Calycosin inhibits lytic replication of Kaposi’s sarcoma-associated herpesvirus by downregulating early growth response 1

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-24 DOI:10.1016/j.phymed.2025.156884

Yue Liu , Jiale Wang , Si-Wei Cheng , Xin Chen , Zhantao Bai , Yan-Heng Zhou

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引用次数: 0

Abstract

Background

Kaposi’s sarcoma-associated herpesvirus (KSHV) is linked to several diseases, including primary effusion lymphoma, multicentric Castleman’s disease, and KSHV inflammatory cytokine syndrome. Current treatment options for KSHV-associated diseases are sometimes ineffective, and antiviral drugs are still lacking. Calycosin (CA), an O-methylated isoflavone found in Astragalus membranaceus, has previously demonstrated strong activity against coxsackievirus B3 (CVB3) and human immunodeficiency virus (HIV), but its effect against KSHV has not been previously reported.

Methods

Viral lytic replication was evaluated via both the relative quantification of viral DNA within cells and the absolute quantification of viral genomes in cellular supernatants. RNA sequencing was employed to identify key genes involved in the anti-KSHV process for CA. Real-time PCR and western blotting were utilized to elucidate gene expression. Ectopic gene expression was delivered by plasmid transfection or lentivirus transduction.

Results

CA dose-dependently inhibited KSHV lytic replication in both KSHV latently infected cells and de novo-infected human umbilical vein endothelial cells (HUVECs) without causing cytotoxicity. Further investigation of the anti-KSHV mechanism revealed that CA downregulated the expression of early growth response 1 (EGR1), consequently suppressing the promoter activity of replication and transcription activator (RTA), which is a crucial switch triggering KSHV from latency to lytic replication. Additionally, CA suppressed inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8) induced by KSHV infection, and this suppression was EGR1 dependent.

Conclusion

This study for the first time reported the function and mechanism of CA in inhibiting the lytic replication of KSHV, providing a new candidate for anti-KSHV agents. Moreover, these findings expand the understanding of the pharmacological values of CA.

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毛蕊异黄酮通过下调早期生长反应抑制卡波西肉瘤相关疱疹病毒的裂解复制

卡波西肉瘤相关疱疹病毒（KSHV）与多种疾病有关，包括原发性积液性淋巴瘤、多中心Castleman病和KSHV炎性细胞因子综合征。目前对kshv相关疾病的治疗方案有时是无效的，而且仍然缺乏抗病毒药物。Calycosin （CA）是一种在黄芪中发现的o -甲基化异黄酮，先前已证明对柯萨奇病毒B3 （CVB3）和人类免疫缺陷病毒（HIV）有很强的活性，但其对KSHV的作用尚未报道。方法通过细胞内病毒DNA的相对定量和细胞上清中病毒基因组的绝对定量来评价病毒的裂解复制。采用RNA测序技术鉴定CA抗kshv过程中涉及的关键基因，采用Real-time PCR和western blotting技术分析基因表达。异位基因通过质粒转染或慢病毒转导传递。结果sca对KSHV潜伏感染细胞和新生感染的人脐静脉内皮细胞（HUVECs）的KSHV裂解复制均有剂量依赖性抑制，但不产生细胞毒性。对抗KSHV机制的进一步研究表明，CA下调了早期生长反应1 （EGR1）的表达，从而抑制了复制和转录激活子（RTA）的启动子活性，RTA是触发KSHV从潜伏期到裂解复制的关键开关。此外，CA抑制KSHV感染诱导的炎症细胞因子，如白细胞介素-6 （IL-6）和白细胞介素-8 (IL-8)，这种抑制依赖于EGR1。结论本研究首次报道了CA抑制KSHV裂解复制的功能和机制，为抗KSHV提供了新的候选药物。此外，这些发现扩大了对CA药理学价值的理解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.