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Drug induced mitochondrial toxicity

Ai-Li Xu, Ming-Chun Jiang, Xiao-Han Chen, Wen-Fang Chen
Icariin is the major bioactive component of Epimedium and has been demonstrated to be a potential drug for age-related diseases. The present study was aimed to investigate the neuroprotective properties of icariin against 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neurotoxicity in MES23.5 cells and the possible mechanisms. MTT assay showed that treatment with MPP(+) attenuated the cell viability in a dose-dependent manner in MES23.5 cells. Icariin pretreatment resulted in an enhancement of survival. Immunocytochemistry analysis revealed that icariin treatment attenuated MPP(+)-induced loss of tyrosine hydroxylase (TH) positive cells...
October 25, 2016: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Ceyda Acilan, Zelal Adiguzel, Buse Cevatemre, Didem Karakas, Engin Ulukaya, Nádia Ribeiro, Isabel Correia, João Costa Pessoa
BACKGROUND: To overcome the hurdles of cisplatin, majorly its toxicity and resistance, there has been extensive search for alternative anti-cancer metal-based compounds. Here, three Cu(II)-complexes, Cu(Sal-Gly)(phen), Cu(Sal-Gly)(pheamine), Cu(Sal-Gly)(phepoxy) are characterized for their interaction with DNA, cytotoxicity and mechanism of action. METHODS: The binding ability of the complexes to Calf-Thymus DNA was evaluated by competition fluorescence studies with thiazole-orange, UV-Vis and circular-dichroism spectroscopic titrations...
October 20, 2016: Biochimica et Biophysica Acta
Madhusudanarao Vuda, Ashwin Kamath
Several commonly used medications impair mitochondrial function resulting in adverse effects or toxicities. Drug induced mitochondrial dysfunction may be a consequence of increased production of reactive oxygen species, altered mitochondrial permeability transition, impaired mitochondrial respiration, mitochondrial DNA damage or inhibition of beta-oxidation of fatty acids. The clinical manifestation depends on the specific drug and its effect on mitochondria. Given the ubiquitous presence of mitochondria and its central role in cellular metabolism, drug-mitochondrial interactions may manifest clinically as hepatotoxicity, enteropathy, myelosuppression, lipodystrophy syndrome or neuropsychiatric adverse effects, to name a few...
October 19, 2016: Mitochondrion
John J Guardiola, Juliane I Beier, K Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS(2) analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed...
October 17, 2016: Toxicology and Applied Pharmacology
Francielle Pelegrin Garcia, Jean Henrique da Silva Rodrigues, Zia Ud Din, Edson Rodrigues-Filho, Tânia Ueda-Nakamura, Rachel Auzély-Velty, Celso Vataru Nakamura
Leishmaniasis is a neglected tropical disease that affects millions of people worldwide. Current therapies mainly rely on antimonial drugs that are inadequate because of their high toxicity and increased drug resistance. An urgent need exists to discover new, more effective, more affordable, and more target-specific drugs. Pathways that are associated with apoptosis-like cell death have been identified in unicellular eukaryotes, including protozoan parasites. In the present study, we studied the mechanism of cell death that is induced by A3K2A3 against L...
October 19, 2016: Apoptosis: An International Journal on Programmed Cell Death
Anliang Huang, Dan Yue, Danying Liao, Liuliu Cheng, Jinhu Ma, Yuquan Wei, Aiping Tong, Ping Cheng
Arsenic trioxide (ATO) has demonstrated clinical efficacy in acute promyelocytic leukemia (APL) and in vitro activity in various solid tumors. As2O3 as single agent exhibits poor efficacy for treatment of hepatocellular carcinoma (HCC) in phase II trial, suggesting that new modalities of treatment with enhanced therapeutic effect and alleviated toxicity are needed for application of As2O3 on patients with HCC. Survivin is the strongest inhibitor of apoptosis protein over-expressed in tumors, which has been proposed as an attractive target for new anticancer interventions...
October 11, 2016: Oncology Reports
Jyun-Wei Chen, Cheng-Chung Chang
Unlike traditional binary nanostructures that construct chemotherapy drugs and photodynamic therapy photosensitizers, we introduce a molecule possessing the chemo-photodynamic dual therapy function. A water-soluble aggregation-induced emission enhancement (AIEE) fluorogen, NV-12P, was designed and synthesized based on asymmetric 1, 6-disubstituted naphthalene and can generate particular reactive oxygen species (ROS) to undergo type I photodynamic therapy (PDT) programme under irradiation. Furthermore, this compound can specifically localize in mitochondria and, after biologically evaluation, cause mitochondrial dysfunction and potent cytotoxicity to cancer cells but not normal cells...
October 17, 2016: ACS Applied Materials & Interfaces
Chengyu Wang, Yin Cheng, Hongyi Liu, Yaping Xu, Hu Peng, Juntian Lang, Jianchun Liao, Haibin Liu, Huanhai Liu, Jingping Fan
BACKGROUND/AIMS: Nasopharyngeal cancer (NPC) is one of the common human malignant diseases all over the world, and chemotherapy remains the main therapy for NPC. However, the survival and life quality of NPC patients are still very poor. Thus, novel and selective anti-tumor agents are pressingly needed. Our previous study identified pectolinarigenin as a novel effective anti-tumor drug candidate for NPC. In this study, we further investigated its anti-tumor activities and explored the potential molecular mechanism...
October 17, 2016: Cellular Physiology and Biochemistry
Marianne Uteng, Andreas Mahl, Nicolau Beckmann, Alessandro Piaia, David Ledieu, Valerie Dubost, Elaine Tritto, Armin Wolf, Pierre Moulin, Li Li, Salah-Dine Chibout, Francois Pognan
The aim of this study was to determine the relative safety of four antiviral drugs (telbivudine, tenofovir, adefovir, entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Spraque-Dawley rats. The antiviral drugs were administered once daily for four weeks by oral gavage at about 10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology and electron microscopic examination...
October 13, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Debasis Nayak, Manisha Kumari, Sripathi Rajachandar, Sarbani Ashe, Neethi Chandra Thathapudi, Bismita Nayak
Reactive oxygen species (ROS) are double edged sword that possesses both beneficial and harmful effects. Although basic research on skin cancer prevention has undergone a huge transformation, cases of recurrence with higher rates of drug resistance are some of its drawbacks. Therefore, targeting mitochondria by ROS overproduction provides an alternate approach for anticancer therapy. In the present study green synthesized silver nanoparticles (AgNPs) were explored for triggering the ROS production in A431 skin carcinoma cells...
October 7, 2016: ACS Applied Materials & Interfaces
Yao-Tsung Yeh, Yen-Nien Hsu, Sheng-Yun Huang, Jian-Sheng Lin, Zi-Feng Chen, Nan-Haw Chow, Shu-Hui Su, Huey-Wen Shyu, Ching-Chiang Lin, Wu-Tein Huang, Hua Yeh, Yu-Chia Chih, Yu-Hsuan Huang, Shu-Jem Su
Benzyl isothiocyanate (BITC) is a cruciferous vegetable-derived compound with anticancer properties in human cancer cells. However, its anticancer potential and underlying mechanisms remain absent in human oral cancer cells. Results indicate that BITC inhibits growth, promotes G2/M phase arrest and triggers apoptosis of OC2 cells with a minimal toxicity to normal cells. BITC-induced cell death was completely prevented by pretreatment with thiol-containing redox compounds including N-acetyl-l-cysteine (NAC), glutathione (GSH), dithiothreitol, and 2-mercaptoethanol, but not free radical scavengers mito-TEMPO, catalase, apocynin, l-NAME and mannitol...
September 28, 2016: Food and Chemical Toxicology
Wiem Chaabane, Malin Lindqvist Appell
Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death...
September 28, 2016: Oncotarget
T A Nissinen, J Degerman, M Räsänen, A R Poikonen, S Koskinen, E Mervaala, A Pasternack, O Ritvos, R Kivelä, J J Hulmi
Doxorubicin is a widely used and effective chemotherapy drug. However, cardiac and skeletal muscle toxicity of doxorubicin limits its use. Inhibiting myostatin/activin signalling can prevent muscle atrophy, but its effects in chemotherapy-induced muscle wasting are unknown. In the present study we investigated the effects of doxorubicin administration alone or combined with activin receptor ligand pathway blockade by soluble activin receptor IIB (sACVR2B-Fc). Doxorubicin administration decreased body mass, muscle size and bone mineral density/content in mice...
September 26, 2016: Scientific Reports
Sai-Qi Wang, Cong Wang, Li-Ming Chang, Kai-Rui Zhou, Jun-Wei Wang, Yu Ke, Dong-Xiao Yang, Hong-Ge Shi, Ran Wang, Xiao-Li Shi, Li-Ying Ma, Hong-Min Liu
Paclitaxel, a taxane, is a cytotoxic chemotherapeutic agent that targets microtubules. It has become a front-line therapy for a broad range of malignancies, including lung, breast, gastric, esophageal, and bladder carcinomas. Although paclitaxel can inhibit tumor development and improve survival, poor solubility, myelotoxicity, allergic reactions, and drug resistance have restricted its clinical application. Paclitaxel is frequently combined with other chemotherapeutics to enhance the antitumor effects and reduce side effects...
September 21, 2016: Oncotarget
Caio M Massari, Adalberto A Castro, Tharine Dal-Cim, Débora Lanznaster, Carla I Tasca
Parkinson's disease (PD) involves the loss of striatal dopaminergic neurons, although other neurotransmitters and brain areas are also involved in its pathophysiology. In rodent models to PD it has been shown statins improve cognitive and motor deficits and attenuate inflammatory responses evoked by PD-related toxins. Statins are the drugs most prescribed to hypercholesterolemia, but neuroprotective effects have also been attributed to statins treatment in humans and in animal models. This study aimed to establish an in vitro model of 6-hydroxydopamine (6-OHDA)-induced toxicity, used as an initial screening test to identify effective drugs against neural degeneration related to PD...
December 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Paromita Kundu, Manasi Das, Kalpalata Tripathy, Sanjeeb K Sahoo
Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain...
October 3, 2016: ACS Chemical Neuroscience
Peng Jiang, Amrita Ray, Leonard P Rybak, Michael J Brenner
RATIONALE: Oxidative stress plays a critical role in gentamicin-induced hair cell death. Previous work has implicated the cytoplasmic transcription factor signal transducer and activator of transcription 1 (STAT1) as a potential mediator of drug-induced ototoxicity, but role in aminoglycosides is largely unknown. This study investigated aminoglycosides-induced cell death, exploring contributions of reactive oxygen species and STAT1 pathway in injury and protection. METHODS: Neonatal murine organ of Corti explants from 2 to 3 day postnatal pups (n = 96) were treated with gentamicin at (4 μM, 50 μM) for 4 to 72 hours, with/without protectants...
October 2016: Otology & Neurotology
A Reis-Mendes, A S Gomes, R A Carvalho, F Carvalho, F Remião, M Pinto, M L Bastos, E Sousa, V M Costa
Mitoxantrone (MTX) is an antineoplastic agent used to treat several types of cancers and on multiple sclerosis, which shows a high incidence of cardiotoxicity. Still, the underlying mechanisms of MTX cardiotoxicity are poorly understood and the potential toxicity of its metabolites scarcely investigated. Therefore, this work aimed to synthesize the MTX-naphthoquinoxaline metabolite (NAPHT) and to compare its cytotoxicity to the parent compound in 7-day differentiated H9c2 cells using pharmacological relevant concentrations (0...
September 14, 2016: Archives of Toxicology
Jing Yang, Yanping Wu, Yan Shen, Changren Zhou, Yi-Fang Li, Rong-Rong He, Mingxian Liu
Halloysite nanotubes (HNTs) are natural aluminosilicates with unique hollow lumen structure, also having high specific area, good biocompatibility, nontoxicity, and low price. Here, we designed a chitosan oligosaccharide-grafted HNTs (HNTs-g-COS) as a doxorubicin (DOX) carrier for treating breast cancer both in vitro and in vivo. The structure of HNTs-g-COS was first characterized by various methods. HNTs-g-COS showed positively charged surface and improved hemocompatibility. DOX-loaded HNTs-g-COS (DOX@HNTs-g-COS) released in cell lysate in a controlled manner...
October 12, 2016: ACS Applied Materials & Interfaces
Yu-Jen Chao, Jui-Fen Chan, Yuan-Hao Howard Hsu
Chemotherapy drugs have been prescribed for the systemic treatment of cancer. We selected three chemotherapy drugs, including methotrexate, mitomycine C and vincristine to inhibit the proliferation of HT1080 human fibrosarcoma cells in S, G2 and M phases of the cell cycle respectively. These chemotherapy drugs showed significant toxicity and growth inhibition to the cancer cells measured by MTT assay. After treated with a 50% inhibitory dosage for 48 hours, these cancer cells showed significant accumulation of cardiolipin (CL), which was a reverse trend of the nutritional deficiency induced arrest at G1 phase...
2016: PloS One
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