CN113476440A - 芝麻素在制备治疗生精功能障碍药物中的用途 - Google Patents
芝麻素在制备治疗生精功能障碍药物中的用途 Download PDFInfo
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- CN113476440A CN113476440A CN202110762768.2A CN202110762768A CN113476440A CN 113476440 A CN113476440 A CN 113476440A CN 202110762768 A CN202110762768 A CN 202110762768A CN 113476440 A CN113476440 A CN 113476440A
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- sesamin
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- dysfunction
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请提供了芝麻素在制备治疗生精功能障碍药物中的用途。实验结果表明,芝麻素能显著提高精子数量及活力;能显著抑制睾丸内部RNF8‑ubH2A/ubH2B通路,对生精功能障碍小鼠具有保护作用。
Description
技术领域
本申请属于生殖系统疾病领域,具体地,本申请提供了芝麻素在制备治疗生精功能障碍药物中的用途。
背景技术
受遗传、环境污染等多方面因素的影响,男性不育症的发病率正逐渐上升,已高达10%~15%,成为继肿瘤和心血管疾病之后危害人类健康和社会稳定的第3大要素。因此,不育症人群的生殖健康情况也被看作是全世界范围内须重点关注的公共卫生问题。男性不育症主要包括生精功能障碍、性功能障碍、内分泌紊乱及睾丸组织损伤。临床上不育患者中,大部分患者表现为睾丸生精功障碍(Testicular spermatogenic dysfunction)。睾丸生精功障碍病因复杂,且往往不是由单一因素所致,其主要与药物、环境、遗传、内分泌、感染、疾病及生活方式有关。目前睾丸生精功障碍临床治疗常以经验治疗为主,但目前尚缺乏疗效确切的治疗药物。辅助生殖技术(Assisted Reproductive Technology,ART)虽然为睾丸生精功障碍的患者提供了生育的可能,但ART技术的成功率仍较低,妊娠率仅为4%-40%,且子代出生缺陷的风险高于自然妊娠。因此研发安全有效的治疗睾丸生精功障碍的药物具有重大的社会价值和研究意义。
芝麻是我国传统油料作物之一,主要成分是油脂、蛋白质、维生素B、维生素E及矿物质、芝麻素、芝麻林素、芝麻酚、卵磷脂、甾醇等,有较高营养价值。2013年KhaniBehnaz等在临床试验中发现,给予25例生精功能障碍男性芝麻治疗后,可提高精子数量和活力,是治疗男性生精功能障碍的一种安全有效的方法。文献报道,维生素C和芝麻乙醇提取物可以通过增加血清中睾酮浓度及抗氧化作用提高雄性Wistar大鼠生育力;Abbasi Zahra等研究发现,芝麻油可改善糖尿病雄Wistar大鼠生殖参数,即在补充芝麻油后,糖尿病大鼠精原细胞总数、精母细胞数、间质细胞/小管细胞数、生殖细胞/支持细胞比值均有不同程度的改善,且可剂量依赖性地提高糖尿病大鼠血浆睾酮浓度。芝麻素是芝麻中主要的天然木脂类生物活性成分,大量存在于芝麻油中,具有抗氧化、抗菌、降血糖等较强的生物活性作用。因此将其发展为治疗生精功能障碍药物具有极高的潜在价值与社会意义。
发明内容
本发明的目的是通过对芝麻素的药理作用研究,发现芝麻素能提高生精功能障碍小鼠模型的精子数量、活力及生殖器官脏器系数,从而提供芝麻素在制备治疗生精功能障碍药物中的用途。
一方面,本发明提供了芝麻素在制备治疗生精功能障碍药物中的用途,所述芝麻素的结构式如式(1)所示:
进一步地,所述药物中芝麻素为唯一活性成分。
进一步地,所述生精功能障碍为生精功能损伤。
进一步地,所述生精功能障碍为精子数量和活力低下并精子畸形。
进一步地,所述药物为注射或者口服剂型。
进一步地,所述药物为口服剂型。
另一方面,本发明提供了增强生精功能和精子活力的非治疗方法,包括施用芝麻素。
进一步地,芝麻素单次应用剂量为50-100mg/kg。
进一步地,芝麻素单次应用剂量为100-200mg/kg。
进一步地,芝麻素单次应用剂量为200mg/kg。
本申请中的非治疗方法包括但不限于保健方法以及科学研究方法,实施对象可以为人或其他哺乳动物如鼠、兔、犬等。
本申请中生精功能障碍的症状或指症包括但不限于生精功能损伤、精子数量和活力低下和精子畸形,睾丸组织中的RNF8-ubH2A/ubH2B通路。
本申请的可用的药物剂型包括各种注射和口服剂型,包括但不限于片剂、胶囊剂、口服液、针剂、粉针剂、透皮给药制剂,特别优选口服剂型。
除芝麻素外,本申请中所述的药物还可以包括药学上可接受的各种辅料/赋形剂,包括但不限于包衣材料、溶剂、增溶剂、粘合剂、稳定剂、抗氧化剂、pH调节剂、矫味剂等,特别优选可用于口服剂型的各种辅料/赋形剂。
本发明的药物中可以包含其他治疗生精功能障碍的中西药药物或保健品,或者本发明的药物可以与这些中西药药物或保健品或手术等治疗手段联合使用。所述中西药药物或保健品包括但不限于抗感染药物、促性腺激素类药物、抗氧化剂类药物、能量代谢和血液循环改善剂。
本发明提供的芝麻素在制备治疗生精功能障碍药物中的用途具有以下有益效果:
(1)芝麻素能显著提高精子数量及活力;
(2)芝麻素能抑制睾丸内部的RNF8-ubH2A/ubH2B通路中的H2A、H2B蛋白的表达以及升高睾丸组织中的RNF8蛋白表达,改善生精功能障碍。
本发明首次证实,芝麻素具有治疗生精功能障碍小鼠的作用,可用于制备生精功能障碍的治疗药物,为此类药物提供了一种新的选择。
附图说明
图1为芝麻素对生精功能障碍小鼠精子参数的影响图;A:精子数量(x108);B:精子活力(%);结果以Mean±SEM(n=10)表示,**p<0.01,***p<0.001与正常组比较,#p<0.05,##p<0.01与模型组比较。
图2为芝麻素对生精功能障碍小鼠DNA损伤的影响。
图3为芝麻素对生精功能障碍小鼠精子染色质凝聚的影响图:A:小鼠精子染色质凝聚(苯胺蓝染色)代表性图像;B:精子染色质凝聚度统计图;a:空白对照组;b:模型组;c:模型+芝麻素200mg/kg组,结果以mean±SEM(n=6)表示.***p<0.001表示与正常组比较,###p<0.001表示与模型组比较。
图4为芝麻素对生精功能障碍小鼠组织形态的影响图:A:小鼠睾丸曲细精管HE染色代表性图像;B:睾丸约翰评分统计图;a:空白对照组;b:模型组;c:模型+芝麻素50mg/kg组,d:模型+芝麻素100mg/kg组,e:模型+芝麻素200mg/kg组,结果以mean±SEM(n=6)表示.***p<0.001表示与正常组比较,###p<0.001表示与模型组比较。
图5为芝麻素对生精功能障碍小鼠精子发生过程的影响图。
图6为芝麻素对生精功能障碍小鼠睾丸组织中RNF8,H2A,H2B表达水平的影响图:A:不同组睾丸组织中RNF8的代表性蛋白质印迹分析图;B:RNF8蛋白表达统计图;C:不同组睾丸组织中H2A,H2B的代表性蛋白质印迹分析图;D:H2A,H2B蛋白表达统计图;结果以mean±SEM(n=6)表示.*p<0.05,***p<0.001表示与正常组比较,#p<0.05,##p<0.01表示与模型组比较。
图7为芝麻素对生精功能障碍小鼠睾丸组织中ub-H2A,ub-H2B的影响图:A:芝麻素对生精功能障碍小鼠睾丸组织ub-H2A,ub-H2B荧光染色代表性图像;B:荧光亮度统计图;结果以mean±SEM(n=6)表示.***p<0.001表示与正常组比较,###p<0.001表示与模型组比较。
具体实施方式
下面结合实施例对本发明作进一步详细的说明,以下实施例中使用的芝麻素均为前述式(1)所示的化合物,可通过商购获得。
实施例1
芝麻素在制备治疗生精功能障碍药物中的用途,其中,芝麻素单次应用剂量为小鼠50mg/kg,药物的剂型为口服剂型。
实施例2
芝麻素在制备治疗生精功能障碍药物中的用途,其中,芝麻素单次应用剂量为小鼠100mg/kg,药物的剂型为口服剂型。
实施例3
芝麻素在制备治疗生精功能障碍药物中的用途,其中,芝麻素单次应用剂量为小鼠200mg/kg,药物的剂型为口服剂型。
下面的动物实验进一步说明了上述实施例1至3的效果:
一、实验材料
1.1动物处理
体重23-27g之间的SPF级ICR雄性成年小鼠,宁夏医科大学实验动物中心繁殖(动物孵育合格批号:SCXK(宁)2020-0001)。动物饲养参照实验动物饲养标准,饲养房12h人工控制昼夜交替,小鼠自由饮水。
1.2实验药品及仪器
本实验中会涉及到的主要药品和试剂包括:芝麻素(购自上海源叶生物公司,纯度≥98%);左卡尼汀(购自美国Alfasigma公司);环磷酰胺(购自江苏盛迪医药有限公司);生理盐水(购自天津大茂化学试剂厂);精子核蛋白染色液(苯胺蓝法)(购自深圳子科生物有限公司);吖啶橙(北京索莱宝生物科技有限公司);GAPDH山羊抗兔和FITC山羊抗兔(购自美国proteintech公司);兔抗H2A、H2B、RNF8、Ubiquityl-Histone H2A(购自英国abcam公司);兔抗Ubiquityl-Histone H2B(购自美国Cell Signaling公司);DAPI(购自北京中杉金桥生物科技公司);全蛋白提取试剂盒(购自南京凯基生物公司);全蛋白定量试剂盒(购自南京凯基生物公司);脱脂奶粉(购自北京索莱宝科技公司);PVDF膜(购自美国Millipore公司);ECL发光液(购自Advansta公司);Marker(10-180KDa)(购自Thermo fisher);羧甲基纤维素钠(购自北京索莱宝有限公司);动物睾丸组织固定液(购自Servicebio有限公司)。
本实验中会涉及到的主要仪器包括:血球计数板(购自上海求精玻璃仪器厂);酶标仪(购自Thermo scientific);电热恒温水浴锅(购自上海精密实验设备有限公司);全自动样品冷冻研磨仪(购自上海净信科技有限公司);SDS-PAGE电泳仪(购自美国Bio-RAD公司);可见荧光成像仪(购自美国Auzre Biosystems);电热恒温鼓风干燥箱(购自上海琅玕实验设备有限公司);荧光显微镜(OLYMPUS);光学显微镜(OLYMPUS);电泳仪、电转仪(Powerpac basic,美国Bio-Rad公司);高速低温离心机(德国Eppendorf)。
1.3实验动物分组及给药
体重24-28g之间的雄性成年ICR小鼠清洁级饲养间适应性喂养3天后,按体重梯度抽样法将其平均分至对照组、模型组、左卡尼汀组和芝麻素50mg/kg、100mg/kg、200mg/kg组。各组动物除正常饲养外,模型组腹腔注射环磷酰胺(Cyclophosphamide,CTX)120mg/kg,每周一次,即构建雄性小鼠生精功能障碍模型。左卡尼汀组给予左卡尼汀(3.03ml/kg)灌胃,芝麻素50mg/kg、100mg/kg、200mg/kg组给予芝麻素(50mg/kg、100mg/kg、200mg/kg)灌胃,每组20只。左卡尼汀组和芝麻素各给药剂量组于每天上午固定时间点连续给药2周,对照组和模型组小鼠均给予相同容量的0.5%羧甲基纤维素钠溶液;以每0.1ml/10g的给药容积灌胃给药;其余实验条件相同。
二、实验过程
(一)脏器系数测定
1.1实验方法:
最后一次给药24h后称重并记录各组小鼠体重。实验结束后,处死小鼠,用手术剪迅速剪开小鼠腹部,充分暴露双侧睾丸,除去周围的脂肪组织及结缔组织,取出睾丸、附睾以及精囊腺,吸干表面的血液后用电子天平准确称取其重量。
1.2实验结果:
结果如表1所示,模型组小鼠生殖器官睾丸,附睾和精囊腺的脏器系数与正常组相比显著下降(p<0.001)。给予芝麻素(50mg/kg、100mg/kg、200mg/kg)治疗的小鼠生殖器官的脏器系数比显著增加(p<0.05,p<0.01,p<0.001),左卡尼汀治疗组也显著增加了生殖器官的脏器系数比(p<0.05)。提示芝麻素对生精功能障碍小鼠生殖器官有一定的改善作用。
***p<0.001与正常组比较,#p<0.05,##p<0.01,###p<0.001与模型组比较
(二)精子参数测定
2.1实验方法:
精子数目:将盛有2ml生理盐水的EP管置于恒温水浴箱内预热至37℃,将小鼠右侧附睾尾称重并在EP管中剪碎水浴5分钟,得到的精子原液用生理盐水稀释4倍,在400倍光镜下计数血细胞计数板上4大格精子的数量并计算。
精子活力:半定量法评估精子活力,每个样本取10μl稀释4倍后的精子混悬液,400倍光镜下观察大约100个精子的游动情况,计算游动精子的比例。
2.2实验结果:
精子参数结果如图1显示,模型组小鼠精子数量及精子活力与正常组相比显著下降(p<0.01,p<0.001),而给予芝麻素(50、100、200mg/kg)治疗后,小鼠精子数量及精子活力与模型组相比显著提高(p<0.05,p<0.01)(图1),提示芝麻素对于少弱精子症小鼠的精子质量有很好的保护作用。
(三)精子DNA损伤的变化
3.1实验方法:
吖啶橙以1mg/mL的浓度溶于蒸馏水中。总共将10μL该溶液放在预热(约70℃)的清洁载玻片上,通过来回移动玻璃棒并风干来铺展。涂有AO的载玻片在室温下储存。然后,将上述精子原液轻轻滴到载玻片上,用盖玻片覆盖,并放入有一层湿纸的培养皿中,静置2小时,让细胞沉淀并使染色最大化,于荧光显微镜下观片、采片。
3.2实验结果
由图2可以看出,在对照组中可以观察到吖啶橙荧光染色后精子图像呈绿色,代表DNA双链的精子,表明精子DNA正常;与对照组相比较,模型组中可以观察到吖啶橙荧光染色后精子图像呈红色和橙色荧光,代表DNA单链的精子,表明精子DNA损伤;给予芝麻素200mg/kg治疗后,与模型组相比较,红色和橙色荧光的精子数量明显减少,表明给予芝麻素治疗后精子DNA损伤明显改善。
(四)精子染色质凝聚的变化
4.1实验方法:
配制洗涤工作液:去适量的10×浓缩洗涤液,以蒸馏水10稀释后即为洗涤工作液;取上述精子原液0.2ml置于2ml离心管中,加入1ml洗涤工作液,用移液枪反复吹打数次,室温2000rpm离心5min,并弃去上清液,保留管底精子沉淀团,重复操作3次;向精子沉淀团里加入工作液0.1ml,制成混合精子悬液,再取10μl稀释100倍,混匀,再取15μl精子悬液,均匀涂于防脱载玻片上,自然干燥;取干燥片子,在涂有精子的片区滴加固定液2-3滴,室温固定10min,蒸馏水冲洗5min,甩去多余水分;在涂有精子的片区滴加苯胺蓝染色液2-4滴,室温染色5min,蒸馏水冲洗5min,甩去多余水分,迅速吹干玻片,镜检。
4.2实验结果:
由图3A可以看出,在对照组(图3a)中可以观察到精子头部着色较浅,表明精子染色质凝聚度较好。在模型组(图3b)中观察到精子头部着色较深,表明精子染色质凝聚度较差。给予芝麻素(200mg/kg)治疗后(图3c),观察到精子头部着色变浅,表明精子染色质凝聚度得到恢复。根据精子染色质凝聚度统计图(图3B)可以看出,与正常组相比较,精子染色质凝聚度差的精子数显著上升;给予芝麻素(200mg/kg)治疗后,与模型组相比较,观察到精子头部着色变浅,表明给予芝麻素治疗后精子染色质凝聚度明显改善。
(五)睾丸组织病理结构的检测
5.1实验方法:
实验结束后,处死小鼠,用手术剪迅速剪开小鼠腹部,充分暴露双侧睾丸,除去周围的脂肪组织及结缔组织,取出睾丸,将其浸泡在动物睾丸组织固定液中,送至Servicebio有限公司进行H.E染色及切白片。
5.2实验结果:
5.2.1睾丸组织结构
睾丸组织进行H.E染色可以看出,对照组小鼠曲细精管形态完整,管腔内可见大量密集成熟精子,各级生精细胞排列整齐(见图4A-a)。模型组睾丸曲细精管萎缩,管腔直径表变小,各级生精细胞排列紊乱,发育停滞,间质组织脱落严重,管腔内精子数量减少或无,整个精子发生过程明显受到抑制(见图4A-b)。给予芝麻素(50、100、200mg/kg)治疗后,与模型组相比,在镜下观察到曲细精管形态逐渐恢复正常,管腔中可见不同时期的生精细胞,排列紧密(见图4A-c、d、e)。约翰评分统计图(见图4B)。
5.2.2精子发生过程
与对照组相比,模型组小鼠曲细精管内圆形精子细胞减少,且精子细胞的晚期发育受到损害,延长期精子细胞数量明显减少;给予芝麻素(200mg/kg)治疗后,与模型组相比,芝麻素组(200mg/kg)组小鼠曲细精管内圆形精子细胞数量增多,但精子细胞的晚期发育逐渐恢复,延长期精子细胞数量增加(见图5)。
(六)Western blot检测小鼠睾丸组织H2A、H2B、RNF8蛋白的表达
6.1实验方法:
使用凯基全蛋白提取试剂盒提取总蛋白,BCA蛋白含量检测试剂盒测定样本总蛋白质浓度并标定蛋白统一浓度。SDS-聚丙烯酰胺凝胶电泳,用将硝酸纤维素膜(PVDF膜)进行湿法转膜。转膜结束后将膜置入5%脱脂奶粉封闭液中封闭2h。封闭结束孵育5%脱脂奶粉稀释的一抗H2A(1:1000)、H2B(1:10000)、RNF8(1:800),4℃过夜,洗膜孵育二抗2h。用PBST洗膜3次,每次10min。滴加蛋白化学发光剂(ECL)进行曝光。采用Image J图像分析软件计算目标蛋白的灰度值,并利用相对应的内参灰度值校正误差。
6.2实验结果:
如图6所示,与正常对照组比较,模型组睾丸中H2A、H2B蛋白表达明显增多(p<0.05),RNF8蛋白表达明显减少(p<0.001);芝麻素(200mg/kg)组小鼠睾丸组织H2A、H2B蛋白表达与模型组比较明显减少(p<0.05),RNF8蛋白表达明显增多(p<0.05);提示芝麻素的保护作用可能通过H2A、H2B、RNF8蛋白的表达与活化,对生精功能障碍小鼠产生保护作用。
(七)睾丸组织ub-H2A及ub-H2B蛋白的表达
7.1实验方法:
采用免疫荧光检测睾丸组织ub-H2A及ub-H2B蛋白的表达。取小鼠睾丸石蜡切片,进行脱蜡处理,用二甲苯浸洗切片3次/5min;再用无水乙醇浸洗切片2次/10min;接着用95%乙醇浸洗切片2次/10min,在蒸馏水中润湿2次/5min。注意在此过程中要避免组织切片干燥。
抗原暴露。室温下,将切片泡在1mM EDTA(配置1L时,称取0.372g EDTA(C10H14N2O8Na2·2H2O)溶解在1L蒸馏水中。调整pH为6.0。)。用微波炉加热泡在EDTA中的玻片使之接近沸腾,保持95-99℃约10分钟。取出玻片,放在实验台上自然冷却30分钟。在蒸馏水中润洗3次/5min。在PBS中润洗3次/5min。
进行免疫染色。将样品在37℃恒温箱中用山羊血清封闭液中封闭60分钟。封闭结束前,按说明书的指示用PBS缓冲液稀释一抗(ub-H2A:1:500,ub-H2B:1:1600)。甩去封闭液,加入稀释的一抗。在4℃孵育过夜。甩去一抗,用PBS润洗5次/5min。7.把荧光素标记的二抗(1:50)稀释在PBS中的,将样品与稀释抗体在37℃恒温箱中避光孵育1小时。用PBS润洗切片5次/5min。涂上含DAPI封片剂后盖上玻片。立即在荧光显微镜下用相应波长激发光观察样品。
7.2实验结果:
由图7A可以看出,在对照组中可以观察到ub-H2A及ub-H2B表达较强并高表达于延长期精子细胞,在模型组中观察到ub-H2A及ub-H2B表达弱。给予芝麻素(200mg/kg)治疗后,观察到睾丸内ub-H2A及ub-H2B表达增强。根据荧光密度统计图(图7B)可以看出,与正常组相比较,模型组ub-H2A及ub-H2B荧光密度显著下降;与模型组相比较,给予芝麻素(200mg/kg)治疗后,ub-H2A及ub-H2B荧光密度显著上升,表明给予芝麻素治疗后可以上调ub-H2A及ub-H2B的表达水平。
Claims (10)
2.根据权利要求1所述的用途,其中所述药物中芝麻素为唯一活性成分。
3.根据权利要求1或2所述的用途,其中所述生精功能障碍为生精功能损伤。
4.根据权利要求1或2所述的用途,其中所述生精功能障碍为精子数量和活力低下并精子畸形。
5.根据权利要求1-4任一项所述的用途,其中所述药物为注射或者口服剂型。
6.根据权利要求5所述的用途,其中所述药物为口服剂型。
7.增强对象生精功能和精子活力的非治疗方法,包括对对象施用芝麻素。
8.根据权利要求7所述的方法,其中芝麻素单次应用剂量为50-100mg/kg。
9.根据权利要求7所述的方法,其中芝麻素单次应用剂量为100-200mg/kg。
10.根据权利要求9所述的方法,其中芝麻素单次应用剂量为200mg/kg。
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