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Involvement of FoxO1, Sp1, and Nrf2 in Upregulation of Negative Regulator of ROS by 15d-PGJ₂ Attenuates H₂O₂-Induced IL-6 Expression in Rat Brain Astrocytes.

ABSTRACT: Excessive production of reactive oxygen species (ROS) by NADPH oxidase (Nox) resulted in inflammation. The negative regulator of ROS (NRROS) dampens ROS generation during inflammatory responses. 15-Deoxy-∆12,14-prostaglandin J₂ (15d-PGJ₂) exhibits neuroprotective effects on central nervous system (CNS). However, whether 15d-PGJ₂-induced NRROS expression was unknown in rat brain astrocytes (RBA-1). NRROS expression was determined by Western blot, RT/real-time PCR, and promoter activity assays. The signaling components were investigated using pharmacological inhibitors or specific siRNAs. The interaction between transcription factors and the NRROS promoter was investigated by chromatin immunoprecipitation assay. Upregulation of NRROS on the hydrogen peroxide (H₂O₂)-mediated ROS generation and interleukin 6 (IL-6) secretion was measured. 15d-PGJ₂-induced NRROS expression was mediated through PI3K/Akt-dependent activation of Sp1 and FoxO1 and established the essential promoter regions. We demonstrated that 15d-PGJ₂ activated PI3K/Akt and following by cooperation between phosphorylated nuclear FoxO1 and Sp1 to initiate the NRROS transcription. In addition, Nrf2 played a key role in NRROS expression induced by 15d-PGJ₂ which was mediated through its phosphorylation. Finally, the NRROS stable clones attenuated the H₂O₂-induced ROS generation and expression of IL-6 through suppressing the Nox-2 activity. These results suggested that 15d-PGJ₂-induced NRROS expression is mediated through a PI3K/Akt-dependent FoxO1 and Sp1 phosphorylation, and Nrf2 cascade, which suppresses ROS generation through attenuating the p47^phox phosphorylation and gp91^phox formation and IL-6 expression in RBA-1 cells. These results confirmed the mechanisms underlying 15d-PGJ₂-induced NRROS expression which might be a potential strategy for prevention and management of brain inflammatory and neurodegenerative diseases.

SUBMITTER: Wang CY

PROVIDER: S-EPMC8784370 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The gut-brain axis is currently being studied as a therapeutic strategy for neurological diseases, especially Alzheimer's disease (AD). Obesity results in the gut microbiota dysbiosis, which includes butyrate-producing bacteria are reduced. Although sodium butyrate (NaB) has emerged as the potential therapeutic substance in AD, there is a lack of detailed results into what signaling pathways affect amyloidogenesis in AD induced by obesity. Thus, we investigated the regulatory role of NaB on amyloidogenesis in neuronal cells under high cholesterol. In our results, we verified that increased amyloid ? peptide (A?) accumulation in the brain of obese mice and a reduction in butyrate-producing bacteria due to the gut microbiota dysbiosis induced by obesity. We showed that NaB decreased the expression levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and A? accumulation induced by high cholesterol in SK-N-MC cells. We demonstrated that NaB was absorbed in cells through sodium-coupled monocarboxylate transporter 1 (SMCT1) and then inhibited high cholesterol-induced A? accumulation. Subsequently, we also observed that reactive oxygen species (ROS) were overproduced because of increased NADPH oxidase 2 (NOX2) expression under high cholesterol. Meanwhile, NaB decreased NOX2 levels through a reduction of NF-?B activity, which ultimately inhibited A? accumulation caused by high cholesterol. We demonstrated that NaB increased the expression levels of p21 under high cholesterol, contributing to p21/NRF2 (Nuclear factor erythroid 2-related factor 2) colocalization, which leads to NRF2 stabilization. NRF2 stabilization causes NF-?B inactivation, followed by NOX2 suppression and superoxide dismutase 1 (SOD1) upregulation. Thus, NaB with SOD1 silencing under high cholesterol did not eliminate excessive ROS, and eventually resulted in A? accumulation. In conclusion, we demonstrated that NaB prevents excessive ROS through NOX2 suppression and SOD1 upregulation by p21/NRF2 pathway, which is critical for inhibiting BACE1-dependent amyloidogenesis in neuronal cells exposed to high cholesterol environment.

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Involvement of FoxO1, Sp1, and Nrf2 in Upregulation of Negative Regulator of ROS by 15d-PGJ₂ Attenuates H₂O₂-Induced IL-6 Expression in Rat Brain Astrocytes.

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Involvement of FoxO1, Sp1, and Nrf2 in Upregulation of Negative Regulator of ROS by 15d-PGJ2 Attenuates H2O2-Induced IL-6 Expression in Rat Brain Astrocytes.

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OmicsDI is part of the ELIXIR infrastructure

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Involvement of FoxO1, Sp1, and Nrf2 in Upregulation of Negative Regulator of ROS by 15d-PGJ₂ Attenuates H₂O₂-Induced IL-6 Expression in Rat Brain Astrocytes.