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1.
Front Endocrinol (Lausanne) ; 12: 671724, 2021.
Article in English | MEDLINE | ID: mdl-34122346

ABSTRACT

Aims/hypothesis: Recurrent hypoglycaemia (RH) is a major side-effect of intensive insulin therapy for people with diabetes. Changes in hypoglycaemia sensing by the brain contribute to the development of impaired counterregulatory responses to and awareness of hypoglycaemia. Little is known about the intrinsic changes in human astrocytes in response to acute and recurrent low glucose (RLG) exposure. Methods: Human primary astrocytes (HPA) were exposed to zero, one, three or four bouts of low glucose (0.1 mmol/l) for three hours per day for four days to mimic RH. On the fourth day, DNA and RNA were collected. Differential gene expression and ontology analyses were performed using DESeq2 and GOseq, respectively. DNA methylation was assessed using the Infinium MethylationEPIC BeadChip platform. Results: 24 differentially expressed genes (DEGs) were detected (after correction for multiple comparisons). One bout of low glucose exposure had the largest effect on gene expression. Pathway analyses revealed that endoplasmic-reticulum (ER) stress-related genes such as HSPA5, XBP1, and MANF, involved in the unfolded protein response (UPR), were all significantly increased following low glucose (LG) exposure, which was diminished following RLG. There was little correlation between differentially methylated positions and changes in gene expression yet the number of bouts of LG exposure produced distinct methylation signatures. Conclusions/interpretation: These data suggest that exposure of human astrocytes to transient LG triggers activation of genes involved in the UPR linked to endoplasmic reticulum (ER) stress. Following RLG, the activation of UPR related genes was diminished, suggesting attenuated ER stress. This may be a consequence of a successful metabolic adaptation, as previously reported, that better preserves intracellular energy levels and a reduced necessity for the UPR.


Subject(s)
Astrocytes/metabolism , Glucose/administration & dosage , Unfolded Protein Response/drug effects , Astrocytes/drug effects , DNA Methylation/drug effects , Dose-Response Relationship, Drug , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress/drug effects , Humans
2.
Acta Neuropathol ; 127(3): 451-8, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24445903

ABSTRACT

Familial cases of frontotemporal dementia (FTD) provide an opportunity to study the pathophysiology of this clinically diverse condition. The C9ORF72 mutation is the most common cause of familial FTD, recent pathological descriptions challenge existing TDP-43 based hypotheses of sporadic FTD pathogenesis. Non-ATG dependent translation of the hexanucleotide expansion into aggregating dipeptide repeat (DPR) proteins may represent a novel pathomechanism. We report detection of the DPR aggregates very early in C9ORF72 FTD development and also describe childhood intellectual disability as a clinical feature preceding dementia. The index case presented with psychiatric symptoms, progressing into typical FTD. Autopsy revealed extensive neuronal DPR aggregates but only minimal TDP-43 pathology. Her intellectually disabled elder son, also carrying the C9ORF72 mutation, died aged 26 years and at autopsy only DPR aggregates without TDP-43 were found. A second son also has intellectual disability, his C9ORF72 status is unknown, but chromosomal microarray revealed no other cause of disability. These cases both extend the existing phenotype of C9ORF72 mutation and highlight the potential significance of DPR translation early in disease development.


Subject(s)
DNA Repeat Expansion , Frontotemporal Dementia/genetics , Intellectual Disability/genetics , Proteins/genetics , Adult , Brain/metabolism , Brain/pathology , C9orf72 Protein , Disease Progression , Family , Fatal Outcome , Female , Frontotemporal Dementia/complications , Frontotemporal Dementia/pathology , Humans , Immunohistochemistry , Intellectual Disability/complications , Intellectual Disability/pathology , Male , Middle Aged , Mothers , Pedigree , White People/genetics
3.
Science ; 321(5890): 839-43, 2008 Aug 08.
Article in English | MEDLINE | ID: mdl-18653847

ABSTRACT

Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes alpha2-chimaerin, a Rac guanosine triphosphatase-activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase alpha2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance alpha2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that alpha2-chimaerin has a critical developmental function in ocular motor axon pathfinding.


Subject(s)
Chimerin 1/genetics , Chimerin 1/metabolism , Duane Retraction Syndrome/genetics , Mutation, Missense , Abducens Nerve/abnormalities , Amino Acid Sequence , Animals , Axons/physiology , Cell Line , Cell Membrane/metabolism , Chick Embryo , Chimerin 1/chemistry , Female , Gene Expression Profiling , Heterozygote , Humans , Male , Molecular Sequence Data , Oculomotor Muscles/embryology , Oculomotor Muscles/innervation , Oculomotor Muscles/metabolism , Oculomotor Nerve/abnormalities , Oculomotor Nerve/embryology , Pedigree
4.
Org Biomol Chem ; 3(14): 2579-87, 2005 Jul 21.
Article in English | MEDLINE | ID: mdl-15999190

ABSTRACT

Certain cancer cells proliferate under conditions of oxidative stress (OS) and might therefore be selectively targeted by redox catalysts. Among these catalysts, compounds containing a chalcogen and a quinone redox centre are particularly well suited to respond to the presence of OS. These catalysts combine the specific electrochemical features of quinones and chalcogens. They exhibit high selectivity and efficiency against oxidatively stressed rat PC12, human Jurkat and human Daudi cells in cell culture, where their mode of action most likely involves the catalytic activation of existent and the generation of new reactive oxygen species. The high efficiency and selectivity shown by these catalysts makes them interesting for the development of anti-cancer drugs.


Subject(s)
Chalcogens/chemistry , Cytochrome Reductases/chemistry , Oxidative Stress , Quinones/chemistry , Animals , Catalysis , Cell Line, Tumor , Chalcogens/pharmacology , Electrochemistry , Humans , Jurkat Cells , Models, Molecular , Molecular Structure , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , PC12 Cells , Quinones/pharmacology , Rats , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/metabolism
5.
Biochem Pharmacol ; 66(10): 2021-8, 2003 Nov 15.
Article in English | MEDLINE | ID: mdl-14599560

ABSTRACT

Tumor cells proliferate under conditions of oxidative stress. A novel therapeutic approach would be to enhance the cellular effects of the reactive oxygen species formed under these conditions by supplementation with a redox catalyst. This provides a means to target and specifically destroy cancer cells via oxidation of redox-sensitive proteins, such as transcription factors, while leaving cells with a normal redox balance largely unaffected. We have previously reported a preliminary observation on the effects of pro-oxidant catalysts that enhance cancer cell death. This paper presents a detailed in vitro investigation into the mechanism of action of synthetic glutathione peroxidase mimics on a model Sp1 transcription factor peptide. The structure and redox potential of these mimics correlate with their ability to catalyze the oxidation of this zinc-binding motif by H(2)O(2) and these compounds promise therapeutic potential by promoting H(2)O(2)-induced PC12 cell death.


Subject(s)
Chalcogens/pharmacology , Oxidative Stress/drug effects , Animals , Catalysis , Electrochemistry , Endothelium, Vascular/drug effects , Humans , Hydrogen Peroxide/pharmacology , Oxidation-Reduction/drug effects , Oxidative Stress/physiology , PC12 Cells , Rats , Zinc/metabolism , Zinc Fingers/drug effects , Zinc Fingers/physiology
6.
FEBS Lett ; 535(1-3): 179-82, 2003 Jan 30.
Article in English | MEDLINE | ID: mdl-12560100

ABSTRACT

The predominance of oxidative stress in many tumour cell environments provides a means to selectively target these cells via protein oxidation. The zinc fingers of transcription factors utilise cysteine thiols for structural zinc coordination. Redox control of DNA binding regulates transcription and therefore the overall rates of proliferation, apoptosis and necrosis in the carcinoma. We report here the adverse effects of glutathione peroxidase (GPx) mimics towards zinc finger motifs and PC12 cell survival. Nanomolar catalyst concentrations facilitated H2O2-induced oxidation of an Sp1 transcription factor fragment. In PC12 cells GPx catalysis triggered a significant increase in cell death, correlating with severity of oxidative stress. As a consequence, we conclude that GPx mimics are potential chemotherapeutic agents.


Subject(s)
Chalcogens/chemistry , Hydrogen Peroxide/pharmacology , Organometallic Compounds/pharmacology , Oxidative Stress/drug effects , PC12 Cells/drug effects , Animals , Antioxidants/pharmacology , Azoles/pharmacology , Catalysis/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Glutathione Peroxidase , Hydrogen Peroxide/chemistry , Isoindoles , Organometallic Compounds/chemistry , Organoselenium Compounds/pharmacology , Oxidation-Reduction/drug effects , PC12 Cells/cytology , Peptide Fragments/chemistry , Peptide Fragments/drug effects , Rats , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/pharmacology , Selenium/chemistry , Sp1 Transcription Factor/chemistry , Tellurium/chemistry , Zinc Fingers/drug effects
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