Epigenetic and Transcriptional Modulator Potential of Epigallocatechin-3-gallate and Genistein on Fetal Hemoglobin Reactivators Genes  

作　　者：Edna Ribeiro Mariana Delgadinho Elisabete Matos Raquel Santos Daniela Sousa Heloísa Galante Miguel Britoa 

机构地区：[1]H&TRC-Health and Technology Research Center,ESTeSL-Escola Superior de Tecnologia da Saúde,Instituto Politécnico de Lisboa,Av.D.João II,Lote 4.69.01,Parque das Nações,Lisboa 1990-096,Portugal [2]Faculty of Sciences of the University of Lisbon,Universidade de Lisboa,Campo Grande 016,Lisboa 1749-016,Portugal

出　　处：《Clinical Complementary Medicine and Pharmacology》2022年第2期39-49,共11页临床补充医学和药理学（英文）

基　　金：an IDI&CA grant IPL/2019/HemoFet_ESTeSL and by H&TRC-Health&Technology Re-search Center,ESTeSL-Escola Superior de Tecnologia da Saúde,Insti-tuto Politécnico de Lisboa.

摘　　要：Background:𝛽-hemoglobinopathies are one of the most common recessive genetic diseases worldwide,with limited treatments available,particularly in developed countries where the prevalence is higher.Pharmacological reactivation of Fetal Hemoglobin(HbF)is a promising therapeutic strategy.However,approximately 25%of the patients do not respond to Hydroxyurea(HU),the first and most commonly used HbF inducing agent approved by the FDA.Objective:Here,we performed an in vitro assessment of transcriptional effects induced by natural bioactive compounds,namely Epigallocatechin-3-gallate(EGCG)and genistein(GN)in globin genes(HBA1,HBB,HBG1 and HBG2)in HbF regulators/silencer genes(KLF1,BCL11A,MYB and BGLT3)and in epigenetic regulator genes(DNMT1,DNMT3A,DNMT3B,HDAC1,HDAC2,HDAC3 and HDAC8).Moreover,we evaluated EGCG’s in vivo effects in hematological parameters of healthy volunteers.Methods:K562 cells were exposed for 72 and 96 h to GN and EGCG at 100,250 and 500 ng/mL.Cell proliferation and viability were measured,and transcriptional levels were evaluated by qRT-PCR.For in vivo assay,complete blood count was determined by flow cytometry and HbF level was determined through HPLC in 30 healthy individuals before and after 225 mg EGCG ingestion per day during a 90-day period.Results:Both compounds impact cellular metabolism and proliferation with no cytotoxic effects.Divergent GN and EGCG effects in globin and BGLT3 expression levels suggest the involvement of divergent signaling pathways.As for the epigenetic potential,EGCG particularly affects HDAC2 and HDAC8 transcription,whereas GN signifi-cantly affects expression patterns of methylation and acetylation modulators.HU appears to have time divergent effects,with greater impact in methylation at 72 h(overregulates DNTM3A)while affecting acetylation mostly at 96 h(downregulates HDAC1 and HDAC8).Additionally,in vivo,EGCG demonstrated a modulator effect in hematopoiesis and HbF induction.Conclusion:Our results advocate EGCG and GN with HbF pharmacological reactivation potent

关 键 词：Epigenetic modulators Fetal hemoglobin GENISTEIN Epigallocatechin-3-gallate In vitro transcriptional effects In vivo hematologic effects 

分 类 号：R73[医药卫生—肿瘤]