人参皂苷化合物K对SIRT1和AMPK的相互调节,以B细胞特异性的方式阻碍了MRL/lpr小鼠从浆细胞到足细胞损伤的转化

IF 6.8 2区 医学 Q1 CHEMISTRY, MEDICINAL Journal of Ginseng Research Pub Date : 2023-12-03 DOI:10.1016/j.jgr.2023.11.006
Ziyu Song , Meng Jin , Shenglong Wang , Yanzuo Wu , Qi Huang , Wangda Xu , Yongsheng Fan , Fengyuan Tian
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摘要

背景:在狼疮肾炎(LN)的初始阶段,免疫复合物的沉积驱动足细胞损伤,这是一个由B细胞参与介导的过程。因此,靶向B细胞亚群代表了LN的潜在治疗方法。人参皂苷化合物K (CK)是人参的一种生物利用成分,对狼疮易感小鼠具有肾炎作用;然而,涉及B细胞亚群的潜在机制仍然难以捉摸。方法给雌性MRL/lpr小鼠灌胃CK(40 mg/kg) 10周,检测肾脏样本的抗dsdna抗体、炎症趋化因子和代谢物谱。检测足细胞功能和超微结构。利用公开的单细胞RNA测序数据和流式细胞术分析来研究B细胞亚群。采用代谢组学分析。采用免疫印迹法和免疫荧光法分析SIRT1和AMPK的表达。结果sck通过抑制循环抗dsdna抗体和减轻全身炎症,减少MRL/lpr小鼠蛋白尿和保护足细胞超微结构。它激活B细胞特异性SIRT1和AMPK,鼠李糖积累,阻碍肾B细胞转化为浆细胞。这种级联反应促进了局部肾脏炎症的消退。CK通过使nephrin和SYNPO的表达正常化,促进沉积的免疫复合物的清除,从而恢复足细胞的形态和流动性。结论sour研究揭示了SIRT1和AMPK之间的协同相互作用,协调肾脏B细胞亚群的恢复。这一过程有效地减轻了免疫复合物的沉积,并保持足细胞的功能。因此,CK成为一种有前景的治疗剂,可能减轻LN期间肾B细胞亚群的过度活跃。
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Reciprocal regulation of SIRT1 and AMPK by Ginsenoside compound K impedes the conversion from plasma cells to mitigate for podocyte injury in MRL/lpr mice in a B cell-specific manner

Background

Deposition of immune complexes drives podocyte injury acting in the initial phase of lupus nephritis (LN), a process mediated by B cell involvement. Accordingly, targeting B cell subsets represents a potential therapeutic approach for LN. Ginsenoside compound K (CK), a bioavailable component of ginseng, possesses nephritis benefits in lupus-prone mice; however, the underlying mechanisms involving B cell subpopulations remain elusive.

Methods

Female MRL/lpr mice were administered CK (40 mg/kg) intragastrically for 10 weeks, followed by measurements of anti-dsDNA antibodies, inflammatory chemokines, and metabolite profiles on renal samples. Podocyte function and ultrastructure were detected. Publicly available single-cell RNA sequencing data and flow cytometry analysis were employed to investigate B cell subpopulations. Metabolomics analysis was adopted. SIRT1 and AMPK expression were analyzed by immunoblotting and immunofluorescence assays.

Results

CK reduced proteinuria and protected podocyte ultrastructure in MRL/lpr mice by suppressing circulating anti-dsDNA antibodies and mitigating systemic inflammation. It activated B cell-specific SIRT1 and AMPK with Rhamnose accumulation, hindering the conversion of renal B cells into plasma cells. This cascade facilitated the resolution of local renal inflammation. CK facilitated the clearance of deposited immune complexes, thus reinstating podocyte morphology and mobility by normalizing the expression of nephrin and SYNPO.

Conclusions

Our study reveals the synergistic interplay between SIRT1 and AMPK, orchestrating the restoration of renal B cell subsets. This process effectively mitigates immune complex deposition and preserves podocyte function. Accordingly, CK emerges as a promising therapeutic agent, potentially alleviating the hyperactivity of renal B cell subsets during LN.

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来源期刊
Journal of Ginseng Research
Journal of Ginseng Research CHEMISTRY, MEDICINAL-INTEGRATIVE & COMPLEMENTARY MEDICINE
CiteScore
11.40
自引率
9.50%
发文量
111
审稿时长
6-12 weeks
期刊介绍: Journal of Ginseng Research (JGR) is an official, open access journal of the Korean Society of Ginseng and is the only international journal publishing scholarly reports on ginseng research in the world. The journal is a bimonthly peer-reviewed publication featuring high-quality studies related to basic, pre-clinical, and clinical researches on ginseng to reflect recent progresses in ginseng research. JGR publishes papers, either experimental or theoretical, that advance our understanding of ginseng science, including plant sciences, biology, chemistry, pharmacology, toxicology, pharmacokinetics, veterinary medicine, biochemistry, manufacture, and clinical study of ginseng since 1976. It also includes the new paradigm of integrative research, covering alternative medicinal approaches. Article types considered for publication include review articles, original research articles, and brief reports. JGR helps researchers to understand mechanisms for traditional efficacy of ginseng and to put their clinical evidence together. It provides balanced information on basic science and clinical applications to researchers, manufacturers, practitioners, teachers, scholars, and medical doctors.
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