Anti-neuroinflammatory Mechanism Of Natural Products Sarcodonin A And Trienomycin A

Alzheimer’s disease has become a major problem threatening human health,which brings a heavy burden to patients and society.However,its etiology is so complex that current drugs can only alleviate symptoms and are difficult to prevent the occurrence and development of Alzheimer’s disease.More and more evidence showed that brain neuroinflammation was not only the pathological feature of Alzheimer’s disease but also likely to be an important etiology.Therefore,screening compounds with anti-neuroinflammation from natural products and using them as a tool for target research has become a new starting point for the treatment of Alzheimer’s disease.In this paper,natural products and their derivatives with significant anti neuritis activity from multiple fungi or actinomycetes were screened,and the molecular mechanism of reversing the M1/M2 polarization of microglia to play a neuroprotective role was explored,to provide useful support for the drug design of neurodegenerative diseases.Firstly,lipopolysaccharide（LPS）-induced mouse microglia（BV-2）and mouse primary microglia were used as neuroinflammation models.Sarcodonin A is a natural product of the fungi Sarcodon scabrosus（Fr.）karst.with in vitro anti-neuroinflammatory activity,was screened.A series of derivatives were obtained through structural modification.It was found that the reasonable modification of 19-hydroxyl and 14-hydroxyl could enhance the anti-neuritis activity of Sarcodonin A;Sarcodonin A（1）and highly active derivative 6 were selected,using LPS-stimulated mouse microglia（BV-2）and human microglia（HMC3）as models,combined with real-time fluorescence quantitative PCR,ELISA and Western blotting.It was verified that 1 and 6 can significantly inhibit the pro-inflammatory M1 marker and promote the anti-inflammatory M2 marker of microglia from three aspects:transcription level,cytokine secretion level,and protein expression level.Further cellular pathway studies showed that compound 6 could selectively inhibit LPS induced phosphorylation of MAPK and nuclear transport of NF-κB p65 subunit which indicated MAPK/NF-κB mediates the anti-neuroinflammatory effect of Sarcodonin A and its derivatives.In addition,the screening of in vitro anti neuritis activity of Trienomycin A isolated from an actinomycete H2S5 isolated from Qinling moss soil showed that it could effectively inhibit the production of NO in BV-2 cells induced by LPS,and the IC₅₀ was as low as 25n M.It can significantly down-regulate the expression of M1 marker proteins i NOS and COX-2.The preliminary mechanism finding showed that Trienomycin A could significantly inhibit the activation of Toll-like receptor 4（TLR4）and downregulate the phosphorylation and nuclear transport of transcription factors NF and STAT3（Ser727）.Previous studies indicated that STAT3 is a potential target of Trienomycin A against pancreatic cancer activity,and to some extent,it provides inspiration for the general mechanism of Trienomycin A activity.