Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites

Cortés-Vieyra, Ricarda; Silva-García, Octavio; Gómez-García, Anel; Gutiérrez-Castellanos, Sergio; Álvarez-Aguilar, Cleto; Baizabal-Aguirre, Víctor M.

doi:10.3389/fimmu.2021.675751

Cited by 35 publications

(27 citation statements)

References 102 publications

(111 reference statements)

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“…However, the fact that GSK-3β expression was upregulated in mouse brain but not in cultured neuronal cells suggests that the upregulation of GSK-3β is not directly mediated by LRRK2. Since it has been reported that GSK-3β expression is promoted by tumor necrosis factor-α (TNF-α) 9) and that LRRK2 upregulates TNF-α via activation of TLR4, 10) thus we speculate that overexpression of LRRK2 in mouse brain increases GSK-3β expression via the TLR4-meditaed TNF-α production. In fact, mRNA level of inflammatory cytokines including of TNF-α was increased in LRRK2 transgenic mouse brain under the experimental conditions (Supplementary material 2).…”

Section: Resultsmentioning

confidence: 88%

Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells

Kawakami

Imai

Tamaki

et al. 2023

Biological & Pharmaceutical Bulletin

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Mutations in leucine rich-repeat kinase 2 (LRRK2) cause autosomal-dominant, late-onset Parkinson's disease (PD). Accumulating evidence indicates that PD-associated LRRK2 mutations induce neuronal cell death by increasing cellular reactive oxygen species levels. However, the mechanism of increased oxidative stress associated with LRRK2 kinase activity remains unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects cells from oxidative stress by inducing the expression of antioxidant genes. In the present, it was found that decreased expression of Nrf2 and mRNA expression of its target genes in Lrrk2-transgenic mouse brain and LRRK2 overexpressing SH-SY5Y cells. Furthermore, knockdown of glycogen synthase kinase-3β (GSK-3β) recovered Nrf2 expression and mRNA expression of its target genes in LRRK2 overexpressing SH-SY5Y cells. We concluded that since Nrf2 is transcriptional factor for antioxidative responses, therefore, reduction of Nrf2 expression by LRRK2 may be part of a mechanism that LRRK2-induces vulnerability to oxidative stress in neuronal cells.

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Section: Resultsmentioning

confidence: 88%

Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells

Kawakami

Imai

Tamaki

et al. 2023

Biological & Pharmaceutical Bulletin

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“…Glucose transporter 4 (GLUT4) is transported to the neuron membrane under the induction of Akt, which improves insulin transport to brain neurons in learning and memory state [23]. Akt also regulates phosphorylation and deactivation of glycogen synthase kinase 3β (GSK-3β), which on the one hand reduces apoptosis signaling in cells, on the other hand, it can also lead to insulin resistance and tau protein hyperphosphorylation, which is a key step in cognitive impairment [24,25,26]. Wnt signaling can regulate cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Novel Biomarkers for Alzheimer's Disease Based on Akt and Wnt Signaling Pathways

Wang,

Li,

Xin

et al. 2024

Preprint

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Background Alzheimer's disease is a neurodegenerative disease that is difficult to reverse. Akt and Wnt play a role in complex cellular signaling, which is important for studying the onset of AD. This study aimed to screen key genes of the Akt and Wnt pathways as potential biomarkers for the early diagnosis and treatment of AD. Methods We searched for differentially expressed genes in the GEO database, constructed candidate gene protein-protein interaction (PPI) networks, and used least absolute shrinkage and selection operator (LASSO) regression analysis and the support vector machine-recursive feature elimination (SVM-RFE) algorithm to screen for key genes. Correlation and functional similarity analyses of key genes, immune infiltration analysis, ceRNA network construction, and drug prediction of key genes were performed. We further validated the expression of key genes in streptozotocin (STZ)-treated AD mice using quantitative reverse transcription (RT-q) PCR. Results Bioinformatic analysis identified five key genes in AD, including PRKACA, CDH3, ATP6V0C, DLL1, and CELSR2. Step-down tests, immunohistochemistry, and silver plate staining confirmed the success of STZ-induced AD in mice. PCR showed that the relative expression of DLL1 mNRA in the AD group was higher than that in the control group, whereas the relative expression of ATP6V0C and PRKACA mRNA in the AD group was lower than the control group, which was consistent with the results of the bioinformatic analysis. Conclusions This study provides a basis for a more comprehensive understanding of the underlying mechanisms of AD. Furthermore, DLL1, ATP6V0C, and PRKACA may be potential intervention targets for AD.

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“…Moreover, Hs GSK-3β was reported to modulate the inflammatory response activated by parasite infections, marked by a dramatic increase in cytokine production [ 48 ]. Cytokine storms are usually implicated in cerebral malaria and liver damage, which can be fatal without treatment [ 49 , 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Bioactivities and Mode of Actions of Dibutyl Phthalates and Nocardamine from Streptomyces sp. H11809

et al. 2022

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Dibutyl phthalate (DBP) produced by Streptomyces sp. H11809 exerted inhibitory activity against human GSK-3β (Hs GSK-3β) and Plasmodiumfalciparum 3D7 (Pf 3D7) malaria parasites. The current study aimed to determine DBP’s plausible mode of action against Hs GSK-3β and Pf 3D7. Molecular docking analysis indicated that DBP has a higher binding affinity to the substrate-binding site (pocket 2; −6.9 kcal/mol) than the ATP-binding site (pocket 1; −6.1 kcal/mol) of Hs GSK-3β. It was suggested that the esters of DBP play a pivotal role in the inhibition of Hs GSK-3β through the formation of hydrogen bonds with Arg96/Glu97 amino acid residues in pocket 2. Subsequently, an in vitro Hs GSK-3β enzymatic assay revealed that DBP inhibits the activity of Hs GSK-3β via mixed inhibition inhibitory mechanisms, with a moderate IC50 of 2.0 µM. Furthermore, the decrease in Km value with an increasing DBP concentration suggested that DBP favors binding on free Hs GSK-3β over its substrate-bound state. However, the antimalarial mode of action of DBP remains unknown since the generation of a Pf 3D7 DBP-resistant clone was not successful. Thus, the molecular target of DBP might be indispensable for Pf survival. We also identified nocardamine as another active compound from Streptomyces sp. H11809 chloroform extract. It showed potent antimalarial activity with an IC50 of 1.5 μM, which is ~10-fold more potent than DBP, but with no effect on Hs GSK-3β. The addition of ≥12.5 µM ferric ions into the Pf culture reduced nocardamine antimalarial activity by 90% under in vitro settings. Hence, the iron-chelating ability of nocardamine was shown to starve the parasites from their iron source, eventually inhibiting their growth.

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Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites

Cited by 35 publications

References 102 publications

Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells

Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells

Identification and Validation of Novel Biomarkers for Alzheimer's Disease Based on Akt and Wnt Signaling Pathways

Bioactivities and Mode of Actions of Dibutyl Phthalates and Nocardamine from Streptomyces sp. H11809

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