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Drug induced mitochondrial toxicity

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https://www.readbyqxmd.com/read/29348560/discovery-of-a-small-molecule-protein-kinase-c%C3%AE-selective-activator-with-promising-application-in-colon-cancer-therapy
#1
Cláudia Bessa, Joana Soares, Liliana Raimundo, Joana B Loureiro, Célia Gomes, Flávio Reis, Miguel L Soares, Daniel Santos, Chetna Dureja, Saumya R Chaudhuri, Cynthia Lopez-Haber, Marcelo G Kazanietz, Jorge Gonçalves, Maria F Simões, Patrícia Rijo, Lucília Saraiva
Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective activator, the 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCδ-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCδ-dependent mitochondrial apoptotic pathway involving caspase-3 activation...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29331652/salinomycin-induces-primary-chicken-cardiomyocytes-death-via-mitochondria-mediated-apoptosis
#2
Xiuge Gao, Yani Zheng, Xiangchun Ruan, Hui Ji, Lin Peng, Dawei Guo, Shanxiang Jiang
Salinomycin, as a polyether ionophore antibiotic, is extensively used as a feed additive against coccidiosis in poultry and as a growth promoter of ruminants worldwide. Owing to its narrow therapeutic index, numerous intoxication have been reported in target/non-target animals by overdosage, misuse or drug interactions as well as human who consumed salinomycin accidently. Salinomycin-induced cardiotoxicity in chicken and non-target animals is considered as a major contributor to animal death. In the current study, we aim to elucidate the underlying mechanism of its myocardial toxicity using primary chicken myocardial cell as an in vitro model...
January 10, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29313218/thallium-induced-toxicity-in-rat-brain-crude-synaptosomal-mitochondrial-fractions-is-sensitive-to-anti-excitatory-and-antioxidant-agents
#3
Marisol Maya-López, María Verónica Mireles-García, Monserrat Ramírez-Toledo, Ana Laura Colín-González, Sonia Galván-Arzate, Isaac Túnez, Abel Santamaría
The mechanisms by which the heavy metal thallium (Tl+) produces toxicity in the brain remain unclear. Herein, isolated synaptosomal/mitochondrial P2 crude fractions from adult rat brains were exposed to Tl+ (5-250 μM) for 30 min. Three toxic endpoints were evaluated: mitochondrial dysfunction, lipid peroxidation, and Na+/K+-ATPase activity inhibition. Concentration-response curves for two of these endpoints revealed the optimum concentration of Tl+ to induce damage in this preparation, 5 μM. Toxic markers were also estimated in preconditioned synaptosomes incubated in the presence of the N-methyl-D-aspartate receptor antagonist kynurenic acid (KYNA, 50 μM), the cannabinoid receptor agonist WIN 55,212-2 (1 μM), or the antioxidant S-allyl-L-cysteine (SAC, 100 μM)...
January 8, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29312593/shikonin-induces-ros-based-mitochondria-mediated-apoptosis-in-colon-cancer
#4
Wenquan Liang, Jianxin Cui, Kecheng Zhang, Hongqing Xi, Aizhen Cai, Jiyang Li, Yunhe Gao, Chong Hu, Yi Liu, Yixun Lu, Ning Wang, Xiaosong Wu, Bo Wei, Lin Chen
Colon cancer is the third most common malignancy worldwide, and chemotherapy is a widely used strategy in clinical therapy. Chemotherapy-resistant of colon cancer is the main cause of recurrence and progression. Novel drugs with efficacy and safety in treating colon cancer are urgently needed. Shikonin, a naphthoquinone derived from the roots of the herbal plant Lithospermum erythrorhizon, has been determined to be a potent anti-tumor agent. The aim of the present study was to detect the underlying anti-tumor mechanism of shikonin in colon cancer...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29305141/dequalinium-based-functional-nanosomes-show-increased-mitochondria-targeting-and-anticancer-effect
#5
Yoonhee Bae, Min Kyo Jung, Seulgi Lee, Su Jeong Song, Ji Young Mun, Eric S Green, Jin Han, Kyung Soo Ko, Joon Sig Choi
Mitochondria are targets with great potential for therapeutics for many human disorders. However, drug delivery systems for such therapeutics remain in need of more efficient mitochondrial-targeting carriers. In this study, we report that nanosomes composed of Dequalinium/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)/DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), called DQA80s, can act in the dual role of mitochondrial-targeting carrier and anticancer agent for therapeutic interventions against mitochondrial diseases...
January 2, 2018: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29298656/pre-clinical-validation-of-mito-targeted-nano-engineered-flavonoids-isolated-from-selaginella-bryopteris-sanjeevani-as-a-novel-cancer-prevention-strategy
#6
Arpit Bhargava, Neelam Pathak, Sriram Seshadri, Neha Bunkar, Subodh Kumar Jain, Dinesh Mishra Kumar, Nirmal Kumar Lohiya, Pradyumna Kumar Mishra
BACKGROUND: Novel bioactive plant secondary metabolites, including flavonoids, offer a spectrum of chemo-protective responses against a range of human tumor models. However, the clinical translation of these promising anti-cancer agents has been hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. OBJECTIVE: To circumvent the challenges associated with herbal drug development and for effective integration into clinical setting, nano-engineering is one of the emerging pragmatic strategy which has promise to deliver therapeutic concentrations of bio-actives upon oral administration...
December 29, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29297235/l-ascorbic-acid-and-%C3%AE-tocopherol-attenuate-arsenic-trioxide-induced-toxicity-in-h9c2-cardiomyocytes-by-the-activation-of-nrf2-and-bcl2-transcription-factors
#7
Radhakrishnan Chandraprabha Vineetha, Prakash Binu, Pettamanna Arathi, Raveendran Harikumaran Nair
Arsenic trioxide (As2O3) is a potent drug for the treatment of acute promyelocytic leukemia (APL) and has achieved remarkable remissions in patients. Unfortunately, clinical reports have shown that the treatment is associated with cardiotoxicity. Many efforts have been made to mitigate drug-mediated cardiac damage using naturally occurring antioxidant compounds possessing free radical scavenging activity. The present investigation aims to explore protective role of L-ascorbic acid (L-AA) and α-tocopherol (α-TOC) from As2O3-induced oxidative stress in H9c2 cardiomyocytes through the evaluation of Nrf2 (nuclear factor erythroid 2-related factor 2) and Bcl-2 (B-cell lymphoma 2) transcription factors...
January 18, 2018: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/29296199/costunolide-enhances-doxorubicin-induced-apoptosis-in-prostate-cancer-cells-via-activated-mitogen-activated-protein-kinases-and-generation-of-reactive-oxygen-species
#8
Jiasheng Chen, Binshen Chen, Zhihui Zou, Wei Li, Yiming Zhang, Jinlin Xie, Chunxiao Liu
The management of castration-resistant prostate cancer (CRPC) is challenging, attributable to a lack of efficacious therapies. Chemotherapy is one of the most important treatments for CRPC. Doxorubicin has been extensively used in many different tumors and is often combined with other drugs to enhance effects and reduce toxicity. Costunolide is a natural sesquiterpene lactone with anti-cancer properties. In this study, we first demonstrated that the combination of costunolide and doxorubicin induced apoptosis significantly more than either drug alone in prostate cancer cell lines...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29275301/cycloartobiloxanthone-induces-human-lung-cancer-cell-apoptosis-via-mitochondria-dependent-apoptotic-pathway
#9
Nattanan Losuwannarak, Boonchoo Sritularak, Pithi Chanvorachote
BACKGROUND: Lung cancer is one of most malignant types of cancer and new anticancer agents are still required. Cycloartobiloxanthone, a flavonoid isolated from stem bark of Artocarpus gomezianus, has potential for being developed for anticancer therapy. MATERIALS AND METHODS: Cytotoxicity of cycloartobiloxanthone was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay against four human lung cancer cell lines (H23, H460, H292 and A549) and their half-maximal inhibitory concentrations (IC50) were assessed...
January 2018: In Vivo
https://www.readbyqxmd.com/read/29233065/understanding-the-role-of-glycogen-synthase-kinase-3-in-l-dopa-induced-dyskinesia-in-parkinson-s-disease
#10
Hojin Choi, Seong-Ho Koh
Levodopa (L-DOPA) is the most commonly used drug for Parkinson's disease (PD), but its long-term use is associated with various complications, including L-DOPA-induced dyskinesia (LID). Many studies have suggested that L-DOPA neurotoxicity and LID are associated with glycogen synthase kinase-3 (GSK-3) activation. Areas covered: LID is caused by striatal dopamine (DA) denervation in PD and pulsatile L-DOPA treatment. These factors lead to dysregulated DA transmission, abnormal intracellular signaling and transcription factors in striatal neurons, and altered gene expression and plasticity at corticostriatal synapses...
December 15, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29233008/non-polar-compounds-of-persian-gulf-sea-cucumber-holothuria-parva-selectively-induce-toxicity-on-skin-mitochondria-isolated-from-animal-model-of-melanoma
#11
Yalda Arast, Nina Seyed Razi, Melika Nazemi, Enayatollah Seydi, Jalal Pourahmad
PURPOSE: Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melonama. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling. MATERIALS AND METHODS: In the present study, selective toxicity and apoptotic effect of three extracts of Holothuria parva (H...
December 12, 2017: Cutaneous and Ocular Toxicology
https://www.readbyqxmd.com/read/29221182/differential-modulation-of-bax-bcl-2-ratio-and-onset-of-caspase-3-7-activation-induced-by-derivatives-of-justicidin-b-in-human-melanoma-cells-a375
#12
Aljawharah Al-Qathama, Simon Gibbons, Jose M Prieto
Diphyllin and its derivatives are well known cytotoxic natural products structurally related to the anti-cancer drug podophyllotoxin. We here study their structure-activity relationship upon human melanoma cells for first time. To this end, human melanoma A375 cells were incubated with Justicidin B and its 4-methoxylated or 4-glycosylated derivatives to evaluate their selective cytotoxicity and study their effects on cell cycle distribution, caspase activation, apoptosis induction using Annexin V-FITC/PI staining, cell morphology and western blot analysis...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29214897/ss-31-peptide-enables-mitochondrial-targeting-drug-delivery-a-promising-therapeutic-alteration-to-prevent-hair-cell-damage-from-aminoglycosides
#13
Xiao Kuang, Shuang Zhou, Weiling Guo, Zhenjie Wang, Yanhui Sun, Hongzhuo Liu
Aminoglycoside-induced hearing loss stems from damage or loss of mechanosensory hair cells in the inner ear. Intrinsic mitochondrial cell death pathway plays a key role in that cellular dysfunction for which no proven effective therapies against oto-toxicities exist. Therefore, the aim of the present study was to develop a new mitochondrial targeting drug delivery system (DDS) that provided improved protection from gentamicin. Particularly, SS-31 peptide-conjugated geranylgeranylacetone (GGA) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were constructed successfully via emulsion-solvent evaporation method...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/29214156/off-target-effects-of-drugs-that-disrupt-human-mitochondrial-dna-maintenance
#14
REVIEW
Matthew J Young
Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs used to treat human immunodeficiency virus (HIV) the cause of acquired immunodeficiency syndrome. Development of severe mitochondrial toxicity has been well documented in patients infected with HIV and administered NRTIs. In vitro biochemical experiments have demonstrated that the replicative mitochondrial DNA (mtDNA) polymerase gamma, Polg, is a sensitive target for inhibition by metabolically active forms of NRTIs, nucleotide reverse transcriptase inhibitors (NtRTIs)...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29207128/nr4a1-induced-increase-in-the-sensitivity-of-a-human-gastric-cancer-line-to-tnf%C3%AE-mediated-apoptosis-is-associated-with-the-inhibition-of-jnk-parkin-dependent-mitophagy
#15
Hongzhu Yan, Feng Xiao, Jue Zou, Chengmin Qiu, Weiwei Sun, Minmin Gu, Li Zhang
Tumor necrosis factor α (TNFα)-based immunotherapy is the vital host defense system against the progression of gastric cancer (GC) as a pro-inflammatory and pro-apoptotic cytokine. However, resistance limits its therapeutic efficiency. Therefore, an increasing number of studies are focusing on the development of drugs or methods with which to enhance the treatment efficacy of TNFα. Nuclear receptor subfamily 4 group A member 1 (NR4A1) has been shown to exert antitumor effects through several mechanisms, such as by inhibiting proliferation, as well as pro-apoptotic and potent pro-oxidant effects...
December 4, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29199262/impaired-bioenergetics-in-clinical-medicine-a-target-to-tackle
#16
Sergej M Ostojic
Mitochondrial energy deficit is considered a key element of different clinical pathologies - from inherited disorders of energy metabolism to drug-induced mitochondrial toxicity, to cardiometabolic and neurodegenerative diseases. However, clinical manifestations of impaired bioenergetics are not easy to recognize, with patient-reported features usually include non-pathognomonic fatigue and weakness, or exercise intolerance, while specific lab tests are missing. Although it is not clear whether poor energetics is a primary deficit or a secondary consequence of specific disorders, improving mitochondrial viability remains a challenging task in both experimental and clinical medicine...
2017: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29197802/developing-the-next-generation-of-graphene-based-platforms-for-cancer-therapeutics-the-potential-role-of-reactive-oxygen-species
#17
REVIEW
Tanveer A Tabish, Shaowei Zhang, Paul G Winyard
Graphene has a promising future in applications such as disease diagnosis, cancer therapy, drug/gene delivery, bio-imaging and antibacterial approaches owing to graphene's unique physical, chemical and mechanical properties alongside minimal toxicity to normal cells, and photo-stability. However, these unique features and bioavailability of graphene are fraught with uncertainties and concerns for environmental and occupational exposure. Changes in the physicochemical properties of graphene affect biological responses including reactive oxygen species (ROS) production...
November 22, 2017: Redox Biology
https://www.readbyqxmd.com/read/29191257/proteasome-inhibitor-mg132-enhances-cisplatin-induced-apoptosis-in-osteosarcoma-cells-and-inhibits-tumor-growth
#18
Farui Sun, Yuanjin Zhang, Lijun Xu, Songbai Li, Xiang Chen, Ling Zhang, Yifan Wu, Jun Li
Although cisplatin has been proved as an integral part of chemotherapy regiment in osteosarcoma (OS) treatment, toxicity issues and chemoresistance hindered the OS therapeutic development. Exploring novel combination therapy methods is required to circumvent the limitations of cisplatin alone. The proteasome inhibitor MG132 has shown its anti-tumor effects in many solid tumors. However, little is known about its effects in combination with cisplatin in osteosarcoma cells. In this study, we examined the effects of MG132 in combination with cisplatin in human osteosarcoma cells (MG-63 and HOS)...
November 30, 2017: Oncology Research
https://www.readbyqxmd.com/read/29190729/increased-mmab-level-in-mitochondria-as-a-novel-biomarker-of-hepatotoxicity-induced-by-efavirenz
#19
Zhimi Tan, Xiaofang Jia, Fang Ma, Yanling Feng, Hongzhou Lu, Jun-O Jin, Dage Wu, Lin Yin, Li Liu, Lijun Zhang
BACKGROUND: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been widely used in the therapy of human immunodeficiency virus (HIV) infection. Some of its toxic effects on hepatic cells have been reported to display features of mitochondrial dysfunction through bioenergetic stress and autophagy, etc. However, alteration of protein levels, especially mitochondrial protein levels, in hepatic cells during treatment of EFV has not been fully investigated. METHODS: We built a cell model of EFV-induced liver toxicity through treating Huh-7 cells with different concentrations of EFV for different time followed by the analysis of cell viability using cell counting kit -8 (CCK8) and reactive oxygen species (ROS) using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox dye...
2017: PloS One
https://www.readbyqxmd.com/read/29189163/alpha-synuclein-proteotoxicity-and-parkinson-s-disease-search-for-neuroprotective-therapy
#20
Upasana Ganguly, Sankha Shubhra Chakrabarti, Upinder Kaur, Anwesha Mukherjee, Sasanka Chakrabarti
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD. The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes...
November 28, 2017: Current Neuropharmacology
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