In this article, we propose an updated version of our previously developed model for predicting drug-side effect associations, applied to two case studies: long QT syndrome and asthma. The classifier accepts the name of a specific drug side effect as input and outputs a list of drugs potentially associated with this side effect. By simulating how drug effects propagate within the interactome using the Random Walk with Restart algorithm, the classifier identifies genes potentially associated with the onset of the side effect. Based on the rationale that the more a drug perturbs these genes, the more likely it is to cause the side effect, the model identifies drugs potentially linked to the onset of the side effect. Moreover, the model enables the categorization of drugs into chemical subclasses using the ClassyFire schema, facilitating the analysis of complex side effects, such as asthma, through more specific mechanisms. The results show that the model identifies both drugs known to be associated with certain side effects, as well as drugs not officially reported by the FDA, demonstrating its generalizability and practical relevance. This method is also adaptable for analyzing other side effects.

Chronic obstructive pulmonary disease (COPD) is a lung disease causing hundred thousand of death each year worldwide and defined as a respiratory and airflow impairment majorly due to large and small airways dysfunctions. COPD could be considered as a syndrome that includes disease axes of variable pathological and clinical conditions. Despite recent advances, the comprehension of the molecular mechanisms responsible for COPD disease spectrum is far to be reached. Moreover, we should also consider continuous smoking exposure, which could lead to variability in the disease mechanisms and progression. Network-based multi-omics data integration can help to study the association between molecular determinants on diverse biomolecular layers in a disease context. In a previous study, we leveraged lung RNA-seq and DNA-methylation data of a COPD-control cohort to build a correlation-based integrated network (called coupled network), that helped to unveil genes involved in immune and inflammatory modulation of COPD. Therefore, in our previous study we highlighted the most important genes of the coupled network and inspected their single contribution to disease-related pathways. In this study we aim to overcome this limitation by performing a pathway activity analysis by considering the expression and DNA methylation profiles of coupled network genes. Moreover, we exploit this analysis to study the possible contribution of coupled network genes to the differential disease progression between current and former smokers patients.

Despite the drug approval process consists of extremely rigorous clinical and preclinical studies, not all side effects are identified before its marketing, posing a significant risk to public health. Furthermore, considering the huge use of economic and human resources, in-silico predictive approaches for the identification of side effects are essential. In this study, we introduce a new method based on random walk with restart algorithm to delineate previously unidentified links between drugs and side effects, and we apply it on the drug-induced Asthma and long QT syndrome. We identified the genes potentially involved in the development of the analyzed side effect by comparing side-effect-related drugs with drugs not known to induce side effects. Analyzing the sets of genes most likely influenced by the perturbation of each individual drug, we observed that, on average, side-effect-related drugs perturb a higher percentage of genes involved in the development of side effects compared to side-effect-unrelated drugs. Based on this finding, we developed a classifier to explore all possible unknown associations between drugs and side effects. This method can be extended to the analysis of other side effects as well.

BACKGROUND: Gene expression is the result of the balance between transcription and degradation. Recent experimental findings have shown fine and specific regulation of RNA degradation and the presence of various molecular machinery purposely devoted to this task, such as RNA binding proteins, non-coding RNAs, etc. A biological process can be studied by measuring time-courses of RNA abundance in response of internal and/or external stimuli, using recent technologies, such as the microarrays or the Next Generation Sequencing devices. Unfortunately, the picture provided by looking only at the transcriptome abundance may not gain insight into its dynamic regulation. By contrast, independent simultaneous measurement of RNA expression and half-lives could provide such valuable additional insight. A computational approach to the estimation of RNAs half-lives from RNA expression time profiles data, can be a low-cost alternative to its experimental measurement which may be also affected by various artifacts. RESULTS: Here we present a computational methodology, called StaRTrEK (STAbility Rates ThRough Expression Kinetics), able to estimate half-life values basing only on genome-wide gene expression time series without transcriptional inhibition. The StaRTrEK algorithm makes use of a simple first order kinetic model and of a [Formula: see text]-norm regularized least square optimization approach to find its parameter values. Estimates provided by StaRTrEK are validated using simulated data and three independent experimental datasets of two short (6 samples) and one long (48 samples) time-courses. CONCLUSIONS: We believe that our algorithm can be used as a fast valuable computational complement to time-course experimental gene expression studies by adding a relevant kinetic property, i.e. the RNA half-life, with a strong biological interpretation, thus providing a dynamic picture of what is going in a cell during the biological process under study.

The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity (i.e., SARS), comorbidity (e.g., cardiovascular diseases), or for their association to drugs tentatively repurposed to treat COVID-19 (e.g., malaria, HIV, rheumatoid arthritis). Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments (e.g., chloroquine, hydroxychloroquine, tocilizumab, heparin), as well as a new combination therapy of 5 drugs (hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir), actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies (e.g., anti-IFNγ, anti-TNFα, anti-IL12, anti-IL1β, anti-IL6), and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.

BACKGROUND: miRNAs regulate the expression of several genes with one miRNA able to target multiple genes and with one gene able to be simultaneously targeted by more than one miRNA. Therefore, it has become indispensable to shorten the long list of miRNA-target interactions to put in the spotlight in order to gain insight into understanding the regulatory mechanism orchestrated by miRNAs in various cellular processes. A reasonable solution is certainly to prioritize miRNA-target interactions to maximize the effectiveness of the downstream analysis. RESULTS: We propose a new and easy-to-use web tool MIENTURNET (MicroRNA ENrichment TURned NETwork) that receives in input a list of miRNAs or mRNAs and tackles the problem of prioritizing miRNA-target interactions by performing a statistical analysis followed by a fully featured network-based visualization and analysis. The statistics is used to assess the significance of an over-representation of miRNA-target interactions and then MIENTURNET filters based on the statistical significance associated with each miRNA-target interaction. In addition, the holistic approach of the network theory is used to infer possible evidences of miRNA regulation by capturing emergent properties of the miRNA-target regulatory network that would be not evident through a pairwise analysis of the individual components. CONCLUSION: MIENTURNET offers the possibility to consistently perform both statistical and network-based analyses by using only a single tool leading to a more effective prioritization of the miRNA-target interactions. This has the potential to avoid researchers without computational and informatics skills to navigate multiple websites and thus to independently investigate miRNA activity in every cellular process of interest in an easy and at the same time exhaustive way thanks to the intuitive web interface. The web application along with a well-documented and comprehensive user guide are freely available at http://userver.bio.uniroma1.it/apps/mienturnet/ without any login requirement.