂O₄,相对分子质量:256.253)是从中草药甘草中分离得到的一种二氢黄酮类化合物,具备抗炎、抗焦亡等多重生物活性。异甘草素可以抑制ROS的产生,并通过抑制P.g-LPS激活的NF-κB/ NLRP3/GSDMD信号转导,抑制NF-κB和消皮素D(Gasdermin-D,GSDMD)的活化,下调NLRP3炎性小体的组装,减少LPS诱导的人牙龈成纤维细胞焦亡和IL-1β释放,缓解炎症反应^[151-152]。此外,异甘草素也可剂量依赖地阻断RANKL介导的RANK-TRAF 6结合、MAPK磷酸化、NF-κB抑制因子α(IκBα)磷酸化和降解、NF-κB p65核转位以及激活蛋白-1(AP-1)的激活,即通过RANK-TRAF6、MAPK、IκBα/NF-κB 和AP-1信号通路抑制RANKL诱导的破骨细胞生成和炎症性骨损失^[153]。

2.20 芒果苷

芒果苷(mangiferin,分子式:C₁₉H₁₈O₁₁,相对分子质量:422.340)主要来源于芒果果实、叶、树皮,知母根茎等,是一种双苯吡酮类黄酮类化合物^[154]。芒果苷一方面可以通过抑制TLR信号传导的激活,包括下游NF-κB、p38 MAPK和JNK的磷酸化,来减少LSP诱导的IL-6产生^[155];也可以下调牙龈上皮JAK1-STAT1/3通路磷酸化水平,来减轻牙周组织中的炎症反应,抑制牙槽骨丢失^[156]。另一方面,芒果苷可以激活TGF-β/Smad2信号通路来促进hPDLSCs的成骨分化,显著促进ALP、COL-1、RUNX2、SMAD5和BMP2蛋白表达及矿化结节的形成^[157]。

综上,黄酮类天然产物对牙周炎的作用机制可能与MAPK、PI3K/AKT、Wnt/β-catenin、TLR4、NLRP3炎性小体、NF-κB、HO-1/Nrf2、iNOS/NO等骨免疫相关的炎症信号通路有关,其主要通过减少促炎细胞因子的表达、缓解牙周膜胶原的降解,抑制氧化应激和破骨细胞生成,促进成骨相关蛋白表达以及抑制口腔牙周病原微生物生长。其中iNOS/NO信号通路抑制单核巨噬细胞向破骨细胞分化,降低破骨细胞活性;HO-1/Nrf2信号通路,可以清除ROS,增加氧化应激因子SOD和GSH的分泌,通过抗氧化应激来减轻牙周炎。木犀草素和杨梅素可以限制牙龈卟啉单胞菌在口腔的生长和生物膜形成,抑制牙龈蛋白酶的蛋白水解活性,下调蛋白酶和黏附素表达。黄芩苷、杨梅素、水飞蓟素、葛根素、橙皮素、异甘草素、芒果苷可以通过调控MAPK信号通路来抑制破骨细胞生成和炎症性骨损失。槲皮素、芦丁、杜鹃素、葛根素、橙皮素都可以通过PI3K/AKT/mTOR信号通路对牙周炎具有抗炎和促成骨作用;而芦丁还有抗氧化作用,一系列研究体现了黄酮类化合物防治牙周炎机制的一致性和差异性。天然产物有多个作用靶点,但大多数实验仅仅证明了个别炎症信号通路对牙周炎的作用,而忽视了细胞内信号通路相互交织、相互作用的复杂性。黄酮类化合物在促进牙周组织重建和骨缺损修复中涉及的信号通路之间是否存在协同或拮抗串扰或上下游关系,有待大规模单细胞转录组学数据的进一步探索。

3 结语与展望

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近年来在牙周炎防治研究中常采用的20个黄酮类天然产物表现出抗炎、抗氧化、抗微生物及促骨组织修复能力,它们通过调节多种炎症经典信号通路下调炎症介质的表达,抑制过度炎症对牙周软硬组织的损伤(图2)。值得注意的是,这类研究普遍存在药理基础研究深度不足、缺乏大量随机临床试验、剂量(含给药途径)-暴露量(血药浓度等药动学参数)-效应关系探索不足的问题,对于其最佳治疗效果和确切靶点仍需要进一步的研究和评估。同时,黄酮类天然产物强大的生物学活性与口服生物利用度低之间常常存在不容忽视的差异与矛盾,如何采用特殊策略,如纳米粒子药物递送系统、结构转化等方式,来增加其口服生物利用度,避免它们在胃肠道中被胃酸降解或代谢,探索肠道菌群对口服黄酮类天然产物生物利用度的影响,以及局部纳米水凝胶给药可能会是黄酮类化合物药物开发与利用的下一个研究热点。

基金

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贵州省科技计划项目资助(黔科合基础-ZK〔2021〕一般439)
遵义市科技计划项目(遵市科合HZ字[2024]340号)
遵义医科大学2018年度学术新苗培养及创新探索专项项目资助(黔科合平台人才〔2018〕5772-010)

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2025年第60卷第2期

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doi: 10.11669/cpj.2025.02.007

接收时间：2024-06-19
首发时间：2025-11-08
出版时间：2025-01-22

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收稿日期：2024-06-19

基金

贵州省科技计划项目资助(黔科合基础-ZK〔2021〕一般439)

遵义市科技计划项目(遵市科合HZ字[2024]340号)

遵义医科大学2018年度学术新苗培养及创新探索专项项目资助(黔科合平台人才〔2018〕5772-010)

作者信息

¹ 遵义医科大学口腔医学院, 贵州遵义 563000

² 贵州省普通高等学校微生物资源与药物开发特色重点实验室, 贵州遵义 563000

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*胡欢,女,博士,副教授,硕士生导师研究方向:口腔微生态及口腔感染性疾病的防治,天然产物发现及生物合成 Tel:(0851)28609493

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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