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维尼非林药理活性研究进展

2014-03-22龚福恺孔庆军王晓琴李照雪

中国药理学与毒理学杂志 2014年6期
关键词:反式白藜芦醇抗氧化

龚福恺,孔庆军,王晓琴,李照雪,张 波

(石河子大学1.药学院,2.省部共建新疆特种资源植物药重点实验室,3.生命科学学院,新疆石河子 832002)

维尼非林药理活性研究进展

龚福恺1,2,孔庆军3,王晓琴1,李照雪1,张 波1,2

(石河子大学1.药学院,2.省部共建新疆特种资源植物药重点实验室,3.生命科学学院,新疆石河子 832002)

维尼非林(viniferin)是白藜芦醇寡聚体的总称,其作为植保素存在于豆科、蓼科、葡萄科、毛茛科和龙脑香科等植物中,并承担抗菌、抗真菌和病毒侵染以及紫外损伤等生理功能。维尼非林具有抗氧化、抗病原微生物、抗炎和抗肿瘤等药理活性,且对心脑血管和神经退行性疾病具有改善和防治作用。本文对近年维尼非林药理活性研究进展进行综述,为其药物开发和应用提供参考。

维尼非林;药理作用

维尼非林(viniferin)是植物茋类化合物的一种,为苯丙酸途径下游的次级代谢产物,是指具有1,2-二苯乙烯骨架的单体及其聚合物的总称,其以白藜芦醇的二聚体和三聚体形式通过脱氢聚合而成。维尼非林多以反式白藜芦醇为基本单元的低聚体类似物存在于植物中。天然的维尼非林是继白藜芦醇之后,新发现的源于白藜芦醇而作用又高于白藜芦醇的化合物,是植物受到病原体侵染或逆境胁迫时所产生的一类植保素,当植物受到病原体〔灰霉葡萄孢 (Botrytis cinerea)和葡萄霜霉病(Plasmopara viticola)〕侵染[1-2]、化学污染(铝剂)[3-4]或外界刺激时如臭氧、紫外线照射和H2O2等,植物体内维尼非林等茋类化合物的含量显著升高[5-7]。近年来,又相继发现其抗氧化、抗肿瘤、心血管和神经保护等作用。本文主要综述近年来维尼非林的发现及其药理活性,为其深入研究提供参考。

1 天然维尼非林的发现

目前,在药学领域研究较多的维尼非林主要有二聚体ε-维尼非林,ω-维尼非林和δ-维尼非林以及三聚体α-维尼非林的顺式和反式异构体。Langcake等[8]将从葡萄科植物(Vitis vinifera L.)中分离得到的一类植物抗毒素命名为维尼非林,并在UV-C照射过的葡萄离体叶片和灰葡萄孢侵染的葡萄叶片中首次发现了白藜芦醇二聚体反式ε-维尼非林,并得到三聚体α-维尼非林和四聚体γ-维尼非林等(图1)。此后,越来越多的研究者开始关注植物中的维尼非林,又发现了γ-2-维尼非林。

已有研究表明,葡萄植株感染灰霉病和赭曲霉毒素A后,植株内会产生具有抗病抗菌作用的反式δ-维尼非林、反式ε-维尼非林和白藜芦醇[9-10]。与此同时,也不断从植物中提取分离到维尼非林,增加了维尼非林这种植保素的来源。目前,维尼非林已可以从多种植物中分离,如豆科(Leguminosae)的槐属(Sophora Linn.)等、蓼科(Polygonaceae)的大黄属(Rheum L.)等、葡萄科(Vitaceae)的葡萄属(Vitis L.)、毛茛科(Ranunculaceae)的芍药属(Paeonia L.)和铁线莲属(Clematis L.)、龙脑香科(Dipterocarpaceae)的杯裂香属(Cotylelobium)、青梅属(Vatica)、坡垒属(Hopea)和娑罗双属(Shorea)以及买麻藤科(Gnetaceae Lindl.)的买麻藤属(Gnetum L.)等(表1)。

2 维尼非林的药理活性

2.1 维尼非林结构特征与抗氧化作用

多羟基茋类化合物大多具有抗氧化作用。一方面,作为体外抗氧化剂;另一方面,由于许多疾病与细胞有氧呼吸中产生的活性氧有关,多羟基茋类化合物更多用于体内抗氧化活性的研究。维尼非林结构上具有酚羟基和不饱和双键,所以推断维尼非林是潜在的天然抗氧化药物。目前,关于维尼非林体内外抗氧化作用的研究中,反式ε-维尼非林的研究较多且深入,其抗氧化作用更明显。

图1 天然维尼非林的结构式.A:白藜芦醇;B:ε-维尼非林;C:ω-维尼非林;D:δ-维尼非林;E:α-维尼非林;F:β-维尼非林〔坡垒苯酚(hopeaphenol)〕;G:γ-维尼非林;H:γ-2-维尼非林.

表1 天然维尼非林的植物来源

2.1.1 维尼非林体外清除自由基的作用

通过植物生长调节剂处理的葡萄植株可产生具有抗氧化作用的反式ε-维尼非林和白皮杉醇。反式ε-维尼非林和δ-维尼非林分别表现出不同的抗氧化作用,反式ε-维尼非林对二甲亚砜溶液中的超氧阴离子有抗氧化作用(半数抑制浓度IC50=0.14 mmol·L-1),而δ-维尼非林则在油/水过氧化自由基系统中表现出最大抗氧化活性,能够使β-胡萝卜素的漂白率被抑制82%[36-37]。通过化学密度泛函理论计算,顺式ε-维尼非林抗氧化能力弱于反式[38]。Toda等[39]发现,从砂生槐中分离得到的α-维尼非林具有羟自由基清除能力。γ-2-维尼非林对自由基在2,2′-连氮基-双-(3-乙 基苯并二 氢 噻 唑 啉-6-磺酸) (ABTS+)中有很强的清除能力(总抗氧化能力TEAC值=5.57 μmol·L-1),可抑制大豆脂肪氧合酶活性(IC50=6.39 μmol·L-1)[40]。

2.1.2 维尼非林体内抗氧化作用

反式ε-维尼非林作用于卵母细胞后可降低卵母细胞凋亡率,使得卵母细胞内谷胱甘肽合成增加,活性氧水平降低[41]。体外实验结果表明,反式ε-维尼非林还可通过降低脂肪氧合酶活性 (IC50=6.7 μmol·L-1)[42],明显抑制脂质过氧化反应[43]。反式ε-维尼非林对低、高密度脂蛋白氧化均有抑制作用,而对高密度脂蛋白氧化的抑制作用更明显[44]。Zghonda等[45]研究了反式ε-维尼非林对血管内皮细胞的抗氧化作用,发现这种抗氧化作用是通过蛋白激酶B,p38丝裂原活化蛋白激酶和细胞外信号调节激酶1/2途径使核转录因子相关因子2分子积累并转录,从而增加细胞内抗氧化酶和血红素氧合酶1来完成的。

2.2 抗病原微生物作用

植保素是植物受病原微生物侵害时自身产生的一类起防卫作用的化合物。植保素在植物的抗病过程中发挥相当重要的作用。维尼非林作为植保素的一种,其抗动、植物病原微生物作用一直被研究者所关注。

2.2.1 抗细菌和抗真菌作用

维尼非林中ε-维尼非林的抗病原微生物作用较为明显。Yuk等[46]报道,反式ε-维尼非林对细菌唾液酸苷酶具有抑制作用(IC50=24.4 μmol·L-1)。Verhagen等[47]报道,成团泛菌(Pa-AF2)、枯草芽孢杆菌(Bs-271)、鲁氏不动杆菌(Al-113)和荧光假单胞杆菌(Pf-CT2)诱导的葡萄植株可产生防御灰霉病的反式白藜芦醇和反式ε-维尼非林。不同品系葡萄感染霜霉后,在霜霉病的初期阶段大量的茋类化合物显著增加,其中包括δ-维尼非林[48]。植株遭受不同病菌侵染时,所产生的维尼非林种类不同,发挥的抗逆性也不同。

ε-维尼非林是抑制假单孢菌属生物膜的化合物之一,反式ε-维尼非林22 μmol·L-1可抑制肠出血性大肠杆菌 O157∶H7生物膜形成,抑制率达到98%[49-50]。Yim等[51]报道,山葡萄中提取的反式ε-维尼非林可有效抑制口腔变形链球菌和血链球菌(MIC=55和27.5 μmol·L-1)。

2.2.2 抗炎作用

Lee等[52]报道,α-维尼非林对前列腺素H2合酶有抑制作用(IC50=7 μmol·L-1),相同浓度下其抑制作用是白藜芦醇的3~4倍。在完全弗氏佐剂型关节炎模型中,α-维尼非林 3~10 mg·kg-1可明显抑制炎症反应[53]。胶原诱导型关节炎模型中,α-维尼非林对环氧合酶2(cyclooxygenase 2,COX-2)有较强抑制作用(IC50=4.9 μmol·L-1),但是对COX-1抑制较弱 (IC50=100 μmol·L-1)。同时α-维尼非林3~10 μmol·L-1能抑制脂多糖活化的小鼠巨噬细胞COX-2的转录,抑制诱导型一氧化氮合酶转录产物的合成(IC50=4.7 μmol·L-1),减少一氧化氮的产生[54]。Chung等[55]报道,α-维尼非林在低浓度时(3 μmol·L-1)抑制细胞外信号调节激酶介导的信号转导及转录激活因子1(signal transducer and activation of transcription-1,STAT-1)丝氨酸(727)磷酸化,而在高浓度时(10 μmol·L-1)才抑制磷酸化蛋白酪氨酸激酶2介导 STAT-1酪氨酸(701) 磷酸化,下调炎症相关基因的表达。α-维尼非林可通过激活核转录因子相关因子2,同时抑制磷脂酰肌醇3激酶,最终减少一氧化氮产生,发挥抗炎作用[17]。Wang等[56]报道,小叶葡萄中提取的反式 ε-维尼非林具有抗炎作用。Zhang等[57]报道,反式ε-维尼非林在220 μmol·L-1时对COX-1和COX-2活性的抑制率分别达到99%和47%。综上所述,维尼非林作用于细胞不同途径和不同靶点,但最终是通过抑制COX-1,COX-2和诱导型一氧化氮合酶活性,而发挥抗炎作用。

2.3 抗肿瘤作用

近年来研究发现,维尼非林对白血病细胞HL-60,乳腺癌细胞MCF-7,结肠癌细胞HCT-116,HT-29和Caco-2,肝癌细胞HepG2,宫颈癌细胞HeLa等具有抗肿瘤作用[59-68]。Kulanthaivel等[58]报道,α-维尼非林可抑制人乳腺癌细胞MCF-7增殖(IC50=3.6 μmol·L-1),对蛋白激酶C具有抑制作用,可抑制全血中自由基的释放(IC50=47 μmol·L-1)。González-Sarrías等[59]报道,α-维尼非林对正常人结肠细胞CCD-18Co无抑制作用,但在6~32 μmol·L-1对人结肠癌细胞HCT-116,HT-29和Caco-2的抑制作用具有时间效应和浓度效应关系,20 μmol·L-1时导致S期阻滞并引起细胞凋亡。ε-维尼非林对骨髓瘤、淋巴瘤、人宫颈癌、人乳腺癌、人肝癌和结肠癌细胞均具有抑制作用。反式ε-维尼非林对U266,RPMI8226,Jurkat,K562,U937,HeLa,MCF-7,HepG2和HT-29细胞的半数抑制率分别为30.8,45.7,83.5,39.3,20.4,47.3,103.9,167.6和198.5 μmol·L-1,与长春新碱联用后可增强长春新碱对HepG2的抗肿瘤作用[60]。顺式ε-维尼非林对HeLa,MCF-7,HepG2和HT-29细胞的半数抑制率分别为135.8,28.4,106.1和66.9 μmol·L-1[61-62]。进一步研究发现,反式ε-维尼非林能够抑制多发性骨髓瘤细胞U266生长,阻滞于G2/M期,同时通过与Fas/FasL的相互作用,活化细胞内胱天蛋白酶,引发细胞凋亡[62]。ε-维尼非林还可通过抑制肿瘤血管新生达到抗肿瘤作用[63]。Empl等[64]研究了γ-2-维尼非林对犬成胶质细胞瘤细胞D-GBM增殖的抑制作用,结果表明,γ-2-维尼非林可抑制D-GBM细胞增殖,促进细胞凋亡,增加细胞内胱天蛋白酶3、胱天蛋白酶7和胱天蛋白酶9的表达。γ-2-维尼非林抑制D-GBM细胞增殖的作用强于白藜芦醇。

α-维尼非林和ε-维尼非林对早幼粒细胞白血病HL-60细胞增殖具有抑制作用(IC50分别为5.94和33 μmol·L-1)[65-66]。α-维尼非林可引起HL-60细胞凋亡,胱天蛋白酶3、胱天蛋白酶8和胱天蛋白酶9表达增加,染色质浓缩,DNA片段化[67]。Quiney等[68]报道,ε-维尼非林可促使B细胞白血病细胞和B细胞慢性淋巴细胞白血病细胞凋亡,乙酰化ε-维尼非林对B细胞白血病细胞凋亡的促进作用更加显著(IC50=6.7 μmol·L-1),这种促凋亡作用是由于细胞内诱导型一氧化氮合酶表达降低,内源性一氧化氮产生减少所致。

在肿瘤治疗中抗肿瘤药物的耐药性已成为临床治疗的一大难题。多耐药相关蛋白1与多种肿瘤耐药性有关。Bobrowska-Hägerstrand等[69]报道,α-维尼非林和反式ε-维尼非林抑制多药耐药相关蛋白1,可调控2′,7′-二(3-羧丙基)-5(6)-羧基-荧光素在完整细胞和红细胞内外囊泡模型中的转运。由此表明,维尼非林能有效地抑制多药耐药相关蛋白1调节的有机阴离子运输,从而减少肿瘤耐药性的产生。

由此可以看出,维尼非林中 α-维尼非林和ε-维尼非林的抗肿瘤活性更为明显,其预防和抗肿瘤作用并不是单一途径或单一靶点,此类化合物为天然抗肿瘤药物的开发提供了相关线索[71]。

2.4 心血管保护作用

Zghonda等[72]报道,反式ε-维尼非林对血管内皮细胞的保护作用强于白藜芦醇单体,反式ε-维尼非林对血管内皮细胞的保护作用是由于一氧化氮的生成使血管内皮细胞增殖,并减少细胞内活性氧产生使细胞免受氧化应激影响。给予自发性高血压大鼠的反式ε-维尼非林(5 mg·kg-1)3周,可明显降低血管舒张压,减轻心脏负荷。Lin等[73]研究发现,反式ε-维尼非林具有抗血管紧张素转换酶和舒张血管的作用。这些结果表明,ε-维尼非林对心血管具有一定的保护作用。

2.5 防治神经退行性疾病

神经退行性疾病是大脑和脊髓细胞神经元衰老死亡的疾病,包括帕金森病和阿尔茨海默病等。Chowdhury等[70]和Rivière等[74]分别报道,ε-维尼非林糖苷、反式ε-维尼非林和ω-维尼非林对β淀粉样蛋白(amyloid β protein,Aβ)沉积有抑制作用。Aβ1-40和Aβ1-42能够诱导交感神经细胞瘤 PC12细胞的死亡。Richard等[75-76]报道,ε-维尼非林糖苷分子与Aβ1-40特征区域之间会形成阻碍聚集的复合物,同时 ε-维尼非林糖苷能有效抑制体外全长Aβ1-40和Aβ1-42沉积。

Kim等[77]和Jeong等[78]分别报道,γ-2-维尼非林和反式ε-维尼非林抑制谷氨酸诱导的神经元死亡、细胞内Ca2+浓度升高及细胞内活性氧产生,改变神经元细胞内凋亡相关蛋白的表达,从而对缺血性脑损伤的神经起到保护作用。Fu等[79]研究报道,反式ε-维尼非林具有一定的神经保护作用,在亨廷顿病中能减少亨廷顿病突变引起的线粒体乙酰化酶3的消耗,对神经细胞起到保护作用。研究发现,反式ε-维尼非林抑制神经突触对去甲肾上腺素(IC50=3.64 μmol·L-1)和5-羟色胺(IC50=30.41 μmol·L-1)的摄取,抑制单胺氧化酶的活性[80]。同样,α-维尼非林对5-羟色胺受体有明显拮抗作用,可能是通过细胞外信号调节激酶1/2下调5-羟色胺受体的活性发挥的[81]。Sung等[14]研究报道,α-维尼非林对乙酰胆碱酯酶有浓度依赖性的抑制作用(IC50=115.8 μmol·L-1),其抑制作用是特定、可逆和非竞争性的,被认为是治疗阿尔茨海默病的潜在天然药物。

2.6 其他药理作用

近年来,随着维尼非林研究的不断深入,维尼非林的其他药理作用不断被发现。Oshima等[82]报道,ε-维尼非林30 mg·kg-1可有效保护CCl4引起的小鼠肝损伤,认为ε-维尼非林可作为潜在的保肝护肝药物进行开发。ε-维尼非林和γ-2-维尼非林被认为是很好的囊性纤维跨膜转运抑制剂,可抑制囊性纤维跨膜转运介导的氯离子的转运,并呈剂量依赖性[83]。此外,反式ε-维尼非林[84]和α-维尼非林[85]还具有降糖作用。

3 展望

维尼非林作为一大类以白藜芦醇低聚形式存在的天然产物,具有相对分子质量大、含量低、活性高和安全性较好等特点。近年来,虽通过多种实验模型发现了维尼非林的药理作用,但对于维尼非林各种生物效应的具体分子机制尚不完全明确。从这类化合物结构共性来看,其抗炎、抗肿瘤和抗氧化等活性均与调节生物氧化还原平衡状态有关,提示其与白藜芦醇具有相似之处。因此,深入研究维尼非林的化学、生物活性和氧化还原的作用机制,可能是其药理作用机制的突破点,也将会为其临床应用提供新的理论依据。

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Advances in pharmacoIogicaI activities of viniferin

GONG Fu-kai1,2,KONG Qing-jun3,WANG Xiao-qin1,LI Zhao-xue1,ZHANG Bo1,2
(1.School of Pharmaceutics,2.Key Laboratory of Xinjiang Endemic Phytomedicine Resources,Ministry of Education,3.School of Life Sciences,Shihezi University,Shihezi832002,China)

Viniferin is the generic term of oligomers of resveratrol,which acts as phytoalexin in Leguminosae,Polygonaceae,Vitaceae,Ranunculaceae,Dipterocarpaceae and other plants.Viniferin plays important physiological roles in protecting against UV damage and resisting bacterial fungal and viral infection in plants.Nevertheless,these oligomers have shown various pharmacological activities including antioxidative activities,anti-pathogenic,anti-inflammatory and anti-tumor activities.This paper review the recent advances in research of viniferins microbes to show their key pharmaceutical activities for pharmaceutic references.

viniferin;pharmacological actions

ZHANG Bo,E-mail:bozhang_lzu@126.com,Tel:(0993)2057670

R285

:A

:1000-3002(2014)06-0914-09

10.3867/j.issn.1000-3002.2014.06.015

Foundation item:The project supported by National Natural Science Foundation of China(31160058);National Natural Science Foundation of China(21362028);and the Key Areas of Science and Technology Project of Xinjiang Production&Construction Corps(2014BA029)

2014-04-23 接受日期:2014-10-14)

(本文编辑:齐春会)

国家自然科学基金(31160058);国家自然科学基金(21362028);新疆兵团重点领域科技攻关项目(2014BA029)

龚福恺 (1989-),男,硕士研究生,主要从事抗肿瘤药理学研究,E-mail:gfkfk@163.com

张 波,E-mail:bozhang_lzu@126.com,Tel:(0993)2057670

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