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Drug induced mitochondrial toxicity

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https://www.readbyqxmd.com/read/28792756/design-synthesis-and-biological-evaluation-of-novel-selenium-containing-isocombretastatins-and-phenstatins-as-antitumor-agents
#1
Yanqing Pang, Baijiao An, Lanlan Lou, Junsheng Zhang, Jun Yan, Ling Huang, Xingshu Li, Sheng Yin
Two series of structurally-related organoselenium compounds designed by fusing the anticancer agent methyl(phenyl)selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC50 values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4), represented the most active compound with IC50 values of 2-34 nM against twelve cancer cell lines, including two drug-resistant cell lines...
August 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28776290/synthesis-characterization-and-evaluation-of-cd-l-proline-2-a-novel-histone-deacetylase-inhibitor-that-induces-epigenetic-modification-of-histone-deacetylase-isoforms-in-a549-cells
#2
Anusha Chidambaram, Arunachalam Sekar, Kavya S H, Ramesh Kumar Chidambaram, Kalaiarasi Arunachalam, Senthilkumar G P, Ravikumar Vilwanathan
Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium-proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis...
August 3, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28762043/customised-in-vitro-model-to-detect-human-metabolism-dependent-idiosyncratic-drug-induced-liver-injury
#3
Laia Tolosa, Nuria Jiménez, Gabriela Pérez, José V Castell, M José Gómez-Lechón, M Teresa Donato
Drug-induced liver injury (DILI) has a considerable impact on human health and is a major challenge in drug safety assessments. DILI is a frequent cause of liver injury and a leading reason for post-approval drug regulatory actions. Considerable variations in the expression levels of both cytochrome P450 (CYP) and conjugating enzymes have been described in humans, which could be responsible for increased susceptibility to DILI in some individuals. We herein explored the feasibility of the combined use of HepG2 cells co-transduced with multiple adenoviruses that encode drug-metabolising enzymes, and a high-content screening assay to evaluate metabolism-dependent drug toxicity and to identify metabolic phenotypes with increased susceptibility to DILI...
July 31, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28759731/antibiotic-drug-piperacillin-induces-neuron-cell-death-through-mitochondrial-dysfunction-and-oxidative-damage
#4
Shan Jiang, Tong Li, Xiao Zhou, Wenjun Qin, Zijun Wang, Yi Liao
Although nerve damage/toxicity has been shown to be one of the side effects in patients given prolonged antibiotic treatment, the mechanisms of the action of antibiotics on neuron cells are not clear. In this work, we investigated the toxicity of piperacillin (an antibiotic that can penetrate blood-brain barrier) on neuron cells and its underlying mechanisms. We show that clinically relevant doses of piperacillin induce apoptosis in SH-SY5Y and human primary neuron cells through activating caspase 3 activity and decreasing Mcl-1 and Bcl-2 levels...
July 31, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28757873/absence-of-relationship-between-mitochondrial-dna-haplogroups-and-cisplatin-induced-hearing-loss
#5
D Graterol, C Mir, C Garcia-Vaquero, I Braña, A N Pardo, M I Rochera-Villach, A Lyakhovich, M E LLeonart, J Lorente
BACKGROUND: Many drugs used for cancer chemotherapy produce reactive oxygen species, thus leading to various complications including nephrotoxicity, cardiotoxicity, and ototoxicity. OBJECTIVE: We have provided a haplogroup analysis of a cohort of cancer patients treated with chemotherapy and compared factors associated with associated hearing loss. STUDY DESIGN AND METHODS: This observational cohort study includes a pure-tone audiometry of the patients who underwent chemotherapeutic treatment...
2017: International Journal of Otolaryngology
https://www.readbyqxmd.com/read/28754872/tunicamycin-induced-endoplasmic-reticulum-stress-promotes-apoptosis-of-prostate-cancer-cells-by-activating-mtorc1
#6
Prasun Guha, Engin Kaptan, Padmaja Gade, Dhananjaya V Kalvakolanu, Hafiz Ahmed
Studies suggest that tunicamycin may work as a therapeutic drug to cancer cells by inducing stress in the endoplasmic reticulum (ER) through unfolded protein response (UPR) and thereby promoting apoptosis. However, mechanisms of the prolonged activation of the UPR under sustained ER stress in the regulation of cell apoptosis are largely unknown. To delineate the role of candidate genes in the apoptotic process under ER stress and to search for new therapeutic strategies to treat metastatic castration resistant prostate cancer, we performed whole genome expression microarray analysis in tunicamycin treated metastatic androgen-insensitive prostate cancer cells, PC-3...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28748471/evaluation-of-mitochondrial-respiration-in-cultured-rat-hepatocytes
#7
Jean-Pierre Marchandeau, Gilles Labbe
Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects, such as lactic acidosis and rhabdomyolysis, in some patients. Several in vitro and in vivo investigations can be performed in order to determine if drugs can disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition pore (MPT). Among these investigations, mitochondrial respiration is a relatively easy test to measure the potential toxicity of a drug...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28748373/novel-combination-of-salinomycin-and-resveratrol-synergistically-enhances-the-anti-proliferative-and-pro-apoptotic-effects-on-human-breast-cancer-cells
#8
Jayant Dewangan, Divya Tandon, Sonal Srivastava, Ajeet Kumar Verma, Ashok Yapuri, Srikanta Kumar Rath
Resveratrol (RES) is a natural polyphenol having anti-proliferative activity against breast cancer cells. RES in combination with other chemo modulatory agents, minimizes toxicity and increases efficacy of the treatment. Salinomycin (SAL), a monocarboxylic polyether ionophore is known for selectively targeting breast cancer stem cells. Purpose of the present study was to investigate whether RES in combination with SAL exerts synergistic anti-proliferative activity on breast cancer cells. We further evaluated the molecular mechanism behind SAL and RES mediated cell death...
July 26, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28733192/pharmacological-evaluation-of-phytochemicals-from-south-indian-black-turmeric-curcuma-caesia-roxb-to-target-cancer-apoptosis
#9
K S Mukunthan, R S Satyan, T N Patel
Curcuma caesia Roxb. (Black turmeric), a perennial herb of the family Zingiberaceae is indigenous to India. C. caesia is used as a spice, food preservative and coloring agent commonly in the Indian subcontinent. Functional parametric pharmacological evaluations like drug ability and toxicity profile of this endangered species is poorly documented. In our present study, among all the extracts of dried C. caesia rhizome viz- hexane, ethyl acetate, methanol and water tested for free radical scavenging capacity by total antioxidant activity (TAO) method, Hexane Rhizome Extract (HRE) was found to possess remarkable activity (1200mg ascorbic acid equivalent/100g)...
July 19, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28726777/humanin-g-hng-protects-age-related-macular-degeneration-amd-transmitochondrial-arpe-19-cybrids-from-mitochondrial-and-cellular-damage
#10
Sonali Nashine, Pinchas Cohen, Marilyn Chwa, Stephanie Lu, Anthony B Nesburn, Baruch D Kuppermann, M Cristina Kenney
Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated...
July 20, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28722244/risk-of-liver-decompensation-with-cumulative-use-of-mitochondrial-toxic-nucleoside-analogues-in-hiv-hepatitis-c-virus-coinfection
#11
Vincent Lo Re Rd, Bret Zeldow, Michael J Kallan, Janet P Tate, Dena M Carbonari, Sean Hennessy, Jay R Kostman, Joseph K Lim, Matthew Bidwell Goetz, Robert Gross, Amy C Justice, Jason A Roy
PURPOSE: Among patients dually infected with human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV), use of antiretroviral therapy (ART) containing mitochondrial toxic nucleoside reverse transcriptase inhibitors (mtNRTIs) might induce chronic hepatic injury, which could accelerate HCV-associated liver fibrosis and increase the risk of hepatic decompensation and death. METHODS: We conducted a cohort study among 1747 HIV/HCV patients initiating NRTI-containing ART within the Veterans Aging Cohort Study (2002-2009) to determine if cumulative mtNRTI use increased the risk of hepatic decompensation and death among HIV-/HCV-coinfected patients...
July 19, 2017: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/28705594/induction-of-abcg2-bcrp-restricts-the-distribution-of-zidovudine-to-the-fetal-brain-in-rats
#12
María Fernanda Filia, Timoteo Marchini, Juan Mauricio Minoia, Martín Ignacio Roma, Fernanda Teresa De Fino, Modesto Carlos Rubio, Guillermo J Copello, Pablo A Evelson, Roxana Noemí Peroni
Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28690189/efavirenz-what-is-known-about-the-cellular-mechanisms-responsible-for-its-adverse-effects
#13
REVIEW
Nadezda Apostolova, Ana Blas-Garcia, Maria J Galindo, Juan V Esplugues
The HIV infection remains an important health problem worldwide. However, due to the efficacy of combined antiretroviral therapy (cART), it has ceased to be a mortal condition, becoming a chronic disease instead. Efavirenz, the most prescribed non-nucleoside analogue reverse transcriptase inhibitor (NNRTI), has been a key component of cART since its commercialization in 1998. Though still a drug of choice in many countries, its primacy has been challenged by the arrival of newer antiretroviral agents with better toxicity profiles and treatment adherence...
July 6, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28689965/ph-and-nir-light-responsive-magnetic-iron-oxide-nanoparticles-for-mitochondria-mediated-apoptotic-cell-death-induced-by-chemo-photothermal-therapy
#14
Yunok Oh, Jae-Young Je, Madhappan Santha Moorthy, Hansoo Seo, Won Ho Cho
Recently, various therapeutic strategies in anticancer drug development are focused to reduce adverse side effects and to enhance the therapeutic efficacy. Mostly, the iron oxide (Fe3O4) nanoparticles have widely been utilized as an efficient drug delivery system towing to their unique properties such as excellent magnetic behavior, considerably low toxicity, easy surface modification and high drug-loading efficacy. In the present study, we synthesized a multifunctional, DMSA coated, water soluble Fe3O4 nanoparticles (Fe3O4@DMSA/DOX) for an effective pH and NIR-light triggered delivery of anticancer drug (DOX) in cancer therapy...
July 6, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28689063/proanthocyanidins-from-uncaria-rhynchophylla-induced-apoptosis-in-mda-mb-231-breast-cancer-cells-while-enhancing-cytotoxic-effects-of-5-fluorouracil
#15
Xiao-Xin Chen, George Pak-Heng Leung, Zhang-Jin Zhang, Jian-Bo Xiao, Li-Xing Lao, Feng Feng, Judith Choi-Wo Mak, Ying Wang, Stephen Cho-Wing Sze, Kalin Yan-Bo Zhang
Breast cancer is the most frequently diagnosed cancer and cause of cancer death in women worldwide. Current treatments often result in systematic toxicity and drug resistance. Combinational use of non-toxic phytochemicals with chemotherapeutic agents to enhance the efficacy and reduce toxicity would be one promising approach. In this study, bioactive proanthocyanidins from Uncaria rhynchophylla (UPAs) were isolated and their anti-breast cancer effects alone and in combination with 5- fluorouracil (5-FU) were investigated in MDA-MB-231 breast cancer cells...
September 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28685843/oxidative-stress-management-in-the-hair-follicle-could-targeting-nrf2-counter-age-related-hair-disorders-and-beyond
#16
REVIEW
Laura Jadkauskaite, Pierre A Coulombe, Matthias Schäfer, Albena T Dinkova-Kostova, Ralf Paus, Iain S Haslam
Widespread expression of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2), which maintains redox homeostasis, has recently been identified in the hair follicle (HF). Small molecule activators of NRF2 may therefore be useful in the management of HF pathologies associated with redox imbalance, ranging from HF greying and HF ageing via androgenetic alopecia and alopecia areata to chemotherapy-induced hair loss. Indeed, NRF2 activation has been shown to prevent peroxide-induced hair growth inhibition...
August 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28684237/monoaminergic-toxicity-induced-by-cathinone-phthalimide-an-in-vitro-study
#17
Susan M Lantz, Hector Rosas-Hernandez, Elvis Cuevas, Bonnie Robinson, Kenner C Rice, William E Fantegrossi, Syed Z Imam, Merle G Paule, Syed F Ali
Bath salts, or synthetic cathinones, have cocaine-like or amphetamine-like properties and induce psychoactive effects via their capacity to modulate serotonin (5-HT) and dopamine (DA). Structurally distinct synthetic cathinones are continuously being generated to skirt existing drug laws. One example of these modified compounds is cathinone phthalimide (CP), which has already appeared on the global market. The lack of toxicological studies on the effects of CP on monoaminergic systems led to the development of the present study in order to generate an acute toxicity profile for CP, and to clarify whether it primarily affects both dopamine and serotonin, like the synthetic cathinones mephedrone and methylone, or primarily affects dopamine, like 3, 4-methylenedioxypyrovalerone (MDPV)...
August 10, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28680449/protective-effects-of-wogonin-against-alzheimer-s-disease-by-inhibition-of-amyloidogenic-pathway
#18
Ding-Siang Huang, Yu-Chen Yu, Chung-Hsin Wu, Jung-Yaw Lin
One of the pathogenic systems of Alzheimer's disease (AD) is the formation of β-amyloid plaques in the brains of patients, and amyloidogenic activity becomes one of the therapeutic targets. Here, we report wogonin, one of the major active constituting components in Scutellaria baicalensis, which has the neuroprotective effects on amyloid-β peptides- (Aβ-) induced toxicity. Oral wogonin treatment improved the performance of triple transgenic AD mice (h-APPswe, h-Tau P301L, and h-PS1 M146V) on the Morris water maze, Y-maze, and novel object recognition...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28664269/pro-apoptotic-cationic-host-defense-peptides-rich-in-lysine-or-arginine-to-reverse-drug-resistance-by-disrupting-tumor-cell-membrane
#19
Yuxuan Dai, Xingguang Cai, Wei Shi, Xinzhou Bi, Xin Su, Miaobo Pan, Huilan Li, Haiyan Lin, Wenlong Huang, Hai Qian
Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1...
June 29, 2017: Amino Acids
https://www.readbyqxmd.com/read/28662902/the-use-of-electronic-neutral-penetrating-peptides-cyclosporin-a-to-deliver-pro-apoptotic-peptide-a-possibly-better-choice-than-positively-charged-tat
#20
Wei Gao, Xiucong Yang, Zhiqiang Lin, Bing He, Dong Mei, Dan Wang, Haoran Zhang, Hua Zhang, Wenbing Dai, Xueqing Wang, Qiang Zhang
Cell-penetrating peptides (CPPs) are increasingly important in transporting macromolecules across cell membranes, but their use remains confined to narrow clinical applications due to the systemic toxicity induced by their positive charges. Several newly discovered electronic neutral penetrating peptides are not attracting much attention because their penetrating capacity is normally far less powerful than cationic or amphiphilic CPPs. In this study, we found the electronic neutral cyclic peptide cyclosporin A (CsA) exhibited 5...
September 10, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
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