Suppression of superoxide/hydrogen peroxide production at mitochondrial site I decreases fat accumulation, improves glucose tolerance and normalizes fasting insulin concentration in mice fed a high-fat diet.

We developed S1QEL1.719, a novel bioavailable S1QEL (suppressor of site I electron leak). S1QEL1.

Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment.

Glioblastoma's (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effective against GBM. In this study, we aimed to identify an effective anti-tumor regimen using pharmacogenomic testing of patient-derived GBM samples, in culture and in vivo.

Functional genomic analysis of adult and pediatric brain tumor isolates.

Background: Adult and pediatric tumors display stark differences in their mutation spectra and chromosome alterations. Here, we attempted to identify common and unique gene dependencies and their associated biomarkers among adult and pediatric tumor isolates using functional genetic lethal screens and computational modeling.

Methods: We performed CRISRP-Cas9 lethality screens in two adult glioblastoma (GBM) tumor isolates and five pediatric brain tumor isolates representing atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine glioma, GBM, and medulloblastoma.

Cannabidiol inhibits RAD51 and sensitizes glioblastoma to temozolomide in multiple orthotopic tumor models.

Background: Cannabidiol (CBD), a nonpsychoactive cannabinoid with a low toxicity profile, has been shown to produce antitumor activity across cancers in part through selective production of reactive oxygen species (ROS) in tumor cells. The alkylating agent, temozolomide (TMZ), is standard of care for treatment of glioblastoma (GBM). It can trigger increased ROS to induce DNA damage.

Superoxide produced by mitochondrial site I inactivates cardiac succinate dehydrogenase and induces hepatic steatosis in Sod2 knockout mice.

Superoxide produced by mitochondria has been implicated in numerous physiologies and pathologies. Eleven different mitochondrial sites that can produce superoxide and/or hydrogen peroxide (O/HO) have been identified in vitro, but little is known about their contributions in vivo. We introduce novel variants of S1QELs and S3QELs (small molecules that suppress O/HO production specifically from mitochondrial sites I and III, respectively, without compromising bioenergetics), that are suitable for use in vivo.

Plate-Based Measurement of Respiration by Isolated Mitochondria.

Measuring respiration rate can be a powerful way to assess energetic function in isolated mitochondria. Current, plate-based methods have several advantages over older, suspension-based systems, including greater throughput and the requirement of only μg quantities of material. In this chapter, we describe a plate-based method for measuring oxygen consumption by isolated adherent mitochondria.

Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions.

Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites that differ markedly in capacity are known to leak electrons to oxygen to produce O and/or HO We discuss their contributions to O/HO production under native conditions in mitochondria oxidizing different substrates and in conditions mimicking physical exercise and the changes in their capacities after caloric restriction. We review the use of S1QELs and S3QELs, suppressors of mitochondrial O/HO generation that do not inhibit oxidative phosphorylation, as tools to characterize the contributions of specific sites and .

Effect of bFGF on HLA-DR expression of human bone marrow-derived mesenchymal stem cells.

There has been a steady rise in the therapeutic applications of bone marrow mesenchymal stem cells (BM-MSCs) because of their unique properties of multilineage differentiation and immune modulation as well as the ease in isolation. However, up-regulation of surface HLA-DR levels when maintaining MSCs in culture under the influence of mitotic factors such as Basic fibroblast growth factor (bFGF) is an area of concern when considering them for the purpose of clinical applications. Thus, we investigated the association of bFGF supplemented to the culture media and the surface expression levels of HLA-DR in BM-MSCs in order to optimize the yield, while keeping HLA-DR levels under permissible levels.