Implication of Let7b/AhR/ARNT/HMGB1/RAGE cascade in neuroplasticity disturbances induced by glucocorticoids and the promising reversible effect of 3,3 diindolymethane: Bidirectional crosstalk of Aryl hydrocarbon receptors

IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2025-02-01 DOI:10.1016/j.bcp.2024.116692
Mai A. Abd-Elmawla , Asmaa A. ElMonier , Enas S. Gad , Haneen Y. Khidr , May A. Azzam
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Abstract

Prolonged exposure to glucocorticoids (GC) disrupts neuronal architecture, hinders neuroplasticity, and triggers neuroinflammation. However, the precise underlying mechanisms have not been studied yet. The current study aimed to investigate the mechanisms of GC-induced neuroinflammatory effects by stimulating the miRNA let7b, aryl hydrocarbon receptor (AhR)/ARNT, HMGB1/RAGE, and other downstream targets. Rats were divided into 4 groups; control, GC (20 mg/kg, S.C.), 3,3′-diindolylmethane (DIM) 50 mg/kg/day, and donepezil (DNZ) 4 mg/kg/day for 21 days. Behavioral tests and histopathological investigations of cerebral cortex were done. Let7b, AhR, ARNT, and cytochrome A1A were estimated using qRT-PCR. HMGB1, RAGE, NQO1and NRF2 were estimated using ELISA, whereas GFAP and TNF-α by immunohistochemical analysis. Keap1 was estimated using Western technique. GSH and TBARS were assessed by colorimetric assay. In the current study, GC elevates the gene expressions of let7b, AhR, ARNT, and cytochrome A1A, along with the protein contents of HMGB1, RAGE, NQO1and NRF2. In addition, GC showed increased GFAP, TNF-α, and TBARS, together with decreased Keap1 and GSH. On the other side, DIM and DNZ reversed all the above-mentioned findings. Collectively, the study documents for the first time the effect of GC in upregulating let7b and activating the AhR/ARNT loop which subsequently stimulates RAGE/HMGB1 and NRF2/Keap1 cascade leading to stimulating further inflammatory and oxidative signaling pathways. Certainly, these effects are responsible for the behavioral fluctuations, the brain’s histological disruption, altered neuroplasticity, and neuroinflammation induced by GC. Moreover, DIM conquers GC-induced neuroinflammation due to its characteristic role in modulating AhR and its downstream targets.

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Let7b/AhR/ARNT/HMGB1/RAGE级联在糖皮质激素诱导的神经可塑性障碍中的意义及3,3二吲哚甲烷的有希望的可逆作用:芳烃受体的双向串扰
长期暴露于糖皮质激素(GC)会破坏神经元结构,阻碍神经可塑性,并引发神经炎症。然而,确切的潜在机制尚未被研究。本研究旨在通过刺激miRNA let7b、芳烃受体(AhR)/ARNT、HMGB1/RAGE等下游靶点,探讨gc诱导神经炎症效应的机制。将大鼠分为4组;对照,GC(20 mg/kg, S.C.), 3,3'-二吲哚甲烷(DIM) 50 mg/kg/d,多奈哌齐(DNZ) 4 mg/kg/d,共21 d。进行行为学试验和大脑皮层组织病理学检查。使用qRT-PCR方法估计Let7b、AhR、ARNT和细胞色素A1A。ELISA法测定HMGB1、RAGE、nqo1、NRF2,免疫组化法测定GFAP、TNF-α。采用Western技术估计Keap1。用比色法测定GSH和TBARS。在本研究中,GC上调了let7b、AhR、ARNT和细胞色素A1A的基因表达,以及HMGB1、RAGE、nqo1和NRF2的蛋白含量。GFAP、TNF-α和TBARS升高,Keap1和GSH降低。另一方面,DIM和DNZ逆转了上述所有发现。总的来说,该研究首次证明了GC在上调let7b和激活AhR/ARNT环中的作用,该环随后刺激RAGE/HMGB1和NRF2/Keap1级联,从而刺激进一步的炎症和氧化信号通路。当然,这些影响是导致GC引起的行为波动、大脑组织破坏、神经可塑性改变和神经炎症的原因。此外,DIM由于其在调节AhR及其下游靶点方面的特殊作用,可以克服gc诱导的神经炎症。
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来源期刊
Biochemical pharmacology
Biochemical pharmacology 医学-药学
CiteScore
10.30
自引率
1.70%
发文量
420
审稿时长
17 days
期刊介绍: Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.
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