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男性睾丸功能障碍临床上表现为精子发生异常、睾酮缺乏或两者共存[1]。近半个世纪以来，全球男性精子浓度逐年下降[2]，全球约有10%~20%的夫妇患有不孕症，其中男性因素占30%~50%[3]。男性性腺功能减退的主要诊断依据是症状和低血清睾酮水平，在一般人群中的患病率为6%~12%，并随着年龄的增长而增加，在2型糖尿病（T2DM）男性中更是高达40%[4]。目前并没有药物能够安全有效地恢复精子发生和睾酮合成。睾丸功能障碍导致的男性性腺功能减退患者，主要采取睾酮替代治疗[1]。但外源性补充睾酮会反馈性抑制内源性睾酮生成，进而抑制精子发生[5]，同时还可能出现红细胞增多、心血管疾病发病率增加等不良反应[6]。
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除先天发育因素外，氧化应激、细胞凋亡、炎症及相关生理途径是导致男性睾丸功能障碍的主要原因。淫羊藿苷（icariin，ICA）、淫羊藿次苷Ⅱ（icariside Ⅱ，ICAⅡ）、槲皮素（quercetin，QUE）具有抗氧化、抗凋亡和调节细胞因子等作用[7]，可用于防治多种慢性和退行性疾病。ICA、ICAⅡ和QUE同样具有治疗睾丸功能障碍的效果，主要表现在：调节下丘脑-垂体轴（hypothalamic-pituitary axis，HPG轴）激素[8]、抑制生精细胞凋亡[9]、维持支持细胞和血睾屏障完整性[10]、改善间质细胞分泌功能[11]等。目前尚没有关于ICA、ICAⅡ和QUE防治睾丸功能障碍的临床研究，但体外实验和动物模型研究发现其治疗效果具有剂量依赖性[12]。本文综述ICA、ICAⅡ和QUE防治睾丸功能障碍的效果、作用机制、体外实验和动物模型治疗的给药策略，以期为中药来源的单体化合物康复治疗睾丸功能障碍的高质量研究提供参考。
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1 ICA、ICAⅡ和QUE的分子结构
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黄酮类化合物是植物多酚的次生代谢物，是一系列以C6-C3-C6为骨架，由一个三碳链连接的两个苯环（a环和b环）组成的化合物，见图1。根据中央三碳链的氧化程度和b环连接位置的差异，黄酮类可分为类黄酮、黄酮醇、黄烷醇、儿茶素、异黄酮、花青素等[7]。ICA、ICAⅡ和QUE属于黄酮醇类，其中ICAⅡ是ICA的主要代谢产物。大鼠口服ICA后约91.2%经肠道菌群水解酶转化为ICAⅡ[13]。
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图1 黄酮类化合物骨架结构和ICA、ICAⅡ、QUE的分子结构
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2 ICA、ICAⅡ和QUE防治睾丸功能障碍的效果
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ICA、ICAⅡ和QUE具有调节HPG轴激素、抑制生精小管病理改变、提高精子数量和活力以及提高睾酮水平的作用，可减轻糖尿病、药物、环境毒素、缺血等各种因素导致的睾丸损伤。
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ICA、ICAⅡ和QUE在体外研究中常用的细胞系有TM4细胞[10]、Cat.FE1489间质细胞[11]、LO2和HepG2细胞[14]、ICR间质细胞[15]、MA-10间质细胞[16]等，常用的诱导损伤模型物质有邻苯二甲酸二（2-乙基己基）酯[di（2-ethylhexyl）phthalate，DEHP]、D-半乳糖（D-galactos，D-gal）、高糖（high glucose，HG）、微囊藻毒素（microcystin-leucine-arginine，MC-LR）、棕榈酸（palmitic acid，PA）、全氟辛烷磺酸（perfluorooctane sulfonate，PFOS）、喹诺酮（quinoceton，QCT）、转化生长因子-β1（transforming growth factor-β1，TGF-β1）等。各研究中ICA处理实验细胞的浓度范围为0~128 µmol/L，处理时间3~48 h，多数研究发现1~4 µmol/L的ICA能显著增加细胞活力[10，17-18]，但Zhou等[19]以100 µmol/L的ICA治疗TM4细胞可减轻MC-LR诱导的细胞毒性。Liu等[20]以10~40 µmol/L的ICAⅡ处理大鼠间质细胞24~48 h后却发现细胞活性受损，睾酮合成能力下降，但该作者并未以更低浓度的ICAⅡ处理细胞，缺乏低浓度ICAⅡ对体外培养间质细胞作用的数据。QUE处理实验细胞的浓度为0~250 µmol/L，处理时间为1~6 h，结果发现其作用具有剂量依赖性，5~30 µmol/L能显著改善细胞活性，高浓度能抑制细胞活性[11，14，16]，见表1。
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ICA、ICAⅡ和QUE在体内研究中常用的实验动物为大鼠和小鼠，通过高脂肪饮食（high-fat-diet，HFD）、腹腔注射链脲佐菌素（streptozotocin，STZ）或各种毒物[如双酚A（bisphenol A，BPA）；氯化镉（cadmium chloride，CdCl2）；环磷酰胺（cyclophosphamide，CP）；左乙拉西坦（levetiracetam，LEV）；纳米二氧化钛（titanium dioxide nanoparticle，NTiO2）；乙酸铅（lead acetate，Pb）；邻苯二甲酸酯（phthalates，PEs）；柳氮磺胺吡啶（sulphasalazine，SASP）]诱导肥胖、糖尿病、毒素睾丸损伤模型。治疗药物以口服或灌胃为主，其作用具有明显的剂量依赖性。睾丸损伤动物模型研究中ICA的剂量为2~200 mg/kg，疗程为2～11周，多数研究表明50~100 mg/kg的ICA能够显著改善睾丸功能障碍[15，18，21-26]，而200 mg/kg的ICA则加重了睾丸氧化应激[21]。但Zhao等[27]以含ICA（2~6 mg/kg）膳食饲养高龄大鼠持续4个月，同样显著改善了与年龄相关的睾丸功能下降。Xu等[28]以不同浓度的ICAⅡ（0.5~4.5 mg/kg）灌胃治疗STZ诱导的生精功能障碍大鼠4周，发现4.5 mg/kg组大鼠的生精功能改善最显著。Chi等[29]以ICAⅡ（5 mg/kg）灌胃治疗14 d，可显著缓解小鼠睾丸缺血再灌注损伤。QUE治疗睾丸损伤大鼠的剂量为10~90 mg/kg，疗程为2~6周，多数研究表明20~75 mg/kg的QUE能够显著改善睾丸损伤[8-9，11，30-31]。但Xia等[32]却发现更高剂量QUE（90 mg/kg）也可改善大鼠睾丸功能。总之，ICA、ICAⅡ和QUE治疗睾丸功能障碍的给药策略差异很大，仍需更多高质量研究。但可以明确的是，过量的ICA、ICAⅡ和QUE并不能持续改善睾丸功能；相反，它可能造成组织和器官氧化损伤以及进一步损害睾丸功能[21]，见表2。
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3 ICA、ICAⅡ和QUE防治睾丸功能障碍的作用机制
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3.1 抗氧化应激和细胞凋亡作用
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适当水平的活性氧自由基（reactive oxygen radicals，ROS）对维持机体功能是必要的，但各种因素导致过量的ROS则会打破氧化-抗氧化系统平衡，加速细胞凋亡，损伤机体功能[33]。机体内源性抗氧化防御系统包括酶促和非酶促途径，前者主要是超氧化物歧化酶（superoxide dismutase，SOD）、过氧化氢酶（catalase，CAT）和谷胱甘肽过氧化物酶（glutathione peroxidase，GPx）；后者包括还原性谷胱甘肽（reduced glutathione，GSH）、维生素A、C和E等[33]。
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ICA、ICAⅡ和QUE可抑制产生ROS酶的活性[14，21]、提高抗氧化物酶活性[21，23]，增强细胞的抗氧化防御系统，维持细胞内氧化还原稳态[34]。其抗氧化应激和细胞凋亡的机制，一是调节核因子-E2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）信号通路，二是调节线粒体通路和内质网应激导致的细胞凋亡，三是与重金属离子螯合[35]。ICA、ICAⅡ和QUE通过激活Nrf2/血红素加氧酶-1（heme oxygenase-1，HO-1）[14，30]、上调雌激素受体α（estrogen receptor α，ERα）[27]、激活AMPK[24]、介导Kelch样ECH关联蛋白1（kelch-like ECH-associated protein 1，KEAP1）降解[36]等途径，促进Nrf2核易位及其结合活性，增强Nrf2的抗氧化反应元件活性，减轻线粒体损伤和凋亡。通过下调Bax和caspase3，上调Bcl-2、增殖细胞核抗原（PCNA）的表达，激活SRIT1-缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）信号通路，可抑制线粒体通路导致的细胞凋亡[25，37]；通过下调葡萄糖调节蛋白78（glucose-regulated protein 78，GRP78）、蛋白激酶RNA样ER激酶（protein kinase RNA-like ER kinase，PERK）等减弱内质网应激（endoplasmic reticulum stress，ERS）诱导的细胞凋亡[38]。ICAⅡ治疗还可减轻小鼠睾丸缺血再灌注损伤导致的氧化应激和细胞凋亡[29]。
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3.2 调节细胞因子作用
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ICA、ICAⅡ和QUE通过调节炎症因子和相关信号通路发挥抗炎作用：一是抑制促炎信号通路，如MAPK和NF-κB；二是激活抗炎信号通路，如糖皮质激素受体（glucocorticoid receptor，GR）、Nrf2和PI3K/AKT[39]。其中涉及多种炎症因子的调节[9，24]，包括下调促炎因子白细胞介素（IL）-1β、IL-5、IL-6、IL-8、IL-12、IL-13、IL-17、肿瘤坏死因子α（tumour necrosis factor-α，TNF-α）、干扰素γ（interferons γ，IFN-γ），上调炎症抑制因子IL-10。
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另外，ICA还可通过调节趋化因子促进细胞迁移和组织再生。体外研究发现1 µmol/L的ICA能够通过上调胰岛素样生长因子1（insulin-like growth factor 1，IGF1）、TGF-β、基质细胞衍生因子1（stromal-cell-derived factor 1，SDF-1）等趋化细胞因子的表达来促进椎间盘来源的干细胞迁移和骨骼形成[40]。IGF1的结构和功能与胰岛素相似，它参与介导生长发育，在肝硬化模型中，IGF1可促进肝再生[41]。Cannarella等[42]发现IGF1可促进体外培养的支持细胞增殖。而ICA治疗能够上调IGF1表达，可通过胰岛素/IGF1信号通路延长秀丽隐杆线虫的寿命[43]。基于上述现象，推测ICA等黄酮类化合物有可能通过调节趋化因子来改善睾丸功能。
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3.3 促进干细胞增殖分化作用
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干细胞/祖细胞存在于每个成人的器官和组织中，如能激活或招募这些内源性干细胞，将在组织损伤修复中发挥重要作用并且更加安全[44]。近年来的一些研究表明植物衍生物可以促进成体干细胞的增殖和分化，比如ICA可通过激活Wnt/β-catenin信号通路[45]、上调miR-335-5p[46]等机制促进骨髓间充质干细胞的增殖和分化；ICAⅡ通过miR-34a/STAT3通路促进脂肪组织来源的干细胞向雪旺细胞分化[47]、通过p38-MAPK信号通路促进大鼠阴茎内源性干细胞的增殖和分化[48]、通过激活阴茎海绵体中的EdU+祖细胞/干细胞进而改善勃起功能[49]。氧化还原信号通路是生殖干细胞行为的重要调控因子[50]，而ICA、ICAⅡ和QUE具有明显的抗氧化作用，所以，它们能否促进睾丸精原干细胞或睾丸间质干细胞的增殖，将是值得深入研究的内容。
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4 结论和展望
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研究表明，ICA、ICAⅡ和QUE具有抗氧化、抗凋亡、调节细胞因子、促进干细胞增殖和分化等作用，在睾丸功能障碍领域具有不同程度的康复治疗效果，治疗效果具有剂量依赖性。但是各药物在不同研究中发挥显著效果的剂量范围较大，ICA为50~100 mg/kg，ICAⅡ为4.5~5 mg/kg，QUE为20~75 mg/kg。这种差异可能与不同模型诱导因素、病理变化、实验设计、黄酮类药物难溶性、药物体内代谢和生物活性等多种原因有关，有待于深入研究[54]。特别是黄酮类化合物难溶于水，会影响口服后的生物利用度，开展提高生物利用度的研究，如微粉化、纳米技术、剂型改变等[54-55]可能会提高药物疗效。
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ICA可促进骨髓间充质干细胞的增殖和分化[46]，ICAⅡ可激活驻留在阴茎海绵体的内源性干细胞，促进血管、神经再生康复，治疗勃起功能障碍[48]。ICA和ICAⅡ对于睾丸精原干细胞、间质干细胞的再生医学康复治疗作用及机制，有待更深入的高质量研究。
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摘要
睾丸功能障碍包括精子生成障碍导致的男性不育症和睾酮合成障碍导致的男性性腺功能减退症。淫羊藿苷、淫羊藿次苷Ⅱ和槲皮素均具有抑制氧化应激和细胞凋亡、调控细胞因子表达及促进细胞增殖分化的作用，可修复睾丸损伤性病理改变，对睾丸功能障碍有康复治疗效果。本研究对近十年来淫羊藿苷、淫羊藿次苷Ⅱ和槲皮素防治睾丸功能障碍的效果、作用机制、体外实验和动物模型治疗给药策略的相关文献进行综述，旨在为黄酮类化合物康复治疗睾丸功能障碍的高质量研究提供参考。
