CN118217286A - 1-mh在减肥、降血脂、脂肪肝和糖尿病治疗中的应用 - Google Patents
1-mh在减肥、降血脂、脂肪肝和糖尿病治疗中的应用 Download PDFInfo
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- CN118217286A CN118217286A CN202410342865.XA CN202410342865A CN118217286A CN 118217286 A CN118217286 A CN 118217286A CN 202410342865 A CN202410342865 A CN 202410342865A CN 118217286 A CN118217286 A CN 118217286A
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Abstract
本发明公开了1‑甲基海因(1‑Methylhydantoin/1‑MH)在制备减肥、降血脂、脂肪肝和糖尿病治疗药物中的应用。本发明中的实验证明1‑甲基海因在无毒浓度下表现出了显著的减轻体重、降血脂、减轻脂肪肝和降血糖活性。因此，1‑甲基海因具有制备减肥、降血脂、脂肪肝和糖尿病治疗药物的应用前景。
Description
本专利申请是发明名称为“1-MH在减肥、降血脂、脂肪肝和糖尿病治疗中的应用”的中国专利202311309706.1的分案申请，这里将其全文引用结合于此。
技术领域
本发明属于生物医药领域，具体涉及1-甲基海因(1-Methylhydantoin/1-MH)在制备减肥、降血脂、脂肪肝和糖尿病治疗药物或保健品中的应用。
背景技术
目前研究证明肥胖是多种疾病的危险因素，包括2型糖尿病、血脂异常、高血压、心脑血管疾病、非酒精性脂肪性肝病、骨关节炎等。大多数肥胖者并不能充分认识到其对人体的危害，能够长期坚持控制热量摄入和体育锻炼的肥胖者更少，如果仅靠生活方式干预，难以达到预期效果，通常需要其他手段辅助治疗。
高血脂是动脉粥样硬化性心血管疾病的重要危险因素，与急性心肌梗死、缺血性卒中等不良心脑血管事件息息相关。脂肪肝是指由于各种原因引起的肝细胞内脂肪堆积过多的病变,如果肝内脂肪蓄积太多,超过肝重量的5％或在组织学上肝细胞大泡性脂肪变性时,称为脂肪肝，其发病率逐年升高，发病率已超过30％，及时处置和治疗脂肪肝可以大大降低肝硬化和肝癌的发病率。糖尿病是一种常见慢性、全身性及代谢性疾病，主要是由于遗传因素和环境因素长期共同作用所导致的。随着人们生活方式和膳食结构的改变，糖尿病发病率逐年上升，严重危害人类健康，是全球面临的重要公共卫生问题之一。糖尿病主要分为胰岛素依赖型糖尿病(I型糖尿病，占总糖尿病患者10％以内)、非胰岛素依赖性糖尿病(II型糖尿病，占总糖尿病患者90％以上)以及其他特殊类型糖尿病。糖尿病多表现出明显的糖脂代谢异常，药物治疗及控制是目前糖尿病治疗的重点。二甲双胍是一类改善II型糖尿病的降糖药物，通过降低肝糖原异生作用，减少小肠吸收葡萄糖，并增加外周组织对葡萄糖的摄取和利用从而改善胰岛素的敏感性。可以预防高危人群的糖尿病并减少大多数糖尿病并发症，是目前临床上应用最为广泛的糖尿病治疗的小分子化合物。但二甲双胍具有较多的毒副作用，如：可抑制消化系统对碳水化合物的正常吸收，造成胃肠道紊乱，引起恶心、腹泻、胃痉挛、腹部肿胀、消化不良等症状；干扰对维生素B12和叶酸的吸收，长期会对神经系统造成一定程度的损伤，进而导致经常感觉头晕、手脚发麻，增加糖尿病患者的神经系统病变风险；较少情况下也会导致乳酸酸中毒的严重疾病，并伴有以下症状：头晕、严重嗜睡、肌肉疼痛、疲倦、发冷、皮肤发蓝/冷、呼吸急/困难、心跳缓慢/不规则、胃痛伴腹泻、恶心或呕吐，极为危险。长期服用则产生耐药性，需与其他药物联用来改善血糖状况。因此，急需开发出一种毒副作用小、治疗效果好的新型糖尿病治疗药物。
1-甲基海因(1-Methylhydantoin/1-MH)是从我国名贵中药材哈蟆油中提取分离的一种活性单体化学成分，其具有活性强、安全性高、良好的水脂分配系数和细胞通透性、口服吸收快、体内维持时间长、分子结构小、化学性质稳定、毒副作用小等特点。自1-甲基海因发现后，陆续有相关研究开展，研究发现其功能主要为止咳[吉林大学学报,2014,40(3):543-547；CN200510017262.X]、平喘[吉林大学学报(医学版),2014,40(03):543-548.]、抗炎[CN201510792749.9；Molecules 2019,24(13),2355；Molecules 2022,27(23),8481]、镇痛[刘镇华南农业大学,2022；吕俊瑾华南农业大学,2022]、治疗肺损伤[PLOS ONE 14(9):e0222521]、抗抑郁[Powder Diffraction,30(2),178-181；中国药理学通报,2013,29(08):1104-1108；]抗肿瘤[中国现代医生,2017,55(19):36-39；China Journal of ModernMedicine,2014,24(9):17-20.]等方面。目前，1-甲基海因在减肥、降血脂、脂肪肝和糖尿病治疗方面尚无相关报道。。
发明内容
申请人采用AML-12细胞和MIN-6细胞胰岛素抵抗模型以及高脂饮食喂养的糖尿病小鼠模型来研究1-甲基海因的治疗脂肪肝、糖尿病、降低血脂和减轻体重的作用。通过研究发现1-甲基海因能够明显促进Akt蛋白磷酸化，修复Akt通路，减轻糖脂毒性所诱导的胰岛素抵抗状态，明显降低糖尿病小鼠模型的血糖、血脂、体重和肝脏组织中脂肪的含量。
一方面，本申请提供了1-甲基海因或其衍生物在制备减肥或控制体重的药物或保健品中的应用。
另一方面，本申请提供了1-甲基海因或其衍生物在制备降血脂或治疗高脂血症的药物或保健品中的应用。
另一方面，本申请提供了1-甲基海因或其衍生物在制备治疗脂肪肝的药物或保健品中的应用。
另一个方面，本申请提供了1-甲基海因或其衍生物在制备治疗糖尿病或控制血糖的药物或保健品中的应用。
进一步地，所述应用中1-甲基海因或其衍生物为所述药物或保健品中的唯一有效成分。
进一步地，所述药物或保健品中还包括药学或保健品中可接受的辅料。
进一步地，所述药物为口服剂型。
进一步地，1-甲基海因具有如下(A)-(F)中至少一项的功能：(A)促进Akt蛋白磷酸化，修复Akt通路，减轻糖脂毒性所诱导的肝细胞损伤和胰岛β细胞中的胰岛素抵抗状态；(B)减轻糖尿病小鼠的葡萄糖耐量受损状态；(C)降低糖尿病小鼠的血糖；(D)降低肥胖小鼠的体重；(E)降低肥胖小鼠的血胆固醇和血脂；(F)降低肥胖小鼠的肝脏组织的肝细胞大泡性脂肪变性和脂肪含量。
另一方面，本申请提供了减肥或控制体重、降血脂或治疗高脂血症、或者治疗糖尿病或控制血糖的药物或保健品，所述药物或保健品中包含1-甲基海因。
进一步地，1-甲基海因或其衍生物为所述药物或保健品中的唯一有效成分。
本申请中1-甲基海因(1-Methylhydantoin/1-MH)，其CAS编号为616-04-6，分子式为C4H6N2O2，分子量为114.10。1-甲基海因、1-Methylhydantoin、1-MH等名称可以交换使用，表示相同的意义。该化合物具体结构如下式：
本领域技术人员可以根据来源、提取/合成工艺、质量要求的区别而使用不同纯度的1-甲基海因。也可以对其进行修饰以达到增强效果，提高稳定性等目的。
本申请的药物或保健品可选片剂、胶囊剂、颗粒剂、散剂、滴丸、微丸、栓剂、灌肠剂、凝胶剂、软膏剂、乳剂、膜剂、糊剂、贴剂、针剂、粉针剂等剂型。
除了上述剂型外，本领域技术人员可以根据药剂学领域的常识和治疗需要而选择其他剂型；并选用适合的辅料，辅料包括但不限于溶剂、助溶剂、渗透压调节剂、缓冲剂、稳定剂、分散剂、抗氧化剂、包衣、胶囊壳、丸芯、填充剂、粘合剂、缓释剂、矫味剂、防腐剂等。
1-甲基海因可以作为药物中的唯一治疗脂肪肝、抗糖尿病、降低体重和降血脂的成分，也可以与其他已知治疗脂肪肝、抗糖尿病、降低体重和降血脂活性成分制备入同一药物组合物中或者与其他治疗脂肪肝、抗糖尿病、降低体重和降血脂活性成分联合使用。
有益效果：
本发明首次发现了1-甲基海因在防治脂肪肝、糖尿病、减肥和降血脂方面的新用途，为制备治疗脂肪肝、糖尿病、减肥和降血脂药物及扩展1-甲基海因的用途提供了新选择，在制药行业具有重要的应用价值。
附图说明
图1为1-甲基海因的结构式。
图2显示1-甲基海因对胰岛素抵抗的影响的实验结果；(A)Western blot法检测肝细胞中Akt蛋白的表达；(B)Western blot法检测胰岛β细胞中Akt蛋白的表达。
图3显示1-甲基海因对T2DM小鼠空腹血糖的影响。与HFD组相比，*p<0.05，**p<0.01，***p<0.001。
图4显示1-甲基海因对T2DM小鼠葡萄糖耐量的影响。(A)各组小鼠灌胃给予1g/kg葡萄糖后，血糖在0-120min期间的变化情况；(B)曲线下面积。所有数据以平均值±标准差来表示。与HFD组相比，*p<0.05，**p<0.01，***p<0.001；与模型组相比，###p<0.001。
图5显示1-甲基海因对T2DM小鼠体重的影响。与HFD组相比，*p<0.05，**p<0.01，***p<0.001。
图6显示1-甲基海因对T2DM小鼠血脂的影响。(A)各组小鼠血甘油三酯的含量；(B)各组小鼠血总胆固醇的含量。
图7显示小鼠肝脏组织形态学分析。将小鼠的肝脏组织固定并进行HE染色(100×，200×)。
图8显示小鼠脂肪组织形态学分析。将小鼠的白色脂肪组织固定并进行HE染色(40×，100×)。
具体实施方式
实施例1：1-甲基海因对肝细胞和胰岛β细胞中胰岛素抵抗通路的影响
AKT通路受损被认为是胰岛素抵抗的一个重要原因，为了探索1-甲基海因对AKT通路的影响，本研究通过糖脂毒性诱导建立了肝细胞及胰岛β细胞的胰岛素抵抗模型，通过蛋白免疫印迹法测定了肝细胞及胰岛β细胞中p-AKT的表达量，来检测细胞胰岛素抵抗的程度。
1.细胞培养
(1)细胞培养液：MIN-6细胞使用含10％ FBS、100U/ml青霉素、0.1mg/ml链霉素和50μMβ-巯基乙醇的DMEM培养基培养；AML-12细胞使用含10％FBS、100U/ml青霉素和0.1mg/ml链霉素的DMEM培养基培养。
(2)细胞复苏：液氮罐中取出细胞，于37℃水浴锅中快速融化，将细胞悬液转移至含3-5ml培养液的离心管中混匀，1000rpm离心5min。离心后吸弃上清液，沉淀用培养液重悬后转移至100mm细胞培养皿中，置于37℃、5％ CO2的细胞培养箱中培养。
(3)细胞传代：当细胞融合度达80-90％时，吸弃培养液，用PBS缓冲液清洗，加入3ml 0.25％胰蛋白酶消化，当镜下观察到细胞形态变圆、间隙增大后立即加入3ml含10％FBS的DMEM培养液终止消化。轻轻吹打使细胞从培养皿脱落，收集细胞悬液至离心管，1000rpm离心5min。离心后吸弃上清，沉淀用培养液重悬后转移至新的培养皿，置于37℃、5％ CO2的细胞培养箱中培养。
(4)细胞冻存：当细胞融合度达80-90％时，常规消化细胞并离心，吸弃上清后，用1ml冻存液重悬沉淀并储存于-80℃冰箱，过夜后转移至液氮长期储存。
2.细胞分组及给药
(1)AML-12细胞胰岛素抵抗模型：细胞用完全培养基重悬，4×105细胞/孔加入六孔板，分为正常对照组、GP组(40mM Glu+400μM PA)、GP+低剂量给药组(1mM 1-甲基海因)、GP+中剂量给药组(2mM 1-甲基海因)、GP+高剂量给药组(4mM 1-甲基海因)、GP+二甲双胍对照组(2mM二甲双胍)。37℃5％CO2培养箱中培养12h贴壁后，更换为无血清培养基处理6h。给予各给药组细胞相应剂量的药物处理12h，弃培养基，给与GP及各给药组的细胞GP及相应剂量的药物处理12h。收板前加入500ng/ml胰岛素孵育15min，液氮速冻后保存至-80℃。
(2)MIN-6细胞胰岛素抵抗模型：细胞用完全培养基重悬，6×105细胞/孔加入六孔板，分为正常对照组、GP组(40mM Glu+400μM PA)、GP+低剂量给药组(1mM 1-甲基海因)、GP+中剂量给药组(2mM 1-甲基海因)、GP+高剂量给药组(4mM 1-甲基海因)、GP+二甲双胍对照组(2mM二甲双胍)。37℃5％CO2培养箱中培养12h贴壁后，更换为无血清培养基处理6h。给予各给药组细胞相应剂量的药物处理12h，之后给与GP及各给药组细胞GP处理12h。收板前加入500ng/ml胰岛素孵育15min，液氮速冻后保存至-80℃。
3.Western Blot实验
1)细胞蛋白提取
(1)细胞裂解：取处理后的细胞，吸弃6孔板中细胞上清，每孔加入60μl蛋白裂解液，使用细胞刮刀刮取贴壁细胞，并转移至1.5ml EP管中。
(2)超声破碎：将装有细胞悬液的EP管放至超声破碎仪中进行超声破碎。4℃、3s超声间隔、1000w超声功率条件下超声3min，使细胞充分裂解。
(3)将超声处理的样品于4℃、12000rpm、离心30min。吸取上清液至新的1.5ml EP管，此上清液即为细胞蛋白提取物，保存于-20℃备用。
(4)配置标准品：使用蛋白裂解缓冲液将10mg/ml BSA标准品倍比稀释为5、2.5、1.25、0.625、0.3125、0.15625、0.078125mg/ml，并设置空白对照。
(5)配置BCA工作液(A:B＝50:1)，缓慢吹打均匀。于酶标板中依次加入2μL标准品和待测样品，每孔加入98μL BCA工作液，37℃培养箱孵育30min。
(6)使用酶标仪检测562nm处各孔吸光度，根据标准蛋白浓度和吸光度值绘制标准曲线并计算样品浓度。
(7)向蛋白样品中加入适量5×SDS-PAGE上样缓冲液，100℃金属浴加热5min，立即进行电泳或置于-20℃冰箱保存。
2)Western blot法检测蛋白表达
(1)SDS-PAGE电泳：取40μg蛋白样品加入上样孔，电泳时浓缩胶采用80V恒压电泳，分离胶处调整电压为120V，待溴酚蓝到达分离胶底部时结束电泳。
(2)转膜：预先将PVDF膜在甲醇中浸泡激活15s，按照负极-滤纸-胶-PVDF膜-滤纸-正极的顺序摆放，放入转膜槽中，于250mA恒定电流下冰浴转膜1.5h。
(3)封闭：取出PVDF膜，使用封闭液室温封闭10min。
(4)抗体孵育：将PVDF膜置于配置好的一抗孵育液中，4℃摇床孵育过夜，TBST漂洗3次，10min/次。室温孵育二抗1h，TBST漂洗3次，10min/次。
(5)显影：配置ECL显影液(A:B＝1:1)，将PVDF膜放入显影液中孵育1min，随后将其放入曝光室中，选择适宜曝光时间并保存图片。
结果如图2所示，与对照组相比，两种细胞在GP处理12h后p-Akt的表达量显著降低，糖脂毒性导致的胰岛素抵抗状态下Akt通路受损。而1-甲基海因能明显促进Akt蛋白磷酸化，减轻糖脂毒性诱导的胰岛素抵抗状态。
实施例2：1-甲基海因降低糖尿病小鼠血糖和减轻糖尿病小鼠葡萄糖耐量受损的作用
为了验证1-甲基海因(1-Methylhydantoin/1-MH)对二型糖尿病(T2DM)的治疗作用，我们构建了HFD诱导的T2DM小鼠模型。将6-7周龄的C57BL/6J雄性小鼠分为正常饲料组(Chow，n＝7)和高脂饮食组(HFD，n＝33)，饲养6周。将成模后的小鼠随机分为模型对照组(HFD，n＝6)、低剂量药物干预组(HFD，50mg/kg 1-MH，n＝7)、中剂量药物干预组(HFD，100mg/kg 1-MH，n＝8)、高剂量药物干预组(HFD，150mg/kg 1-MH，n＝8)及二甲双胍药物干预组(HFD，200mg/kg，n＝4)，均为灌胃给药。每周监测小鼠体重、空腹9h血糖。给药3周后行口服葡萄糖耐量试验(Orak glucose tolerance test，OGTT)：小鼠过夜禁食，血糖仪检测0min血糖，接着予以葡萄糖溶液(1g/kg)灌胃，分别检测15、30、60、90和120min血糖。
与对照组相比，高脂饲喂的各组小鼠空腹血糖明显升高(p＜0.01)；与HFD组相比，1-甲基海因给药一周后，各给药组小鼠的空腹血糖无明显变化，给药两周后，中高剂量组小鼠的空腹血糖有明显下降(p＜0.05)；给药三周后各给药组小鼠的空腹血糖均显著降低(p＜0.01)(如图3所示)。葡萄糖耐量是指机体对血糖浓度的调节能力，其受损是糖尿病患者最重要的特征之一。第9周，各组小鼠禁食不禁水12h(从晚上9点禁食到第二天早上9点)后灌胃给予1g/kg葡萄糖，然后在相应的时间点测量血糖。由图4的(A)部分可以看出，各组小鼠的血糖均先呈上升的趋势，在15min达到最高点，随后逐渐下降并趋于平稳。如图4的(B)部分所示，与Chow组相比，HFD组的AUC值有明显的上升(p<0.001)，而与HFD组相比，各给药组的AUC则显著下降(p<0.05)，表明1-甲基海因能够减轻T2DM小鼠的葡萄糖耐量受损，改善T2DM小鼠的血糖稳态。
与模型组相比较，1-甲基海因给药组血糖明显降低，减轻T2DM小鼠的葡萄糖耐量受损状态，改善T2DM小鼠的血糖稳态，呈现出一定的浓度依赖性，表明1-甲基海因对糖尿病具有明显的治疗作用。
实施例3：1-甲基海因减轻肥胖小鼠体重以及降低肥胖小鼠血胆固醇和血脂及减轻脂肪肝病理改变的作用
上述各组小鼠每周监测小鼠体重、给药4周后结束试验，处理小鼠。取血清标本：小鼠禁食6h，自由饮水。水合氯醛麻醉后采用摘眼球取血法收集小鼠血标本。离心，收集上清，于-80℃保存；组织标本：分离小鼠各部位脂肪组织、肝脏及胰腺组织，称重并记录。少部分组织用多聚甲醛固定，后续用于切片处理，剩余组织保存于-80℃备用。
如图5所示，HFD饲喂6周后，与Chow组相比，HFD组小鼠的体重显著升高(p＜0.001)。而给予1-甲基海因(1-Methylhydantoin/1-MH)干预后各给药组小鼠的体重增长趋势减缓，特别是中剂量(p＜0.05)、高剂量组(p＜0.001)小鼠在给药三周后体重显著低于HFD组，表明1-甲基海因具有明显的减肥降低体重作用。
研究表明，高脂血症在胰岛素抵抗的发病机制中起着关键作用，过高的血脂会导致胰岛β细胞出现脂毒性，抑制β细胞分泌胰岛素，从而导致糖尿病的发生。为了探索1-甲基海因(1-Methylhydantoin/1-MH)对与糖尿病相关的高血脂是否有防治作用，我们检测了各组小鼠血清中的总胆固醇及甘油三酯的含量。图6的结果表明，与Chow组相比，HFD组小鼠血清的总胆固醇和甘油三酯含量均有所增加，其中总胆固醇有显著性差异(p<0.05)，而给予1-甲基海因后中剂量组小鼠的血总胆固醇显著降低(p<0.05)，甚至其含量与正常小鼠没有明显差别。说明1-甲基海因能减轻T2DM小鼠的血脂积累，特别是降低总胆固醇的含量。
摄入高脂饮食是引发肥胖的重要因素之一，会使肝脏及脂肪的组织形态发生明显变化，进而影响正常的能量代谢。如图7所示，HE染色显示Chow组肝细胞形态、中心静脉和门静脉区位置、肝细胞索和肝窦结构均正常，组织结构完整透明，无病理征象，而HFD组与之相比则结构紊乱，部分肝组织中出现炎性细胞浸润、空泡变性，提示脂质沉积较多，呈现典型脂肪肝的病理变化；当给予1-甲基海因后，各给药组肝细胞排列正常，细胞核结构清晰，炎症细胞减少，提示肝脏脂肪变性程度及损伤程度明显改善。如图8所示，与Chow组相比，HFD组小鼠的脂肪组织也发生明显变化，具体表现为脂肪细胞明显增生肥大。当给予1-甲基海因后，脂肪组织的空腔变小，脂肪细胞肥大增生的现象也明显减轻。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (3)
1.1-甲基海因在制备治疗脂肪肝的药物中的应用；所述应用中1-甲基海因为所述药物中的唯一有效成分，所述1-甲基海因的剂量为50mg-150mg/kg。
2.根据权利要求1所述的应用，所述药物中还包括药学可接受的辅料。
3.根据权利要求1所述的应用，所述药物为口服剂型。
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