scholarly journals NOGEA: Network-Oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning

2020 ◽  
Author(s):  
Zihu Guo ◽  
Yingxue Fu ◽  
Chao Huang ◽  
Chunli Zheng ◽  
Ziyin Wu ◽  
...  
Keyword(s):  
Gene Networks ◽  
Drug Repositioning ◽  
High Reliability ◽  
Rapid Development ◽  
Small Neighborhood ◽  
Specific Gene ◽  
Master Genes ◽  
Disease Initiation ◽  
Disease Specific

AbstractRapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes on the interactome network, which provides a new way for predicting new drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

scholarly journals Publisher Correction: c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

2019 ◽  
Vol 20 (3) ◽  
pp. 374-374
Author(s):  
Leona Gabryšová ◽  
Marisol Alvarez-Martinez ◽  
Raphaëlle Luisier ◽  
Luke S. Cox ◽  
Jan Sodenkamp ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Gene Networks ◽  
Specific Gene ◽  
Disease Specific

scholarly journals Drug REpurposing using AI/ML tools - for Rare Diseases (DREAM-RD): A case study with Fragile X Syndrome (FXS)

2020 ◽  
Author(s):  
Kavitha Agastheeswaramoorthy ◽  
Aarti Sevilimedu
Keyword(s):  
Fragile X Syndrome ◽  
Drug Repositioning ◽  
Fragile X ◽  
Drug Repurposing ◽  
Machine Learning Algorithms ◽  
Specific Gene ◽  
Drug Induced ◽  
Approved Drugs ◽  
Disease Specific

AbstractDrug repositioning is emerging as an increasingly relevant option for rare disease therapy and management. Various methods for identifying suitable drug candidates have been tried and range from clinical symptomatic repurposing to data driven strategies which are based on the disease-specific gene or protein expression, modification, signalling and physiological perturbation profiles. The use of Artificial Intelligence (AI) and machine learning algorithms (ML) allows one to combine diverse data sets, and extract disease-specific data profiles which may not be intuitive or apparent from a subset of data. In this case study with Fragile X syndrome and autism, we have used multiple computational methodologies to extract profiles, which are then combined to arrive at a comprehensive signature (disease DEG). This DEG was then used to interrogate the large collection of drug-induced perturbation profiles present in public databases, to find appropriate small molecules to reverse or mimic the disease-profiles. We have labelled this pipeline Drug Repurposing using AI/ML tools - for Rare Diseases (DREAM-RD). We have shortlisted over 100 FDA approved drugs using the aforementioned pipeline, which may potentially be useful to ameliorate autistic phenotypes associated with FXS.

scholarly journals iPSC-derived hepatocytes from patients with nonalcoholic fatty liver disease display a disease-specific gene expression profile

2020 ◽  
Author(s):  
Caroline C. Duwaerts ◽  
Chris L. Her ◽  
Nathaniel J. Phillips ◽  
Holger Willenbring ◽  
Aras N. Mattis ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Human Subjects ◽  
Specific Gene ◽  
Common Disease ◽  
Nonalcoholic Fatty Liver ◽  
Disease Specific

Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease worldwide.1 Animal models are widely used to investigate the mechanisms of fatty liver disease, but they do not faithfully represent NAFLD in humans.2 Thus, there is strong interest in studying NAFLD pathogenesis directly in humans whenever possible. One strategy that is gaining momentum is to utilize iPSC-derived hepatocytes from individual human subjects in complex cell/organ platforms with the goal of reproducing a NAFLD-like state in vitro.3-6 Our group has taken a different approach, positing that iPSC-Heps from a population of NAFLD patients would provide independent insight into the human disease. In this study we generated iPSCs and iPSC-Heps from a well-defined cohort of NAFLD patients. Our objective was to determine whether as a group, in the absence of any metabolic challenge, they exhibit common disease-specific signatures that are distinct from healthy controls.

scholarly journals c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

2018 ◽  
Vol 19 (5) ◽  
pp. 497-507 ◽  
Author(s):  
Leona Gabryšová ◽  
Marisol Alvarez-Martinez ◽  
Raphaëlle Luisier ◽  
Luke S. Cox ◽  
Jan Sodenkamp ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Gene Networks ◽  
Specific Gene ◽  
Disease Specific

scholarly journals Network analysis allows to unravel breast cancer molecular features and to identify novel targets

2019 ◽  
Author(s):  
Aurora Savino ◽  
Lidia Avalle ◽  
Emanuele Monteleone ◽  
Irene Miglio ◽  
Alberto Griffa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Biology ◽  
Gene Networks ◽  
High Reliability ◽  
Expression Patterns ◽  
Transcriptional Networks ◽  
Specific Gene ◽  
Breast Cancer Dataset ◽  
Molecular Features

AbstractThe behaviour of complex biological systems is determined by the orchestrated activity of many components interacting with each other, and can be investigated by networks. In particular, gene co-expression networks have been widely used in the past years thanks to the increasing availability of huge gene expression databases. Breast cancer is a heterogeneous disease usually classified either according to immunohistochemical features or by expression profiling, which identifies the 5 subtypes luminal A, luminal B, basal-like, HER2-positive and normal-like. Basal-like tumours are the most aggressive subtype, for which so far no targeted therapy is available.Making use of the WGCNA clustering method to reconstruct breast cancer transcriptional networks from the METABRIC breast cancer dataset, we developed a platform to address specific questions related to breast cancer biology. In particular, we obtained gene modules significantly correlated with survival and age of onset, useful to understand how molecular features and gene expression patterns are organized in breast cancer. We next generated subtype-specific gene networks and in particular identified two modules that are significantly more connected in basal-like breast cancer with respect to all other subtypes, suggesting relevant biological functions. We demonstrate that network centrality (kWithin) is a suitable measure to identify relevant genes, since we could show that it correlates with clinical features and that it provides a mean to select potential upstream regulators of a module with high reliability. Finally, we showed the feasibility of adding meaning to the networks by combining them with independently obtained data related to activated pathways.In conclusion, our platform allows to identify groups of genes highly relevant in breast cancer and possibly amenable to drug targeting, due to their ability to regulate survival-related gene networks. This approach could be successfully extended to other BC subtypes, and to all tumor types for which enough expression data are available.

Epithelial Organotypic Cultures: A Viable Model to Address Mechanisms of Carcinogenesis by Epitheliotropic Viruses

2018 ◽  
Vol 18 (4) ◽  
pp. 246-255 ◽  
Author(s):  
Lara Termini ◽  
Enrique Boccardo
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Experimental Models ◽  
Biological Research ◽  
Specific Gene ◽  
Specific Cell ◽  
Organotypic Cultures ◽  
Skin Physiology

In vitro culture of primary or established cell lines is one of the leading techniques in many areas of basic biological research. The use of pure or highly enriched cultures of specific cell types obtained from different tissues and genetics backgrounds has greatly contributed to our current understanding of normal and pathological cellular processes. Cells in culture are easily propagated generating an almost endless source of material for experimentation. Besides, they can be manipulated to achieve gene silencing, gene overexpression and genome editing turning possible the dissection of specific gene functions and signaling pathways. However, monolayer and suspension cultures of cells do not reproduce the cell type diversity, cell-cell contacts, cell-matrix interactions and differentiation pathways typical of the three-dimensional environment of tissues and organs from where they were originated. Therefore, different experimental animal models have been developed and applied to address these and other complex issues in vivo. However, these systems are costly and time consuming. Most importantly the use of animals in scientific research poses moral and ethical concerns facing a steadily increasing opposition from different sectors of the society. Therefore, there is an urgent need for the development of alternative in vitro experimental models that accurately reproduce the events observed in vivo to reduce the use of animals. Organotypic cultures combine the flexibility of traditional culture systems with the possibility of culturing different cell types in a 3D environment that reproduces both the structure and the physiology of the parental organ. Here we present a summarized description of the use of epithelial organotypic for the study of skin physiology, human papillomavirus biology and associated tumorigenesis.

scholarly journals A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ying Liu ◽  
Wenjie Liu ◽  
Ziqiang Yu ◽  
Yan Zhang ◽  
Yinghua Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoporosis Treatment ◽  
Inhibitory Effect ◽  
Specific Gene ◽  
Actin Ring ◽  
Treatment Target ◽  
Significant Inhibitory Effect ◽  
Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

scholarly journals Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus

2021 ◽  
Vol 11 (8) ◽  
pp. 973
Author(s):  
Maria Cristina Petralia ◽  
Rosella Ciurleo ◽  
Alessia Bramanti ◽  
Placido Bramanti ◽  
Andrea Saraceno ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Clinical Manifestations ◽  
Antipsychotic Agents ◽  
Standards Of Care ◽  
Specific Gene ◽  
Contributing Factors ◽  
Healthy Donors ◽  
Dorsolateral Prefrontal ◽  
Inflammatory Processes ◽  
Disease Specific

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

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