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Drug induced mitochondrial toxicity

Peng Sun, Jing-Jie Zhu, Ting Wang, Qi Huang, Yu-Ren Zhou, Bang-Wei Yu, Hua-Liang Jiang, He-Yao Wang
As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD)-induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group...
March 8, 2018: Biochimica et Biophysica Acta
Erzsebet Polyak, Julian Ostrovsky, Min Peng, Stephen D Dingley, Mai Tsukikawa, Young Joon Kwon, Shana E McCormack, Michael Bennett, Rui Xiao, Christoph Seiler, Zhe Zhang, Marni J Falk
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials...
February 23, 2018: Molecular Genetics and Metabolism
Wenxing Zhu, Lujiang Hao, Xinli Liu, Borrás-Hidalgo Orlando, Yuyu Zhang
Epothilones constitute a new class of microtubule-stabilizing anticancer agents with promising preclinical and clinical activity. However, its systemic application still causes some toxic side effects. To reduce these undesired effects, advanced drug delivery systems based on cell targeting carriers are needed currently. In this study, the high quality bacterial ghosts of the probiotic Escherichia coli Nissle 1917 (EcN) were prepared in a large scale and retained fully intact surface structures for specific attachment to mammalian cells...
March 9, 2018: Drug Development and Industrial Pharmacy
Tal Teitz, Jie Fang, Asli N Goktug, Justine D Bonga, Shiyong Diao, Robert A Hazlitt, Luigi Iconaru, Marie Morfouace, Duane Currier, Yinmei Zhou, Robyn A Umans, Michael R Taylor, Cheng Cheng, Jaeki Min, Burgess Freeman, Junmin Peng, Martine F Roussel, Richard Kriwacki, R Kiplin Guy, Taosheng Chen, Jian Zuo
Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration-approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss...
March 7, 2018: Journal of Experimental Medicine
Jennifer M Reinhart, Warren Rose, Daniel J Panyard, Michael A Newton, Tyler K Liebenstein, Jeremiah Yee, Lauren A Trepanier
The lymphocyte toxicity assay (LTA) is a proposed surrogate marker of sulfonamide antibiotic hypersensitivity. In the LTA, peripheral blood mononuclear cells (PBMCs) undergo apoptosis more readily in hypersensitive versus tolerant patients when exposed to drug-hydroxylamine metabolites in vitro. The purpose of this study was to identify key gene transcripts associated with increased cytotoxicity from sulfamethoxazole-hydroxylamine in human PBMCs in the LTA. The LTA was performed on PBMCs of 10 patients hypersensitive to trimethoprim-sulfamethoxazole (HS) and 10 drug-tolerant controls (TOL), using two cytotoxicity assays: YO-PRO (n = 20) and MTT (n = 12)...
April 2018: Pharmacology Research & Perspectives
Chandrasekar Balachandran, Jebiti Haribabu, Kumaramangalam Jeyalakshmi, Nattamai S P Bhuvanesh, Ramasamy Karvembu, Nobuhiko Emi, Suresh Awale
Three novel complexes (1, 3 and 4) ligating N-substituted isatin thiosemicarbazone derivatives have been synthesized and their structural and biological characteristics have been compared with those of the known analogs (2, 5-7 and 8). In addition, the structure of the representative ligands (L1, L3 and L4) and complex (4) was confirmed by single crystal X-ray diffraction method. All the complexes (1-8) were assessed for their cytotoxic property against a panel of four human cancer cells such as HepG-2 (liver), MOLM-14 (acute monocytic leukemia), U937 (histiocytic lymphoma)...
February 24, 2018: Journal of Inorganic Biochemistry
Jarno E J Wolters, Simone G J van Breda, Jonas Grossmann, Claudia Fortes, Florian Caiment, Jos C S Kleinjans
We performed a multiple 'omics study by integrating data on epigenomic, transcriptomic, and proteomic perturbations associated with mitochondrial dysfunction in primary human hepatocytes caused by the liver toxicant valproic acid (VPA), to deeper understand downstream events following epigenetic alterations in the mitochondrial genome. Furthermore, we investigated persistence of cross-omics changes after terminating drug treatment. Upon transient methylation changes of mitochondrial genes during VPA-treatment, increasing complexities of gene-interaction networks across time were demonstrated, which normalized during washout...
February 28, 2018: Toxicology Letters
Shweta Kaushik, Hari Shyam, Ramesh Sharma, Anil K Balapure
BACKGROUND: Despite advancements in the prognosis and management of breast cancer, it remains a major cause of mortality in women worldwide. Centchroman (CC), an oral contraceptive has been found to exhibit anti-cancer potential against a wide range of cancer including breast cancer. PURPOSE: The present study is intended to evaluate the ability of soy isoflavone Daidzein (DZ) in enhancing the efficacy of CC in Human Breast Cancer Cells (HBCCs). METHODS/STUDY DESIGN: Sulforhodamine B assay was employed to determine the cytotoxicity induced by 10 µM CC & 50 µM DZ separately and together in MCF-7/MDA MB-231 HBCCs and non-tumorigenic Human Mammary Epithelial Cells (HMECs) MCF-10A as a control...
February 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Aline Steinmetz, Luiza Steffens, Ana Moira Morás, Flávia Prezzi, Elizandra Braganhol, Jenifer Saffi, Rafael Scorsatto Ortiz, Helena M T Barros, Dinara Jaqueline Moura
Cocaine is one of the most popular illicit drug worldwide. Due its great addictive potential, which leads to euphoria and hyperactivity, it is considered a public health concern. At the central nervous system, the drug acts inhibiting catecholamine re-uptake. It is now known that in addition to the toxicity of the drug itself, the contaminants present in the street drug have raised concern about the harmful effects on health. Toxicological in vivo and in vitro studies have demonstrated the toxic effects of cocaine correlated with the generation of reactive oxygen species (ROS), which in turn lead to oxidative damage to the cells...
February 20, 2018: Chemico-biological Interactions
Blanca Laffon, Natalia Fernández-Bertólez, Carla Costa, Fátima Brandão, João Paulo Teixeira, Eduardo Pásaro, Vanessa Valdiglesias
Iron oxide nanoparticles (ION) have attracted much attention because of their particular physico-chemical properties, including superparamagnetism. These features make them suitable for many purposes and several interesting biomedical applications, such as to increase contrast in magnetic resonance imaging (MRI), as drug delivery systems and as hyperthermia agents. However, they have also shown to be easily accumulated in diverse tissues and induce toxicity at different levels. This chapter reviews the different cellular and molecular effects induced by ION reported from in vitro studies with human and non-human cell lines...
2018: Advances in Experimental Medicine and Biology
Claudia G Fresta, Aishik Chakraborty, Manjula B Wijesinghe, Angela M Amorini, Giacomo Lazzarino, Giuseppe Lazzarino, Barbara Tavazzi, Susan M Lunte, Filippo Caraci, Prajnaparamita Dhar, Giuseppe Caruso
Engineered nanoparticles are finding a wide spectrum of biomedical applications, including drug delivery and capacity to trigger cytotoxic phenomena, potentially useful against tumor cells. The full understanding of their biosafety and interactions with cell processes is mandatory. Using microglial (BV-2) and alveolar basal epithelial (A549) cells, in this study we determined the effects of engineered carbon nanodiamonds (ECNs) on cell viability, nitric oxide (NO) and reactive oxygen species (ROS) production, as well as on energy metabolism...
February 14, 2018: Cell Death & Disease
Jan Jakub Lica, Grzegorz Jan Grabe, Mateusz Heldt, Majus Misiak, Patrycja Bloch, Marcin Serocki, Marta Switalska, Joanna Wietrzyk, Maciej Baginski, Andrzej Hellmann, Edward Borowski, Andrzej Skladanowski
Proliferation and expansion of leukemia is driven by Leukemic Stem Cells (LSCs). Multidrug resistance (MDR) of LSCs is one of the main reasons of failure and relapses in Acute Myeloid Leukemia (AML) treatment. Here we show that maintaining HL-60 at low cell culture density or applying a 240-day treatment with anthrapyridazone (BS-121) increased the percentage of primitive cells which include LSCs determining the overall stage profile. This change manifested in: morphology, expression of both cell surface markers and redox-state proteins as well as mitochondrial potential...
February 12, 2018: Stem Cells and Development
Jiekun Xuan, Zhen Ren, Tao Qing, Letha Couch, Leming Shi, William H Tolleson, Lei Guo
Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726...
February 7, 2018: Toxicology
Cesar Armando Lancheros Contreras, Milena Trevisan Pelegrino, Danielle Kian, Eliandro Reis Tavares, Priscila Mazzochi Hiraiwa, Samuel Goldenberg, Celso Vataru Nakamura, Lucy Megumi Yamauchi, Phileno Pinge-Filho, Amedea Barozzi Seabra, Sueli Fumie Yamada Ogatta
BACKGROUND: Chagas' disease, caused by Trypanosoma cruzi, was described for the first time over a hundred years ago. Nonetheless, clinically available drugs still lack effective and selective properties. Nitric oxide (NO) produced by activated macrophages controls the progression of disease by killing the parasite. METHODS AND RESULTS: Here, chitosan nanoparticles (CS NPs) were synthesized and mercaptosuccinic acid (MSA), the NO donor precursor, was encapsulated into CS NPs, forming MSA-CS NPs, which had hydrodynamic size of 101...
February 8, 2018: Current Pharmaceutical Design
Ayman N Abunimer, Heba Mohammed, Katherine L Cook, David R Soto-Pantoja, Maria Mercedes Campos, Mones S Abu-Asab
We have previously described the process by which mitochondria donate their membranes for the formation of autophagosomes, and in this study we show that the same process could be involved in drug sequestration and exocytosis resulting in multidrug-resistant cancerous cells. We examine the implications of mitochondrial vesicle formation of mitoautophagosomes (MAPS) in response to the cytotoxic drug MKT-077, which targets mortalin, in a drug-resistant breast carcinoma cell line overexpressing P-glycoprotein (P-gp)...
February 8, 2018: Ultrastructural Pathology
Xiang Gao, Jia Li, Mingying Wang, Shengtao Xu, Weiwei Liu, Linghe Zang, Zhanlin Li, Huiming Hua, Jinyi Xu, Dahong Li
Natural derived enmein-type diterpenoids exert cytotoxicity against a wide range of human cancer cells. Yet their medicinal applications are hindered by insufficient potency for chemotherapy. Hence, a series of novel enmein-type diterpenoid hybrids coupled with nitrogen mustards were designed and synthesized to increase antitumor efficacy while reducing systemic toxicity. Most conjugates exhibited stronger antiproliferative activities than parent diterpenoids and nitrogen mustards, especially for multidrug-resistant tumor cell line Bel-7402/5-FU...
February 25, 2018: European Journal of Medicinal Chemistry
Nayana George, Minjun Chen, Nancy Yuen, Christine M Hunt, Ayako Suzuki
We examined the effect of gender, age, and drug properties on liver events reporting frequency (RF) to assess patient- and drug-related risks for drug-induced liver injury (DILI). We performed a data-mining analysis of the WHO VigiBase™ to 1) identify drugs with gender- and age-biased RF and 2) characterize drug properties using the Liver Toxicity Knowledge Base. Age-, gender-specific Empirical Bayes Geometric Mean of relative reporting ratio of liver events with 90% confidence interval (CI) was calculated for 375 drugs with DILI potential...
January 29, 2018: Regulatory Toxicology and Pharmacology: RTP
Patricia Andrea Garavaglia, María Fernanda Rubio, Marc Laverrière, Laura Mónica Tasso, Laura Edith Fichera, Joaquín J B Cannata, Gabriela Andrea García
Several ortho-naphthoquinones (o-NQs) have trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Previously, we demonstrated that the aldo-keto reductase from this parasite (TcAKR) reduces o-NQs, such as β-lapachone (β-Lap) and 9,10-phenanthrenequinone (9,10-PQ), with concomitant reactive oxygen species (ROS) production. Recent characterization of TcAKR activity and expression in two T. cruzi strains, CL Brener and Nicaragua, showed that TcAKR expression is 2.2-fold higher in CL Brener than in Nicaragua...
February 5, 2018: Parasitology
Christopher R Chitambar
Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials...
February 5, 2018: Metal Ions in Life Sciences
Aiany C Simões-Alves, Reginaldo C Silva-Filho, Glauber Ruda F Braz, Severina Cassia A Silva, Aline Isabel da Silva, Claudia J Lagranha, Mariana P Fernandes
Recent studies have shown that exposure to fluoxetine treatment induces excessive production of ROS, and alters the antioxidant defense system in various tissues and cell types, mainly the liver. When fluoxetine is administered intraperitoneally, the drug rapidly reaches high concentrations in the liver, has potentially multiple toxic effects on energy metabolism in rat liver mitochondria. The aim of this study was to evaluate the effect of pharmacological treatment with fluoxetine during critical period for development on the mitochondrial bioenergetics and oxidative stress in liver of rat adult...
February 1, 2018: Journal of Cellular Biochemistry
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