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Mitochondrial pharmacology

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https://www.readbyqxmd.com/read/28812237/pharmacological-effects-on-ceroid-lipofuscin-and-neuronal-structure-in-cln3-%C3%A2-ex7-8-mouse-brain-cultures
#1
Douglas E Brenneman, David A Pearce, Attila Kovacs, Shawn DeFrees
Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3 (∆ex7/8) ) has been explored. Dissociated brain cultures from Cln3 (∆ex7/8) knock-in mice were compared to wild type (WT) for effects on granules of ceroid lipofuscin (CL) and neuronal structure. Utilizing high content image analysis of CL granules identified with antibodies to mitochondrial ATP synthase subunit c or tripeptidyl peptidase-1, significant increases in the areas for both immunoreactive granules were observed in Cln3 (∆ex7/8) cultures in comparison to WT...
August 15, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28807815/bcl-xl-knockout-attenuates-mitochondrial-respiration-and-causes-oxidative-stress-that-is-compensated-by-pentose-phosphate-pathway-activity
#2
Annika Pfeiffer, Julia Schneider, Diones Bueno, Amalia Dolga, Timo-Daniel Voss, Jan Lewerenz, Verena Wüllner, Axel Methner
Bcl-xL is an anti-apoptotic protein that localizes to the outer mitochondrial membrane and influences mitochondrial bioenergetics by controlling Ca(2+) influx into mitochondria. Here, we analyzed the effect of mitochondrial Bcl-xL on mitochondrial shape and function in knockout (KO), wildtype and rescued mouse embryonic fibroblast cell lines. Mitochondria of KO cells were more fragmented, exhibited a reduced ATP concentration, and reduced oxidative phosphorylation (OXPHOS) suggesting an increased importance of ATP generation by other means...
August 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28799509/update-on-pharmacological-treatment-of-progressive-myoclonus-epilepsies
#3
Edoardo Ferlazzo, Dorothee Kasteleijn-Nolst Trenite, Gerrit-Jan de Haan, Felix Felix Nitschke, Saija Ahonen, Sara Gasparini, Berge A Minassian
BACKGROUND: Progressive myoclonus epilepsies (PMEs) are a group of rare inherited diseases featuring a combination of myoclonus, seizures and variable degree of cognitive impairment. Despite extensive investigations, a large number of PMEs remain undiagnosed. In this review, we focus on the current pharmacological approach to PMEs. METHODS: References were mainly identified through PubMed search until February 2017 and backtracking of references in pertinent studies...
August 9, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28798154/a-novel-synthetic-analogue-of-%C3%AF-3-17-18-epoxy-eicosatetraenoic-acid-activates-tnf-receptor-1-ask1-jnk-signaling-to-promote-apoptosis-in-human-breast-cancer-cells
#4
Herryawan Ryadi Eziwar Dyari, Tristan Rawling, Yongjuan Chen, William Sudarmana, Kirsi Bourget, Julie M Dwyer, Sarah E Allison, Michael Murray
A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1)...
August 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28796779/dose-and-timing-of-injections-for-effective-cyclosporine-a-pretreatment-before-renal-ischemia-reperfusion-in-mice
#5
Sandrine Lemoine, Bruno Pillot, Lionel Augeul, Maud Rabeyrin, Annie Varennes, Gabrielle Normand, Delphine Baetz, Michel Ovize, Laurent Juillard
BACKGROUND: There is experimental evidence that lethal ischemia-reperfusion injury (IRI) is largely due to mitochondrial permeability transition pore (mPTP) opening, which can be prevented by cyclosporine A (CsA). The aim of our study is to show that a higher dose of CsA (10 mg/kg) injected just before ischemia or a lower dose of CsA (3 mg/kg) injected further in advance of ischemia (1 h) protects the kidneys and improves mitochondrial function. METHODS: All mice underwent a right unilateral nephrectomy followed by 30 min clamping of the left renal artery...
2017: PloS One
https://www.readbyqxmd.com/read/28791889/symbiotic-origin-of-aging
#6
Edward Greenberg, Sergei Vatolin
Normally aging cells are characterized by an unbalanced mitochondrial dynamic skewed toward punctate mitochondria. Genetic and pharmacological manipulation of mitochondrial fission/fusion cycles can contribute to both accelerated and decelerated cellular or organismal aging. In this work, we connect these experimental data with the symbiotic theory of mitochondrial origin to generate new insight into the evolutionary origin of aging. Mitochondria originated from autotrophic α-proteobacteria during an ancient endosymbiotic event early in eukaryote evolution...
August 9, 2017: Rejuvenation Research
https://www.readbyqxmd.com/read/28790886/molecular-bases-of-brain-preconditioning
#7
Oleg G Deryagin, Svetlana A Gavrilova, Khalil L Gainutdinov, Anna V Golubeva, Vyatcheslav V Andrianov, Guzel G Yafarova, Sergey V Buravkov, Vladimir B Koshelev
Preconditioning of the brain induces tolerance to the damaging effects of ischemia and prevents cell death in ischemic penumbra. The development of this phenomenon is mediated by mitochondrial adenosine triphosphate-sensitive potassium ([Formula: see text]) channels and nitric oxide signaling (NO). The aim of this study was to investigate the dynamics of molecular changes in mitochondria after ischemic preconditioning (IP) and the effect of pharmacological preconditioning (PhP) with the [Formula: see text]-channels opener diazoxide on NO levels after ischemic stroke in rats...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28783712/machine-learning-for-predicting-lifespan-extending-chemical-compounds
#8
Diogo G Barardo, Danielle Newby, Daniel Thornton, Taravat Ghafourian, João Pedro de Magalhães, Alex A Freitas
Increasing age is a risk factor for many diseases; therefore developing pharmacological interventions that slow down ageing and consequently postpone the onset of many age-related diseases is highly desirable. In this work we analyse data from the DrugAge database, which contains chemical compounds and their effect on the lifespan of model organisms. Predictive models were built using the machine learning method random forests to predict whether or not a chemical compound will increase Caenorhabditis elegans' lifespan, using as features Gene Ontology (GO) terms annotated for proteins targeted by the compounds and chemical descriptors calculated from each compound's chemical structure...
July 18, 2017: Aging
https://www.readbyqxmd.com/read/28782414/protective-effect-of-neuropeptide-apelin-13-on-6-hydroxydopamine-induced-neurotoxicity-in-sh-sy5y-dopaminergic-cells-involvement-of-its-antioxidant-and-antiapoptotic-properties
#9
Elham Pooresmaeili-Babaki, Saeed Esmaeili-Mahani, Mehdi Abbasnejad, Hadi Ravan
Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the loss of brain dopaminergic neurons. Beside pharmacologic and symptomatic treatment of PD the neuroprotective therapy has recently attracted more attention. Apelin, a novel neuropeptide, and its receptors have numerous reported roles in regulating brain functions. In addition, this peptide has potent neuroprotective effects in some neurodegenerative situations. Here, the effects of apelin-13 were investigated in a cell model of PD...
August 7, 2017: Rejuvenation Research
https://www.readbyqxmd.com/read/28777375/inhibition-of-bcl-xl-prevents-pro-death-actions-of-%C3%AE-n-bcl-xl-at-the-mitochondrial-inner-membrane-during-glutamate-excitotoxicity
#10
Han-A Park, Pawel Licznerski, Nelli Mnatsakanyan, Yulong Niu, Silvio Sacchetti, Jing Wu, Brian M Polster, Kambiz N Alavian, Elizabeth A Jonas
ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ΔN-Bcl-xL. We now report that a high concentration of ABT-737 (1 μM), or a more selective Bcl-xL inhibitor WEHI-539 (5 μM) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10 nM) or WEHI-539 (10 nM) is neuroprotective...
August 4, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28777255/endogenous-and-agonist-induced-opening-of-mitochondrial-big-vs-small-ca2-sensitive-k-channels-on-cardiac-cell-and-mitochondrial-protection
#11
David F Stowe, Meiying Yang, James S Heisner, Amadou K S Camara
Both big (BKCa) and small (SKCa) conductance Ca-sensitive K channels are present in mammalian cardiac cell mitochondria (m). We used pharmacological agonists and antagonists of BKCa and SKCa channels to examine the importance of endogenous opening of these channels and the relative contribution of either or both of these channels to protect against contractile dysfunction and reduce infarct size after ischemia reperfusion (IR) injury through a mitochondrial protective mechanism. Following global cardiac IR injury of ex vivo perfused guinea pig hearts we found the following: both agonists NS1619 (for BKCa) and DCEB (for SKCa) improved contractility; BKCa antagonist paxilline (PAX) alone or with SKCa antagonist NS8593 worsened contractility and enhanced infarct size; both antagonists PAX and NS8593 obliterated protection by their respective agonists; BKCa and SKCa antagonists did not block protection afforded by SKCa and BKCa agonists, respectively; and all protective effects by the agonists were blocked by scavenging superoxide anions (O2) with TBAP...
August 4, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28771714/multifunctional-curcumin-mediate-multitherapeutic-effects
#12
Adeeb Shehzad, Munibah Qureshi, Muhammad Nabeel Anwar, Young Sup Lee
Inflammation can promote the development of arthritis, obesity, cardiovascular, type II diabetes, pancreatitis, metabolic and neurodegenerative diseases, and certain types of cancer. Compounds isolated from plants have been practiced since ancient times for curing various ailments including inflammatory disorders and to support normal physiological functions. Curcumin (diferuloylmethane) is a yellow coloring agent, extracted from turmeric that has been used for the prevention and treatment of various inflammatory diseases...
August 3, 2017: Journal of Food Science
https://www.readbyqxmd.com/read/28765878/grifola-frondosa-polysaccharides-induce-breast-cancer-cell-apoptosis-via-the-mitochondrial-dependent-apoptotic-pathway
#13
Yizhi Zhang, Dejun Sun, Qingjin Meng, Wanxu Guo, Qiuhui Chen, Ying Zhang
Grifola frondosa, a type of food and medical fungus, has been shown to exhibit various pharmacological activities, including anticancer effects. As the most typical cancer diagnosed among female patients, breast cancer remains a huge concern threatening human health globally. In the present study, the anti-breast cancer effects of Grifola frondosa polysaccharides (GFPs) and the underlying mechanisms were investigated in MCF-7 and MDA-MB-231 cells, as well as in nude mice bearing MCF-7 tumor xenografts. GFPs exerted cytotoxic effects on the cells, as indicated by a decrease in cell viability, and an increase in the apoptototic rate, lactate dehydrogenase release and reactive oxygen species accumulation, inducing mitochondrial dysfunction...
July 26, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28760703/berberine-induced-cardioprotection-and-sirt3-modulation-in-doxorubicin-treated-h9c2-cardiomyoblasts
#14
Ana R Coelho, Tatiana R Martins, Renata Couto, Cláudia Deus, Cláudia V Pereira, Rui F Simões, Albert A Rizvanov, Filomena Silva, Teresa Cunha-Oliveira, Paulo J Oliveira, Teresa L Serafim
Doxorubicin (DOX) is one of the most widely used anti-neoplastic agents. However, treatment with DOX is associated with cumulative cardiotoxicity inducing progressive cardiomyocyte death. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates the activity of proteins involved in apoptosis, autophagy and metabolism. Our hypothesis is that pharmacological modulation by berberine (BER) pre-conditioning of Sirt3 protein levels decreases DOX-induced cardiotoxicity. Our results showed that DOX induces cell death in all experimental groups...
July 28, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28754950/development-of-hydroxybenzoic-based-platforms-as-a-solution-to-deliver-dietary-antioxidants-to-mitochondria
#15
José Teixeira, Catarina Oliveira, Ricardo Amorim, Fernando Cagide, Jorge Garrido, José A Ribeiro, Carlos M Pereira, António F Silva, Paula B Andrade, Paulo J Oliveira, Fernanda Borges
Oxidative stress and mitochondrial dysfunction have been associated with metabolic and age-related diseases. Thus, the prevention of mitochondrial oxidative damage is nowadays a recognized pharmacological strategy to delay disease progression. Epidemiological studies suggested an association between the consumption of polyphenol-rich diet and the prevention of different pathologies, including diseases with a mitochondrial etiology. The development of mitochondrial-targeted antioxidants based on dietary antioxidants may decrease mitochondrial oxidative damage...
July 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28754352/3-iodothyronamine-reduces-insulin-secretion-in-vitro-via-a-mitochondrial-mechanism
#16
Ina Lehmphul, Carolin S Hoefig, Josef Köhrle
PURPOSE: 3-iodothyronamine (3-T1AM), a decarboxylated and deiodinated thyroid hormone metabolite, leads at pharmacological doses to hypoinsulinemia, hyperglucagonemia and hyperglycemia in vivo. As the pancreatic Langerhans islets express thyroid hormone transmembrane transporters (THTT), we tested the hypothesis that not only plasma membrane-mediated 3-T1AM binding to and activation of G-protein coupled receptors, but also 3-T1AM metabolite(s) generated by 3-T1AM uptake and metabolism might decrease glucose-stimulated insulin secretion (GSIS)...
July 25, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28753972/food-derived-antioxidant-polysaccharides-and-their-pharmacological-potential-in-neurodegenerative-diseases
#17
REVIEW
Haifeng Li, Fei Ding, Lingyun Xiao, Ruona Shi, Hongyu Wang, Wenjing Han, Zebo Huang
Oxidative stress is known to impair architecture and function of cells, which may lead to various chronic diseases, and therefore therapeutic and nutritional interventions to reduce oxidative damages represent a viable strategy in the amelioration of oxidative stress-related disorders, including neurodegenerative diseases. Over the past decade, a variety of natural polysaccharides from functional and medicinal foods have attracted great interest due to their antioxidant functions such as scavenging free radicals and reducing oxidative damages...
July 19, 2017: Nutrients
https://www.readbyqxmd.com/read/28744974/obestatin-regulates-cardiovascular-function-and-promotes-cardioprotection-through-the-nitric-oxide-pathway
#18
Claudia Penna, Francesca Tullio, Saveria Femminò, Carmine Rocca, Tommaso Angelone, Maria C Cerra, Maria Pia Gallo, Iacopo Gesmundo, Alessandro Fanciulli, Maria Felice Brizzi, Pasquale Pagliaro, Giuseppe Alloatti, Riccarda Granata
Patients with ischaemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown...
July 26, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28744811/evidence-of-vanillin-binding-to-camkiv-explains-the-anti-cancer-mechanism-in-human-hepatic-carcinoma-and-neuroblastoma-cells
#19
Huma Naz, Mohd Tarique, Parvez Khan, Suaib Luqman, Shahzaib Ahamad, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Human calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a member of Ser/Thr kinase family, and is associated with different types of cancer and neurodegenerative diseases. Vanillin is a natural compound, a primary component of the extract of the vanilla bean which possesses varieties of pharmacological features including anti-oxidant, anti-inflammatory, anti-bacterial and anti-tumor. Here, we have investigated the binding mechanism and affinity of vanillin to the CAMKIV which is being considered as a potential drug target for cancer and neurodegenerative diseases...
July 25, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28739801/sustained-o-glcnacylation-reprograms-mitochondrial-function-to-regulate-energy-metabolism
#20
Ee Phie Tan, Steven R McGreal, Stefan Graw, Robert Tessman, Scott J Koppel, Pramod Dhakal, Zhen Zhang, Miranda Machacek, Natasha E Zachara, Devin C Koestler, Kenneth R Peterson, John P Thyfault, Russell H Swerdlow, Partha Krishnamurthy, Luciano DiTacchio, Udayan Apte, Chad Slawson
Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with β-linked N-acetylglucosamine (O-GlcNAcylation) via overexpression of the O-GlcNAc regulating enzymes O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in O-GlcNAcylation either by pharmacological or genetic manipulation also alters metabolic function...
July 24, 2017: Journal of Biological Chemistry
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