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Mitochondrial pharmacology

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https://www.readbyqxmd.com/read/28339608/inhibition-of-arachidonate-15-lipoxygenase-prevents-4-hydroxynonenal-induced-protein-damage-in-male-germ-cells%C3%A2
#1
Elizabeth G Bromfield, Bettina P Mihalas, Matthew D Dun, R John Aitken, Eileen A McLaughlin, Jessica L H Walters, Brett Nixon
Lipid peroxidation products, such as 4-hydroxynonenal (4HNE), are causative agents responsible for extensive protein damage within the male and female germlines. Recently, we have demonstrated that 4HNE production can initiate the proteolytic degradation of the molecular chaperone Heat Shock Protein A2 (HSPA2) in male germ cells. These events may be partially responsible for HSPA2 deficiency in the spermatozoa of patients that repeatedly fail in vitro fertilization. Given this, mechanisms that limit the production of 4HNE will be highly advantageous for the preservation of male fertility...
February 2, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28332584/akt-targeting-as-a-strategy-to-boost-chemotherapy-efficacy-in-non-small-cell-lung-cancer-through-metabolism-suppression
#2
Marion Le Grand, Raphael Berges, Eddy Pasquier, Marie-Pierre Montero, Laurence Borge, Alice Carrier, Sophie Vasseur, Veronique Bourgarel, Duje Buric, Nicolas André, Diane Braguer, Manon Carré
Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332488/parkinson-disease
#3
REVIEW
Werner Poewe, Klaus Seppi, Caroline M Tanner, Glenda M Halliday, Patrik Brundin, Jens Volkmann, Anette-Eleonore Schrag, Anthony E Lang
Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability...
March 23, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28330852/a-controlled-release-mitochondrial-protonophore-reverses-hypertriglyceridemia-nonalcoholic-steatohepatitis-and-diabetes-in-lipodystrophic-mice
#4
Abudukadier Abulizi, Rachel J Perry, João Paulo G Camporez, Michael J Jurczak, Kitt Falk Petersen, Patricia Aspichueta, Gerald I Shulman
Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled-release mitochondrial protonophore (CRMP) that produces mild liver-targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F-1 mice) of severe lipodystrophy and diabetes...
March 22, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28330689/evaluation-of-methohexital-as-an-alternative-to-propofol-in-a-high-volume-outpatient-pediatric-sedation-service
#5
Nicholas E Jones, Michael S Kelleman, Harold K Simon, Jana A Stockwell, Courtney McCracken, Michael D Mallory, Pradip P Kamat
BACKGROUND: Propofol is a preferred agent for many pediatric sedation providers because of its rapid onset and short duration of action. It allows for quick turn around times and enhanced throughput. Occasionally, intravenous (IV) methohexital (MHX), an ultra-short acting barbiturate is utilized instead of propofol. OBJECTIVE: Describe the experience with MHX in a primarily propofol driven outpatient sedation program and to see if it serves as an acceptable alternative when propofol is not the preferred pharmacologic option...
March 8, 2017: American Journal of Emergency Medicine
https://www.readbyqxmd.com/read/28329063/lysosomal-proteolysis-is-associated-with-exercise-induced-improvement-of-mitochondrial-quality-control-in-aged-hippocampus
#6
Li Luo, Jia-Ru Dai, Shan-Shan Guo, A-Ming Lu, Xiao-Fang Gao, Yan-Rong Gu, Xiao-Fei Zhang, Hai-Dong Xu, Yan Wang, Zhou Zhu, Lisa J Wood, Zheng-Hong Qin
Exercise improves cognitive function in older adults, but the underlying mechanism is largely unknown. Both lysosomal degradation and mitochondrial quality control decline with age. We hypothesized that exercise ameliorates age-related cognitive decline through the improvement of mitochondrial quality control in aged hippocampus, and this effect is associated with lysosomal proteolysis. Sixteen to eighteen-month old male Sprague Dawley rats underwent swim exercise training for 10 weeks. The exercise regimen prevented cognitive decline in aged rats, reduced oxidative stress, and rejuvenated mitochondria in the aged hippocampus...
January 19, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/28322600/renal-mitochondrial-response-to-low-temperature-in-non-hibernating-and-hibernating-species
#7
George J Dugbartey, Maarten C Hardenberg, Wendelinde F Kok, Ate Boerema, Hannah V Carey, James Staples, Robert H Henning, Hjalmar Bouma
SIGNIFICANCE: Therapeutic hypothermia is commonly applied to limit ischemic injury in organ transplantation, during cardiac and brain surgery and after cardiopulmonary resuscitation. In these procedures, the kidneys are particularly at risk for ischemia/reperfusion injury (IRI), likely due to their high rate of metabolism. Although hypothermia mitigates ischemic kidney injury, it is not a panacea. Residual mitochondrial failure is thought to be a key event triggering loss of cellular homeostasis, and potentially cell death...
March 21, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28320189/tempol-4-hydroxy-tempo-inhibits-anoxia-induced-progression-of-mitochondrial-dysfunction-and-associated-neurobehavioral-impairment-in-neonatal-rats
#8
Puneet K Samaiya, Gopeshwar Narayan, Ashok Kumar, Sairam Krishnamurthy
BACKGROUND: Anoxia leads to a robust generation of reactive oxygen species/nitrogen species which can result in mitochondrial dysfunction and associated cell death in the cerebral cortex of neonates. AIM: The present study investigated the pharmacological role of tempol in the treatment of rat neonatal cortical mitochondrial dysfunction induced insult progression (day-1 to day-7) and associated neurobehavioral alterations post-anoxia. METHODS: Rat pups of 30h age or postnatal day 2 (PND2) were randomly divided into 5 groups (n=5 per group): (1) Control; (2) Anoxia; (3) Anoxia+Tempol 75mg/kg; (4) Anoxia+Tempol 150mg/kg; and (5) Anoxia+Tempol 300mg/kg, and subjected to two episode of anoxia (10min each) at 24h of time interval in an enclosed chamber supplied with 100% N2...
April 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28320040/mitochondria-as-a-target-for-the-cardioprotective-effects-of-cydonia-oblonga-mill-and-ficus-carica-l-in-doxorubicin-induced-cardiotoxicity
#9
Saman Gholami, Mir-Jamal Hosseini, Leila Jafari, Fatemeh Omidvar, Mohammad Kamalinejad, Vida Mashayekhi, Seyed Hojjat Hosseini, Azin Kardan, Jalal Pourahmad, Mohammad Reza Eskandari
Quince (Cydonia oblonga Mill.) and fig (Ficus carica L.) exhibit a broad spectrum of pharmacological activities. Regarding the cardiotoxic effect of doxorubicin (DOX) is mediated mainly through mitochondrial oxidative stress and dysfunction; the present study evaluated the cardioprotective effects of the aqueous extracts of Cydonia oblonga Mill. fruit (ACO) and Ficus carica L. fruit (AFC) against DOX-induced cardiotoxicity. Cardiomyocytes toxicity was induced in male Sprague Dawley rats by intraperitoneal (ip) injections of 2...
March 20, 2017: Drug Research
https://www.readbyqxmd.com/read/28317242/chemical-screening-identifies-rock-as-a-target-for-recovering-mitochondrial-function-in-hutchinson-gilford-progeria-syndrome
#10
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Hyo Jei Claudia Choi, Chul Won Jung, Gyu Ree Kim, Young-Sam Lee, Sang Chul Park
Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent...
March 19, 2017: Aging Cell
https://www.readbyqxmd.com/read/28315274/role-of-%C3%AF-1-receptors-in-learning-and-memory-and-alzheimer-s-disease-type-dementia
#11
Tangui Maurice, Nino Goguadze
The present chapter will review the role of σ1 receptor in learning and memory and neuroprotection , against Alzheimer's type dementia. σ1 Receptor agonists have been tested in a variety of pharmacological and pathological models of learning impairments in rodents these last past 20 years. Their anti-amnesic effects have been explained by the wide-range modulatory role of σ1 receptors on Ca(2+) mobilizations, neurotransmitter responses, and particularly glutamate and acetylcholine systems, and neurotrophic factors...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28314479/new-insights-into-the-effects-and-mechanism-of-a-classic-traditional-chinese-medicinal-formula-on-influenza-prevention
#12
Huan Chen, Chong Jie, Lu-Ping Tang, He Meng, Xiao-Bo Li, Yan-Bing Li, Le-Xing Chen, Chang Yan, Hiroshi Kurihara, Yi-Fang Li, Rong-Rong He
BACKGROUND: KangBingDu (KBD) is a classic traditional Chinese medicinal formula widely used to treat influenza. However, little information is available from controlled studies regarding the anti-influenza pharmacological activities of KBD and its underlying mechanisms, at least partly due to the lack of appropriate study models. PURPOSE: We hypothesized that KBD might provide a protection against influenza infection by reducing the host's susceptibility to viruses...
April 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28298952/insights-for-oxidative-stress-and-mtor-signaling-in-myocardial-ischemia-reperfusion-injury-under-diabetes
#13
REVIEW
Dajun Zhao, Jian Yang, Lifang Yang
Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28292968/micu1-alleviates-diabetic-cardiomyopathy-through-mitochondrial-ca-2-dependent-antioxidant-response
#14
Lele Ji, Fengzhou Liu, Zhe Jing, Qichao Huang, Ya Zhao, Haiyan Cao, Jun Li, Chun Yin, Jinliang Xing, Fei Li
Diabetic cardiomyopathy is a major cause of mortality in diabetic patients, but specific strategies for prevention or treatment of diabetic cardiomyopathy have not been clarified yet. MICU1 is a key regulator of mitochondria Ca(2+) uptake, which plays important roles in regulating mitochondrial oxidative phosphorylation and redox balance. However, to date, the significance of MICU1 in diabetic hearts has never been investigated. Here, we demonstrated that MICU1 was downregulated in db/db mouse heart, which contributes to myocardial apoptosis in diabetes...
March 14, 2017: Diabetes
https://www.readbyqxmd.com/read/28290602/ajs1669-a-novel-small-molecule-muscle-glycogen-synthase-activator-improves-glucose-metabolism-and-reduces-body-fat-mass-in-mice
#15
Kazuhiro Nakano, Sen Takeshita, Noriko Kawasaki, Wataru Miyanaga, Yoriko Okamatsu, Mizuki Dohi, Tadakiyo Nakagawa
Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl)phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P)...
March 7, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28286181/amplifying-mitochondrial-function-rescues-adult-neurogenesis-in-a-mouse-model-of-alzheimer-s-disease
#16
Kevin Richetin, Manon Moulis, Aurélie Millet, Macarena S Arràzola, Trinovita Andraini, Jennifer Hua, Noélie Davezac, Laurent Roybon, Pascale Belenguer, Marie-Christine Miquel, Claire Rampon
Adult hippocampal neurogenesis is strongly impaired in Alzheimer's disease (AD). In several mouse models of AD, it was shown that adult-born neurons exhibit reduced survival and altered synaptic integration due to a severe lack of dendritic spines. In the present work, using the APPxPS1 mouse model of AD, we reveal that this reduced number of spines is concomitant of a marked deficit in their neuronal mitochondrial content. Remarkably, we show that targeting the overexpression of the pro-neural transcription factor Neurod1 into APPxPS1 adult-born neurons restores not only their dendritic spine density, but also their mitochondrial content and the proportion of spines associated with mitochondria...
March 10, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28283884/resveratrol-and-brain-mitochondria-a-review
#17
REVIEW
Fernanda Rafaela Jardim, Fernando Tonon de Rossi, Marielle Xavier Nascimento, Renata Gabriele da Silva Barros, Paula Agrizzi Borges, Isabella Cristina Prescilio, Marcos Roberto de Oliveira
Resveratrol (3,4',5-trihydroxystilbene; C14H12O3) is a polyphenolic phytoalexin found in grapes, berries, peanuts, and wines. Resveratrol has been viewed as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent. Moreover, it has been reported that resveratrol modulates mitochondrial function, redox biology, and dynamics in both in vitro and in vivo experimental models. Resveratrol also attenuates mitochondrial impairment induced by certain stressors. Resveratrol upregulates, for example, mitochondria-located antioxidant enzymes, decreasing the production of reactive species by these organelles...
March 10, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28282614/inhibition-of-drp1-protects-against-senecionine-induced-mitochondria-mediated-apoptosis-in-primary-hepatocytes-and-in-mice
#18
Xiao Yang, Hua Wang, Hong-Min Ni, Aizhen Xiong, Zhengtao Wang, Hiromi Sesaki, Wen-Xing Ding, Li Yang
Pyrrolizidine alkaloids (PAs) are a group of compounds found in various plants and some of them are widely consumed in the world as herbal medicines and food supplements. PAs are potent hepatotoxins that cause irreversible liver injury in animals and humans. However, the mechanisms by which PAs induce liver injury are not clear. In the present study, we determined the hepatotoxicity and molecular mechanisms of senecionine, one of the most common toxic PAs, in primary cultured mouse and human hepatocytes as well as in mice...
March 2, 2017: Redox Biology
https://www.readbyqxmd.com/read/28282037/sk2-channels-regulate-mitochondrial-respiration-and-mitochondrial-ca-2-uptake
#19
Birgit Honrath, Lina Matschke, Tammo Meyer, Lena Magerhans, Fabiana Perocchi, Goutham K Ganjam, Hans Zischka, Cornelius Krasel, Albert Gerding, Barbara M Bakker, Moritz Bünemann, Stefan Strack, Niels Decher, Carsten Culmsee, Amalia M Dolga
Mitochondrial calcium ([Ca(2+)]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca(2+)]m uptake upon SK channel activation as detected by time lapse mitochondrial Ca(2+) measurements with the Ca(2+)-binding mitochondria-targeted aequorin and FRET-based [Ca(2+)]m probes...
March 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28281653/nix-restores-mitophagy-and-mitochondrial-function-to-protect-against-pink1-parkin-related-parkinson-s-disease
#20
Brianada Koentjoro, Jin-Sung Park, Carolyn M Sue
Therapeutic targets are needed to develop neuroprotective treatments for Parkinson's disease (PD). Mitophagy, the selective autophagic elimination of dysfunctional mitochondria, is essential for the maintenance of mitochondrial integrity and is predominantly regulated by the PINK1/Parkin-mediated pathway. Loss of function mutations in Parkin and PINK1 cause an accumulation of dysfunctional mitochondria, leading to nigral neurodegeneration and early-onset PD with a high penetrance rate. We previously identified an asymptomatic homozygous Parkin mutation carrier who had not developed PD by her eighth decade despite the loss of functional Parkin...
March 10, 2017: Scientific Reports
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