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Mitochondrial pharmacology

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https://www.readbyqxmd.com/read/28538623/impact-of-a-novel-pi3-kinase-inhibitor-in-preventing-mitochondrial-dna-damage-and-damage-associated-molecular-pattern-accumulation-results-from-the-biochronicity-project
#1
George E Black, Kyle K Sokol, Donald M Moe, Jon Simmons, David Muscat, Victor Pastukh, Gina Capley, Olena Gorodnya, Mykhalo Ruchko, Mark B Roth, Mark Gillespie, Matthew J Martin
BACKGROUND: Despite improvements in the management of severely injured patients, development of multiple organ dysfunction syndrome (MODS) remains a morbid complication of traumatic shock. One of the key attributes of MODS is a profound bioenergetics crisis, for which the mediators and mechanisms are poorly understood. We hypothesized that metabolic uncoupling using an experimental PI3-kinase inhibitor, LY294002 (LY), may prevent mitochondrial abnormalities that lead to the generation of mitochondrial DNA (mtDNA) damage and the release of mtDNA damage associated molecular patterns (DAMPs) METHODS: 16 swine were studied using LY294002 (LY), a non-selective PI3-KI: Animals were assigned to Trauma only (TO, N=3); LY drug only (LYO, N=3); and Experimental (N=10), trauma + drug (LY+T) groups...
May 22, 2017: Journal of Trauma and Acute Care Surgery
https://www.readbyqxmd.com/read/28531964/non-electron-transfer-chain-mitochondrial-defects-differently-regulate-hif-1%C3%AE-degradation-and-transcription
#2
Antonina N Shvetsova, Daniela Mennerich, Juha M Kerätär, J Kalervo Hiltunen, Thomas Kietzmann
Mitochondria are the main consumers of molecular O2 in a cell as well as an abundant source of reactive oxygen species (ROS). Both, molecular oxygen and ROS are powerful regulators of the hypoxia-inducible factor-1α-subunit (HIF-α). While a number of mechanisms in the oxygen-dependent HIF-α regulation are quite well known, the view with respect to mitochondria is less clear. Several approaches using pharmacological or genetic tools targeting the mitochondrial electron transport chain (ETC) indicated that ROS, mainly formed at the Rieske cluster of complex III of the ETC, are drivers of HIF-1α activation...
May 8, 2017: Redox Biology
https://www.readbyqxmd.com/read/28526869/blocking-of-carnitine-palmitoyl-transferase-1-potently-reduces-stress-induced-depression-in-rat-highlighting-a-pivotal-role-of-lipid-metabolism
#3
Anne Skøttrup Mørkholt, Ove Wiborg, Jette G K Nieland, Søren Nielsen, John Dirk Nieland
Major depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism and mutations in CPT1a causing reduced function is hypothesized to have a protective role in the development of depression. Moreover, CPT1a is found to be upregulated in suicide patients with history of depression...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28526717/major-contribution-of-the-3-6-7-class-of-trpc-channels-to-myocardial-ischemia-reperfusion-and-cellular-hypoxia-reoxygenation-injuries
#4
Xiju He, Shoutian Li, Benju Liu, Sebastian Susperreguy, Karina Formoso, Jinghong Yao, Jinsong Kang, Anbing Shi, Lutz Birnbaumer, Yanhong Liao
The injury phase after myocardial infarcts occurs during reperfusion and is a consequence of calcium release from internal stores combined with calcium entry, leading to cell death by apoptopic and necrotic processes. The mechanism(s) by which calcium enters cells has(ve) not been identified. Here, we identify canonical transient receptor potential channels (TRPC) 3 and 6 as the cation channels through which most of the damaging calcium enters cells to trigger their death, and we describe mechanisms activated during the injury phase...
May 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28526134/molecular-biology-digest-of-cell-mitophagy
#5
I Matic, D Strobbe, F Di Guglielmo, M Campanella
The homeostasis of eukaryotic cells relies on efficient mitochondrial function. The control of mitochondrial quality is framed by the combination of distinct but interdependent mechanisms spanning biogenesis, regulation of dynamic network, and finely tuned degradation either through ubiquitin-proteasome system or autophagy (mitophagy). There is continuous evolution on the pathways orchestrating the mitochondrial response to stress signals and the organelle adaptation to quality control during acute and subtle dysfunctions...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28521061/extracellular-camp-activates-molecular-signalling-pathways-associated-with-sperm-capacitation-in-bovines
#6
Carlos Agustín I Alonso, Claudia E Osycka-Salut, Luciana Castellano, Andreína Cesari, Nicolás Di Siervi, Adrián Mutto, Anders Johannisson, Jane M Morrell, Carlos Davio, Silvina Perez-Martinez
STUDY QUESTION: Is extracellular cAMP involved in the regulation of signalling pathways in bovine sperm capacitation? SUMMARY ANSWER: Extracellular cAMP-induced sperm capacitation through the activation of different signalling pathways that involve phospholipase C (PLC), PKC/ERK1-2 signalling and an increase in sperm Ca2+ levels, as well as soluble AC and cAMP/protein kinase A (PKA) signalling. WHAT IS KNOWN ALREADY: In order to fertilize the oocyte, ejaculated spermatozoa must undergo a series of changes in the female reproductive tract, known as capacitation...
May 18, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28515690/brain-renin-angiotensin-system-and-microglial-polarization-implications-for-aging-and-neurodegeneration
#7
REVIEW
Jose L Labandeira-Garcia, Ana I Rodríguez-Perez, Pablo Garrido-Gil, Jannette Rodriguez-Pallares, Jose L Lanciego, Maria J Guerra
Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28515179/arginase-2-mediates-renal-ischemia-reperfusion-injury
#8
Wesley M Raup-Konsavage, Ting Gao, Timothy K Cooper, Sidney M Morris, W Brian Reeves, Alaa S Awad
Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia/reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine (a) whether renal arginase activity or expression is increased in renal IRI and (b) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (WT) and arginase-2 deficient (Arg2(-/-) ) mice subjected to bilateral renal ischemia for 28min followed by reperfusion for 24h...
May 17, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28511953/small-conductance-ca-2-activated-k-channels-in-the-plasma-membrane-mitochondria-and-the-er-pharmacology-and-implications-in-neuronal-diseases
#9
REVIEW
Birgit Honrath, Inge Krabbendam, Carsten Culmsee, Amalia Dolga
Ca(2+)-activated K(+) (KCa) channels regulate after-hyperpolarization in many types of neurons in the central and peripheral nervous system. Small conductance Ca(2+)-activated K(+) (KCa2/SK) channels, a subfamily of KCa channels, are widely expressed in the central and peripheral nervous system, and in the cardiovascular system. Voltage-independent SK channels are activated by alterations in intracellular Ca(2+) ([Ca(2+)]i) which facilitates the opening of these channels through binding of Ca(2+) to calmodulin that is constitutively bound to the SK2 C-terminus...
May 13, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28504707/regulation-of-mitochondrial-biogenesis-in-erythropoiesis-by-mtorc1-mediated-protein%C3%A2-translation
#10
Xin Liu, Yuannyu Zhang, Min Ni, Hui Cao, Robert A J Signer, Dan Li, Mushan Li, Zhimin Gu, Zeping Hu, Kathryn E Dickerson, Samuel E Weinberg, Navdeep S Chandel, Ralph J DeBerardinis, Feng Zhou, Zhen Shao, Jian Xu
Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification...
May 15, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28504211/ectopic-adenine-nucleotide-translocase-activity-controls-extracellular-adp-levels-and-regulates-the-f1-atpase-mediated-hdl-endocytosis-pathway-on-hepatocytes
#11
G Cardouat, T Duparc, S Fried, B Perret, S Najib, L O Martinez
Ecto-F1-ATPase is a complex related to mitochondrial ATP synthase which has been identified as a plasma membrane receptor for apolipoprotein A-I (apoA-I), the major protein of high-density lipoprotein (HDL), and has been shown to contribute to HDL endocytosis in several cell types. On hepatocytes, apoA-I binding to ecto-F1-ATPase stimulates extracellular ATP hydrolysis into ADP, which subsequently activates a P2Y13-mediated HDL endocytosis pathway. Interestingly, other mitochondrial proteins have been found to be expressed at the plasma membrane of several cell types...
May 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28503778/a-topical-zinc-ionophore-blocks-tumorigenic-progression-in-uv-exposed-skh-1-high-risk-mouse-skin
#12
Rebecca Justiniano, Jessica Perer, Anh Hua, Mohammad Fazel, Andrea Krajisnik, Christopher M Cabello, Georg T Wondrak
Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States representing a considerable public health burden. Pharmacological suppression of skin photo-carcinogenesis has shown promise in preclinical and clinical studies, but more efficacious photochemopreventive agents are needed. Here, we tested feasibility of harnessing pharmacological disruption of intracellular zinc-homeostasis for photochemoprevention in vitro and in vivo. Employing the zinc-ionophore and FDA-approved microbicidal agent zinc pyrithione (ZnPT), used worldwide in over-the-counter (OTC) topical consumer products, we first demonstrated feasibility of achieving ZnPT-based intracellular Zn(2+) -overload in cultured malignant keratinocytes (HaCaT-ras II-4; SCC-25) employing membrane-permeable fluorescent probes...
May 15, 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/28500966/synthesis-of-novel-benzylidene-analogues-of-betulinic-acid-as-potent-cytotoxic-agents
#13
Nidhi Gupta, Santosh K Rath, Jasvinder Singh, Arem Qayum, Shashank Singh, Payare L Sangwan
Different benzylidene derivatives (15a-o and 16a-o) of betulinic acid were designed and synthesized in an effort to develop potent anticancer agents. All the synthesized derivatives along with betulinic acid were evaluated for cytotoxicity against a panel of five different human cancer cell lines A-549 (Lung), PC-3 (Prostate), HCT 116 (Colon), MCF-7 (Breast) and MIA PaCa-2 (Pancreatic) using SRB assay. Pharmacological results showed that compounds 15b, 15c, 15i, 15k, 16a-c and 16l were found to have promising cytotoxic profile against various cancer cell lines tested (IC50 1-2 μM)...
April 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28498645/licochalcone-a-suppresses-specificity-protein-1-as-a-novel-target-in-human-breast-cancer-cells
#14
Tae-Ho Kang, Ji-Hye Seo, Hana Oh, Goo Yoon, Jung-Il Chae, Jung-Hyun Shim
Licochalcone A (LCA), isolated from the root of Glycyrrhiza inflata, are known to have medicinal effect such as anti-oxidant, anti-bacterial, anti-viral and anti-cancer. Though, as a pharmacological mechanism regulator, anti-cancer studies on LCA were not investigated in human breast cancer. We investigated the anti-proliferative and apoptotic effect of LCA in human breast cancer cells MCF-7 and MDA-MB-231 through MTS assay, PI staining, Annexin-V/7-AAD assay, mitochondrial membrane potential assay, multi-caspase assay, RT-PCR, Western blot analysis and anchorage-independent cell transformation assay...
May 12, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28495589/reduced-fak-stat3-signaling-contributes-to-er-stress-induced-mitochondrial-dysfunction-and-death-in-endothelial-cells
#15
Kalpita Banerjee, Matt P Keasey, Vladislav Razskazovskiy, Nishant P Visavadiya, Cuihong Jia, Theo Hagg
Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy...
May 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28492973/fast-therapeutic-hypothermia-prevents-post-cardiac-arrest-syndrome-through-cyclophilin-d-mediated-mitochondrial-permeability-transition-inhibition
#16
Vincent Jahandiez, Martin Cour, Thomas Bochaton, Maryline Abrial, Joseph Loufouat, Abdallah Gharib, Annie Varennes, Michel Ovize, Laurent Argaud
The opening of the mitochondrial permeability transition pore (PTP), which is regulated by the matrix protein cyclophilin D (CypD), plays a key role in the pathophysiology of post-cardiac arrest (CA) syndrome. We hypothesized that therapeutic hypothermia could prevent post-CA syndrome through a CypD-mediated PTP inhibition in both heart and brain. In addition, we investigated whether specific pharmacological PTP inhibition would confer additive protection to cooling. Adult male New Zealand White rabbits underwent 15 min of CA followed by 120 min of reperfusion...
July 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28490746/pathogenic-p62-sqstm1-mutations-impair-energy-metabolism-through-limitation-of-mitochondrial-substrates
#17
Fernando Bartolome, Noemi Esteras, Angeles Martin-Requero, Claire Boutoleau-Bretonniere, Martine Vercelletto, Audrey Gabelle, Isabelle Le Ber, Tadashi Honda, Albena T Dinkova-Kostova, John Hardy, Eva Carro, Andrey Y Abramov
Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y)...
May 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28488010/neuroprotective-effect-of-oxysophocarpine-by-modulation-of-mapk-pathway-in-rat-hippocampal-neurons-subject-to-oxygen-glucose-deprivation-and-reperfusion
#18
Peng Zhao, Ren-Yuan Chang, Ning Liu, Jing Wang, Ru Zhou, Xue Qi, Yue Liu, Lin Ma, Yang Niu, Tao Sun, Yu-Xiang Li, Yan-Ping He, Jian-Qiang Yu
Oxysophocarpine (OSC), an alkaloid isolated from Sophora flavescens Ait, has been traditionally used as a medicinal agent based on the observed pharmacological effects. In this study, the direct effect of OSC against neuronal injuries induced by oxygen and glucose deprivation (OGD) in neonatal rat primary-cultured hippocampal neurons and its mechanisms were investigated. Cultured hippocampal neurons, which were exposed to OGD for 2 h followed by a 24 h reoxygenation, were used as an in vitro model of ischemia and reperfusion...
May 9, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28487636/elamipretide-ss-31-ameliorates-isoflurane-induced-long-term-impairments-of-mitochondrial-morphogenesis-and-cognition-in-developing-rats
#19
Jing Wu, Shuangying Hao, Xiao-Ru Sun, Hui Zhang, Huihui Li, Hongting Zhao, Mu-Huo Ji, Jian-Jun Yang, Kuanyu Li
Mitochondria are supposed to be involved in the early pathogenesis of general anesthesia (GA)-induced neurotoxicity and long-term cognitive deficits in developing brains. However, effective pharmacologic agents targeted on mitochondria during GA exposure are lacking. This study explores the protective effects of mitochondrion-targeted antioxidant elamipretide (SS-31) on mitochondrial morphogenesis and cognition in developing rats exposed to isoflurane. Rat pups at postnatal day (PND) 7 were exposed to 1.5% isoflurane for 6 h following intraperitoneal administration of elamipretide or vehicle with 30 min interval...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28481747/pharmacological-preconditioning-with-diazoxide-in-the-experimental-hypothermic-circulatory-arrest-model
#20
Henri Johannes Haapanen, Oiva Arvola, Johanna Herajärvi, Tuomas Anttila, Hannu Tuominen, Ulla Puistola, Peeter Karihtala, Kai Kiviluoma, Tatu Juvonen, Vesa Anttila
Hypothermic circulatory arrest includes a remarkable risk for neurological injury. Diazoxide, a mitochondrial adenosine triphosphate-dependent potassium ion (K+ATP) channel opener, is known to have cardioprotective effects. We assessed its efficacy in preventing ischemic injury in a clinically relevant animal model. Methods: Eighteen piglets were randomized into a diazoxide group (n = 9) and a control group (n = 9). Animals underwent 60 minutes of hypothermic circulatory arrest at 18°C. Diazoxide (5 mg/kg + 10 mL NaOH + 40 mL NaCl) was infused during the cooling phase...
April 30, 2017: Heart Surgery Forum
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