Research Progress of Chemical Constituents and Pharmacological Effects of Common Medicinal Plants of Ilex

CHENGGong, ZHANGJianhong, YUANHuwei, ZHENGBingsong, YANDaoliang

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Chinese Agricultural Science Bulletin ›› 2024, Vol. 40 ›› Issue (8) : 30-37. DOI: 10.11924/j.issn.1000-6850.casb2023-0318

Research Progress of Chemical Constituents and Pharmacological Effects of Common Medicinal Plants of Ilex

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Abstract

Plants of Ilex have high medicinal value. They generally contain triterpenoids, flavonoids and other chemical components. They can reduce blood lipids, protect cardiovascular and cerebrovascular systems, and fight bacteria and inflammation in clinical practice. With the development of science and technology and the discovery of the medicinal value of Ilex, great progress has been made in the research of Ilex. This paper summarized the research progress of chemical constituents and pharmacological activities of commonly used medicinal plants of Ilex in recent years and put forward relevant suggestions, which would provide reference for the systematic research of Ilex in the future and facilitated the better utilization of resources.

Key words

Ilex / medicinal value / chemical composition / pharmacological activity

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CHENG Gong , ZHANG Jianhong , YUAN Huwei , ZHENG Bingsong , YAN Daoliang. Research Progress of Chemical Constituents and Pharmacological Effects of Common Medicinal Plants of Ilex. Chinese Agricultural Science Bulletin. 2024, 40(8): 30-37 https://doi.org/10.11924/j.issn.1000-6850.casb2023-0318

0 引言

冬青科(Aquifoliaceae)冬青属(Ilex)植物在全世界约有超过400种,中国约有200余种,仅有冬青属一属,主要分布于长江流域以南各省区,为中国南方常绿阔叶林的常见树种[1-2]。近年来,该属植物的药用价值备受重视。三萜及其皂苷、黄酮等多种化学成分多存在于该属植物叶中,多用于清热解毒、消炎、镇咳、止痛等。为加快推进冬青属药用植物的开发利用,本研究综述了近年来关于冬青属药用植物的研究进展,展望冬青属植物未来的研究方向,以期为其深入开发利用提供参考。

1 药用资源及成分

在民间,利用冬青属植物治疗疾病已经有很长的历史。迄今为止,已被证实可药用的冬青属植物约40多种[3]表1列举了国内外常用冬青属药用植物的基本信息及其药用价值[4-9]。冬青属植物常被用于治疗与心脑血管和炎症相关的疾病。例如:大叶冬青的水煎液具有抗氧化、抗菌消炎等作用,可用于治疗口齿疼痛、目赤等症;毛冬青的根、叶具有消炎止痛、清热解毒、祛痰等作用,经常被用来治疗心脑血管疾病;铁冬青的叶、树皮入药,具有较强的抗血栓和消炎镇痛作用;冬青的叶有清热解毒、活血等功效等。
表1 几种常用冬青属药用植物信息及药用价值
中文名 别名 拉丁学名 主要分布地区 食用方式 药用价值
大叶冬青 宽叶冬青 Ilex latifolia 浙江、广西 叶入药、泡饮、水煎 疏风清热;明目生津
铁冬青 救必应 Ilex rotunda 广东、广西 茎皮、叶、根入药 清热解毒;利湿止痛
毛冬青 茶叶冬青 Ilex pubescens 广东、福建 根入药 清热解毒;止痛消炎
苦丁茶冬青 Ilex Kudingcha 广西 叶入药、泡饮、水煎 清热解毒;祛暑
枸骨 老虎刺 Ilex cornuta 江苏、安徽 叶入药、泡饮 清热养阴;补肝益肾
冬青 四季青 Ilex chinensis 广东、福建 叶、根和树皮入药 清热解毒;消肿祛瘀
秤星树 梅叶冬青 Ilex asprella 广东、广西 根、叶入药 清热解毒;消肿散瘀
广东冬青 Ilex kwangtungensis 浙江、江西 根入药 消肿止痛;清热解毒
小果冬青 细果冬青 Ilex micrococca 安徽、福建 树皮入药 止痛
榕叶冬青 仿腊树 Ilex ficoidea 安徽、浙江 根入药 消肿止痛;治疗跌打损伤
尾叶冬青 江南冬青 Ilex wilsonii 广东、云南 根、叶入药 清热解毒;消肿止痛
黄毛冬青 Ilex dasyphylla 江西、广西 根入药 清热解毒
大果冬青 见水蓝 Ilex macrocarpa 陕西、四川 根入药 清热解毒;润肺止咳
香冬青 Ilex suaveolens 浙江、云南 根入药 清热解毒;活血止血
具柄冬青 落霜红 Ilex pedunculosa 安徽、湖北 叶入药 祛风除湿;散瘀止血
绿冬青 亮叶冬青 Ilex viridis 安徽、福建 根、叶入药 溶血解毒;祛腐生新
三花冬青 小冬青 Ilex triflora 安徽、浙江 根入药 疮疡肿毒;跌打损伤
海南冬青 山绿茶 Ilex hainanensis 海南、贵州 叶入药 清热平肝;利咽解毒
珊瑚冬青 毛枝珊瑚冬青 Ilex corallina 甘肃、湖北 叶、根、皮入药 抑菌、清热解毒
巴拉圭冬青 Ilex paraguariensis 阿根廷、巴西 叶入药、泡饮 解乏;利尿;抗炎
欧洲冬青 Ilex europaeus 欧洲、非洲 叶入药 利尿;缓解发烧症状
冬青属植物中含有多种化学成分,主要为三萜及其皂苷、黄酮类、木脂素、糖脂类等化合物。其中三萜类化合物因其广泛的生物活性和特有的结构特点成为冬青属植物中分布广泛、数量众多的化合物,而五环三萜又是三萜类化合物中最广泛的一类三萜化合物,主要可分为乌苏烷型、齐墩果烷型、羽扇豆烷型、苦丁内酯型。三萜类化合物主要是以游离和成苷形式存在于冬青属植物的根、叶、茎皮等部位[10-13]。近年来的研究中又陆续从冬青属植物中发现了许多化合物,表2总结了近年来在冬青属植物中首次分离得到的化合物。
表2 冬青属植物中分离鉴定的化合物
时间/年 来源 化合物 文献
2018 大叶冬青 3,9-二[2,4-二叔丁基-苯氧基]-2,4,8,10-四氧杂-3,9-二磷杂螺[5.5]-十一烷 [14]
2018 岗梅 3-O-[β-D-吡喃葡萄糖基-( 1→4)-β-D-葡萄糖醛酸甲酯基]坡模酸-28-O-β-D-吡喃葡萄糖苷 [15]
2018 秤星树 asprellinoids A-C [16]
2018 毛冬青 lexlignan B;ilexpublignoside;pubzenoside [17]
2018 冬青 ilexchinenosides J-M ;ilexchinenosides N-Q [18]
2018 铁冬青 rotundinosides E-K [19]
2018 秤星树 asprenols A-H [20]
2018 冬青 ilexchinenin A;ilexchinenin B;ilexchinenosides A-I [21]
2019 秤星树 asprellosides A-K [22]
2019 华中枸骨 (2S)-7-methoxy-3 ',4 '-dihydroxy-5,8-quinoflavan [23]
2019 毛冬青 pubescenosides L-M ; pubescenosidesN-P [24]
2019 枸骨 皮树脂醇;(+)-松脂醇;(+)-去氢催吐萝芙叶醇;ilexcornutoside A-E
(6R,9R)-3-氧代-α-紫罗兰醇-9-O-β-D-吡喃葡萄糖苷
[25]
2020 大叶冬青 ILP50-2;ILBP80-2A;ILBP80-2B;ILBP80-2C [26]
2020 枸骨 ilexcornutosides A-C;ilexcornutosides D-E [27]
2021 冬青 ilexchinenosides R-V;ilexchinenosides W-X [28]
2021 扣树 3-[2-(2-hydroxyphenyl)acetoxy]benzoic acid;dhurrin 6′-O-caffeate;(3E,5Z)-di-O-caffeoylquinate [29]
2022 铁冬青 3β,23α-dihydroxyurs-12,19(29)-dien-28-oic acid;rotundosides A-E;rotundarpenes A-B [30]
2022 巴拉圭冬青 mateoside I; mateoside II; matxeosideIII [31]

2 药理活性

2.1 抗炎抗毒作用

从秤星树中提取到的Asprellcosides B可以减少病毒复制,与血凝素结合可以抑制甲型流感病毒,在临床上可用于治疗流感[32]。枸骨果实中分离得到的一种多糖LCFP‐3有很强的抗炎活性,其可以有效减少脂多糖(LPS)诱导的一氧化氮(NO)的产生,且具有剂量依赖性[33]。铁冬青提取物 Rotundic acid (RA)可以显著抑制白细胞介素-6 (IL-6)、肿瘤坏死因子-α (TNF-α)和活性氧(ROS)等的生成,此外还可以增强抗氧化防御系统重要因子的活性,从而产生抗炎作用,对LPS诱导的急性肺损伤(ALI)具有保护作用,在临床上可用于治疗肺部炎症[34]。在非酒精性脂肪性肝病小鼠模型中,海南冬青提取物Ilexhainanoside D与Ilexsaponin A1结合可以有效改善肠道屏障功能,减少LPS含量,从而减轻炎症,显著降低非酒精性脂肪性肝病的严重程度[35]
苦丁茶提取物dicaffeoylquinic acids(DiCQAs)具有强大抗炎活性,可以减少促炎细胞因子产生,降低体内炎症水平,抑制NF-κB和MAPKs通路,此外还可以调节肠道菌群、改善结肠组织完整性,减轻结肠组织炎症,缓解炎症性肠病的典型症状,在临床上可做为炎症预防及治疗肠病药物使用[36-38]。在LPS诱导的肠道损伤小猪模型中,holly polyphenols通过减少血液中促炎细胞因子、改变肠道微生物群成分以及促进短链脂肪酸(SCFA)的产生来缓解肠道损伤,同时减少肠道炎症[39]。口服铁冬青水提取物可以显著抑制IL-6和TNF-a在结肠组织中的释放和表达并减弱其他促炎介质的体内转录[40]。秤星树提取物可以通过调节MAPK等信号通路来抑制促炎细胞因子活性,有效缓解小鼠的耳水肿和爪水肿,并呈剂量相关,临床上可做为抗炎药物使用[41]。铁冬青在溃疡性结肠炎小鼠模型中通过缓解结肠组织的氧化应激和凋亡、降低血清髓过氧化物酶和LPS水平和促进肠黏膜屏障恢复等来缓解症状,对溃疡性结肠炎有治疗作用[42]。利用毛冬青三萜皂苷(IPTS)治疗LPS诱导的肠损伤小鼠时,发现其可以通过下调PLA2G5的表达、影响TRP通道、降低丙二醛(MDA)水平、升高超氧化物歧化酶(SOD)活性和介导IgA相关的肠道免疫信号通路等途径来缓解氧化应激损伤、降低炎症因子表达、保护肠屏障和调节肠道免疫系统,从而改善肠损伤[43]。用毛冬青汤对膝关节镜术后患者进行治疗可以降低血清中红细胞沉降率(ESR)和C反应蛋白(CRP)水平,再配合冰敷等治疗手段,从而起到抗血小板聚集和消炎等作用,有效减轻术后引起的膝关节疼痛和肿胀[44]

2.2 抗癌作用

巴拉圭冬青提取物可以通过诱导细胞凋亡来减少结肠癌细胞增殖,在小鼠肿瘤模型中,可以显著抑制血管生成和肿瘤生长,在临床上可以用作草药或功能性食物来治疗结肠癌[45]。给肺腺癌小鼠口服巴拉圭冬青提取物可使绿原酸和槲皮素含量增加,从而对端脑和间脑产生不同的神经保护作用,以减轻癌症相关的神经炎症和损伤[46]。大叶冬青多酚(ILTPs)可以提高乳酸脱氢酶(LDH)和ROS水平,促进人肺癌细胞A549(A549细胞)凋亡,并随着ILTPs浓度的增加,A549细胞增殖能力下降,另外还可降低PI3K和Akt蛋白的表达,可以做为一种具有强抑癌作用的天然功能性食品材料[47]。大叶冬青叶中三萜类成分27-O-p-(E)-coumaroyl ursolic acid可以通过抑制乳腺癌细胞进入有丝分裂期来降低肿瘤细胞增殖活性,从而促进癌细胞形态变化及脱落,同时呈剂量依赖型抑制EGFR酪氨酸激酶的活性,对人乳腺癌和宫颈癌有治疗作用[48-50]
铁冬青酸(RA)是铁冬青、毛冬青等植物种子、树皮和树叶中的一种五环三萜化合物,具有抗炎等作用。杨彩梅研究发现RA对人肺腺癌细胞A549和PC9的增殖、水平及纵向迁移和侵袭能力具有抑制作用,并降低酪氨酸蛋白激酶2(JAK2)和转录激活蛋白3(STAT3)的蛋白表达量和mRNA表达水平,且均呈浓度依赖性[51]。研究发现RA结合放射治疗通过增强放射治疗诱导ataxia-telangiectasia mutated(ATM)和肿瘤抑制基因p53蛋白的表达效果,从而促进乳腺癌细胞株MCF-7细胞的凋亡,有效抑制乳腺癌的活力[52]。RA通过调节AKT/mTOR和MAPK通路显著抑制肝癌细胞HepG2的迁移和侵袭,从而促进其凋亡,同时还对肝细胞癌(HCC)有抗血管生成能力[53]。RA可有效拮抗抑癌基因let-7f-5p对结直肠癌细胞Caco2调节时产生的副作用,从而抑制Caco2细胞的增殖[54]。综上所述,临床上RA有成为抗癌药物的潜力。
从秤星树根中分离得到的一种酸性多糖IAPS-2可以提高抗肿瘤细胞因子的活性,在肿瘤小鼠模型中通过调节肿瘤相关巨噬细胞(TAMs)的功能以抑制肿瘤的生长,提高小鼠存活率,可以在临床上利用其强大的抗肿瘤活性进行肿瘤免疫治疗[55]。毛冬青甲素(IA)可以有效抑制人白血病K562细胞的增殖,且与时间呈正相关,同时细胞凋亡数量也随着药物溶度增加而增加,另外还可以通过上调自噬相关蛋白LC3的表达从而诱导K562细胞自噬,临床上可以用IA配合化疗来治疗白血病[56]

2.3 心脑血管疾病治疗

枸骨中的三萜皂苷成分可以降低H2O2诱导的细胞内ROS的产生,有效保护H9c2心肌细胞免受H2O2诱导的凋亡,在临床上可用于治疗和预防心血管疾病[57]。毛冬青药通过cAMP和钙离子信号通路来调节血小板聚集和血栓形成、减轻炎症反应、促进血管新生和维持血管完整性等,临床上可用于治疗冠心病[58]
白荣钰等[59]和易欢等[60]利用IPTS治疗动脉粥样硬化(AS)大鼠,对其粪便和尿液进行研究,发现IPTS可以增加粪便中的富马酸盐含量和尿液中的柠檬酸盐、尿氨酸、胞嘧啶和黄嘌呤含量,从而改善大鼠的能量代谢紊乱、核苷酸代谢紊乱和氨基酸代谢紊乱,还能通过增加粪便中的丁酸含量和降低尿液中的TMAO含量有效调节肠道菌群宿主共代谢,另外也可以通过增加拟杆菌等益生菌的相对丰度、降低大肠杆菌等致病菌的相对丰度等来抑制病原菌入侵、调节肠道菌群结构和改善部分肠道菌群基因功能,临床上可以用于治疗AS[61]。患有AS时,炎性因子会通过浸润血管内皮细胞(HUVEC)导致细胞炎性损伤及细胞凋亡。在TNF-α诱导建立的HUVEC炎性损伤和凋亡模型中,研究发现IPTS可以通过减少ICAM-1、MMP-9等炎症相关蛋白的表达、线粒体膜电位的降低和细胞核浓染以及激活细胞自噬来改善细胞形态损伤、提高细胞活性、减少炎症和抑制细胞凋亡,临床上可以用IPTS预防和改善HUVEC炎性损伤和凋亡以减轻AS症状[62]
骨髓间充质干细胞(BMSCs) 可分化成为多种细胞,具有分泌营养因子和调节免疫等功能,将其定向迁移到受损组织中可以有效修复组织,是临床中常用的一种辅助治疗手段。李庆双等[63]研究发现IA可以有效促进BMSCs的增殖,并通过上调CXCR4的表达来提高其迁移能力并利于其迁移到脑缺血区组织,对脑梗死的治疗有积极作用。曹迪[64]对毛冬青总提物(IP)、总皂苷(IPTS)和非皂苷部位(IPNT)3个组分抗血栓效果进行研究,结果表明IP治疗效果最为显著,其次为IPTS,而IPNT未体现出治疗作用,其中IP可以通过改善血管内皮的受损程度、抑制血小板聚集及调节花生四烯酸代谢和相关脂质代谢来发挥抗血栓作用。
毛冬青皂酮胶囊是毛冬青总黄酮和总皂苷组成的混合物,可以有效降低炎症水平。胡科等[65]和康乐等[66]分别利用毛冬青皂酮胶囊对急性脑梗死和短暂脑缺血发作(TIA)大鼠进行治疗,结果表明毛冬青皂酮胶囊可以通过下调NF-κBp65表达水平,进而降低体内血清炎性因子IL-1β和TNF-α水平来降低炎性反应,还能有效改善血液流变学指标、降低神经功能评分、血浆中溶血磷脂酸(LPA)及血清中CRP的水平以及减少脑神经细胞病理变化,从而发挥对急性脑梗死和TIA的治疗和预防作用。在心肌缺血/再灌注损伤(MIRI)小鼠模型中,救必应活性成分之一的具栖冬青苷(PE)可以通过改善血流动力学指标、减少心肌梗死面积、提高SOD活性以及降低心脏脏器指数、MDA含量和CTnI水平来改善心肌收缩及舒张功能、缓解心肌组织及细胞损伤、减少心肌细胞坏死、降低炎症反应,说明PE对急性MIRI较好的保护和治疗作用[67]

2.4 减轻疼痛作用

邹清容等[68]和禤丽萍等[69]对腹部手术患者用毛冬青水煎液清洗伤口并湿敷,发现毛冬青水煎液具有消肿止痛、减少创面渗液以及促进创面肉芽组织生长和血液循环等作用,能有效缩短伤口愈合时间、减轻病人疼痛感[70]
冬青油是从冬青树叶提取的天然精油,具有清热解毒、消炎杀菌的作用。胡佩欣等[71]和姜丽[72]研究发现用冬青油对大肠息肉摘除术病人和小儿食滞腹痛患儿进行腹部按摩可以刺激胃肠蠕动,有助于肠道内气体排出,从而减轻腹部症状,另外舒适的按摩也会使病人精神放松、心情舒畅,减少负面情绪,提高住院满意度。
梁华丽[73]利用毛冬青叶浓缩液联合聚维酮碘治疗Ⅰ、Ⅱ度烧伤,结果表明该治疗方法可以通过促进创面皮肤修复、减少感染风险从而缩短创面愈合时间及减轻疼痛,且该方法具有成本低、无不良反应等优势,适合在临床中推广应用。

2.5 降脂消肥作用

苦丁茶提取物DiCQAs可以降低肝脏中脂肪组织质量和炎症因子浓度,减少肝脏中脂质合成相关基因的表达,增加肝脏中参与脂质降解的基因的表达,从而减少脂肪积累,有很强的抗肥胖药物潜力[74]。花叶冬青提取物在代谢紊乱大鼠模型中,通过减轻动脉粥样硬化、改善肝脏结构等加速肝脏脂肪分解,对脂质代谢有积极影响[75]。刘伟等[76]利用苦丁茶水提取物对胆固醇脂血症小鼠进行灌胃给药,发现其能够显著降低小鼠血清总胆固醇及低密度脂蛋白胆固醇并可以有效缓解肝脏脂肪堆积,另外对血清中多不饱和溶血磷脂酰胆碱(Lyso-PC)成分有回调和改善作用,说明该提取物具有肝脏保护及降血脂作用,可以对脂质代谢类疾病进行预防和治疗。

2.6 免疫调节作用

从大叶冬青中分离出的一种多糖ILP50-2可以通过增强巨噬细胞的吞噬能力、促进IL-6和TNF-α等的释放来进行免疫调节[77]。舒翔等[78]对小鼠脾脏淋巴细胞研究发现,脾脏淋巴细胞的增殖、SOD、总抗氧化能力(T-AOC)、谷胱甘肽过氧化物酶(GSH-Px)和过氧化氢酶(CAT)活性均与苦丁茶冬青多糖浓度成正比,苦丁茶冬青多糖还能显著降低MDA含量以及促进脾脏淋巴细胞分泌NO,说明苦丁茶冬青多糖可以通过提高细胞抗氧化、增殖能力等途径来提高免疫力,可以做为保健产品开发利用。

2.7 其他

苦丁茶提取物在衰老小鼠模型中,通过改善肝脾等组织形态、降低促炎因子浓度、增加抗炎因子浓度以及调节SOD和CAT等的基因和蛋白表达而发挥抗衰老作用[79]。对几种冬青属植物抗菌活性进行对比研究发现,银边构骨叶冬青(Ilex aquifolium 'Argentea Marginata')和构骨叶冬青(Ilex aquifolium)的抑菌活性最强,其提取物可以显著降低金黄色葡萄球菌的生物膜活性,临床上可用于尿路感染治疗 ,另外其体内有较多绿原酸和芦丁,也可以用于治疗肥胖、消化问题[80]。广西毛冬青根可以通过保护放射性脑损伤小鼠海马区细胞的形态结构及抑制神经胶质细胞活化,从而改善小鼠的认知功能障碍,为临床上治疗放射性脑损伤提供了新思路[81]

3 展望

冬青属植物资源在全球十分丰富,具有很大药用价值和经济价值。其含有的三萜类、多酚类、黄酮类等多种化合物,在消炎止痛、心脑血管系统保护、抗病毒等方面发挥出极大作用,表3列举了部分冬青属药用植物中化合物的药理活性。另外,人们还常将该属植物制作成功能饮料和食品来进行保健,从而提高免疫力。但目前国内外大部分研究都集中在毛冬青、铁冬青、大叶冬青等个别植物中的三萜及其皂苷方面,同时对于其药理作用研究大多集中在肿瘤和心脑血管治疗方面。因此,有必要深入研究冬青属药用植物的药理,筛选出更多的活性物质并深入发掘其在临床治疗上的用途。随着对冬青属植物的进一步研究,相信该属植物会给我们的生产生活带来更多益处。
表3 部分冬青属药用植物中的化学成分及药理活性
化合物 来源 药理活性 文献
(2S)-7-methoxy-3′,4′-dihydroxy-5,8-quinoflavan 华中枸骨(Ilex centrochinensis) 抗炎活性 [23]
Pubescenoside N;Pubescenoside O 毛冬青(Ilex pubescens) 抗血小板聚集 [24]
rotundarpenes A-B 铁冬青(Ilex rotunda) 抗炎活性 [30]
matesaponin 1;matesaponin 2 巴拉圭冬青(Ilex paraguariensis) 抗肥胖活性 [31]
Asprellcosides B 秤星树(Ilex asprella) 抗病毒活性 [32]
LCFP-3 枸骨(Ilex cornuta) 抗炎活性 [33]
Rotundic acid 铁冬青(Ilex rotunda) 抗炎活性 [34]
Ilexhainanoside D 海南冬青(Ilex hainanensis) 抗炎活性;改善肠道屏障 [35]
dicaffeoylquinic acids 苦丁茶(Ilex Kudingcha) 抗炎活性; [36-38]
27-O-p-(E)-coumaroyl ursolic acid 大叶冬青(Ilex latifolia) 抗癌作用 [50]
IAPS-2 秤星树(Ilex asprella) 抗肿瘤活性 [55]
ILP50-2 大叶冬青(Ilex latifolia) 免疫调节活性 [77]
4,5-dicaffeoylquinic acid 铁冬青(Ilex rotunda) 治疗中枢神经系统 [82]

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The effect of holly polyphenols (HP) on intestinal inflammation and microbiota composition was evaluated in a piglet model of lipopolysaccharide (LPS)-induced intestinal injury. A total of twenty-four piglets were used in a 2 × 2 factorial design including diet type and LPS challenge. After 16 d of feeding with a basal diet supplemented with or without 250 mg/kg HP, pigs were challenged with LPS (100 μg/kg body weight) or an equal volume of saline for 4 h, followed by analysis of disaccharidase activities, gene expression levels of several representative tight junction proteins and inflammatory mediators, the SCFA concentrations and microbiota composition in intestinal contents as well as proinflammatory cytokine levels in plasma. Our results indicated that HP enhanced intestinal disaccharidase activities and reduced plasma proinflammatory cytokines including TNF-α and IL-6 in LPS-challenged piglets. Moreover, HP up-regulated mRNA expression of intestinal tight junction proteins such as claudin-1 and occludin. In addition, bacterial 16S rRNA gene sequencing showed that HP altered hindgut microbiota composition by enriching Prevotella and enhancing SCFA production following LPS challenge. These results collectively suggest that HP is capable of alleviating LPS-triggered intestinal injury by improving intestinal disaccharidase activities, barrier function and SCFA production, while reducing intestinal inflammation.
[40]
CHEN GANG, HAN Y Q, FENG YUAN, et al. Extract of Ilex rotunda Thunb alleviates experimental colitis-associated cancer via suppressing inflammation-induced miR-31-5p/YAP overexpression[J]. Phytomedicine, 2019, 62:152941.
[41]
YANG X Y, GAO X L, DU B Z, et al. Ilex asprella aqueous extracts exert in vivo anti-inflammatory effects by regulating the NF-κB, JAK2/STAT3, and MAPK signaling pathways[J]. Journal of ethnopharmacology, 2018, 225:234-243.
Ilex asprella (Hook. et Arn.) Champ. ex Benth. (IA) is a representative medicinal plant from the South of the Five Ridges of China. Its roots (RIA) and stems (SIA) have been traditionally used for the inflammation-related diseases, such as acute and chronic pharyngitis, cough, and sore throats.To evaluate the in vivo anti-inflammatory effects of IA extracts to provide evidence for its traditional use and to enhance the knowledge of the medicinal properties of IA.Models of xylene-induced ear edema in mice and carrageenan-induced paw edema in rats were used for the pharmacological evaluations. The mice were randomly divided into eight groups (n = 10 per group): a model group, a positive control group [dexamethasone (Dex), 10 mg/kg, intragastrically (i.g.)], RIA aqueous extract groups with three dosages (30, 15, and 7.5 mg/kg, i.g.), and SIA aqueous extract groups with three dosages (60, 30, and 15 mg/kg, i.g.). The rats were randomly divided into eight groups (n = 6 per group): a model group, a positive control group [acetylsalicylic acid (ASA), 300 mg/kg, i.g.], RIA groups with three dosages (80, 40, and 20 mg/kg, i.g.) and SIA aqueous extract groups with three dosages (160, 80, and 40 mg/kg, i.g.). Histological examinations of the ear and paw tissues were observed by hematoxylin-eosin (HE) staining, and neutrophil elastase levels were assessed in ear tissues by immunohistochemical analysis. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by ELISAs, and expression levels of TNF-α, IL-6, and IL-1β in rat paw tissues were measured by RT-PCR. The signal transduction proteins p65, IκBα, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinases (p38), extracellular regulated protein kinases (ERK1/2), and c-Jun N-terminal kinase (JNK) in the rat paw tissues were investigated by western blot analyses. RIA and SIA were characterized by HPLC and LC-MS analyses, and the components were confirmed by comparison with isolated compounds.Intragastric administration with RIA (30 mg/kg) and SIA (60, 30 mg/kg) significantly mitigated ear edema in mice. RIA administration at 80 and 40 mg/kg reduced paw edema in rats 2‒3 h after injection. SIA administration with 160 mg/kg inhibited paw edema in rats after the injection of carrageenan for 1‒4 h, and SIA administration at 80 mg/kg inhibited paw edema after the injection of carrageenan for 2‒4 h. Meanwhile, RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced inflammatory cell infiltration in the ear and paw tissues and infiltration of neutrophil leukocytes in rat paw tissues. RIA (80, 40, and 20 mg/kg) and SIA (160, 80, and 40 mg/kg) notably inhibited the increases of TNF-α, IL-6 and IL-1β in the serum and mRNA expression in the rat paw tissues. RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced the p-p65/p-IκBα, p-JAK2/p-STAT3, and p-p38/p-ERK1/2/p-JNK levels in the pathological tissues of the animals. Phenolic acids and triterpenoids likely contributed to the anti-inflammatory activity.Both RIA and SIA aqueous extracts showed anti-inflammatory effects in vivo in a dose-independent manner (20‒80 and 40‒160 mg/kg, respectively). The underlying mechanisms are mediated by inhibiting the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β via regulation of the NF-κB, JAK2/STAT3, and MAPK signaling pathways. The present results provided pharmacological evidence that stems are alternative medicinal parts of IA but function at different doses. Additionally, this study supports the use of IA as an anti-inflammatory herbal medicine.Copyright © 2018 Elsevier B.V. All rights reserved.
[42]
LI YAO, YANG XU, YUAN J N, et al. Ilex rotunda thunb protects against Dextran Sulfate Sodium-induced ulcerative colitis in mice by restoring the intestinal mucosal barrier and modulating the Oncostatin M/Oncostatin M receptor pathway[J]. Frontiers in pharmacology, 2022, 13:819826-819826.
Ilex rotunda Thunb (IR) is a traditional Chinese medicine used for the clinical treatment of gastric ulcers and duodenal ulcers; however, the effect of IR on ulcerative colitis (UC) and its underlying mechanism remains unclear. This study investigated the therapeutic effect of IR on UC mice induced by dextran sulfate sodium (DSS) as well as the potential underlying mechanism. The main components of IR were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Then we established a model of UC mice by administering 2.0% DSS for 7 days followed by 2 weeks of tap water for three cycles and administered IR. On day 56, the disease activity index (DAI), colon length, pathological changes, and inflammatory response of the colon tissue of mice were assessed. The oxidative stress and apoptosis of colon tissue were detected, and the integrity of the intestinal mucosal barrier was evaluated to assess the effect of IR. Furthermore, the relationship between oncostatin M (OSM) and its receptor (OSMR) in addition to the IR treatment of UC were evaluated using a mouse model and Caco2 cell model. The results showed that IR significantly alleviated the symptoms of UC including rescuing the shortened colon length; reducing DAI scores, serum myeloperoxidase and lipopolysaccharide levels, pathological damage, inflammatory cell infiltration and mRNA levels of interleukin one beta, tumor necrosis factor alpha, and interleukin six in colon tissue; alleviating oxidative stress and apoptosis by decreasing kelch-like ECH-associated protein 1 expression and increasing nuclear factor-erythroid factor 2-related factor 2 and heme oxygenase-1 protein expression; and promoting the regeneration of epithelial cells. IR also promoted the restoration of the intestinal mucosal barrier and modulated the OSM/OSMR pathway to alleviate UC. It was found that IR exerted therapeutic effects on UC by restoring the intestinal mucosal barrier and regulating the OSM/OSMR pathway.
[43]
王莹, 陈冰莹, 伍钰蓉, 等. 基于转录组学研究毛冬青三萜皂苷对脂多糖诱导小鼠肠损伤的保护作用及其机制[J]. 中草药, 2022, 53(22):7102-7111.
[44]
江斌, 杨承伟, 何华锋. 毛冬青汤对膝关节镜术后患者血清ESR、CRP水平的影响[J]. 内蒙古中医药, 2021, 40(1):14-15.
[45]
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[46]
CITTADINI MARIA C, REPOSSI GASTON, ALBRECHT CLAUDIA, et al. Effects of bioavailable phenolic compounds from Ilex paraguariensis on the brain of mice with lung adenocarcinoma.[J]. Phytotherapy research: PTR, 2019, 33(4):1142-1149.
[47]
CHEN JING, DU Y S, LONG Y Y, et al. Polyphenols in Ilex latifolia Thunb. inhibit human lung cancer cell line A549 by regulation of the PI3K-Akt signaling pathway.[J]. BMC Complementary medicine and therapies, 2022, 22(1):85.
The leaves of the plant Ilex latifolia Thunb. can be made into Kuding tea, which is a drink rich in polyphenols. This study aimed to observe the effect of Ilex latifolia Thunb. polyphenols (ILTPs) on human lung cancer cell line A549 (A549 cells) by regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway.In vitro cultured cells were treated with ILTPs; the proliferation of A549 cells and BEAS-2B human normal lung epithelial cells (Beas-2B cells) was observed using the 3-(4,5-dimethylazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the survival status of A549 cells was observed by fluorescence staining. The expression of A549 cells was observed by quantitative polymerase chain reaction (qPCR) assay and Western blot analysis, while the compound composition of ILTPs was detected using high-performance liquid chromatography (HPLC).The experimental results showed that the proliferation of Beas-2B cells was unaffected by treatment with 0-500 μg/mL of ILTPs, whereas the decreased proliferation of A549 cells was observed with the increasing concentrations of ILTPs. Additionally, ILTPs elevated the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) and promoted apoptosis in A549 cells. The results of qPCR experiments showed that ILTPs upregulated caspase-9 mRNA expression and downregulated phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), B-cell lymphoma-2 (Bcl-2), nuclear factor-κB (NF-κB), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 alpha (HIF-1α), and cyclooxygenase-2 (COX-2) expression in A549 cells. The Western blot analysis results also showed that ILTPs could reduce the protein expression of PI3K and Akt. The HPLC results showed that the main compounds present in the ILTPs were rutin, kaempferol, isochlorogenic acid A, isochlorogenic acid B, and isochlorogenic acid C.Thus, this study indicated that the polyphenols of I. latifolia act as a class of natural functional food materials that potently suppress cancer by exerting their inhibitory effects on A549 cell proliferation through five key polyphenolic compounds.© 2022. The Author(s).
[48]
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[49]
臧莉, 王宏婷, 王存琴. 大叶冬青叶中27-CAUA对人乳腺癌MDA-MB-468细胞增殖的影响[J]. 皖南医学院学报, 2021, 40(6):519-522.
[50]
臧莉. 大叶冬青叶中27-O-p-(E)-coumaroyl ursolic acid抑制乳腺癌细胞作用及其机制研究[D]. 芜湖: 皖南医学院, 2021.
[51]
杨彩梅. 铁冬青酸对人肺腺癌细胞增殖、迁移和侵袭能力的影响[D]. 合肥: 安徽医科大学, 2022.
[52]
WANG ZHONG-FENG, SUN WEN-YI, YU DE-HAI, et al. Rotundic acid enhances the impact of radiological toxicity on MCF-7 cells through the ATM/p53 pathway.[J]. International journal of oncology, 2018, 53(5):2269-2277.
[53]
GAURAB ROY, GUAN SU, LIU H X, et al. Rotundic acid induces dna damage and cell death in hepatocellular carcinoma through AKT/mTOR and MAPK pathways[J]. Frontiers in oncology, 2019, 9:545.
Hepatocellular carcinoma (HCC) is the fourth largest cause of cancer-related deaths worldwide with limited therapeutic interventions. Renewed interest in natural products as drug leads has resulted in a paradigm shift toward the rapid screening of medicinal plants for the discovery of new chemical entities. Rotundic acid (RA), a plant-derived triterpenoid, has been anecdotally reported to possess anti-inflammatory and cardio-protective abilities. The present study highlights the anti-cancer efficacy of RA on HCC and. The inhibitory effects of RA on HCC cell viability was determined by MTT. Soft agar colony formation and clonogenic assays also showed that RA inhibited HCC cell proliferation. Flow cytometry, confocal, and western blot results further indicated that RA induced cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways. Besides the suppression of migration and invasion, tube formation and VEGF-ELISA revealed the anti-angiogenic abilities of RA on HCC. Moreover, RA also inhibited tumor growth in a HepG2 xenograft mouse model. To our best knowledge, this is the first extensive study of the anticancer activity of RA on HCC. The results demonstrate that RA could be a potential drug candidate for HCC treatment.
[54]
CHEN GANG, ZHANG LIN, CHEN L Y, et al. Rotundic acid regulates the effects of Let-7f-5p on Caco2 cell proliferation[J]. Anti-cancer agents in medicinal chemistry, 2021, 21(7):902-909.
Nowadays, the interaction between natural products and microRNAs provides\na promising field for exploring the chemopreventive agents for various cancers. As a member of microRNAs,\nthe expression of let-7f-5p is universally downregulated in Colorectal Cancer (CRC). The present study\naimed to uncover the function of let-7f-5p in the proliferation of human colon cancer cell line Caco2 and explored\nchemopreventive agents from natural resources that can prevent the development of CRC.
[55]
LI QIU, HAO Z H, HONG Y T, et al. Reprogramming tumor associated macrophage phenotype by a Polysaccharide from Ilex asprella for Sarcoma immunotherapy[J]. International journal of molecular sciences, 2018, 19(12):3816.
We report here the discovery of an acidic polysaccharide, namely IAPS-2, from the root of Ilex asprella, with anti-tumor activity via a repolarizing tumor associated macrophages (TAMs) phenotype. We obtained IAPS-2 polysaccharide from this herb based on acidity and found that IAPS-2 expressed the activity of promoting the secretion of anti-tumor cytokines in macrophages. Furthermore, we evaluated its anti-tumor effect on TAM cells, through the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) signaling. In particular, in the tumor murine model, IAPS-2 demonstrated that it could significantly inhibit the growth of tumors via modulating the function of TAMs and increase the animal survival rate. In summary, IAPS-2, with a clearly illustrated chemical composition, potent anti-tumor activity, and a solid mechanism of action, may be developed into a valuable therapeutic tool for cancer immunotherapy.
[56]
陈颖. 毛冬青甲素对白血病K562细胞自噬性凋亡LC3通路调控影响的研究[D]. 长沙: 湖南中医药大学, 2019.
[57]
YU D H, ZHU Z Y, WANG MEI, et al. Triterpenoid saponins from Ilex cornuta protect H9c2 cardiomyocytes against H2O2-induced apoptosis by modulating Ezh2 phosphorylation[J]. Journal of ethnopharmacology, 2021, 269:113691.
[58]
冯思颖, 黄敏玲, 吴威妮, 等. 基于网络药理学探讨黄芩、毛冬青药治疗冠心病的作用机制[J]. 现代中西医结合杂志, 2020, 29(28):3133-3138,3184.
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白荣钰, 易欢, 邱静文, 等. 毛冬青三萜皂苷对动脉粥样硬化大鼠粪便和尿液代谢组学的影响[J]. 南京中医药大学学报, 2022, 38(5):424-431.
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[61]
白荣钰, 易欢, 陈丰连, 等. 毛冬青三萜皂苷对动脉粥样硬化大鼠肠道菌群的影响[J]. 中草药, 2021, 52(20):6245-6253.
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[63]
李庆双, 郑关毅, 张碧琴, 等. 毛冬青甲素对大鼠骨髓间充质干细胞增殖及迁移的影响[J]. 中国药理学通报, 2018, 34(3):358-364.
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胡科, 张保朝, 贾东佩, 等. 毛冬青皂酮胶囊对急性脑梗死模型大鼠神经保护作用[J]. 中医学报, 2020, 35(9):1950-1956.
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杨爱萍, 张启春, 宋祎, 等. 具柄冬青苷对大鼠急性心肌缺血/再灌注损伤的保护作用研究[J]. 中国药理学通报, 2021, 37(4):484-489.
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邹清容, 禤丽萍, 吕一燕, 等. 毛冬青对妇产科手术感染伤口疼痛的影响[J]. 黑龙江医学, 2018, 42(4):362-363.
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禤丽萍, 吕一燕, 邹清容, 等. 毛冬青外治妇产科腹部术后切口感染40例[J]. 中国民族民间医药, 2018, 27(1):126-127,132.
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吕一燕, 陈端, 黄涛, 等. 毛冬青液在妇产科术后腹部切口感染的应用效果[J]. 广西医学, 2018, 40(6):689-691.
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胡佩欣, 柴计委, 望华南, 等. 冬青油腹部按摩对内镜下大肠息肉摘除术围术期病人负性情绪的影响[J]. 全科护理, 2022, 20(31):4398-4400.
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姜丽. 冬青油腹部按摩治疗小儿食滞腹痛疗效观察[J]. 临床医药文献电子杂志, 2019, 6(36):36.
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梁华丽. 毛冬青叶浓缩液联合聚维酮碘治疗Ⅰ、Ⅱ度烧伤的疗效观察[J]. 中国现代药物应用, 2018, 12(21):209-211.
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XIE M H, CHEN G J, WAN PENG, et al. Effects of dicaffeoylquinic acids from Ilex kudingcha on Lipid metabolism and intestinal microbiota in high-fat-diet fed mice[J]. Journal of agricultural and food chemistry, 2018, 67(1):171-183.
[75]
PACHURA NATALIA, KUPAZYNSKI ROBERT, LEWANDO WSKA KAMILA, et al. Biochemical and molecular investigation of the effect of Saponins and Terpenoids derived from leaves of Ilex aquifolium on lipid metabolism of obese zucker rats[J]. Molecules, 2022, 27(11):3376.
Ilex paraguariensis, the holly tree, is a plant with recognized biological properties, whose aqueous infusions are known as “Yerba mate”, that regulate lipid metabolism, reduce obesity, and improve brain stimulation. In the present study, the effect of standardized saponin and terpenoid fractions of a European taxon, Ilex aquifolium, on blood biochemical parameters in a rat model of metabolic disorder, (fa/fa) Zucker, are presented. The profiles of the volatile fractions of two species and six European varieties of Ilex were investigated. After selecting the best variety, the saponin and terpenoid fractions were isolated and standardized, and animals were fed 10 mg kg−1 b.w. for 8 weeks. A statistically significant decrease in liver adiposity was observed, confirmed by histology and quantitative identification (gas chromatography–mass spectrometry analyses of hepatic lipids. RT-qPCR analysis of gene expression in the aorta revealed that the administration of the terpenoid fraction downregulated LOX-1, suggesting a reduction in atherosclerotic stimuli. In addition, a statistically significant reduction (p < 0.05) in PPARγ for the saponin fraction was observed in the liver. The expression of the ACAT-1 gene in the liver, responsible for the formation of cholesterol esters, increased significantly in the group receiving the terpenoid fraction compared to the control, which was also confirmed by the analysis of individual blood biochemical parameters. The opposite effect was observed for saponins. Taking the above into account, it is shown for the first time that Ilex aquifolium can be a source of compounds that positively influence lipid metabolism.
[76]
刘伟, 向星亮, 黄荣增, 等. 苦丁茶对高胆固醇脂血症小鼠血清多不饱和溶血磷脂酰胆碱的改善作用[J]. 中国医院药学杂志, 2018, 38(1):54-58.
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SHI Z Y, AN L J, ZHANG S J, et al. A heteropolysaccharide purified from leaves of Ilex latifolia displaying immunomodulatory activity in vitro and in vivo[J]. Carbohydrate polymers, 2020, 245:116469.
[78]
舒翔, 程明, 王辉, 等. 苦丁茶冬青多糖对小鼠脾脏淋巴细胞的免疫调节和抗氧化作用[J]. 食品工业科技, 2022, 43(17):387-393.
[79]
MU J F, YANG F P, TAN FANG, et al. Determination of polyphenols in ilex kudingcha and insect tea (leaves altered by animals) by ultra-high-performance liquid chromatography-triple quadrupole mass Spectrometry (UHPLC-QqQ-MS) and comparison of their anti-aging effects[J]. Frontiers in pharmacology, 2021, 11:600219.
Ilex kudingcha C.J. Tseng tea and insect tea, as traditional Chinese teas, are favored for their original craftsmanship, unique flavor, and biological functionality. In this study, ultra high-performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-QqQ-MS) was used to analyze the bioactive components of the extracts of Ilex kudingcha and insect tea, and D-galactose-induced aging mice were used to compare the in vivo anti-aging effects of Ilex kudingcha and insect tea extracts. The results were remarkable, UHPLC-QqQ-MS analysis showed that ITP contains 29 ingredients, while IKDCP contains 26 ingredients. However, due to the large differences in the content of the main chemical components in IKDCP and ITP, the effects are equally different. At the same time, the in vivo research results suggesting that the anti-aging effects of IKDCP and ITP (500 mg/kg) include the regulation of viscera indices of major organs; improvement in liver, skin, and spleen tissue morphology; decreased production of inflammatory cytokines; up regulation of SOD, CAT, GSH, GSH-PX, and T-AOC and down regulation of NO and MDA levels in serum and liver tissue; reductions in the concentration of pro-inflammatory factors, and increases in the concentration of anti-inflammatory factor. RT-qPCR and western blot assay also showed that IKDCP and ITP affect anti-aging by regulating the gene and protein expression of GSH-PX, GSH1, SOD1, SOD2, and CAT. The overall results indicate that ITP is more effective in treating oxidative damage in aging mice induced by D-galactose. Thus, ITP appears to be an effective functional drink owing to its rich nutritional components and anti-aging activities.
[80]
PALUCH EMIL, OKINCZYC PIOTR, ZWYRZYKOWSKWOD ZINSKA ANNA, et al. Composition and antimicrobial activity of Ilex leaves water extracts[J]. Molecules, 2021, 26(24):7442.
Plants from the Ilex genus are known for properties such as antimicrobial and anti-inflammatory activity, can act as antiobesity agents and thus can be helpful in medicine. Some holly species, such as Ilex paraguariensis (widely known in the form of popular beverage: yerba mate), have been investigated, while others have been partially researched or remain unknown. Therefore, we performed qualitative and quantitative phytochemical analyses and screened antimicrobial properties of lesser-studied species (I. aquifolium L., I. aquifolium ‘Argentea Marginata’ and I. × meserveae ‘Blue Angel’). I. paraguariensis was used as a standard species for comparison purposes. Investigations were performed on water extracts due to their expected activity and composition. Antimicrobial research included evaluating minimal inhibitory, bactericidal (Staphylococcus aureus and Escherichia coli) and fungicidal concentration (Candida albicans, Alternaria alternata, Fusarium oxysporum, and Aspergillus niger) of extracts. The influence of the extracts on the production, eradication, and viability of bacterial biofilms was also analysed. It was established that Ilex paraguariensis possesses the richest profile of hydroxycinnamic acids derivatives in terms of component concentration and diversity. Ilex spp., especially I. × meserveae, contain a slightly higher amount of flavonoids and more different flavonoid derivatives than I. paraguariensis. However, the strongest antibacterial activity was shown by I. aquifolium L. and its cultivar ‘Argentea Marginata’ in terms of minimal inhibitory, bactericidal and fungicidal concentration, and biofilm assays. Extracts from both species significantly reduced the biofilm viability of S. aureus as well, which may be of use in the production of multicomponent lavaseptics, antiseptics, diuretics (supporting urinary tract infection therapy) and, due to their action on fungi, additives to growth media for specific fungi. The significant content of saponins enables Ilex extracts to be used as natural emulsifiers, for example, in cosmetics. Moreover, relatively high chlorogenic acid and rutin content may suggest use of Ilex spp. to treat obesity, digestive problems, in chemoprevention, and as preservatives in the food industry.
[81]
张馨月, 李婷, 何改改, 等. 广西毛冬青根对放射脑损伤小鼠认知功能障碍的改善作用及其机制研究[J]. 广西医科大学学报, 2022, 39(9):1363-1370.
[82]
KIM CHANGKWON, AHN JEONGJUN, YU JAYEON, et al. Analysis of antioxidant constituents from Ilex rotunda and evaluation of their blood-brain barrier permeability[J]. Antioxidants, 2022, 11(10):1989.
Ilex rotunda Thunb., has been used to treat common cold, tonsillitis, and eczema. It is also a source of antioxidants. However, information regarding its antioxidative phytochemical composition is still incomplete and limited. In this present study, we initially determined DPPH radical scavenging activity of the extracts of I. rotunda fruits, twigs, and leaves. Among them, the twig extract exhibited a potential of antioxidant capacity. Based on antioxidant effect guided experiments, extraction condition using 80% EtOH was then optimized. DPPH and ABTS radical scavenging assays were also performed for fractions. The n-butanol fraction showed the highest antioxidant effect. Using chromatographic methods, eight marker compounds (1–8) were further isolated. Their structures were determined by spectroscopic and mass data. Method validation was employed to quantitate contents of these eight marker compounds. Subsequently, the HPLC-DPPH method was used to evaluate the contribution of certain compounds to total antioxidant activity of the extract. Lastly, parallel artificial membrane permeability assay for blood–brain barrier (PAMPA-BBB) was applied to investigate brain-penetrable antioxidants from I. rotunda extract. As a result, compound 7 (4,5-dicaffeoylquinic acid) showed significant antioxidant activity and penetration across the BBB via transcellular passive diffusion. Our findings suggested that compound 7 can be used as a therapeutic potential candidate in natural product-based central nervous system (CNS) drug discovery.
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