The adaptor protein c-Cbl-associated protein (CAP) limits pro-inflammatory cytokine expression by inhibiting the NF-κB pathway

Vdovenko, Daria; Bachmann, M F; Wijnen, Winandus J; Hottiger, Michael O.; Eriksson, Urs; Valaperti, Alan

doi:10.1016/j.intimp.2020.106822

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…The level of Sorbin and SH3 domain-containing protein 2 (SORBS2) lowered in the brains of APP/PS1 mice. SORBS2 suppressed the expression of IL-6 and partially blocked the NF-κB-p65 pathway after Toll-like receptor stimulation [ 27 ]. The level of Plexin-B2 (PLXNB2) was enhanced in the brains of APP/PS1 mice.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, the downregulated SORBS2 was observed in the heart tissues of LPS-treated C57BL/6 mice [ 42 ]. The silence of SORBS2 in mouse embryonic fibroblasts led to the higher expression of IL-6 RNA [ 27 ]. Accordingly, VB regulated the levels of PLXNB2 and SORBS2 in brains of APP/PS1 mice, LPS-induced BV2 cells, and Aβ 1-42 -exposed N2a cells, which implied the neuroprotection of VB was related to the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

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The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

et al. 2022

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Verbascoside (VB) is a phenylethanoid glycoside extracted from the herbaceous plant Verbascum sinuatum and plays a neuroprotective role in Alzheimer’s disease (AD). The goal of this study was to explore the neuroprotective mechanism of VB. Based on the proteomics analysis, immunohistochemistry, immunofluorescence, Western blot, and ELISA were utilized to explore the neuroprotective mechanism of VB in context of neuroinflammation in APP/PS1 mice, LPS-induced BV2 cells, and/or Aβ1-42-stimulated N2a cells. Proteomic analysis demonstrated that the neuroprotection of VB correlated closely to its anti-inflammatory effect. VB significantly blocked microglia and astrocyte against activation in brains of APP/PS1 mice, suppressed the generation of IL-1β as well as IL-6, and boosted that of IL-4, IL-10 and TGF-β in vivo, which were analogous to results acquired in vitro. Furthermore, VB effectively restrained the phosphorylation of IKKα+β, IκBα, and NF-κB-p65 in APP/PS1 mice; LPS-induced BV2 cells, and Aβ1-42-stimulated N2a cells and lowered the tendency of NF-κB-p65 translocation towards nucleus in vitro. These results demonstrate that the neuroprotective effect of VB correlates to the modulation of neuroinflammation via NF-κB-p65 pathway, making VB as a hopeful candidate drug for the prevention and treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

et al. 2022

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“…It was hypothesized that competing endogenous RNAs (ceRNAs) enable lncRNAs and miRNAs to form extensive regulatory networks in cells (Salmena et al, 2011). Previous studies have indicated that lncRNAs play pivotal roles in osteogenesis (Schmitz et al, 2016;Uszczynska-Ratajczak et al, 2018;Yang et al, 2018;Silva et al, 2019;Lanzillotti et al, 2021); they regulate osteoblastic differentiation through canonical signaling pathways and key transcription factors. However, the molecular functions and mechanisms of lncRNA-miRNA-mRNA networks in the early stages of osteogenesis in BMSCs have not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNAs LOC100126784 and POM121L9P Derived From Bone Marrow Mesenchymal Stem Cells Enhance Osteogenic Differentiation via the miR-503-5p/SORBS1 Axis

Xin

Sun

et al. 2021

Front. Cell Dev. Biol.

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Long non-coding RNAs (lncRNAs) play pivotal roles in mesenchymal stem cell differentiation. However, the mechanisms by which non-coding RNA (ncRNA) networks regulate osteogenic differentiation remain unclear. Therefore, our aim was to identify RNA-associated gene and transcript expression profiles during osteogenesis in bone marrow mesenchymal stem cells (BMSCs). Using transcriptome sequencing for differentially expressed ncRNAs and mRNAs between days 0 and 21 of osteogenic differentiation of BMSCs, we found that the microRNA (miRNA) miR-503-5p was significantly downregulated. However, the putative miR-503-5p target, sorbin and SH3 domain containing 1 (SORBS1), was significantly upregulated in osteogenesis. Moreover, through lncRNA-miRNA-mRNA interaction analyses and loss- and gain-of-function experiments, we discovered that the lncRNAs LOC100126784 and POM121L9P were abundant in the cytoplasm and enhanced BMSC osteogenesis by promoting SORBS1 expression. In contrast, miR-503-5p reversed this effect. Ago2 RNA-binding protein immunoprecipitation and dual-luciferase reporter assays further validated the direct binding of miR-503-5p to LOC100126784 and POM121L9P. Furthermore, SORBS1 knockdown suppressed early osteogenic differentiation in BMSCs, and co-transfection with SORBS1 small interfering RNAs counteracted the BMSCs’ osteogenic capacity promoted by LOC100126784- and POM121L9P-overexpressing lentivirus plasmids. Thus, the present study demonstrated that the lncRNAs LOC100126784 and POM121L9P facilitate the osteogenic differentiation of BMSCs via the miR-503-5p/SORBS1 axis, providing potential therapeutic targets for treating osteoporosis and bone defects.

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“…and TNF-α expression in the mouse embryonic fibroblasts, 71 and Chen et al demonstrated that the level of SORBS2 was lower in the brains of AD model mice compared to wild type mice, 68 implying a role of SORBS2 in regulating neuroinflammation. In a human study of families that multiply affected by AD, Lee et al reported that genetic variation in SORBS2 was associated with age at onset of AD.…”

Section: Discussionmentioning

confidence: 99%

“…As SORBS2 is well known for its role in AD and neuroinflammation 68 , 69 and has also been associated with PM 2.5 exposure in rats, 70 our findings contribute to the growing body of evidence of SORBS2 expression playing a role in PM 2.5 associated changes in neuropathology markers of AD. SORBS2 was found to repress IL‐6 and TNF‐α expression in the mouse embryonic fibroblasts, 71 and Chen et al. demonstrated that the level of SORBS2 was lower in the brains of AD model mice compared to wild type mice, 68 implying a role of SORBS2 in regulating neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Differential DNA methylation in the brain as potential mediator of the association between traffic‐related PM_2.5 and neuropathology markers of Alzheimer's disease

Li,

Liang,

Ebelt

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONGrowing evidence indicates that fine particulate matter (PM2.5) is a risk factor for Alzheimer's disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as a potential mediator of this association.METHODSWe assessed genome‐wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD‐related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors’ residential traffic‐related PM2.5 exposure 1, 3, and 5 years prior to death. We used a combination of the Meet‐in‐the‐Middle approach, high‐dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs.RESULTSPM2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty‐four CpG sites were identified as mediators of the association between PM2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation.DISCUSSIONOur findings suggest differential DNAm related to neuroinflammation mediates the association between traffic‐related PM2.5 and AD.Highlights First study to evaluate the potential mediation effect of DNA methylation for the association between PM2.5 exposure and neuropathological changes of Alzheimer's disease. Study was based on brain tissues rarely investigated in previous air pollution research. Cg10495669, assigned to RBCK1 gene playing a role in inflammation, was associated consistently with 1‐year, 3‐year, and 5‐year traffic‐related PM2.5 exposures prior to death. Meet‐in‐the‐middle approach and high‐dimensional mediation analysis were used simultaneously to increase the potential of identifying the differentially methylated CpGs. Differential DNAm related to neuroinflammation was found to mediate the association between traffic‐related PM2.5 and Alzheimer's disease.

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The adaptor protein c-Cbl-associated protein (CAP) limits pro-inflammatory cytokine expression by inhibiting the NF-κB pathway

Cited by 10 publications

References 32 publications

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

Long Non-coding RNAs LOC100126784 and POM121L9P Derived From Bone Marrow Mesenchymal Stem Cells Enhance Osteogenic Differentiation via the miR-503-5p/SORBS1 Axis

Differential DNA methylation in the brain as potential mediator of the association between traffic‐related PM_2.5 and neuropathology markers of Alzheimer's disease

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The adaptor protein c-Cbl-associated protein (CAP) limits pro-inflammatory cytokine expression by inhibiting the NF-κB pathway

Cited by 10 publications

References 32 publications

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

Long Non-coding RNAs LOC100126784 and POM121L9P Derived From Bone Marrow Mesenchymal Stem Cells Enhance Osteogenic Differentiation via the miR-503-5p/SORBS1 Axis

Differential DNA methylation in the brain as potential mediator of the association between traffic‐related PM2.5 and neuropathology markers of Alzheimer's disease

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Differential DNA methylation in the brain as potential mediator of the association between traffic‐related PM_2.5 and neuropathology markers of Alzheimer's disease