Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response
GATA-3 is a master regulator of preadipocyte differentiation and function. Pharmacological or genetic targeting of GATA-3 will allow us to understand the function of GATA-3 in regulating metabolism, insulin signaling, and inflammation. Pyrrothiogatain, a novel small molecule inhibitor of GATA family...
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2025-01-01
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| author | Shamma Almuraikhy Maha Alser Khaled Naja Aisha Al-Malki Nayef A. Mazloum Mohamed A. Elrayess |
| author_facet | Shamma Almuraikhy Maha Alser Khaled Naja Aisha Al-Malki Nayef A. Mazloum Mohamed A. Elrayess |
| author_sort | Shamma Almuraikhy |
| collection | DOAJ |
| description | GATA-3 is a master regulator of preadipocyte differentiation and function. Pharmacological or genetic targeting of GATA-3 will allow us to understand the function of GATA-3 in regulating metabolism, insulin signaling, and inflammation. Pyrrothiogatain, a novel small molecule inhibitor of GATA family proteins, has emerged as a promising tool for modulating GATA-3 activity. This study aims to investigate the specificity of Pyrrothiogatain in regulating GATA-3-mediated preadipocyte differentiation and adipokine secretion under normal and pathological conditions. Wild-type and GATA-3 knockout 3T3-L1 cells were treated with different concentrations of Pyrrothiogatain in the presence and absence of 4-hydroxy-2-nonenal (4HNE), an inducer of oxidative stress and impairment of adipogenesis. As expected, GATA-3 knockout cells exhibited enhanced adipogenic capacity, characterized by increased cell and lipid droplet sizes, and upregulated expression of key adipogenic markers including CEBPβ, PPARγ, and PGC-1α. Pyrrothiogatain treatment reduced cell proliferation in both wild-type and GATA-3 knockout 3T3-L1 cells, but did not alter their adipogenic capacity. Furthermore, Pyrrothiogatain lowered secreted IL-6 levels and attenuated 4-HNE-induced TNF-α elevation in wild-type, but not in GATA-3 knockout cells. Co-treatment of 4-HNE and Pyrrothiogatain led to increased cell size, suggesting complex interactions between oxidative stress and GATA protein inhibition. This effect was similar to GATA-3 knockout cells, indicating Pyrrothiogatain’s potential to modulate cellular stress responses independently of GATA-3 inhibition. These results reveal that Pyrrothiogatain’s effects on adipocyte biology extend beyond simple GATA-3 inhibition. While GATA-3 knockout primarily affects adipogenesis, Pyrrothiogatain modulates inflammatory responses and potentially cellular stress mechanisms without directly impacting adipocyte differentiation. This study provides new insights into the multifaceted actions of Pyrrothiogatain and highlights its potential as a therapeutic agent for lowering inflammation and oxidative-stress-related aspects of metabolic disorders, distinct from the direct modulation of adipogenesis. |
| format | Article |
| id | doaj-art-7e2a2b5bb57c4d3c961f7c741b6197ee |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-7e2a2b5bb57c4d3c961f7c741b6197ee2025-01-24T13:26:40ZengMDPI AGCells2073-44092025-01-0114210010.3390/cells14020100Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory ResponseShamma Almuraikhy0Maha Alser1Khaled Naja2Aisha Al-Malki3Nayef A. Mazloum4Mohamed A. Elrayess5Biomedical Research Center, Qatar University, Doha P.O. Box 2713, QatarBiomedical Research Center, Qatar University, Doha P.O. Box 2713, QatarBiomedical Research Center, Qatar University, Doha P.O. Box 2713, QatarDepartment of Microbiology and Immunology, Weill Cornell Medicine-Qatar (WCM-Q), Qatar Foundation, Doha P.O. Box 24144, QatarDepartment of Microbiology and Immunology, Weill Cornell Medicine-Qatar (WCM-Q), Qatar Foundation, Doha P.O. Box 24144, QatarBiomedical Research Center, Qatar University, Doha P.O. Box 2713, QatarGATA-3 is a master regulator of preadipocyte differentiation and function. Pharmacological or genetic targeting of GATA-3 will allow us to understand the function of GATA-3 in regulating metabolism, insulin signaling, and inflammation. Pyrrothiogatain, a novel small molecule inhibitor of GATA family proteins, has emerged as a promising tool for modulating GATA-3 activity. This study aims to investigate the specificity of Pyrrothiogatain in regulating GATA-3-mediated preadipocyte differentiation and adipokine secretion under normal and pathological conditions. Wild-type and GATA-3 knockout 3T3-L1 cells were treated with different concentrations of Pyrrothiogatain in the presence and absence of 4-hydroxy-2-nonenal (4HNE), an inducer of oxidative stress and impairment of adipogenesis. As expected, GATA-3 knockout cells exhibited enhanced adipogenic capacity, characterized by increased cell and lipid droplet sizes, and upregulated expression of key adipogenic markers including CEBPβ, PPARγ, and PGC-1α. Pyrrothiogatain treatment reduced cell proliferation in both wild-type and GATA-3 knockout 3T3-L1 cells, but did not alter their adipogenic capacity. Furthermore, Pyrrothiogatain lowered secreted IL-6 levels and attenuated 4-HNE-induced TNF-α elevation in wild-type, but not in GATA-3 knockout cells. Co-treatment of 4-HNE and Pyrrothiogatain led to increased cell size, suggesting complex interactions between oxidative stress and GATA protein inhibition. This effect was similar to GATA-3 knockout cells, indicating Pyrrothiogatain’s potential to modulate cellular stress responses independently of GATA-3 inhibition. These results reveal that Pyrrothiogatain’s effects on adipocyte biology extend beyond simple GATA-3 inhibition. While GATA-3 knockout primarily affects adipogenesis, Pyrrothiogatain modulates inflammatory responses and potentially cellular stress mechanisms without directly impacting adipocyte differentiation. This study provides new insights into the multifaceted actions of Pyrrothiogatain and highlights its potential as a therapeutic agent for lowering inflammation and oxidative-stress-related aspects of metabolic disorders, distinct from the direct modulation of adipogenesis.https://www.mdpi.com/2073-4409/14/2/100GATA-3Pyrrothiogatainadipogenesisinflammationoxidative stress |
| spellingShingle | Shamma Almuraikhy Maha Alser Khaled Naja Aisha Al-Malki Nayef A. Mazloum Mohamed A. Elrayess Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response Cells GATA-3 Pyrrothiogatain adipogenesis inflammation oxidative stress |
| title | Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response |
| title_full | Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response |
| title_fullStr | Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response |
| title_full_unstemmed | Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response |
| title_short | Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response |
| title_sort | targeted inhibition of gata 3 by pyrrothiogatain implications for adipocyte biology and inflammatory response |
| topic | GATA-3 Pyrrothiogatain adipogenesis inflammation oxidative stress |
| url | https://www.mdpi.com/2073-4409/14/2/100 |
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