Trilobatin rescues cognitive impairment of Alzheimer’s disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway

Gao, Jianmei; Zhang, Xun; Shu, Guotao; Chen, Nana; Zhang, Jianyong; Xu, Fan; Li, Fēi; Liu, Yuangui; Wei, Yu; He, Yuqi; Shi, Jingshan; Gong, Qihai

doi:10.1038/s41401-022-00888-5

Cited by 42 publications

(15 citation statements)

References 51 publications

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“…Through the analysis of the joint algorithm, we finally obtained 10 genes most associated with AD as Hub genes (NOX5, DUOX2, ALOX15B, CDKN2A, BAP1, HMGB1, IFNA17, BRD4, P4HB, PPARD). DUOX2 ( Samadi et al, 2011 ), CDKN2A ( Tedde et al, 2011 ; Antonell et al, 2016 ), HMGB1 ( Alabed et al, 2021 ; Tanaka et al, 2021 ; Gao et al, 2022 ), BRD4 ( Nikkar et al, 2022 ; Zhang et al, 2022 ) and PPARD ( Holzapfel et al, 2006 ; Helisalmi et al, 2008 ) have been experimentally validated in the pathogenesis of AD, but NOX5, ALOX15, B, BAP1, IFNA17 and P4HB have never been studied to confirm their association with AD. The current study demonstrates that NOX5 is highly expressed in the CNS and that upregulation of its expression level can induce inflammation by mediating COX2 activation or the PG pathway ( Marqués et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Discovery and validation of Ferroptosis-related molecular patterns and immune characteristics in Alzheimer’s disease

Cong

Liang

et al. 2022

Front. Aging Neurosci.

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BackgroundTo date, the pathogenesis of Alzheimer’s disease is still not fully elucidated. Much evidence suggests that Ferroptosis plays a crucial role in the pathogenesis of AD, but little is known about its molecular immunological mechanisms. Therefore, this study aims to comprehensively analyse and explore the molecular mechanisms and immunological features of Ferroptosis-related genes in the pathogenesis of AD.Materials and methodsWe obtained the brain tissue dataset for AD from the GEO database and downloaded the Ferroptosis-related gene set from FerrDb for analysis. The most relevant Hub genes for AD were obtained using two machine learning algorithms (Least absolute shrinkage and selection operator (LASSO) and multiple support vector machine recursive feature elimination (mSVM-RFE)). The study of the Hub gene was divided into two parts. In the first part, AD patients were genotyped by unsupervised cluster analysis, and the different clusters’ immune characteristics were analysed. A PCA approach was used to quantify the FRGscore. In the second part: we elucidate the biological functions involved in the Hub genes and their role in the immune microenvironment by integrating algorithms (GSEA, GSVA and CIBERSORT). Analysis of Hub gene-based drug regulatory networks and mRNA-miRNA-lncRNA regulatory networks using Cytoscape. Hub genes were further analysed using logistic regression models.ResultsBased on two machine learning algorithms, we obtained a total of 10 Hub genes. Unsupervised clustering successfully identified two different clusters, and immune infiltration analysis showed a significantly higher degree of immune infiltration in type A than in type B, indicating that type A may be at the peak of AD neuroinflammation. Secondly, a Hub gene-based Gene-Drug regulatory network and a ceRNA regulatory network were successfully constructed. Finally, a logistic regression algorithm-based AD diagnosis model and Nomogram diagram were developed.ConclusionOur study provides new insights into the role of Ferroptosis-related molecular patterns and immune mechanisms in AD, as well as providing a theoretical basis for the addition of diagnostic markers for AD.

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Section: Discussionmentioning

confidence: 99%

Discovery and validation of Ferroptosis-related molecular patterns and immune characteristics in Alzheimer’s disease

Cong

Liang

et al. 2022

Front. Aging Neurosci.

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“…Theacrine, a purine alkaloid found in Chinese tea has been shown to activate SIRT3 and restore mitochondrial functions in multiple animal models of PD, namely, 6-OHDA-treated rats, MPTP-treated mice and zebrafish [ 184 ]. Trilobatin, a plant-based sweetener, inhibits Aβ (25-35) action, activates Sirt3/SOD2 signaling and reduces neuroinflammation both in vivo (APP/PS1 transgenic mice) and in vitro (Aβ 25–35 -treated BV2 cells) models [ 185 ]. The anti-apoptotic action of sesamin and sesamol, compounds derived from sesame seeds, involves the activation of SIRT1 and SIRT3 [ 186 ].…”

Section: Translational Significance Of Sirt3 Activationmentioning

confidence: 99%

A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

Tyagi

Pugazhenthi

2023

IJMS

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SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3’s functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise. SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. The pure form of Alzheimer’s disease (AD) is rare, and it has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3’s roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.

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“…There are various approaches to the study of cognition in a neutral setup, mainly the novel object recognition (NOR) test (Sawangjit et al., 2018; Winters & Reid, 2010), which makes use of the animal's curiosity for novelty; the spatial object recognition (SOR) test (Lopes da Cunha et al., 2019), which is specifically used for spatial memory studies; and the Y‐maze (Gao et al., 2022), which is used for working memory studies. The present paradigms can be used for testing learned memory behaviors that are not associated with aversion or reward.…”

Section: Commentarymentioning

confidence: 99%

An Open‐Field‐Based Unimodal Object Recognition Test (OF‐UORT) for Assessment of Chronic Stress Effects on Visual and Tactile Unimodal Cognition in Mice

Wang,

You,

Wang

2023

Current Protocols

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The open field (OF) test is a widely used behavioral assay in animal studies to assess locomotion, emotion, and cognition. In open‐field‐based object recognition tasks, the open arena is equipped with combinations of objects to allow the examination of various aspects of learning and memory. In this article, we provide a protocol for open‐field‐based unimodal memory tests that assess tactile or visual unimodal cognitive behavior in mice. These tests do not require mice to be restricted from eating or drinking and do not involve aversive stimuli, such as electric shock, high‐decibel sound waves, bright light, or forced swimming. Inside the apparatus, mice can freely and spontaneously explore the objects and the environment. Sniffing of, or direct contact with, objects is considered a cognitive exploration of the objects, and the timing and number of such behaviors can be recorded. During the acquisition phase, two identical objects are provided. After an intertrial interval, the retrieval phase is initiated, during which one object is replaced with a new object that is different from the previous one. Decorative clear domes are used prevent direct tactile contact with the objects, whereas infrared illumination is used to block visual information from the objects. By alternating the access to visual or tactile features of the objects in the acquisition and retrieval phases, the experimenters can assess visual or tactile unimodal cognition. Here, we describe our own instrumentation and application for experiments, and demonstrate that the modified device is capable of testing visual or tactile unimodal cognition in mice. Although easy to perform, this task/test can accurately reflect unimodal cognitive performance in mice, which can provide solid and reproducible data support to related studies. © 2023 Wiley Periodicals LLC.Basic Protocol 1: Validation of the open‐field‐based unimodal object recognition testBasic Protocol 2: Evaluation of chronic stress effects on unimodal cognition using the open‐field‐based unimodal cognitive test

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Trilobatin rescues cognitive impairment of Alzheimer’s disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway

Cited by 42 publications

References 51 publications

Discovery and validation of Ferroptosis-related molecular patterns and immune characteristics in Alzheimer’s disease

Discovery and validation of Ferroptosis-related molecular patterns and immune characteristics in Alzheimer’s disease

A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

An Open‐Field‐Based Unimodal Object Recognition Test (OF‐UORT) for Assessment of Chronic Stress Effects on Visual and Tactile Unimodal Cognition in Mice

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