Microbial transformation of artemisinin by Aspergillus terreus

Abstract Background Artemisinin (1) and its derivatives are now being widely used as antimalarial drugs, and they also exhibited good antitumor activities. So there has been much interest in the structural modification of artemisinin and its derivatives because of their effective bioactivities. The microbial transformation is a promising route to obtain artemisinin derivatives. The present study focuses on the microbial transformation of artemisinin by Aspergillus terreus. Results During 6 days at 28 °C and 180 rpm, Aspergillus terreus transformed artemisinin to two products. They were identified as 1-deoxyartemisinin (2) and 4α-hydroxy-1-deoxyartemisinin (3) on the basis of their spectroscopic data. Conclusions The microbial transformation of artemisinin by Aspergillus terreus was investigated, and two products (1-deoxyartemisinin and 4α-hydroxy-1-deoxyartemisinin) were obtained. This study is the first to report on the microbial transformation of artemisinin by Aspergillus terreus

Biotransformation of Artemisinin by Aspergillus niger

Biotransformation of artemisinin (1) by Aspergillus niger was investigated. During 12 days at 28 °C and pH 6.0, A. niger transformed artemisinin into four products. They were identified as 3β-hydroxy-4,12-epoxy-1-deoxyartemisinin (2), artemisinin G (3), 3,13-epoxyartemisinin (4), and 4α-hydroxy-1-deoxyartemisinin (5). Products 2 and 4 are new compounds and are being reported here for the first time. The product 4 contains a 3,13-epoxy structure. This is the first report of epoxidation of artemisinin using microbial strains. The product 4 still has an intact peroxide bridge and therefore can be used as a scaffold for further structural modification using chemical and biological methods in the search for new antimalarial drugs

A Novel Dihydroxylated Derivative of Artemisinin from Microbial Transformation

Microbial transformation of artemisinin (1) by Cunninghamella elegans was investigated. Four isolated products were identified as 6β-hydroxyartemisinin (2), 7α-hydroxyartemisinin (3), 7β-hydroxyartemisinin (4), and 6β,7α-dihydroxyartemisinin (5). The structures were elucidated by spectroscopic and X-ray crystallographic analysis. Product 5 is a novel compound and being reported here for the first time. It features two hydroxyl groups in its structure, and this is the first report on dihydroxylation of the artemisinin skeleton. Quantitative structure-activity relationship and molecular modeling studies indicate the modification of artemisinin skeleton will increase antimalarial activity and water solubility. The chemical syntheses of artemisinin derivatives at C6 or C7 position are impossible due to the lack of functional groups. 6β,7α-Dihydroxyartemisinin is hydroxylated at both 6β- and 7α-positions of artemisinin skeleton at the same time. Therefore, this new compound would be a good scaffold for further structural modification in the search for more potent antimalarial drugs

Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner

Hepatosteatosis is characterized by abnormal accumulation of triglycerides (TG), leading to prolonged and chronic inflammatory infiltration. To date, there is still a lack of effective and economical therapies for hepatosteatosis. Oridonin (ORI) is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens. In this paper, we showed that ORI exerted significant protective effects against hepatic steatosis, inflammation and fibrosis, which was dependent on LXRα signaling. It is reported that LXRα regulated lipid homeostasis between triglyceride (TG) and phosphatidylethanolamine (PE) by promoting ATGL and EPT1 expression. Therefore, we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα-dependent manner, and the results showed the TG reduction and PE elevation. In detail, hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes, respectively. Taken together, the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders

Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor

BackgroundLiver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far.MethodsThe anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors.ResultsWe demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis.ConclusionWe demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs