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Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response
Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with Nuclear factor kappa B (NF-κB). . GSK3 is also a suppressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. A...
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2022
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| _version_ | 1867613421610991616 |
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| access_status_str | Open Access |
| author | Yousef, Mohamed H |
| author_browse | Yousef, Mohamed H |
| author_facet | Yousef, Mohamed H |
| author_sort | Yousef, Mohamed H |
| collection | Thesis |
| description | Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with Nuclear factor kappa B (NF-κB). . GSK3 is also a suppressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies, Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition.
The anti-inflammatory effects of paralog-selective GSK3 inhibitors were evaluated as a function of the reductive capacity of each to mitigate LPS-induced activation of SIM-A9 microglia. The Griess method was employed to detect the nitrate-lowering capacity of selective GSK3 inhibition. Real-time PCR was used to assess post-treatment expression levels of pro-inflammatory markers and antioxidant genes; pro-inflammatory cytokines were assayed by ELISA. Nuclear lysates of treated cells were examined for Nrf2 and NF-κB accumulation by immunoblotting. Finally, to infer whether the counter-inflammatory activity of GSK3 inhibition was Nrf2-dependent, DsiRNA-mediated knockdown of Nrf2 was attempted.
Results from our experiments reveal a superior anti-inflammatory and anti-oxidative efficacy for GSK3β-selective inhibition, compared to GSK3α-selective and non-selective pan-inhibition; hence use of selective GSK3β inhibitors is likely to be more propitious than non-selective dual inhibitors administered at comparable doses. Moreover, our results suggest that the anti-inflammatory effects of GSK3 inhibition is not Nrf2 dependent. |
| format | Thesis |
| id | oai:fount.aucegypt.edu:etds-2903 |
| institution | American University in Cairo (Egypt) |
| last_indexed | 2026-06-10T12:35:53.165Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from AUC Knowledge Fountain — bepress |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | AUC Knowledge Fountain |
| publisherStr | AUC Knowledge Fountain |
| record_format | dspace |
| source_str | AUC Knowledge Fountain — bepress |
| spelling | oai:fount.aucegypt.edu:etds-2903 Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response Yousef, Mohamed H Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with Nuclear factor kappa B (NF-κB). . GSK3 is also a suppressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies, Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition. The anti-inflammatory effects of paralog-selective GSK3 inhibitors were evaluated as a function of the reductive capacity of each to mitigate LPS-induced activation of SIM-A9 microglia. The Griess method was employed to detect the nitrate-lowering capacity of selective GSK3 inhibition. Real-time PCR was used to assess post-treatment expression levels of pro-inflammatory markers and antioxidant genes; pro-inflammatory cytokines were assayed by ELISA. Nuclear lysates of treated cells were examined for Nrf2 and NF-κB accumulation by immunoblotting. Finally, to infer whether the counter-inflammatory activity of GSK3 inhibition was Nrf2-dependent, DsiRNA-mediated knockdown of Nrf2 was attempted. Results from our experiments reveal a superior anti-inflammatory and anti-oxidative efficacy for GSK3β-selective inhibition, compared to GSK3α-selective and non-selective pan-inhibition; hence use of selective GSK3β inhibitors is likely to be more propitious than non-selective dual inhibitors administered at comparable doses. Moreover, our results suggest that the anti-inflammatory effects of GSK3 inhibition is not Nrf2 dependent. 2022-01-31T08:00:00Z thesis application/pdf https://fount.aucegypt.edu/etds/1882 https://fount.aucegypt.edu/context/etds/article/2903/viewcontent/Mohamed_H._Yousef_Thesis.pdf https://fount.aucegypt.edu/context/etds/article/2903/filename/1/type/additional/viewcontent/Mohamed_H._Yousef_Library_Declaration_Form.doc Theses and Dissertations AUC Knowledge Fountain GSK3; paralog selectivity; microglia; neuroinflammation; neurodegenerative diseases; oxidative stress; Nrf2; NF-κB Biological Phenomena, Cell Phenomena, and Immunity Biotechnology Immune System Diseases Immunity Immunopathology Nervous System Diseases Neurosciences Pharmacology |
| spellingShingle | GSK3; paralog selectivity; microglia; neuroinflammation; neurodegenerative diseases; oxidative stress; Nrf2; NF-κB Biological Phenomena, Cell Phenomena, and Immunity Biotechnology Immune System Diseases Immunity Immunopathology Nervous System Diseases Neurosciences Pharmacology Yousef, Mohamed H Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response |
| title | Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response |
| title_full | Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response |
| title_fullStr | Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response |
| title_full_unstemmed | Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response |
| title_short | Selective GSK3β inhibition mediates an Nrf2-independent anti-inflammatory microglial response |
| title_sort | selective gsk3β inhibition mediates an nrf2 independent anti inflammatory microglial response |
| topic | GSK3; paralog selectivity; microglia; neuroinflammation; neurodegenerative diseases; oxidative stress; Nrf2; NF-κB Biological Phenomena, Cell Phenomena, and Immunity Biotechnology Immune System Diseases Immunity Immunopathology Nervous System Diseases Neurosciences Pharmacology |
| url | https://fount.aucegypt.edu/etds/1882 https://fount.aucegypt.edu/context/etds/article/2903/viewcontent/Mohamed_H._Yousef_Thesis.pdf https://fount.aucegypt.edu/context/etds/article/2903/filename/1/type/additional/viewcontent/Mohamed_H._Yousef_Library_Declaration_Form.doc |
| work_keys_str_mv | AT yousefmohamedh selectivegsk3binhibitionmediatesannrf2independentantiinflammatorymicroglialresponse |