Discovery of Synergistic Drug Combinations for Colorectal Cancer Driven by Tumor Barcode Derived from Metabolomics "Big Data".

The accumulation of cancer metabolomics data in the past decade provides exceptional opportunities for deeper investigations into cancer metabolism. However, integrating a large amount of heterogeneous metabolomics data to draw a full picture of the metabolic reprogramming and to discover oncometabolites of certain cancers remains challenging. In this study, a tumor barcode constructed based upon existing metabolomics "big data" using the Bayesian vote-counting method is proposed to identify oncometabolites in colorectal cancer (CRC). Specifically, a panel of oncometabolites of CRC was generated from 39 clinical studies with 3202 blood samples (1332 CRC vs. 1870 controls) and 990 tissue samples (495 CRC vs. 495 controls). Next, an oncometabolite-protein network was constructed by combining the tumor barcode and its involved proteins/enzymes. The effect of anti-cancer drugs or drug combinations was then mapped into this network by the random walk with restart process. Utilizing this network, potential Irinotecan (CPT-11)-sensitizing agents for CRC treatment were discovered by random forest and Xgboost. Finally, a compound named MK-2206 was highlighted and its synergy with CPT-11 was validated on two CRC cell lines. To summarize, we demonstrate in the present study that the metabolomics "big data"-based tumor barcodes and the subsequent network analyses are potentially useful for drug combination discovery or drug repositioning.

Chemogenomics analysis of drug targets for the treatment of acute promyelocytic leukemia.

The main challenges in treating acute promyelocytic leukemia (APL) are currently early mortality, relapse, refractory disease after induction therapy, and drug resistance to ATRA and ATO. In this study, a computational chemogenomics approach was used to identify new molecular targets and drugs for APL treatment. The transcriptional profiles induced by APL were compared with those induced by genetic or chemical perturbations. The genes that can reverse the transcriptional profiles induced by APL when perturbed were considered to be potential therapeutic targets for APL. Drugs targeting these genes or proteins are predicted to be able to treat APL if they can reverse the APL-induced transcriptional profiles. To improve the target identification accuracy of the above correlation method, we plotted the functional protein association networks of the predicted targets by STRING. The results determined PML, RARA, SPI1, HDAC3, CEBPA, NPM1, ABL1, BCR, PTEN, FOS, PDGFRB, FGFR1, NUP98, AFF1, and MEIS1 to be top candidates. Interestingly, the functions of PML, RARA, HDAC3, CEBPA, NPM1, ABL, and BCR in APL have been previously reported in the literature. This is the first chemogenomics analysis predicting potential APL drug targets, and the findings could be used to guide the design of new drugs targeting refractory and recurrent APL.

Effect of Nicotinamide Against Candida albicans.

Nicotinamide (NAM) has a long history in clinical applications and can be safely used for treating various diseases. In recent years, NAM was found to exhibit antimicrobial activities, inhibiting the growth of Plasmodium falciparum, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV). Here we investigated the activity of NAM against Candida albicans, one of the most prevalent human fungal pathogens. Our results showed that NAM exhibited significant antifungal activity against C. albicans, including fluconazole-resistant isolates. NAM could also effectively suppress biofilm formation. In addition, NAM exhibited antifungal activity against non-Candida albicans species and Cryptococcus neoformans. Combination of NAM and fluconazole showed an even strong antifungal activity. The antifungal activity of NAM was further confirmed in a mouse model of disseminated candidiasis. Confocal laser scanning microscopy revealed that NAM increased cell wall ß-glucans exposure and chitin content while decreased mannan level. Furthermore, by screening the C. albicans homozygous deletion mutant library, the C. albicans mutant lacking GIN4, which encodes a septin regulatory protein kinase and is essential for the maintenance of cell wall integrity, was identified to be high sensitive to NAM. These findings suggested that NAM might exhibit antifungal activities through affecting cell wall organization.

Development and Application of an UHPLC-MS/MS Method for Comparative Pharmacokinetic Study of Eight Major Bioactive Components from Yin Chen Hao Tang in Normal and Acute Liver Injured Rats.

Yin Chen Hao Tang (YCHT) is one of the most famous hepatoprotective herbal formulas in China, but its pharmacokinetic investigation in model rats has been rarely conducted. In this study, the hepatic injury model was caused by intraperitoneal injections of carbon tetrachloride (CCl4), and YCHT was orally administered to the model and normal rats. An ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established to analyze the plasma pharmacokinetics of eight major bioactive ingredients from YCHT in both the normal and liver injured rats. The calibration curves presented good linearity (r > 0.9981) in the concentration range. The relative standard deviation (RSD%) of inter- and intraday precision was within 9.55%, and the accuracy (RE%) ranged from -10.72% to 2.46%. The extraction recovery, matrix effect, and stability were demonstrated to be within acceptable ranges. The lower limit of detection (LLOD) and lower limit of quantitation (LLOQ) were around 0.1 ng/mL and 0.5 ng/mL, respectively, which were much lower than those in other related researches. Results reveal that there are significant differences in the pharmacokinetics of scoparone, geniposide, rhein, aloe-emodin, physcion, and chrysophanol in hepatic injured rats as compared to those in control except for scopoletin and emodin. Our experimental results provide a meaningful reference for the clinical dosage of YCHT in treating liver disorders, and the improvement of LLOD and LLOQ can also broaden the range of our method's application, which is very suitable for quantitating these eight compounds with low levels.

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability - A Network Pharmacology and Transcriptomics Approach.

Purpose: This study aimed to identify the active components of Fuzheng Huayu (FZHY) formula and the mechanism by which they inhibit the viability of hepatic stellate cells (HSCs) by a combination of network pharmacology and transcriptomics. Methods: The active components of FZHY formula were screened out by text mining. Similarity match and molecular docking were used to predict the target proteins of these compounds. We then searched the STRING database to analyze the key enriched processes, pathways and related diseases of these target proteins. The relevant networks were constructed by Cytoscape. A network analysis method was established by integrating data from above network pharmacology with known transcriptomics analysis of quiescent HSCs-activated HSCs to identify the most possible targets of the active components in FZHY formula. A cell-based assay (LX-2 and T6 cells) and surface plasmon resonance (SPR) analysis were used to validate the most possible active component-target protein interactions (CTPIs). Results: 40 active ingredients in FZHY formula and their 79 potential target proteins were identified by network pharmacology approach. Further network analysis reduced the 79 potential target proteins to 31, which were considered more likely to be the target proteins of the active components in FZHY formula. In addition, further enrichment analysis of 31 target proteins indicated that the HIF-1, PI3K-Akt, FoxO, and chemokine signaling pathways may be the primary pathways regulated by FZHY formula in inhibiting the HSCs viability for the treatment of liver fibrosis. Of the 31 target proteins, peroxisome proliferator activator receptor gamma (PPARG) was selected for validation by experiments at the cellular and molecular level. The results demonstrated that schisandrin B, salvianolic acid A and kaempferol could directly bind to PPARG, decreasing the viability of HSCs (T6 cells and LX-2 cells) and exerting anti-fibrosis effects. Conclusion: The active ingredients of FZHY formula were successfully identified and the mechanisms by which they inhibit HSC viability determined, using network pharmacology and transcriptomics. This work is expected to benefit the clinical application of this formula.

Corrigendum to "Development and Application of an UHPLC-MS/MS Method for Comparative Pharmacokinetic Study of Eight Major Bioactive Components from Yin Chen Hao Tang in Normal and Acute Liver Injured Rats".

[This corrects the article DOI: 10.1155/2018/3239785.].

Identification of Annexin A2 as a target protein for plant alkaloid matrine.

Matrine is a plant alkaloid and a major active component in the Chinese medical herb Sophora flavescens. Matrine has shown potent anti-cancer activities but its molecular target(s) and mechanism are still unknown. Using the photo-affinity labeling approach, for the first time, Annexin A2 was identified as a direct-binding target of matrine in cancer cells.