8,683 results match your criteria isoforms caused


Overexpression of MRP3 in HeLa-UGT1A9 Cells Enhances Glucuronidation Capability of the Cells.

Curr Drug Metab 2021 Jul 16. Epub 2021 Jul 16.

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, Houston, TX77204, United States.

Background: The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low systemic bioavailability of flavonoids.

Objective: The study aims to investigate the dynamic interplay between multiple UGTs and multiple efflux transporters inside the cells.

Methods: A new HeLa-UGT1A9-MRP3 cell was established to overexpress two dominant efflux transporters MRP3 and BCRP, and two UGT isoforms UGT1A9 and UGT1A3. Read More

View Article and Full-Text PDF

Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia.

Cell Death Dis 2021 Jul 17;12(8):716. Epub 2021 Jul 17.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Human iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms. Read More

View Article and Full-Text PDF

Cardiac Morphology and Collagen Deposition in A Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Knockout Mouse model.

J Med Clin Res Rev 2021 ;5(1)

Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Glucose-6-phosphatase-- β (3), one of multiple isoforms of glucose-6-phosphatase, catalyzes the final step in gluconeogenesis. It is known that mutated G6P3 is associated with severe neutropenia in addition to congenital heart defects, but little is known about the histological changes in cardiac tissue as a result of mutated or deleted G6PC3.

Objectives: We sought to further characterize the histological alterations caused by deleted G6PC3 and determine the role of collagen deposition, myocyte proliferation and apoptosis in these changes. Read More

View Article and Full-Text PDF
January 2021

Remarkable recent changes in the genetic diversity of the avirulence gene AvrStb6 in global populations of the wheat pathogen Zymoseptoria tritici.

Mol Plant Pathol 2021 Jul 14. Epub 2021 Jul 14.

Department of Biointeractions and Crop Protection, Rothamsted Research, Harpenden, UK.

Septoria tritici blotch (STB), caused by the fungus Zymoseptoria tritici, is one of the most economically important diseases of wheat. Recently, both factors of a gene-for-gene interaction between Z. tritici and wheat, the wheat receptor-like kinase Stb6 and the Z. Read More

View Article and Full-Text PDF

PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.

EMBO J 2021 Jul 13:e105603. Epub 2021 Jul 13.

UK Dementia Research Institute at Cardiff, Cardiff, UK.

Variants identified in genome-wide association studies have implicated immune pathways in the development of Alzheimer's disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. Read More

View Article and Full-Text PDF

Levo-tetrahydropalmatine inhibits α4β2 nicotinic receptor response to nicotine in cultured SH-EP1 cells.

Acta Pharmacol Sin 2021 Jul 12. Epub 2021 Jul 12.

Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.

Nicotine, a major component of tobacco, is highly addictive and acts on nicotinic acetylcholine receptors (nAChRs) to stimulate reward-associated circuits in the brain. It is well known that nAChRs play critical roles in mediating nicotine reward and addiction. Current FDA-approved medications for smoking cessation are the antidepressant bupropion and the nicotinic partial agonist varenicline, yet both are limited by adverse side effects and moderate efficacy. Read More

View Article and Full-Text PDF

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.

Aging (Albany NY) 2021 07 12;13(13):17097-17117. Epub 2021 Jul 12.

Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, USA.

Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer's Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. Read More

View Article and Full-Text PDF

Tracking structural modifications and oxidative status of myofibrillar proteins from silver carp (Hypophthalmichthys molitrix) fillets treated by different stunning methods and in vitro oxidizing conditions.

Food Chem 2021 Jul 1;365:130510. Epub 2021 Jul 1.

Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China. Electronic address:

In order to explain the increased susceptibility of stunning-stressed fillets to oxidative modifications, effect of stunning methods (percussion and gill cut) and in vitro metal-catalyzed oxidation on structural changes and oxidative status of myofibrillar proteins (MPs) from silver carp fillets was examined. In comparison to the percussion group, oxidized MPs (10 mM HO) from gill cut-stunned fillets exhibited higher extent of structural disintegration as well as elevated carbonyl levels. Using label-free proteomics, isoforms of myosin heavy chain and actin were major proteins underwent oxidative modifications including monooxidation of methionine, dioxidation of aromatic amino acids, adduction of lipid peroxidation products with aliphatic amino acids, and the carbonylation of lysine and arginine into semialdehydes. Read More

View Article and Full-Text PDF

Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice.

Front Immunol 2021 21;12:702025. Epub 2021 Jun 21.

Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, Brazil.

Physical exercise is considered a fundamental strategy in improving insulin sensitivity and glucose uptake in skeletal muscle. However, the molecular mechanisms underlying this regulation, primarily on skeletal muscle glucose uptake, are not fully understood. Recent evidence has shown that Rho-kinase (ROCK) isoforms play a pivotal role in regulating skeletal muscle glucose uptake and systemic glucose homeostasis. Read More

View Article and Full-Text PDF

Diseases caused by mutations in the Na/K pump α1 gene ATP1A1.

Am J Physiol Cell Physiol 2021 Jul 7. Epub 2021 Jul 7.

Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, grid.416992.1Texas Tech University Health Sciences Center, Lubbock, TX, United States.

Human cell survival requires function of the Na/K pump; the heteromeric protein that hydrolyzes ATP to extrude Na and import K across the plasmalemma, thereby building and maintaining their electrochemical gradients. Numerous dominant diseases caused by mutations in genes encoding for Na/K pump catalytic (α) subunit isoforms highlight the importance of this protein. Here, we review literature describing disorders caused by missense mutations in ATP1A1, the gene encoding the ubiquitously expressed α1 isoform of the Na/K pump. Read More

View Article and Full-Text PDF

ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants.

Neurogenetics 2021 Jul 3. Epub 2021 Jul 3.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Read More

View Article and Full-Text PDF

Mitochondrial -GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis.

Cancers (Basel) 2021 Jun 12;13(12). Epub 2021 Jun 12.

Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland.

-GlcNAcylation is a cell glucose sensor. The addition of -GlcNAc moieties to target protein is catalyzed by the -Linked -acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. Read More

View Article and Full-Text PDF

Molecular Mechanisms of the Deregulation of Muscle Contraction Induced by the R90P Mutation in Tpm3.12 and the Weakening of This Effect by BDM and W7.

Int J Mol Sci 2021 Jun 12;22(12). Epub 2021 Jun 12.

Laboratory of Molecular Basis of Cell Motility, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky Ave., 194064 Saint Petersburg, Russia.

Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. Read More

View Article and Full-Text PDF

Simultaneous studies of gene expression and alternative polyadenylation in primary human immune cells.

Methods Enzymol 2021 16;655:349-399. Epub 2021 Jun 16.

Gene Regulation, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; IBMC-Instituto de Biologia Molecular e Celular, Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. Electronic address:

Transcription termination in eukaryotic cells involves the recognition of polyadenylation signals (PAS) that signal the site of pre-mRNA cleavage and polyadenylation. Most eukaryotic genes contain multiple PAS that are used by alternative polyadenylation (APA), a co-transcriptional process that increases transcriptomic diversity and modulates the fate of the mRNA and protein produced. However, current tools to pinpoint the relationship between mRNAs in different subcellular fractions and the gene expression outcome are lacking, particularly in primary human immune cells, which, due to their nature, are challenging to study. Read More

View Article and Full-Text PDF

Gamma-decanolactone: Preliminary evaluation as potential antiparkinsonian drug.

Eur J Pharmacol 2021 Sep 23;906:174276. Epub 2021 Jun 23.

Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy. University of Santiago de Compostela (USC), Campus Vida s/n, 15782, Santiago de Compostela, Spain. Electronic address:

Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone (GD) effect in vitro to inhibit the A and B isoforms of human monoamine oxidase (hMAO) enzyme and their citotoxicity in human hepatoma cell line (HepG2). Also, binding studies to A, A A and A adenosine receptors were performed. Read More

View Article and Full-Text PDF
September 2021

Context-dependent modulation of aggressiveness of pediatric tumors by individual oncogenic RAS isoforms.

Oncogene 2021 Jun 25. Epub 2021 Jun 25.

Department of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.

A prototypic pediatric cancer that frequently shows activation of RAS signaling is embryonal rhabdomyosarcoma (ERMS). ERMS also show aberrant Hedgehog (HH)/GLI signaling activity and can be driven by germline mutations in this pathway. We show, that in ERMS cell lines derived from sporadic tumors i. Read More

View Article and Full-Text PDF

High fat diet alters male seminal plasma composition to impair female immune adaptation for pregnancy in mice.

Endocrinology 2021 Jun 25. Epub 2021 Jun 25.

The Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 5005 Australia.

Paternal experiences and exposures prior to conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects, through modulating the female reproductive tract immune response after mating. To investigate whether paternal obesity affects seminal plasma immune-regulatory activity, C57Bl/6 male mice were fed an obesogenic high fat diet (HFD) or control diet (CD) for 14 weeks. Read More

View Article and Full-Text PDF

Collagen transport and related pathways in Osteogenesis Imperfecta.

Hum Genet 2021 Aug 24;140(8):1121-1141. Epub 2021 Jun 24.

Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. Read More

View Article and Full-Text PDF

Inhibitory effects of quercetin and its major metabolite quercetin-3-O-β-D-glucoside on human UDP-glucuronosyltransferase 1A isoforms by liquid chromatography-tandem mass spectrometry.

Exp Ther Med 2021 Aug 6;22(2):842. Epub 2021 Jun 6.

Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

Quercetin is a flavonoid that is widely present in plant-derived food. Quercetin-3-O-β-D-glucoside (Q3GA) is a predominant metabolite of quercetin in animal and human plasma. The inhibitory effects of the UDP-glucuronosyl transferases (UGTs) caused by herbal components may be a key factor for the clinical assessment of herb-drug interactions (HDIs). Read More

View Article and Full-Text PDF

Implications of Synthetic Modifications of the Cardiotonic Steroid Lactone Ring on Cytotoxicity.

J Membr Biol 2021 Jun 14. Epub 2021 Jun 14.

Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro Oeste Dona Lindu, Av Sebastião Gonçalves Coelho, 400, Bairro Chanadour, Divinópolis, MG, 35501-296, Brazil.

Na,K-ATPase (NKA) and cardiotonic steroids (CTS) have shown potent cytotoxic and anticancer effects. Here, we have synthesized a series of CTS digoxin derivatives (γ-benzylidene) with substitutions in the lactone ring and evaluated the cytotoxicity caused by digoxin derivatives in tumor and non-tumor cells lines, as well as their effects on NKA. The cytotoxicity assay was determined in HeLa, A549, and WI-26 VA4 after they were treated for 48 h with increased concentrations of CTS. Read More

View Article and Full-Text PDF

Phosphorylation of meprin β controls its cell surface abundance and subsequently diminishes ectodomain shedding.

FASEB J 2021 07;35(7):e21677

Biochemical Institute, Unit for Degradomics of the Protease Web, University of Kiel, Kiel, Germany.

Meprin β is a zinc-dependent metalloprotease exhibiting a unique cleavage specificity with strong preference for acidic amino acids at the cleavage site. Proteomic studies revealed a diverse substrate pool of meprin β including the interleukin-6 receptor (IL-6R) and the amyloid precursor protein (APP). Dysregulation of meprin β is often associated with pathological conditions such as chronic inflammation, fibrosis, or Alzheimer's disease (AD). Read More

View Article and Full-Text PDF

Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation.

J Exp Clin Cancer Res 2021 Jun 12;40(1):194. Epub 2021 Jun 12.

Department of Heavy Ion Radiation Medicine, Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.

Bcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. Read More

View Article and Full-Text PDF

Secretory Phospholipase A Enzymes in Acute Lung Injury.

Cell Biochem Biophys 2021 Jun 8. Epub 2021 Jun 8.

Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.

The secretory phospholipase A (sPLA) group of secreted enzymes hydrolyze phospholipids and lead to the production of multiple biologically active lipid mediators. sPLAs and their products (e.g. Read More

View Article and Full-Text PDF

CX3CL1 Overexpression Prevents the Formation of Lung Metastases in Trastuzumab-Treated MDA-MB-453-Based Humanized Tumor Mice (HTM).

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Department of Gynecology and Obstetrics, Technical University of Munich, 81675 Munich, Germany.

CX3CL1 is a multifunctional chemokine that is involved in numerous biological processes, such as immune cell attraction and enhanced tumor immune cell interaction, but also in enhancing tumor cell proliferation and metastasis. The multifarious activity is partially determined by two CX3CL1 isoforms, a membrane-bound and a soluble version generated by proteolytic cleavage through proteases. Here, we investigated the impact of CX3CL1 overexpression in MDA-MB-453 and SK-BR-3 breast cancer cells. Read More

View Article and Full-Text PDF

Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy.

Int J Mol Sci 2021 May 15;22(10). Epub 2021 May 15.

Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53266, USA.

The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. Read More

View Article and Full-Text PDF

Loss of Fis1 impairs proteostasis during skeletal muscle aging in Drosophila.

Aging Cell 2021 06 1;20(6):e13379. Epub 2021 Jun 1.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan.

Increased levels of dysfunctional mitochondria within skeletal muscle are correlated with numerous age-related physiopathological conditions. Improving our understanding of the links between mitochondrial function and muscle proteostasis, and the role played by individual genes and regulatory networks, is essential to develop treatments for these conditions. One potential player is the mitochondrial outer membrane protein Fis1, a crucial fission factor heavily involved in mitochondrial dynamics in yeast but with an unknown role in higher-order organisms. Read More

View Article and Full-Text PDF

Tau mis-splicing correlates with motor impairments and striatal dysfunction in a model of tauopathy.

Brain 2021 Jun 1. Epub 2021 Jun 1.

Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Buenos Aires, Argentina.

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein Tau, which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in tau pre-mRNA produces equal amounts of protein isoforms with either three (3 R) or four (4 R) microtubule binding domains. Imbalance in the 3 R : 4 R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as Progressive Supranuclear Palsy and Corticobasal Degeneration. Read More

View Article and Full-Text PDF

Elimination of endogenous high molecular weight FGF2 prevents pressure-overload-induced systolic dysfunction, linked to increased FGFR1 activity and NR1D1 expression.

Cell Tissue Res 2021 May 31. Epub 2021 May 31.

St. Boniface Hospital Albrechtsen Research Centre, Institute of Cardiovascular Sciences, Winnipeg, Canada.

Fibroblast growth factor 2 (FGF2), produced as high (Hi-) and low (Lo-) molecular weight isoforms, is implicated in cardiac response to injury. The role of endogenous FGF2 isoforms during chronic stress is not well defined. We investigated the effects of endogenous Hi-FGF2 in a mouse model of simulated pressure-overload stress achieved by transverse aortic constriction (TAC) surgery. Read More

View Article and Full-Text PDF

Cysteine modification by ebselen reduces the stability and cellular levels of 14-3-3 proteins.

Mol Pharmacol 2021 May 24. Epub 2021 May 24.

University of Bergen, Norway

The 14-3-3 proteins constitute a family of regulatory adapter proteins with many binding partnersand biological functions, and are considered promising drug targets in cancer and neuropsychiatry.By screening 1280 small-molecule drugs using differential scanning fluorimetry (DSF), we found 15 compounds that decreased the thermal stability of 14-3-3ζ. Among these compounds, ebselen was identified as a covalent, destabilizing ligand of 14-3-3 isoforms ζ, ε, γ and η. Read More

View Article and Full-Text PDF

Evidence for a synergistic effect of post-translational modifications and genomic composition of eEF-1α on the adaptation of .

Ecol Evol 2021 May 18;11(10):5484-5496. Epub 2021 Mar 18.

Department of Forest Mycology and Plant Pathology Swedish University of Agricultural Sciences Uppsala Sweden.

Genetic variation plays a fundamental role in pathogen's adaptation to environmental stresses. Pathogens with low genetic variation tend to survive and proliferate more poorly due to their lack of genotypic/phenotypic polymorphisms in responding to fluctuating environments. Evolutionary theory hypothesizes that the adaptive disadvantage of genes with low genomic variation can be compensated for structural diversity of proteins through post-translation modification (PTM) but this theory is rarely tested experimentally and its implication to sustainable disease management is hardly discussed. Read More

View Article and Full-Text PDF