Rheumatoid arthritis is a chronic inflammatory autoimmune disease, causing articular and extra-articular dysfunctions among patients, and it could result in irreversible joint damages or disability if untreated. A traditional Chinese medicine formula, Huayu-Qiangshen-Tongbi (HT) formula, has been observed successful in controlling rheumatoid arthritis progression in traditional Chinese medicine clinics. In this study, we conducted a systematic analysis of the HT formula with a purpose of proposing for its potential mechanism of action using network pharmacological methods. The potential targets of the formula were collected and screened according to the topological features of their protein–protein interaction network, and we subsequently validated our prediction results through in vitro experiments. We proposed that the HT formula could interfere with the bone metabolism and the inflammatory pathways of the body. The experimental validation results indicated that HT formula could exhibit anti-inflammatory effects by regulating several signaling pathways specifically the Toll-like receptor signaling pathway, phosphoinositide-3-kinase–Akt signaling pathway, hypoxia-inducible factor 1 signaling pathway, mitogen-activated protein kinase signaling pathway and activator protein 1 signaling pathway.
The 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR) is the last step key enzyme of the methylerythritol phosphate (MEP) pathway, synthesizing isopentenyl diphosphate and its allyl isomer dimethylallyl diphosphate, which is important for regulation of isoprenoid biosynthesis. Here the full-length cDNA of HDR, designated TwHDR (GenBank Accession No. KJ933412.1), was isolated from Tripterygium wilfordii for the first time. TwHDR has an open reading frame (ORF) of 1386 bp encoding 461 amino acids. TwHDR exhibits high homology with HDRs of other plants, with an N-terminal conserved domain and three conserved cysteine residues. TwHDR cDNA was cloned into an expression vector and transformed into an Escherichia coli hdr mutant. Since loss-of-function E.coli hdr mutant is lethal, the result showed that transformation of TwHDR cDNA rescued the E.coli hdr mutant. This complementation assay suggests that the TwHDR cDNA encodes a functional HDR enzyme. The expression of TwHDR was induced by methyl-jasmonate (MJ) in T. wilfordii suspension cells. The expression of TwHDR reached the highest level after 1 h of MJ treatment. These results indicate that we have identified a functional TwHDR enzyme, which may play a pivotal role in the biosynthesis of diterpenoid triptolide in T. wilfordii.
Herbal formulae have a long history in clinical medicine in Asia. While the complexity of the formulae leads to the complex compound-target interactions and the resultant multi-target therapeutic effects, it is difficult to elucidate the molecular/therapeutic mechanism of action for the many formulae. For example, the Hua-Yu-Qiang-Shen-Tong-Bi-Fang (TBF), an herbal formula of Chinese medicine, has been used for treating rheumatoid arthritis. However, the target information of a great number of compounds from the TBF formula is missing. In this study, we predicted the targets of the compounds from the TBF formula via network analysis and in silico computing. Initially, the information of the phytochemicals contained in the plants of the herbal formula was collected, and subsequently computed to their corresponding fingerprints for the sake of structural similarity calculation. Then a compound structural similarity network infused with available target information was constructed. Five local similarity indices were used and compared for their performance on predicting the potential new targets of the compounds. Finally, the Preferential Attachment Index was selected for it having an area under curve (AUC) of 0.886, which outperforms the other four algorithms in predicting the compound-target interactions. This method could provide a promising direction for identifying the compound-target interactions of herbal formulae in silico.
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