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(5R)-5-hydroxytriptolide inhibits the inflammatory cascade reaction in astrocytes.

ABSTRACT: Many studies have shown that (5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether (5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM (5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 ?g/mL lipopolysaccharide for 24 hours. The generation of nitric oxide was detected by Griess reagents. Astrocyte marker glial fibrillary acidic protein was measured by immunohistochemical staining. The levels of tumor necrosis factor-? and interleukin-1? in the culture supernatant were assayed by enzyme linked immunosorbent assay. Nuclear factor-?B/p65 expression was examined by immunofluorescence staining. The phosphorylation of inhibitor of nuclear factor I?B-? and the location of nuclear factor-?B/P65 were determined using western blot assay. Our data revealed that (5R)-5-hydroxytriptolide inhibited the generation of nitric oxide, tumor necrosis factor-? and interleukin-1? from primary astrocytes activated by lipopolysaccharide, decreased the positive reaction intensity of glial fibrillary acidic protein, reduced the expression of tumor necrosis factor alpha and interleukin-1? in culture supernatant, inhibited the phosphorylation of I?B-? and the translocation of nuclear factor-?B/P65 to the nucleus. These results have confirmed that (5R)-5-hydroxytriptolide inhibits lipopolysaccharide-induced glial inflammatory response and provides cytological experimental data for (5R)-5-hydroxytriptolide in the treatment of neurodegenerative diseases.

SUBMITTER: Cui YQ

PROVIDER: S-EPMC6375032 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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(5R)-5-hydroxytriptolide inhibits the inflammatory cascade reaction in astrocytes.

Cui Yan-Qiu YQ Zheng Yan Y Tan Gui-Lian GL Zhang Dong-Mei DM Wang Jun-Ya JY Wang Xiao-Min XM

Neural regeneration research 20190501 5

Many studies have shown that (5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether (5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM (5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation mo ...[more]

PMID: 30688278

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Project description:Tripterygium is a traditional Chinese medicine that has widely been used in the treatment of rheumatic disease. (5R)-5-hydroxytriptolide (LLDT-8) is an extracted compound from Tripterygium, which has been shown to have lower cytotoxicity and relatively higher immunosuppressive activity when compared to Tripterygium. However, our understanding of LLDT-8-induced epigenomic impact and overall regulatory changes in key cell types remains limited. Doing so will provide critically important mechanistic information about how LLDT-8 wields its immunosuppressive activity. The purpose of this study was to assess the effects of LLDT-8 on transcriptome including mRNAs and long non-coding RNA (lncRNAs) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) by a custom genome-wide microarray assay. Significant differential expressed genes were validated by QPCR. Our work shows that 394 genes (281 down- and 113 up-regulated) were significantly differentially expressed in FLS responding to the treatment of LLDT-8. KEGG pathway analysis showed 20 pathways were significantly enriched and the most significantly enriched pathways were relevant to Immune reaction, including cytokine-cytokine receptor interaction (P = 4.61 × 10-13), chemokine signaling pathway (P = 1.01 × 10-5) and TNF signaling pathway (P = 2.79 × 10-4). Furthermore, we identified 618 highly negatively correlated lncRNA-mRNA pairs from the selected significantly differential lncRNA and mRNA including 27 cis-regulated and 591 trans-regulated lncRNA-mRNAs modules. KEGG and GO based function analysis to differential lncRNA also shown the enrichment of immune response. Finally, lncRNA-transcription factor (TF) and lncRNA-TF-mRNA co-expression network were constructed with high specific network characteristics, indicating LLDT-8 would influence the expression network within the whole FLS cells. The results indicated that the LLDT-8 would mainly influence the FLS cells systemically and specially in the process of immune related pathways.

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(5R)-5-hydroxytriptolide inhibits the inflammatory cascade reaction in astrocytes.

Publications

(5R)-5-hydroxytriptolide inhibits the inflammatory cascade reaction in astrocytes.

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