Abstract: Royal jelly is a traditional health-care product with complex chemical composition. It is secreted from the mandibular glands and hypopharyngeal glands of nurse worker bees. Royal jelly has been demonstrated to have a variety of biological functions and has been used in the field of traditional medicine, health care products and cosmetics. In this review, we reported the studies for the essential biological functions of royal jelly such as antibacterial, anti-inflammatory, anti-tumor and antioxidant, as well as its regulatory effects on immunity, blood pressure, cholesterol, blood glucose homeostasis and nerves of human beings. By summarizing the relevant researches over the last decade, we aim to provide insights into the biological functions and pharmacological activities and to provide reference to comprehensively evaluate the health care and medicinal value of royal jelly.

Key words: royal jelly    major royal jelly proteins    fatty acids    biological function    pharmacological activity    

蜂王漿(royal jelly, RJ)是青年工蜂(5~15日齡)頭部上顎腺和咽下腺共同分泌的淡黃色漿狀物，是飼喂蜂王、3日齡內(nèi)工蜂和雄蜂幼蟲的特殊營養(yǎng)物質(zhì)[1]。蜂王漿是決定蜜蜂級型分化的關(guān)鍵物質(zhì)，能夠促進(jìn)蜂王及3日齡內(nèi)幼蟲的生長發(fā)育，誘導(dǎo)蜜蜂幼蟲發(fā)育成蜂王[2-3]。蜂王終生食用蜂王漿，其體型大，長壽(3~5年)且具有孕育后代的能力；而工蜂只在幼蟲期前3 d食用蜂王漿，之后逐步開始被飼喂工蜂漿(摻有蜂蜜和花粉的蜂王漿混合物)直到發(fā)育成年，該混合物與蜂王漿中蛋白質(zhì)、脂類等營養(yǎng)物質(zhì)含量差異顯著，且花粉中大量的多不飽和脂肪酸(polyunsaturated fatty acid, PUFA)會增加對工蜂的氧化損傷，這些可能是造成工蜂體型小，壽命短(30~60 d)，生殖器官發(fā)育不完全的重要原因[2, 4-5]。

蜂王漿是蜂群中重要的營養(yǎng)物質(zhì)，也是公認(rèn)的對人類健康有益的營養(yǎng)物質(zhì)。在中國和日本，蜂王漿作為功能性保健品和化妝品在市場上大規(guī)模銷售，深受廣大消費(fèi)者喜愛，并將其譽(yù)為“超級食品”[6-7]。目前，蜂王漿在細(xì)胞、動物模型、人類健康以及疾病的治療和預(yù)防中被廣泛研究[8]，已發(fā)現(xiàn)在抗菌、抗炎、抗氧化、抗腫瘤、免疫力調(diào)節(jié)、降壓、降膽固醇以及調(diào)節(jié)血糖穩(wěn)態(tài)和保護(hù)神經(jīng)系統(tǒng)等方面發(fā)揮作用[7, 9-10]。

隨著分子生物學(xué)、蛋白質(zhì)組學(xué)及小分子檢測技術(shù)的發(fā)展，蜂王漿的特殊化學(xué)成分、生物學(xué)功能等引起了國內(nèi)外學(xué)者的關(guān)注。為了更好地了解蜂王漿的理化性質(zhì)、生物學(xué)功能，筆者對近十年相關(guān)報(bào)道進(jìn)行綜述，以期為進(jìn)一步研究蜂王漿對人類健康的影響提供思路。

1 蜂王漿的化學(xué)組分和理化性質(zhì)

蜂王漿是一種黏稠的漿狀物，具有特殊的芳香氣味，口感酸澀(pH 4.0~4.5)，略帶甜味，部分溶于水，其風(fēng)味和特殊組分的形成易受蜜源、季節(jié)和采收時間的影響[11-12]。蜂王漿的主要成分包括水(60%~ 70%)、蛋白質(zhì)(9%~18%)、碳水化合物(7%~18%)、脂類(3%~8%)、礦物質(zhì)(1%~3%)、維生素和少量未知成分[13]。

蜂王漿易降解變性，溫度、儲存時間等因素均會對蜂王漿的質(zhì)量造成影響。在常溫儲藏條件下蜂王漿中游離氨基酸的總量隨著時間的延長呈下降趨勢，且隨著儲藏溫度升高，蔗糖的水解作用增強(qiáng)，葡萄糖和果糖含量迅速升高[14]。因此，適宜的儲存條件是保證蜂王漿質(zhì)量的必要條件，一些研究表明，將蜂王漿儲存在-20 ℃或者更低溫的環(huán)境中，能基本保持其品質(zhì)不變[15]。

蛋白質(zhì)是蜂王漿中的主要組成成分，目前所發(fā)現(xiàn)的許多蜂王漿生物學(xué)功能與蜂王漿蛋白有著密切的聯(lián)系。王漿主蛋白(major royal jelly proteins, MRJPs)約占蜂王漿總蛋白含量的90%，在調(diào)控蜂王行為及生理功能等方面起著非常重要的作用[16]。目前已知的MRJPs成員有MRJP1(也被稱為royalactin)、MRJP2、MRJP3、MRJP4、MRJP5、MRJP6、MRJP7、MRJP8、MRJP9和MRJP-ψ[16]。MRJP1是蜂王表觀遺傳驅(qū)動因素，可作為誘導(dǎo)雌性蜜蜂發(fā)生級型分化的主要王漿蛋白，受關(guān)注度最高，其蛋白結(jié)構(gòu)已被成功解析[2, 17]。除MRJPs外，王漿蛋白還包括Royalisin、Jelleine和Aspimin等，相對含量較少，其中Jelleine和Royalisin具有一定的抗菌作用[6]。此外，中華蜜蜂MRJP2可通過直接屏蔽細(xì)胞膜保護(hù)昆蟲和哺乳動物細(xì)胞免受氧化損傷，并表現(xiàn)出抗活性氧的DNA保護(hù)活性[18]。

蜂王漿中含有豐富的脂質(zhì)，由脂肪酸和少量甾醇組成，占新鮮物質(zhì)的4%~8%，占凍干制品的15%~30%，在發(fā)揮蜂王漿生物學(xué)功能方面同樣起到了重要作用[19]。目前，蜂王漿乙醚提取物中88%的物質(zhì)由以下6類脂肪酸組成，即10-羥基-2-癸烯酸(10-HDA)、3，10-二羥基癸酸(3, 10-DDA)、10-羥基癸酸(10-HDAA)、8-羥基辛酸、2-癸烯-1，10-二烯酸、(Z)-9-羥基-2-癸烯酸，其中特征性脂肪酸10-HDA和10-HDAA(后者是前者的前體物質(zhì))占蜂王漿有機(jī)酸總量的60%~80%[19-20]。10-HDA是蜂王漿中最豐富的脂肪酸類物質(zhì)，在多種生物學(xué)功能中發(fā)揮作用[14]。例如：10-HDA能通過抑制組蛋白去乙酰化酶，對意大利蜜蜂的級型分化進(jìn)行表觀遺傳控制[21]；10-HDA作為一種強(qiáng)大的抗菌劑，能有效保護(hù)蜂巢內(nèi)蜜蜂幼蟲免受細(xì)菌感染[22]。另外，蜂王漿中10-HDA含量穩(wěn)定，可作為判定蜂王漿等級的重要標(biāo)志[23]。

2 蜂王漿的生物學(xué)功能 2.1 抗菌

蜂王漿對真菌、革蘭陽性菌、革蘭陰性菌、支原體等具有獨(dú)特的抗菌活性[24-25]。其中的有效抗菌物質(zhì)包括10-HDA[26]、Royalisin[27]、Jelleines[24]、Apalbumin2a[28]、MRJP1、MRJP2和MRJP4等[29]。另外，Isidorow等[30]發(fā)現(xiàn)，蜂蜜中的抗菌物質(zhì)可能部分來自于蜂王漿中的C8-C12脂肪酸以及不飽和脂肪酸。

2019年，科學(xué)家首次在蜂王漿中成功分離出含有外泌體樣囊泡(exosome-like vesicles, ELVs)的蛋白質(zhì)，通過對其抗菌特性的評價發(fā)現(xiàn)，ELVs對金黃色葡萄球菌具有抑菌、殺菌和生物膜抑制作用(抑制50%的生物膜形成)，這表明蜂王漿中的ELVs有助于預(yù)防或治療傷口源性感染[31]。

2.2 抗炎及創(chuàng)傷修復(fù)

在動物試驗(yàn)中，食用蜂王漿可減少醋酸誘導(dǎo)結(jié)腸炎大鼠結(jié)腸損傷部位中肥大細(xì)胞(mast cell, MC)數(shù)量和受損面積，有效保護(hù)大鼠結(jié)腸黏膜免受醋酸的傷害[32]。后續(xù)試驗(yàn)中進(jìn)一步發(fā)現(xiàn)，蜂王漿可促進(jìn)細(xì)胞再生，保護(hù)大鼠結(jié)腸黏膜免受2, 4, 6-三硝基苯磺酸誘導(dǎo)的結(jié)腸炎的侵襲[33, 34]。

促炎細(xì)胞因子(IL-1、IL-8、TNF-α等)、核因子-κB(NF-κB)信號通路的過度產(chǎn)生和激活在腸炎、類風(fēng)濕性關(guān)節(jié)炎(rheumatoid arthritis, RA)等慢性炎癥中起重要作用[26]。研究表明，蜂王漿中10-HDA、10-HDAA和SEA均呈劑量依賴性抑制主要炎性介質(zhì)、促炎細(xì)胞因子和一氧化氮(NO)的釋放。這3種脂肪酸類物質(zhì)在調(diào)節(jié)一些關(guān)鍵炎癥基因的同時還可調(diào)控參與絲裂原活化蛋白激酶(mitogen activated protein kinases, MAPK)和NF-κB信號通路的蛋白，其中10-HDA的調(diào)節(jié)作用較為突出[35-36]。另外，10-HDA還能促進(jìn)受體拮抗細(xì)胞因子IL-1ra的產(chǎn)生，IL-1ra可抑制腫瘤細(xì)胞增長及主要促炎細(xì)胞因子IL-1的產(chǎn)生[26]。

不僅如此，蜂王漿的抗炎與創(chuàng)傷修復(fù)作用間還存在緊密聯(lián)系[37]。動物試驗(yàn)顯示，應(yīng)用蜂王漿治療口腔黏膜炎及胃潰瘍，可加快創(chuàng)面的愈合速度，有效保護(hù)口腔黏膜和胃黏膜[38-39]。蜂王漿可通過抑制生物膜的形成和細(xì)菌的黏附(平均減少50%以上)而消除耐甲氧西林金黃色葡萄球菌(methicillin-resistant Staphylococcus aureus, MRSA)感染并促進(jìn)創(chuàng)面愈合[40]。此外，蜂王漿中富含再生生長因子、抗菌肽等，在與其他常規(guī)治療相結(jié)合治療足潰瘍時更安全、有效[41]。Pedyphar軟膏(5%天然蜂王漿和1%泛醇)即是以蜂王漿為主要功能性組分為糖尿病足潰瘍創(chuàng)面提供堿性環(huán)境，從而促進(jìn)傷口愈合，并有助于根除感染[41]。因此，蜂王漿及其相關(guān)制劑可作為治療糖尿病足潰瘍及其他創(chuàng)傷類疾病的輔助治療藥物。

2.3 抗氧化

蜂王漿是天然的抗氧化劑，蛋白酶N(protease N)水解的蜂王漿蛋白具有較高的抗氧化活性，其中Phe-Asp、Trp-Val、Leu-Trp、Trp-Leu四種二肽抗氧化活性相對較強(qiáng)[42]。在體外試驗(yàn)中發(fā)現(xiàn)，酪氨酸二肽Lys-Tyr、Arg-Tyr和Tyr-Tyr具有較強(qiáng)的羥自由基清除活性，這些肽能通過清除抗氧化系統(tǒng)中的活性氧(reactive oxygen species, ROS)來起到抗氧化的作用[43]。

酶處理蜂王漿(enzyme-treated royal jelly, ERJ)通過抑制脂多糖(lipopolysaccharide, LPS)誘導(dǎo)的巨噬細(xì)胞內(nèi)ROS和NO的產(chǎn)生，提高超氧化物歧化酶(superoxide dismutase, SOD)活性和谷胱甘肽(glutathione, GSH)水平，達(dá)到抗氧化作用，因此，將ERJ作為抗氧化劑添加到人和動物的飲食中將有很大的應(yīng)用前景[44]。MRJP2可作為抗氧化劑在蜂王漿中發(fā)揮重要作用，它通過降低氧化應(yīng)激和半胱氨酸蛋白酶-3(caspase-3)活性水平來誘導(dǎo)微生物細(xì)胞凋亡，進(jìn)而提高正常細(xì)胞存活率，保護(hù)哺乳動物和昆蟲細(xì)胞免受氧化應(yīng)激的影響[18]。

臨床研究表明，補(bǔ)充蜂王漿可以通過提高糖尿病患者紅細(xì)胞中谷胱甘肽過氧化物酶(glutathione-peroxidase, GSH-Px)和SOD的活性，降低丙二醛(malondialdehyde, MDA)水平，從而減少氧化應(yīng)激對機(jī)體造成的傷害[45]。蜂王漿的抗氧化應(yīng)激作用在修復(fù)H2O2誘導(dǎo)的小鼠胚胎成纖維細(xì)胞(NIH-3T3)損傷，改善細(xì)胞生長停滯和細(xì)胞凋亡中起關(guān)鍵作用，能有效延緩氧化應(yīng)激造成的NIH-3T3衰老[46]。

氧化應(yīng)激可能與帕金森病(parkinson’s disease, PD)的發(fā)病機(jī)制密切相關(guān)[47]。蜂王漿具有良好的抗氧化活性，其中脂肪酸衍生物4-羥基-2-癸烯酸乙酯(HPO-DAEE)預(yù)處理人神經(jīng)母細(xì)胞瘤SH-SY5Y細(xì)胞能減少ROS的產(chǎn)生；NRF2是抗氧化反應(yīng)的主要調(diào)節(jié)因子，HPO-DAEE通過激活NrF2-抗氧化反應(yīng)元件(antioxidant response element, ARE)和真核細(xì)胞起始因子2α-ARE通路來誘導(dǎo)機(jī)體對氧化應(yīng)激產(chǎn)生適應(yīng)性反應(yīng)，保護(hù)細(xì)胞免受氧化應(yīng)激損傷[47]。因此，應(yīng)用蜂王漿可能對PD的癥狀起到緩解作用。順鉑(cisplatin, CP)可誘導(dǎo)大鼠發(fā)生腎功能衰竭，蜂王漿聯(lián)合CP治療時，氧化應(yīng)激指標(biāo)和生化指標(biāo)均有改善，因此，蜂王漿可部分逆轉(zhuǎn)CP引起的腎組織的病理改變[48]。蜂蜜和蜂王漿聯(lián)合應(yīng)用還可使CP誘導(dǎo)的肝氧化應(yīng)激生物標(biāo)志物出現(xiàn)改善[49]。

綜上，蜂王漿抗氧化作用的主要機(jī)制包括增強(qiáng)總抗氧化能力和提高SOD、GSH-Px活性，以及降低MDA水平等，并且可對多系統(tǒng)及器官起到很好的保護(hù)作用。

2.4 免疫調(diào)節(jié)

免疫調(diào)節(jié)機(jī)制在維持機(jī)體內(nèi)環(huán)境穩(wěn)態(tài)中發(fā)揮重要作用，如果免疫調(diào)節(jié)功能下降，機(jī)體就會受到影響，并發(fā)生與自身免疫性相關(guān)的疾病。研究表明，蜂王漿中10-HDA可提高免疫器官胸腺和脾的免疫功能，說明蜂王漿可能在提高機(jī)體免疫力和免疫性疾病的治療中發(fā)揮作用[50]。

Dzopalic等[51]闡明了蜂王漿中脂肪酸類物質(zhì)3, 10-DDA具有促進(jìn)人單核細(xì)胞來源的樹突狀細(xì)胞(monocyte-derived dendritic cells, MoDCs)成熟和刺激輔助性T細(xì)胞1(T helper cells, Th1)極化的能力。隨后，Mihajlovic等[52-53]報(bào)道了蜂王漿脂肪酸中10-HDA和3, 10-DDA均具有顯著的免疫調(diào)節(jié)作用及劑量依賴性。其中，低濃度10-HDA和3, 10-DDA可支持Th1免疫應(yīng)答，3, 10-DDA還可支持Th17免疫應(yīng)答，這是刺激免疫系統(tǒng)對抗腫瘤和感染性物質(zhì)所必需的。而高劑量10-HDA可抑制人外周血單個核細(xì)胞(peripheral blood mononuclear cell, PBMC)增殖和MoDCs的功能和成熟，降低IL-1β和TNF-α的產(chǎn)生，抑制Th1型和Th2型免疫應(yīng)答。基于這些活性，10-HDA可能是一種有效的免疫抑制劑。因此，在蜂王漿發(fā)揮免疫調(diào)節(jié)作用時，10-HDA和3, 10-DDA可能起至關(guān)重要的作用。研究表明，蜂王漿中10-HDA可能通過阻斷p38和JNK-AP-1信號通路抑制膠原酶1(collagenase 1, MMP-1)和基質(zhì)溶酶1(stromelysin 1, MMP-3)活性，減輕MMPs對類風(fēng)濕性關(guān)節(jié)炎(RA，自身免疫病)患者關(guān)節(jié)造成的損壞[54]。

在蜂王漿對甲狀腺機(jī)能亢進(jìn)機(jī)體自身免疫功能影響的試驗(yàn)中顯示，用蜂王漿治療甲狀腺機(jī)能亢進(jìn)，可改變Th1/Th2細(xì)胞因子的比例，增加IFN-γ的產(chǎn)生和誘導(dǎo)健康淋巴細(xì)胞的增殖[55]。因此，蜂王漿可作為免疫調(diào)節(jié)因子用于治療甲狀腺機(jī)能亢進(jìn)。另外，蜂王漿可通過升高兒童系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus, SLE)患者CD4+淋巴細(xì)胞含量和CD4+/CD8+淋巴細(xì)胞比例，來提高機(jī)體免疫力。經(jīng)過3個月的蜂王漿治療，SLE患者的癥狀得到顯著改善[56]。

2.5 抗腫瘤

蜂王漿在癌癥的預(yù)防和輔助治療等方面具有很大潛力。Miyata和Sakai[57]研究表明，蜂王漿可抑制多種惡性腫瘤細(xì)胞的增殖，刺激其凋亡，影響惡性腫瘤患者，尤其是接受抗癌藥治療的患者體內(nèi)各種趨化因子、抗氧化劑和生長因子的產(chǎn)生以及腫瘤相關(guān)分子的表達(dá)，可有效降低藥物對機(jī)體的危害程度。

蜂王漿脂肪酸中10-HDA具有一定的抗腫瘤活性，同時靜脈注射腫瘤細(xì)胞和蜂王漿時可顯著抑制小鼠肺部轉(zhuǎn)移瘤的形成及轉(zhuǎn)移，而在腫瘤發(fā)生前或腫瘤發(fā)生后單獨(dú)腹腔或皮下注射蜂王漿時，對乳腺轉(zhuǎn)移瘤的形成無影響[58]。因此，蜂王漿作為一種干預(yù)手段對腫瘤生長有明顯的抑制作用。另外，在腫瘤細(xì)胞模型中，10-HDA還可抑制血管內(nèi)皮生長因子(vascular endothelial growth factor, VEGF)誘導(dǎo)的血管生成[59-60]。VEGF是一種促血管生成蛋白，腫瘤依賴腫瘤細(xì)胞在缺氧時釋放VEGF來引發(fā)新生血管的形成，進(jìn)而促進(jìn)自身的生長[61]。因此，10-HDA可通過抑制血管過度形成而間接抑制腫瘤生長。最新研究顯示，MRJP2及其預(yù)測亞型X1可通過抑制TNF-α、混合譜系激酶結(jié)構(gòu)域樣蛋白(mixed lineage kinase domain-like protein, MLKL)和細(xì)胞內(nèi)反應(yīng)種類，減輕CCl4誘導(dǎo)的肝細(xì)胞壞死，并通過抑制人肝癌細(xì)胞(HepG2)生長，誘導(dǎo)半胱氨酸蛋白酶凋亡，起到抗癌作用[62]。

蜂王漿可抑制腫瘤細(xì)胞的增殖，其中的脂溶性提取物對人神經(jīng)母細(xì)胞瘤(human neuroblastoma, SH-SY5Y)細(xì)胞具有一定的抗增殖活性，可以預(yù)防和減緩SH-SY5Y細(xì)胞的發(fā)生和生長[63]；蜂王漿體外蛋白消化產(chǎn)物能抑制胃癌細(xì)胞SGC-7901的增殖并誘導(dǎo)其發(fā)生凋亡[64]。另外，Zhang等[65]研究發(fā)現(xiàn)，蜂王漿可以減緩小鼠乳腺腫瘤的發(fā)展，提高血清、肝和腎的抗氧化能力，其預(yù)防性治療效果尤為顯著。蜂王漿還可作為治療癌癥的輔助藥物，阿霉素(doxorubicin, DOX)是治療前列腺癌等多種惡性腫瘤的藥物，經(jīng)蜂王漿處理可增強(qiáng)小劑量DOX對前列腺癌細(xì)胞PC3的細(xì)胞毒作用，避免因長期大劑量使用DOX對機(jī)體正常細(xì)胞造成損傷和產(chǎn)生耐藥性[66]。

2.6 血壓調(diào)節(jié)

高血壓是影響全球疾病負(fù)擔(dān)和全球死亡率的最大單一因素，現(xiàn)在因不良習(xí)慣、壓力以及嘈雜的社會環(huán)境所致的高血壓疾病正逐年上升[67]。Matsui等[68]利用反相高效液相色譜技術(shù)從蜂王漿水解液中分離得到11個血管緊張素轉(zhuǎn)換酶(angiotensin I-converting enzyme, ACE)抑制肽，其中有一部分來源于蜂王漿蛋白，說明蜂王漿蛋白可能是抑制ACE活性、降低血管收縮壓的重要物質(zhì)。

Fan等[69]將MRJP1基因插入小鼠血管平滑肌細(xì)胞(vessel smooth muscle cell, VSMC)中發(fā)現(xiàn)，MRJP1可通過減少能量和遺傳物質(zhì)的供應(yīng)，抑制肌絲運(yùn)動來降低VSMC的收縮和遷移，起到抑制血壓升高的作用。VSMC是動脈壁的重要組成部分，它的異常遷移和收縮是高血壓和動脈粥樣硬化等多種心血管疾病的重要刺激因子。因此，將MRJP1整合到VSMC中，揭示了蜂王漿與降壓活性相關(guān)的功能和機(jī)制，為利用其治療高血壓提供了新的思路。

2.7 膽固醇調(diào)節(jié)

大量研究表明，蜂王漿可以通過改善血脂狀態(tài)降低患心血管疾病的風(fēng)險(xiǎn)[70]。MRJPs具有較高的膽汁結(jié)合力，特別是MRJP1和MRJP2可通過抑制膽固醇在空腸中的膠束溶解度來減低膽固醇的吸收，破壞膽汁酸在回腸的重吸收，促使過多的膽固醇從糞便中排除，從而起降低膽固醇的作用[71]。另外，有研究表明，MRJP1和MRJP2通過提高輕度高膽固醇血癥患者的脫氫異雄酮硫酸鹽(DHEA-S)等性激素的濃度，降低血清總膽固醇(serum total cholesterol, TC)和低密度脂蛋白膽固醇(low-density lipoprotein cholesterol, LDL-c)水平[72]。LDL-c超標(biāo)一般被認(rèn)為是心血管疾病的前兆，攝入蜂王漿后極低密度脂蛋白(very-low-density lipoprotein, VLDL)降低可能是引起TC和LDL-c降低的主要原因[73]。

高脂、高糖飲食和不規(guī)律的生活方式會提升膽固醇水平，膽固醇過高將引起一系列心腦血管疾病的發(fā)生。在動物試驗(yàn)中發(fā)現(xiàn)，蜂王漿能顯著降低高膽固醇飼料誘導(dǎo)的去卵巢兔(動脈粥樣硬化兔)及動脈粥樣硬化雄兔的血脂水平，抑制氧化應(yīng)激水平和炎癥反應(yīng)，提高機(jī)體NO水平；有效保護(hù)血管內(nèi)皮功能[74-75]。

2.8 對血糖穩(wěn)態(tài)的影響

蜂王漿攝入可提高2型糖尿病(diabetes mellitus, type 2, T2DM)患者的總抗氧化能力，降低穩(wěn)態(tài)模型胰島素抵抗指數(shù)[76]。此外，蜂王漿可顯著改善糖尿病患者的TC、高密度脂蛋白(high-density lipoprotein, HDL)、低密度脂蛋白(low-density lipoprotein, LDL)、VLDL、三酰甘油和載脂蛋白A-1的水平；降低氧化應(yīng)激指標(biāo)，提高抗氧化酶水平，有效改善患者的血糖狀況、血脂譜和氧化應(yīng)激[77]。

血清載脂蛋白(apolipoprotein, Apo)A-I與ApoB是心血管疾病的最強(qiáng)預(yù)測因子，補(bǔ)充蜂王漿可增加T2DM患者ApoA-I水平，改善ApoB/ApoA-I比值，有效降低冠心病并發(fā)癥帶來的風(fēng)險(xiǎn)[78-79]。另外，蜂王漿可能會改善糖尿病或高糖情況下人血管內(nèi)皮細(xì)胞的異常狀態(tài)，對高糖或糖尿病引起的心血管疾病有一定的預(yù)防作用[80]。因此，蜂王漿的抗氧化、抗高血壓活性及膽固醇調(diào)節(jié)功能可能會降低胰島素抵抗和糖尿病并發(fā)癥風(fēng)險(xiǎn)。

通過對補(bǔ)充蜂王漿的糖尿病女性患者進(jìn)行調(diào)查發(fā)現(xiàn)，補(bǔ)充蜂王漿可能在控制糖尿病預(yù)后方面具有積極的作用[45]。蜂王漿可通過增加抗氧化酶和降低血糖水平來修復(fù)糖尿病大鼠的脾組織[81]，通過提高總抗氧化能力和CAT含量，降低MDA含量來改善鏈脲霉素(streptozocin, STZ)誘導(dǎo)的大鼠肝、胰腺氧化損傷[82]。另外，蜂王漿還可顯著升高糖尿病大鼠尿液中尿素、總蛋白和白蛋白水平，降低尿肌酐和尿酸水平，有效改善大鼠腎組織病理變化[83]。

然而，補(bǔ)充蜂王漿對健康人或糖尿病患者血糖及糖代謝的影響一直備受爭議。Mahboobi等[84]將所有關(guān)于蜂王漿與糖尿病相關(guān)研究進(jìn)行匯總分析后發(fā)現(xiàn)，蜂王漿攝入對空腹血糖及糖化血紅蛋白水平?jīng)]有明顯改善。另有研究表明，蜂王漿可改善大鼠血漿胰島素和三酰甘油水平及穩(wěn)態(tài)模型評估比率(HOMA-R，胰島素抵抗指數(shù))，但對血糖水平無明顯影響[10]。在以上研究中還發(fā)現(xiàn)，胰島素抵抗與氧化應(yīng)激水平的變化有關(guān)，蜂王漿可能是利用其抗氧化作用來改善胰島素抵抗的。不同的研究結(jié)果可能是由于研究過程中不同方法、實(shí)驗(yàn)對象、環(huán)境以及實(shí)驗(yàn)所使用的蜂王漿品質(zhì)差異等復(fù)雜因素所致[11-12]。因此，了解蜂王漿與血糖的關(guān)系還需要進(jìn)行更深入的研究。

2.9 對神經(jīng)系統(tǒng)的營養(yǎng)和保護(hù)

蜂王漿對神經(jīng)的調(diào)節(jié)和保護(hù)功能早有研究，其特有成分AMP N1氧化物可促進(jìn)神經(jīng)干細(xì)胞分化[85-86]。AMP N1氧化物能抑制大鼠嗜鉻細(xì)胞瘤PC12細(xì)胞生長并通過激活細(xì)胞外信號調(diào)節(jié)激酶1/2(extracellular signal-regulated kinases 1 or 2, ERK 1/2)促進(jìn)神經(jīng)突觸生長，該氧化物可能是蜂王漿中唯一具有誘導(dǎo)神經(jīng)突觸生長的物質(zhì)[87-88]。另外，蜂王漿中各種活性物質(zhì)可能在腦細(xì)胞中發(fā)揮不同的作用，在整個培養(yǎng)過程中，10-HDA促進(jìn)神經(jīng)干細(xì)胞神經(jīng)發(fā)生，并在增加神經(jīng)元生成的同時減少星形膠質(zhì)細(xì)胞的生成[86]。

神經(jīng)干/祖細(xì)胞(neural stem cell/neural progenitor cells, NS/NPC)對認(rèn)知障礙有一定調(diào)節(jié)作用，蜂王漿可通過刺激受損傷的海馬齒狀回再生，增加海馬齒狀回顆粒細(xì)胞數(shù)量，來改善海馬齒狀回內(nèi)NS/NPC的功能[89]。食用蜂王漿可提高小鼠海馬環(huán)磷酸腺苷(cyclic adenosine monophosphate, CAMP)水平，對改善認(rèn)知功能有一定輔助作用[90]。蜂王漿可增加甲狀腺功能減退癥(hypothyroidism, HT)大鼠海馬神經(jīng)元微管相關(guān)蛋白2(microtubule-associated protein 2, MAP-2)的表達(dá)，明顯減輕HT大鼠的退行性變化[91]。

蜂王漿具有神經(jīng)保護(hù)作用，可防止脊髓損傷后發(fā)生脂質(zhì)過氧化反應(yīng)，增強(qiáng)內(nèi)源性酶和非酶抗氧化防御系統(tǒng)，蜂王漿處理能顯著減少脊髓損傷誘導(dǎo)的凋亡細(xì)胞數(shù)量[9]。β-淀粉樣蛋白(amyloid-β, Aβ)在腦內(nèi)的積聚是阿爾茨海默病(alzheimer disease, AD)的典型病理特征，對APP/PS_1小鼠進(jìn)行3個月的蜂王漿治療可減輕小鼠腦內(nèi)Aβ斑塊的形成，明顯改善其認(rèn)知功能障礙和空間記憶能力[90, 92]。純化的蜂王漿多肽還可通過下調(diào)分泌酶(β-secretase, BACE1)來抑制N2a/β695細(xì)胞(應(yīng)用于淀粉樣蛋白發(fā)生途徑產(chǎn)生Aβ的體外模型)外源β-淀粉樣蛋白40(beta-amyloid 40, Aβ1-40)和Aβ1-42的產(chǎn)生，對神經(jīng)起到保護(hù)作用，并有效改善試驗(yàn)兔的行為缺陷和腦圖像結(jié)構(gòu)[92-93]。

血腦屏障(blood brain barrier, BBB)受損后通透性增加，腦內(nèi)組織間液的滲出增多，會導(dǎo)致早期AD患者智力和認(rèn)知能力下降[94]。最新研究顯示，蜂王漿中10-HDA通過激活PI3K、AKT和AMPK信號通路降低脂多糖(lipopolysaccharide, LPS)誘導(dǎo)的BBB通透性，對BBB受損有一定保護(hù)作用[95]。因此，蜂王漿減輕Aβ積聚的能力和對BBB及神經(jīng)的保護(hù)功能，可能在AD的預(yù)防和治療中起到關(guān)鍵作用。

過度的神經(jīng)炎癥會促進(jìn)各種神經(jīng)退行性疾病的發(fā)生，蜂王漿中脂肪酸類物質(zhì)10-HDA和10-HDAA對神經(jīng)炎有一定的抑制作用，進(jìn)一步說明蜂王漿可能會對神經(jīng)退行性疾病及神經(jīng)炎相關(guān)疾病的治療帶來積極作用[96-97]。另外，蜂王漿干預(yù)可調(diào)節(jié)高脂高糖誘導(dǎo)的自主神經(jīng)功能紊亂，改善心臟的收縮和舒張功能，延緩動脈粥樣硬化的發(fā)展[74, 80]。綜上所述，蜂王漿對神經(jīng)的營養(yǎng)、保護(hù)功能將有望應(yīng)用于神經(jīng)系統(tǒng)相關(guān)疾病的預(yù)防和治療中。

2.10 其他

除以上生物學(xué)功能和藥理作用外，蜂王漿還具有抗衰老、改善骨質(zhì)、緩解焦慮等諸多保健作用。

研究表明，Royalactin(即MRJP1)是一種多能性因子，能在實(shí)現(xiàn)胚胎干細(xì)胞自我更新的同時促進(jìn)幼稚多能性基因調(diào)控網(wǎng)絡(luò)的出現(xiàn)，當(dāng)純化的Royalactin加入培養(yǎng)物后可在無白血病抑制因子的情況下維持小鼠胚胎干細(xì)胞的自我更新和多能性。這一發(fā)現(xiàn)將推動干細(xì)胞被更好地利用，并為多能性的研究提供一個新方向[98]。一項(xiàng)新的研究發(fā)現(xiàn)，MRJP3能通過結(jié)合并穩(wěn)定蜂王漿中的RNA，起到在個體之間共享RNA的作用[99]。因此，當(dāng)工蜂攝入標(biāo)記的RNA后，這些RNA可隨蜂王漿傳遞到幼蟲體內(nèi)，這種傳播方式將推動蜂群產(chǎn)生特定病原體的社會免疫[99]。

在一項(xiàng)臨床試驗(yàn)中，31名42~83歲的健康志愿者連續(xù)服用蜂王漿(3 g·d-1)6個月后發(fā)現(xiàn)，他們的精神狀態(tài)、紅細(xì)胞生成和葡萄糖耐受能力均有所改善[100-101]。蜂王漿還可通過促進(jìn)老年大鼠皮膚中膠原蛋白形成和增加表皮含水量，使皮膚恢復(fù)彈性，減緩皮膚衰老[102-103]。microRNA(miR)-129-5p在皮膚光老化和自然衰老過程中具有調(diào)控作用，應(yīng)用蜂王漿可下調(diào)紫外線輻射誘導(dǎo)的人真皮微血管內(nèi)皮細(xì)胞(human dermal microvascular endothelial cells, HDMEC)中miR-129-5p的表達(dá)，調(diào)控HDMEC的增殖，并可能通過維持HDMEC數(shù)量來防止皮膚衰老[104]。另外，蜂王漿主蛋白還具抗疲勞的作用[105]。因此，在化妝品及保健品領(lǐng)域蜂王漿具有很大的應(yīng)用前景。

蜂王漿還具有改善骨質(zhì)的作用，Kaku等[106]發(fā)現(xiàn)，蜂王漿處理可抑制膠原交聯(lián)的減少，促進(jìn)膠原蛋白修飾酶的編碼和交聯(lián)基因的表達(dá)，通過調(diào)節(jié)I型膠原的翻譯后修飾來起到增強(qiáng)骨質(zhì)的作用。此外，蜂王漿還可增強(qiáng)去卵巢大鼠的骨硬度[107]。

最新研究表明，蜂王漿及其脂肪酸類物質(zhì)(特別是10-HDA)能通過抑制腎上腺皮質(zhì)酮的生物合成，改善小鼠應(yīng)激誘導(dǎo)的焦慮和抑郁癥狀[108]。蜂王漿能促進(jìn)小鼠褐色脂肪組織(brown adipose tissue, BAT)代謝產(chǎn)熱，改善與飲食相關(guān)的肥胖、脂肪肝和葡萄糖耐受不良，有望作為未來人們對抗肥胖和代謝紊亂的新型膳食補(bǔ)充劑[109]。此外，MRJP2及其亞型X1，特別是MRJP2，可有效抑制丙型和乙型肝炎病毒在體外的早期侵染和復(fù)制，這為抗病毒藥物的研發(fā)提供了新的思路[110]。蜂王漿還可通過直接刺激淚腺分泌來恢復(fù)干眼癥患者的淚液量，改善干眼癥患者眼部不適和視覺障礙[111]。

3 小結(jié)與展望

蜂王漿成分復(fù)雜，其中含有的特殊化合物如MRJPs、10-HDA和抗菌肽等，在蜂王漿的各種活性功能及引申出的藥理作用中起著關(guān)鍵的作用。隨著MRJP1蛋白結(jié)構(gòu)的解析，為蜂王漿蛋白單體藥理作用機(jī)制的發(fā)掘揭開了序幕[17]。

蜂王漿的眾多生物學(xué)功能既是獨(dú)立存在的，又是相互聯(lián)系的。獨(dú)立存在時，蜂王漿中的ELVs可抑制和殺滅金黃色葡萄球菌[31]；Phe-Asp、Trp-Val和Arg-Tyr等抗氧化肽可清除抗氧化系統(tǒng)中的活性氧[43]。相互聯(lián)系時，多種活性物質(zhì)的功能可協(xié)同增強(qiáng)：如在傷口愈合過程中，蜂王漿的抗菌活性為創(chuàng)面提供一個堿性環(huán)境，抑制生物膜的形成和細(xì)菌的黏附；抗炎活性可抑制巨噬細(xì)胞產(chǎn)生促炎細(xì)胞因子，防止傷口發(fā)生炎性反應(yīng)；蜂王漿又可作為免疫調(diào)節(jié)因子，提高機(jī)體免疫力，進(jìn)一步促進(jìn)傷口愈合[40-41, 55]。另外，蜂王漿抗氧化和抗高血壓活性及抗高膽固醇血癥活性相結(jié)合時，還可能降低胰島素抵抗和糖尿病并發(fā)癥的風(fēng)險(xiǎn)[78-80]。

蜂王漿及其衍生物具有非常廣泛的藥用價值，目前在高血壓、高膽固醇血癥、糖尿病、癌癥、神經(jīng)調(diào)節(jié)、中老年疾病、生殖及內(nèi)分泌系統(tǒng)疾病中均有涉及，已被證明對多種疾病具有顯著的預(yù)防及治療作用[112-113]。同時，蜂王漿對心血管、神經(jīng)和消化系統(tǒng)及腎、肺等臟器具有保護(hù)作用。

有研究表明，在某些情況下首次攝入RJ后會出現(xiàn)過敏反應(yīng)，如有過敏性疾病史的人(阿爾茨海默病、哮喘或過敏性鼻炎患者)，應(yīng)在醫(yī)生指導(dǎo)下謹(jǐn)慎服用蜂王漿[114]。在一項(xiàng)動物試驗(yàn)中發(fā)現(xiàn)，蜂王漿可促進(jìn)未成熟雌性大鼠卵泡的生長和發(fā)育，其作用機(jī)制可能是通過對生殖系統(tǒng)的抗氧化和雌激素效應(yīng)來發(fā)揮作用的[112]。那么，攝入蜂王漿是否會對青年女性生殖參數(shù)造成影響還是未知的。目前，關(guān)于蜂王漿可能存在的副作用研究還不夠充分，如過敏反應(yīng)、類激素成分等是否會帶來不良后果還有待進(jìn)一步論證[112, 114-115]。另外，蜂王漿具有一定的劑量依賴性，在不同個體或疾病中探究其安全、有效的應(yīng)用劑量同樣重要。因此，日后需要更多的臨床試驗(yàn)來證實(shí)蜂王漿在人體模型中的有效性，積極發(fā)現(xiàn)和利用這一天然產(chǎn)物中特有的活性物質(zhì)組分，使其在疾病的預(yù)防和治療中發(fā)揮更好的作用。

致謝: 感謝浙江省農(nóng)業(yè)科學(xué)院陳伊凡老師和中國農(nóng)業(yè)科學(xué)院蜜蜂研究所張文文老師對本論文寫作中的指導(dǎo)。

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