Understanding the mechanisms of the pharmacological effects of herbal formulae from traditional Chinese medicine (TCM) is important for their appropriate application. However, this understanding has been impeded by the complex nature of herbal formulae. A herbal formula is a mixture of hundreds of chemical ingredients with multiple potential targets. The effects produced by an entire herbal formula cannot be adequately explained by considering separately each ingredient in it. This is a recognised problem that remains in need of methods to solve it. Here we introduce a holistic analysis method to decipher the molecular mechanisms of herbal formulae. This method combines chemical and therapeutic properties with network pharmacology, using a novel approach to evaluate the importance of the targets and ingredients of herbal formulae. We used the Liu-Wei-Di-Huang (LWDH) pill, a classic herbal formula, as an example to illustrate our method and validated some results by a following experiment. We revealed the core molecular targets and bioprocess network of the pharmacological effects of LWDH and inferred its therapeutic indications. This method provides a novel strategy to understand the mechanisms of herbal formulae in a holistic way and implies new applications of classic herbal formulae.
Tongue diagnosis is a unique method in traditional Chinese medicine (TCM). This is the first investigation on the association between traditional tongue diagnosis and the tongue coating microbiome using next-generation sequencing. The study included 19 gastritis patients with a typical white-greasy or yellow-dense tongue coating corresponding to TCM Cold or Hot Syndrome respectively, as well as eight healthy volunteers. An Illumina paired-end, double-barcode 16S rRNA sequencing protocol was designed to profile the tongue-coating microbiome, from which approximately 3.7 million V6 tags for each sample were obtained. We identified 123 and 258 species-level OTUs that were enriched in patients with Cold/Hot Syndromes, respectively, representing "Cold Microbiota" and "Hot Microbiota". We further constructed the tongue microbiota-imbalanced networks associated with Cold/Hot Syndromes. The results reveal an important connection between the tongue-coating microbiome and traditional tongue diagnosis, and illustrate the potential of the tongue-coating microbiome as a novel holistic biomarker for characterizing patient subtypes.
Supplementary data are available at Bioinformatics online.
Cold Syndrome and Hot Syndrome are thousand-year-old key therapeutic concepts in traditional Chinese medicine (TCM), which depict the loss of body homeostasis. However, the scientific basis of TCM Syndrome remains unclear due to limitations of current reductionist approaches. Here, we established a network balance model to evaluate the imbalanced network underlying TCM Syndrome and find potential biomarkers. By implementing this approach and investigating a group of chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG) patients, we found that with leptin as a biomarker, Cold Syndrome patients experience low levels of energy metabolism, while the CCL2/MCP1 biomarker indicated that immune regulation is intensified in Hot Syndrome patients. Such a metabolism-immune imbalanced network is consistent during the course from CSG to CAG. This work provides a new way to understand TCM Syndrome scientifically, which in turn benefits the personalized medicine in terms of the ancient medicine and complex biological systems.
The FOXC family of transcription factors (FOXC1 and FOXC2) plays essential roles in the regulation of embryonic, ocular, and cardiac development. Mutations and abnormal expression of FOXC proteins are implicated in genetic diseases as well as cancer. In this study, we determined two crystal structures of the DNA-binding domain (DBD) of human FOXC2 protein, in complex with different DNA sites. The FOXC2-DBD adopts the winged-helix fold with helix H3 contributing to all the base specific contacts, while the N-terminus, wing 1, and the C-terminus of FOXC2-DBD all make additional contacts with the phosphate groups of DNA. Our structural, biochemical, and bioinformatics analyses allow us to revise the previously proposed DNA recognition mechanism and provide a model of DNA binding for the FOXC proteins. In addition, our structural analysis and accompanying biochemical assays provide a molecular basis for understanding disease-causing mutations in FOXC1 and FOXC2.
Bacterial colonisation of the gut is involved in the development of colitis-associated colorectal cancer. However, it remains unclear how the gut microbiota dynamically shifts correlating with colorectal carcinogenesis. Here, we reveal the longitudinal shifts in the microbial community that occur with colitis-associated colorectal cancer. High-throughput sequencing results for the bacterial 16S rRNA gene (V3 region) were compared for azoxymethane/dextran sodium sulphate-treated mice and control mice. We found that microbial community structure was significantly altered by chronic colitis. Microbes in the species Streptococcus luteciae, Lactobacillus hamster, Bacteroides uniformis and Bacteroides ovatus were increased during colorectal carcinogenesis. Histological measurements for a molecular network including six interconnected key factors from inflammation to cancer, namely p65, p53, COX-2, PPARγ, CCR2 and β-catenin, indicated that the microbiome modifications were correlated with molecular pathogenesis of colitis-associated colorectal cancer. Phylotype modifications after each AOM/DSS cycle were identified. A longitudinal microbial network was then constructed for the gut microbiome and showed that the phylotype shifts during this process were complex and highly dynamic. This work may provide a deeper understanding of the role of the microbiota and microbe-host interactions in colitis-associated colorectal cancer.
Colon cancer is one of the most common types of gastrointestinal cancers and the fourth cause of cancer death worldwide. To discover novel diagnostic biomarkers for colon cancer and investigate potential mechanisms of oncogenesis, quantitative proteomic approach using iTRAQ-tagging and 2D-LC-MS/MS was performed to characterize proteins alterations in colon cancer and non-neoplastic colonic mucosa (NNCM) using laser capture microdissection-harvested from the two types of tissues, respectively. As a result, 188 DEPs were identified, and the differential expression of two DEPs (DCN and HSPD1) was further verified by Western blotting and immunohistochemistry. KEGG pathway analysis disclosed that the DEPs were related to signaling pathways associated with cancer; furthermore, DCN and HSPD1 are in the relative central hub position among protein-protein interaction subnetwork of the DEPs. The results not only shed light on the mechanism by the DEPs contributed to colonic carcinogenesis, but also showed that DCN and HSPD1 are novel potential biomarkers for the diagnosis of colon cancer.
Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.
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