Neuroinflammation is defined as the activation of the brain's innate immune system upon injury. Cytokine release is a significant hallmark of neuroinflammation, and leads to neuronal death and neurogenerative disease. Palmitate, release cytokines via the Toll-like receptor (TLR) based NFkB inflammatory pathway. Additionally, histone deacetylases (HDAC) is associated with the upregulation of cytokine and NF-kB expressions. NF-kB is a transcription factor that upregulates the gene expression of proinflammatory cytokines; they are bound to the Ikβα complex in the inhibitory state and activated upon degradation of the Ikβα complex by the IKK complex. The major gap that this project aims to investigate is the role of HDACS, specifically in the palmitate treated astrocytes. I hypothesize that HDACs lead to the activation of the IKK complex to translocate NF-kB components in the nucleus to upregulate cytokine expression in palmitate treated astrocytes. This study demonstrates the impact of HDACs on cytokine expression upon palmitate treatment and molecular mechanisms involved. Pro-inflammatory cytokine IL-6, was significantly upregulated upon palmitate treatment, and treatment with palmitate and HDAC inhibitor valproic acid downregulated the expression of the cytokines. However, there was no significant change in cytokine expression when treated with valproic acid alone, suggesting that HDACs are involved in the palmitate induced cytokine pathway. Our results also suggest that HDACs impact cytokine expression through its catalytic activity, i.e., histone acetylation, or protein-protein interactions with the IKK complex. The latter is based on molecular docking analysis.
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