Qingshen granules inhibits dendritic cell glycolipid metabolism to alleviate renal fibrosis via PI3K-AKT-mTOR pathway.

Autor: Zhou WJ; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China., Liang W; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China., Hu MX; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China., Ma YK; Department of Pharmacy, the 902nd Hospital of the PLA Joint Logistics Support Force, Bengbu, China., Yu S; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China., Jin C; Department of Pharmacy, Sir Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China., Li JQ; School of Pharmacy, South-Central Minzu University, Wuhan, China., Wang C; Institute of Clinical Pharmacology, Anhui Medical University, the Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China., Wang CZ; Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, China., Gong P; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China., Wu QQ; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China., Wu CG; Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China. Electronic address: cgwu@ahtcm.edu.cn., Wang YP; Department of Nephrology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China. Electronic address: wypwyp54@aliyun.com., Liu TT; School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China. Electronic address: liutingting@ahmu.edu.cn.
Jazyk: angličtina
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2024 Dec; Vol. 135, pp. 156148. Date of Electronic Publication: 2024 Oct 10.
DOI: 10.1016/j.phymed.2024.156148
Abstrakt: Background: Qingshen exhibits anti-inflammatory and immunoregulation effects to renal damage. Dendritic cells (DCs) play a critical role in regulating the pathologic inflammatory environment in renal fibrosis (RF).
Purpose: To investigate the immune modulation mechanism of qingshen granule (QSG) in RF, particularly focusing on the role of DCs.
Methods/study Design: Adenine-induced RF animal models were used to study the pharmacological effects of QSG and the immune cells differentiation and function. Glucose uptake, non-esterified fatty acids secretion, mitochondrial membrane potential (MMP) detection, and qPCR were used to explore the effect of QSG to glucose and lipid metabolism in DCs and T cells. The effect of QSG to PI3K-AKT-mTOR axis and the modulation of mTOR to PD-L1 were explored by co-culture experiments, co-immunoprecipitation and western blot assays. The interaction of DCs/CD8 + T cells and renal tubular epithelial cells (RTECs) was investigated to demonstrate the direct action and/or the immune-mediated regulation of QSG to RF. The components of QSG in the serum were determined by HPLC. And the effect of active ingredients and formula to DCs and T cells was analyzed by cell experiments in vitro.
Results: QSG reduced nephritic histopathological damage and suppressed the release of proinflammatory cytokines in adenine-induced RF mice. Of note, QSG decreased the levels of CD86, MHC-II, and CCR7 on DCs, while, increased PD-L1 expression on DCs in RF. The results demonstrated that QSG promoted the maturation and inhibited the migration of DCs, and QSG decreased the antigen presenting of DCs to T cells. Additionally, QSG reduced the MMP and glucose/lipid utilization ratio in DCs. QSG also down-regulated the level of targeted metabolic genes included glucose transporter 1 (Glut1), sterol-regulatory element-binding protein 1 (Srebp1), acetyl-CoA carboxylase alpha (Acaca), phosphomevalonate kinase (Pmvk), and up-regulated sirtuin2 (Sirt2) in DCs. In terms of mechanism, QSG inhibited the metabolism-related PI3K-AKT-mTOR pathway, followed by regulating the interaction of mTOR with PD-L1 to enhance the membrane stability of PD-L1. Besides, HPLC analysis identified five active ingredients in QSG. The specific anti-inflammatory and immunosuppressive actions of these ingredients were found to be weaker than QSG as a whole. Finally, inhibiting DC function by QSG disrupted the communication among DCs, T cells, and RTECs. This disruption was associated with low expression of α-smooth muscle actin (α-SMA) and collagen type I (Col-I) in the kidney.
Conclusions: QSG inhibits DC metabolism and function via the PI3K-AKT-mTOR pathway to alleviate RF. The study highlights the importance of the specific composition of the formula in targeting DC-mediated immune regulation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier GmbH. All rights reserved.)
Databáze: MEDLINE
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