Since traditional drug research and development is often time-consuming and high-risk, there is an increasing interest in establishing new medical indications for approved drugs, referred to as drug repositioning, which provides a relatively low-cost and high-efficiency approach for drug discovery. With the explosive growth of large-scale biochemical and phenotypic data, drug repositioning holds great potential for precision medicine in the post-genomic era. It is urgent to develop rational and systematic approaches to predict new indications for approved drugs on a large scale. In this paper, we propose the two-pass random walks with restart on a heterogenous network, TP-NRWRH for short, to predict new indications for approved drugs. Rather than random walk on bipartite network, we integrated the drug-drug similarity network, disease-disease similarity network and known drug-disease association network into one heterogenous network, on which the two-pass random walks with restart is implemented. We have conducted performance evaluation on two datasets of drug-disease associations, and the results show that our method has higher performance than six existing methods. A case study on the Alzheimer’s disease showed that nine of top 10 predicted drugs have been approved or investigational for neurodegenerative diseases. The experimental results show that our method achieves state-of-the-art performance in predicting new indications for approved drugs. We proposed a two-pass random walk with restart on the drug-disease heterogeneous network, referred to as TP-NRWRH, to predict new indications for approved drugs. Performance evaluation on two independent datasets showed that TP-NRWRH achieved higher performance than six existing methods on 10-fold cross validations. The case study on the Alzheimer’s disease showed that nine of top 10 predicted drugs have been approved or are investigational for neurodegenerative diseases. The results show that our method achieves state-of-the-art performance in predicting new indications for approved drugs.

Background: Polysaccharide isolated from Bletilla striata, a well known traditional Chinese medicine (Bletilla striata polysaccharide [BSP]) has been found to play important roles in endothelial cells proliferation, inducible nitric oxide stimulation, wound healing acceleration and other processes. Recent studies found that B. striata has anti oxidative properties, however, potential anti aging effects of BSP in whole organisms has not been characterized. Objective: To investigate whether BSP has anti aging effects on Caenorhabditis elegans. Materials and Methods: After treatment with BSP, the lifespan, locomotion ability, and stress resistance of C. elegans was determined. To provide insight into the underlying mechanism for the anti aging effect of BSP, we measured its effect on bacterial growth, brood size of C. elegans, and the insulin/insulin like growth factor (IGF) signaling pathway. Results: After BSP treatment, the lifespan of C. elegans was extended, and its locomotion ability and stress resistance were increased. BSP was found to have no effect on bacterial growth or on reproduction of C. elegans, However, mRNA levels of age-1 and hcf-1 were reduced after BSP treatment. Additionally, we observed that BSP did not extend the lifespan of daf 16 mutant animals. Conclusion: BSP produces an anti aging effect on C. elegans through the insulin/IGF signaling pathway and holds promise for future development as a functional food.

Caenorhabditis elegansis an important non-mammalian alternative assay model for toxicological study. Previous study has indicated that exposure to multi-walled carbon nanotubes (MWCNTs) dysregulated the transcriptional expression ofmir-259. In this study, we examined the molecular basis formir-259in regulating MWCNTs toxicity in nematodes. Mutation ofmir-259induced a susceptible property to MWCNTs toxicity and MWCNTs exposure induced a significant increase inmir-259::GFPin pharyngeal/intestinal valve and reproductive tract, implying thatmir-259might mediate a protection mechanisms for nematodes against MWCNTs toxicity. RSKS-1, a putative ribosomal protein S6 kinase, acted as the target formir-259in regulating MWCNTs toxicity and mutation ofrsks-1suppressed the susceptible property ofmir-259mutant to MWCNTs toxicity. Moreover,mir-259functioned in pharynx-intestinal valve and RSKS-1 functioned in pharynx to regulate MWCNTs toxicity. Furthermore, RSKS-1 regulated MWCNTs toxicity by suppressing the function of AAK-2-DAF-16 signaling cascade. Our results will strengthen our understanding the microRNAs mediated protection mechanisms for animals against the toxicity from certain nanomaterials.

Previous studies have showed that wheat gluten hydrolysate (WGH) has the anti-oxidative property. In the present study, we examined the possible safety property of WGH and the beneficial effects of WGH to extend lifespan and induce stress resistance using nematode Caenorhabditis elegans as the in vivo assay system. We found that WGH at concentrations of 0.1–1 mg/mL did not cause lethality, influence development, alter locomotion behavior and brood size, and induce significant intestinal autofluorescence and reactive oxygen species (ROS) production in young adults. Treatment with 0.1–1 mg/mL of WGH significantly extended lifespans of nematodes under the normal conditions. Moreover, WGH treatment significantly inhibited the induction of intestinal autofluorescence and suppressed the decrease in locomotion behavior during the aging process of nematodes. Furthermore, pre-treatment with 1 mg/mL of WGH significantly suppressed the adverse effects caused by heat-stress or oxidative stress on nematodes as indicated by the alterations of both lifespan and intestinal ROS production. Therefore, WGH treatment is relatively safe and has beneficial effects on nematodes under both the normal conditions and the stress conditions.

In organisms, high glucose can cause several aspects of toxicity, including the lifespan reduction. Paeoniflorin is the major component of Paeoniaceae plants. Nevertheless, the possible effect of paeoniflorin to suppress high glucose toxicity in reducing lifespan and underlying mechanism are largely unclear. Thus, in this study, we examined the possible effect of paeoniflorin in suppressing high glucose (50 mM)-induced lifespan reduction and the underlying mechanism in Caenorhabditis elegans. Administration with 16–64 mg/L paeoniflorin could prolong the lifespan in glucose treated nematodes. Accompanied with this beneficial effect, in glucose treated nematodes, expressions of daf-2 encoding insulin receptor and its downstream kinase genes (age-1, akt-1, and akt-2) were decreased and expression of daf-16 encoding FOXO transcriptional factor was increased by 16–64 mg/L paeoniflorin administration. Meanwhile, the effect of paeoniflorin in extending lifespan in glucose treated nematodes was enhanced by RNAi of daf-2, age-1, akt-1, and akt-2 and inhibited by RNAi of daf-16. In glucose treated nematodes followed by paeoniflorin administration, the increased lifespan caused by daf-2 RNAi could be suppressed by RNAi of daf-16, suggesting that DAF-2 acted upstream of DAF-16 to regulate pharmacological effect of paeoniflorin. Moreover, in glucose treated nematodes followed by paeoniflorin administration, expression of sod-3 encoding mitochondrial Mn-SOD was inhibited by daf-16 RNAi, and the effect of paeoniflorin in extending lifespan in glucose treated nematodes could be suppressed by sod-3 RNAi. Molecular docking analysis indicated the binding potential of paeoniflorin with DAF-2, AGE-1, AKT-1, and AKT-2. Therefore, our results demonstrated the beneficial effect of paeoniflorin administration in inhibiting glucose-induced lifespan reduction by suppressing signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16-SOD-3 in insulin signaling pathway.