A Novel Decoy That Interrupts G93A-Superoxide Dismutase Gain of Interaction with Malate Dehydrogenase Improves Survival in an Amyotrophic Lateral Sclerosis Cell Model

Mali, Yael; Zisapel, Nava

doi:10.1021/jm900631m

Cited by 15 publications

(9 citation statements)

References 19 publications

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“…Subsequently, increased binding of HIF‐1α to the HRE in the 5′ promoter region of VEGF enhances its expression, leading to increased intracellular levels of VEGF . In addition to hypoxia, intracellular levels of HIF‐1α are upregulated by proinflammatory cytokines, such as IL‐1 and TNF growth factors , and mutant proteins such as mSOD1 , which is presumably caused by suppression of HIF‐1α‐PHD . Elevated intrathecal levels of a variety of proinflammatory cytokines in ALS patients are likely to contribute to the increase in the level of HIF‐1α.…”

Section: Discussionmentioning

confidence: 99%

Impaired Cytoplasmic–Nuclear Transport of Hypoxia‐Inducible Factor‐1α in Amyotrophic Lateral Sclerosis

et al. 2013

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We investigated the mechanisms underlying abnormal vascular endothelial growth factor (VEGF) production in amyotrophic lateral sclerosis (ALS). We immunohistochemically studied VEGF, its receptors VEGFR1 and 2, and hypoxia-inducible factor-1α (HIF-1α) in autopsied ALS spinal cords. We also chronologically assessed the expression of HIF-1α, karyopherin β1, karyopherin β-cargo protein complex inhibitors and nuclear pore complex proteins in G93A mutant superoxide dismutase 1 (mSOD1) transgenic mice at presymptomatic, symptomatic and end stages. In ALS patients, compared with controls, HIF-1α immunoreactivity in the cytoplasm of anterior horn cells (AHCs) was significantly increased, while immunoreactivities for VEGF and VEGFRs were significantly decreased. Similar changes in HIF-1α and VEGF levels were observed in mSOD1 transgenic mice. HIF-1α co-localized with karyopherin β1 in the cytoplasm of AHCs and karyopherin β1 co-localized with nucleoporin 62 (Nup62) on the nuclear envelope. From the presymptomatic stage of mSOD1 transgenic mice, karyopherin β1 immunoreactivity in AHC nuclei significantly decreased and morphological irregularities of the Nup62-immunostained nuclear envelope became more pronounced with disease progression. Thus, in AHCs from mSOD1 transgenic mice, transport of cytoplasmic HIF-1α to the nuclear envelope and into the nucleus is impaired from the presymptomatic stage, suggesting that impaired cytoplasmic-nuclear transport of HIF-1α through the nuclear pore might precede motor neuron degeneration.

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Section: Discussionmentioning

confidence: 99%

Impaired Cytoplasmic–Nuclear Transport of Hypoxia‐Inducible Factor‐1α in Amyotrophic Lateral Sclerosis

et al. 2013

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“…Cell lines mostly included standard SOD1 G93A transfected mice cells. However, other G93A-transfected sources included SH-SY5Y cells ( Carri et al, 1997 ; Goos et al, 2007 ; Pesaresi et al, 2011 ), NSC-34 cells ( Liu et al, 2002 ; Ferri et al, 2008 ; Mali and Zisapel, 2009 ; Crippa et al, 2010 ), yeast ( Gunther et al, 2004 ; Kloppel et al, 2010 ), and bacteria ( Singh et al, 1998 ).…”

Section: Methodsmentioning

confidence: 99%

Seeking homeostasis: temporal trends in respiration, oxidation, and calcium in SOD1 G93A Amyotrophic Lateral Sclerosis mice

Irvin

Kim

Mitchell

2015

Front. Cell. Neurosci.

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Impairments in mitochondria, oxidative regulation, and calcium homeostasis have been well documented in numerous Amyotrophic Lateral Sclerosis (ALS) experimental models, especially in the superoxide dismutase 1 glycine 93 to alanine (SOD1 G93A) transgenic mouse. However, the timing of these deficiencies has been debatable. In a systematic review of 45 articles, we examine experimental measurements of cellular respiration, mitochondrial mechanisms, oxidative markers, and calcium regulation. We evaluate the quantitative magnitude and statistical temporal trend of these aggregated assessments in high transgene copy SOD1 G93A mice compared to wild type mice. Analysis of overall trends reveals cellular respiration, intracellular adenosine triphosphate, and corresponding mitochondrial elements (Cox, cytochrome c, complex I, enzyme activity) are depressed for the entire lifespan of the SOD1 G93A mouse. Oxidant markers (H2O2, 8OH2′dG, MDA) are initially similar to wild type but are double that of wild type by the time of symptom onset despite early post-natal elevation of protective heat shock proteins. All aspects of calcium regulation show early disturbances, although a notable and likely compensatory convergence to near wild type levels appears to occur between 40 and 80 days (pre-onset), followed by a post-onset elevation in intracellular calcium. The identified temporal trends and compensatory fluctuations provide evidence that the “cause” of ALS may lay within failed homeostatic regulation, itself, rather than any one particular perturbing event or cellular mechanism. We discuss the vulnerabilities of motoneurons to regulatory instability and possible hypotheses regarding failed regulation and its potential treatment in ALS.

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“…It has been shown that PCK1 is involved in the processes of small molecule biochemistry, carbohydrate metabolism, molecular transport, and response to drugs including 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD), 3H-1,2-dithiole-3-thione (D3T), and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) [63]. MDH1 (malate dehydrogenase 1) in this pathway has been reported to be relevant with drug toxicity [64, 65]. Another gene in this pathway worth mentioning is AQP1 (Aquaporin-1), which was highly expressed in endothelial cell membranes and involved in water transfer across or into these cells.…”

Section: Resultsmentioning

confidence: 99%

Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

Lei

Zheng

et al. 2013

BioMed Research International

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Drug combinatorial therapy could be more effective in treating some complex diseases than single agents due to better efficacy and reduced side effects. Although some drug combinations are being used, their underlying molecular mechanisms are still poorly understood. Therefore, it is of great interest to deduce a novel drug combination by their molecular mechanisms in a robust and rigorous way. This paper attempts to predict effective drug combinations by a combined consideration of: (1) chemical interaction between drugs, (2) protein interactions between drugs' targets, and (3) target enrichment of KEGG pathways. A benchmark dataset was constructed, consisting of 121 confirmed effective combinations and 605 random combinations. Each drug combination was represented by 465 features derived from the aforementioned three properties. Some feature selection techniques, including Minimum Redundancy Maximum Relevance and Incremental Feature Selection, were adopted to extract the key features. Random forest model was built with its performance evaluated by 5-fold cross-validation. As a result, 55 key features providing the best prediction result were selected. These important features may help to gain insights into the mechanisms of drug combinations, and the proposed prediction model could become a useful tool for screening possible drug combinations.

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A Novel Decoy That Interrupts G93A-Superoxide Dismutase Gain of Interaction with Malate Dehydrogenase Improves Survival in an Amyotrophic Lateral Sclerosis Cell Model

Cited by 15 publications

References 19 publications

Impaired Cytoplasmic–Nuclear Transport of Hypoxia‐Inducible Factor‐1α in Amyotrophic Lateral Sclerosis

Impaired Cytoplasmic–Nuclear Transport of Hypoxia‐Inducible Factor‐1α in Amyotrophic Lateral Sclerosis

Seeking homeostasis: temporal trends in respiration, oxidation, and calcium in SOD1 G93A Amyotrophic Lateral Sclerosis mice

Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

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