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Anti-inflammatory effects of ?-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

ABSTRACT: Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized ?-galactosylceramide (?-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 ?-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-? production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1?, and IL-6 at the mRNA level and the expression of TNF-? at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-?B and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-? production but also on the DNA binding activities of NF-?B and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-?B and AP-1 activities.

SUBMITTER: Jeong YH

PROVIDER: S-EPMC3921125 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

Jeong Yeon-Hui YH Kim Yongju Y Song Heebum H Chung Young Sun YS Park Seung Bum SB Kim Hee-Sun HS

PloS one 20140211 2

Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity ...[more]

PMID: 24523867

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Project description:Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

Dataset Information

Anti-inflammatory effects of ?-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

Publications

Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

Similar Datasets

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