CN116997336A - 含有非典型pkc激活剂的用于控糖的组合物 - Google Patents
含有非典型pkc激活剂的用于控糖的组合物 Download PDFInfo
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- CN116997336A CN116997336A CN202280017050.3A CN202280017050A CN116997336A CN 116997336 A CN116997336 A CN 116997336A CN 202280017050 A CN202280017050 A CN 202280017050A CN 116997336 A CN116997336 A CN 116997336A
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- diabetic
- pkc
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- glucose
- prostratin
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及用于控糖的组合物,其用于调节小肠中代谢的葡萄糖的量。根据本发明,该组合物可以通过改善小肠中的葡萄糖代谢并促进血糖通过粪便排泄来降低血液中的葡萄糖浓度,从而可以有效地预防、减轻或治疗代谢性疾病。
Description
技术领域
本发明涉及用于调节葡萄糖的组合物,其调节在小肠中代谢的葡萄糖的量,并且更具体地,涉及用于调节葡萄糖的组合物,所述组合物含有非典型PKC激活剂作为活性成分,以及用于预防或治疗代谢性疾病的含有非典型PKC激活剂作为活性成分的药物组合物。
背景技术
糖尿病是由多种诱发因素引起的并且以持续高血糖水平(高血糖症)为特征的慢性代谢性疾病。细胞需要胰岛素来利用血糖,并且胰岛素由胰腺中的胰岛分泌并具有降低餐后血糖水平的作用。胰岛素是由胰腺β细胞分泌的激素,并且调节碳水化合物和脂肪代谢。胰岛素还刺激靶细胞(肝脏、肌肉和脂肪细胞等)从血液中吸收和储存葡萄糖。在正常人中,胰岛素的作用是将体内的血糖转化成能量并降低血糖水平。相反地,在糖尿病患者中,胰岛素分泌不正常,或者即使胰岛素分泌正常,胰岛素受体出现问题也可能导致胰岛素失去控制血糖的能力,从而导致血糖水平升高。糖尿病大致可分为两种类型。在1型糖尿病或胰岛素依赖型糖尿病(IDDM)中,患者产生很少或不产生胰岛素(调节葡萄糖利用的激素)。胰腺β细胞被自身免疫机制破坏,导致胰岛素缺乏。因此,血液中的葡萄糖不能被吸收至细胞内,导致糖尿病。相反地,在2型糖尿病或非胰岛素依赖型糖尿病(NIDDM)中,体内仍产生胰岛素。这就是获得性糖尿病,占所有糖尿病的超过80%。即使胰腺β细胞分泌足够量的胰岛素,它也不被吸收至细胞内,从而导致高血糖状态。2型糖尿病患者对胰岛素的作用是抵抗的,这刺激主要胰岛素敏感组织(肌肉、肝脏和脂肪组织)中的葡萄糖和脂质代谢。这种对胰岛素缺乏反应性导致胰岛素介导的肌肉中葡萄糖摄取、氧化和储存的激活不充分,以及胰岛素介导的对脂肪组织中的脂解和肝脏中的葡萄糖产生和分泌的抑制不充分。
糖尿病影响全球超过1.5亿人,并且糖尿病患者的数量近年来迅速增加。根据世界卫生组织提供的数据,预计到2030年,糖尿病患者将超过3.6亿。此外,即使在韩国,随着生活方式的改变以及以肉类为主的饮食习惯和缺乏运动的增加,糖尿病患者的发病率也在迅速增加,并且糖尿病的发病年龄也在下降。确诊糖尿病后,为了控制血糖水平而限制饮食,生活质量下降,并且引发各种并发症的风险。因此,将血糖水平控制在正常范围内的技术的开发仍在继续。例如,韩国专利号10-1983982公开了使用desPro36激动肽-4(1-39)-Lys6-NH2和格列酮治疗糖尿病的技术,以及韩国专利申请公开号10-2006-0020548公开了使用银耳(Tremella fuciformis)的粗多糖提取物治疗糖尿病的技术。然而,这些相关技术仅旨在将血液中存在的高浓度葡萄糖转移至体内的其他部位,并且存在不能将葡萄糖释放出体外的问题。
因此,本发明人进行了广泛的尝试来筛选诱导小肠中葡萄糖吸收增加的药物,并且因此已筛选出prostratin和巨大戟醇-3-当归酸酯(ingenol-3-angelate)(它们是PKC激活剂)作为具有葡萄糖调节能力的化合物,并且已发现给药prostratin的糖尿病模型小鼠的小肠中葡萄糖吸收增加以及葡萄糖通过粪便的排泄增加,从而完成本发明。
发明内容
本发明的目的是为了提供用于调节葡萄糖的组合物,所述组合物诱导小肠中的葡萄糖吸收增加。
本发明的另一目的是为了提供用于预防或治疗代谢性疾病的组合物,所述组合物含有调节葡萄糖的化合物作为活性成分。
本发明的又一目的是为了提供用于预防或减轻代谢性疾病的功能食品组合物,所述组合物含有调节葡萄糖的化合物作为活性成分。
然而,本发明欲实现的目的不限于上述目的,并且本领域技术人员根据以下描述将清楚地理解本文中未提及的目的。
为了实现上述目的,本发明提供了用于调节葡萄糖的组合物,所述组合物含有非典型PKC激活剂作为活性成分。
本发明还提供了用于预防或治疗代谢性疾病的组合物,所述组合物含有非典型PKC激活剂作为活性成分。
本发明还提供了用于预防或治疗代谢性疾病的方法,所述方法包括给药非典型PKC激活剂的步骤。
本发明还提供了非典型PKC激活剂用于预防或治疗代谢性疾病的用途。
本发明还提供了非典型PKC激活剂在生产用于预防或治疗代谢性疾病的药物中的用途。
本发明还提供了用于预防或减轻代谢性疾病的功能食品组合物,所述组合物含有非典型PKC激活剂作为活性成分。
附图说明
图1显示了PKC亚型的分类。PKC大致分为传统或经典、新型和非典型亚家族,并且图1显示了每个亚家族的基因名称、蛋白名称、结构域和配体。
图2显示了用prostratin和巨大戟醇-3-当归酸酯各自处理IEC-6细胞和IEC-18细胞后,通过蛋白质印迹分析细胞裂解物中蛋白变化的结果。
图3显示了用prostratin和巨大戟醇-3-当归酸酯各自处理IEC-6和IEC-18细胞后,检查2-DG摄取的结果。
图4显示了用prostratin和巨大戟醇-3-当归酸酯各自处理IEC-18细胞后,证实PKCζ和GLUT1的活性增加的结果。
图5A显示了分析在PKCζ转染的IEC-6细胞和IEC-18细胞中PKCζ、p-GLUT1和GLUT1表达的结果,图5B显示了分析在PKCζ转染的HEK293细胞中PKCζ、p-GLUT1和GLUT1表达的结果,以及图5C显示了分析在PKCζ转染的IEC-18细胞中2-DG摄取的结果。
图6显示了用PKCζ抑制剂(ZIP)处理prostratin处理的或巨大戟醇处理的EC-6细胞和IEC-18细胞后,测量葡萄糖摄取的结果。
图7显示了用PKCα、PKCδ、PKCζ和PKCι各自的siRNA转染IEC-6细胞系,然后用prostratin处理每个细胞系后,通过蛋白质印迹分析p-GLUT1和GLUT1表达变化的结果。
图8显示了用PKCα、PKCδ、PKCζ和PKCι各自的siRNA转染IEC-6细胞系,然后用prostratin和巨大戟醇(ingenol)各自处理每个细胞系后,检查2-DG摄取变化的结果。
图9A显示了向C57BL6小鼠单次皮下注射巨大戟醇或prostratin并向小鼠腹腔给药2g/kg的葡萄糖后,进行IP葡萄糖耐量试验的结果,并且图9B显示了向C57BL6小鼠给药prostratin2周并腹腔给药2g/kg葡萄糖后,进行IP葡萄糖耐量试验的结果。
图10显示了每天向糖尿病模型小鼠各自腹腔注射prostratin(0.5mg/kg)和巨大戟醇(1μg/kg)40天后,进行体重测量(左)和腹腔葡萄糖耐量试验(右)的结果。
图11A显示了从给药prostratin1个月的糖尿病模型小鼠收集的肠中18FDG的射线照相结果,图11B显示了测量收集的肠的粪便样品中18FDG的量的结果,以及图11C显示了通过γ计数仪测量小肠的十二指肠、空肠和回肠中的18FDG吸收量的结果。
图12显示了在从给药prostratin1个月的糖尿病模型小鼠中收集小肠后,用针对PKCζ的抗体对十二指肠、空肠和回肠进行免疫组织化学染色的结果。左侧显示了光学显微镜在100×放大倍率下的成像结果,以及右侧显示了在400×放大倍率下的成像结果。
图13显示了从给药prostratin1个月的糖尿病模型小鼠中收集的小肠的空肠内腔的顶端膜部分的电子显微镜图像。
具体实施方式
除非另有定义,否则本说明书中使用的所有技术和科学术语具有与本公开所属领域的技术人员通常理解的相同含义。通常,本说明书中使用的命名法是本领域公知的且常用的。
在本发明中,进行基于AI的药物筛选,以选择与Hb-EGF(诱导小肠中的葡萄糖吸收增加的EGFR配体)表现出相似或更佳效果的药物,结果,选择prostratin和巨大戟醇-3-当归酸酯(以下简称“巨大戟醇”)作为候选药物。prostratin和巨大戟醇-3-当归酸酯均作为蛋白激酶C(PKC)的激活剂。
在本发明的一种实施方式中,证实了在用prostratin和巨大戟醇处理的肠上皮细胞系(IEC-6和IEC-18)中,p-GLUT1和GLUT1(细胞膜中参与葡萄糖摄取的蛋白)的表达增加,并且2-DG(葡萄糖类似物)的摄取也增加。
在本发明的另一种实施方式中,证实了当将prostratin给药至糖尿病模型小鼠(db/db小鼠)时,腹腔葡萄糖耐量增加,导致给药prostratin的小鼠组的葡萄糖代谢改善和体重显著减轻。
因此,在一方面,本发明涉及用于调节葡萄糖的组合物,所述组合物含有非典型PKC激活剂作为活性成分。
在本发明中,非典型PKC可以是PKC zeta(PKCζ)或PKC iota(PKCι)。
PKC家族分为三个亚家族:传统或经典亚型(PKCα、PKCβ和PKCγ)、新型亚型(PKCδ、PKCε、PKCη和PKCθ)和非典型亚型(PKCζ和PKCλ/ι)。激活每种亚型PKC的配体根据亚家族而异。经典亚型由Ca2+、DAG和PIP2激活,并且新型亚型由DAG和脂质激活。非典型PKC没有C2和C1结构域,因此具有不被Ca2+和DAG激活的特性。此外,已知非典型PKC与蛋白诸如极性调节因子(PAR6)相互作用,因为它们含有Phox和Bem 1(PB1)结构域(图1)。
在本发明的一种实施方式中,用传统PKC(PKCα)、新型PKC(PKCδ)和非典型PKC(PKCζ和PKCι)各自的siRNA转染IEC-6细胞系,并在48小时后用prostratin(1μM)处理,并提取总蛋白和进行蛋白质印迹。结果,证实了在阴性对照组(siNeg)中prostratin增加GLUT1(p-GLUT1)的表达,在用PKCζ和PKCι(它们是非典型PKC)各自的siRNA处理的细胞组(即使细胞组用prostratin处理)中未增加(图7)。因此,证实了PKCζ和PKCι在由prostratin增加GLUT1(p-GLUT1)活性的机制中发挥重要作用。
在本发明中,调节葡萄糖可以包括调节小肠中的葡萄糖吸收或葡萄糖排泄。
在本发明的一种实施方式中,从给药prostratin(0.5mg/kg)1个月的糖尿病模型小鼠(db/db小鼠)收集的肠的射线照相结果证实,用prostratin处理的db/db小鼠的小肠中葡萄糖吸收显著高于负载体组。另外,证实了给药prostratin的小鼠的粪便样品中葡萄糖排泄较高(图11)。
在本发明中,非典型PKC激活剂可以选自由prostratin或其盐、prostratin衍生物或其盐、巨大戟醇-3-当归酸酯或其盐以及巨大戟醇-3-当归酸酯衍生物或其盐组成的组。
“prostratin”是具有以下式1结构的化合物,其是蛋白激酶C的调节剂,并且已知对癌症和其他疾病诸如阿尔茨海默病表现出有前景的治疗潜力,并且据报道口服给药prostratin抑制人胰腺肿瘤(Wang,Man-Tzu et al.,Cell.16:1237,2015)。
[式1]
本发明中使用的“巨大戟醇-3-当归酸酯”具有以下式2的结构,也称为“巨大戟醇甲基丁烯酸酯”,并且可以以商品名“Picato”商购获得。这是在南欧大戟(Euphorbiapeplus)植物的汁液中发现的物质并且已知诱导细胞死亡。该药物的凝胶制剂已获得美国食品药品监督管理局(FDA)和欧洲药品管理局(EMA)批准用于外用治疗光化性角化病。
[式2]
在本发明中,用于调节葡萄糖的组合物能够诱导血糖摄取到小肠,优选小肠的十二指肠、空肠和回肠中的细胞中,并通过粪便排泄血糖。
在本发明中,“回肠”是小肠的远端部分并且位于空肠和大肠之间。小肠是位于胃和大肠之间的消化器官,并且在解剖学上由三部分组成:十二指肠、空肠和回肠。正常地,超过5岁的人的小肠长约7m,其比大肠长4至5倍,但其厚度为2.5至3cm,这比大肠(约7.6cm)薄得多。十二指肠长约25至30cm,以及空肠长约2.5m,空肠是小肠的中部部分。回肠长约3.6m并且在回盲瓣处与结肠相连。回盲瓣将消化的物质传递至大肠中并防止回流至小肠中。由于消化,营养物质通过小肠绒毛扩散并递送至血液中。小肠内的黏膜有许多皱纹,并且在其表面上有绒毛。通常,大部分来自胃的食糜在十二指肠和空肠中消化和吸收,它们对应于小肠的起始和中部。相比之下,已知回肠的消化和吸收相对较低(糖尿病管理交互式病例研究(Diabetes Management Interactive Case Study),2016)。本发明的组合物具有增加十二指肠、空肠和回肠中葡萄糖吸收的作用。
此外,根据本发明的用于调节葡萄糖的组合物不仅具有促进血糖通过粪便排泄的作用,而且具有改善葡萄糖代谢的作用,因此可以用于有效预防、减轻或治疗代谢性疾病。
因此,在另一方面,本发明涉及用于预防或治疗代谢性疾病的组合物,所述组合物含有非典型PKC激活剂作为活性成分。
在本发明中,非典型PKC可以是PKC zeta(PKCζ)或PKC iota(PKCι)。
在本发明中,调节葡萄糖可以包括调节小肠中的葡萄糖吸收和葡萄糖排泄。
在本发明中,非典型PKC激活剂可以选自由prostratin或其盐、prostratin衍生物或其盐、巨大戟醇-3-当归酸酯或其盐以及巨大戟醇-3-当归酸酯衍生物或其盐组成的组。
在本发明中,“代谢性疾病”是指由于各种原因诸如能量摄入过量或激素失调导致体内能量代谢异常,导致脂肪过度合成或蓄积而引起的疾病。具体地,代谢性疾病可以是肥胖、糖尿病性疾病、高血压、高脂血症、高甘油三酯血症、高胆固醇血症、脂肪肝或动脉硬化。
在本发明中,“糖尿病性疾病”的实例包括但不限于,糖尿病以及由急性高血糖症引起的并发症,诸如糖尿病酮症酸中毒、糖尿病性酸中毒、糖尿病性黄色瘤、糖尿病性肌萎缩、糖尿病性酮症、糖尿病性昏迷、糖尿病性胃疾病、糖尿病性坏疽、糖尿病性溃疡、糖尿病并发症、糖尿病性腹泻、糖尿病性微血管病变、糖尿病性子宫体硬化、糖尿病性心肌病、糖尿病性神经病变、糖尿病性肾病、糖尿病性大疱病、糖尿病性白内障、糖尿病性皮肤病、糖尿病性硬肿症、糖尿病视网膜病变、糖尿病脂质渐进性坏死或糖尿病性血液循环障碍。
在本发明中,“糖尿病”是由血液中葡萄糖浓度升高引起的疾病,并且糖尿病病程的增加导致因慢性并发症导致失明、终末期肾功能衰竭、神经系统疾病、下肢截肢、感染性疾病等的风险迅速增加。特别地,作为糖尿病并发症,脑血管疾病和心血管疾病所占比例最大。已报道约3/4的糖尿病死亡是由于糖尿病并发症造成的,并且糖尿病病程每持续10年,心血管并发症的死亡风险也增加24%。据报道,与正常人相比,糖尿病患者的冠状动脉疾病患病率是正常人的两倍,外周血管疾病患病率高出约三倍。已知糖尿病中动脉粥样硬化的多种原因,包括高血糖、脂质代谢异常、高胰岛素血症、高血压和凝血机制的改变。已知占糖尿病超过95%的2型(非胰岛素依赖型)糖尿病的发病机制是由两种原因造成的,即胰岛素分泌疾患和胰岛素抵抗的复合疾患。换言之,糖尿病是由于这种复合疾患表现出慢性高血糖症状的疾病。
在本发明中,“糖尿病酮症酸中毒”是糖尿病患者发生的最重要的急性代谢并发症,并且是由于水分和糖的丢失以及血液中酸性代谢物过度蓄积而引起的疾病,其由利用脂肪而不是糖来获取身体所需的能量而导致的。糖尿病酮症酸中毒由胰岛素抵抗或胰岛素缺乏导致。当胰岛素不足时,葡萄糖无法进入细胞中并在血液中蓄积。结果,细胞未接收葡萄糖,并且从而利用脂肪作为能量来源。脂肪代谢产生脂肪酸和甘油,其中甘油为细胞提供部分能量,但脂肪酸被代谢成酮,导致酸中毒。酸中毒增加钾从细胞进入血管中的运动,由于利尿作用导致高钾尿症,从而导致全身钾耗竭。
在本发明中,“肥胖”可以意指由能量失衡导致的体内脂肪过多的病症或疾病,并且是指由于各种原因导致体内能量代谢不良而合成或蓄积过量脂肪的疾病。
在还一方面,本发明涉及用于预防或治疗代谢性疾病的方法,所述方法包括给药非典型PKC激活剂的步骤。
在又一方面,本发明涉及非典型PKC激活剂用于预防或治疗代谢性疾病的用途。
在还又一方面,本发明涉及非典型PKC激活剂在生产用于预防或治疗代谢性疾病的药物中的用途。
在其他方面,本发明涉及用于预防或减轻代谢性疾病的功能食品组合物,其含有非典型PKC激活剂作为活性成分。
在本发明中,非典型PKC可以是PKC zeta(PKCζ)或PKC iota(PKCι)。
在本发明中,调节葡萄糖可以包括调节小肠中的葡萄糖吸收和葡萄糖排泄。
在本发明中,非典型PKC激活剂可以选自由prostratin或其盐、prostratin衍生物或其盐、巨大戟醇-3-当归酸酯或其盐以及巨大戟醇-3-当归酸酯衍生物或其盐组成的组。
在本发明的一种实施方式中,“预防”可以包括但不限于,通过使用本发明的组合物能够阻断、抑制或延迟由代谢性疾病引起的症状的任何作用。
在本发明的一种实施方式中,“减轻”可以包括但不限于,通过使用本发明的组合物能够减轻或有益地改变由代谢性疾病引起的症状的任何作用。
在本发明的一种实施方式中,“治疗”是指为了缓解和/或减轻目标疾病而进行的一系列动作。关于本发明的目的,治疗包括通过显著增加肠中吸收的葡萄糖的量来改善葡萄糖代谢的作用。
在本发明的一种实施方式中,“药物组合物”是指为了特定目的而给药的组合物。为了本发明的目的,本发明的药物组合物用于预防或治疗糖尿病或糖尿病并发症,并且可以含有其中涉及的化合物和药学上可接受的载体、赋形剂或稀释剂。
此外,根据本发明的药物组合物含有基于组合物总重量的0.1至50wt%的量的本发明的活性成分。本发明的组合物中可以含有的载体、赋形剂和稀释剂的实例包括但不限于,乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。
在本发明的一种实施方式中,“给药”意指通过任何合适的方法将本发明的组合物引入患者体内,并且本发明的组合物可以通过任何通用途径给药,只要其能够达到靶组织。
组合物可以口服、腹腔内、静脉内、肌内、皮下、真皮内、鼻内、肺内、肠内、腔内、腹腔内或鞘内给药,但不限于此。在本发明中,有效量可以根据多种因素确定,包括疾病的类型,疾病的严重程度,组合物中含有的活性成分和其他成分的类型和含量,制剂的类型,患者的年龄、体重、一般健康状况、性别和饮食,给药时间,给药的途径,组合物的分泌速率,治疗周期和同时使用的药物。此外,本发明的药物组合物可以单独给药或与本领域已知的其他疗法诸如化疗和手术一起施用,用于治疗目标代谢性疾病。另外,本发明的药物组合物可以与旨在促进血糖降低的其他治疗(例如本领域熟知的那些治疗)联合施用。还可以使用其他标准递送方法,诸如基因枪法递送或离体治疗。
在本发明的一种实施方式中,“食品组合物”可以以多种方式用于预防或减轻本发明中的目标代谢性疾病。包含本发明的组合物作为活性成分的食品组合物可以制备成各种食品的形式,诸如饮料、口香糖、茶、维生素复合物、粉末、颗粒、片剂、胶囊、糖果点心、年糕、面包等。本发明的食品组合物即使出于预防目的而长期服用也可以安全地使用,因为它是由现有食品组分组成的改良食品,具有很小的毒性和副作用。当本发明的组合物被包含在食品组合物中时,其可以以基于总重量的0.1至100wt%的量添加。此处,当食品组合物以饮料的形式制备时,除了以指定比例含有食品组合物之外,没有特别限制。在这种情况下,食品组合物可以含有各种调味剂或天然碳水化合物作为常规饮料中的添加成分。天然碳水化合物的实例包括传统糖,诸如单糖(例如,葡萄糖等)、二糖(例如,蔗糖等)、多糖(例如,糊精、环糊精等)和糖醇诸如木糖醇、山梨糖醇、赤藓糖醇等。调味剂的实例包括天然调味剂(索马甜、甜菊提取物(例如,莱鲍迪甙A、甘草甜素等)和合成调味剂(糖精、阿斯巴甜)。此外,本发明的食品可以含有各种营养素、维生素、矿物质(电解质)、调味剂诸如合成调味剂和天然调味剂、着色剂、增量剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料中使用的碳化剂等。这些组分可以单独使用或组合使用。基于100重量份的本发明的组合物,这些添加剂的比例通常选自0.1至100重量份的范围,但不限于此。
[实施例]
下文中,将参考实施例更详细地描述本发明。这些实施例仅用于说明本发明,并且对于本领域技术人员而言显而易见的是,本发明的范围不应被解释为受这些实施例的限制。
实施例1:筛选增加小肠的回肠中葡萄糖吸收的药物
为了筛选与Hb-EGF(诱导回肠中葡萄糖吸收增加的EGFR配体)具有相似或更佳效果的药物,进行Arontier基于AI的药物筛选(Arontier,Korea)。
使用由Arontier Co.,Ltd.开发的REMEDY平台筛选与Hb-EGF相似的候选化合物(Lamb et al.,Science,313:1929~1935,2006;Subramanian et al.,Cell,171:1437~1452,2017)。
结果,筛选出作为非典型PKC激活剂的prostratin和巨大戟醇-3-当归酸酯。
实施例2:评价用prostratin和巨大戟醇-3-当归酸酯各自处理后小肠细胞系中GLUT转运蛋白表达水平
对于肠上皮细胞IEC-6细胞(ATCC CRL-1592)和IEC-18细胞(ATCC CRL-1589)的培养,使用补充有10%胎牛血清(FBS)和青霉素-链霉素的Dulbecco改良Eagle培养基(DMEM)在37℃下在含有10% CO2和90%空气的潮湿气氛中培养细胞,每3至4天传代培养。在实验中,将IEC-6细胞和IEC-18细胞分别以2×105个细胞/培养皿的密度接种在6孔培养皿中。6天后,当细胞密度达到1.5×105个细胞/cm2时,收集培养物并使用。prostratin购自Sigma-Aldrich(货号P0077)并使用。巨大戟醇购自Sigma-Aldrich(货号SML1318)并使用。
用prostratin和巨大戟醇各自以30nM、100nM和300nM处理IEC-6细胞和IEC-18细胞30分钟,收集细胞裂解物,并通过蛋白质印迹分析其蛋白表达水平。
蛋白质印迹分析如下进行。
根据标准程序制备总细胞蛋白裂解物并进行蛋白质印迹分析。简言之,将细胞在冰上冷却,用冰冷的磷酸盐缓冲盐水洗涤2次,并在含有1mM苯甲基磺酰氟和1×蛋白酶抑制剂(Sigma-Aldrich)的缓冲液中裂解。使用Bradford测定试剂盒(Bio-Rad,Hercules,CA,USA)测量蛋白浓度。通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳分离细胞裂解物中的等量蛋白,并将其转移到膜上,然后与作为一抗的抗PKCα(Cell Signaling Technology,USA)、抗PKCδ(CCell Signaling Technology,USA)、抗PKCζ(Cell Signaling Technology,USA)、抗p-GLUT1(Abcam,GB)、抗GLUT1(Abcam,GB)和抗GLUT2(Novus Biological,USA)在4℃下孵育过夜。
用TBST(含有0.05%吐温20的Tris缓冲盐水)洗涤印迹3次,并且然后与辣根过氧化物酶(HRP)缀合的二抗在25℃下孵育1小时。作为二抗,使用驴抗兔IgG-HRP抗体(1:5000,Santa Cruz)和驴抗小鼠IgG-HRP抗体(1:5000,Santa Cruz)。使用SuperSignal West Pico化学发光底物(Thermo Fisher Scientific,MA,USA)检测免疫反应性。
结果,如图2中所示,证实了所有浓度(30、100和300nM)的巨大戟醇-3-当归酸酯和prostratin各自促进IEC-6和IEC-18细胞中的GLUT1磷酸化。证实了与蛋白定量标志物Na/KATP酶相比,prostratin和巨大戟醇-3-当归酸酯各自增加p-GLUT1和GLUT1(葡萄糖转运蛋白)的表达。
实施例3:评价用prostratin和巨大戟醇-3-当归酸酯各自处理后小肠细胞系中细胞内葡萄糖摄取
用prostratin和巨大戟醇(100nM)各自处理IEC-6细胞和IEC-18细胞10分钟,并且然后分析收集的细胞裂解物中2-脱氧-D-葡萄糖(2-DG)的摄取。
通过测量葡萄糖浓度,确定用prostratin和巨大戟醇各自处理时葡萄糖摄取(2-DG摄取)的变化。
在低浓度葡萄糖培养基和无血清DMEM中用prostratin和巨大戟醇各自处理24小时后测量葡萄糖的量。根据生产商的说明,使用葡萄糖测定试剂盒(Cayman Chemical)检测IEC-6和IEC-18细胞中的葡萄糖水平。使用Gen5分光光度计(BioTek,Winooski,VT,USA)测量吸光度信号。
结果,如图3中所示,证实了用prostratin和巨大戟醇各自处理增加细胞内葡萄糖(2-DG)摄取。
实施例4:证实prostratin和巨大戟醇-3-当归酸酯各自对小肠细胞系中PKC和GLUT1的激活
用prostratin(2μM)和巨大戟醇(0.1μM)各自处理IEC-18细胞0、15和60分钟后,通过蛋白质印迹分析PKC和GLUT1蛋白的表达。
结果,如图4中所示,证实了prostratin和巨大戟醇各自增加PKCζ和GLUT1的活性。此外,还证实prostratin比巨大戟醇更快速地将PKC和GLUT1移位至细胞膜。
实施例5:证实PKCζ诱导小肠细胞系中GLUT1介导的葡萄糖摄取
通过转染产生转染细胞系,使得PKCζ在IEC-6细胞、IEC-18细胞和HEK293(ATCCCRL-1573)细胞中瞬时过表达。
将大鼠PKCζ表达质粒(Korea Gene Bank)亚克隆至pCDNA3.1(Addgene,USA)中。在转染前一天,将IEC-6细胞和IEC-18细胞分别以每培养皿0.5×106个的密度接种在6孔培养皿中。根据生产商的说明,使用Polyjet转染试剂(SignaGen)用表达质粒转染细胞。转染的细胞在裂解前在37℃下培养48小时,并用巨大戟醇(0.1μM)处理。收集作为对照组的空载体感染的细胞组、PKCζ转染的细胞组、用巨大戟醇处理的野生型细胞组和用巨大戟醇处理的转染细胞组的细胞裂解物,并进行蛋白质印迹。
在蛋白质印迹中,Na/K ATP酶被用作膜内参(loading control)。
结果,如图5A和5B中所示,可以证实与空载体处理的阴性对照组相比,在巨大戟醇处理组中PKCζ被激活并移位至细胞膜,并且GLUT1移位。在PKCζ过表达细胞系中,即使在未用巨大戟醇处理的组中,p-GLUT1和GLUT1的表达也比阴性对照组更高。
此外,测量过表达PKCζ的转染IEC-18细胞系中的2-DG摄取。结果,如图5C中所示,证实了与对照组相比,在PKCζ过表达的IEC-18细胞系中2-DG摄取显著增加。
因此,证实了非典型PKC高表达的细胞系中2-DG摄取显著增加。
实施例6:证实通过PKCζ抑制剂处理抑制prostratin和巨大戟醇的葡萄糖摄取作用
将EC-6细胞和IEC-18细胞,其中非典型PKC通过prostratin(100nM)和巨大戟醇(100nM)处理被激活,用1μM的特异性抑制PKCζ的ZIP(假底物衍生的PKCζ抑制肽,R&Dsystem,USA)处理,以及然后测量其中的葡萄糖摄取。
结果,如图6中所示,证实了当用prostratin(100nM)和巨大戟醇(100nM)各自处理IEC-6或IEC-18细胞时,细胞中的6-磷酸葡萄糖增加,但当用prostratin或巨大戟醇与PKCζ抑制剂ZIP联合处理细胞时,细胞中6-磷酸葡萄糖的摄取减少至阴性对照组(NT)中6-磷酸葡萄糖的摄取。
实施例7:确定非典型PKC(ζ+ι)在prostratin介导的GLUT1激活中的作用
为了确定何种PKC亚型通过prostratin和巨大戟醇各自诱导GLUT1激活,使用RNAiMax(Invitrogen)用传统PKC(PKCα)、新型PKC(PKCδ)和非典型PKC(PKCζ和PKCι)各自的50nM siRNA转染IEC-6细胞系。48小时后,用prostratin(1μM)处理细胞,以及提取总蛋白并进行蛋白质印迹。
使用的siRNA序列如下所示。
PKCαsiRNA:GGGAUGUCAGAGAGCAUGCCUUCUU(SEQ ID NO:1)
PKCδsiRNA:CUCACAGUACUUCCUCUGU(SEQ ID NO:2)
PKCζsiRNA:GCUGAGAUCUGUAUCGCUCUCAACU(SEQ ID NO:3)
PKCιsiRNA:GGACAAUGUACUGCUAGACUCUGAA(SEQ ID NO:4)
结果,如图7中所示,证实了在阴性对照组(siNeg)中prostratin增加GLUT1(p-GLUT1)的表达,在用非典型PKC(PKCζ和PKCι)的siRNA处理的细胞组(即使细胞组用prostratin处理)中也增加。
因此,证实了PKCζ和PKCι在prostratin增加GLUT1(p-GLUT1)活性的机制中发挥重要作用。
实施例8:确定非典型PKC(ζ+ι)在prostratin和巨大戟醇各自增加葡萄糖摄取中的作用
为了确定何种PKC亚型通过prostratin和巨大戟醇各自处理可诱导IEC细胞中葡萄糖摄取(2DG摄取)增加,用传统PKC(PKCα)、新型PKC(PKCδ)和非典型PKC(PKCζ和PKCι)各自的siRNA转染IEC-6细胞系,如实施例7中所述。48小时后,用prostratin(1μM)或巨大戟醇(100nM)处理细胞,并分析其中的2DG摄取。
结果,如图8中所示,证实了阴性对照组(siNeg)中的2DG摄取通过用prostratin和巨大戟醇各自处理而增加,但非典型PKC(PKCζ和PKCι)敲低组中的2DG摄取即使通过prostratin和巨大戟醇各自的处理也没有增加。
因此,证实了PKCζ和PKCι在用prostratin和巨大戟醇各自处理诱导的葡萄糖摄取中发挥重要作用。
实施例9:评价小鼠动物模型中各自给药prostratin和巨大戟醇的葡萄糖代谢改善作用
9-1:证实单次给药改善葡萄糖代谢
将12只C57BL6小鼠禁食12小时后,通过进行腹腔葡萄糖测试来测量空腹血糖。此后,将巨大戟醇(4μg/kg)和prostratin(1mg/kg)分别皮下注射到巨大戟醇给药组(4只小鼠)和prostratin给药组中,并且将每kg的小鼠2g的葡萄糖(2g/kg葡萄糖)在生理盐水中稀释并腹腔给药至每只小鼠。此后,在15分钟、30分钟、60分钟、90分钟和120分钟时进行IP葡萄糖耐量试验。
结果,如图9A中所示,证实了在30分钟和60分钟时,与阴性对照组(负载体)相比,prostratin给药组中的葡萄糖代谢显著改善,并且与阴性对照组相比,巨大戟醇给药组中的葡萄糖代谢也得到改善。
9-2:证实给药2周后葡萄糖代谢的改善
使用渗透泵将prostratin以0mg/kg、0.5mg/kg和1mg/kg的浓度给药至C57BL6小鼠2周,随后禁食12小时。然后,将每kg小鼠2g葡萄糖(2g/kg葡萄糖)在生理盐水中稀释,并腹腔给药至每只小鼠。此后,在15分钟、30分钟、60分钟、90分钟和120分钟时进行IP葡萄糖耐量试验。
结果,如图9B中所示,证实了2小时内葡萄糖变化曲线下的所有面积值均得到改善。
实施例10:评价prostratin和巨大戟醇各自给药对糖尿病模型小鼠的体重和葡萄糖代谢改善的作用
每天将prostratin(0.5mg/kg)和巨大戟醇(1μg/kg)各自腹腔内注射至db/db小鼠(Jackson Laboratory)持续40天,db/db小鼠由于缺乏瘦素受体而被称为代表性糖尿病模型,并且然后测量每只小鼠的体重。
结果,如图10中所示,证实了在将巨大戟醇的浓度增加至第28天时的2μg/kg后,第30天的体重减轻显示出统计学显著性。在给药0.5mg/kgprostratin的组中,给药第11天当日和之后的体重减轻与对照组(负载体组)相比显示出统计学显著性。
在药物给药后的第17天,进行腹腔葡萄糖耐量试验(IPGTT)。图10显示了在IPGTT前禁食12小时后各自注射prostratin和巨大戟醇后15分钟进行2g/kg IPGTT的结果。在给药1μg/kg巨大戟醇的组中,在葡萄糖给药后240分钟时出现血糖改善作用。证实了在给药prostratin(0.5mg/kg)的组中,在30至240分钟的整个时间段内,葡萄糖的改善优于对照组(负载体组)。
实施例11:评价prostratin给药对糖尿病模型小鼠中葡萄糖吸收和排泄的改善作用
收集已给药0.5mg/kg prostratin1个月的db/db小鼠(Jackson Laboratory)的肠,并对其进行18FDG(氟脱氧葡萄糖,DuChemBio)的射线照相。18FDG购自DuChemBio,并通过尾静脉注射200μCi至每只小鼠。
此外,测量通过用5mL的PBS洗涤收集的小肠获得的粪便样品中的18FDG,并用γ计数仪测量小肠的十二指肠、空肠和回肠的18FDG摄取。
结果,如图11A中所示,从射线照相证实,用prostratin处理的db/db小鼠的小肠中的葡萄糖吸收显著高于对照组(负载体组)的小肠中的葡萄糖吸收。
另外,如图11B中所示,作为检查粪便样品中的葡萄糖排泄的结果,证实了来自给药prostratin的小鼠的粪便流体中的葡萄糖排泄较高。另外,如图11C中所示,小肠的所有十二指肠、空肠和回肠中的葡萄糖吸收均增加超过一倍。
实施例12:评价prostratin给药对糖尿病模型小鼠的空肠和回肠中非典型PKC向膜移位的作用
向db/db小鼠给药prostratin(0.5mg/kg)或负载体1个月后,收集小肠,并用福尔马林固定十二指肠、空肠和回肠,用抗PKCζ抗体(Abcam,USA)进行免疫组织化学染色,并用光学显微镜在100×和400×放大倍数下成像。
结果,如图12中所示,可以证实,在十二指肠中,prostratin给药组和对照组(负载体)之间没有显著差异,而在空肠和回肠中,prostratin给药组中PKCζ的位置倾向于从细胞质集中在内腔的顶端膜中。
实施例13:prostratin给药的糖尿病模型小鼠的空肠内腔的电镜观察
向db/db小鼠给药prostratin(0.5mg/kg)或负载体1个月后,收集小肠,并用电子显微镜观察空肠内腔的顶端膜部分。
结果,如图13中所示,证实了prostratin给药组的空肠微绒毛附近的糖萼比对照组(负载体)分泌更多,并且prostratin给药组的小肠细胞中线粒体的数量增加,表明细胞内代谢活跃。
工业实用性
根据本发明,可能改善小肠中的葡萄糖代谢并促进血糖排泄到粪便中,因此降低血糖浓度,从而预防、减轻或治疗代谢性疾病。
尽管已经参考特定特征详细描述了本发明,但是对于本领域技术人员而言显而易见的是,该描述仅是其优选的实施方式,并且不限制本发明的范围。因此,本发明的实质范围将由所附权利要求及其等同方案来限定。
序列表自由文本
附电子文件。
序列表
<110> 延世大学校 产学协力团
阿伦提尔公司
<120> 含有非典型PKC激活剂的用于控糖的组合物
<130> P20-B205
<160> 4
<170> KoPatentIn 3.0
<210> 1
<211> 25
<212> RNA
<213> 人工序列
<220>
<223> PKC siRNA
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<212> RNA
<213> 人工序列
<220>
<223> PKC siRNA
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cucacaguac uuccucugu 19
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<212> RNA
<213> 人工序列
<220>
<223> PKC siRNA
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gcugagaucu guaucgcucu caacu 25
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<212> RNA
<213> 人工序列
<220>
<223> PKC siRNA
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ggacaaugua cugcuagacu cugaa 25
Claims (14)
1.一种用于调节葡萄糖的组合物,所述组合物包含非典型PKC激活剂作为活性成分。
2.根据权利要求1所述的组合物,其中,所述PKC是PKC zeta(PKCζ)或PKC iota(PKCι)。
3.根据权利要求1所述的组合物,其中,所述调节葡萄糖包括调节小肠中的葡萄糖吸收或葡萄糖排泄。
4.根据权利要求1所述的组合物,其中所述非典型PKC激活剂选自由prostratin或其盐、prostratin衍生物或其盐、巨大戟醇-3-当归酸酯或其盐以及巨大戟醇-3-当归酸酯衍生物或其盐组成的组。
5.一种用于预防或治疗代谢性疾病的组合物,所述组合物包含非典型PKC激活剂作为活性成分。
6.根据权利要求5所述的组合物,其中,所述PKC是PKC zeta(PKCζ)或PKC iota(PKCι)。
7.根据权利要求5所述的组合物,所述组合物调节小肠中的葡萄糖吸收。
8.根据权利要求5所述的组合物,其中,所述非典型PKC激活剂选自由prostratin或其盐、prostratin衍生物或其盐、巨大戟醇-3-当归酸酯或其盐以及巨大戟醇-3-当归酸酯衍生物或其盐组成的组。
9.根据权利要求5所述的组合物,所述组合物调节小肠中的葡萄糖吸收或葡萄糖排泄。
10.根据权利要求5所述的组合物,其中,所述代谢性疾病是糖尿病性疾病、肥胖症、高血压、高脂血症、高甘油三酯血症、高胆固醇血症、动脉硬化或脂肪肝疾病。
11.根据权利要求10所述的组合物,其中,所述糖尿病性疾病选自由以下组成的组:糖尿病、糖尿病酮症酸中毒、糖尿病性酸中毒、糖尿病性黄色瘤、糖尿病性肌萎缩、糖尿病性酮症、糖尿病性昏迷、糖尿病性胃疾病、糖尿病性坏疽、糖尿病性溃疡、糖尿病并发症、糖尿病性腹泻、糖尿病性微血管病变、糖尿病性子宫体硬化、糖尿病性心肌病、糖尿病性神经病变、糖尿病性肾病、糖尿病性大疱病、糖尿病性白内障、糖尿病性皮肤病、糖尿病性硬肿症、糖尿病性视网膜病变、糖尿病脂质渐进性坏死和糖尿病性血液循环障碍。
12.一种用于预防或减轻代谢性疾病的功能食品组合物,所述功能食品组合物包含非典型PKC激活剂作为活性成分。
13.根据权利要求1所述的功能食品组合物,所述功能食品组合物调节小肠中的糖吸收或葡萄糖排泄。
14.根据权利要求13所述的功能食品组合物,其中所述非典型PKC激活剂选自由prostratin或其盐、prostratin衍生物或其盐、巨大戟醇-3-当归酸酯或其盐以及巨大戟醇-3-当归酸酯衍生物或其盐组成的组。
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