scholarly journals Mitochondrial Toxicity of Tenofovir Dipivoxil Fumarate in HK-2 Cells

2016 ◽  
Author(s):  
Qihui Luo ◽  
Junjun Zhao ◽  
Xinglei Feng ◽  
Zhengli Chen ◽  
Wen Zeng ◽  
...  
Keyword(s):  
Mitochondrial Toxicity

scholarly journals TAMI-38. CYSTEINE-PROMOTING COMPOUNDS INDUCE MITOCHONDRIAL TOXICITY IN GLIOBLASTOMA THROUGH ALTERED PYRUVATE AND SERINE METABOLISM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii221-ii221
Author(s):  
Evan Noch ◽  
Laura Palma ◽  
Isaiah Yim ◽  
Bhavneet Binder ◽  
Elisa Benedetti ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Glucose Deprivation ◽  
Tumor Metabolism ◽  
Metabolic Phenotype ◽  
Low Grade ◽  
Mitochondrial Toxicity ◽  
Human Cancers ◽  
Pathway Gene

Abstract Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the metabolic alterations that are specific to GBM and that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through System Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Metabolic tracing experiments with 13C6-glucose demonstrate that L-serine is rapidly depleted in GBM cells upon treatment with NAC and CTX, and exogenous serine rescues NAC- and CTX-mediated cell growth inhibition. In addition, these compounds reduce GBM mitochondrial pyruvate transport. We show that cysteine-promoting compounds reduce cell growth and induce mitochondrial toxicity in GBM, which may be due to rapid serine depletion and reduced mitochondrial pyruvate transport. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.

scholarly journals Adamantane Carboxylic Acids Demonstrate Mitochondrial Toxicity Consistent with Oil Sands-Derived Naphthenic Acids

2021 ◽  
pp. 100092
Author(s):  
Kate I. Rundle ◽  
Mahmoud S. Sharaf ◽  
Don Stevens ◽  
Collins Kamunde ◽  
Michael R. Heuvel
Keyword(s):  
Carboxylic Acids ◽  
Oil Sands ◽  
Naphthenic Acids ◽  
Mitochondrial Toxicity

Magnetic nanostructured lipid carrier for dual triggered curcumin delivery: Preparation, characterization and toxicity evaluation on isolated rat liver mitochondria

2021 ◽  
pp. 088532822110346
Author(s):  
Mohammad Yoozbashi ◽  
Hamid Rashidzadeh ◽  
Mehraneh Kermanian ◽  
Somayeh Sadighian ◽  
Mir-Jamal Hosseini ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Nanostructured Lipid Carrier ◽  
Mitochondrial Toxicity ◽  
X Ray Diffraction ◽  
Temperature Dependent ◽  
Reducing Ability ◽  
Transmission Electron

In this research, magnetic nanostructured lipid carriers (Mag-NLCs) were synthesized for curcumin (CUR) delivery. NLCs are drug-delivery systems prepared by mixing solid and liquid (oil) lipids. For preparation of NLCs, cetylpalmitate was selected as solid lipid and fish oil as liquid lipid. CUR-Mag-NLCs were prepared using high-pressure homogenization technique and were characterized by methods including X-ray diffraction (XRD), transmission electron microscopy (TEM), vibrating sample magnetometer (VSM), and dynamic light scattering (DLS). The CUR-Mag-NLCs were developed as a particle with a size of 140 ± 3.6 nm, a polydispersity index of 0.196, and a zeta potential of −22.6 mV. VSM analysis showed that the CUR-Mag-NLCs have excellent magnetic properties. Release rate of the drug was higher at 42 °C than 37 °C, indicating that release of the synthesized nanoparticles is temperature-dependent. Evaluation of mitochondrial toxicity was done using the isolated rats liver mitochondria including glutathione (GSH), malondialdehyde (MDA), and the ferric- reducing ability of plasma (FRAP) assays to study biosafety of the CUR-Mag-NLCs. Results of In vitro study on the isolated mitochondria revealed that both CUR-Mag-NLCs and curcumin have no specific mitochondrial toxicity.

scholarly journals 1616. Mechanism of Thrombocytopenia Induced by Oxazolidinones Antibiotics (Linezolid, Tedizolid): Demonstration of Impairment of Megakaryocyte Differentiation From Human Hematopoietic Stem Cells associated with Mitochondrial Toxicity

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S801-S801
Author(s):  
Paul M Tulkens ◽  
Tamara V Milosevic ◽  
Gaëlle Vertenoeil ◽  
William Vainchenker ◽  
Stefan N Constantinescu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Cytochrome C ◽  
Hematopoietic Stem Cells ◽  
Cytochrome C Oxidase ◽  
Panel Member ◽  
Human Model ◽  
Mitochondrial Toxicity ◽  
Review Panel ◽  
Hematopoietic Stem

Abstract Background Linezolid causes thrombocytopenia, which limits its use. In cell culture and in tissues from treated patients, linezolid impairs mitochondrial protein synthesis (due to structural similarities and common binding sites between bacterial and mitochondrial ribosomes). Recent studies have shown that mitochondria act as a key relay in the process leading from activation of the thrombopoietin receptor to megakaryocytes differentiation. Methods Validated ex-vivo human model of hematopoietic stem cells (HSC) differentiation for (i) measuring megakaryocytes, granulocyte-monocytes, and burst-forming unit-erythroids colony formation; (ii) differentiation into megakaryocytes (conversion of CD34+ into CD41+/CD42+ cells; morphology) and proplatelets formation, (iii) mitochondrial toxicity (electron microscopy; cytochrome c-oxidase activity [partly encoded by the mitochondrial genome]). Results We show that linezolid (and the recently approved tedizolid), both at concentrations corresponding to their human serum concentrations) inhibit the maturation of HSC into fully differentiated megakaryocytes (CD41 and CD42-positive cells) and the formation of proplatelets. Optic and Electron microscopy) showed an impairment of the formation of typical megakaryocytes (lack of large polylobulated nuclei and of intracellular demarcation membrane system [required for platelet formation]), together with disappearance of the internal structure of mitochondria. Biochemical studies showed a complete suppression of the activity of cytochrome c-oxidase (a key enzyme of the mitochondrial respiratory chain). Conclusion Our study provides for the first time insights in the mechanism of thrombocytopenia induced by linezolid and tedizolid, identifying mitochondria as their target and showing that the drugs will impair the differentiation of hematopoietic stem cells into mature platelets-releasing megakaryocytes. It illustrates how mitochondria dysfunction may play a key role in toxicology and diseases, while paving the way for rational approaches for the design and screening of less toxic derivatives for the benefit of future patients. Disclosures Paul M. Tulkens, MD, PhD, Bayer (Consultant, Advisor or Review Panel member, Speaker’s Bureau)Menarini (Speaker’s Bureau)Merck (Advisor or Review Panel member, Speaker’s Bureau)Trius (now part of Merck) (Advisor or Review Panel member, Research Grant or Support) Françoise Van Bambeke, PharmD, PhD, Bayer (Speaker’s Bureau)

scholarly journals Hydrogen sulfide attenuates homocysteine‐induced osteoblast dysfunction by inhibiting mitochondrial toxicity

2019 ◽  
Vol 234 (10) ◽  
pp. 18602-18614 ◽  
Author(s):  
Yuankun Zhai ◽  
Jyotirmaya Behera ◽  
Suresh C. Tyagi ◽  
Neetu Tyagi
Keyword(s):  
Hydrogen Sulfide ◽  
Mitochondrial Toxicity

scholarly journals Sources, mechanisms, and consequences of chemical-induced mitochondrial toxicity

Toxicology ◽  
2017 ◽  
Vol 391 ◽  
pp. 2-4 ◽  
Author(s):  
Joel N. Meyer ◽  
Sherine S.L. Chan
Keyword(s):  
Mitochondrial Toxicity
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