Selenium regulates the mitogen-activated protein kinase pathway to protect broilers from hexavalent chromium-induced kidney dysfunction and apoptosis.

Hexavalent chromium [Cr (VI)] is a common environmental pollutant. Although selenium (Se) can antagonize the toxicity of Cr (VI), the specific underlying mechanism has not been identified. To investigate this mechanism, we used potassium dichromate (K2Cr2O7) and selenium-rich yeast (SeY) to construct single Cr (VI)- and combined Se/Cr (VI)-exposed broiler models during a 42-day period. Broilers were randomly assigned to the control (C), SeY (Se), SeY + Cr (VI) (Se/Cr), and Cr (VI) (Cr) groups. The antagonistic mechanisms of Se and Cr (VI) were evaluated using histopathological evaluation, serum and tissue biochemical tests, real-time fluorescence quantitative polymerase chain reaction, and western blotting. The results suggested that Se alleviated the morphological and structural damage to renal tubules and glomeruli, while reducing the organ index, creatinine levels, and blood urea nitrogen levels in the kidneys of Cr (VI)-exposed broilers. Furthermore, Cr (VI) reduced the levels of superoxide dismutase and glutathione, and increased the levels of malondialdehyde, in broiler kidney tissues. However, Se alleviated Cr (VI)-induced oxidative stress by increasing the levels of superoxide dismutase and glutathione, and decreasing the levels of malondialdehyde, within a certain range. Compared to the C group, the levels of p38, JNK, p-p38, p-JNK, p-p38/p38, and p-JNK/JNK significantly increased, whereas those of ERK, p-ERK, and p-ERK/ERK decreased, in the Cr group. Compared to the Cr group, the levels of p38, JNK, p-p38, p-JNK, p-p38/p38, and p-JNK/JNK significantly decreased, whereas those of ERK, p-ERK, and p-ERK/ERK increased, in the Se/Cr group. Furthermore, the levels of p53, c-Myc, Bax, Cyt-c, caspase-9, and caspase-3 significantly increased, and those of Bcl-2 and Bcl-2/Bax significantly decreased, following Cr (VI) exposure, while Se restored the expression of these genes. In conclusion, our findings suggest that SeY can protect against Cr (VI)-induced dysfunction and apoptosis by regulating the mitogen-activated protein kinase pathway activated by oxidative stress in broiler kidney tissues.

TOB1 Blocks Intestinal Mucosal Inflammation Through Inducing ID2-Mediated Suppression of Th1/Th17 Cell Immune Responses in IBD.

BACKGROUND & AIMS: TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell-related autoimmunity, its role in modulating T cell-mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). METHODS: TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4+ T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1-/-CD4+ T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1-/- mice by trinitrobenzene sulfonic acid enema and in Rag1-/- mice reconstituted with Tob1-/-CD45RBhighCD4+ T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4+ T cells of Tob1-/- mice were sorted to determine transcriptome differences by RNA sequencing. RESULTS: TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4+ T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4+ T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1-/- mice through trinitrobenzene sulfonic acid enema or in Rag1-/- mice reconstituted with Tob1-/-CD45RBhighCD4+ T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4+ T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation. CONCLUSIONS: TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD.

HuoXue JieDu formula improves diabetic retinopathy in rats by regulating microRNAs.

ETHNOPHARMACOLOGICAL RELEVANCE: HuoXue JieDu Formula (HXJDF) originates from classical formulas and was formed based on clinical experience. It is composed of Euonymus alatus (Thunb.) Siebold, Panax notoginseng (Burkill) F.H. Chen, the roots of Anguina kirilowii (Maxim.) Kuntze, and Coptis omeiensis (C. Chen) C.Y.Cheng. HXJDF prevents the deterioration of diabetic retinopathy. AIM OF THE STUDY: To evaluate the effects of HXJDF on diabetic retinopathy in rats and investigate the roles of miRNAs in the effects of HXJDF. MATERIALS AND METHODS: A single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg) was used to induce diabetes in rats. Rats were divided into three groups: normal, diabetic, and diabetic + HXJDF. Rats were treated with HXJDF (15.4 g/kg) or water by oral gavage for twelve weeks. At the end of the treatment, rats were anaesthetized, and retinal haemodynamic changes were measured. Then, the retinas were removed and examined by haematoxylin and eosin (HE) staining and TUNEL assays. In addition, miRNA expression profiling was performed using miRNA microarrays and further validated by quantitative real-time PCR (qRT-PCR). RESULTS: Diabetes reduced peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV) and central retinal vein velocity (CRV) but increased the resistance index (RI) and pulsatility index (PI). In addition, in the diabetic group, retinal cell arrangement was disordered and loosely arranged, the retinal thickness and retinal ganglion cell (RGC) number decreased, and retinal cell apoptosis increased. In addition, 11 miRNAs were upregulated and 4 miRNAs were downregulated. After treatment, HXJDF improved retinal haemodynamics and morphologic changes, restored retinal thickness and RGC number and decreased retinal cell apoptosis. Furthermore, the changes in miRNA expression were significantly abolished by HXJDF. CONCLUSION: HXJDF may prevent DR by regulating the expression of miRNAs.

The roles of Qishen granules recipes, Qingre Jiedu, Wenyang Yiqi and Huo Xue, in the treatment of heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Recipes (Qingre Jiedu (QJ), Wenyang Yiqi (WYYQ) and Huo Xue (HX)) in Qishen granules (QSG) are believed to synergistically exert cardio-protective effects. However, the underlying pattern of each decomposed recipe in QSG and their synergistic effects in the treatment of heart failure (HF) are not clear. OBJECTIVE: The purpose of this study is to explore the biological contributions of decomposed recipes to therapeutic effects of QSG and reveal the pharmacological mechanism of QSG in treating HF. MATERIALS AND METHODS: The therapeutic effects of QSG or its recipes on heart failure were examined in wet-lab at both transcription and phenotypic level using HF Sprague-Dawley rats. Sequencing and transcriptome analyses were performed using in silico approaches including identification of differentially expressed genes, pathway enrichment and protein-protein interaction network studies. Specially, an optimized in silico quantitative pathway analysis that maximally extracted gene expression information was developed to reveal differentially expressed pathways (DEPs) among various groups, and is publicly available as R package QPA on GitHub (https://github.com/github-gs/QPA). Finally, the HF-related genes predicted using DEP approach were validated by quantitative real-time polymerase chain reaction and western blot. RESULTS: Multiple key genes and the associated signaling pathways were shown to be highly relevant for the therapeutic effect of QSG. Decreased expression of Spp1 gene required for inflammatory signaling and profibrotic signaling were observed in failing hearts treated with QJ, WYYQ and HX. Decreased expression of Cx3cr1 gene required for inflammatory signaling was observed in failing hearts treated with WYYQ and HX. Decreased expression of Myc gene required for oxidative stress and Fgfr2 gene required for profibrotic signaling were observed in failing hearts treated with HX and WYYQ, respectively. Increased expression of Adcy1 gene required for cAMP-PKA signaling cascade was observed in failing hearts treated with WYYQ and HX. CONCLUSIONS: Our study suggests that QJ, WYYQ and HX recipes in QSG achieve synergistic and complementary therapeutic effects through alleviating inflammatory responses, attenuating ventricular remodeling and enhancing myocardial energy supply.

Gut microbiota contributes to the distinction between two traditional Chinese medicine syndromes of ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is considered to be closely associated with alteration of intestinal microorganisms. According to the traditional Chinese medicine (TCM) theory, UC can be divided into two disease syndromes called Pi-Xu-Shi-Yun (PXSY) and Da-Chang-Shi-Re (DCSR). The relationships among gut microbiota, TCM syndromes, and UC pathogenesis have not been well investigated. AIM: To investigate the role of gut microbiota in UC and the distinction of microbiota dysbiosis between PXSY and DCSR syndromes. METHODS: From May 2015 to February 2016, UC patients presenting to LongHua Hospital who met the established inclusion and exclusion criteria were enrolled in this retrospective study. Fresh stool specimens of UC patients with PXSY or DCSR were collected. The feces of the control group came from the health examination population of Longhua Hospital. The composition of gut bacterial communities in stool samples was determined by the pyrosequencing of 16S ribosomal RNA. The high-throughput sequencing reads were processed with QIIME, and biological functions were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. RESULTS: The composition of gut bacterial communities in 93 stool samples (30 healthy controls, 32 patients with PXSY syndrome, and 31 patients with DCSR syndrome) was determined by the pyrosequencing of 16S ribosomal RNA. Beta diversity showed that the composition of the microbiota was different among the three groups. At the family level, Porphyromonadaceae, Rikeneliaceae, and Lachnospiraceae significantly decreased while Enterococcus, Streptococcus, and other potential pathogens significantly increased in UC patients compared to healthy subjects. At the genus level, Parabacteroides, Dorea, and Ruminococcus decreased while Faeca-libacterium showed increased abundance in UC compared to healthy controls. Five differential taxa were identified between PXSY and DCSR syndromes. At the genus level, a significantly increased abundance of Streptococcus was observed in DCSR patients, while Lachnoclostridium increased in PXSY patients. The differential functional pathways of the gut microbiome between the PXSY and DCSR groups mainly included lipid metabolism, immunity, and the metabolism of polypeptides. CONCLUSION: Our study suggests that the gut microbiota contributes to the distinction between the two TCM syndromes of UC.

Antiapoptosis and Antifibrosis Effects of Qishen Granules on Heart Failure Rats via Hippo Pathway.

Qishen granules (QSG) are a famous formula with cardioprotective properties to heart failure (HF). The aim of this study was to investigate the underlying mechanism of QSG on apoptosis and fibrosis in the treatment of HF. HF model was induced by left anterior descending artery ligation on Sprague-Dawley rats. Transcriptome analysis was used to investigate the regulatory pathways of QSG on HF. Interestingly, downregulated genes of QSG were significantly enriched in Hippo pathway which plays a crucial role in regulating cell apoptosis and proliferation. We found that QSG inhibited the expressions of proapoptotic key proteins P-53 and fibrosis-related proteins TGF-ß1, SMAD3, and CTGF. Further, we conducted research on the key proteins in the Hippo pathway upstream of CTGF and P-53. The results showed that MST1, P-MST1, P-LATS1, and RASSF1A that exert proapoptotic function were downregulated after QSG intervention. Similarly, P-YAP and P-TAZ, mediating self-degradation and apoptosis, were both observably decreased after QSG administration. Taken together, QSG are shown to be likely to exert cardioprotective effects by inhibiting the progression of apoptosis and fibrosis through Hippo pathway.

Decomposing the Mechanism of Qishen Granules in the Treatment of Heart Failure by a Quantitative Pathway Analysis Method.

Qishen granules (QSG) have beneficial therapeutic effects for heart failure, but the effects of decomposed recipes, including Wenyang Yiqi Huoxue (WYH) and Qingre Jiedu (QJ), are not clear. In this study, the efficacy of WYH and QJ on heart failure is evaluated by using transverse aortic constriction (TAC) induced mice and the significantly changed genes in heart tissues were screened with a DNA array. Furthermore, a new quantitative pathway analysis tool is developed to evaluate the differences of pathways in different groups and to identify the pharmacological contributions of the decomposed recipes. Finally, the related genes in the significantly changed pathways are verified by a real-time polymerase chain reaction and a Western blot. Our data show that both QJ and WYH improve the left ventricular ejection fraction, which explain their contributions to protect against heart failure. In the energy metabolism, QJ achieves the therapeutic effects of QSG through nicotinamide nucleotide transhydrogenase (Nnt)-mediated mechanisms. In ventricular remodeling and inflammation reactions, QJ and WYH undertake the therapeutic effects through 5'-nucleotidase ecto (Nt5e)-mediated mechanisms. Together, QJ and WYH constitute the therapeutic effects of QSG and play important roles in myocardial energy metabolism and inflammation, which can exert therapeutic effects for heart failure.

A Review of Chinese Herbal Medicine for the Treatment of Chronic Heart Failure.

Heart failure is one of the major causes of mortality worldwide and it is the end stage of several cardiovascular diseases. Traditional Chinese medicine has been used in the management of heart failure for a long time. Only until recently, well-designed clinical trials have been put into practice to study the efficacies of Chinese herbs. Extensive studies have also been carried out to explore the underlying mechanisms of pharmaceutical actions of Chinese herbs. In this study, we will summarize the frequently used Chinese herbs, formulae and patent Chinese drugs in treating patients with heart failure and review published clinical evaluations of Chinese herbs in treating cardiovascular diseases. The mechanisms by which Chinese herbs exert cardio-protective effects will also be reviewed. In the end, we will point out the limitations of current studies and challenges facing modernization of traditional Chinese medicine.

Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of non-alcoholic fatty liver disease.

Beneficial effects of the Chinese herbal medicine Qushi Huayu Decoction (QHD) were observed with non-alcoholic fatty liver disease (NAFLD) patients and animal models. The impact of QHD or its active components (geniposide and chlorogenic acid, GC) on NAFLD liver transcriptome and gut microbiota was examined with NAFLD rats. Increased expression for genes required for glutathione production and decreased expression for genes required for lipid synthesis was observed in NAFLD livers treated with QHD and GC. GC treatment decreased serum LPS, which could be explained by reduced mucosal damage in the colon of GC-treated rats. Further, our data suggest an increased abundance of Treg-inducing bacteria that stimulated the Treg activity in GC treated colon, which in turn down-regulated inflammatory signals, improved gut barrier function and consequently reduced hepatic exposure to microbial products. Our study suggests that QHD simultaneously enhanced the hepatic anti-oxidative mechanism, decreased hepatic lipid synthesis, and promoted the regulatory T cell inducing microbiota in the gut.

Multipronged Therapeutic Effects of Chinese Herbal Medicine Qishenyiqi in the Treatment of Acute Myocardial Infarction.

Background: Based on global gene expression profile, therapeutic effects of Qishenyiqi (QSYQ) on acute myocardial infarction (AMI) were investigated by integrated analysis at multiple levels including gene expression, pathways involved and functional group. Methods: Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham-operated, AMI model (left anterior descending coronary artery ligation) and QSYQ-treated group. Cardiac tissues were obtained for analysing digital gene expression. Sequencing and transcriptome analyses were performed collaboratively, including analyses of differential gene expression, gene co-expression network, targeted attack on network and functional grouping. In this study, a new strategy known as keystone gene-based group significance analysis was also developed. Results: Analysis of top keystone QSYQ-regulated genes indicated that QSYQ ameliorated ventricular remodeling (VR), which is an irreversible process in the pathophysiology of AMI. At pathway level, both well-known cardiovascular diseases and cardiac signaling pathways were enriched. The most remarkable finding was the novel therapeutic effects identified from functional group analysis. This included anti-inflammatory effects mediated via suppression of arachidonic acid lipoxygenase (LOX) pathway and elevation of nitric oxide (NO); and amelioration of dyslipidaemia mediated via fatty acid oxidation. The regulatory patterns of QSYQ on key genes were confirmed by western blot, immunohistochemistry analysis and measurement of plasma lipids, which further validated the therapeutic effects of QSYQ proposed in this study. Conclusions: QSYQ exerts multipronged therapeutic effects on AMI, by concurrently alleviating VR progression, attenuating inflammation induced by arachidonic acid LOX pathway and NO production; and ameliorating dyslipidaemia.

Screening Ingredients from Herbs against Pregnane X Receptor in the Study of Inductive Herb-Drug Interactions: Combining Pharmacophore and Docking-Based Rank Aggregation.

The issue of herb-drug interactions has been widely reported. Herbal ingredients can activate nuclear receptors and further induce the gene expression alteration of drug-metabolizing enzyme and/or transporter. Therefore, the herb-drug interaction will happen when the herbs and drugs are coadministered. This kind of interaction is called inductive herb-drug interactions. Pregnane X Receptor (PXR) and drug-metabolizing target genes are involved in most of inductive herb-drug interactions. To predict this kind of herb-drug interaction, the protocol could be simplified to only screen agonists of PXR from herbs because the relations of drugs with their metabolizing enzymes are well studied. Here, a combinational in silico strategy of pharmacophore modelling and docking-based rank aggregation (DRA) was employed to identify PXR's agonists. Firstly, 305 ingredients were screened out from 820 ingredients as candidate agonists of PXR with our pharmacophore model. Secondly, DRA was used to rerank the result of pharmacophore filtering. To validate our prediction, a curated herb-drug interaction database was built, which recorded 380 herb-drug interactions. Finally, among the top 10 herb ingredients from the ranking list, 6 ingredients were reported to involve in herb-drug interactions. The accuracy of our method is higher than other traditional methods. The strategy could be extended to studies on other inductive herb-drug interactions.

Integrating clinical indexes into four-diagnostic information contributes to the Traditional Chinese Medicine (TCM) syndrome diagnosis of chronic hepatitis B.

Traditional Chinese Medicine (TCM) treatment has been commonly used to treat Chronic Hepatitis B (CHB) in Asian countries based on TCM syndrome diagnosis, also called "ZHENG". The syndrome is identified through the four-diagnostic methods, with certain degree of subjectivity and ambiguity from individual doctors. Normally those CHB patients also receive series of parameters from modern clinical examination, while they are routinely believed to be unrelated with the TCM syndrome diagnosis. In this study, we investigated whether these biomedical indexes in modern medicine could be beneficial to TCM syndrome diagnostics in an integrative way. Based on 634 patient samples from health controls and three subtypes of CHB syndromes, a two-view based hierarchical classification model was tested for TCM syndromes prediction based on totally 222 parameters integrated from both TCM practice and modern clinical tests. The results indicated that the performance of syndrome classification based on a proper integration of TCM and modern clinical indexes was significantly higher than those based on one view of parameters only. Furthermore, those indexes correlated with CHB syndrome diagnosis were successfully identified for CM indexes and biochemical indexes respectively, where potential associations between them were hinted to the MAPK signaling pathway.

HIM-herbal ingredients in-vivo metabolism database.

BACKGROUND: Herbal medicine has long been viewed as a valuable asset for potential new drug discovery and herbal ingredients' metabolites, especially the in vivo metabolites were often found to gain better pharmacological, pharmacokinetic and even better safety profiles compared to their parent compounds. However, these herbal metabolite information is still scattered and waiting to be collected. DESCRIPTION: HIM database manually collected so far the most comprehensive available in-vivo metabolism information for herbal active ingredients, as well as their corresponding bioactivity, organs and/or tissues distribution, toxicity, ADME and the clinical research profile. Currently HIM contains 361 ingredients and 1104 corresponding in-vivo metabolites from 673 reputable herbs. Tools of structural similarity, substructure search and Lipinski's Rule of Five are also provided. Various links were made to PubChem, PubMed, TCM-ID (Traditional Chinese Medicine Information database) and HIT (Herbal ingredients' targets databases). CONCLUSIONS: A curated database HIM is set up for the in vivo metabolites information of the active ingredients for Chinese herbs, together with their corresponding bioactivity, toxicity and ADME profile. HIM is freely accessible to academic researchers at http://www.bioinformatics.org.cn/.

Towards a bioinformatics analysis of anti-Alzheimer's herbal medicines from a target network perspective.

With the growth of aging population all over the world, a rising incidence of Alzheimer's disease (AD) has been recently observed. In contrast to FDA-approved western drugs, herbal medicines, featured as abundant ingredients and multi-targeting, have been acknowledged with notable anti-AD effects although the mechanism of action (MOA) is unknown. Investigating the possible MOA for these herbs can not only refresh but also extend the current knowledge of AD pathogenesis. In this study, clinically tested anti-AD herbs, their ingredients as well as their corresponding target proteins were systematically reviewed together with applicable bioinformatics resources and methodologies. Based on above information and resources, we present a systematically target network analysis framework to explore the mechanism of anti-AD herb ingredients. Our results indicated that, in addition to the binding of those symptom-relieving targets as the FDA-approved drugs usually do, ingredients of anti-AD herbs also interact closely with a variety of successful therapeutic targets related to other diseases, such as inflammation, cancer and diabetes, suggesting the possible cross-talks between these complicated diseases. Furthermore, pathways of Ca(2+) equilibrium maintaining upstream of cell proliferation and inflammation were densely targeted by the anti-AD herbal ingredients with rigorous statistic evaluation. In addition to the holistic understanding of the pathogenesis of AD, the integrated network analysis on the MOA of herbal ingredients may also suggest new clues for the future disease modifying strategies.

Quantitatively integrating molecular structure and bioactivity profile evidence into drug-target relationship analysis.

BACKGROUND: Public resources of chemical compound are in a rapid growth both in quantity and the types of data-representation. To comprehensively understand the relationship between the intrinsic features of chemical compounds and protein targets is an essential task to evaluate potential protein-binding function for virtual drug screening. In previous studies, correlations were proposed between bioactivity profiles and target networks, especially when chemical structures were similar. With the lack of effective quantitative methods to uncover such correlation, it is demanding and necessary for us to integrate the information from multiple data sources to produce an comprehensive assessment of the similarity between small molecules, as well as quantitatively uncover the relationship between compounds and their targets by such integrated schema. RESULTS: In this study a multi-view based clustering algorithm was introduced to quantitatively integrate compound similarity from both bioactivity profiles and structural fingerprints. Firstly, a hierarchy clustering was performed with the fused similarity on 37 compounds curated from PubChem. Compared to clustering in a single view, the overall common target number within fused classes has been improved by using the integrated similarity, which indicated that the present multi-view based clustering is more efficient by successfully identifying clusters with its members sharing more number of common targets. Analysis in certain classes reveals that mutual complement of the two views for compound description helps to discover missing similar compound when only single view was applied. Then, a large-scale drug virtual screen was performed on 1267 compounds curated from Connectivity Map (CMap) dataset based on the fused similarity, which obtained a better ranking result compared to that of single-view. These comprehensive tests indicated that by combining different data representations; an improved assessment of target-specific compound similarity can be achieved. CONCLUSIONS: Our study presented an efficient, extendable and quantitative computational model for integration of different compound representations, and expected to provide new clues to improve the virtual drug screening from various pharmacological properties. Scripts, supplementary materials and data used in this study are publicly available at http://lifecenter.sgst.cn/fusion/.

Virtual drug screen schema based on multiview similarity integration and ranking aggregation.

The current drug virtual screen (VS) methods mainly include two categories. i.e., ligand/target structure-based virtual screen and that, utilizing protein-ligand interaction fingerprint information based on the large number of complex structures. Since the former one focuses on the one-side information while the later one focuses on the whole complex structure, they are thus complementary and can be boosted by each other. However, a common problem faced here is how to present a comprehensive understanding and evaluation of the various virtual screen results derived from various VS methods. Furthermore, there is still an urgent need for developing an efficient approach to fully integrate various VS methods from a comprehensive multiview perspective. In this study, our virtual screen schema based on multiview similarity integration and ranking aggregation was tested comprehensively with statistical evaluations, providing several novel and useful clues on how to perform drug VS from multiple heterogeneous data sources. (1) 18 complex structures of HIV-1 protease with ligands from the PDB were curated as a test data set and the VS was performed with five different drug representations. Ritonavir ( 1HXW ) was selected as the query in VS and the weighted ranks of the query results were aggregated from multiple views through four similarity integration approaches. (2) Further, one of the ranking aggregation methods was used to integrate the similarity ranks calculated by gene ontology (GO) fingerprint and structural fingerprint on the data set from connectivity map, and two typical HDAC and HSP90 inhibitors were chosen as the queries. The results show that rank aggregation can enhance the result of similarity searching in VS when two or more descriptions are involved and provide a more reasonable similarity rank result. Our study shows that integrated VS based on multiple data fusion can achieve a remarkable better performance compared to that from individual ones and, thus, serves as a promising way for efficient drug screening, taking advantages of the rapidly accumulated molecule representations and heterogeneous data in the pharmacological area.

Novel natural inhibitors of CYP1A2 identified by in silico and in vitro screening.

Inhibition of cytochrome P450 (CYP) is a major cause of herb-drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb-drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.

Discrimination of approved drugs from experimental drugs by learning methods.

BACKGROUND: To assess whether a compound is druglike or not as early as possible is always critical in drug discovery process. There have been many efforts made to create sets of 'rules' or 'filters' which, it is hoped, will help chemists to identify 'drug-like' molecules from 'non-drug' molecules. However, among the chemical space of the druglike molecules, the minority will be approved drugs. Classifying approved drugs from experimental drugs may be more helpful to obtain future approved drugs. Therefore, discrimination of approved drugs from experimental ones has been done in this paper by analyzing the compounds in terms of existing drugs features and machine learning methods. RESULTS: Four methodologies were compared by their performance to classify approved drugs from experimental ones. The best results were obtained by SVM, in which the accuracy is 0.7911, the sensitivity is 0.5929, and the specificity is 0.8743. Based on the results, consensus model was developed to effectively discriminate drugs, which further pushed the correct classification rate up to 0.8517, sensitivity up to 0.7242, specificity up to 0.9352. The applications on the Traditional Chinese Medicine Ingredients Database (TCM-ID) tested the methods. Therefore this model has been proven to be a potent tool for identifying drug molecules. CONCLUSION: The studies would have potential applications in the research of combinatorial library design and virtual high throughput screening for drug discovery.

HIT: linking herbal active ingredients to targets.

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.