什么是漆黄素(会员版)
漆黄素(Fisetin,又名非瑟酮)是多酚类黄酮中的一种植物黄酮醇(7,3′,4′-黄酮-3-醇),分子式C15H10O6,分子量286.24;它是一种脂溶性的天然化合物,难溶于水1。
目录:
1.漆黄素是什么
2.食物来源
3.生物活性
3.1.抗氧化
3.2.抗炎
3.3.抗癌、抗增殖
3.4.模拟热量限制
3.5. Senolytic治疗剂
3.6.阻断mTOR通路
4.非瑟酮潜在益处
3.2.抗炎
3.3.抗癌、抗增殖
3.4.模拟热量限制
3.5. Senolytic治疗剂
3.6.阻断mTOR通路
4.1.抗衰老效应
4.2.认知记忆和脑神经
4.3.心血管健康
4.4.糖尿病及并发症
4.5.防癌抗癌
4.6.其他作用
5.副作用和注意事项
4.2.认知记忆和脑神经
4.3.心血管健康
4.4.糖尿病及并发症
4.5.防癌抗癌
4.6.其他作用
5.1.可能得副作用
5.2.与药物相互作用
6.用量参考5.2.与药物相互作用
7.成分与产品
7.1.产品成分
7.2.产品形式
8.参考文献7.2.产品形式
漆黄素是什么
漆黄素(Fisetin,又名非瑟酮)是多酚类黄酮中的一种植物黄酮醇(7,3′,4′-黄酮-3-醇),分子式C15H10O6,分子量286.24;它是一种脂溶性的天然化合物,难溶于水1。非瑟酮存在于许多植物中,例如漆树科木蜡树(Rhus succedanea L.,或称日本野漆树)2;它也能在许多水果和蔬菜中找到,如草莓、苹果、柿子、洋葱和黄瓜3,作为这些植物黄色或赭色的色素。图1,漆黄素结构(来源:互联网)
1891年,奥地利化学家Josef Herzig首次描述了非瑟酮的化学式4。在许多实验室测定中研究表明,非瑟酮具有许多活性5,6。与现在知名的白藜芦醇和槲皮素等植物化学素相比,非瑟酮被忽视了太久。直到最近几年,研究人员才对它的药用潜力越来越感兴趣。其中,以作为Senolytics的非凡效力而引人注目6。尽管基于动物和细胞的研究结果很有希望,但研究仍处于早期阶段,且临床研究很少。
食物来源
许多水果和蔬菜都含有漆黄素7。非瑟酮浓度最高的食物来源见下表8。图2. 漆黄素在一些食物中的含量
生物活性
3.1.抗氧化:漆黄素已在实验室研究中被证明可以上调谷胱甘肽(GSH),一种关键的内源性抗氧化剂5,9。漆黄素作为还原剂具有直接活性,与活性氧发生化学反应以中和它们5。研究表明,非瑟酮停留在细胞膜上,防止细胞膜中的脂质受到氧化损伤5。与其他黄酮类化合物一样,它拥有平面结构,具有多个碳环。由于一个环上有两个羟基,另一个环中有一个羟基,因此非瑟酮具有给电子能力,可以有效清除自由基5。
3.2.抗炎:
在实验室对细胞进行的研究中,非瑟酮抑制几种促炎细胞因子的活性,包括肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)和核因子κB(NF-κB)9。它通过关闭促进炎症的途径和减少促炎化合物的产生来减少炎症10。抗炎作用是由于Sirt1使促炎转录因子NF-κB脱酰化11。
3.3.抗癌、抗增殖:
漆黄素在实验室对细胞和模型动物进行的研究中显示出抗癌活性,并似乎可阻断PI3K/AKT/mTOR途径12,以及其他诱导细胞凋亡激活和预防细胞凋亡抵抗的机制13。在实验室研究中,非瑟酮已被证明是一种抗增殖剂,以多种方式干扰细胞周期9。体外筛选已确定非瑟酮是一种抗有丝分裂的化合物14。
3.4.模拟热量限制
通过限制热量的饮食减少食物摄入已被证明可以减缓衰老、延长寿命和提高对疾病的抵抗力15。研究已经确定了受这种饮食影响的细胞途径。除其他好处外,热量限制(CR)可以16:
- 降低mTOR的活性,mTOR是一种与衰老、体重增加和慢性疾病有关的蛋白质;
- 增强调节细胞健康的蛋白质sirtuins的功能;
- 增加AMPK的活性,AMPK是一种调节新陈代谢的酶,以及
- 促进自噬,增强细胞“内务管理”.
研究发现,漆黄素对每一种途径都有类似的效应,模仿热量限制的作用5,10,14,17。例如,Sirtuins蛋白保护细胞免受损伤,并有助于使其保持峰值状态。但Sirtuins功能随着年龄的增长而减弱,导致对疾病的易感性增加和快速衰老18,19;AMPK活性也会随着年龄的增长而下降,增加代谢功能恶化、肥胖、糖尿病等的风险20。
几项临床前研究表明,非瑟酮可增加Sirtuin功能和AMPK活性21-23。这可保护细胞,以维持年轻健康状态。
3.5. Senolytic治疗剂
研究发现,漆黄素的Senolytic效力大约是槲皮素的二倍24。它已被证明是野生型小鼠的一种有效Senolytic试剂,具有延长寿命、降低组织衰老标志物和减少与年龄相关的病理作用6。对衰老的人脐静脉内皮细胞的细胞培养研究表明,非瑟酮通过抑制抗凋亡蛋白Bcl-xL诱导细胞凋亡25。截至2018年10月,美国正在进行一项临床试验,以确定非瑟酮是否能有效减少炎症,改善老年人的虚弱和骨骼健康等26。
3.6.阻断mTOR通路
mTOR对能量和生长的需求会让细胞陷入失控:代谢废物堆积、无法及时清除。mTOR反应过度活跃与癌症、糖尿病、肥胖和神经退行性疾病有关。通过阻断这一途径,非瑟酮有助于清除废物并增强细胞代谢27-30其中,最有趣的部分是:阻断mTOR可以延长寿命。事实上,阻断mTOR是在所有生物体中可延长寿命的主要干预措施之一31,32。这是因为一旦mTOR被阻断,自噬就会被激活(一个循环利用受损细胞成分的过程)31,32。
非瑟酮潜在益处
以下作用主要基于细胞和动物研究。仍然没有临床证据支持非瑟酮用于本节所列的任何疾病或健康益处。4.1.抗衰老效应
衰老细胞是指停止正常功能并可能对周围组织造成损伤的衰老细胞。它们失去了生长或分裂的能力,拒绝死亡,因此被称为“僵尸细胞”。衰老细胞不断积聚是导致机体衰老的主因之一,这些细胞停止分裂、受损并开始释放炎症分子33,34;它们逐渐损害健康组织,导致许多与年龄相关的疾病,从骨质疏松症、心脏、脑部疾病和癌症34,35。而去除衰老细胞可以缓解炎症,改善身体功能,延长动物的寿命34,35。
某些植物化合物能够在不损害健康细胞的情况下破坏衰老细胞,因此可能作为Senolytic治疗剂36,37。Senolytics是一种能够破坏衰老细胞的化合物。它们在对抗衰老和与年龄相关的疾病、减缓甚至逆转衰老过程方面有着巨大的前景38,39。
近年来,人们对漆黄素的兴趣主要集中在它有助于减缓衰老和延长健康寿命的潜力上6,40。在2018年对10种此类化合物进行的一项基于细胞的研究中,非瑟酮是最有效的一种;在老年小鼠中,非瑟酮清除衰老细胞,使其寿命延长10%以上6,41。其他研究表明,非瑟酮能使酵母的寿命延长50%以上,果蝇的寿命延长20%以上42,43。
发表在《衰老》(Ageing)杂志上的一项细胞研究表明,非瑟酮消除了约70%的衰老细胞,同时对健康、正常的人体细胞没有伤害37。由于这项研究,研究人员对非瑟酮的 Senotheraputics(清除衰老细胞疗法)特性尤其感兴趣。
4.2.认知记忆和脑神经
4.2.1.改善认知
服用非瑟酮的老年大鼠记忆力和学习能力都有所改善。细胞研究表明,非瑟酮激活了大脑中与存储记忆有关的通路44,45。在另一项研究中,非瑟酮预防了暴露于毒素的小鼠的记忆丧失45。
非瑟酮可以很容易地穿过小鼠的血脑屏障。这一点很重要,因为目前仍在争论像非瑟酮这样的化合物是否能在大脑中达到足够高的水平来改善其功能46,47。
4.2.2.抑郁和焦虑
通过提高血清素和去甲肾上腺素水平,非瑟酮可减少小鼠的抑郁和焦虑。血清素和去甲肾上腺素是在情绪中起关键作用的神经递质48-50。
4.2.3.神经退行性疾病
在阿尔茨海默病(即老年痴呆)和亨廷顿症等神经退行性疾病中,大脑小胶质细胞的免疫细胞被过度激活。这会引起炎症并损害健康的脑细胞。在细胞研究中,非瑟酮提高了大脑抗氧化水平,并阻止小胶质细胞释放炎症化合物以应对细菌毒素51,52。
阿尔茨海默病涉及大脑中淀粉样斑块和tau蛋白的积聚。非瑟酮通过激活去除这些有害蛋白质的过程(自噬)降低了脑细胞中tau蛋白水平53。在患有淀粉样斑块的小鼠中,非瑟酮改善了记忆,减少了炎症,并防止了脑细胞功能的丧失。在患有阿尔茨海默氏症的小鼠中,它减少了淀粉样斑块的堆积和脑细胞的损失54。
亨廷顿症是一种脑细胞被破坏的遗传运动障碍。在患有亨廷顿症的小鼠模型中,漆黄素能够改善身体功能下降并延长寿命55。
在肌萎缩侧索硬化症(ALS,或运动神经元病)中,控制肌肉的脑细胞会死亡。漆黄素改善了ALS小鼠的平衡和肌肉协调,并提高了存活率56。
4.2.4.预防中风和毒素:
非瑟酮可保护脑细胞,减少小鼠和大鼠中风引起的炎症和损伤47,57,58。在另一项针对兔子的研究中,非瑟酮预防了中风引起的平衡丧失、能量不足和眼球运动失控59。细胞研究表明,非瑟酮降低了大脑中免疫细胞的活性,而免疫细胞是中风后炎症和脑损伤的罪魁祸首51,57。
一项随机、对照临床研究表明,非瑟酮可以将中风治疗窗口期延长二小时60。虽然这二小时的延长时间看起来不算太长,但它可以显著增加受益于血栓溶解和/或血栓清除(血管内血栓切除术)保脑治疗的中风患者人数。
4.2.5.金属铝毒性:
已知铝对大脑有毒,与阿尔茨海默病有关。在小鼠中,非瑟酮减少了铝引起的大脑炎症和氧化应激61,62。在细胞中,非瑟酮通过清除受损或不需要的蛋白质来促进脑细胞的存活63。
4.2.6.癫痫症:
在脑损伤小鼠模型中,非瑟酮通过减少氧化应激来预防癫痫发作64。非瑟酮还可以减少暴露于化学物质和电击的小鼠的癫痫发作和死亡。它通过提高神经递质GABA(镇静作用)的水平和减少大脑中的氧化损伤来做到这一点65。
总之,通过减少氧化应激和炎症,非瑟酮可保护大脑,改善认知和心理健康。不过,需要进行临床试验来证实其对大脑有益的效果。
4.3.心血管健康
4.3.1.降低高胆固醇
非瑟酮降低了喂食高脂肪饮食的大鼠的高总胆固醇、LDL胆固醇和甘油三酯。在糖尿病大鼠中,它使HDL水平翻了一番,并将LDL水平减半。一项细胞研究表明,非瑟酮通过在胆汁中释放更多胆固醇来降低胆固醇水平66-68。
细胞研究表明,非瑟酮可以防止巨噬细胞的免疫细胞氧化和摄入LDL胆固醇。当巨噬细胞摄入氧化的LDL时,它们会产生脂肪斑块,引起动脉硬化并导致心脏病69,70。
4.3.2.循环与高血压
在大鼠中,非瑟酮改善了高脂肪饮食引起的血液流动不良71。试管实验表明,非瑟酮有助于放松和扩张血管,有助于改善血液流动和降低血压72,73。
4.3.3.心脏保护
在心壁异常增厚的大鼠中,非瑟酮保护心脏细胞免受氧化应激,并改善心脏功能74。它还保护心脏组织和线粒体功能免受大鼠心脏病发作的损害75。根据动物和细胞研究,非瑟酮可以通过降低高胆固醇水平、改善循环和保护心脏免受氧化应激来支持心脏健康。
在一项动物研究中,心脏病发作后摄入非瑟酮可显著降低心房颤动的风险,心房颤动是一种常见的心律失常,会增加中风或心力衰竭的可能性76。
4.4.糖尿病及并发症
在多项动物研究中,非瑟酮使糖尿病大鼠和小鼠的血糖水平恢复到健康动物的水平。它通过下列路径提高了它们控制血糖水平的能力68,77-80:
- 增加胰岛素水平
- 增加将糖转化为能量的酶
- 清除血液中的糖,将其作为糖原储存在肝脏中
- 降低肝脏从乳酸和氨基酸中制糖的能力
非瑟酮减缓糖尿病白内障的进展,并通过阻断炎症和氧化应激来保护糖尿病小鼠的肾脏。它还通过提高抗氧化剂水平来保护糖尿病大鼠的肝脏免受高血糖水平的影响81,82,79。
糖尿病的另一个并发症是动脉硬化和心脏病。在一项细胞研究中,非瑟酮防止高糖引起血管炎症83,84。
非瑟酮可能通过改善血糖控制和预防组织损伤来帮助治疗糖尿病,但尚需要开展临床研究佐证。
4.5.防癌抗癌
炎症与结肠癌的生长、扩散和对化疗的抵抗有关。在一项对37名接受化疗的结肠癌患者的临床研究中,非瑟酮(100mg/天,为期7周)降低了炎症标志物(IL-8和hs-CRP)。然而,作者没有报告对肿瘤生长和进展的影响85。
在大鼠中,非瑟酮减少了由真菌毒素引起的氧化应激和肝癌的生长86。在小鼠身上,它阻止了肺癌的生长,并提高了由烟草烟雾中的毒素引起的低抗氧化水平。它使小鼠的肺肿瘤生长减少了67%,与化疗药物联合使用时减少了92%。它还阻止了为癌症提供营养的新血管的生长87,88。
另一项研究发现,非瑟酮可使患有黑色素瘤的小鼠的肿瘤生长减少66%89。某些类型的前列腺癌是由雄性激素如睾酮和二氢睾酮(DHT)引起的。非瑟酮通过阻断癌细胞上的睾酮和DHT受体来减缓小鼠前列腺肿瘤的生长90。
非瑟酮还通过减少炎症和提高抗氧化水平来保护大鼠免受化疗对肾脏的损伤91。在细胞研究中,非瑟酮会导致程序性细胞死亡,并阻止多种癌症细胞系的生长和扩散92-96。
尽管非瑟酮的广泛抗癌作用和无毒性是很有希望的,但尚不能确定其结果是否会转化为人类。
4.6.其他作用:
4.6.1.肝脏保护
在老鼠身上,非瑟酮通过帮助动物更快地处理酒精来保护肝脏免受酒精的伤害。它还减少了氧化应激,从而防止肝损伤97。
在喂食高脂肪饮食的小鼠和大鼠中,非瑟酮减少了肝脏中脂肪的积累。它的作用是增加分解脂肪的酶,减少产生新脂肪的酶98,99。
4.6.2.缓解疼痛
糖尿病经常引起神经损伤和疼痛。非瑟酮降低了糖尿病小鼠和神经损伤小鼠对疼痛的敏感性。它降低了氧化应激,增加了脊髓神经中的血清素和GABA活性,从而缓解疼痛感48,100。
4.6.3.骨质流失
雌激素保持骨骼健康。绝经后,雌激素水平低会使女性面临骨质疏松症的风险。衰老引起的炎症增加也会削弱骨骼101,102。非瑟酮改善了低雌激素水平和炎症小鼠的骨密度,防止了骨丢失。在细胞中,它通过降低破骨细胞的活性发挥作用101-103。
4.6.4.皮肤益处
- 紫外线防护与皮肤老化:胶原蛋白赋予皮肤结构和弹性。在人类皮肤细胞中,非瑟酮可以防止紫外线/阳光照射下胶原蛋白的分解,这是皮肤衰老的关键因素。它还减少了紫外线引起的炎症和氧化应激104。
应用于小鼠皮肤,非瑟酮可以防止皮肤细胞的异常生长、DNA损伤和UVB射线引起的炎症。它还通过增强皮肤胶原蛋白来减少皱纹的形成105,106。
- 湿疹:湿疹皮肤炎通常用类固醇霜治疗,这通常有严重的副作用。在一项研究中,非瑟酮减少了湿疹小鼠的皮肤炎症、肿胀和发红107。
有可能保护皮肤免受过度紫外线照射,这会导致皮肤损伤和衰老,并缓解湿疹。不过,临床试验测试是有必要的。
4.6.5.微生物感染
在一项研究中,非瑟酮通过干扰李斯特菌躲避免疫系统的能力,帮助预防李斯特菌感染108。在另一项细胞研究中,它对两种导致免疫系统较弱的人感染的真菌(C.gatti和C.neoformans)具有活性。它会削弱真菌生存所需的化合物麦角甾醇的产生109,110。
非瑟酮也可能有助于寄生虫(L.amazonensis)引起的感染。它阻断精氨酸酶的活性,精氨酸蛋白酶是该寄生虫保护自身所需的一种酶111,112。
4.6.6.过敏反应
IgE抗体和T免疫细胞激活肥大细胞和嗜碱性粒细胞,进而引发过敏反应。在细胞研究中,非瑟酮阻止T细胞和IgE激活这些细胞引起炎症113,114。类似地,非瑟酮也能阻止暴露于过敏原的小鼠体内的IgE抗体激活肥大细胞。反过来,它阻止了组胺和其他炎症化合物的释放115。
4.6.7.炎症性肠病
在炎症性肠病(IBD)的小鼠模型中,非瑟酮通过阻断NF-κB活性和恢复抗氧化水平来减少结肠的损伤和炎症116。
副作用及注意事项
5.1.可能的副作用
即使在高剂量下,在动物研究中也没有发现非瑟酮副作用或毒性的证据。当然,需要进行临床研究来确认其安全性117。在结肠癌患者的一项临床试验中,非瑟酮受试组报告了胃部不适。不过,这可能不是非瑟酮引起的不良反应,因为受试者都在接受化疗,安慰剂组也报告了同样的胃部不适85。
孕期、哺乳期和儿童:由于缺乏安全性研究,不宜服用。
5.2.与药物相互作用
肝脏使用与血液稀释剂华法林(香豆素)相同的途径来处理非瑟酮。因此,非瑟酮可以增强华法林的作用118,119。
如前所述,非瑟酮能显著降低糖尿病动物的血糖。与降血糖药物的组合可能进一步降低血糖水平77-80。
用量参考
一般建议用量为50-150mg/天,最多500mg/天。在一项针对癌症患者的临床研究中,100mg/天可有效减少炎症85。
正在在进行的一项临床试验中,研究非瑟酮对老年人炎症、骨骼健康和虚弱的影响,将连续两天以20mg/kg的高剂量使用非瑟酮。对于体重约70kg的人来说,这大约是1400mg/天26。在这项研究的结果公布之前,不建议服用如此高的剂量。
一些研究人员怀疑补充非瑟酮的益处,因为口服时吸收不良。但从理论上讲,至少有一种简单的方法可以增加它的吸收:与脂肪一起服用。因为非瑟酮是脂溶性的,类似于槲皮素等其他黄酮类化合物。鱼油和其他油提高了槲皮素的生物利用度,它们可能对非瑟酮也有同样的作用120,121。
即便如此,将漆黄素结合成小脂肪样分子(脂质体)的新配方可能是最有效的解决方案。这大大提高了它的吸收120,121。据报道,采用脂质体口服配方可提高非瑟酮高达47倍的吸收率121。
成分和产品
7.1.产品成分:国际市场上,非瑟酮原料绝大多数来源于漆树科植物木蜡树(Rhus succedanea,又名日本野漆树)和黄栌(Cotinus coggygria)提取物。
- 注册成分:Novusetin,纯度达95%,来源于加拿大,获得加拿大卫生部天然产品编号(NPN#80117026);并拥有一项美国专利#7897637 B2,用于增强记忆力。
- 专有成分1:如上所述,采用脂质体(Liposome)配方可大大提高漆黄素吸收率121。
- 专有成分2:一种与胡芦巴籽提取物的天然化合物(半乳甘露聚糖)的专有配方(Bio-fisetin)可提高非瑟酮生物利用度(吸收)高达25倍,但相关研究数据仍未公开发表122。
7.2.产品形式:
- 粉基配方(硬胶囊):配料为粉基,建议随餐服用,提高吸收。
- 油基配方(软胶囊):配料为油基,比粉基硬胶囊更易吸收。
- 脂质体漆黄素:采用脂质体包埋,可显著提高生物利用度。
了解更多的产品具体形式、购买路径等,可参阅本网有关专文:漆黄素(概述) >>
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