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Mitochondrial dysfunction

Aline G Pereira, Michael L Jaramillo, Aline P Remor, Alexandra Latini, Carla E Davico, Mariana L da Silva, Yara M R Müller, Dib Ammar, Evelise M Nazari
Glyphosate (N-phosphonomethyl-glycine) (GLY) is the active ingredient of the most used herbicides in the world. GLY is applied in formulated products known as glyphosate-based herbicides (GBH), which could induce effects that are not predicted by toxicity assays with pure GLY. This herbicide is classified as organophosphorus compound, which is known to induce neurotoxic effects. Although this compound is classified as non-neurotoxic by regulatory agencies, acute exposure to GBH causes neurological symptoms in humans...
June 11, 2018: Chemosphere
Feng-Yang Wang, Xiao-Ming Tang, Xia Wang, Ke-Bin Huang, Hai-Wen Feng, Zhen-Feng Chen, You-Nian Liu, Hong Liang
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL1 Cl]Cl [L1  = (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL2 Cl]Cl [L2  = (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2)...
June 9, 2018: European Journal of Medicinal Chemistry
Lilian Cristina Pereira, Luiz Felipe Cabral Miranda, Mariana Furio Franco-Bernardes, Maria Julia Tasso, Filipe Valente Duarte, Ana Teresa Inácio Varela, Anabela Pinto Rolo, Carlos Manuel Marques Palmeira, Daniel Junqueira Dorta
Brominated flame retardants are used in consumer goods to increase product resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are the most commonly employed class of brominated flame retardants because they are inexpensive and can effectively prevent flame from spreading. PBDEs are persistent, can bioaccumulate, are transported over long distances, and display toxicity. However, their toxic mechanisms of action have not been well established. Because mitochondria are recognized as the main energy-producing cell organelle and play a vital role in cellular function maintenance, here we apply mitochondria as an experimental model to evaluate the toxic effects of the PBDE congener BDE-153 (Hexa-BDE) at concentrations ranging from 0...
June 20, 2018: Chemico-biological Interactions
Yun Qian, Qixin Han, Xiaotian Zhao, Jialin Song, Yuan Cheng, Zhiwei Fang, Yuanming Ouyang, Wei-En Yuan, Cunyi Fan
Peripheral nerve defect is a common and severe kind of injury in traumatic accidents. Melatonin can improve peripheral nerve recovery by inhibiting oxidative stress and inflammation after traumatic insults. In addition, it triggers autophagy pathways to increase regenerated nerve proliferation and to reduce apoptosis. In this study, we fabricated a melatonin-controlled-release scaffold to cure long-range nerve defects for the first time. 3D manufacture of melatonin/polycaprolactone nerve guide conduit increased Schwann cell proliferation and neural expression in vitro and promoted functional, electrophysiological and morphological nerve regeneration in vivo...
June 23, 2018: Journal of Pineal Research
Britney N Lizama, Amy M Palubinsky, Vineeth A Raveendran, Annah M Moore, Joel D Federspiel, Simona G Codreanu, Daniel C Liebler, BethAnn McLaughlin
C-terminus of HSC70-interacting protein (CHIP, STUB1 ) is a ubiquitously expressed cytosolic E3-ubiquitin ligase. CHIP-deficient mice exhibit cardiovascular stress and motor dysfunction prior to premature death. This phenotype is more consistent with animal models in which master regulators of autophagy are affected rather than with the mild phenotype of classic E3-ubiquitin ligase mutants. The cellular and biochemical events that contribute to neurodegeneration and premature aging in CHIP KO models remain poorly understood...
June 22, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Liang Shu, Ben Chen, Bin Chen, Hai Xu, Guoxiang Wang, Yian Huang, Yingya Zhao, Hui Gong, Min Jiang, Lidian Chen, Xu Liu, Yun Wang
Ischemic stroke not only induces neuron death in the infarct area but also structural and functional damage of the surviving neurons in the surrounding peri-infarct area. In the present study, we first identified cofilin rod, a pathological rod-like aggregation, formed in neurons of in vivo ischemic stroke animal model and induced neuronal impairment. Cofilin rods formed only on the ipsilateral side of the middle cerebral artery occlusion and reperfusion (MCAO-R) rat brain and showed the highest density in peri-infarct area...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
Germán A Colareda, Alicia E Consolini
OBJECTIVES: Low-flow ischemia (LFI) is consequent to coronary disease and produces cardiac stunning during reperfusion (R). Energetic performance and mechanisms of Ca2+ handling during LFI/R are not known. Moreover, cardioprotection of the phytoestrogen genistein (Gen) remains to be demonstrated in LFI/R. The aim was to study the mechanisms of the stunning consequent to LFI/R and the effects of Gen on both sexes. METHODS: Rat ventricles were perfused inside a calorimeter to measure maximal pressure development (P) and total heat rate (Ht) before and during exposition to LFI/R...
June 21, 2018: Journal of Pharmacy and Pharmacology
Thao V Nguyen, Andrea C Alfaro, Fabrice Merien, Ronald Lulijwa, Tim Young
Copper is a common contaminant in aquatic environments, which may cause physiological dysfunction in marine organisms. However, the toxicity mechanisms of copper in marine bivalves is not fully understood. In this study, we applied an integrated approach that combines flow cytometry and Gas Chromatography-Mass Spectrometry (GC-MS)-based metabolomics to characterize cellular and molecular mechanisms of copper immunotoxicity in New Zealand Greenshell™ mussel (Perna canaliculus) haemolymph. Flow cytometric results showed significant increases in haemocyte mortality, production of reactive oxygen species and apoptosis (via alteration of caspase 3/7 and mitochondrial membrane potential) of haemocytes exposed to increasing total concentrations of Cu2+ (62...
June 22, 2018: Metallomics: Integrated Biometal Science
Mattia Vicario, Domenico Cieri, Marisa Brini, Tito Calì
The presynaptic protein alpha-synuclein (α-syn) is unequivocally linked to the development of Parkinson's disease (PD). Not only it is the major component of amyloid fibrils found in Lewy bodies but mutations and duplication/triplication in its gene are responsible for the onset of familial autosomal dominant forms of PD. Nevertheless, the precise mechanisms leading to neuronal degeneration are not fully understood. Several lines of evidence suggest that impaired autophagy clearance and mitochondrial dysfunctions such as bioenergetics and calcium handling defects and alteration in mitochondrial morphology might play a pivotal role in the etiology and progression of PD, and indicate the intriguing possibility that α-syn could be involved in the control of mitochondrial function both in physiological and pathological conditions...
2018: Frontiers in Neuroscience
Paula A Q Videira, Margarida Castro-Caldas
Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting about 6.3 million people worldwide. PD is characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra pars compacta , resulting into severe motor symptoms. The cellular mechanisms underlying dopaminergic cell death in PD are still not fully understood, but mitochondrial dysfunction, oxidative stress and inflammation are strongly implicated in the pathogenesis of both familial and sporadic PD cases...
2018: Frontiers in Neuroscience
Jung Hyun Park, Hyeong Jun Ku, Jae Kyeom Kim, Jeen-Woo Park, Jin Hyup Lee
Heart failure is a frequent unfavorable outcome of pathological cardiac hypertrophy. Recent increase in dietary fructose consumption mirrors the rise in prevalence of cardiovascular diseases such as cardiac hypertrophy leading to concerns raised by public health experts. Mitochondria, comprising 30% of cardiomyocyte volume, play a central role in modulating redox-dependent cellular processes such as metabolism and apoptosis. Furthermore, mitochondrial dysfunction is a key cause of pathogenesis of fructose-induced cardiac hypertrophy...
June 21, 2018: Scientific Reports
Kim R Kampen, Sergey O Sulima, Benno Verbelen, Tiziana Girardi, Stijn Vereecke, Gianmarco Rinaldi, Jelle Verbeeck, Joyce Op de Beeck, Anne Uyttebroeck, Jules P P Meijerink, Anthony V Moorman, Christine J Harrison, Pieter Spincemaille, Jan Cools, David Cassiman, Sarah-Maria Fendt, Pieter Vermeersch, Kim De Keersmaecker
The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression...
June 21, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Andrea Pellagatti, Richard N Armstrong, Violetta Steeples, Eshita Sharma, Emmanouela Repapi, Shalini Singh, Andrea Sanchi, Aleksandar Radujkovic, Patrick Horn, Hamid Dolatshad, Swagata Roy, John Broxholme, Helen Lockstone, Stephen Taylor, Aristoteles Giagounidis, Paresh Vyas, Anna Schuh, Angela Hamblin, Elli Papaemmanuil, Sally Killick, Luca Malcovati, Marco L Hennrich, Anne-Claude Gavin, Anthony D Ho, Thomas Luft, Eva Hellström-Lindberg, Mario Cazzola, Christopher W J Smith, Stephen Smith, Jacqueline Boultwood
SF3B1, SRSF2 and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the impact of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34+ cells of 84 MDS patients. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis and mitochondrial dysfunction, suggesting common mechanisms of action in MDS...
June 21, 2018: Blood
T Dung Nguyen, Michael Schwarzer, Andrea Schrepper, Paulo A Amorim, Daniel Blum, Claudia Hain, Gloria Faerber, Judith Haendeler, Joachim Altschmied, Torsten Doenst
BACKGROUND: Insulin resistance in diabetes mellitus has been associated with mitochondrial dysfunction. Defects at the level of mitochondria are also characteristic of heart failure. We assessed changes in cardiac insulin response and mitochondrial function in a model of pressure overload-induced heart failure. METHODS AND RESULTS: Rats underwent aortic banding to induce pressure overload. At 10 weeks, rats showed cardiac hypertrophy and pulmonary congestion, but left ventricular dilatation and systolic dysfunction were only evident after 20 weeks...
June 21, 2018: Journal of the American Heart Association
Yumi Ueki, Veronika Shchepetkina, Frances Lefcort
Familial dysautonomia (FD) is an autosomal recessive disorder marked by developmental and progressive neuropathies. It is caused by an intronic point mutation in the inhibitor of kappa B kinase complex-associated protein (IKAP, also called ELP1) gene IKBKAP/ELP1 , a component of the Elongator complex. Due to variation in tissue-specific splicing, the mutation primarily affects the nervous system. One of the most debilitating hallmarks of FD that affects patients' quality of life is progressive blindness. To determine the pathophysiological mechanisms that are triggered by the absence of IKAP in the retina, we generated retina-specific Ikbkap conditional knockout (CKO) mice using a Pax6-Cre , which abolished Ikbkap expression in all the cell types of the retina...
June 21, 2018: Disease Models & Mechanisms
Michael Karlsson, Bryan Pukenas, Sanjeev Chawla, Johannes K Ehinger, Ross Plyler, Madeline Stolow, Melissa Gabello, Matilda Hugerth, Eskil Elmér, Magnus J Hansson, Susan Margulies, Todd Justen Kilbaugh
Mitochondrial dysfunction is thought to be a hallmark of traumatic brain injury (TBI), and plays a pivotal role in the resulting cellular injury. Cyclophilin D-mediated activation of the mitochondrial permeability transition pore has been suggested to contribute to this secondary injury cascade. The compound cyclosporine possesses neuroprotective properties that has been attributed to the desensitization of mitochondrial permeability transition pore activation. In vivo animal experiments have demonstrated neuroprotective effects of cyclosporine in more than 20 independent experimental studies in a multitude of different experimental models...
June 21, 2018: Journal of Neurotrauma
Salvador Meseguer, Joaquin Panadero, Carmen Navarro-González, Magda Villarroya, Rachid Boutoual, Giacomo Pietro Comi, M-Eugenia Armengod
The pathomechanisms underlying oxidative phosphorylation (OXPHOS) diseases are not well-understood, but they involve maladaptive changes in mitochondria-nucleus communication. Many studies on the mitochondria-nucleus cross-talk triggered by mitochondrial dysfunction have focused on the role played by regulatory proteins, while the participation of miRNAs remains poorly explored. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is mostly caused by mutation m.3243A>G in mitochondrial tRNALeu(UUR) gene...
June 18, 2018: Biochimica et Biophysica Acta
Qutuba G Karwi, Golam M Uddin, Kim L Ho, Gary D Lopaschuk
To maintain its high energy demand the heart is equipped with a highly complex and efficient enzymatic machinery that orchestrates ATP production using multiple energy substrates, namely fatty acids, carbohydrates (glucose and lactate), ketones and amino acids. The contribution of these individual substrates to ATP production can dramatically change, depending on such variables as substrate availability, hormonal status and energy demand. This "metabolic flexibility" is a remarkable virtue of the heart, which allows utilization of different energy substrates at different rates to maintain contractile function...
2018: Frontiers in Cardiovascular Medicine
Josh Allen, Raquel Romay-Tallon, Kyle J Brymer, Hector J Caruncho, Lisa E Kalynchuk
Human and animal studies suggest an intriguing link between mitochondrial diseases and depression. Although depression has historically been linked to alterations in monoaminergic pharmacology and adult hippocampal neurogenesis, new data increasingly implicate broader forms of dampened plasticity, including plasticity within the cell. Mitochondria are the cellular powerhouse of eukaryotic cells, and they also regulate brain function through oxidative stress and apoptosis. In this paper, we make the case that mitochondrial dysfunction could play an important role in the pathophysiology of depression...
2018: Frontiers in Neuroscience
Deepaneeta Sarmah, Harpreet Kaur, Jackson Saraf, Kanchan Vats, Kanta Pravalika, Madhuri Wanve, Kiran Kalia, Anupom Borah, Akhilesh Kumar, Xin Wang, Dileep R Yavagal, Kunjan R Dave, Pallab Bhattacharya
Stroke is a debilitating condition which is also the second leading cause of death and disability worldwide. Despite the benefits and promises shown by numerous neuroprotective agents in animal stroke models, their clinical translation has not been a complete success. Hence, search for treatment options have directed researchers towards utilising stem cells. Mitochondria has a major involvement in the pathophysiology of stroke and a number of other conditions. Stem cells have shown the ability to transfer mitochondria to the damaged cells and to help revive cell energetics in the recipient cell...
June 20, 2018: Translational Stroke Research
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