The ALOXE3 gene variants from patients with Dravet syndrome decrease gene expression and enzyme activity

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

Download Full-text

Hepatocellular expression of glucose-6-phosphatase is unaltered during hepatic regeneration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.275.4.g717 ◽

1998 ◽

Vol 275 (4) ◽

pp. G717-G722 ◽

Cited By ~ 3

Author(s):

Wisam F. Zakko ◽

Carl L. Berg ◽

John L. Gollan ◽

Richard M. Green

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Protein Expression ◽

Partial Hepatectomy ◽

Initial Phase ◽

Physiological Function ◽

Liver Homogenate ◽

Hepatic Regeneration ◽

Mrna Levels ◽

Microsomal Enzyme

Gluconeogenesis and glycogenolysis are essential hepatic functions required for glucose homeostasis. During the initial phase of hepatic regeneration, the immediate-early genes (IEG) are rapidly expressed, and the IEG RL-1 encodes for glucose-6-phosphatase (G-6- Pase). G-6- Pase is a microsomal enzyme essential for gluconeogenesis and glycogenolysis. This study employs a partial-hepatectomy model to examine the expression and activity of G-6- Pase. After partial hepatectomy, rat hepatic G-6- Pase gene expression is transcriptionally regulated, and mRNA levels are increased ≈30-fold. However, in contrast to this rapid gene induction, microsomal enzyme activity is unchanged after partial hepatectomy. Western blotting demonstrates that microsomal G-6- Pase protein expression is also unchanged after partial hepatectomy, and similar results are also noted in whole liver homogenate. Thus, despite marked induction in gene expression of the IEG G-6- Pase after partial hepatectomy, protein expression and enzyme activity remain unchanged. These data indicate that, although this hepatocyte IEG is transcriptionally regulated, the physiologically important level of regulation is posttranscriptional. This highlights the importance of correlating gene expression of IEG with protein expression and physiological function.

Download Full-text

Supplementation of Siberian sturgeon (Acipenser baerii) diet with barberry (Berberis vulgaris) fruit extract: Growth performance, hemato-biochemical parameters, digestive enzyme activity, and growth-related gene expression

Aquaculture ◽

10.1016/j.aquaculture.2021.736750 ◽

2021 ◽

pp. 736750

Author(s):

Farshad Ramezani ◽

Seyed Pezhman Hosseini Shekarabi ◽

Mehdi Shamsaei Mehrgan ◽

Farhad Foroudi ◽

Houman Rajabi Islami

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Growth Performance ◽

Biochemical Parameters ◽

Digestive Enzyme ◽

Siberian Sturgeon ◽

Related Gene ◽

Fruit Extract ◽

Acipenser Baerii ◽

Berberis Vulgaris

Download Full-text

Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/8023935 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Krzysztof Michalak ◽

Aleksandra Sobolewska-Włodarczyk ◽

Marcin Włodarczyk ◽

Justyna Sobolewska ◽

Piotr Woźniak ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Enzyme Activity ◽

Antibiotic Therapy ◽

Effective Treatment ◽

Social Problem ◽

Fenton Reaction ◽

Current Paper ◽

Bivalent Cations

Long-term fluoroquinolone-associated disability (FQAD) after fluoroquinolone (FQ) antibiotic therapy appears in recent years as a significant medical and social problem, because patients suffer for many years after prescribed antimicrobial FQ treatment from tiredness, concentration problems, neuropathies, tendinopathies, and other symptoms. The knowledge about the molecular activity of FQs in the cells remains unclear in many details. The effective treatment of this chronic state remains difficult and not effective. The current paper reviews the pathobiochemical properties of FQs, hints the directions for further research, and reviews the research concerning the proposed treatment of patients. Based on the analysis of literature, the main directions of possible effective treatment of FQAD are proposed: (a) reduction of the oxidative stress, (b) restoring reduced mitochondrion potential ΔΨm, (c) supplementation of uni- and bivalent cations that are chelated by FQs and probably ineffectively transported to the cell (caution must be paid to Fe and Cu because they may generate Fenton reaction), (d) stimulating the mitochondrial proliferation, (e) removing FQs permanently accumulated in the cells (if this phenomenon takes place), and (f) regulating the disturbed gene expression and enzyme activity.

Download Full-text

Rats fed a high sucrose diet have altered heart antioxidant enzyme activity and gene expression

Life Sciences ◽

10.1016/s0024-3205(02)01846-5 ◽

2002 ◽

Vol 71 (11) ◽

pp. 1303-1312 ◽

Cited By ~ 51

Author(s):

Jérôme Busserolles ◽

Wioletta Zimowska ◽

Edmond Rock ◽

Yves Rayssiguier ◽

Andrzej Mazur

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Antioxidant Enzyme ◽

Antioxidant Enzyme Activity ◽

Sucrose Diet ◽

High Sucrose Diet ◽

High Sucrose

Download Full-text

Abstract 12905: Gene Expression and Expression Quantifying Trait Loci Analysis of Left Atrium of Patients With Post-operative Atrial Fibrillation

Circulation ◽

10.1161/circ.132.suppl_3.12905 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Martin I Sigurdsson ◽

Mahyar Heydarpour ◽

Louis Saddic ◽

Tzuu-Wang Chang ◽

Stanton K Shernan ◽

...

Keyword(s):

Gene Expression ◽

Atrial Fibrillation ◽

Left Atrium ◽

High Throughput ◽

Specific Gene ◽

Eqtl Analysis ◽

Gene Variants ◽

Nucleotide Polymorphisms ◽

Novel Genes ◽

Trait Loci

Introduction: The majority of information on the genetic background of atrial fibrillation (AF) results from genomic DNA variant analysis without consideration of tissue expression. Hypothesis: Analysis of tissue-specific gene expression in left atrium (LA) can further understanding of the molecular mechanism of identified AF risk variants, and identify novel genes and gene variants associated with AF. Methods: We isolated mRNA from samples of the LA free wall taken during mitral valve surgery in 62 Caucasian individuals. Gene expression in the LA was compared between patients who did and did not have post-operative AF (poAF) using high-throughput RNA expression. Using genotypes of 1.4 million single nucleotide polymorphisms (SNP) we performed cis expression quantifying trait loci (eQTL) analysis, correlating gene expression of each gene with the genotypes of adjacent (<1Mbp) SNPs. Results: We identified 23 differentially expressed genes in the LA of patients with poAF, including three potassium channel genes (KCNA7, KCNH8 and KCNK17). The largest expression difference was in LOC645323, a long non-coding RNA. The expression of PITX2, ZFHX3 and KCNN3, previously shown to be associated with AF, did not differ between patients with and without poAF. We identified 12,476 cis eQTL relationships in the LA, several of those included genetic regions and genes previously associated with AF. We confirmed an eQTL relationship between rs3744029 genotype and the expression of MYOZ1. Furthermore we describe a novel eQTL relationship between rs6795970 genotype and the expression of the SCN10A gene. Conclusions: We have analysed the human LA expression via high-throughput RNA sequencing, and identified novel genes and gene variants likely involved in the molecular pathophysiology of AF.

Download Full-text