Biology subjects

OConnell, T. M.

Publications and source records attributed to OConnell, T. M..

4 recordsLinked to original sources

bioRxiv2025

Osteocyte Differentiation Requires Glycolysis, But Mature Osteocytes Display Metabolic Flexibility

Recent research has identified metabolic pathways which play key roles in the differentiation and function of osteoblasts and osteoclasts. However, the mechanisms by which osteocytes, the most numerous cells in bone, meet their energetic demands are still unknown. To address this, we used the IDG-SW3 osteocyte cell line to examine changes in metabolism during differentiation from late osteoblasts to mature osteocytes. There was a significant increase in the expression of glycolysis genes (including Pkm and Ldha), glucose consumption and lactate production during late differentiation of these cells. This was concurrent with the onset of the expression of mature osteocyte markers. Inhibition of glycolysis using the glucose analogue 2-deoxy-d-glucose (2-DG) inhibited IDG-SW3 cell mineralization and differentiation into osteocytes. To examine the effect of glycolysis inhibition on mature osteocytes, we treated differentiated IDG-SW3 cells and long bone osteocytes with 2-DG. Glycolysis inhibition resulted in decreased expression of the bone formation inhibitor Sost and mineralization inhibitor Fgf23. Concurrently, there was an increase in genes associated with lipolysis (Lpl) fatty acid {beta}-oxidation (Ppar{delta} and Cpt1a). Treatment of differentiated IDG-SW3 cells with the unsaturated fatty acid oleic acid increased Cpt1a expression and downregulated Sost and Fgf23. Application of mechanical stress to IDG-SW3 cells resulted in upregulation of oxidative metabolism, Ppar{delta} and Cpt1a expression. Long and short chain acylcarnitines were increased in the cortical bone of axially loaded tibiae compared to non-loaded controls, indicative of increased {beta}-oxidation. Overall, our data suggests that while glycolysis is essential for osteocyte differentiation, mature osteocytes are metabolically flexible. Furthermore, {beta}-oxidation may play an important role in the osteocyte response to mechanical stress.

cell biology↗

bioRxiv2025

Synergistic Antitumor Activity of SUMO1 degrader and Oxaliplatin through G6PD Inhibition in Colorectal Cancer

Colorectal cancer (CRC) stands as one of the primary causes of death despite advancements in targeted therapies and chemotherapeutic methods. The oxaliplatin-based chemotherapy, such as the FOLFOX, remains limited by its toxic side effects and the development of drug resistance. The current studies demonstrate redox homeostasis as an important therapeutic target in cancer cells through the discovery of glucose-6-phosphate dehydrogenase (G6PD) as their major controller of oxidative stress and survival. In this study, we investigated the therapeutic potential of HB007 in combination with FOLFOX in CRC. Treatment with HB007 decreased the enzyme activity of G6PD and generated high ROS concentrations, which subsequently induced intrinsic apoptosis. When combined with FOLFOX, which also induces ROS and inhibits G6PD activity, HB007 showed synergistic cytotoxicity in vitro, in colon patient-derived 3D organoids, and in vivo patient-derived xenograft model, including FOLFOX-resistant tumors. The combination treatment mechanistically targeted G6PD activity, disrupted redox balance, and activated apoptosis without affecting G6PD protein level. These findings suggest that G6PD inhibition by HB007 enhances the efficacy of FOLFOX, suggesting a strategy to overcome chemoresistance and improve therapy in advanced CRC.

cancer biology↗

bioRxiv2024

Pathway Volcano: An interactive tool for pathway guided visualization of differential expression data

SummaryThe increasing size and complexity of omics datasets can make effective visualization and interpretation very challenging. Differential expression datasets as from RNA-sequencing and proteomics can contain many thousands of features and even after filtering for significance there can be hundreds or thousands of features to consider. A common tool for visualizing this type of data is the volcano plot where each feature is plotted as log2 transformed fold change along the x-axis and the negative log10 of a p-value along the y-axis. These plots provide a useful visualization of the largest and most significant changes, but the majority of the features are often crowded and overlapping near the "cone" of the volcano. In order to provide a biologically informative way to simplify the visualization and interpretation of these types of datasets we developed the Pathway Volcano tool. This R-Shiny based software utilizes the Reactome API to select specific pathways and then filters the volcano plots to show only the data associated with those pathways. In this manner, many of the significant features in the crowded section of the volcano plot can be revealed to support the impact of specified pathways. This tool provides a range of interactive features to interrogate the data along with the ability to download png files and tables with pathway associated data. Availability and implementationPathway Volcano is a freely available R Shiny package. The program was developed in R version 4.3.3 using R Studio version 2024.09.1 Build 394. Running the app locally requires the packages ggplot2 (1), plotly (2), shiny (3) dplyr (4) and ReactomeContentServer (5). The full code and documentation including example datasets are available at https://github.com/thoconne/PathwayVolcano Contactthoconne@iu.edu

bioinformatics↗

bioRxiv2023

Viime-Path: An Interactive Metabolic Pathway Generation Tool for Metabolomics Data Analysis

IntroductionA primary objective of metabolomics studies is identifying the critical metabolic pathways that are altered under specific conditions. There are a number of tools such as enrichment or over-representation algorithms which can identify pathways, but tools for visualizing these pathways beyond static diagrams are limited. ObjectivesDevelopment of an open-source software tool to enable users to generate metabolic pathway diagrams that can be interactively adjusted to allow for the most lucid and meaningful representation of the data. The ability to input and integrate multiple metabolic pathways and interactively adjust could facilitate the identification of novel metabolic pathways. MethodsThe Viime-Path software package utilizes the metabolic pathways in the Reactome Database. The initial pathway layouts are generated using the Human-like Orthogonal Network Layout (HOLA) algorithm which was designed to take such datasets and map them onto orthogonal network layouts using aesthetic principles derived from the analysis of human-generated networks. The software is written in TypeScript and Vue, utilizing the WebCola graph layout library and D3.js for visualization primitives. ResultsWe have created an easy-to-use, web-based, open-source tool to easily import metabolic pathways from the Reactome database. The tool allows for interactive optimization of pathways to best represent the most salient features for a given analysis. The tool is available on GitHub at https://github.com/girder/viime-path. ConclusionsThe Viime-Path tool will enable the metabolomics community to interactively draw metabolic pathway networks with options to adjust specific components and layout, thus providing new levels of clarity and focus.

cancer biology↗