Stem Cell Research Blog, 20 Aug 2009
WASHINGTON - Researchers at Tel Aviv University have offered new hope for people with incurable neurodegenerative diseases like Huntington’s, Alzheimer’s, and Parkinson’s by showing that the viability of stem cells created from a patient’s own bone marrow can be determined using MRI tracking methods.
Sunday, August 30, 2009
Saturday, August 29, 2009
The role of iron in mitochondrial function.
Biochim Biophys Acta. 2009 Jul;1790(7):629-36. Epub 2008 Oct 7.
Levi S, Rovida E.Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milano, Italy. levi.sonia@hsr.it
Levi S, Rovida E.Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milano, Italy. levi.sonia@hsr.it
Tuesday, August 25, 2009
Limitations in a frataxin knockdown cell model for Friedreich ataxia in a high-throughput drug screen
OPEN ACCESS
Nadege Calmels , Herve Seznec , Pascal Villa , Laurence Reutenauer , Marcel Hibert , Jacques Haiech , Pierre Rustin , Michel Koenig and Helene Puccio
BMC Neurology 2009, 9:46doi:10.1186/1471-2377-9-46
Published:
24 August 2009
Abstract (provisional)
Pharmacological high-throughput screening (HTS) represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA). FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC) proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay.
Methods
Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA.
Results
The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model.
Conclusions
Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive HTS in the future.
FULL TEXT: http://www.biomedcentral.com/content/pdf/1471-2377-9-46.pdf
Nadege Calmels , Herve Seznec , Pascal Villa , Laurence Reutenauer , Marcel Hibert , Jacques Haiech , Pierre Rustin , Michel Koenig and Helene Puccio
BMC Neurology 2009, 9:46doi:10.1186/1471-2377-9-46
Published:
24 August 2009
Abstract (provisional)
Pharmacological high-throughput screening (HTS) represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA). FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC) proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay.
Methods
Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA.
Results
The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model.
Conclusions
Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive HTS in the future.
FULL TEXT: http://www.biomedcentral.com/content/pdf/1471-2377-9-46.pdf
M.P.1.02 SNT-MC17/idebenone in the treatment of Friedreich’s ataxia: Preliminary safety data from a 12-month European randomized, placebo-controlled s
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T9T-4WWHRS8-F&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=0027bdaeef768126216c15a42f58f113
M.P.1.02 SNT-MC17/idebenone in the treatment of Friedreich’s ataxia: Preliminary safety data from a 12-month European randomized, placebo-controlled study
J.B. Schulz1, T. Meier2 and G.L. Holder2
1University Medical Center, RWTH Aachen, Department of Neurology, Aachen, Germany
2Santhera Pharmaceuticals (Switzerland) Ltd., Liestal, Switzerland
M.P.1.02 SNT-MC17/idebenone in the treatment of Friedreich’s ataxia: Preliminary safety data from a 12-month European randomized, placebo-controlled study
J.B. Schulz1, T. Meier2 and G.L. Holder2
1University Medical Center, RWTH Aachen, Department of Neurology, Aachen, Germany
2Santhera Pharmaceuticals (Switzerland) Ltd., Liestal, Switzerland
Saturday, August 15, 2009
Frataxin deficiency induces schwann cell inflammation and death.
Biochim Biophys Acta. 2009 Aug 10
Lu C, Schoenfeld R, Shan Y, Tsai C, Hammock B, Cortopassi G.
Department of Molecular Biosciences, University of California, Davis, California, 95616.
Lu C, Schoenfeld R, Shan Y, Tsai C, Hammock B, Cortopassi G.
Department of Molecular Biosciences, University of California, Davis, California, 95616.
The Interaction of Mitochondrial Iron with Manganese Superoxide Dismutase*
J. Biol. Chem., Vol. 284, Issue 34, 22633-22640, August 21, 2009
Amornrat Naranuntarat
1 , Laran T. Jensen , Samuel Pazicni
, James E. Penner-Hahn , and Valeria C. Culotta2
12 From the From the
Keywords: Superoxide dismutase 2 (SOD2), mitochondrial enzymes, manganese, iron, iron-sulfur cluster biogenesis, Isu proteins.
Related Topic:
"Manganese Is the Link between Frataxin and Iron-Sulfur Deficiency in the Yeast Model of Friedreich Ataxia",
Verónica Irazusta, Elisa Cabiscol, Gemma Reverter-Branchat, ,Joaquim Ros2 , and Jordi Tamarit
"Manganese Is the Link between Frataxin and Iron-Sulfur Deficiency in the Yeast Model of Friedreich Ataxia",
Verónica Irazusta, Elisa Cabiscol, Gemma Reverter-Branchat, ,
From the Grup de Bioquímica de l'Estrés Oxidatiu, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, 25008 Lleida, Spai.
J. Biol. Chem., Vol. 281, Issue 18, 12227-12232, May 5, 2006Thursday, August 13, 2009
FDA Clarifies Access to Investigational Drugs
By Cole Petrochko, Staff Writer, MedPage Today
Published: August 13, 2009
WASHINGTON -- The FDA has issued two final rules expanding access to investigational drugs for seriously ill patients who have no alternatives and regulating drug developers' charges for those medicines.
Published: August 13, 2009
WASHINGTON -- The FDA has issued two final rules expanding access to investigational drugs for seriously ill patients who have no alternatives and regulating drug developers' charges for those medicines.
Wednesday, August 12, 2009
Mitochondrial Dysfunction Leads to Nuclear Genome Instability via an Iron-Sulfur Cluster Defect
Comment: Although in the FA we have not problems with the mtDNA, the genetic information of frataxin is in nDNA, this is a very interesting article.
Cell, Volume 137, Issue 7, 26 June 2009, Pages 1247-1258
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10D8-J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=978708264&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8d80ad217bf0eefe71a1bba6364c95a
Joshua R. Veatch1, 2, Michael A. McMurray1, 2, 3, Zara W. Nelson1 and Daniel E. Gottschling1, ,
1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA
2The Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA
3Present address: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA
Keywords: mitochondrial genome (mtDNA), inestability of the nuclear genome, defect in iron-sulfur cluster (ISC) biogenesis, ISC protein biogenesis.
Cell, Volume 137, Issue 7, 26 June 2009, Pages 1247-1258
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4WM10D8-J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=978708264&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8d80ad217bf0eefe71a1bba6364c95a
Joshua R. Veatch1, 2, Michael A. McMurray1, 2, 3, Zara W. Nelson1 and Daniel E. Gottschling1, ,
1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA
2The Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA
3Present address: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA
Keywords: mitochondrial genome (mtDNA), inestability of the nuclear genome, defect in iron-sulfur cluster (ISC) biogenesis, ISC protein biogenesis.
Saturday, August 8, 2009
Cardiac involvement in Friedreich's ataxia: our experience.
Minerva Cardioangiol. 2009 Apr;57(2):269-70.
Not abstrac
Fazio G., Vitello D., D’Angelo L., Visconti C., Trapani R., Fabiano A., Di Gesaro G., Novo G., Novo S.
Not abstrac
Friday, August 7, 2009
Nitrative and Oxidative Stress in Toxicology and Disease
OPEN ACCESS
ToxSci Advance Access published online on August 5, 2009 Toxicological Sciences, doi:10.1093/toxsci/kfp179
Ruth A. Roberts1, Debra L. Laskin2, Charles V. Smith3, Fredika M. Robertson4, Erin M.G. Allen5, Jonathan A. Doorn5 and William Slikker6
1 AstraZeneca R&D Safety Assessment, Alderley Park, UK 2 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 3 Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 4 Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 5 College of Pharmacy, University of Iowa, Iowa City, IA 6 NCTR, USFDA, Jefferson, AR
ruth.roberts@astrazeneca.com
Received June 15, 2009; revision received July 22, 2009; accepted July 24, 2009
Abstract
Persistent inflammation and the generation of reactive oxygen and nitrogen species play pivotal roles in tissue injury during disease pathogenesis and as a reaction to toxicant exposures. The associated oxidative and nitrative stress promote diverse pathologic reactions including neurodegenerative disorders, atherosclerosis, chronic inflammation, cancer, and premature labor and stillbirth. These effects occur via sustained inflammation, cellular proliferation and cytotoxicity and via induction of a proangiogenic environment. For example, exposure to the ubiquitous air pollutant ozone leads to generation of reactive oxygen and nitrogen species in lung macrophages that play a key role in subsequent tissue damage. Similarly, studies indicate that genes involved in regulating oxidative stress are altered by anesthetic treatment resulting in brain injury, most notable during development. In addition to a role in tissue injury in the brain, inflammation and oxidative stress are implicated in Parkinson's disease, a neurodegenerative disease characterized by the loss of dopamine neurons. Recent data suggest a mechanistic link between oxidative stress and elevated levels of DOPAL, a neurotoxin endogenous to dopamine neurons. These findings have significant implications for development of therapeutics and identification of novel biomarkers for PD pathogenesis. Oxidative and nitrative stress is also thought to play a role in creating the pro-inflammatory microenvironment associated with the aggressive phenotype of inflammatory breast cancer. An understanding of fundamental concepts of oxidative and nitrative stress can underpin a rational plan of treatment for diseases and toxicities associated with excessive production of reactive oxygen and nitrogen species.
© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgThe online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.
Full text: http://toxsci.oxfordjournals.org/cgi/reprint/kfp179v1
ToxSci Advance Access published online on August 5, 2009 Toxicological Sciences, doi:10.1093/toxsci/kfp179
Ruth A. Roberts1, Debra L. Laskin2, Charles V. Smith3, Fredika M. Robertson4, Erin M.G. Allen5, Jonathan A. Doorn5 and William Slikker6
1 AstraZeneca R&D Safety Assessment, Alderley Park, UK 2 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 3 Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 4 Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 5 College of Pharmacy, University of Iowa, Iowa City, IA 6 NCTR, USFDA, Jefferson, AR
ruth.roberts@astrazeneca.com
Received June 15, 2009; revision received July 22, 2009; accepted July 24, 2009
Abstract
Persistent inflammation and the generation of reactive oxygen and nitrogen species play pivotal roles in tissue injury during disease pathogenesis and as a reaction to toxicant exposures. The associated oxidative and nitrative stress promote diverse pathologic reactions including neurodegenerative disorders, atherosclerosis, chronic inflammation, cancer, and premature labor and stillbirth. These effects occur via sustained inflammation, cellular proliferation and cytotoxicity and via induction of a proangiogenic environment. For example, exposure to the ubiquitous air pollutant ozone leads to generation of reactive oxygen and nitrogen species in lung macrophages that play a key role in subsequent tissue damage. Similarly, studies indicate that genes involved in regulating oxidative stress are altered by anesthetic treatment resulting in brain injury, most notable during development. In addition to a role in tissue injury in the brain, inflammation and oxidative stress are implicated in Parkinson's disease, a neurodegenerative disease characterized by the loss of dopamine neurons. Recent data suggest a mechanistic link between oxidative stress and elevated levels of DOPAL, a neurotoxin endogenous to dopamine neurons. These findings have significant implications for development of therapeutics and identification of novel biomarkers for PD pathogenesis. Oxidative and nitrative stress is also thought to play a role in creating the pro-inflammatory microenvironment associated with the aggressive phenotype of inflammatory breast cancer. An understanding of fundamental concepts of oxidative and nitrative stress can underpin a rational plan of treatment for diseases and toxicities associated with excessive production of reactive oxygen and nitrogen species.
© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgThe online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.
Full text: http://toxsci.oxfordjournals.org/cgi/reprint/kfp179v1
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