Traumatic brain injury (TBI) promotes neural stem/progenitor cell (NSC) proliferation in an attempt to initiate innate repair mechanisms. However, all immature neurons in the CNS are required to migrate from their birthplace to their final destination to develop into functional neurons. Here we assessed the destination of adult-born neurons following TBI. We found that a large percentage of immature neurons migrated past their normal stopping site at the inner granular cell layer (GCL), and became misplaced in the outer GCL of the hippocampal dentate gyrus. The aberrant migration of adult-born neurons in the hippocampus occurred 48 hours after TBI, and lasted for 8 weeks, resulting in a great number of newly generated neurons misplaced in the outer GCL in the hippocampus. Those misplaced neurons were able to become mature and differentiate into granular neurons, but located ectopically in the outer GCL with reduced dendritic complexity after TBI. The adult-born neurons at the misplaced position may make wrong connections with inappropriate nearby targets in the pre-existing neural network. These results suggest that although stimulation of endogenous NSCs following TBI might offer new avenues for cell-based therapy, additional intervention is required to further enhance successful neurogenesis for repairing the damaged brain.
BackgroundDrug repositioning is a cost-efficient and time-saving process to drug development compared to traditional techniques. A systematic method to drug repositioning is to identify candidate drug's gene expression profiles on target disease models and determine how similar these profiles are to approved drugs. Databases such as the CMAP have been developed recently to help with systematic drug repositioning.MethodsTo overcome the limitation of connectivity maps on data coverage, we constructed a comprehensive in silico drug-protein connectivity map called DMAP, which contains directed drug-to-protein effects and effect scores. The drug-to-protein effect scores are compiled from all database entries between the drug and protein have been previously observed and provide a confidence measure on the quality of such drug-to-protein effects.ResultsIn DMAP, we have compiled the direct effects between 24,121 PubChem Compound ID (CID), which were mapped from 289,571 chemical entities recognized from public literature, and 5,196 reviewed Uniprot proteins. DMAP compiles a total of 438,004 chemical-to-protein effect relationships. Compared to CMAP, DMAP shows an increase of 221 folds in the number of chemicals and 1.92 fold in the number of ATC codes. Furthermore, by overlapping DMAP chemicals with the approved drugs with known indications from the TTD database and literature, we obtained 982 drugs and 622 diseases; meanwhile, we only obtained 394 drugs with known indication from CMAP. To validate the feasibility of applying new DMAP for systematic drug repositioning, we compared the performance of DMAP and the well-known CMAP database on two popular computational techniques: drug-drug-similarity-based method with leave-one-out validation and Kolmogorov-Smirnov scoring based method. In drug-drug-similarity-based method, the drug repositioning prediction using DMAP achieved an Area-Under-Curve (AUC) score of 0.82, compared with that using CMAP, AUC = 0.64. For Kolmogorov-Smirnov scoring based method, with DMAP, we were able to retrieve several drug indications which could not be retrieved using CMAP. DMAP data can be queried using the existing C2MAP server or downloaded freely at: http://bio.informatics.iupui.edu/cmapsConclusionsReliable measurements of how drug affect disease-related proteins are critical to ongoing drug development in the genome medicine era. We demonstrated that DMAP can help drug development professionals assess drug-to-protein relationship data and improve chances of success for systematic drug repositioning efforts.
BackgroundNetwork pharmacology has emerged as a new topic of study in recent years. It aims to study the myriad relationships among proteins, drugs, and disease phenotypes. The concept of molecular connectivity maps has been proposed to establish comprehensive knowledge links between molecules of interest in a given biological context. Molecular connectivity maps between drugs and genes/proteins in specific disease contexts can be particularly valuable, since the functional approach with these maps helps researchers gain global perspectives on both the therapeutic profiles and toxicological profiles of candidate drugs.MethodsTo assess drug pharmacological effect, we assume that "ideal" drugs for a patient can treat or prevent the disease by modulating gene expression profiles of this patient to the similar level with those in healthy people. Starting from this hypothesis, we build comprehensive disease-gene-drug connectivity relationships with drug-protein directionality (inhibit/activate) information based on a computational connectivity maps (C2Maps) platform. An interactive interface for directionality annotation of drug-protein pairs with literature evidences from PubMed has been added to the new version of C2Maps. We also upload the curated directionality information of drug-protein pairs specific for three complex diseases - breast cancer, colorectal cancer and Alzheimer disease.ResultsFor relevant drug-protein pairs with directionality information, we use breast cancer as a case study to demonstrate the functionality of disease-specific searching. Based on the results obtained from searching, we perform pharmacological effect evaluation for two important breast cancer drugs on treating patients diagnosed with different breast cancer subtypes. The evaluation is performed on a well-studied breast cancer gene expression microarray dataset to portray how useful the updated C2Maps is in assessing drug efficacy and toxicity information.ConclusionsThe C2Maps platform is an online bioinformatics resource that provides biologists with directional relationships between drugs and genes/proteins in specific disease contexts based on network mining, literature mining, and drug effect annotating. A new insight to assess overall drug efficacy and toxicity can be provided by using the C2Maps platform to identify disease relevant proteins and drugs. The case study on breast cancer correlates very well with the existing pharmacology of the two breast cancer drugs and highlights the significance of C2Maps database.
Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.
Breast cancer is one of the leading causes of death among women, more so than all other cancers. The accurate diagnosis of breast cancer is very difficult due to the complexity of the disease, changing treatment procedures and different patient population samples. Diagnostic techniques with better performance are very important for personalized care and treatment and to reduce and control the recurrence of cancer. The main objective of this research was to select feature selection techniques using correlation analysis and variance of input features before passing these significant features to a classification method. We used an ensemble method to improve the classification of breast cancer. The proposed approach was evaluated using the public WBCD dataset (Wisconsin Breast Cancer Dataset). Correlation analysis and principal component analysis were used for dimensionality reduction. Performance was evaluated for well-known machine learning classifiers, and the best seven classifiers were chosen for the next step. Hyper-parameter tuning was performed to improve the performances of the classifiers. The best performing classification algorithms were combined with two different voting techniques. Hard voting predicts the class that gets the majority vote, whereas soft voting predicts the class based on highest probability. The proposed approach performed better than state-of-the-art work, achieving an accuracy of 98.24%, high precision (99.29%) and a recall value of 95.89%.
Maladaptive signaling by pro-inflammatory cytokines (PICs) such as Tumor Necrosis Factor α (TNFα), Interleukin-1β (IL1β), and Interferon ɣ (IFNɣ), can activate downstream signaling cascades that are implicated in the development and progression of multiple inflammatory diseases. Despite playing critical roles in pathogenesis, the availability of in vivo models in which to model tissue-specific induction of PICs is limited. To bridge this gap, we have developed a novel multi-gene expression system dubbed: Cre-Enabled and Tetracycline-Inducible transgenic system for conditional, tissue-specific expression of Pro-Inflammatory Cytokines (CETI-PIC3). This binary transgenic system permits the stoichiometric co-expression of TNFα, IL1β, IFNɣ, and an H2B-GFP fluorescent reporter gene in a dose dependent manner. Furthermore, cytokine mis-expression is enabled only in tissue domains that can be defined by Cre recombinase expression. We have validated this system in zebrafish using an insulin:cre line. In doubly transgenic fish, quantitative real-time polymerase chain reaction (qRT-PCR) demonstrated increased expression levels of IFNɣ, IL1β, and TNFα mRNA. Moreover, specific expression in pancreatic β cells was demonstrated by both TNF-α immunofluorescence and GFP fluorescence. Cytokine-overexpressing islets elicited specific responses: β cells exhibited increased expression of genes associated with reactive oxidative species (ROS)- mediated stress and endoplasmic reticulum (ER) stress, surveilling and infiltrating macrophages were increased, and β cell death was promoted. This powerful and versatile model system can be used for modeling, analysis, and therapy development of diseases with an underlying inflammatory etiology.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory cytokines following induction with doxycycline (second hit). These hits promoted fat accumulation and liver inflammation, as demonstrated by the high expression of inflammatory cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with pioglitazone, a drug shown to be beneficial for NAFLD in humans, and measured a sharp reduction in liver lipid accumulation. These results demonstrate new utility for zebrafish in modeling early NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions.
In this paper, we propose DeCoST (Drug Repurposing from Control System Theory) framework to apply control system paradigm for drug repurposing purpose. Drug repurposing has become one of the most active areas in pharmacology since the last decade. Compared to traditional drug development, drug repurposing may provide more systematic and significantly less expensive approaches in discovering new treatments for complex diseases. Although drug repurposing techniques rapidly evolve from “one: disease-gene-drug” to “multi: gene, dru” and from “lazy guilt-by-association” to “systematic model-based pattern matching,” mathematical system and control paradigm has not been widely applied to model the system biology connectivity among drugs, genes, and diseases. In this paradigm, our DeCoST framework, which is among the earliest approaches in drug repurposing with control theory paradigm, applies biological and pharmaceutical knowledge to quantify rich connective data sources among drugs, genes, and diseases to construct disease-specific mathematical model. We use linear–quadratic regulator control technique to assess the therapeutic effect of a drug in disease-specific treatment. DeCoST framework could classify between FDA-approved drugs and rejected/withdrawn drug, which is the foundation to apply DeCoST in recommending potentially new treatment. Applying DeCoST in Breast Cancer and Bladder Cancer, we reprofiled 8 promising candidate drugs for Breast Cancer ER+ (Erbitux, Flutamide, etc.), 2 drugs for Breast Cancer ER- (Daunorubicin and Donepezil) and 10 drugs for Bladder Cancer repurposing (Zafirlukast, Tenofovir, etc.).
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