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Mitochondrial toxicity

Wenxin Hu, Zhiming Wang, Hongjin Zheng
Mitochondrial accumulation of intracellular amyloid beta (Aβ) peptides is present in the brains of individuals with Alzheimer's disease (AD), as well as in related mouse models of AD. This accumulation is extremely toxic because Aβ disrupts the normal functions of many mitochondrial proteins, resulting in significant mitochondrial dysfunction. Therefore, understanding the mitochondrial accumulation of Aβ is useful for future pharmaceutical design of drugs to address mitochondrial dysfunction in AD. However, the detailed molecular mechanism of this accumulation process remains elusive...
June 20, 2018: Journal of Biological Chemistry
Kristina Henz, Aoula Al-Zebeeby, Marion Basoglu, Simone Fulda, Gerald M Cohen, Shankar Varadarajan, Meike Vogler
Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure...
June 1, 2018: Biological Chemistry
Elise Drangsholt, Marie Vangstad, Sergey Zakharov, Knut Erik Hovda, Dag Jacobsen
Methanol mass poisoning is a global problem with high fatality rates and often severe sequelae in survivors. Patients typically present late to the hospital with severe metabolic acidosis followed by a rapid deterioration in their clinical status. The hypothesis "Circulus hypoxicus" describes the metabolic acidosis following methanol poisoning as a self-enhancing hypoxic circle responsible for methanol toxicity. We wanted to test the validity of this hypothesis by an observational study based on 35 patients from the methanol outbreaks in Norway (2004) and the Czech Republic (2012)...
June 20, 2018: Basic & Clinical Pharmacology & Toxicology
Cristiane Cecatto, Alessandro Wajner, Carmen Regla Vargas, Simone Magagnin Wajner, Alexandre Umpierrez Amaral, Moacir Wajner
Patients affected by long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency predominantly present severe liver and cardiac dysfunction, as well as neurological symptoms during metabolic crises, whose pathogenesis is still poorly known. In this study, we demonstrate for the first time that pathological concentrations of 3-hydroxypalmitic acid (3HPA), the long-chain hydroxyl fatty acid (LCHFA) that most accumulates in LCHAD deficiency, significantly decreased adenosine triphosphate-linked and uncoupled mitochondrial respiration in intact cell systems consisting of heart fibers, cardiomyocytes, and hepatocytes, but less intense in diced forebrain...
June 20, 2018: Journal of Cellular Biochemistry
Marco Pelin, Laura Fusco, Cristina Martín, Silvio Sosa, Javier Frontiñán-Rubio, Jose Miguel González-Domínguez, Mario Durán-Prado, Ester Vázquez, Maurizio Prato, Aurelia Tubaro
The extraordinary physicochemical properties of graphene-based nanomaterials (GBNs) make them promising tools in nanotechnology and biomedicine. Considering the skin contact as one of the most feasible exposure routes to GBNs, the mechanism of toxicity of two GBNs (few-layer-graphene, FLG, and graphene oxide, GO) towards human HaCaT skin keratinocytes was investigated. Both materials induced a significant mitochondrial membrane depolarization: 72 h cell exposure to 100 μg mL-1 FLG or GO increased mitochondrial depolarization by 44% and 56%, respectively, while the positive control valinomycin (0...
June 19, 2018: Nanoscale
Kariyappa Vijay, Poorigali Raghavendra-Rao Sowmya, Bangalore Prabhashankar Arathi, Shivaprasad Shilpa, Hulikere Jagdish Shwetha, Marisiddaiah Raju, Vallikannan Baskaran, Rangaswamy Lakshminarayana
The combination of carotenoids and doxorubicin (DOX) selectively alters oxidative stress-mediated apoptosis in breast cancer cells. Primarily, cytotoxic efficiency of carotenoids (β-carotene, BC; lutein, LUT; astaxanthin, AST; or fucoxanthin, FUCO) either with or without a minimal cytotoxic dose of DOX was evaluated in MCF-7 (0.12 μM) and MDA-MB-231 cells (0.28 μM). The higher cell growth inhibition of BC and/or LUT with DOX was selected for testing in further cell-based assays. Low-dose DOX significantly enhanced cytotoxicity in carotenoid (<5 μM)-treated cells compared to high-dose DOX (>1 μM) or carotenoid (20 μM) treatment alone...
June 18, 2018: Food and Chemical Toxicology
Xiao-Xin Chen, Kar Ho Lam, Yibin Feng, Kai Xu, Stephen C W Sze, Chi Wai Tang, George P H Leung, Calvin Kai-Fai Lee, Jun Shi, Zhijun Yang, Sheng-Tao Li, Zhang-Jin Zhang, Yanbo Zhang
Worldwide, colorectal cancer (CRC) is a deleterious disease causing millions of death annually. 5-Fluorouracil (5-FU) is a first-line chemotherapy for CRC, but chemoresistance and gastrointestinal mucositis limit its efficacy. Polyphenol-rich foods are increasingly popular due to their potential beneficial role in cancer. Ellagitannins is a group of phenolic compounds commonly found in pomegranate, strawberries, raspberries, etc. The objective of this study was to explore whether ellagitannins from pomegranate (PETs) could ameliorate 5-FU-induced intestinal mucositis and enhance its efficacy against CRC...
June 19, 2018: Journal of Agricultural and Food Chemistry
Elena Gazzano, Loretta Lazzarato, Barbara Rolando, Joanna Kopecka, Stefano Guglielmo, Costanzo Costamagna, Konstantin Chegaev, Chiara Riganti
Antitumor chemotherapy remains one of the most important challenge of the medicinal chemistry. Emerging research in chemotherapy is focused on exploiting the biochemical differences between cancer cell and normal cell metabolism in order to reduce the side effects and increase antitumor therapy efficacy. The higher mitochondrial transmembrane potential of cancer cells compared to not-transformed cells favors the intra-mitochondrial accumulation of cationic drugs in the former. This feature could be exploited to allow selective delivery of antineoplastic drugs to the cancer cells...
2018: Frontiers in Pharmacology
Jiezhang Mo, Derun Lin, Jingzhen Wang, Ping Li, Wenhua Liu
Zinc pyrithione (ZPT) is widely used as a substitute booster biocide for tributyltin and is also an additive to antidandruff shampoos and medical cosmetic products. ZPT and pyrithione have been detected in different environmental matrices and biota, suggesting that it may pose health threats to aquatic organisms and even humans. The present study used HepG2 cells, a human hepatoma cell line, to study the hepatotoxicity of ZPT (0.1-5.0 μM). ZPT treatment caused marked viability reduction and induced apoptosis depending on its dose used...
June 15, 2018: Ecotoxicology and Environmental Safety
Indira Singh Chauhan, G SubbaRao, Jai Shankar, Lalit Kumar Singh Chauhan, Govind J Kapadia, Neeloo Singh
Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L...
June 15, 2018: Parasitology International
Cristina Monteiro, José Miguel P Ferreira de Oliveira, Francisco Pinho, Verónica Bastos, Helena Oliveira, Francisco Peixoto, Conceição Santos
Cadmium (Cd) accumulation is known to occur predominantly in kidney and liver; however, low-level long-term exposure to Cd may also result in bone damage. Few studies have addressed Cd-induced toxicity in osteoblasts, particularly upon cell mitochondrial energy processing and putative associations with oxidative stress in bone. To assess the influence of Cd treatment on mitochondrial function and oxidative status in osteoblast cells, human MG-63 cells were treated with Cd (up to 65 μM) for 24 or 48 h. Intracellular reactive oxygen species (ROS), lipid and protein oxidation and antioxidant defense mechanisms such as total antioxidant activity (TAA) and gene expression of antioxidant enzymes were analyzed...
June 18, 2018: Journal of Toxicology and Environmental Health. Part A
Alyse N Steves, Adam Turry, Brittany Gill, Danielle Clarkson-Townsend, Joshua M Bradner, Ian Bachli, W Michael Caudle, Gary W Miller, Anthony W S Chan, Charles A Easley
Per- and polyfluoroalkyl substances (PFASs) represent a highly ubiquitous group of synthetic chemicals used in products ranging from water and oil repellents and lubricants to firefighting foam. These substances can enter and accumulate in multiple tissue matrices in up to 100% of people assessed. Though animal models strongly identify these compounds as male reproductive toxicants, with exposed rodents experiencing declines in sperm count, alterations in hormones, and DNA damage in spermatids, among other adverse outcomes, human studies report conflicting conclusions as to the reproductive toxicity of these chemicals...
June 18, 2018: Systems Biology in Reproductive Medicine
Bagher Farhood, Nasser Hashemi Goradel, Keywan Mortezaee, Neda Khanlarkhani, Ensieh Salehi, Maryam Shabani Nashtaei, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Hengameh Fallah, Masoud Najafi
Nowadays, using ionizing radiation (IR) is necessary for clinical, agricultural, nuclear energy or industrial applications. Accidental exposure to IR after a radiation terror or disaster poses a threat to human. In contrast to the old dogma of radiation toxicity, several experiments during the last two recent decades have revealed that intercellular signaling and communications play a key role in this procedure. Elevated level of cytokines and other intercellular signals increase oxidative damage and inflammatory responses via reduction/oxidation interactions (redox system)...
June 17, 2018: Journal of Cell Communication and Signaling
Seong-Ho Ok, Jeong-Min Hong, Soo Hee Lee, Ju-Tae Sohn
Lipid emulsion has been shown to be an effective treatment for systemic toxicity induced by local anesthetics, which is reflected in case reports. A systemic review and meta-analysis confirm the efficacy of this treatment. Investigators have suggested mechanisms associated with the lipid emulsion-mediated recovery of cardiovascular collapse caused by local anesthetic systemic toxicity; these mechanisms include lipid sink, a widely accepted theory in which highly soluble local anesthetics (particularly bupivacaine) are absorbed into the lipid phase of plasma from tissues (e...
2018: International Journal of Medical Sciences
Ravi Sakthivel, Dicson Sheeja Malar, Kasi Pandima Devi
In the present study, the antiproliferative activity of phytol and its mechanism of action against human lung adenocarcinoma cell line A549 were studied in detail. Results showed that phytol exhibited potent antiproliferative activity against A549 cells in a dose and time-dependent manner with an IC50 value of 70.81 ± 0.32 μM and 60.7 ± 0.47 μM at 24 and 48 h, respectively. Phytol showed no adverse toxic effect in normal human lung cells (L-132), but mild toxic effect was observed when treated with maximum dose (67 and 84 μM)...
June 13, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Adrian Florea, Andrei Patrick Varga, Horea Vladi Matei
We tested the ability of bee venom (BV), melittin (Mlt), and phospholipase A2 (PLA) - used in 5 concentrations each (5, 10, 15, 20 and 40 μg/100 μl) - to promote ultrastructural changes and reorganization of cristae in vitro in mitochondria isolated from rat adrenal cortex after a protocol optimized by us. Thus, apart from two control grups (CI and CS), in which the mitochondria were suspended into saline buffer and isolation medium respectively, 15 more groups of mitochondria were constituted, corresponding to the five different doses of the three substance tested (BV5 to M40; M5 to M40 and P5 to P40)...
June 9, 2018: Micron: the International Research and Review Journal for Microscopy
Vered Behar, Hadas Pahima, Adi Kozminsky-Atias, Nir Arbel, Emmanuel Loeb, Max Herzberg, Oren M Becker
Overexpression of hexokinase 2 (HK2), and its binding to VDAC1 on the outer mitochondrial membrane of cancer cells, is key to their metabolic reprogramming to aerobic glycolysis, which enables them to proliferate. We describe Comp-1, an allosteric small molecule that selectively detaches HK2 from the mitochondria. Detachment of HK2 reduces glycolysis and triggers apoptosis in cancer cells, without affecting HK1 expressing normal cells. The anti-cancer activity of Comp-1 was demonstrated in the UVB-damaged skin model in SKH-1 mice...
June 13, 2018: Journal of Investigative Dermatology
Dong Gil Lee, Min Kyoung Kam, Kyung Min Kim, Han Seop Kim, Oh-Shin Kwon, Hyun-Shik Lee, Dong-Seok Lee
Iron is an essential element for neuronal as well as cellular functions. However, Iron overload has been known to cause neuronal toxicity through mitochondrial fission, dysregulation of Ca2+ , endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) production. Nevertheless, the precise mechanisms of iron-induced oxidative stress and mitochondria- and ER-related iron toxicity in neuronal cells are not fully understood. In this study, we demonstrated that iron overload induces ROS production earlier in the ER than in the mitochondria, and peroxiredoxin 5 (Prx5), which is a kind of antioxidant induced by iron overload, prevents iron overload-induced mitochondrial fragmentation mediated by contact with ER and translocation of Drp1, by inhibiting ROS production and calcium/calcineurin pathway in HT-22 mouse hippocampal neuronal cells...
June 12, 2018: International Journal of Biochemistry & Cell Biology
Alice Biosa, Irene Arduini, Maria Eugenia Soriano, Valentina Giorgio, Paolo Bernardi, Marco Bisaglia, Luigi Bubacco
The preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta is responsible for the motor impairment associated with Parkinson's disease. Dopamine is a highly reactive molecule, which is usually stored inside synaptic vesicles where it is stabilized by the ambient low pH. However, free cytosolic dopamine can auto-oxidize, generating reactive oxygen species, and lead to the formation of toxic quinones. In the present work, we have analyzed the mechanisms through which the dysfunction of dopamine homeostasis could induce cell toxicity, by focusing in particular on the damage induced by dopamine oxidation products at the mitochondrial level...
June 15, 2018: ACS Chemical Neuroscience
Peter M DiGeronimo, Nicholas A Crossland, Angela Jugan, Javier G Nevarez, Thomas N Tully, Dawn E Evans
A 5-year-old sexually intact male Toulouse goose ( Anser anser domesticus) was presented for ataxia, polyuria, and polydipsia. The goose was cachectic and exhibited head tremors. Results of plasma biochemical analysis and point-of-care glucometry revealed persistent hyperglycemia. Despite supportive care and oral glipizide, the goose died within 48 hours of presentation. Necropsy revealed severe pancreatic atrophy and fibrosis with regionally extensive cerebellar encephalomalacia and generalized Purkinje cell degeneration and necrosis...
June 2018: Journal of Avian Medicine and Surgery
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