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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Oct 28;48(10):1611–1620. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.230146

绿原酸改善炎症性疾病的研究进展

Research progress of chlorogenic acid in improving inflammatory diseases

LING Xinping 1,2, YAN Wei 1, YANG Fen 2, JIANG Shuling 1, CHEN Fuqing 2, LI Na 2,✉
Editors: 宋 柳, 郭 征
PMCID: PMC10929889  PMID: 38432890

Abstract

Long-term inflammation will develop into chronic inflammation and become inflammatory diseases. Antibiotics are commonly used in clinical practice to treat inflammatory diseases. But patients are prone to drug resistance. So we need to find new treatment. Chlorogenic acid is an organic compound extracted from honeysuckle and other plants. Its anti-inflammatory activity is strong, and it has a significant anti-inflammatory effect on inflammatory diseases in various systems. It has been shown that chlorogenic acid can regulate inflammation-related signaling pathways, such as nuclear factor κB (NF-κB) canonical signaling pathway, NF-κB atypical signaling pathway, nuclear factor-erythroid 2-related factor 2 (Nrf2) canonical signaling pathway, and Nrf2 atypical signaling pathway, etc. It can up-regulate the expression of anti-inflammatory cytokines such as interleukin （IL)-4, IL-10, IL-13 and down-regulate the expression of pro-inflammatory cytokine such as IL-1β, IL-6, and IL-8. Although chlorogenic acid has a strong anti-inflammatory effect, but clinical trials and application still face many difficulties. In the future, the anti-inflammatory molecular mechanism of chlorogenic acid should be further studied to explore its clinical application value and improve new ideas for the treatment of inflammatory diseases.

Keywords: chlorogenic acid, signal pathway, cytokines, anti-inflammatory effect

炎症是由感染、组织损伤或有害刺激等引起的反应，是一个复杂的生理病理过程，主要表现为红、肿、热、痛及功能障碍[1]，其进一步发展，则可能导致多种慢性炎症性疾病[2]。常见的炎症性疾病有神经炎、肺炎、肝炎、肠炎、肾炎、关节炎等，病程长且易复发。目前通常使用抗生素进行抗炎治疗，但抗生素会使患者产生耐药性[3]，损伤肝、肾等器官，易导致过敏等不良反应。

绿原酸(chlorogenic acid，CGA)提取自金银花等植物，具有抗菌、抗炎、抗肿瘤、抗病毒等生物活性[4]，多应用于炎症性疾病的实验研究。笔者通过对CGA在神经系统、呼吸系统、消化系统、泌尿系统、运动系统、生殖系统及其他系统炎症性疾病中的抗炎作用及相关机制进行综述，旨在为CGA抗炎机制的深入研究及临床运用提供理论依据。

1. CGA

CGA是一种有机化合物，化学式为C16H18O9，结构式见图1 [5]，是由咖啡酸与奎尼酸生成的缩酚酸，属于植物体在有氧呼吸过程中经莽草酸途径产生的一种苯丙素类化合物，广泛存在于植物的多酚类次生代谢产物中。CGA抗炎效果突出，与抗生素相比具有价格较低、更易获得、安全性较高、不良反应较少的优点，可通过调节信号通路和细胞因子，减轻氧化应激，从而改善炎症性疾病。

图1.

图1

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绿原酸结构式[5]

Figure 1 Structural formula of chlorogenic acid[5]

2. CGA在不同系统炎症性疾病中的作用

2.1. CGA改善神经系统炎症性疾病

神经系统由神经组织组成，分为中枢神经系统和周围神经系统。中枢神经系统包括脑和脊髓，周围神经系统包括脑神经和脊神经。神经炎是各种病变引起周围神经炎症性疾病的总称。在大鼠神经炎实验[6-9]中，CGA通过调节去泛素化酶圆柱瘤蛋白(cylindromatosis，CYLD)/核因子κB(nuclear factor κB，NF-κB)信号通路，下调白细胞介素(interleukin，IL)-1β、IL-6和肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)表达，从而减少炎症细胞因子，减轻深低温停循环引起的神经炎[6]。使用CGA干预脊髓损伤(spinal cord injury，SCI)模型大鼠，发现其通过Toll样受体(Toll-like receptor，TLR)4/髓样分化因子88(myeloid differentiation factor 88，MyD88)/NF-κB信号通路抑制SCI诱导的炎症，进而恢复神经元功能[7]。在新生大鼠缺氧缺血性脑损伤模型中，CGA通过激活沉默信息调节因子1(silence information regulator 1，SIRT1)调节核转录因子红系2相关因子2(nuclear factor-erythroid 2-related factor 2，Nrf2)/NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor family pyrin domain containing 3，NLRP3)信号通路，降低诱导型一氧化氮合酶(inducible nitric oxide synthase，iNOS)、IL-1β和 TNF-α的表达水平，减轻氧化应激和炎症，最后抑制神经元凋亡[8]。Shah等[9]注射CGA治疗大脑中动脉闭塞手术诱发的大鼠局灶性脑缺血，发现其减少脑细胞活性氧，减轻氧化应激，降低NF-κB、IL-1β、IL-6和TNF-α的表达水平，起到抗炎作用。

神经炎症与中枢神经中小胶质细胞系BV2活化引起的脑组织炎症应激有关。在小鼠细胞炎症研究[10-12]中，CGA减弱BV2细胞活化，减轻氧化应激和炎症反应，主要表现为抑制TLR3信号通路，从而降低单纯疱疹病毒性脑炎细胞模型中TLR3及其下游分子β干扰素TIR结构域衔接蛋白(TIR-domain-containing adapter-inducing interferon-β，TRIF)的mRNA及干扰素(interferon，IFN)-α的表达水平[10]；在脂多糖诱导的BV2细胞炎症应激中，NF-κB/NLRP3信号通路被CGA抑制，进而降低TNF-α、IL-1β、iNOS和IL-12的表达水平，且升高IL-10的表达水平[11]。Singh等[12]证明CGA通过抑制NF-κB信号通路，降低BV2细胞中NF-κB、TNF-α和iNOS的表达水平，减轻四氢吡啶诱导小鼠中毒后的神经炎症。

用CGA治疗小鼠阿尔茨海默病(Alzheimer's disease，AD)后神经损伤评分降低，脑源性神经营养因子、神经生长因子、5-羟色胺和5-羟基吲哚乙酸蛋白的表达水平升高，iNOS、IL-6、TNF-α、NLRP3、IL-1β和凋亡相关斑点样蛋白(apoptosis associated speckle-like protein，ASC)的表达水平显著降低，AD小鼠的神经损伤减轻[13]。CGA通过调节TLR4/NF-κB信号通路发挥保护作用，逆转神经变性和神经行为的改变，改善三甲基氯化锡诱导的神经炎症[14]。除此之外，CGA可升高超氧化物歧化酶(superoxide dismutase，SOD)-2、IL-4及IL-13的表达水平，减少IL-2、TNF-α和4-羟基壬烯醛(4-hydroxynonenal，4-HNE)的产生，预防暂时性脑缺血引起的沙鼠神经炎症[15]。

综上，CGA通过调节CYLD/NF-κB、TLR4/MyD88/NF-κB、Nrf2/NLRP3、NF-κB/NLRP3和TLR4/NF-κB信号通路，恢复神经元功能，逆转大脑神经变性和神经行为的改变，减轻神经细胞炎症反应，展现出良好的抗炎特性。

2.2. CGA改善呼吸系统炎症性疾病

呼吸系统包括鼻、咽、喉、气管、支气管、肺及胸膜等组织。CGA具有抗炎特性，可改善鼻炎和肺炎。

2.2.1. CGA改善鼻炎

鼻炎是由病毒、细菌、过敏原、各种理化因子以及某些全身性疾病引起的鼻腔黏膜炎症。在小鼠鼻炎中，CGA主要通过调节辅助性T(helper T，Th)细胞及其细胞因子发挥抗炎作用[16-17]。CGA调节Th1/Th2细胞平衡，降低IL-4、IL-5和IL-13的表达水平，降低小鼠揉鼻和打喷嚏频率，减轻鼻炎[16]。Shi等[17]证明CGA可减少黏液分泌、黏膜厚度、嗜酸性粒细胞以及杯状细胞数量，同时降低IL-17的表达水平，减少CD4+T和Th17细胞数量。

2.2.2. CGA改善肺炎

病原微生物、理化因素、免疫损伤、过敏及药物可导致肺炎。CGA可通过抑制NLRP3来改善肺组织炎症[18-20]。其抑制NLRP3进而降低胱天蛋白酶(caspase，Casp)-1、IL-6和TNF-α的表达水平，升高IL-10的表达水平，减轻炎症细胞浸润[18]；抑制NLRP3，降低IL-1β及TNF-α的表达水平，减轻急性肺损伤炎症反应[19]；CGA联合左氧氟沙星干预肺炎克雷伯菌(klebsiella pneumoniae，Kp)肺炎小鼠，主要通过抑制NLRP3通路，进而降低IL-6、TNF-α的表达水平，最终减轻肺部感染[20]。此外，CGA激活SIRT1后抑制高迁移率族蛋白1(high mobility group box 1，HMGB1)乙酰化水平及核转位，促进巨噬细胞向M2型巨噬细胞极化，逆转肺炎[21]。而在大鼠肺损伤实验中，CGA明显降低支气管肺泡灌洗液(bronchoalveolar lavage，BALF)中IL-1β、IL-8和TNF-α的含量，升高总SOD(total SOD，T-SOD)和过氧化氢酶(catalase，CAT)的含量，改善肺组织病理学变化，减轻氧化损伤和肺部炎症[22]。

在小鼠急性肺损伤模型中，CGA降低BALF中IL-6、TNF-α含量和髓过氧化物酶(myeloperoxidase，MPO)活性及细胞间黏附分子-1(intercellular adhesion molecule-1，ICAM-1)和NF-κB p65的磷酸化水平[23]。研究[24]表明CGA干预脓毒症大鼠后，可能通过激活Nrf2信号通路，上调SOD、B淋巴细胞瘤-2(B cell lymphoma-2，Bcl-2)基因、血红素氧合酶1(heme oxygenase-1，HO-1)的表达，下调IL-1β、IL-6、TNF-α、Bcl-2相关X蛋白(Bcl-2 related X protein，Bax)及丙二醛(maleicdialdehyde，MDA)的表达。通过CGA的干预，上述实验中的肺部炎症均得到了缓解[23-24]。CGA抑制活性氧/硫氧还蛋白结合蛋白(thioredoxin interacting protein，TXNIP)/NLRP3信号通路，降低IL-1β、IL-6、TNF-α、Casp-1、MDA及活性氧的表达，有效减轻肺部的炎症[25]。

在抑制呼吸系统炎症性疾病的过程中，CGA通过调节Th细胞及其细胞因子，发挥减轻鼻炎的作用；通过抑制NLRP3、活性氧/TXNIP/NLRP3及激活Nrf2信号通路，有效减轻肺部炎症。

2.3. CGA改善消化系统炎症性疾病

消化道和消化腺组成消化系统。CGA具有的抗炎特性，也可改善消化系统疾病中常见的肝炎和肠炎。

2.3.1. CGA改善肝炎

肝炎发生的高危因素包括微生物感染、长期高脂肪饮食以及自身免疫失调等。CGA通过调节Nrf2信号通路，升高还原型谷胱甘肽(glutathione，GSH)、HO-1、SOD和CAT的表达水平，降低MDA、NLRP3、IL-1β、IL-6和TNF-α的表达水平[26]；通过抑制HMGB1及热激蛋白60(heat shock protein 60，HSP60)介导的炎症反应，降低IL-1β、TNF-α、iNOS、环氧合酶(cyclooxygenase，COX)-2、谷丙转氨酶(glutamic-pyruvic transaminase，GPT)和谷草转氨酶(glutamic-oxaloacetic transaminase，GOT)的表达水平[27]，进而抑制肝炎的进展。而CGA亦通过调节其他信号通路达到减轻肝脏炎症的作用[28-29]。Yuan等[28]发现CGA抑制TLR4信号通路及TLR4表达，下调磷酸化IκB(phosphorylated IκB，p-IκB)、IFN-γ及ICAM-1、血管细胞黏附分子-1、内皮细胞白细胞黏附分子-1的mRNA。另有研究[29]表明CGA参与TLR4/NF-κB信号通路，调节肝微粒体酶细胞色素P450 2E1/Nrf-2信号通路。

大量研究[30-32]表明，CGA通过减轻氧化应激，增强抗氧化反应，减少肝细胞凋亡，减轻肝炎。1)CGA降低血清GPT、GOT、乳酸脱氢酶(lactate dehydrogenase，LDH)、COX-2、iNOS、Bax、Casp-3及Casp-9的表达水平，增强内源性抗氧化反应[30]；2)CGA通过升高谷胱甘肽过氧化酶、GSH、SOD及CAT的表达水平，提高抗氧化的能力，但降低过氧化脂质(lipid peroxide，LPO)、一氧化氮(nitric oxide，NO)、TNF-α、IL-1β及IL-6的含量，减轻肝炎[31]；3)CGA与α-硫辛酸联合应用以调控线粒体减少肝细胞凋亡，抑制Bcl-2/Bax和细胞色素C的表达，减轻肝损伤时的氧化应激[32]。

CGA通过减轻肝细胞损伤及炎症细胞浸润发挥抗炎作用。Miao等[33]发现CGA可减少胶原沉积，抑制肝星状细胞激活，减轻肝细胞损伤和肝纤维化，最终减轻非酒精性脂肪性肝炎。在代谢综合征大鼠模型的饲料中添加CGA后，血浆肝酶、GPT和GOT活性降低，炎症细胞浸润减少[34]。在另一研究[35]中，CGA通过调节肠道微生物，增加有益菌数量来提高胰升糖素样肽-1水平，进而改善肝脏脂肪变性和炎症反应。

2.3.2. CGA改善肠炎

病原微生物感染、免疫机制异常会导致肠炎。多项研究[36-39]指出，把CGA添加于右旋糖酐硫酸钠诱导的结肠炎小鼠模型饮食中，可有效减轻肠炎。具体机制为：通过抑制丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)/细胞外信号调控的蛋白激酶(extracellular regulated protein kinases，ERK)/c-Jun氨基端蛋白激酶(c-Jun amino-terminal kinase，JNK)信号通路，减少ERK1/2、磷酸化JNK和p38的表达[36]；减轻结肠组织中炎症细胞浸润，抑制磷脂酰肌醇-3-激酶/蛋白激酶B(phosphatidyinositol-3-kinases/protein kinase B，PI3K/Akt)信号通路，降低转录激活因子3、Bax、Casp-8、Casp-9、HO-1及NF-κB p65的表达水平[37]；降低MPO的活性，减少中性粒细胞浸润，抑制TNF-α的表达，降低结肠中的疾病活动指数[38]；抑制微RNA155(microRNA 155，miR-155)表达，下调NLRP3相关基因表达，降低Casp-1 p45、Casp-1 p20、磷酸化NF-κB的表达水平[39]。

有证据[40-42]指出，把CGA添加在小猪日粮中，可改善其肠道黏膜炎症。CGA通过下调IL-1β、IL-6、TNF-α、Casp-3、Casp-9及脂肪酸合成酶(fatty acid synthase，FAS)表达，上调Bcl-2、血清免疫球蛋白G和分泌免疫球蛋白A表达，控制细胞调亡，保护肠道黏膜形态[40]；抑制TLR4/NF-κB信号通路，激活Nrf2/HO-1信号通路，降低TLR4、NF-κB、IL-1β、IL-6及TNF-α的表达水平，升高HO-1的表达水平[41]；通过调节PI3K/Akt和NF-κB抑制剂α(inhibitor NF-κBα，IκBα)/NF-κB信号通路，降低IκBα和NF-κB的磷酸化水平，提高抗氧化酶含量，减轻肠细胞上皮炎症和损伤[42]。在IL-10敲除的炎症性肠病小鼠中，CGA阻断NF-κB信号通路，抑制iNOS、IL-1β及TNF-α的表达，发挥抗炎作用，改善肠炎[43]。CGA可以减轻镉诱导的大鼠肠损伤，降低二价金属离子共转运体的表达水平，限制镉吸收，减轻氧化应激和绒毛损伤，提高屏障功能和免疫调节能力，减轻肠道炎症反应[44]。

CGA还通过减少结肠中类杆菌的生长及类杆菌源性内毒素的积累，增加紧密连接蛋白的表达，减轻炎症并保护肠道完整性[45]。CGA添加到热应激组鸡的日粮中后，可抑制IL-1β和TNF-α的表达，提高肠道总抗氧化能力(total antioxidative capability， T-AOC)和T-SOD的活性，调整肠道菌群[46]。在高脂饮食引起大鼠结肠黏膜损伤中，CGA组肠道菌群多样性和丰度增加，提示肠道屏障功能提高，肠道炎症有所改善[47]。而在体外实验中，CGA降低TNF-α、Bax、Casp-3和COX-2的表达水平，减轻猪空肠上皮细胞系IPEC-J2细胞炎症、减少细胞凋亡[48]；Palócz等[49]发现CGA与植物乳杆菌2142上清液联合应用能降低活性氧的含量，抑制COX-2 mRNA的表达、降低IL-6及IL-8的表达水平，最终减轻细胞炎症。

因此，CGA调节TLR4、NF-κB信号通路，激活Nrf2抗氧化途径，上调抗氧化基因表达，增强内源性抗氧化反应，恢复肝抗氧化能力，减少肝细胞凋亡，最终减轻肝炎。CGA通过抑制MAPK/ERK/JNK、PI3K/Akt和NF-κB信号通路，激活Nrf2信号通路，下调IL-1β、IL-6、IL-8、Bax、Casp-8、Casp-9、COX-2、FAS及TNF-α的表达，调节肠道微生物菌群，从而发挥抑制肠炎的作用。

2.4. CGA改善泌尿系统炎症性疾病

泌尿系统包括肾、输尿管、膀胱及尿道。肾炎是CGA干预的常见泌尿系统疾病之一。CGA可减轻药物的肾毒性，减轻实验鼠肾组织的氧化应激反应和炎症，改善肾功能。CGA通过调节NF-κB信号通路减轻肾炎[50-51]。研究[50]证明CGA通过激活NF-κB信号通路，升高SOD、Bcl-2和GSH-Px的表达水平，降低Bax、MDA及血尿素氮(blood urea nitrogen，BUN)的表达水平；另外，其调控NF-κB和Nrf2/HO-1信号通路，降低IL-1β、IL-6及TNF-α的表达水平[51]。先用他莫昔芬诱导大鼠肾炎2周后，再用CGA灌胃干预，结果显示黄嘌呤氧化酶(xanthine oxidase，XO)、MPO、LPO、NO、Casp-3及Casp-9含量降低，肾氧化应激反应和炎症被减轻[52]。CGA干预肾损伤小鼠后，IL-1β、TNF-α、Bax及Casp-3的表达被抑制，Bcl-2的表达被激活，肾组织炎症减轻[53]。

在急性肾损伤(acute kidney injury，AKI)模型鼠中，CGA通过抑制机体炎症反应、减轻氧化应激，激活Nrf2信号通路，促进Nrf2核易位及下游HO-1和醌氧化还原酶1蛋白的表达，同时降低BUN、血肌酐、TNF-α、IL-6、IL-1β、IL-18、MDA和活性氧的含量，从而改善AKI[54]。徐静红等[55]证实CGA能调节TLR4/NF-κB信号通路发挥抗炎作用，降低BUN、TNF-α、血肌酐、IL-6和IL-1β的表达水平，显著抑制NF-κB p65的磷酸化及TLR4的表达。在脓毒症致AKI大鼠中，CGA激活Nrf2信号通路，下调BUN和肾损伤分子-1(kidney injury molecule-1，KIM-1)，抑制TNF-α、IL-6、IL-1β和IL-18的表达，从而改善肾功能[56]。此外，CGA降低血肌酐、BUN、IL-1β、IL-6、TNF-α、Bax、Casp-3、TLR4的表达及p-NF-κB p65/NF-κB p65、p-IκBα/IκBα，上调Bcl-2蛋白的表达，从而对糖尿病肾病大鼠肾功能起保护作用[57]。在泌尿系统炎症性疾病中，CGA通过激活 NF-κB信号通路，调控Nrf2、Nrf2/HO-1、TLR4/NF-κB信号通路，抑制肾炎症反应、减轻氧化应激。

2.5. CGA改善运动系统炎症性疾病

运动系统由骨、骨连结和骨骼肌3个部分组成。关节炎是运动系统最主要的炎症性疾病。关节炎由自身免疫紊乱、感染等多种因素造成。在骨关节炎细胞实验中，CGA可改善炎症[58-60]。CGA通过提升人SW-1353软骨细胞活力，抑制iNOS、NO、前列腺素E2、COX-2和基质金属蛋白酶-13的表达来减轻炎症[58]。Zada等[59]发现CGA上调Nrf2和NF-κB信号通路，保护细胞免受氧化应激损伤，从而抑制软骨C28/I2细胞的炎症。CGA干预IL-1β诱导的颞下颌关节软骨细胞损伤后，抑制TNF-α、IL-6和基质金属蛋白酶-13的mRNA表达，同时抑制Wnt-5A/酪氨酸激酶样孤儿受体2(receptor tyrosine kinase-like orphan receptor 2，Ror2)信号通路中Wnt-5A和Ror2的表达[60]。CGA通过调节与Nrf2相关的细胞氧化还原稳态，降低IL-1β和TNF-α的表达水平，促进受损关节软骨的恢复[61]。因此，CGA通过上调Nrf2和NF-κB信号通路，抑制Wnt-5A/Ror2信号通路来减轻关节炎，进而改善运动系统的炎症性疾病。

2.6. CGA改善生殖系统炎症性疾病

生殖腺、生殖管道和附属器官等组成生殖系统。男性生殖腺为睾丸，女性生殖腺为卵巢，生殖管道包括输卵管、子宫与阴道。细菌突破防御入侵子宫内膜，造成子宫内膜炎。CGA可减轻BALB/c小鼠子宫内膜炎症损伤，激活Kelch样环氧氯丙烷相关蛋白-1(kelch-like epichlorohydrin protein-1，Keap1)/Nrf2信号通路后下调TNF-α、IL-1β及IL-6的mRNA[62]。在子宫内膜上皮细胞炎症中，CGA与黄芪甲苷共同干预可抑制TLR4介导的NF-κB信号通路，降低IL-1β、IL-6及IL-8的表达水平，进而改善炎症[63]。在睾丸炎症反应实验中[64-65]，CGA激活Nrf2信号通路后下调 IL-1β、IL-6、TNF-α，Bax及Casp-3的表达，减轻凋亡反应[64]；用添加CGA的饲料(1 000 mg/kg)喂养热应激小鼠，MDA含量显著降低，GSH、Nrf2、TLR2的mRNA表达量提高，CGA通过调节Nrf2信号通路缓解氧化应激，进而改善睾丸炎症并提高小鼠的生殖功能[65]。

CGA可改善或阻止生殖系统炎症性疾病进程，主要机制为激活Keap1/Nrf2信号通路，抑制NF-κB信号通路，进而改善小鼠子宫内膜炎；同时CGA可调节Nrf2信号通路，缓解睾丸的氧化应激，减轻凋亡反应，提高实验鼠的生殖功能。

2.7. CGA改善其他系统的炎症性疾病

CGA对于其他系统中的炎症性疾病亦有一定的抑制作用。在Gong等[66]的研究中，CGA促进Nrf2表达，提高视网膜神经节细胞(retinal ganglion cell，RGC)活力，减少细胞凋亡，减轻氧化应激损伤。CGA上调微管相关蛋白轻链3-II型与微管相关蛋白轻链3-I型的蛋白质表达比值，降解过氧化氢破坏的细胞器，从而恢复RGC-5细胞活性[67]。在牙周炎实验中[68-69]，Huang等[68]发现CGA通过半胱氨酸白三烯受体1(cysteine leukotriene receptor 1，CysLT1R)/Nrf2/NLRP3信号通路抑制人牙龈成纤维细胞中CysLT1R、NLRP3、ASC及Casp-1的表达，抑制IL-1β和IL-8的表达；调节TLR4/MyD88介导的NF-κB、PI3K/Akt和MAPK信号通路，减弱iNOS和前列腺素E2[69]，最终减轻牙周炎。

使用CGA干预心肌梗死大鼠，可增加抗氧化酶活性，激活IL-4、IL-10、SOD及CAT的表达，抑制IL-1β、IL-6、TNF-α及IFN-γ的表达，减轻心肌梗死后的炎症[70]。耿晶等[71]证实CGA对大鼠心肌缺血再灌注损伤有保护作用，降低肌酸激酶同工酶、LDH、IL-6、TNF-α、MEK/p-ERK的含量，具体机制可能与抑制MEK/ERK信号通路有关。在牛乳腺上皮细胞炎症实验[72]中，CGA干预后，NF-κB p65、TNF-α、IL-1β及IL-6的表达水平降低，牛乳腺上皮细胞炎症得到抑制。Gong课题组[73]发现CGA可通过激活牛乳腺上皮细胞的活力，降低IL-6和IL-8的表达水平，升高K-酪蛋白(kappa-Casein，K-CN)的表达水平，最终减轻乳腺炎。

由此可见，CGA在视觉系统、心血管系统等系统的炎症性疾病中也发挥抗炎作用，具体表现为调节CysLT1R/Nrf2/NLRP3、TLR4/MyD 88、PI3K/Akt、MAPK、MAPK/NF-κB信号通路，下调IL-1β、IL-6、IL-8、IL-12α、TNF-α及IFN-γ的表达，上调IL-4、IL-10、SOD、CAT及K-CN的表达。

CGA在不同系统炎症性疾病中的抗炎作用可见图2。

图2.

图2

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CGA在不同系统炎症性疾病中的抗炎作用

Figure 2 Anti-inflammatory effect of CGA on inflammatory diseases of different systems

CGA plays an anti-inflammatory role in the nervous system, respiratory system, digestive system, urinary system, motor system, and reproductive system. On the one hand, it regulates NF-κB, CYLD/NF-κB, TLR4/MyD88/NF-κB, TLR4/NF-κB, IκBα/NF-κB, Nrf2, Nrf2/NLRP3, Nrf2/HO-1, Keap1/Nrf2, NLRP3, NF-κB/NLRP3, ROS/TXNIP/NLRP3, TLR4, MAPK/ERK/JNK, PI3K/Akt, and WNT-5A/Ror2 signaling pathways. On the other hand, it regulates the expression of inflammatory mediators. The expressions of CAT, GSH, HO-1, IL-10, IL-13, NOQ-1, SOD, and TLR2 are increased, the expression of Bax, COX-2, Cas-1 p45, Cas-1 p20, Casp-3, Casp-8, Casp-9, IL-1β, IL-5, IL-6, IL-8, IL-17, iNOS, LPO, MMP-13, TNF-α, NO, PGE-2, and TLR4 are decreased. NF-κB: Nuclear factor κB; CYLD: Cylindromatosis; TLR4: Toll-like receptor 4; MyD88: Myeloid differentiation factor 88; Nrf2: Nuclear factor-erythroid 2-related factor 2; NLRP3: NOD-like receptor family pyrin domain containing 3; IκBα: Inhibitor NF-κB α; HO-1: Heme oxygenase-1; Keap1: Kelch-like epichlorohydrin protein-1; ROS: Reactive oxygen species; TXNIP: Thioredoxin interacting protein; MAPK: Mitogen-activated protein kinase; ERK: Extracellular regulated protein kinases; JNK: C-Jun amino-terminal kinase; PI3K: Phosphatidyinositol-3-kinases; Akt: Protein kinase B; Ror2: Receptor tyrosine kinase-like orphan receptor 2; IL: Interleukin; SOD: Superoxide dismutase; NOQ-1: Quinone oxidoreductase 1; GSH: Glutathione; CAT: Catalase; Bcl-2:B-cell lymphoma 2; Bax: Bcl-2 related X protein; COX-2: Cyclooxygenase-2; Casp: Caspase; iNOS: Inducible nitric oxide synthase; TNF-α: Tumor necrosis factor-α; LPO: Lipid hydroperoxide; NO: Nitric oxide; PGE-2: Prostaglandin E-2; MMP-13: Matrix metalloproteinase-13.

3. 结 语

CGA作为一种有机化合物，在不同系统的炎症性疾病中发挥抗炎作用。一方面，通过调节信号通路，如NF-κB典型、NF-κB非典型、Nrf2典型、Nrf2非典型信号通路等；另一方面，通过调节炎症细胞因子，降低IL-1β、IL-6及IL-8等促炎细胞因子的表达水平，升高IL-4、IL-10及IL-13等抑炎细胞因子的表达水平。CGA干预消化系统、神经系统和呼吸系统的炎症性疾病的研究较多，而在循环系统、生殖系统等中的相关研究较少。相对于体内实验而言，其体外实验较少，且具体浓度及干预时间尚未明确。但CGA有极大潜力和应用前景，应进一步探索其抗炎的具体分子机制，做进一步的研发，使其更好地为人类所用。

基金资助

江西省自然科学基金(20224BAB206054)。

This work was supported by the Natural Science Foundation of Jiangxi Province, China (20224BAB206054)。

利益冲突声明

作者声称无任何利益冲突。

作者贡献

凌鑫萍 文献检索和分析，论文撰写；晏伟 论文构思及修改；杨芬 文献整理与汇总；江淑玲 论文修改；陈福清 文献查阅与分析；李娜 论文指导、修改及校正。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023101611.pdf

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