CN117582432A - 杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用 - Google Patents
杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用,属于生物医药技术领域。杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用。本发明实验结果表明,杨梅黄酮通过改善心肌功能损伤、氧化应激反应,缓解细胞凋亡、细胞焦亡等来实现缓解心脏毒性的目的,且无明显副作用,具有良好的安全性,可提高肿瘤患者的生存质量,具有良好的药用前景。综上,杨梅黄酮具有良好的心脏保护作用及低毒安全等特点,且有较高的经济性,具有发展成为新一代的心脏保护药物的潜力。
Description
技术领域
本发明属于生物医药技术领域,具体涉及杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用。
背景技术
阿霉素(Doxorubicin,DOX)是一种广泛使用于治疗血液系统恶性肿瘤和实体瘤的蒽环类化疗药物,在临床上对对淋巴瘤、乳腺癌、食道癌、骨肉瘤等肿瘤具有良好的治疗效果。阿霉素主要通过抑制DNA合成、干扰拓扑异构酶II活性和诱导氧化应激来杀伤癌细胞。然而,阿霉素会产生剂量依赖性的心脏毒性副作用,最终可能导致不可逆的心肌损伤和心力衰竭,极大地限制了其在临床的使用。DOX诱导心脏毒性的机制复杂,主要包括氧化应激、炎症反应、细胞凋亡、纤维化和自噬失调、线粒体损伤、内质网应激,钙离子稳态失衡等。
目前,预防蒽环类药物毒性的心脏保护策略主要包括使用心脏保护剂或降低化疗药累积用量以减轻心脏毒性效力。右雷佐生(Dexrazoxane,DEX)是美国FDA唯一批准用于治疗阿霉素心脏毒性的具有铁螯合活性心脏保护剂,但临床治疗中已发现右雷佐生可能降低蒽环类药物抗肿瘤效果,诱发继发性恶性肿瘤病加重骨髓抑制。此外,右雷佐生价格昂贵、给药剂量大(建议剂量为阿霉素5~10倍),目前对于右雷佐生的临床应用策略仍存在较大争议。因此,研发新一代安全、高效的心脏保护药物预防或减少蒽环类药物心脏毒性,具有重要的临床应用价值。
杨梅黄酮别名杨梅素、杨梅酮(Myricetin,MYR,C15H10O8,5,7-三羟基-2-(3,4,5-三羟基苯基)-4H-1-苯并呋喃-4-酮),是一种天然黄酮类物质,广泛存在于许多天然植物中,包括藤茶、黑杨梅的果实、树皮和叶子等。药理学已证实,杨梅黄酮具有多种生物活性,包括抗氧化、抗炎、抗菌、抗肿瘤、调节血脂血糖、抗纤维化、神经退行性保护以及心血管保护作用等。已有研究证实杨梅黄酮可一定程度上缓解抗癌药物5-氟尿嘧啶(5-FU)诱导的心脏损伤,也可减轻脂多糖(LPS)诱导的心肌功能损伤,具有较好抗炎、抗氧化应激、抗细胞凋亡的能力,具有作为心脏毒性保护药物的潜力。然而,迄今为止,尚未有杨梅黄酮用于缓解蒽换类化疗药物DOX心脏毒性保护药物的应用和保护机制研究报道。
发明内容
有鉴于此,本发明的目的在于提供一种杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用,杨梅黄酮作为活性物质,通过改善心肌功能损伤、氧化应激反应,缓解细胞凋亡、细胞焦亡等来实现缓解心脏毒性的目的。
本发明提供了杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用。
优选的,所述心脏毒性由阿霉素引起的心脏毒性。
优选的,所述药物具有以下至少一种功能:缓解心肌功能损伤、缓解心肌细胞凋亡、缓解心肌细胞焦亡、减轻心脏氧化应激和减轻心肌细胞纤维化。
优选的,所述缓解心肌功能损伤包括提高心脏脏器系数、修复心肌组织损伤、缓解心肌损伤标志物水平异常升高和抑制脑钠肽基因表达。
优选的,所述缓解心肌细胞凋亡包括减少心肌细胞凋亡数量和下调Bax和Bcl-2且Bcl-2/Bax比值升高。
优选的,所述缓解心肌细胞焦亡包括抑制焦亡相关基因的表达水平。
优选的,所述减轻心脏氧化应激包括提高SOD和CAT酶活性和降低MDA含量和MPO酶活。
优选的,所述药物的剂量包括口服剂;
所述口服剂包括以下至少一种:片剂、胶囊剂、颗粒剂、混悬剂和溶液剂。
优选的,所述杨梅黄酮对临床患者的给药剂量为0.1~5mg/kg。
优选的,所述杨梅黄酮的结构式如式I所示;
本发明提供了杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用。本发明以阿霉素诱导的心脏毒性动物模型为实验对象,分别从发挥预防和治疗作用两个角度评估杨梅黄酮的药效,结果表明,无论是预防还是治疗方面,杨梅黄酮均具有缓解心肌功能损伤、缓解心肌细胞凋亡、缓解心肌细胞焦亡、减轻心脏氧化应激和减轻心肌细胞纤维化的作用,且无明显副作用,安全性优于右雷佐生,可提高肿瘤患者的生存质量,具有良好的药用前景。综上,杨梅黄酮具有良好的心脏保护作用及低毒安全等特点,且有较高的经济性,有望发展成为新一代的心脏保护药物。
同时,所述应用涉及的杨梅黄酮来源于多种天然植物,包括藤茶、黑杨梅的果实、树皮和叶子等,原料易于获取,且我国具有良好的资源优势,做好相关产品开发具有重要的临床价值和社会价值。
进一步的,本发明提供的应用中具体限定了药物为口服剂。将杨梅黄酮以口服制剂的形式应用于缓解阿霉素心脏毒性的药物中,用药简单方便,易于实现。
附图说明
图1为实施例1中,杨梅黄酮对阿霉素诱导心脏功能紊乱和组织学损伤的影响结果;A:心脏脏器系数;B:心脏组织H&E染色;C:血清心肌肌钙蛋白I(cTnI)含量;D:血清谷草转氨酶(AST)活性;E:血清乳酸脱氢酶(LDH)活性;F:B型脑钠肽基因(BNP)的表达水平;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图2为实施例1中,杨梅黄酮对阿霉素诱导的心脏氧化应激的影响结果;A:心脏组织丙二醛(MDA)含量;B:血清抗髓过氧化物酶(MPO)活性;C:血清超氧化物歧化酶(SOD)活性;D:过氧化氢酶(CAT)活性;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图3为实施例1中,杨梅黄酮对阿霉素诱导的心肌细胞调亡的影响结果;A:心脏组织TUNEL染色;B、C:凋亡相关基因Bax、Bcl2基因的表达水平;D:Bcl2/Bax的比例;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图4为实施例1中,杨梅黄酮对阿霉素诱导的心肌细胞焦亡和纤维化的影响结果;A-C:细胞焦亡相关基因Caspase1、ASC、NLRP3的表达水平;D:心脏组织Sirius-red染色;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图5为实施例2中,杨梅黄酮阿霉素诱导心脏功能紊乱和组织学损伤的影响结果;A:心脏组织H&E染色;B:血清心肌肌钙蛋白T(cTnT)含量;C:血清谷草转氨酶(AST)活性;D:血清谷丙转氨酶(ALT)活性;E:血清乳酸脱氢酶(LDH)活性;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图6为实施例2中,杨梅黄酮对阿霉素诱导的心脏氧化应激和细胞凋亡的影响结果;A:心脏组织丙二醛(MDA)含量;B:组织超氧化物歧化酶(SOD)活性;C、D:氧化应激相关基因keap-1、SOD1的表达水平;D-F:凋亡相关基因P-53、Bax、Bcl2基因的表达水平以及G:Bcl2/Bax比例;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图7为实施例2中,杨梅黄酮对阿霉素诱导的心肌细胞焦亡和纤维化的影响结果;A-C:细胞焦亡相关基因Caspase1、ASC、IL-1β的表达水平;D:心脏组织Sirius-red染色;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05;
图8为实施例2中,杨梅黄酮对阿霉素诱导的能量代谢紊乱的影响结果;A-F:能量代谢相关基因AMPK、AMPK-α、PGC-1α、PPAR-α、CPT1b及Atp5e的表达水平;#:与空白对照组比,P<0.05;*:与DIC模型组比,P<0.05。
具体实施方式
本发明提供了杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用。
在本发明中,所述杨梅黄酮(Myricetin,MYR),CAS:529-44-2,98%,结构式如式I所示。本发明实施例中,所述杨梅黄酮购自于上海阿拉丁生化科技股份有限公司(中国上海)。
在本发明中,所述心脏毒性优选由阿霉素引起的心脏毒性。在本发明实施例中,以阿霉素诱导的心脏毒性动物模型为实验对象,来评估杨梅黄酮对于预防和/或治疗心脏毒性的药效。
在本发明中,所述药物优选具有以下至少一种功能:缓解心肌功能损伤、缓解心肌细胞凋亡、缓解心肌细胞焦亡、减轻心脏氧化应激和减轻心肌细胞纤维化。所述缓解心肌功能损伤优选包括提高心脏脏器系数、修复心肌组织损伤、缓解心肌损伤标志物水平异常升高和抑制脑钠肽基因表达。所述缓解心肌细胞凋亡优选包括减少心肌细胞凋亡数量和下调Bax和Bcl-2且Bcl-2/Bax比值升高。所述缓解心肌细胞焦亡优选包括抑制焦亡相关基因的表达水平。所述减轻心脏氧化应激优选包括提高SOD和CAT酶活性和降低MDA含量和MPO酶活。实施例结果表明,阿霉素诱导的DIC小鼠心脏脏器系数显著降低,黄梅黄酮预防或治疗给药后一定程度升高了心脏脏器系数。H&E染色结果显示,模型小鼠的心脏存在心肌纤维排列紊乱、胞质空质化和局部炎性细胞浸润等病理变化,杨梅黄酮治疗有效改善了心肌细胞形态和排列,一定程度上减轻心肌组织的损伤。阿霉素还导致小鼠心脏功能紊乱,模型小鼠的心脏损伤标志物cTnI含量以及AST、LDH等酶活显著升高;杨梅黄酮预防和治疗给药后有效缓解了心脏损伤标志物水平的异常升高,同时抑制了脑钠肽(BNP)基因表达,促进机体的钠平衡。此外,阿霉素处理还导致了氧化应激的产生,促使心脏组织中MDA含量和MPO酶活显著升高,SOD和CAT酶活显著降低;杨梅黄酮预防和.或治疗给药后一定程度提高了SOD和CAT的酶活性,降低了MDA含量和MPO酶活,有效缓解了小鼠氧化应激反应。TUNEL染色结果显示,模型小鼠心脏细胞凋亡的现象明显,杨梅黄酮处理减少了凋亡细胞数量。同时在转录水平上,杨梅黄酮下调了Bax和Bcl-2的表达水平,同时使Bcl-2/Bax比值升高,以减轻阿霉素诱导细胞凋亡。Sirius-red染色结果显示,模型小鼠心肌纤维化较明显,而杨梅黄酮预防和治疗给药有效缓解了阿霉素诱导的纤维化,同时抑制了细胞焦亡相关基因Caspase1、ASC、NLRP3的表达水平。
在本发明中,所述药物的剂型优选包括口服剂。所述口服剂包括以下至少一种:片剂、胶囊剂、颗粒剂、混悬剂和溶液剂。本发明对所述药物的制备方法没有特殊限制,采用本领域所熟知的药物种类即可。
在本发明中,所述杨梅黄酮的小鼠给药剂量优选为1~50mg/kg,更优选为5~25mg/kg。可见,本发明所述杨梅黄酮通过极低药量即可达到预防和/或治疗心脏毒性的药效,较其他类似化合物有明显的优势。
下面结合实施例对本发明提供的杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
杨梅黄酮对阿霉素诱导心脏毒性的治疗作用
一、实验材料
SPF级8周龄雄性C57BL/6小鼠,体重约20~22g,购自中国国家实验动物资源中心(中国上海),于浙江省农业科学院动物中心饲养,室温约22℃,湿度约50%,12小时明暗周期,自由获取鼠粮和饮用水。
杨梅黄酮(Myricetin,MYR,CAS:529-44-2,98%)购自于上海阿拉丁生化科技股份有限公司(中国上海)。
盐酸阿霉素(Doxorubicin,DOX,CAS:25316-40-9,98%)购自于上海源叶生物科技有限公司(中国上海)。
心肌肌钙蛋白I(cTnI)、谷草转氨酶(AST)、乳酸脱氢酶(LDH)、丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、抗髓过氧化物酶(MPO)等试试剂盒均购自于南京建成生物工程研究所(中国南京)。
Trizol试剂、反转录试剂盒、Green试剂盒均购自于诺唯赞生物科技股份有限公司(中国南京)。
二、实验方法
1.动物造模和分组:小鼠于实验条件下驯化一周后用于实验模型的构建,对实验组小鼠单次腹腔注射阿霉素(DOX,15mg/kg·bw)构建急性心脏损伤(DIC)模型,实验分组包括空白对照组(CON)、阿霉素急性心脏损伤模型组(DIC)、杨梅黄酮给药治疗组(MYR-5、25、50),针对杨梅黄酮设置5mg/kg、25mg/kg、50mg/kg剂量,造模后第2天开始灌胃给药治疗,连续给药7天,第9天解剖取样,取各组小鼠的心脏组织、血清样本,-80℃保存以备后续分析。
2.生理生化指标检测:根据试剂盒说明书检测心脏功能相关生理生化指标:包括心肌肌钙蛋白T(cTnT)、谷草转氨酶(AST)、谷丙转氨酶(ALT)、乳酸脱氢酶(LDH);检测氧化应激相关指标:包括丙二醛(MDA)、超氧化物歧化酶(SOD)。
3.基因表达水平检测:取10-20mg小鼠心脏组织样品于2mLEP管中,使用Trizol试剂提取组织总RNA,使用利用超微量紫外可见分光光度计检测RNA样品浓度及纯度,使用反转录试剂盒进行反转录合成cDNA。使用Green试剂盒,以GADPH为内参基因,使用RT-qPCR检测小鼠心脏组织中的氧化应激、细胞凋亡、细胞焦亡等相关目的基因的表达水平。具体步骤如下:
表1RT-qPCR使用的引物序列对
表2RT-qPCR反应体系
采用表1引物对目的基因mRNA转录水平进行RT-qPCR检测,按照表2配制反应体系,扩增条件如下:95℃保持1min(预变性);95℃保持10s,60℃保持30s,40个循环。每个循环反应延伸阶段完成时通过检测体系荧光强度,记录Ct值,通过2-ΔΔCt法计算基因相对表达水平。
4.心脏组织学病理学检查:随机选取小鼠心脏组织,于4%中性多聚甲醛溶液中固定过夜,石蜡包埋,用于后续染色分析:进行苏木精-伊红(H&E)染色,用于表征心脏组织学损伤情况;进行末端脱氧核苷酸转移酶介导的dUTP原位切口末端标记(TUNEL)染色,用于表征心肌细胞凋亡情况;进行天狼星红(Sirius-red)染色,用于表征心肌组织纤维化情况;染色的切片于光学显微镜下观察并拍照记录典型视野。
三、实验结果
与对照组(CON)相比,阿霉素诱导的DIC小鼠的心脏脏器系数显著降低;与DIC组比,黄梅黄酮治疗后一定程度升高了心脏脏器系数。H&E染色结果显示,DIC组小鼠的心脏存在心肌纤维排列紊乱、胞质空质化和局部炎性细胞浸润等病理变化,杨梅黄酮治疗有效改善了心肌细胞形态和排列(图1中A-B)。
阿霉素还导致小鼠心脏功能紊乱,DIC组小鼠的心脏损伤标志物cTnI含量以及AST、LDH等酶活显著升高和提高脑钠肽(BNP)基因表达;杨梅黄酮治疗处理有效缓解了心脏损伤标志物水平的异常升高,同时抑制了脑钠肽(BNP)基因表达,促进机体的钠平衡(图1中C-F)。
除此之外,阿霉素处理还导致了氧化应激的产生,促使心脏组织中MDA含量和MPO酶活显著升高,SOD和CAT酶活显著降低;杨梅黄酮治疗处理一定程度提高了SOD和CAT酶活性,降低了MDA含量和MPO酶活,有效缓解了小鼠氧化应激反应(图2)。
TUNEL染色结果显示,DIC小鼠心脏细胞凋亡的现象明显,MYR处理减少了凋亡细胞数量。在转录水平上,杨梅黄酮下调了Bax和Bcl-2的表达水平,同时使Bcl-2/Bax比值升高,以减轻阿霉素诱导细胞凋亡(图3)。
Sirius-red染色结果显示,DIC组小鼠心肌纤维化较明显,而杨梅黄酮治疗处理有效缓解了阿霉素诱导的纤维化,同时抑制了细胞焦亡相关基因Caspase1、ASC、NLRP3的表达水平(图4)。
实施例2
杨梅黄酮对阿霉素诱导的心脏毒性的预防作用
一、实验材料
SPF级8周龄雄性C57BL/6小鼠,体重约20~22g,购自中国国家实验动物资源中心(中国上海),于浙江省农业科学院动物中心饲养,室温约22℃,湿度约50%,12小时明暗周期,自由获取鼠粮和饮用水。
杨梅黄酮(Myricetin,MYR,CAS:529-44-2,98%)购自于上海阿拉丁生化科技股份有限公司(中国上海)。
盐酸阿霉素(Doxorubicin,DOX,CAS:25316-40-9,98%)购自于上海源叶生物科技有限公司(中国上海)。
心肌肌钙蛋白T(cTnT)、天冬氨酸转氨酶(AST)、乳酸脱氢酶(LDH)、丙二醛(MDA)、超氧化物歧化酶(SOD)等试剂盒均购自于南京建成生物工程研究所(中国南京)。
Trizol试剂、反转录试剂盒、Green试剂盒均购自于诺唯赞生物科技股份有限公司(中国南京)。
二、实验方法
1.动物造模和分组:小鼠于实验条件下驯化一周后用于实验模型的构建,实验分组包括空白对照组(CON)、阿霉素急性心脏损伤模型组(DIC)、杨梅黄酮给药预防组(MYR-1、5),针对杨梅黄酮设置1mg/kg、5mg/kg剂量,给药预防组每日灌胃两种剂量的杨梅黄酮悬浮液,连续给药30天,空白对照组每日灌胃等体积的溶剂。实验第28天,对实验组小鼠单次腹腔注射阿霉素(DOX,15mg/kg·bw)构建急性心脏损伤(DIC)模型,第31天解剖取样,取各组小鼠的心脏组织、血清样本,-80℃保存以备后续分析。
2.生理生化指标检测:根据试剂盒说明书检测心脏功能相关生理生化指标:包括心肌肌钙蛋白I(cTnI)、天冬氨酸转氨酶(AST)、乳酸脱氢酶(LDH);检测氧化应激相关指标:包括超氧化物歧化酶(SOD)、丙二醛(MDA)。
3.基因表达水平低检测:与实施例1中方法相同。
4.心脏组织病理学检查:类似地,随机选取小鼠心脏组织,于4%中性多聚甲醛溶液中固定过夜,石蜡包埋,用于后续染色分析:进行苏木精-伊红(H&E)染色,用于表征心脏组织学损伤情况进行天狼星红(Sirius-red)染色,用于表征心肌组织纤维化情况;染色的切片于光学显微镜下观察并拍照记录典型视野。
三、实验结果
H&E染色结果显示,阿霉素导致小鼠心脏组织纤维排列紊乱,部分胞质空质化,杨梅黄酮的预处理可有效预防这些组织病理的出现(图5中A)。同时,阿霉素的处理导致了心脏功能损伤标志物cTnT、AST、ALT及LDH水平显著升高,杨梅黄酮预处理可以有效预防指标的异常变化,使其趋于对照组的水平(图5中B-E)。
类似地,杨梅黄酮预处理也可有效降低小鼠心脏组织氧化损伤,减少组织MDA水平,提高SOD酶活,还一定程度调控了氧化应激相关基因keap-1、SOD1的表达水平(图6中A-D)。
阿霉素会导致心肌细胞凋亡,杨梅黄酮预处理可以调控相关基因P-53、Bax、Bcl2的表达,减轻细胞凋亡(图6中E-H)。
阿霉素会导致心肌细胞焦亡,阿霉素显著抑制相关基因Caspase1、ASC表达水平,杨梅黄酮预处理可促进它们的表达,同时抑制IL-1β表达水平,以缓解细胞焦亡(图7中A-C)。
Sirius-red染色结果显示,阿霉素导致小鼠心脏组织出现显著的纤维化,而杨梅黄酮预处理有效缓解了DOX诱导的纤维化(图7中D)。
另一方面,阿霉素处理还抑制了能量代谢相关通路的表达,而杨酶黄酮预处理可激活AMPK-PPARα-CPT1b信号通路,促进脂肪酸氧化并产生ATP,进而缓解阿霉素诱导的氧化应激、细胞凋亡以及纤维化等过程(图8)。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.杨梅黄酮在制备预防和/或治疗心脏毒性的药物中的应用。
2.根据权利要求1所述应用,其特征在于,所述心脏毒性由阿霉素引起的心脏毒性。
3.根据权利要求1所述应用,其特征在于,所述药物具有以下至少一种功能:缓解心肌功能损伤、缓解心肌细胞凋亡、缓解心肌细胞焦亡、减轻心脏氧化应激和减轻心肌细胞纤维化。
4.根据权利要求1所述应用,其特征在于,所述缓解心肌功能损伤包括提高心脏脏器系数、修复心肌组织损伤、缓解心肌损伤标志物水平异常升高和抑制脑钠肽基因表达。
5.根据权利要求1所述应用,其特征在于,所述缓解心肌细胞凋亡包括减少心肌细胞凋亡数量和下调Bax和Bcl-2且Bcl-2/Bax比值升高。
6.根据权利要求1所述应用,其特征在于,所述缓解心肌细胞焦亡包括抑制焦亡相关基因的表达水平。
7.根据权利要求1所述应用,其特征在于,所述减轻心脏氧化应激包括提高SOD和CAT酶活性和降低MDA含量和MPO酶活。
8.根据权利要求1所述应用,其特征在于,所述药物的剂量包括口服剂;
所述口服剂包括以下至少一种:片剂、胶囊剂、颗粒剂、混悬剂和溶液剂。
9.根据权利要求1所述应用,其特征在于,所述杨梅黄酮对临床患者的给药剂量为0.1~5mg/kg。
10.根据权利要求1~9中任意一项所述应用,其特征在于,所述杨梅黄酮的结构式如式I所示;
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