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Derivatives of sarcodonin A isolated from Sarcodon scabrosus reversed LPS-induced M1 polarization in microglia through MAPK/NF-κB pathway.
- Source :
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Bioorganic Chemistry . Aug2022, Vol. 125, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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Abstract
- [Display omitted] • Six new derivatives (2 – 7) of Sarcodonin A (1) were semi-synthesized. • 6 showed higher anti-neuroinflammatory effects in LPS-activated primary microglia. • 6 showed higher anti-neuroinflammatory effects in LPS-induced microglial cell lines. • 6 reversed LPS-induced microglia M1 polarization through MAPK/NF-κB pathway. Emerging evidence suggests the regulation of microglial phenotype balance between M1 and M2 will be a potential therapeutic strategy for microglia-mediated neuroinflammation in Alzheimer's disease (AD). Herein, we evaluated the anti-neuroinflammatory effects and the underlying mechanism of a natural cyathane diterpenoid sarcodonin A (1) derived from the mushroom Sarcodon scabrosus and its six new derivatives (2–7). Lipopolysaccharide (LPS)-activated primary microglia and microglia cell lines were used as models. The nitrite test and immunostaining showed that the derivative named 6 was more effective in inhibiting neuroinflammation. qRT-PCR, ELISA, and western blotting revealed that 6 showed more significant suppression on mRNA and protein expression of proinflammatory M1 markers of TNF-α, IL-6, IL-1β, iNOS, and COX-2, while more obvious potentiation on mRNA and protein levels of anti-inflammatory M2 markers of IL-10 and ARG-1. In mechanism, western blotting demonstrated that 6 inhibited LPS-induced activation of MAPK, and prevented LPS-stimulated nuclear translocation of NF-κB p65. Molecular docking revealed that 1 and 6 constructed interactions with iNOS. Collectively, the present study indicated that 1 and 6 might support neuroprotection by reversing LPS-induced microglia M1 polarization, implying that sarcodonin A can be a promising candidate for developing new therapeutics against AD by targeting microglia-mediated neuroinflammation. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MICROGLIA
*ALZHEIMER'S disease
*WESTERN immunoblotting
*MOLECULAR docking
Subjects
Details
- Language :
- English
- ISSN :
- 00452068
- Volume :
- 125
- Database :
- Academic Search Index
- Journal :
- Bioorganic Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 157389879
- Full Text :
- https://doi.org/10.1016/j.bioorg.2022.105854