Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's disease

Liao, Yan; Xu, Jiahui; Qin, Biyan; Shi, Jie; Qin, Caolitao; Xie, Fang; Ou, Shiyu; Tang, Jing; Wang, Weidong; Wu, Fengfei; Bai, Lan

doi:10.1016/j.freeradbiomed.2021.05.018

Cited by 15 publications

(14 citation statements)

References 30 publications

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“…During obesity, adipose tissue macrophages polarize to M1-type macrophages, which then release inflammatory cytokines such as TNF-α [ 28 ].The infiltrating macrophages interact with adipocytes in a paracrine fashion to further increase the secretion of proinflammatory cytokines [ 12 ].This crosstalk between adipocytes and macrophages causes a vicious cycle in obese adipose tissue [ 29 ].Taking these previous reports and the present study into consideration, increased AOPPs in CKD could contribute to macrophage migration to adipocytes and its changing polarization then induces adipose tissue inflammation. Recently, Liao et al reported that AOPPs induced autophagy impairment in macrophages by suppressing the nuclear translocation of transcription factor EB (TFEB) through the activation of the PI3K-AKT-mTOR pathway [ 30 ]. Autophagy impairment in macrophages has been shown to induce M1 polarization [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Advanced Oxidation Protein Products Contribute to Chronic-Kidney-Disease-Induced Adipose Inflammation through Macrophage Activation

Arimura

Watanabe

Kato

et al. 2023

Toxins

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Fat atrophy and adipose tissue inflammation can cause the pathogenesis of metabolic symptoms in chronic kidney disease (CKD). During CKD, the serum levels of advanced oxidation protein products (AOPPs) are elevated. However, the relationship between fat atrophy/adipose tissue inflammation and AOPPs has remained unknown. The purpose of this study was to investigate the involvement of AOPPs, which are known as uremic toxins, in adipose tissue inflammation and to establish the underlying molecular mechanism. In vitro studies involved co-culturing mouse-derived adipocytes (differentiated 3T3-L1) and macrophages (RAW264.7). In vivo studies were performed using adenine-induced CKD mice and AOPP-overloaded mice. Fat atrophy, macrophage infiltration and increased AOPP activity in adipose tissue were identified in adenine-induced CKD mice. AOPPs induced MCP-1 expression in differentiated 3T3-L1 adipocytes via ROS production. However, AOPP-induced ROS production was suppressed by the presence of NADPH oxidase inhibitors and the scavengers of mitochondria-derived ROS. A co-culturing system showed AOPPs induced macrophage migration to adipocytes. AOPPs also up-regulated TNF-α expression by polarizing macrophages to an M1-type polarity, and then induced macrophage-mediated adipose inflammation. In vitro data was supported by experiments using AOPP-overloaded mice. AOPPs contribute to macrophage-mediated adipose inflammation and constitute a potential new therapeutic target for adipose inflammation associated with CKD.

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Section: Discussionmentioning

confidence: 99%

Advanced Oxidation Protein Products Contribute to Chronic-Kidney-Disease-Induced Adipose Inflammation through Macrophage Activation

Arimura

Watanabe

Kato

et al. 2023

Toxins

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“…To investigate the mechanism of Nod protection intestinal epithelial cell pyroptosis in depth, a network pharmacological prediction analysis found that PI3K/Akt might be involved. The PI3K/Akt pathway not only plays a key role in promoting the pyroptosis of microglial cells, podocytes and renal tubular epithelial cells [48][49][50][51] , but also participates in colitis [52][53][54] . To determine whether the PI3K/Akt pathway mediates the anti-colitis effect of Nod, we detected PI3K/Akt related proteins in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

Nodakenin ameliorated TNBS-induced experimental colitis in mice by inhibiting intestinal epithelial cell pyroptosis

Geng

Huang

et al. 2023

Preprint

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Background and Aims Pyroptosis of intestinal epithelial cells is associated with intestinal barrier dysfunction and the intestinal inflammatory symptoms of Crohn's disease (CD). The natural plant monomer, nodakenin (Nod), inhibits NOD-like receptor protein 3 (NLRP3) expression, and this study aimed to evaluate its effect on CD-like colitis, as well as possible mechanisms. Methods Using TNBS intervention mice as CD animal models, the therapeutic effect of Nod on CD-like colitis in mice was explored through disease activity index (DAI) analysis, weight change, histological analysis, inflammatory factor expression and intestinal barrier function. In addition, the direct effect of Nod on the pyroptosis of intestinal epithelial cells was explored by immunofluorescence and western blot detection in LPS-/ATP-induced colon organoid models. Furthermore, through bioinformatics and in vivo and in vitro experimental verification, the potential mechanism by which Nod protects intestinal epithelial cells was explored. Results Nod intervention improved colitis and intestinal barrier function in TNBS-induced mice, as demonstrated by improvements in weight loss, DAI, tissue inflammation score, proinflammatory factor expression, and intestinal permeability. In addition, Nod inhibited the pyroptosis of intestinal epithelial cells in colitis mice and LPS-/ATP-induced colon organoids, as well as the expression of key pyroptosis regulators, such as NLRP3, GSDMD-N, and cleaved-caspase-1. Mechanistically, Nod inhibited the activation of PI3K/Akt signalling a in intestinal epithelial cells in TNBS-induced mice and LPS-/ATP-induced colonic organoids. Conclusions Nod restrained the pyroptosis of intestinal epithelial cells to protect the intestinal barrier of CD-like colitis by inhibiting PI3K/Akt signalling, this may provide a new option for the treatment of Crohn's disease.

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“…Their results have demonstrated that autophagy in the uterine vessel microenvironment is critical for controlling vascular permeability in murine uterus. In addition, it has been repored that AOPPs impair autophagic flux in macrophage by inducing lysosomal dysfunction through the PI3K-Akt-mTOR pathway, and play an important role in Crohn’s disease progression ( Liao et al, 2021 ). Activated autophagy has been reported in the placentae of women with PE ( Nakashima et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Advanced Oxidative Protein Products Drive Trophoblast Cells Into Senescence by Inhibiting the Autophagy: The Potential Implication of Preeclampsia

Wang

2022

Front. Cell Dev. Biol.

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Introduction: Advanced oxidation protein products (AOPPs), the novel marker of oxidative stress, have been found to be elevated in preeclampsia (PE). To date, the effect of AOPPs on the senescence of trophoblast cells is still unclear. In this study, we investigated whether AOPPs promoted the senescence of trophoblast cells and explored the underlying mechanisms of AOPPs-induced aging process which may facilitate the progression of PE.Methods: The trophoblast cell line HTR-8/SV neo cells were cultured in the presence of PBS, AOPPs, AOPPs plus an anti-oxidant N-acetyl-L-cysteine (NAC). In some experiments, cells were pre-treated with rapamycin (an activator of autophagy), 3-MA (an inhibitor of autophagy), or cyclic pifithrin-α (PFT-α, an antagonist of p53), and then treated with AOPPs. Cellular senescence was analyzed by measuring the levels of senescence-associated β-galactosidase (SA β-Gal), senescence-associated heterochromatin foci (SAHF), mitochondrial membrane potential (ΔΨm), and cell cycle. Cell autophagic flux was analyzed by measuring tandem fluorescence-tagged LC3 reporter (mCherry-EGFP-LC3). Levels of p53, phosphorylated p53 (p-p53), p21, BECN1, p62, p-mTOR and p-p70S6K were measured by western blot.Results: Treatment with AOPPs significantly increased the levels of SA β-Gal and SAHF, the percentage of cells in the G0/G1 phase, and decreased cell ΔΨm compared with the control group. Co-treatment with NAC and AOPPs significantly reversed AOPPs-induced senescence. Pre-treatment with rapamycin or 3-MA significantly inhibited or promoted AOPPs-induced senescence, respectively. In addition, administration of AOPPs significantly decreased the numbers of mCherry+EGFP+ autophagosomes and mCherry+EGFP- autolysosomes in cells compared with cells treated with PBS. Furthermore, AOPPs significantly increased the levels of proteins p-p53, p21, p-mTOR and p-p70S6K compared with the control group. Pre-treatment with rapamycin or PFT-α significantly down-regulated the levels of SA β-Gal, SAHF, p-p53, p21, autophagy related protein p62, the percentage of cells in the G0/G1 phase, and significantly up-regulated ΔΨm, autophagy related protein BECN1, autophagosomes and autolysosomes compared with cells only treated with AOPPs.Conclusion: AOPPs may induce trophoblast cell senescence by inhibiting the autophagy process in a p53/mTOR/p70S6K-dependent pathway.

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Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's disease

Cited by 15 publications

References 30 publications

Advanced Oxidation Protein Products Contribute to Chronic-Kidney-Disease-Induced Adipose Inflammation through Macrophage Activation

Advanced Oxidation Protein Products Contribute to Chronic-Kidney-Disease-Induced Adipose Inflammation through Macrophage Activation

Nodakenin ameliorated TNBS-induced experimental colitis in mice by inhibiting intestinal epithelial cell pyroptosis

Advanced Oxidative Protein Products Drive Trophoblast Cells Into Senescence by Inhibiting the Autophagy: The Potential Implication of Preeclampsia

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