酒精干预CyPD的表达影响mPTP所致心肌损伤机制
Mechanism of Alcohol-Mediated CyPD Regulation in mPTP-Dependent Myocardial Injury
DOI: 10.12677/acm.2025.1551560, PDF, HTML, XML,   
作者: 胡 彬:南华大学附属怀化医院,湖南 衡阳;申 强*:湖南医药学院总医院心血管内科,湖南 怀化
关键词: 酒精mPTPCyPD心肌损伤Alcohol mPTP CyPD Myocardial Injury
摘要: CyPD是构成mPTP的基本组成部分之一,且有一些明确的证据支持CyPD是mPTP的主要调节因子;CyPD仍是唯一被遗传学证明的mPTP开放因子;CyPD的表达增加能够经历多种翻译后修饰,如磷酸化、氧化、乙酰化和硝酰化调控mPTP的打开。mPTP的长期开放能够引起线粒体功能障碍,进而导致心肌损伤,目前已有研究表明酒精能够使线粒体上mPTP上CyPD的表达增加及CyPD mRNA表达增加,但酒精通过何种机制引起线粒体上CyPD的表达增加目前尚不清楚,本文就酒精可能通过哪些机制引起CyPD的表达发生变化做一综述。
Abstract: CyPD is one of the fundamental components of mPTP, and substantial evidence indicates that CyPD serves as the primary regulatory factor of mPTP. Moreover, CyPD remains the only genetically validated factor responsible for the opening of mPTP. Enhanced expression of CyPD undergoes various post-translational modifications, including phosphorylation, oxidation, acetylation, and nitroacylation, which collectively regulate the opening of mPTP. The sustained opening of mPTP can lead to mitochondrial dysfunction, thereby causing myocardial injury. Current research demonstrates that alcohol increases the expression of both CyPD and CyPD mRNA in mPTP on mitochondria; however, the precise mechanism underlying alcohol-induced upregulation of CyPD expression on mitochondria remains elusive. This review aims to explore the potential mechanisms by which alcohol may induce changes in CyPD expression.
文章引用:胡彬, 申强. 酒精干预CyPD的表达影响mPTP所致心肌损伤机制[J]. 临床医学进展, 2025, 15(5): 1807-1813. https://doi.org/10.12677/acm.2025.1551560

1. 前言

酒精,作为一种极具成瘾性并且在全球普及的一种有害物质,长期过度摄入(男性每日超过80克,女性超过40克,通常持续5年以上)可能会导致酒精性心肌病(Alcoholic Cardiomyopathy, ACM)的发生。甚至在短时间内大量饮用,也可能引发急性酒精性心肌损伤,这一机制包括能量生成障碍、细胞凋亡和自噬、心脏纤维化、蛋白质合成异常、氧化应激等[1]-[4]。在心肌病的发生发展中,线粒体功能障碍导致细胞凋亡的增加在心肌病的占比逐渐加大,随着研究愈发深入,对心脏组织中线粒体功能异常的研究逐渐引起人们的关注。而mPTP (线粒体通道转换孔)是线粒体功能稳态调节中的关键环节,在细胞内代谢平衡管理中起着重要作用。在正常生理状况下,mPTP以周期性的方式开启,以确保细胞功能的稳定[5]。然而,环境压力或病理条件可能导致mPTP异常开启,导致离子失衡和线粒体形态变化,从而引发细胞凋亡。

2. 线粒体通透性转换孔(mPTP)

mPTP是线粒体双层膜上的一种蛋白质通道,在调节线粒体内外物质交换方面发挥重要作用。mPTP的病理性开放会打乱线粒体稳态,最终导致细胞死亡。mPTP的打开受到多种不同因素的调控,包括与蛋白质、钙离子、氧化应激、pH值和脂质的相互作用。mPTP是一种由许多种蛋白质组成的非特异性通道,随着研究的深入,不断地有新的理论被提出。目前的理论认为,线粒体内膜上的腺苷酸转运体(ANT)和F-ATP合成酶,以及线粒体外膜上的电压依赖性阴离子通道(VDAC)和基质中的亲环蛋白D (CyPD)是构成mPTP的基本组成部分[4]-[6]。mPTP长时间(不可逆)开放可以通过妨碍ATP的生成、加重线粒体的渗透变化和肿胀,促使线粒体嵴的结构重塑等,最终引起细胞凋亡和坏死。

3. 亲环蛋白(CyPD)及其对mPTP的调控机制

CyPD是构成mPTP的基本组成部分之一,亲环蛋⽩D (Cyclophilin D, CyPD)是⼀种线粒体基质蛋⽩,具有顺式–反式肽基脯氨酸异构酶(PPIase)活性[7],参与线粒体通透性转变和细胞死亡起始的调控[8]。CyPD由肽基脯氨酸顺式反式异构酶F (PPIF)基因编码。在细胞应激机制中,和CyPD关系最为密切的是氧化应激,氧化应激可以诱导细胞死亡,氧化应激可促进CyPD从基质向线粒体内膜的易位[9]-[12]。这使得CyPD可以结合ANT并触发mPTP的开[13]。在mPTP的三个组成部分,即VDAC、ANT和CyPD中,CyPD被认为是mPTP形成的关键组成部分[14] [15]

另外,CyPD不仅是MPTP的重要组成部分,⽽且还与各种其他各种蛋⽩质相互作⽤。这些CyPD-蛋⽩相互作⽤作为mPTP形成和细胞死亡的信号。在氧化应激过程中,p53在线粒体基质中积累并与CyPD发⽣物理相互作⽤,从⽽触发MPTP开放和坏死[16]。在脑缺⾎/再灌注(I/R)损伤过程中观察到p53-CyPD复合物的形成[17];CyPD与线粒体内膜上的ANT相关,有助于MPTP的开放[18]。这种结合导致了线粒体基质的胶体渗透性溶胀,线粒体内膜电位(ψm)的耗散和ROS [19]的产⽣。CyPD与ANT的相互作⽤似乎是MPTP复合物形成过程中最重要的⼀步[20];其次,糖原合成酶激酶3β (GSK-3β)会直接磷酸化CyPD,磷酸化的CyPD能够介导mPTP的开放。在AD (阿尔茨海默病)中,研究表明Aβ与CyPD的相互作⽤,CyPD与线粒体Aβ的相互作⽤增强了线粒体、神经元和突触的应激[21]。从而介导了mPTP的开放。而CyPD表达的增加能够促进CyPD-蛋⽩相互作⽤,从而增加mPTP的开放。

4. CyPD的调控

4.1. 目前对CyPD调控机制研究

主要体现在对CyPD的活性及表达调控中,CyPD的活性可以通过翻译后修饰来调节,包括乙酰化和磷酸化等修饰方式;有研究表明,在啮齿动物心肌细胞和人胚胎肾细胞中,GSK-3β通过CyPD磷酸化(Ser191)作为mPTP的调节剂[22];在哺乳动物精子中,GSK-3α可能通过CyPD的磷酸化参与mPTP的打开,GSK3抑制剂BIO显著降低精子中的CyPD水平。通过抑制了GSK3磷酸化促进的CyPD磷酸化下调增强了CyPD的降解,增强了获能过程中的精子活力[23];这说明GSK-3能够通过影响CyPD的乙酰化和磷酸化来影响其活性。

4.2. CyPD表达的调控

在中心法则中,蛋白质是由mRNA翻译而来,其表达的水平受到mRNA转录水平的调控,在基因的转录和翻译中,蛋白质的合成过程受到一些酶、转录因子、基因启动子等的调控,通常情况下,mRNA水平和蛋白质表达水平一致。而CyPD的表达目前研究表明受以下因素影响。一方面,在骨分化过程中,Rubens等人的研究结果表明,BMP/Smad信号通路可以通过与CyPD基因启动子结合,调节CyPD基因的转录水平,从而影响CyPD的表达;另一方面,其他与Runx激活相关的转录因子也可能直接或间接地对CyPD的转录起调控作用[24] [25];其中RUNX (转录因子)受PI3k/AKT/PTEN信号通路下游靶点调控[26]。对TCGA数据的查询显示,AKT和PI3K基因表达与RUNX1和RUNX2呈正相关[27],而在PCa患者样本中观察到RUNX2蛋白的过度表达和PTEN蛋白的部分丢失[28] [29];纯合缺失PTEN增加RUNX2 mRNA和蛋白质表达,表明PTEN基因剂量对于控制RUNX2基因表达至关重要[30];再者,酒精的代谢产物ROS (活性氧)可以诱导CyPD mRNA的显著上调,其可能是ROS对CypD的复制、转录过程中的DNA聚合酶等关键酶进行调控,从而增加其表达。导致细胞损伤[31]。其次,Wang Long等人的研究表明,IQC (异槲皮素)能够通过调节AKT/Bcl-2信号通路降低VDAC1、ANT1和CyPD mRN的表达水平;从而保护心肌细胞线粒体膜通透性的变化,抑制细胞从线粒体内膜释放到细胞质,形成凋亡小体,诱导细胞凋亡,降低THP诱导的心脏毒性。这说明Bcl-2能够影响CyPD mRN的表达水平,从而影响CyPD的表达;另外,目前的研究表明,mTORC1通过磷酸化4EBP和S6K1促进蛋白质合成;mTORC1磷酸化S6K1,导致其通过PDK1激活,进而促进mRNA翻译启动。S6K1介导的PDCD4磷酸化导致其降解,解除对翻译启动因子eIF4A的抑制,从而促进蛋白质合成和细胞增殖[32],mTOR信号通路在心、肺、脑等脏器中普遍表达,mTOR是PI3K/AKT通路的一个重要下游靶点通路,存在于两个复合物中,分别称为mTOR复合物1 (mTORC1)和mTOR复合物2 (mTORC2) [33],这说明CyPD的合成过程可能会受到mTORC1的影响。

5. 酒精对mPTP上CyPD的表达影响

5.1. 酒精能够导致心肌细胞线粒体上CyPD的表达及转录水平的提高

酒精能够导致心肌细胞线粒体上CyPD的表达及转录水平的提高,但是酒精如何导致CyPD的表达升高,目前尚不清楚。目前的研究表明,酒精可以直接或间接影响CyPD的表达从而调控mPTP。其机制可能与酒精及其代谢产物能够影响调控CyPD基因的信号通路有关,从而使CyPD的基因复制与转录水平升高。同样地,研究表明,酒精在体内的代谢过程中产物,如ROS、乙醛等,也同样可以导致CyPD的表达增加,导致细胞损伤。尤其是ROS,目前有研究表明,ROS可以诱导CyPD mRNA的显著上调,根据目前的研究,CyPD mRNA的表达水平可能受到GSK-3、Bcl-2、mTOR、PETN等PI3K/AKT下游信号通路的调控。这表明ROS诱导CyPD mRNA的上调机制和PI3K/AKT信号通路有关,而乙醛导致CyPD的表达增加的机制目前暂不明确。

5.2. 酒精在代谢过程中能够导致ROS (活性氧)的积累

酒精在代谢过程中,会产生大量的ROS。ROS可以诱导CyPD mRNA的显著上调,也有研究表明,其可能是ROS对CyPD的复制、转录过程中的DNA聚合酶等关键酶进行调控,从而增加其表达。而CyPD的复制、转录过程中的DNA聚合酶受到PI3K/AKT信号通路的影响。在Li Xiaoping等人的研究中,阿霉素可以诱导线粒体ROS的生成增加、mPTP的开放,进而导致线粒体损伤,而司美格鲁肽可以通过上调PI3K/AKT信号通路减弱阿霉素诱导的线粒体损伤,在加入LY294002 (PI3K抑制剂后),司美格鲁肽减轻阿霉素诱导的线粒体ROS的生成增加、mPTP的开放作用被阻断[34];这说明ROS和PI3K/AKT信号通路也存在联系,在Wang Wenxun等人的研究中,HSYA (羟基红花黄素A)可以通过调节Nrf2/Keap1信号通路,减轻酒精消耗引起的氧化应激引起的酒精性肝损伤。而Nrf2/Keap1信号通路受到PI3K/Akt的上游调控,PI3K/Akt通路可激活Nrf2/Keap1抗氧化防御系统。Nrf2是一种重要的抗氧化转录因⼦,在酒精诱导的氧化应激中起着至关重要的作用。

6. 酒精对PI3K/AKT信号通路的影响

6.1. PI3K/AKT信号通路的介绍

磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B (PKB/AKT)信号通路是细胞中调控细胞生长、增殖、运动、代谢和存活的核心信号通路之一[35]。PI3K/AKT信号通路通过激活下游效应物,调控细胞周期转换、生长和增殖,在多种生理功能的调控中起着至关重要的作用。该通路能够通过调节心肌细胞的大小和存活、血管生成过程以及炎症反应参与多种人类疾病的发病过程,如心脏疾病[36]。目前已有研究表明PI3K/AKT通路参与了汞、脂多糖、阿霉素、表柔比星、等多种物质诱导的心肌损伤过程[37]-[39];AKT有三种亚型,包括AKT1、AKT2和AKT33个亚型,分别由PKBα、PKBβ和PKBγ编码[40]。前两种亚型在脑、心、肺中普遍表达且表达水平较高[41]。生长因子和g蛋白偶联受体可以刺激P2和P3诱导AKT募集到质膜,在质膜Thr308位点磷酸化,并被PDK1激活[42]。随后的Ser473残基磷酸化是AKT充分发挥活性所必需的。AKT激活后,AKT可以磷酸化许多下游靶标,如TSC2、GLUT、GSK-3和mTOR等,这些下游靶点通路能调控细胞生长、存活、增殖、糖代谢等一系列生命活动,进而参与癌症、心血管疾病、糖尿病及神经系统疾病等发生发展。

6.2. 酒精对PI3K/Akt信号通路的影响

目前最新研究表明,酒精能够影响PI3K/AKT通路,在Guo、Huang等人的研究中,乙醇诱导的胃溃疡组的p-PI3K、PI3K、p-AKT和AKT水平明显下调(p < 0.05),而LF (甘草黄酮类化合物)治疗组明显增强了这些蛋白的表达(p < 0.05)。此外,LF的给药可逆转乙醇诱导的Bax和caspase-3的增加,而LF治疗可以通过激活PI3K/AKT信号通路来抑制凋亡,从而改善酒精诱导的胃溃疡。

7. 总结与展望

综上所述,酒精能够导致心肌细胞线粒体上CyPD的表达及转录水平的提高,但是酒精如何导致CyPD的表达升高,目前尚不清楚。目前的研究表明,酒精可以直接或间接影响CyPD的表达从而调控mPTP。其机制可能与酒精或其代谢产物能够影响调控CyPD基因的信号通路有关,从而使CyPD的基因复制与转录水平升高。酒精在体内的代谢产物,如ROS、乙醛等,也同样可以影响CyPD的表达,导致细胞损伤。尤其是ROS,一方面,目前有研究表明,ROS可以诱导CyPD mRNA的显著上调,在加入LY294002 (PI3K抑制剂)后,ROS生成增加;这说明PI3K/AKT通路与ROS相关,另一方面,根据目前的研究,PI3K/AKT通路参与了H2O2、汞、脂多糖、表柔比星、阿霉素等多种物质诱导的心肌损伤过程。这些物质对心肌的损伤涉及GSK-3、Bcl-2、mTOR、PETN等PI3K/AKT通路的下游靶点参与,而GSK-3、Bcl-2、mTOR、PETNP等均受到PI3K/AKT通路的调控,并且能直接或间接影响CyPD的表达,CyPD作为心肌细胞线粒体上mPTP开放的关键蛋白,其表达的升高能够导致mPTP开放的阈值减低,从而加重心肌细胞的损伤;目前新出现的科学证据指出,酒精的摄入能够影响PI3K/AKT信号通路[43],而酒精的代谢过程中的产物ROS能够明显上调CyPD mRNA,其受到PI3K/AKT信号通路的影响。根据目前的研究,酒精或其代谢产物能够影响PI3K/AKT通路,而PI3K/AKT通路又能影响CyPD的表达,我们有理由推测酒精有可能通过PI3K/AKT通路干预CyPD的表达,从而导致心肌损伤。为酒精性心肌病的防治提供了新思路。

NOTES

*通讯作者。

参考文献

[1] Readnower, R.D., Hubbard, W.B., Kalimon, O.J., Geddes, J.W. and Sullivan, P.G. (2021) Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology. Cells, 10, Article 199.
https://doi.org/10.3390/cells10020199
[2] Sautchuk, R., Kalicharan, B.H., Escalera-Rivera, K., Jonason, J.H., Porter, G.A., Awad, H.A., et al. (2022) Transcriptional Regulation of Cyclophilin D by BMP/Smad Signaling and Its Role in Osteogenic Differentiation. eLife, 11, e75023.
https://doi.org/10.7554/elife.75023
[3] Georgios, A. and Elizabeth, M. (2020) Cyclophilin D: An Integrator of Mitochondrial Function. Frontiers in Physiology, 11, Article 595.
https://doi.org/10.3389/fphys.2020.00595
[4] Wong, C.X., Tu, S.J. and Marcus, G.M. (2023) Alcohol and Arrhythmias. JACC: Clinical Electrophysiology, 9, 266-279.
https://doi.org/10.1016/j.jacep.2022.10.023
[5] WHO (2021) Development of an Action Plan to Implement the Global Strategy to Reduce Harmful Use of Alcohol in the Eastern Mediterranean Region. Eastern Mediterranean Health Journal, 27, 1239-1240.
https://doi.org/10.26719/emhj.21.076
[6] Day, E. and Rudd, J.H.F. (2019) Alcohol Use Disorders and the Heart. Addiction, 114, 1670-1678.
https://doi.org/10.1111/add.14703
[7] Mogos, M.F., Salemi, J.L., Phillips, S.A. and Piano, M.R. (2019) Contemporary Appraisal of Sex Differences in Prevalence, Correlates, and Outcomes of Alcoholic Cardiomyopathy. Alcohol and Alcoholism, 54, 386-395.
https://doi.org/10.1093/alcalc/agz050
[8] Yusupova, A.O. (2014) Alcoholic Cardiomyopathy: Basic Aspects of Epidemiology, Pathogenesis and Pharmacotherapy. Rational Pharmacotherapy in Cardiology, 10, 651-658.
https://doi.org/10.20996/1819-6446-2014-10-6-651-658
[9] Hu, Q., Chen, H., Shen, C., Zhang, B., Weng, X., Sun, X., et al. (2022) Impact and Potential Mechanism of Effects of Chronic Moderate Alcohol Consumption on Cardiac Function in Aldehyde Dehydrogenase 2 Gene Heterozygous Mice. Alcoholism: Clinical and Experimental Research, 46, 707-723.
https://doi.org/10.1111/acer.14811
[10] Belosludtsev, K.N., Dubinin, M.V., Belosludtseva, N.V. and Mironova, G.D. (2019) Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochemistry (Moscow), 84, 593-607.
https://doi.org/10.1134/s0006297919060026
[11] Fernández-Solà, J. (2020) The Effects of Ethanol on the Heart: Alcoholic Cardiomyopathy. Nutrients, 12, Article 572.
https://doi.org/10.3390/nu12020572
[12] Kent, A.C., El Baradie, K.B.Y. and Hamrick, M.W. (2021) Targeting the Mitochondrial Permeability Transition Pore to Prevent Age‐Associated Cell Damage and Neurodegeneration. Oxidative Medicine and Cellular Longevity, 2021, Article ID: 6626484.
https://doi.org/10.1155/2021/6626484
[13] Auger, K.R., Serunian, L.A., Soltoff, S.P., Libby, P. and Cantley, L.C. (1989) PDGF-Dependent Tyrosine Phosphorylation Stimulates Production of Novel Polyphosphoinositides in Intact Cells. Cell, 57, 167-175.
https://doi.org/10.1016/0092-8674(89)90182-7
[14] Ruderman, N.B., Kapeller, R., White, M.F. and Cantley, L.C. (1990) Activation of Phosphatidylinositol 3-Kinase by Insulin. Proceedings of the National Academy of Sciences, 87, 1411-1415.
https://doi.org/10.1073/pnas.87.4.1411
[15] Andjelković, M., Maira, S., Cron, P., Parker, P.J. and Hemmings, B.A. (1999) Domain Swapping Used to Investigate the Mechanism of Protein Kinase B Regulation by 3-Phosphoinositide-Dependent Protein Kinase 1 and Ser473 Kinase. Molecular and Cellular Biology, 19, 5061-5072.
https://doi.org/10.1128/mcb.19.7.5061
[16] Panwar, V., Singh, A., Bhatt, M., Tonk, R.K., Azizov, S., Raza, A.S., et al. (2023) Multifaceted Role of mTOR (Mammalian Target of Rapamycin) Signaling Pathway in Human Health and Disease. Signal Transduction and Targeted Therapy, 8, Article No. 375.
https://doi.org/10.1038/s41392-023-01608-z
[17] Ilha, J., do Espírito-Santo, C.C. and de Freitas, G.R. (2018) mTOR Signaling Pathway and Protein Synthesis: From Training to Aging and Muscle Autophagy. In: Xiao, J., Ed., Muscle Atrophy, Springer, 139-151.
https://doi.org/10.1007/978-981-13-1435-3_7
[18] Zhang, R., Li, G., Zhang, Q., Tang, Q., Huang, J., Hu, C., et al. (2018) Hirsutine Induces mPTP-Dependent Apoptosis through ROCK1/PTEN/PI3K/GSK3β Pathway in Human Lung Cancer Cells. Cell Death & Disease, 9, Article No. 598.
https://doi.org/10.1038/s41419-018-0641-7
[19] Sun, Q., Jia, N., Li, X., Yang, J. and Chen, G. (2019) Grape Seed Proanthocyanidins Ameliorate Neuronal Oxidative Damage by Inhibiting GSK-3β-Dependent Mitochondrial Permeability Transition Pore Opening in an Experimental Model of Sporadic Alzheimer’s Disease. Aging, 11, 4107-4124.
https://doi.org/10.18632/aging.102041
[20] Morita, M., Gravel, S., Chénard, V., Sikström, K., Zheng, L., Alain, T., et al. (2013) mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation. Cell Metabolism, 18, 698-711.
https://doi.org/10.1016/j.cmet.2013.10.001
[21] Guo, Y., Wu, Y., Huang, T., Huang, D., Zeng, Q., Wang, Z., et al. (2024) Licorice Flavonoid Ameliorates Ethanol-Induced Gastric Ulcer in Rats by Suppressing Apoptosis via PI3K/AKT Signaling Pathway. Journal of Ethnopharmacology, 325, Article 117739.
https://doi.org/10.1016/j.jep.2024.117739
[22] Fayaz, S., Raj, Y. and Krishnamurthy, R. (2015) CYPD: The Key to the Death Door. CNS & Neurological Disorders-Drug Targets, 14, 654-663.
https://doi.org/10.2174/1871527314666150429113239
[23] Park, S.H. and Gye, M.C. (2024) Inhibition of Mitochondrial Cyclophilin D, a Downstream Target of Glycogen Synthase Kinase 3α, Improves Sperm Motility. Reproductive Biology and Endocrinology, 22, Article No. 15.
https://doi.org/10.1186/s12958-024-01186-x
[24] Wang, R.N., Green, J., Wang, Z., Deng, Y., Qiao, M., Peabody, M., et al. (2014) Bone Morphogenetic Protein (BMP) Signaling in Development and Human Diseases. Genes & Diseases, 1, 87-105.
https://doi.org/10.1016/j.gendis.2014.07.005
[25] Gauba, E., Chen, H., Guo, L. and Du, H. (2019) Cyclophilin D Deficiency Attenuates Mitochondrial F1fo ATP Synthase Dysfunction via OSCP in Alzheimer’s Disease. Neurobiology of Disease, 121, 138-147.
https://doi.org/10.1016/j.nbd.2018.09.020
[26] Ashe, H., Krakowiak, P., Hasterok, S., Sleppy, R., Roller, D.G. and Gioeli, D. (2021) Role of the Runt‐Related Transcription Factor (RUNX) Family in Prostate Cancer. The FEBS Journal, 288, 6112-6126.
https://doi.org/10.1111/febs.15804
[27] Farina, N.H., Zingiryan, A., Akech, J.A., Callahan, C.J., Lu, H., Stein, J.L., et al. (2016) A MicroRNA/Runx1/Runx2 Network Regulates Prostate Tumor Progression from Onset to Adenocarcinoma in TRAMP Mice. Oncotarget, 7, 70462-70474.
https://doi.org/10.18632/oncotarget.11992
[28] Zhang, H., Pan, Y., Zheng, L., Choe, C., Lindgren, B., Jensen, E.D., et al. (2011) FOXO1 Inhibits Runx2 Transcriptional Activity and Prostate Cancer Cell Migration and Invasion. Cancer Research, 71, 3257-3267.
https://doi.org/10.1158/0008-5472.can-10-2603
[29] Bai, Y., Yang, Y., Yan, Y., Zhong, J., Blee, A.M., Pan, Y., et al. (2019) RUNX2 Overexpression and PTEN Haploinsufficiency Cooperate to Promote CXCR7 Expression and Cellular Trafficking, AKT Hyperactivation and Prostate Tumorigenesis. Theranostics, 9, 3459-3475.
https://doi.org/10.7150/thno.33292
[30] Haiyan, F., Hao, T., Fa, J., et al. (2023) CypD Induced ROS Output Promotes Intracranial Aneurysm Formation and Rupture by 8-OHdG/NLRP3/MMP9 Pathway. Redox Biology, 67, Article 102887.
https://doi.org/10.1016/j.redox.2023.102887
[31] Wang, L., Ma, J., Chen, C., Lin, B., Xie, S., Yang, W., et al. (2024) Isoquercitrin Alleviates Pirarubicin-Induced Cardiotoxicity in vivo and in vitro by Inhibiting Apoptosis through Phlpp1/AKT/Bcl-2 Signaling Pathway. Frontiers in Pharmacology, 15, Article 1315001.
https://doi.org/10.3389/fphar.2024.1315001
[32] Yang, M., Lu, Y., Piao, W. and Jin, H. (2022) The Translational Regulation in mTOR Pathway. Biomolecules, 12, Article 802.
https://doi.org/10.3390/biom12060802
[33] Paquot, N. (2019) The Metabolism of Alcohol. Revue Medicale de Liege, 74, 265-267.
[34] Li, X., Luo, W., Tang, Y., Wu, J., Zhang, J., Chen, S., et al. (2024) Semaglutide Attenuates Doxorubicin-Induced Cardiotoxicity by Ameliorating BNIP3-Mediated Mitochondrial Dysfunction. Redox Biology, 72, Article 103129.
https://doi.org/10.1016/j.redox.2024.103129
[35] Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y. and Wei, X. (2019) Targeting PI3K in Cancer: Mechanisms and Advances in Clinical Trials. Molecular Cancer, 18, Article No. 26.
https://doi.org/10.1186/s12943-019-0954-x
[36] Ghafouri-Fard, S., Khanbabapour Sasi, A., Hussen, B.M., Shoorei, H., Siddiq, A., Taheri, M., et al. (2022) Interplay between PI3K/AKT Pathway and Heart Disorders. Molecular Biology Reports, 49, 9767-9781.
https://doi.org/10.1007/s11033-022-07468-0
[37] Chen, B., Hung, M., Wang, H., Yeh, L., Pandey, S., Chen, R., et al. (2018) GABA Tea Attenuates Cardiac Apoptosis in Spontaneously Hypertensive Rats (SHR) by Enhancing PI3K/Akt‐Mediated Survival Pathway and Suppressing Bax/Bak Dependent Apoptotic Pathway. Environmental Toxicology, 33, 789-797.
https://doi.org/10.1002/tox.22565
[38] Chen, Y., Sivalingam, K., Shibu, M.A., Peramaiyan, R., Day, C.H., Shen, C., et al. (2019) Protective Effect of Fisetin against Angiotensin II-Induced Apoptosis by Activation of IGF-IR-PI3K-Akt Signaling in H9c2 Cells and Spontaneous Hypertension Rats. Phytomedicine, 57, 1-8.
https://doi.org/10.1016/j.phymed.2018.09.179
[39] Liu, M., Li, Z., Liang, B., Li, L., Liu, S., Tan, W., et al. (2018) Hydrogen Sulfide Ameliorates Rat Myocardial Fibrosis Induced by Thyroxine through PI3K/AKT Signaling Pathway. Endocrine Journal, 65, 769-781.
https://doi.org/10.1507/endocrj.ej17-0445
[40] Sánchez-Alegría, K., Flores-León, M., Avila-Muñoz, E., Rodríguez-Corona, N. and Arias, C. (2018) PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions. International Journal of Molecular Sciences, 19, Article 3725.
https://doi.org/10.3390/ijms19123725
[41] Altomare, D.A., Lyons, G.E., Mitsuuchi, Y., Cheng, J.Q. and Testa, J.R. (1998) Akt2 mRNA Is Highly Expressed in Embryonic Brown Fat and the AKT2 Kinase Is Activated by Insulin. Oncogene, 16, 2407-2411.
https://doi.org/10.1038/sj.onc.1201750
[42] Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. and Bilanges, B. (2010) The Emerging Mechanisms of Isoform-Specific PI3K Signalling. Nature Reviews Molecular Cell Biology, 11, 329-341.
https://doi.org/10.1038/nrm2882
[43] Wang, W., Liu, M., Fu, X., Qi, M., Zhu, F., Fan, F., et al. (2024) Hydroxysafflor Yellow a Ameliorates Alcohol-Induced Liver Injury through PI3K/Akt and Stat3/NF-κB Signaling Pathways. Phytomedicine, 132, Article 155814.
https://doi.org/10.1016/j.phymed.2024.155814