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The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells
Glycogen synthase kinase-3 (GSK-3), an enzyme that modulates glucose metabolism, has been recognized as an essential target in major inflammatory diseases based on its great specificity in substrate recognition. GSK-3β has been connected to cancer, obesity, liver diseases, and neurological diseases....
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2025
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| _version_ | 1867613424184197120 |
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| access_status_str | Open Access |
| author | Oyewole, Oluwaseyi |
| author_browse | Oyewole, Oluwaseyi |
| author_facet | Oyewole, Oluwaseyi |
| author_sort | Oyewole, Oluwaseyi |
| collection | Thesis |
| description | Glycogen synthase kinase-3 (GSK-3), an enzyme that modulates glucose metabolism, has been recognized as an essential target in major inflammatory diseases based on its great specificity in substrate recognition. GSK-3β has been connected to cancer, obesity, liver diseases, and neurological diseases. Nonetheless, the other GSK-3 isoform, GSK-3α, is much less studied. Previous studies from our laboratory showed that inhibiting GSK-3α potentially confers an anti-inflammatory response when tested on microglia. However, little has been documented regarding the exact mechanism by which GSK-3α exerts its effect. One of the potential mechanisms involving its anti-inflammatory effect could be partially attributed to activating the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway. This study examines whether the inhibition of GSK-3α confers an anti-inflammatory and antioxidant response independent of the Nrf2 pathway. Our result showed that inhibiting GSK-3α in LPS-stimulated RAW 264.7 cells downregulate nitrate production. Real-time PCR results indicated that inhibiting GSK-3α in LPS-stimulated macrophages attenuates the expression of the proinflammatory genes Tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS), and interleukin 6 (IL-6). Remarkably, at the translation level, the protein expression levels of iNOS and TNF-α were also denounced. Interestingly, our study provides further insight into the anti-inflammatory role of GSK-3α in post-transcriptional studies as evidenced in the downregulation of two mRNAs, in particular, miR-21 and miR-155, implicated in inflammatory-related diseases post GSK-3α inhibition. Our molecular assay showed that the Nrf2-regulated genes: Osgin1 (Oxidative Stress Induced Growth Inhibitor 1) and HO-1(Heme oxygenase-1) were upregulated in response to treatment with GSK-3α inhibitor when compared to their control counterparts. Collectively, our results indicate the role of GSK-3α in modulating inflammatory responses and suggest Nrf2 as a possible pathway that mediate the anti-inflammatory and antioxidant benefits of GSK-3α inhibition. |
| format | Thesis |
| id | oai:fount.aucegypt.edu:etds-3429 |
| institution | American University in Cairo (Egypt) |
| last_indexed | 2026-06-10T12:35:55.364Z |
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| provenance_str_mv | Harvested via OAI-PMH from AUC Knowledge Fountain — bepress |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | AUC Knowledge Fountain |
| publisherStr | AUC Knowledge Fountain |
| record_format | dspace |
| source_str | AUC Knowledge Fountain — bepress |
| spelling | oai:fount.aucegypt.edu:etds-3429 The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells Oyewole, Oluwaseyi Glycogen synthase kinase-3 (GSK-3), an enzyme that modulates glucose metabolism, has been recognized as an essential target in major inflammatory diseases based on its great specificity in substrate recognition. GSK-3β has been connected to cancer, obesity, liver diseases, and neurological diseases. Nonetheless, the other GSK-3 isoform, GSK-3α, is much less studied. Previous studies from our laboratory showed that inhibiting GSK-3α potentially confers an anti-inflammatory response when tested on microglia. However, little has been documented regarding the exact mechanism by which GSK-3α exerts its effect. One of the potential mechanisms involving its anti-inflammatory effect could be partially attributed to activating the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway. This study examines whether the inhibition of GSK-3α confers an anti-inflammatory and antioxidant response independent of the Nrf2 pathway. Our result showed that inhibiting GSK-3α in LPS-stimulated RAW 264.7 cells downregulate nitrate production. Real-time PCR results indicated that inhibiting GSK-3α in LPS-stimulated macrophages attenuates the expression of the proinflammatory genes Tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS), and interleukin 6 (IL-6). Remarkably, at the translation level, the protein expression levels of iNOS and TNF-α were also denounced. Interestingly, our study provides further insight into the anti-inflammatory role of GSK-3α in post-transcriptional studies as evidenced in the downregulation of two mRNAs, in particular, miR-21 and miR-155, implicated in inflammatory-related diseases post GSK-3α inhibition. Our molecular assay showed that the Nrf2-regulated genes: Osgin1 (Oxidative Stress Induced Growth Inhibitor 1) and HO-1(Heme oxygenase-1) were upregulated in response to treatment with GSK-3α inhibitor when compared to their control counterparts. Collectively, our results indicate the role of GSK-3α in modulating inflammatory responses and suggest Nrf2 as a possible pathway that mediate the anti-inflammatory and antioxidant benefits of GSK-3α inhibition. 2025-01-31T08:00:00Z thesis application/pdf https://fount.aucegypt.edu/etds/2385 https://fount.aucegypt.edu/context/etds/article/3429/viewcontent/oluwaseyi_seun_oyewole_thesis.pdf Theses and Dissertations AUC Knowledge Fountain Inflammation Glycogen synthase kinase-3 Nrf2 Oxidative stress Inflammatory responses Biotechnology Immunity Other Life Sciences |
| spellingShingle | Inflammation Glycogen synthase kinase-3 Nrf2 Oxidative stress Inflammatory responses Biotechnology Immunity Other Life Sciences Oyewole, Oluwaseyi The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells |
| title | The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells |
| title_full | The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells |
| title_fullStr | The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells |
| title_full_unstemmed | The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells |
| title_short | The Role of GSK-3α Inhibition in Attenuating LPS-Induced Inflammation in RAW 264.7 Cells |
| title_sort | role of gsk 3α inhibition in attenuating lps induced inflammation in raw 264 7 cells |
| topic | Inflammation Glycogen synthase kinase-3 Nrf2 Oxidative stress Inflammatory responses Biotechnology Immunity Other Life Sciences |
| url | https://fount.aucegypt.edu/etds/2385 https://fount.aucegypt.edu/context/etds/article/3429/viewcontent/oluwaseyi_seun_oyewole_thesis.pdf |
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