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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Derivatives of sarcodonin A isolated from Sarcodon scabrosus reversed LPS-induced M1 polarization in microglia
Chen-Yu Cao1, Ying-Xiang Yang1, Zhao Xie1
1Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
Abstract:
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.
Insights
Sarcodonin A and its derivative 6 show potential for Alzheimer's disease (AD) therapy by reducing neuroinflammation. They balance microglial phenotypes from M1 to M2, inhibiting inflammatory markers and supporting neuroprotection.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Microglial phenotype modulation is a potential therapeutic strategy for Alzheimer's disease (AD)-related neuroinflammation.
- Alzheimer's disease is characterized by chronic neuroinflammation driven by microglial activation.
Purpose of the Study:
- To evaluate the anti-neuroinflammatory effects of sarcodonin A and its derivatives.
- To elucidate the underlying mechanisms of their action on microglial phenotypes.
Main Methods:
- Lipopolysaccharide (LPS)-activated primary microglia and cell lines were used as models.
- Assays included nitrite tests, immunostaining, qRT-PCR, ELISA, western blotting, and molecular docking.
- The effects on M1 and M2 microglial markers and inflammatory pathways (MAPK, NF-κB) were assessed.
Main Results:
- Derivative 6 demonstrated superior inhibition of neuroinflammation compared to sarcodonin A.
- Compound 6 significantly suppressed pro-inflammatory M1 markers (TNF-α, IL-6, IL-1β, iNOS, COX-2) and enhanced anti-inflammatory M2 markers (IL-10, ARG-1).
- Mechanistically, compound 6 inhibited MAPK activation, NF-κB p65 nuclear translocation, and showed interaction with iNOS via molecular docking.
Conclusions:
- Sarcodonin A and derivative 6 show promise in reversing LPS-induced M1 microglial polarization.
- These compounds may offer neuroprotection by targeting microglia-mediated neuroinflammation in Alzheimer's disease.
- Sarcodonin A derivatives represent potential therapeutic candidates for AD treatment.
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