CN114209709A - D-核糖在制备改善药物性心脏毒性药物或食品中的应用 - Google Patents
D-核糖在制备改善药物性心脏毒性药物或食品中的应用 Download PDFInfo
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Abstract
本发明揭示了一种D‑核糖在制备改善药物性心脏毒性的药物或食品中的应用，尤其在制备改善由抗癌药物阿霉素所致心脏毒性的药物中或食品中的应用。本发明揭示的D‑核糖的新应用，为新药和肿瘤营养制剂的研发提供了基础。
Description
技术领域
本发明属于医药技术领域，具体涉及一种D-核糖在制备改善药物性心脏毒性药物或食品中的应用。
背景技术
阿霉素 (Doxorubicin，DOX) 是一种临床常用的高效蔥环类抗肿瘤药物，用于治疗血液系统肿瘤和实体肿瘤如急性白血病、淋巴瘤、乳腺癌、胃癌、软组织肉瘤和卵巢癌等恶性肿瘤。然而，在临床应用过程中，其对正常细胞也具有毒性作用，尤其是不可逆的心脏毒性。临床表现为心功能不全、扩张性心肌病、心肌炎或充血性心力衰竭。这不仅极大地影响了患者的生存质量，也严重制约阿霉素的临床应用。因此，寻找有效缓解其心脏毒性的物质成为临床上亟待解决的问题。
D-核糖是一种五碳醛糖，临床上主要应用于改善由于心肌缺血缺氧引起的疲劳。正常情况下，心脏主要利用脂肪酸氧化供能，但心脏疾病伴随能量代谢重编程，脂肪酸氧化能力降低，心肌能量缺乏，导致心力衰竭。补充D-核糖可绕过磷酸戊糖途径的限速步骤快速补充能量，缓解心力衰竭。
阿霉素对正常细胞的毒性主要来自于线粒体功能破坏及氧自由基的产生，而心肌细胞内抗氧化酶的含量相对降低，更容易受到自由基的损害。作为一种高度分化的终末细胞，心肌细胞在出生后就停止分裂增生，其死亡将导致心肌细胞数量的减少，从而引起心脏结构和功能的改变，DOX诱导的心肌细胞死亡是心脏疾病发生发展的关键，然而，至今DOX心脏毒性的作用机制尚未完全阐明。
发明内容
为了解决现有技术的不足，本发明提供了一种D-核糖在制备改善药物性心脏毒性药物或食品中的应用。
本发明的目的通过以下技术方案来实现：
D-核糖在制备改善药物性心脏毒性药物或食品中的应用。
优选地，D-核糖在制备改善蔥环类抗肿瘤药物引起的心脏毒性药物或食品中的应用。
优选地，所述D-核糖在制备改善由抗癌药物阿霉素所致心脏毒性的药物中的应用。
优选地，所述D-核糖的有效量是每日1-60克，至少一天两次给予，其给予方式为口服或静脉注射。
优选地，D-核糖在制备肿瘤放化疗营养制剂中的应用。
优选地，D-核糖在制备用于通过抑制铁死亡改善阿霉素介导心脏毒性的药物或食品中的应用。
铁死亡（Ferroptosis）是一种铁依赖性的、区别于细胞凋亡、细胞坏死、细胞自噬的新型的细胞程序性死亡方式。近期的研究结果表明，铁死亡在DOX介导的心脏毒性中起到重要作用，铁死亡抑制剂FER-1可以减轻DOX介导的心脏毒性。然而，用于改善心肌能量代谢的D-核糖是否可以通过抑制铁死亡发挥改善DOX介导的心脏毒性的作用尚未见报道。本发明首次揭示了D-核糖可以通过抑制铁死亡发挥改善DOX介导的心脏毒性。
本发明通过提供了一种D-核糖在改善阿霉素心脏毒性中的应用，为新药研发和制备肿瘤营养制剂提供了科学依据；提供了一种有效的抗蔥环类抗肿瘤药心脏毒性的保护剂，尤其是抗阿霉素心脏毒性的保护剂，有效地减轻了由此带来的毒副作用，从而扩大了阿霉素的临床应用范围，并改善患者的预后；首次提供了口服D-核糖在减轻蔥环类抗肿瘤药物的心脏毒性的证据。
附图说明
图1为本发明实施例结束时各处理组中试验小鼠血清CK水平；
图2为本发明实施例结束时各处理组中试验小鼠血清CK-MB水平；
图3为本发明实施例结束时各处理组中试验小鼠血清LDH水平；
图4为本发明实施例中各处理组小鼠心肌组织病理检测结果；
图5为本发明实施例中各处理组小鼠心脏氧化应激指标水平；
图6为本发明实施例中各处理组小鼠心脏ATP水平；
图7为本发明实施例中各处理组小鼠心脏总铁水平；
图8为本发明实施例中各处理组小鼠的心脏SIRT1/PGC-1α的蛋白表达水平；
图9为本发明实施例中各处理组小鼠心脏铁死亡相关蛋白表达水平；
图10为本发明实施例中各处理组小鼠的心脏SIRT3/p53/GPX4/xCT的蛋白表达水平；
图11为本发明实施例中各处理组小鼠心脏凋亡相关蛋白表达水平。
具体实施方式
以下将结合附图本本发明的构思、具体结构及产生的技术效果作进一步的说明，以充分地了解本发明的目的、特征和效果。
实验设计与分组：40只ICR雄性小鼠随机分为:正常对照组（Con）、阿霉素组（DOX）、低剂量D-核糖（LDR）组和高剂量D-核糖(HDR)组，每组10只，各组小鼠的处理如下：
正常对照组（Con）：小鼠腹腔注射生理盐水；
阿霉素组（DOX）：小鼠腹腔注射阿霉素15mg/kg；
低剂量D-核糖（LDR）组：D-核糖0.9mg/kg，早晚各一次灌胃给药一周后，小鼠腹腔注射阿霉素15mg/kg；
高剂量D-核糖(HDR)组：D-核糖1.8mg/kg，早晚各一次灌胃给药一周后，小鼠腹腔注射阿霉素15mg/kg。
待结束时各处理组中试验小鼠的体重、心脏指数水平如下表所示：
| Con | DOX | LDR | HDR | |
| 初始体重(g) | 34.70±0.38 | 34.58±0.33 | 34.620.73 | 34.59±0.51 |
| 终体重(g) | 41.78±0.31 | 37.85±0.74* | 38.72±0.93 | 39.31±0.55 |
| 心脏质量(g) | 0.19±0.007 | 0.18±0.005 | 0.17±0.006 | 0.19±0.005 |
| 心脏指数(mg/g) | 4.52±0.16 | 4.66±0.15 | 4.43±0.06 | 4.72±0.11 |
并对处理组中实验小鼠血清CK、CK-MB和LDH水平进行检测，其结果如图1-图3所示，与正常组相比较，阿霉素组小鼠血清CK、CK-MB和LDH活性水平均显著升高(P < 0.05)，与阿霉素组相比，D-核糖能够显著降低接受大剂量阿霉素(15毫克/公斤体重)注射的小鼠血清LDH和CK-MB的水平，降低心脏损伤。
阿霉素处理2天后各处理组小鼠在取血后，迅速处死取出心脏，用10%的福尔马林固定2-3天，经过脱水、透明、浸蜡、包埋后进行石蜡处理切片，HE染色。如图4所示，显微镜观察，与正常对照组相比，阿霉素组心肌细胞出现空泡变性，心肌细胞排列紊乱，细胞间隙明显增宽，而高剂量D-核糖联合阿霉素处理组，可明显改善DOX引起的病理损伤现象。
按照试剂盒说明书，检测血清乳酸脱氢酶(LDH)、肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)；制作心脏组织匀浆，测定组织内超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、过氧化氢酶(CAT)及丙二醛(MDA)活性；测定心脏组织ATP水平和总铁含量，其结果如图5-图7所示。氧化应激结果如图5所示，与正常组相比，阿霉素组可显著增加心脏组织内脂质过氧化产物MDA的含量(P < 0.05)，并降低心脏组织抗氧化酶T-SOD、CAT、GSH、GSH-PX活力(P < 0.05)；而在高剂量D-核糖干预后，与阿霉素组相比，小鼠心脏组织内MDA含量显著下降，抗氧化酶水平显著升高。ATP含量测定结果如图6所示，与正常组比较，阿霉素可显著降低心脏组织内ATP含量(P < 0.05)；与阿霉素组比较，D-核糖低剂量组ATP含量有一定升高，但无显著性差异(P > 0.05)，而D-核糖高剂量组ATP含量显著升高(P < 0.05)。心脏组织总铁含量测定结果如图7所示，各组之间总铁含量无明显差异。这说明D-核糖可能通过增加抗氧化酶活力、ATP含量改善阿霉素诱导的心脏毒性。
提取心脏组织蛋白，利用蛋白免疫印迹法(Western blot)，检测谷胱甘肽过氧化酶4（GPX4）、胱氨酸转运蛋白系统 Xc-(xCT)、沉默信息调节因子1(Sirt1)，铁蛋白重链1(FTH1)、铁转运蛋白1(FPN1)，p53蛋白(p53)，血红素氧合酶-1 ( HO-1)的表达。 凋亡相关蛋白Bcl-2， Bax， Caspase3等的表达水平，结果如图8-图11所示。
Sirt1/PGC-1α通路相关蛋白如图8所示，与正常组相比，阿霉素会显著下调Sirt1、PGC-1α蛋白表达；而高剂量D-核糖可以显著上调Sirt1、PGC-1α蛋白表达。铁死亡相关蛋白表达结果如图9所示，与正常组相比，阿霉素可显著增加心肌组织内HO-1和FTH1蛋白的表达水平，降低GPX4、xCT表达水平(P < 0.05)；结合图10所示，与阿霉素组相比，D-核糖高剂量组HO-1表达水平显著降低，FTH1、xCT、GPX4表达水平显著性升高(P < 0.05)，但D-核糖低剂量组无显著性差异(P > 0.05)。凋亡通路相关蛋白表达结果如图11所示，与正常组小鼠相比，阿霉素可显著增加小鼠心肌组织内促凋亡蛋白Bax、Capsase3表达水平，降低抗凋亡蛋白Bcl-2表达水平(P < 0.05)；与阿霉素组相比，D-核糖低剂量组Bax表达水平有一定降低，Bcl-2表达水平有一定升高，但无显著性差异(P > 0.05)；而D-核糖高剂量组Bax表达水平明显降低，Bcl-2表达水平明显升高(P < 0.05)。以上结果提示，D-核糖对阿霉素心脏损伤的保护作用可能与其抑制氧化应激、铁死亡以及细胞凋亡相关。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (6)
1.D-核糖在制备改善药物性心脏毒性药物或食品中的应用。
2.D-核糖在制备改善蔥环类抗肿瘤药物引起的心脏毒性药物或食品中的应用。
3.如权利要求2所述的应用，其特征在于：所述D-核糖在制备改善由抗癌药物阿霉素所致心脏毒性的药物或食品中的应用。
4.如权利要求3所述的应用，其特征在于：所述D-核糖的有效量是1-60克/每日，至少一天两次给予，其给予方式为口服或静脉注射。
5.D-核糖在制备肿瘤放化疗营养制剂中的应用。
6.D-核糖在制备用于通过抑制铁死亡改善阿霉素介导心脏毒性的药物或食品中的应用。
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