scholarly journals Effect of a Valine Load Test on Plasma Alpha-Keto Acids in Friedreich Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 239-242 ◽  
Author(s):  
A. Barbeau ◽  
M. Bertrand ◽  
R. Bouchard ◽  
G.L. Gauthier ◽  
J.P. Bouchard
Keyword(s):  
General Trend ◽  
Genetic Defect ◽  
Friedreich Ataxia ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Load Test ◽  
Keto Acids ◽  
Branched Chain

SUMMARY:To test the physiological significance in vivo of our previous in vitro finding of reduced valine dehydrogenase (VDH) activity inpatients with Friedreich’s Ataxia, we subjected ataxic patients and controls to an oral valine load test (1.0g) and measured the levels of branched chain α-keto acids in the plasma for 24 hours. We demonstrated a significantly higher peak for α-keto isovaleric acid in Friedreich’s Ataxia and a general trend towards higher than control values in all other α-keto acids measured, and at all times in the experiment. These changes are compatible with the postulated defect in regulation of the activity of VDH in this illness, but because of their small amplitude, they also indicate that a VDH – deficiency is not the genetic defect in Friedreich’s A taxia.

scholarly journals SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

2019 ◽  
Vol 47 (20) ◽  
pp. 10728-10743 ◽  
Author(s):  
Carlotta Bon ◽  
Riccardo Luffarelli ◽  
Roberta Russo ◽  
Silvia Fortuni ◽  
Bianca Pierattini ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Monogenic Disease ◽  
Transcriptional Level ◽  
Gene Encoding ◽  
Mitochondrial Aconitase ◽  
Non Coding Rnas ◽  
Gaa Repeats

Abstract Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.

scholarly journals Glucose Tolerance and Erythrocyte Insulin Receptors in Friedreich's Ataxia

1979 ◽  
Vol 6 (2) ◽  
pp. 233-239 ◽  
Author(s):  
P. Draper ◽  
D. Shapcott ◽  
A. Larose ◽  
J. Stankova ◽  
F. Levesque ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
Family Members ◽  
Insulin Response ◽  
Insulin Binding ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Insulin Metabolism

SummaryDetailed in vivo and in vitro studies of glucose and insulin metabolism in Friedreich's ataxia patients and unaffected family members have further defined the extent of the abnormalities in carbohydrate metabolism. The high incidence of glucose intolerance and a hyper-insulinemic response to a glucose challenge in a high percentage of Friedreich's ataxia patients has been confirmed. An increased incidence of glucose intolerance among hétérozygotes is suggested, while the siblings show a more normal distribution of diabetes and a nearly normal insulin response to the glucose tolerance test. Human growth hormone patterns are normal for all groups.Preliminary studies of insulin binding to erythrocytes suggest a difference in the binding characteristics among diabetic Friedreich's ataxia patients, while the binding in the non-diabetic Friedreich's ataxia group is similar to that of non-diabetic controls. Results from a small group of non-diabetic siblings suggest a normal insulin binding, while a tendency toward increased binding at low insulin concentrations among diabetic family members is noted.

scholarly journals Leukocyte Valine Dehydrogenase Activity in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 235-238 ◽  
Author(s):  
A. Barbeau ◽  
T. Cloutier ◽  
M. Charbonneau
Keyword(s):  
Enzyme Activity ◽  
Dehydrogenase Activity ◽  
Normal Control ◽  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Control Subjects ◽  
Keto Acids

SUMMARY:We studied the activity of valine dehydrogenase (VDH) in leukocytes of 14 Friedreich’s ataxia patients and of 14 normal control subjects. There was a significant 26% mean decrease in enzyme activity in the patients, a finding which could be responsible for the chronic accumulation of some α-keto acids with toxic metabolic consequences in that disease. However the deficiency was not present in all patients with the typical symptoms, nor was its magnitude sufficient to be considered the primary genetic defect in Friedreich’s A taxia.

scholarly journals Pyruvate Metabolism in Friedreich's Ataxia

1976 ◽  
Vol 3 (4) ◽  
pp. 379-338 ◽  
Author(s):  
A. Barbea ◽  
R.F. Butterworth ◽  
T. Ngo ◽  
G. Breton ◽  
S. Melançon ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Bimodal Distribution ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
In Vivo Tests ◽  
Show Evidence ◽  
Lipoamide Dehydrogenase ◽  
Prolonged Response

SUMMARY:Friedreich's ataxia patients show evidence of an abnormally elevated and prolonged response of pyruvate and lactate to a glucose load, with normal fasting levels. However, there is a bimodal distribution of this response with high and low pyruvate responders. This trait appears to be determined genetically, However, although in vivo tests suggest low oxidation of pyruvate, we were unable to confirm any in vitro impairment of each of the components of the pyruvate dehydrogenase (PDH) complex. We conclude that the defect is in the metabolic regulation of PDH, probably at the E3 (lipoamide dehydrogenase) step.

scholarly journals The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 875
Author(s):  
Karlijn Pellikaan ◽  
Geeske M. van Woerden ◽  
Lotte Kleinendorst ◽  
Anna G. W. Rosenberg ◽  
Bernhard Horsthemke ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Single Nucleotide Polymorphism Array ◽  
Genetic Defect ◽  
Missense Variant ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Pituitary Hormone ◽  
Negative Effect

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

Branched chain amino Acids as in vitro and in vivo Anti-Oxidation Compounds

2021 ◽  
pp. 3899-3904
Author(s):  
Moath Alqaraleh ◽  
Violet Kasabri ◽  
Ibrahim Al-Majali ◽  
Nihad Al-Othman ◽  
Nihad Al-Othman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Amino Acids ◽  
Branched Chain Amino Acids ◽  
Raw 264.7 ◽  
Raw 264.7 Cell ◽  
Branched Chain ◽  
Raw 264.7 Cell Line

Background and aims: Branched chain amino acids (BCAAs) can be tightly connected to metabolism syndrome (MetS) which can be counted as a metabolic indicator in the case of insulin resistance (IR). The aim of this study was to assess the potential role of these acids under oxidative stress. Material and Methods: the in vitro antioxidant activity of BCAAs was assessed using free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) scavenging assays. For further check, a qRT-PCR technique was madefor detection the extent of alterations in gene expression of antioxidative enzymes (catalase and glutathione peroxidase (Gpx)) in lipopolysaccharides (LPS(-induced macrophages RAW 264.7 cell line. Additionally, BCAAs antioxidant activity was evaluated based on plasma H2O2 levels and xanthine oxidase (XO) activity in prooxidative LPS-treated mice. Results: Different concentrations of BCAAs affected on DPPH radical scavenging activity but to lesser extent than the ascorbic acid. Besides, BCAAs obviously upregulated the gene expression levels of catalases and Gpx in LPS-modulated macrophage RAW 264.7 cell line. In vivo BCAAs significantly minimized the level of plasma H2O2 as well as the activity of XO activity under oxidative stress. Conclusion: our current findings suggest that BCAAs supplementation may potentially serve as a therapeutic target for treatment of oxidative stress occurs with atherosclerosis, IR-diabetes, MetS and tumorigenesis.

scholarly journals Role of BrnQ1 and BrnQ2 in Branched-Chain Amino Acid Transport and Virulence in Staphylococcus aureus

2014 ◽  
Vol 83 (3) ◽  
pp. 1019-1029 ◽  
Author(s):  
Julienne C. Kaiser ◽  
Sameha Omer ◽  
Jessica R. Sheldon ◽  
Ian Welch ◽  
David E. Heinrichs
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Gene ◽  
Defined Medium ◽  
Infection Model ◽  
Content Type ◽  
Virulence Gene Expression ◽  
Branched Chain Amino Acid ◽  
Branched Chain

The branched-chain amino acids (BCAAs; Ile, Leu, and Val) not only are important nutrients for the growth ofStaphylococcus aureusbut also are corepressors for CodY, which regulates virulence gene expression, implicating BCAAs as an important link between the metabolic state of the cell and virulence. BCAAs are either synthesized intracellularly or acquired from the environment.S. aureusencodes three putative BCAA transporters, designated BrnQ1, BrnQ2, and BrnQ3; their functions have not yet been formally tested. In this study, we mutated all threebrnQparalogs so as to characterize their substrate specificities and their roles in growthin vitroandin vivo. We demonstrated that in the community-associated, methicillin-resistantS. aureus(CA-MRSA) strain USA300, BrnQ1 is involved in uptake of all three BCAAs, BrnQ2 transports Ile, and BrnQ3 does not have a significant role in BCAA transport under the conditions tested. Of the three, only BrnQ1 is essential for USA300 to grow in a chemically defined medium that is limited for Leu or Val. Interestingly, we observed that abrnQ2mutant grew better than USA300 in media limited for Leu and Val, owing to the fact that this mutation leads to overexpression ofbrnQ1. In a murine infection model, thebrnQ1mutant was attenuated, but in contrast,brnQ2mutants had significantly increased virulence compared to that of USA300, a phenotype we suggest is at least partially linked to enhancedin vivoscavenging of Leu and Val through BrnQ1. These data uncover a hitherto-undiscovered connection between nutrient acquisition and virulence in CA-MRSA.

scholarly journals Pharmacological modulation of cell functional activity with valproic acid and erythropoietin

2019 ◽  
Vol 5 (2) ◽  
pp. 89-99
Author(s):  
Polina A. Golubinskaya ◽  
Marina V. Sarycheva ◽  
Svetlana Y. Burda ◽  
Maksim V. Puzanov ◽  
Natalya A. Nadezhdina ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Antiepileptic Drug ◽  
Axial Skeleton ◽  
Pharmacological Modulation ◽  
Inhibition Of Growth ◽  
Acid Effect ◽  
Branched Chain ◽  
Growth Of Tumor

Introduction: Valproic acid (VA) is carboxylic acid with a branched chain, which is used as an antiepileptic drug. Valproic acid influence on cells in vivo: VA, which is an antiepileptic drug, is also a teratogen, which causes defects of a neural tube and an axial skeleton, although the mechanisms are not yet fully clear. Valproic acid influence on mesenchymal stem cells (MSC) in vitro: It is shown that valproic acid reduces the intracellular level of oxygen active forms. Valproic acid effect on tumor cells: VA inhibits tumor growth through several mechanisms, including the cell cycle stop, differentiation induction and inhibition of growth of tumor vessels. Valproic acid influence on enzymes: It affects mainly GSK-3. Valproic acid influence on animals’ cells: It is shown that VA can significantly improve an ability to develop in vitro and improve nuclear reprogramming of embryos. Erythropoietin (EPO): Is an hypoxia-induced hormone and a cytokine, which is necessary for normal erythropoiesis. EPO is widely used in in vitro experiments. Conclusion: Thus, the influence of VA and EPO on cells can be used in cell technologies.

scholarly journals Molecular Mechanisms Underlying the Positive Stringent Response of the Bacillus subtilis ilv-leu Operon, Involved in the Biosynthesis of Branched-Chain Amino Acids

2008 ◽  
Vol 190 (18) ◽  
pp. 6134-6147 ◽  
Author(s):  
Shigeo Tojo ◽  
Takenori Satomura ◽  
Kanako Kumamoto ◽  
Kazutake Hirooka ◽  
Yasutaro Fujita
Keyword(s):  
Amino Acids ◽  
Bacillus Subtilis ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Stringent Response ◽  
Branched Chain Amino Acids ◽  
Base Substitution ◽  
Branched Chain

ABSTRACT Branched-chain amino acids are the most abundant amino acids in proteins. The Bacillus subtilis ilv-leu operon is involved in the biosynthesis of branched-chain amino acids. This operon exhibits a RelA-dependent positive stringent response to amino acid starvation. We investigated this positive stringent response upon lysine starvation as well as decoyinine treatment. Deletion analysis involving various lacZ fusions revealed two molecular mechanisms underlying the positive stringent response of ilv-leu, i.e., CodY-dependent and -independent mechanisms. The former is most likely triggered by the decrease in the in vivo concentration of GTP upon lysine starvation, GTP being a corepressor of the CodY protein. So, the GTP decrease derepressed ilv-leu expression through detachment of the CodY protein from its cis elements upstream of the ilv-leu promoter. By means of base substitution and in vitro transcription analyses, the latter (CodY-independent) mechanism was found to comprise the modulation of the transcription initiation frequency, which likely depends on fluctuation of the in vivo RNA polymerase substrate concentrations after stringent treatment, and to involve at least the base species of adenine at the 5′ end of the ilv-leu transcript. As discussed, this mechanism is presumably distinct from that for B. subtilis rrn operons, which involves changes in the in vivo concentration of the initiating GTP.

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