Kailin Tang

The information of protein targets and small molecule has been highly valued by biomedical and pharmaceutical research. Several protein target databases are available online for FDA-approved drugs as well as the promising precursors that have largely facilitated the mechanistic study and subsequent research for drug discovery. However, those related resources regarding to herbal active ingredients, although being unusually valued as a precious resource for new drug development, is rarely found. In this article, a comprehensive and fully curated database for Herb Ingredients' Targets (HIT, http://lifecenter.sgst.cn/hit/) has been constructed to complement above resources. Those herbal ingredients with protein target information were carefully curated. The molecular target information involves those proteins being directly/indirectly activated/inhibited, protein binders and enzymes whose substrates or products are those compounds. Those up/down regulated genes are also included under the treatment of individual ingredients. In addition, the experimental condition, observed bioactivity and various references are provided as well for user's reference. Derived from more than 3250 literatures, it currently contains 5208 entries about 1301 known protein targets (221 of them are described as direct targets) affected by 586 herbal compounds from more than 1300 reputable Chinese herbs, overlapping with 280 therapeutic targets from Therapeutic Targets Database (TTD), and 445 protein targets from DrugBank corresponding to 1488 drug agents. The database can be queried via keyword search or similarity search. Crosslinks have been made to TTD, DrugBank, KEGG, PDB, Uniprot, Pfam, NCBI, TCM-ID and other databases.

AIMS: Left atrial (LA) enlargement is associated with atrial fibrillation (AF). However, it is controversial whether dilated atrium can predict post-ablation AF recurrence. We undertook a systematic review and meta-analysis to analyse the association between LA diameter and AF recurrence after single circumferential pulmonary vein isolation (CPVI) and explore the potential mechanism. METHODS AND RESULTS: Electronic databases and bibliographies of retrieved studies were searched. The anteroposterior diameters of LA were available in all included studies, which were measured at end-systole by M-mode transthoracic echocardiography. Subgroup analysis was conducted based on the duration of follow-up. Weighted mean difference (WMD) and 95% confidence interval (CI) were calculated using random-effect or fixed-effect model, depending on statistical heterogeneity. Twenty-two studies with a total of 3750 individuals met the inclusion criteria. The summary WMD of LA diameter between patients with and without recurrence was 1.87 mm (95% CI 1.26-2.48, P< 0.001). Meta-regression analysis of the 22 studies indicated that study design, duration of follow-up, and measurement of asymptomatic recurrences were significant sources of heterogeneity. Sensitivity analysis suggested that the difference in LA diameter between patients with and without recurrences persisted regardless of the duration of follow-up. CONCLUSION: Dilated LA significantly increases the risk of AF recurrence after single CPVI. This is especially applicable to the patients with long-term follow-up.

Literature-described targets of herbal ingredients have been explored to facilitate the mechanistic study of herbs, as well as the new drug discovery. Though several databases provided similar information, the majority of them are limited to literatures before 2010 and need to be updated urgently. HIT 2.0 was here constructed as the latest curated dataset focusing on Herbal Ingredients' Targets covering PubMed literatures 2000-2020. Currently, HIT 2.0 hosts 10 031 compound-target activity pairs with quality indicators between 2208 targets and 1237 ingredients from more than 1250 reputable herbs. The molecular targets cover those genes/proteins being directly/indirectly activated/inhibited, protein binders, and enzymes substrates or products. Also included are those genes regulated under the treatment of individual ingredient. Crosslinks were made to databases of TTD, DrugBank, KEGG, PDB, UniProt, Pfam, NCBI, TCM-ID and others. More importantly, HIT enables automatic Target-mining and My-target curation from daily released PubMed literatures. Thus, users can retrieve and download the latest abstracts containing potential targets for interested compounds, even for those not yet covered in HIT. Further, users can log into 'My-target' system, to curate personal target-profiling on line based on retrieved abstracts. HIT can be accessible at http://hit2.badd-cao.net.

B-cell epitope information is critical to immune therapy and vaccine design. Protein epitopes can be significantly affected by glycosylation, while no methods have considered this till now. Based on previous versions of Spatial Epitope Prediction of Protein Antigens (SEPPA), we here present an enhanced tool SEPPA 3.0, enabling glycoprotein antigens. Parameters were updated based on the latest and largest dataset. Then, additional micro-environmental features of glycosylation triangles and glycosylation-related amino acid indexes were added as important classifiers, coupled with final calibration based on neighboring antigenicity. Logistic regression model was retained as SEPPA 2.0. The AUC value of 0.794 was obtained through 10-fold cross-validation on internal validation. Independent testing on general protein antigens resulted in AUC of 0.740 with BA (balanced accuracy) of 0.657 as baseline of SEPPA 3.0. Most importantly, when tested on independent glycoprotein antigens only, SEPPA 3.0 gave an AUC of 0.749 and BA of 0.665, leading the top performance among peers. As the first server enabling accurate epitope prediction for glycoproteins, SEPPA 3.0 shows significant advantages over popular peers on both general protein and glycoprotein antigens. It can be accessed at http://bidd2.nus.edu.sg/SEPPA3/ or at http://www.badd-cao.net/seppa3/index.html. Batch query is supported.

The identification of synergistic chemotherapeutic agents from a large pool of candidates is highly challenging. Here, we present a Ranking-system of Anti-Cancer Synergy (RACS) that combines features of targeting networks and transcriptomic profiles, and validate it on three types of cancer. Using data on human β-cell lymphoma from the Dialogue for Reverse Engineering Assessments and Methods consortium we show a probability concordance of 0.78 compared with 0.61 obtained with the previous best algorithm. We confirm 63.6% of our breast cancer predictions through experiment and literature, including four strong synergistic pairs. Further in vivo screening in a zebrafish MCF7 xenograft model confirms one prediction with strong synergy and low toxicity. Validation using A549 lung cancer cells shows similar results. Thus, RACS can significantly improve drug synergy prediction and markedly reduce the experimental prescreening of existing drugs for repurposing to cancer treatment, although the molecular mechanism underlying particular interactions remains unknown.