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Drug induced mitochondrial toxicity

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https://www.readbyqxmd.com/read/28627468/a-novel-chalcone-derivative-lqfm064-induces-breast-cancer-cells-death-via-p53-p21-kit-and-pdgfra
#1
Bruna Lannuce Silva Cabral, Artur Christian Garcia da Silva, Renato Ivan de Ávila, Alane Pereira Cortez, Rangel Magalhães Luzin, Luciano Morais Lião, Eric de Souza Gil, Gérman Sanz, Boniek G Vaz, José R Sabino, Ricardo Menegatti, Marize Campos Valadares
This study shows the design, synthesis and antitumoral potential evaluation of a novel chalcone-like compound, (E)-3- (3, 5-di-ter-butyl-4-hydroxyphenyl)-1- (4-hydroxy-3-methoxyphenyl) prop-2-en-1-one [LQFM064) (4)], against human breast adenocarcinoma MCF7 cells. Some toxicological parameters were also investigated. LQFM064) (4) exhibited cytotoxic activity against MCF7 cells (IC50=21μM), in a concentration dependent-manner, and triggered significant changes in cell morphology and biochemical/molecular parameters, which are suggestive of an apoptosis inductor...
June 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28615926/mechanistic-modelling-of-drug-induced-liver-injury-investigating-the-role-of-innate-immune-responses
#2
Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration...
2017: Gene Regulation and Systems Biology
https://www.readbyqxmd.com/read/28611662/an-antifungal-mechanism-of-protolichesterinic-acid-from-the-lichen-usnea-albopunctata-lies-in-the-accumulation-of-intracellular-ros-and-mitochondria-mediated-cell-death-due-to-apoptosis-in-candida-tropicalis
#3
S N Kumar, C Mohandas
Candida species causes superficial and life-threatening systemic infections and are difficult to treat due to the resistance of these organism to various clinically used drugs. Protolichesterinic acid is a well-known lichen compound. Although the antibacterial activity of protolichesterinic acid has been reported earlier, the antifungal property and its mechanism of action are still largely unidentified. The goal of the present investigation is to explore the anticandidal activity and mechanism of action of protolichesterinic acid, especially against Candida tropicalis...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28611451/beta-sitosterol-and-daucosterol-phytosterols-identified-in-grewia-tiliaefolia-perturbs-cell-cycle-and-induces-apoptotic-cell-death-in-a549-cells
#4
Tamilselvam Rajavel, Ramar Mohankumar, Govindaraju Archunan, Kandasamy Ruckmani, Kasi Pandima Devi
Lung cancer is the leading cause of cancer related deaths both in developed and developing countries. Since majority of the existing therapeutic methods harms both normal and malignant cells, a viable alternative is to switch into safe and beneficial traditional medicinal plants. Hence the present study was framed to identify selective anti-lung cancer agents from the medicinal plant Grewia tiliaefolia (GT). Cell viability experiments showed that benzene extract of GT (BGT) leaf effectively inhibited the growth of A549 cells, while being non-toxic to normal human lung L132 and PBMC cells...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28604124/test-systems-in-drug-discovery-for-hazard-identification-and-risk-assessment-of-human-drug-induced-liver-injury
#5
Richard J Weaver, Catherine Betts, Eric A G Blomme, Helga H J Gerets, Klaus Gjervig Jensen, Philip G Hewitt, Satu Juhila, Gilles Labbe, Michael J Liguori, Natalie Mesens, Monday O Ogese, Mikael Persson, Jan Snoeys, James L Stevens, Tracy Walker, B Kevin Park
Introduction The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities...
June 12, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28577870/mitochondria-as-the-target-for-the-modulatory-effect-of-curcumin-in-oxaliplatin-induced-toxicity-in-isolated-rat-liver-mitochondria
#6
Mohammad Waseem, Suhel Parvez, Heena Tabassum
BACKGROUND AND AIMS: To explore hepatoprotective action of curcumin (CMN, a bioflavonoid) on oxaliplatin (Oxa)-triggered mitochondrial oxidative stress and respiratory chain complexes in liver of rats. Oxa is a ubiquitously utilized platinum-based chemotherapeutic agent commonly used for the treatment of colorectal cancer. Mitochondria have recently emerged as targets for anticancer drugs in several kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. There is a dearth of evidence involving the role of mitochondria in mediating Oxa-evoked hepatotoxicity and its underlying mechanism is still debatable...
January 2017: Archives of Medical Research
https://www.readbyqxmd.com/read/28557718/combination-clearance-therapy-and-barbiturate-coma-for-severe-carbamazepine-overdose
#7
Asya Agulnik, Daniel P Kelly, Rebecca Bruccoleri, Christopher Yuskaitis, Darius Ebrahimi-Fakhari, Mustafa Sahin, Michele M Burns, Daniel S Kohane
A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ∼280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.74 µmol/L). The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination...
May 2017: Pediatrics
https://www.readbyqxmd.com/read/28537927/wx-132-18b-a-novel-microtubule-inhibitor-exhibits-promising-anti-tumor-effects
#8
Fang Guan, Rui Ding, Qi Zhang, Wei Chen, Feifei Li, Long Long, Wei Li, Linna Li, Dexuan Yang, Lan Xie, Shoujun Yuan, Lili Wang
Cancer drug researchers have been seeking microtubule-inhibiting agents (MIAs) with higher bioactivity and lower toxicity than currently marketed drugs. WX-132-18B, a novel structural compound synthesized at our institute, specifically bound to the colchicine-binding site on tubulin rather than the vinblastine site, and concentration-dependently reduced microtubule content via depolymerization. It exhibited the same cellular phenotypic profiles as the classic MIAs (colchicine, vincristine, and taxol), including inducing cell cycle arrest at the G2/M phase, triggering tumor cell apoptosis, promoting nuclear membrane permeability, reducing mitochondrial membrane potential, and disrupting the redox system balance...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28536862/mechanisms-of-hepatotoxicity-associated-with-the-monocyclic-%C3%AE-lactam-antibiotic-bal30072
#9
Franziska Paech, Simon Messner, Jochen Spickermann, Mathias Wind, Anne-Hortense Schmitt-Hoffmann, Anne Therese Witschi, Brett A Howell, Rachel J Church, Jeff Woodhead, Marc Engelhardt, Stephan Krähenbühl, Martina Maurer
BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations...
May 23, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28511367/neurobehavioural-changes-in-a-hemiparkinsonian-rat-model-induced-by-rotenone
#10
REVIEW
Sukala Puthuparambil Maniyath, Narayanan Solaiappan, Muthusamy Rathinasamy
INTRODUCTION: Rotenone, a mitochondrial complex I inhibitor is used as a neurotoxin agent to reproduce the neuropathological, and behavioural feature of Parkinson's Disease (PD) in rat. Due to acute and chronic exposure of rotenone with various doses through different routes of administration, mortality is being reported. Low dose takes a longer duration to produce PD symptoms in animals. This present study was designed to create hemiparkinsonian 'partial' lesion model by rotenone at a single moderate dose in two sites of striatum in albino rats and also to assess its toxicity by behavioural parameters and by microscopic study...
March 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28507435/mesoporous-silica-nanoparticles-trigger-mitophagy-in-endothelial-cells-and-perturb-neuronal-network-activity-in-a-size-and-time-dependent-manner
#11
Antonina Orlando, Emanuela Cazzaniga, Maria Tringali, Francesca Gullo, Andrea Becchetti, Stefania Minniti, Francesca Taraballi, Ennio Tasciotti, Francesca Re
PURPOSE: Mesoporous silica nanoparticles (MSNPs) are excellent candidates for biomedical applications and drug delivery to different human body areas, the brain included. Although toxicity at cellular level has been investigated, we are still far from using MSNPs in the clinic, because the mechanisms involved in the cellular responses activated by MSNPs have not yet been elucidated. MATERIALS AND METHODS: This study used an in vitro multiparametric approach to clarify relationships among size, dose, and time of exposure of MSNPs (0...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28496041/a-rapid-mitochondrial-toxicity-assay-utilizing-rapidly-changing-cell-energy-metabolism
#12
Yosuke Sanuki, Tetsuro Araki, Osamu Nakazono, Kazuyuki Tsurui
Drug-induced liver injury is a major cause of safety-related drug-marketing withdrawals. Several drugs have been reported to disrupt mitochondrial function, resulting in hepatotoxicity. The development of a simple and effective in vitro assay to identify the potential for mitochondrial toxicity is thus desired to minimize the risk of causing hepatotoxicity and subsequent drug withdrawal. An in vitro test method called the "glucose-galactose" assay is often used in drug development but requires prior-culture of cells over several passages for mitochondrial adaptation, thereby restricting use of the assay...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28486401/drug-induced-liver-injury-cascade-of-events-leading-to-cell-death-apoptosis-or-necrosis
#13
REVIEW
Andrea Iorga, Lily Dara, Neil Kaplowitz
Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR)...
May 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28466458/rip1-dependent-reactive-oxygen-species-production-executes-artesunate-induced-cell-death-in-renal-carcinoma-caki-cells
#14
Anil Kumar Chauhan, Kyoung-Jin Min, Taeg Kyu Kwon
Artesunate is a well-known anti-malarial drug originated from artemisinin as a Chinese herb and has been reported to have anti-cancer potential in many cancer cells. In the present study, we examined the efficacy of artesunate against the renal carcinoma Caki cells and explored its mechanism of cytotoxicity. A steep decline in cell viability within 18 h was recorded upon artesunate exposure, but pretreatment of z-VAD-FMK had no effect on the loss of the cell viability by artesunate. On the other hand, necrostatin-1 pretreatment and knockdown of RIP-1 significantly reduced the cytotoxicity of artesunate against Caki cell...
May 2, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28463418/use-of-primary-rat-hepatocytes-for-prediction-of-drug-induced-mitochondrial-dysfunction
#15
Cong Liu, Shuichi Sekine, Binbin Song, Kousei Ito
Mitochondrial dysfunction plays a central role in drug-induced liver injury. To evaluate drug-induced mitochondrial impairment, several isolated mitochondria- or cell line-based assays have been reported. Among them, culturing HepG2 cells in galactose provides a remarkable method to assess mitochondrial toxicity by activating mitochondrial aerobic respiration. We applied this assay to primary rat hepatocytes by culturing cells in galactose and hyperoxia to enhance the evaluation of metabolism-related drug-induced mitochondrial toxicity...
May 2, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28458133/scutellarin-derivatives-as-apoptosis-inducers-design-synthesis-and-biological-evaluation
#16
Tong Han, Jia Li, Jingjing Xue, He Li, Fanxing Xu, Keguang Cheng, Dahong Li, Zhanlin Li, Ming Gao, Huiming Hua
To explore novel antitumor agents with high efficiency and low toxicity, a series of NO-donating scutellarin derivatives (14-17) were synthesized and the antiproliferative activities against MCF-7, HCT-116, PC-3 and HepG2 cancer cell lines were assessed. Among them, compound 14b was the strongest with IC50 values of 2.96 μM, 7.25 μM, 0.09 μM and 0.50 μM, respectively, and displayed low toxicity against normal human liver L-O2 cells with an IC50 of 47.96 μM, showing good selectivity between normal and malignant liver cells...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28456571/erythropoietin-activates-sirt1-to-protect-human-cardiomyocytes-against-doxorubicin-induced-mitochondrial-dysfunction-and-toxicity
#17
Lan Cui, Jiabin Guo, Qiang Zhang, Jian Yin, Jin Li, Wei Zhou, Tingfen Zhang, Haitao Yuan, Jun Zhao, Li Zhang, Paul L Carmichael, Shuangqing Peng
The hormone erythropoietin (EPO) has been demonstrated to protect against chemotherapy drug doxorubicin (DOX)-induced cardiotoxicity, but the underlying mechanism remains obscure. We hypothesized that silent mating type information regulation 2 homolog 1 (SIRT1), an NAD(+)-dependent protein deacetylase that activates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), plays a crucial role in regulating mitochondrial function and mediating the beneficial effect of EPO. Our study in human cardiomyocyte AC16 cells showed that DOX-induced cytotoxicity and mitochondrial dysfunction, as manifested by decreased mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential, and increased mitochondrial superoxide accumulation, can be mitigated by EPO pretreatment...
April 27, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28456516/identification-of-novel-1-indolyl-acetate-5-nitroimidazole-derivatives-of-combretastatin-a-4-as-potential-tubulin-polymerization-inhibitors
#18
Yong-Fang Yao, Zhong-Chang Wang, Song-Yu Wu, Qing-Fang Li, Chen Yu, Xin-Yi Liang, Peng-Cheng Lv, Yong-Tao Duan, Hai-Liang Zhu
Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC50 values ranging from 15 to 40nM), especially HeLa cells (with IC50 values of 15nM), based on the cellular cytotoxicity assay results...
August 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28455219/ph-sensitive-polymeric-nanoparticles-for-co-delivery-of-doxorubicin-and-curcumin-to-treat-cancer-via-enhanced-pro-apoptotic-and-anti-angiogenic-activities
#19
Jinming Zhang, Jingjing Li, Zhi Shi, Yang Yang, Xi Xie, Simon MingYuen Lee, Yitao Wang, Kam W Leong, Meiwan Chen
Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancer. The combination of drugs with pro-apoptotic and anti-angiogenic activities is potentially effective in treating human hepatocellular carcinoma (HCC). Herein, we developed a co-delivery system for doxorubicin (Dox), a pro-apoptotic drug, and curcumin (Cur), a potent drug for antiangiogenesis, in pH-sensitive nanoparticles (NPs) constituted with amphiphilic poly(β-amino ester) copolymer...
April 25, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28454919/new-amino-acid-schiff-base-derived-from-s-allyl-cysteine-and-methionine-alleviates-carbon-tetrachloride-induced-liver-dysfunction
#20
Periyasamy Ratha, Loganathan Chitra, Ancy Iruthayaraj, Poomani Kumaradhas, Thayumanavan Palvannan
In spite of the tremendous stride in modern medicine, conventional drugs used in the hepatotoxic management are mostly inadequate. The present study aims in the synthesis of novel Schiff base compound derived using s-ally cystiene and methionine. The newly synthesized compound, 2-((2-((2-(allylthio)-1-carboxyethyl)imino)ethylidene)amino)-4-(methylthio)butanoic acid (ACEMB) was characterized using UV-visible spectrophotometer, FTIR, (1)HNMR, and GC-MS. ACEMB showed potent in vitro antioxidant property. Chronic administration of ACEMB prior to CCl4 intoxication: i) attenuated the leakage of liver injury markers, such as, enzymes (AST, ALT, GGT, ALP and LDH) and biomolecules (bilirubin) into the blood circulation; ii) normalized the concentration of total proteins, albumin and globulin to control level; and iii) protected the liver against dyslipidemia...
April 25, 2017: Biochimie
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