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Yao, Shuihong, Xuemei Jia, Fei Wang, Liuxue Sheng, Pengxia Song, Yanhui Cao, Hongjuan Shi, et al. "CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3." PLOS Pathogens 17, no. 2 (February 4, 2021): e1009294. http://dx.doi.org/10.1371/journal.ppat.1009294.
Повний текст джерелаАнотація:
Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs that can decoy other RNAs to inhibit their functions. Kaposi’s sarcoma (KS), caused by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), is a highly angiogenic and invasive vascular tumor of endothelial origin commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) induces cell invasion, angiogenesis and cellular transformation; however, the role of circRNAs is largely unknown in the context of KSHV vIRF1. Herein, transcriptome analysis identified 22 differentially expressed cellular circRNAs regulated by vIRF1 in an endothelial cell line. Among them, circARFGEF1 was the highest upregulated circRNA. Mechanistically, vIRF1 induced circARFGEF1 transcription by binding to transcription factor lymphoid enhancer binding factor 1 (Lef1). Importantly, upregulation of circARFGEF1 was required for vIRF1-induced cell motility, proliferation and in vivo angiogenesis. circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p. Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p. Knockdown of GLRX3 impaired cell motility, proliferation and angiogenesis induced by vIRF1. Taken together, vIRF1 transcriptionally activates circARFGEF1, potentially by binding to Lef1, to promote cell oncogenic phenotypes via inhibiting miR-125a-3p and inducing GLRX3. These findings define a novel mechanism responsible for vIRF1-induced oncogenesis and establish the scientific basis for targeting these molecules for treating KSHV-associated cancers.
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Johansson, Catrine, Annette K. Roos, Sergio J. Montano, Rajib Sengupta, Panagis Filippakopoulos, Kunde Guo, Frank von Delft, Arne Holmgren, Udo Oppermann, and Kathryn L. Kavanagh. "The crystal structure of human GLRX5: iron–sulfur cluster co-ordination, tetrameric assembly and monomer activity." Biochemical Journal 433, no. 2 (December 22, 2010): 303–11. http://dx.doi.org/10.1042/bj20101286.
Повний текст джерелаАнотація:
Human GLRX5 (glutaredoxin 5) is an evolutionarily conserved thiol–disulfide oxidoreductase that has a direct role in the maintenance of normal cytosolic and mitochondrial iron homoeostasis, and its expression affects haem biosynthesis and erythropoiesis. We have crystallized the human GLRX5 bound to two [2Fe–2S] clusters and four GSH molecules. The crystal structure revealed a tetrameric organization with the [2Fe–2S] clusters buried in the interior and shielded from the solvent by the conserved β1-α2 loop, Phe69 and the GSH molecules. Each [2Fe–2S] cluster is ligated by the N-terminal activesite cysteine (Cys67) thiols contributed by two protomers and two cysteine thiols from two GSH. The two subunits co-ordinating the cluster are in a more extended conformation compared with iron–sulfur-bound human GLRX2, and the intersubunit interactions are more extensive and involve conserved residues among monothiol GLRXs. Gel-filtration chromatography and analytical ultracentrifugation support a tetrameric organization of holo-GLRX5, whereas the apoprotein is monomeric. MS analyses revealed glutathionylation of the cysteine residues in the absence of the [2Fe–2S] cluster, which would protect them from further oxidation and possibly facilitate cluster transfer/acceptance. Apo-GLRX5 reduced glutathione mixed disulfides with a rate 100 times lower than did GLRX2 and was active as a glutathione-dependent electron donor for mammalian ribonucleotide reductase.
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Chen, H. H. "AB0009 DIFFERENTIALLY EXPRESSED GENES BETWEEN FLARE OF PALINDROMIC RHEUMATISM AND ACTIVE RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1140.1–1140. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3007.
Повний текст джерелаАнотація:
BackgroundAlthough the mechanisms of palindromic rheumatism (PR) is still unclear, an association between PR and rheumatoid arthritis (RA) has been well recognized in previous studies, with one to two-thirds of PR patients developing RA during a period of follow-up. RNA sequencing (RNA-Seq) is a next-generation sequencing (NGS) method that measures genome-wide RNA abundance. Using RNA-Seq to identify the DEGs between flare PR and active RA could help elucidate the pathogenic mechanisms of PR flare and find novel genes to predict RA progression.ObjectivesThe aim of this study is to identify gene expression signatures between PR flare and active RA using whole blood RNA-seq.MethodsWe collected clinical data, and blood samples from 12 flare PR patients and 12 active RA (defined as DAS28-ESR≥3.2) patients from Taichung Veterans General hospital. We obtained high-quality RNA by using PAXGene tube for whole blood sampling and PAXGene blood RNA Kit to extract RNA. Cuffdiff (Cufflinks option) output was filtered for differentially expressed genes (DEGs) with p-value < 0.05. Gene set enrichment analysis (GSEA) were performed using the GSEA version 4.0.0 with immunologic gene sets (C7 sets containing 4872 gene sets) from The Molecular Signatures Database (MSigDB). According to GSEA web suggestion, a false discovery rate (FDR) < 0.25 with a p-value < 0.05 was considered statistically significant. We obtained rank ordered gene list from GSEA.ResultsWe compared flare PR and active RA using GSEA. Five of the top 12 enrichment in phenotype with flare PR was related to lipopolysaccharide (LPS), which was found in the outer membrane of Gram-negative bacteria. And other pathways were also related to immune response, e.g., B cell, T cell and macrophage. In active RA, the characteristic gene expressions were associated with immune response, such as genes up-regulated in dendritic cells, genes down-regulated in B cell, and genes up-regulated in T cells.We obtained top 3 differential gene expressions in flare PR patients and top 3 differential gene expressions in active RA patients. FCGBP, GLRX3 and RTN4R genes were significantly associated with immune response in flare PR patients. And we observed that 3 genes had statistically significant t-test result (FCGBP, p-value< 0.001; GLRX3, p-value< 0.001; RTN4R, p-value< 0.001) (Figure 1a, 1b and 1c). This result showed that FCGBP, GLRX3 and RTN4R may play an important role on immune response related to flare PR. In active RA patients, 3 genes had statistically significant t-test result (HK3, p-value< 0.001; HIST1H2AI, p-value= 0.002; BST1, p-value<0.001) (Figure 1d, 1e and 1f).Figure 1.Differential gene expressions between flare PR and active RA. (a) FCGBP, (b) GLRX3, (c) RTN4R, (d) HK3, (e) HIST1H2AI, (f) BST1ConclusionGSEA analyses showed that five of the top 12 enrichment in flare PR was related to LPS and other pathways were related to immune responses of B cell, T cell and macrophage. However, in active RA, the characteristic gene expressions included genes up-regulated in dendritic cells, genes down-regulated in B cell, and genes up-regulated in T cells, suggeting different physiological pathways from flare of PR.Disclosure of InterestsNone declared
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Pandya, Pinakin, Alex Braiman, and Noah Isakov. "PICOT (GLRX3) is a positive regulator of stress-induced DNA-damage response." Cellular Signalling 62 (October 2019): 109340. http://dx.doi.org/10.1016/j.cellsig.2019.06.005.
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Wang, Dong, ZhiMing Wang, and YiMing Tao. "Prognostic Values of BolA Family Member Expression in Hepatocellular Carcinoma." BioMed Research International 2022 (August 16, 2022): 1–10. http://dx.doi.org/10.1155/2022/8360481.
Повний текст джерелаАнотація:
The BolA gene family member (BOLA1–3) plays an important role in regulating normal and pathological biological processes including liver tumorigenesis. However, their expression patterns as prognostic factors in hepatocellular carcinoma (HCC) patients have not to be elucidated. We examined the transcriptional expressions and survival data of BolA family member in patients with HCC from online databases including ONCOMINE, TCGA, UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, SurvExpress, cBioPortal, and Exobase. Network molecular interaction views of BolA family members and their neighborhoods were constructed by the IntAct web server. In our research, we had found that the expression levels of BolA /2/3 mRNA were higher in HCC tissue than in normal liver tissues from TGCA databases. Moreover, the BolA family gene expression level is significantly associated with distinct tumor pathological grade, TMN stage, and overall survival (OS). The BolA family can be considered as prognostic risk biomarkers of HCC. A small number of BolA gene-mutated samples were detected in the HCC tissue. IntAct analysis revealed that BolA1/2/3 was closely associated with the GLRX3 expression in HCC, which is implicated in the regulation of the cellular iron homeostasis and tumor growth. Furthermore, prognostic values of altered BolAs and their neighbor GLRX3 gene in HCC patients were validated by SurvExpress analysis. In conclusion, the membrane BolA family identified in this study provides very useful information for the mechanism of hepatic tumorigenesis.
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Burns, Mannix, Syed Husain Mustafa Rizvi, Yuko Tsukahara, David R. Pimentel, Ivan Luptak, Naomi M. Hamburg, Reiko Matsui, and Markus M. Bachschmid. "Role of Glutaredoxin-1 and Glutathionylation in Cardiovascular Diseases." International Journal of Molecular Sciences 21, no. 18 (September 16, 2020): 6803. http://dx.doi.org/10.3390/ijms21186803.
Повний текст джерелаАнотація:
Cardiovascular diseases are the leading cause of death worldwide, and as rates continue to increase, discovering mechanisms and therapeutic targets become increasingly important. An underlying cause of most cardiovascular diseases is believed to be excess reactive oxygen or nitrogen species. Glutathione, the most abundant cellular antioxidant, plays an important role in the body’s reaction to oxidative stress by forming reversible disulfide bridges with a variety of proteins, termed glutathionylation (GSylation). GSylation can alter the activity, function, and structure of proteins, making it a major regulator of cellular processes. Glutathione-protein mixed disulfide bonds are regulated by glutaredoxins (Glrxs), thioltransferase members of the thioredoxin family. Glrxs reduce GSylated proteins and make them available for another redox signaling cycle. Glrxs and GSylation play an important role in cardiovascular diseases, such as myocardial ischemia and reperfusion, cardiac hypertrophy, peripheral arterial disease, and atherosclerosis. This review primarily concerns the role of GSylation and Glrxs, particularly glutaredoxin-1 (Glrx), in cardiovascular diseases and the potential of Glrx as therapeutic agents.
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a Kim, Sun, Soo Been Park, and Si Young Song. "GLRX3, a novel secretory biomarker of pancreatic cancer based on pancreatic cancer stem cell characteristics." Pancreatology 13, no. 4 (July 2013): S3. http://dx.doi.org/10.1016/j.pan.2013.07.070.
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Picou, Frederic, Jean-Claude Chomel, Marie Christine Bene, Marc G. Berger, Thierry Fest, Valerie Ugo, Eric Lippert, et al. "Prediction of One-Year Molecular Response to Imatinib at Diagnosis of Chronic Myeloid Leukemia By Scoring Gene Expression Levels of Antioxidant Enzymes." Blood 132, Supplement 1 (November 29, 2018): 3024. http://dx.doi.org/10.1182/blood-2018-99-118297.
Повний текст джерелаАнотація:
Abstract Introduction Frontline treatment of patients in chronic phase of chronic myeloid leukemia(CP-CML) is classically based on tyrosine kinase inhibitors (TKI). Imatinib was introduced in 1998, then second- and third-generation TKIs have been developed. This therapeutic arsenal suggest a possible personalized treatment. The choice of TKI could be guided on the one hand by the potential adverse effects depending on the co-morbidities and on the other hand, the efficiency of treatment since an optimal response during the first year is a therapeutic goal (Baccarani M et al. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol 2015, 94 Suppl 2:S141-7). Treatment inefficacy may be related to the persistence of quiescent leukemic cells, characterized by a decreased metabolic activity and redox metabolism inducing a low proliferation rate athough the BCR-ABL mutation is present. The level of reactive oxygen species (ROS) being regulated by antioxidant enzymes, we hypothesized that scoring gene expression levels of major antioxidant enzymes could be of clinical interest when considering the response to imatinib. By combining the gene expression profiles of CP-CML patients at the time of diagnosis and their molecular response (BCR-ABL1/ABL1 ratio) at one-year, we determined a theranostic Imatinib-Response Score (IRS) potentially useful to optimize therapeutic decisions (patent # WO2016083742). Methods The expression of antioxidant genes was quantified from blood samples collected from 122 CP-CML patients at diagnosis and 102 healthy volunteers (HealthOx protocol, ClinicalTrials.gov # NCT02789839). Sokal-scores were calculated and all patients were treated with imatinib for at least one year. Quantification of the BCR-ABL1/ABL1 ratio allowed to determine of the one-year response according to the ELN definition (optimal: BCR-ABL1/ABL1 ≤ 0.1%, warning: BCR-ABL1/ABL1 0.1-1%, failure: BCR-ABL1/ABL1 > 1%). RNA extraction was performed after red blood cell lysis and RNA quality was checked with a 2100 Bioanalyzer (Agilent). The expression of antioxidant genes (SOD1, SOD2, SOD3, CAT, TXN, TXN2, GLRX, GLRX2, GLRX3, GLRX5, GPX1, GPX2, GPX3, GPX4, GPX7, GSR, PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, PRDX6) and 3 housekeeping genes (ACTB, B2M, RPL13A) was quantified by RT-qPCR (LightCycler® 480 and UPL technology, Roche). All targets were concomitantly analyzed in triplicates and average values from patients and aged-matched healthy controls were used to determine Relative Quantification (RQ) values by the 2-ΔΔCt method. Mutations in the ABL kinase domain were studied by direct sequencing. IRS were determined by logarithmic logistic regression performed thanks to the glm() function of the stats package (R v3.2.2 software). The generalized linear model was obtained by logistic regression with weighted RQ and was validated by split-sample strategy (10,000 repeats). Samples were divided into two groups ("learning" and "test" groups) randomly mixing optimal responses and failures. Results and conclusion None of the patients had a mutation in the BCR-ABL kinase domain. The expression levels of numerous antioxidant genes were different when considering optimal response and failure to imatinib treatment. A multifactorial strategy by linear combination of normalized RQ values was used to calculate IRS, which allowed for an efficient discrimination between optimal response(IRS = -3.42±1.44) and failure (IRS = 1.76±0.64) (p-value = 1.4 10-9). The probability of one-year response to imatinib was assessed by empirical cumulative distribution function. This function allowed the prediction of optimal response and failure. As expected, the IRS values of patients with a warning response, not used to build the mathematical model (external validation), were located between those of optimal response and failure. Interestingly, the IRS was not correlated with Sokal-score of CP-CML patients (R2= 0.0333), reinforcing its potential usefulness for clinical management. Altogether, this retrospective multicentric study allowed the determination of a molecular score to predict imatinib response. This simple biological strategy using diagnosis blood sample of CP-CML patients will benefit from prospective studies to adapt therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Philpott, Caroline C., Avery G. Frey, Moon-Suhn Ryu, Daniel Palenchar, Justin Wildemann, Ajay A. Vashisht, James Wohlschlegel, and Kymberly Bullough. "Special Delivery: The Role of Iron Chaperones in the Distribution of Iron in Developing Red Cells." Blood 126, no. 23 (December 3, 2015): SCI—45—SCI—45. http://dx.doi.org/10.1182/blood.v126.23.sci-45.sci-45.
Повний текст джерелаАнотація:
Abstract Iron is an essential nutrient for every cell in the human body, yet it can also be a potent cellular toxin. Iron is essential because enzymes that require iron co-factors (namely, heme, iron-sulfur clusters, mononuclear and diiron centers) are involved in virtually every major metabolic process in the cell. Hundreds of iron, zinc, copper, and manganese proteins are expressed in human cells, yet little is known about the mechanisms by which these metalloproteins acquire their native metal ligands and avoid mis-metallation. Significant advances have been made in understanding the delivery of iron to iron-dependent enzymes in the cytosol. Poly(rC)-binding proteins (PCBPs) are multifunctional adaptors that mediate interactions between single-stranded nucleic acids, iron cofactors, and other proteins, affecting the fate and activity of the components of these interactions. PCBP1 is an iron-binding protein that delivers iron to ferritin in human cells via a direct protein-protein interaction and can be described as an iron chaperone. PCBP2, a human paralog of PCBP1, is also involved in the delivery of iron to ferritin, both in yeast cells and in human cells, suggesting that PCBP1 and PCBP2 work together in iron delivery. PCBP1 and PCBP2 can also deliver iron to the two major families of non-heme iron enzymes: the mononuclear and dinuclear iron-dependent oxygenases. The prolyl hydroxylases (PHDs) are mononuclear iron enzymes that regulate the degradation of hypoxia inducible factor 1 (HIF1). Misregulation of the HIF transcription factors leads to the development of a variety of cancers in humans. Cells depend on the iron chaperones PCBP1 and PCBP2 to maintain iron in the enzymatic active site of PHDs and the related enzyme, asparagyl hydroxylase and to maintain proper regulation of HIF1a, especially under conditions of iron limitation. Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme that is required for the posttranslational modification of a single lysine residue on eukaryotic initiation factor 5A (eIF5A). EIF5A and the conversion of this conserved lysine to hypusine are essential in all eukaryotes, as it enables the translation of peptides containing polyproline sequences. We found that cells depleted of PCBP1 or PCBP2 exhibited reduced activity of DOHH, which was due to a loss of iron in the active site of the enzyme. Thus, PCBPs are basic components of a cytosolic iron delivery system that serves both of the major classes of non-heme iron enzymes in the cytosol. Recent work has indicated that a second type of iron delivery system in the cytosol is mediated by a monothiol glutaredoxin, Glrx3, which, in vitro, can bind and transfer iron-sulfur clusters to recipient apo-iron-sulfur proteins. We have determined that PCBP1 directly interacts with Glrx3-containing complexes and can affect the coordination of iron-sulfur clusters by Glrx3. The huge flux of iron through the developing erythroid cell represents unique challenges for the utilization of cellular iron. We have examined the role of PCBPs as iron chaperones in terminal erythroid differentiation. The role of ferritin in erythroid cell maturation is controversial, but our data indicate that ferritin, PCBPs and NCOA4 are critical factors in erythrocyte development. The flux of iron through ferritin via the lysosome appears to be critical for the transfer of iron to mitochondria for heme synthesis. Disclosures No relevant conflicts of interest to declare.
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Vignon, Christine, Marie-Thérèse Georget, Yves Levern, Elfi Ducrocq, Marie-Christine Bernard, Marie-Hélène Estienne, Dominique Kerboeuf, et al. "Bone Marrow Mesenchymal Stromal Cells Regulate the Metabolism of H2O2 In Human Leukemic Cells." Blood 116, no. 21 (November 19, 2010): 1058. http://dx.doi.org/10.1182/blood.v116.21.1058.1058.
Повний текст джерелаАнотація:
Abstract Abstract 1058 Redox metabolism plays an important role in self-renewal and differentiation of hematopoietic cells and it has been recently established by the Guy Sauvageau's group (Institute for Research in Immunology and Cancer, Montréal, QC) that glutathione peroxydase 3 (GPx-3) promotes competitiveness of Hoxa9-Meis1 induced leukemic stem cells in which Gpx3 overexpression is concomitant of a decrease in H2O2 level and inactivation of p38 MAPK (Herault O et al, ASH annual meeting, 2010 - submitted). Leukemic cells located in the bone marrow (BM) are interacting with a microenvironment which plays a crucial role in the development and progression of leukemia. Mesenchymal stromal cells (MSCs) constitute a population of multipotential cells giving rise to the different hematopoietic microenvironmental cells (adipocytes, osteoblasts, chondrocytes, and vascular-smooth muscle-like hematopoietic supportive stromal cells). The aim of our study was to evaluate the effects of MSC-contact on the GPx-3/H2O2/p38 MAPK axis in human leukemic cells and to assess the cell cycle changes associated with the modification of H2O2 metabolism. BM MSCs were obtained from informed and consenting patients undergoing orthopedic surgery, following a procedure approved by the local ethical committee. Nucleated cells harvested from the iliac crest were seeded (5.104 cells per cm2) in α-MEM supplemented with 10% fetal calf serum (FCS), 20 mmol/l L-glutamine, and 100 units/mL penicillin G. Cells were incubated at 37°C in 95% humidified air and 5% CO2. When fully confluent, the layer of adherent cells was trypsinized (0.25% trypsin-EDTA), and the cells were resuspended in culture medium and seeded at 103 cells per cm2 (passage 1 - P1). BM MSCs were used at P2 in all experiments. The three-lineage mesenchymal differentiation of the BM MSCs used was systematically checked by culturing cells in adipogenic, chondrogenic, and osteogenic induction media as previously described (Delorme et al, Blood 2008, 111:2631). The human KG1a leukemic cell line (FAB M0/M1 CD34+ leukemic cells) was cultured in RPMI 1640 with 20 mmoL/L L-glutamine supplemented with 10% FCS, 100 units/mL penicillin G, and 100 mg/mL streptomycin. KG1a cells were seeded at 1.5 105 cells/cm2 and cocultured with MSCs for 72 h. We have defined two distinct localizations of leukemic cells relative to MSC layer: those in supernatant (non-adherent cells) and cells adhering on the surface of MSCs. The expression of antioxydative enzymes, H2O2 level, p38 MAPK activation (T180/Y182), cell cycle, proliferation and immunophenotype of these two cell fractions were evaluated at day 0 and day 3. The expression of SOD1, SOD2, SOD3, CAT, TXN, TXN2, GLRX, GLRX2, GLRX3, GLRX5, PRDX, PRDX2, PDRX3, PRDX4, PRDX5, PRDX6, GPX1, GPX2, GPX3, GPX4, GPX5, GPX6, GPX7 and GSR antioxydative genes and CDKN1A (p21CIP1) gene was quantified by qRT-PCR (Universal ProbeLibrary, Roche). SDS-PAGE and western-blot experiments were realized to quantify GPx-3 expression and p38 MAPK activation. Flow cytometry studies were performed: (a) to quantify H2O2 level by dichlorodihydrofluorescein diacetate (DCF-DA) staining; (b) to analyze the cell cycle by staining with 7-aminoactinomycin D (7AAD), Alexa Fluor®488-conjugated anti-human Ki67 and Alexa Fluor®488-conjugated anti-phospho-histone H3 (ser10) antibodies; (c) to track the cell divisions with carboxyfluorescein diacetate N-succinimidyl ester (CFSE). Supernatant of MSCs did not modify the GPx-3/H2O2/p38 MAPK axis in KG1a cells. Conversely, when compared with cells in the supernatant of MSCs, adhering KG1a cells were characterized by the exclusive overexpression of GPX3 antioxydative gene, the induction of GPx-3 production, a major decrease in H2O2 concentration and the inactivation of p38 MAPK. These effects were concomitant of cell cycle inhibition: increase in G0 phase, decrease in S and M phase, overexpression of CDKN1A and reduced mitotic activity (CFSE). Altogether these findings suggest that the bone marrow microenvironment plays a key role in the regulation of the oxidative metabolism of leukemic cells by promoting the inhibition of the H2O2/p38 MAPK axis via the induction of GPx-3. Modulation of the GPx-3/H2O2/p38 MAPK pathway by targeting of microenvironmental interactions in leukemia may have clinical relevance and it will be important to verify if these results can be extended in vivo to other models of human leukemias. Disclosures: No relevant conflicts of interest to declare.
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Camponeschi, Francesca, Nihar Ranjan Prusty, Sabine Annemarie Elisabeth Heider, Simone Ciofi-Baffoni, and Lucia Banci. "GLRX3 Acts as a [2Fe–2S] Cluster Chaperone in the Cytosolic Iron–Sulfur Assembly Machinery Transferring [2Fe–2S] Clusters to NUBP1." Journal of the American Chemical Society 142, no. 24 (May 20, 2020): 10794–805. http://dx.doi.org/10.1021/jacs.0c02266.
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Ershov, Pavel V., Yuri V. Mezentsev, Arthur T. Kopylov, Evgeniy O. Yablokov, Andrey V. Svirid, Aliaksandr Ya Lushchyk, Leonid A. Kaluzhskiy, et al. "Affinity Isolation and Mass Spectrometry Identification of Prostacyclin Synthase (PTGIS) Subinteractome." Biology 8, no. 2 (June 20, 2019): 49. http://dx.doi.org/10.3390/biology8020049.
Повний текст джерелаАнотація:
Prostacyclin synthase (PTGIS; EC 5.3.99.4) catalyzes isomerization of prostaglandin H2 to prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. At present, limited data exist on functional coupling and possible ways of regulating PTGIS due to insufficient information about protein–protein interactions in which this crucial enzyme is involved. The aim of this study is to isolate protein partners for PTGIS from rat tissue lysates. Using CNBr-activated Sepharose 4B with covalently immobilized PTGIS as an affinity sorbent, we confidently identified 58 unique proteins by mass spectrometry (LC-MS/MS). The participation of these proteins in lysate complex formation was characterized by SEC lysate profiling. Several potential members of the PTGIS subinteractome have been validated by surface plasmon resonance (SPR) analysis. SPR revealed that PTGIS interacted with full-length cytochrome P450 2J2 and glutathione S-transferase (GST). In addition, PTGIS was shown to bind synthetic peptides corresponding to sequences of for GSTA1, GSTM1, aldo-keto reductase (AKR1A1), glutaredoxin 3 (GLRX3) and histidine triad nucleotide binding protein 2 (HINT2). Prostacyclin synthase could potentially be involved in functional interactions with identified novel protein partners participating in iron and heme metabolism, oxidative stress, xenobiotic and drugs metabolism, glutathione and prostaglandin metabolism. The possible biological role of the recognized interaction is discussed in the context of PTGIS functioning.
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Özenver, Nadire, and Thomas Efferth. "Identification of Prognostic and Predictive Biomarkers and Druggable Targets among 205 Antioxidant Genes in 21 Different Tumor Types via Data-Mining." Pharmaceutics 15, no. 2 (January 28, 2023): 427. http://dx.doi.org/10.3390/pharmaceutics15020427.
Повний текст джерелаАнотація:
(1) Background: Oxidative stress is crucial in carcinogenesis and the response of tumors to treatment. Antioxidant genes are important determinants of resistance to chemotherapy and radiotherapy. We hypothesized that genes involved in the oxidative stress response may be valuable as prognostic biomarkers for the survival of cancer patients and as druggable targets. (2) Methods: We mined the KM Plotter and TCGA Timer2.0 Cistrome databases and investigated 205 antioxidant genes in 21 different tumor types within the context of this investigation. (3) Results: Of 4347 calculations with Kaplan–Meier statistics, 84 revealed statistically significant correlations between high gene expression and worse overall survival (p < 0.05; false discovery rate ≤ 5%). The tumor types for which antioxidant gene expression was most frequently correlated with worse overall survival were renal clear cell carcinoma, renal papillary cell carcinoma, and hepatocellular carcinoma. Seventeen genes were clearly overexpressed in tumors compared to their corresponding normal tissues (p < 0.001), possibly qualifying them as druggable targets (i.e., ALOX5, ALOX5AP, EPHX4, G6PD, GLRX3, GSS, PDIA4, PDIA6, PRDX1, SELENOH, SELENON, STIP1, TXNDC9, TXNDC12, TXNL1, TXNL4A, and TXNRD1). (4) Conclusions: We concluded that a sub-set of antioxidant genes might serve as prognostic biomarkers for overall survival and as druggable targets. Renal and liver tumors may be the most suitable entities for this approach.
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Hoffman, Sidra M., Jane E. Tully, Karolyn G. Lahue, Vikas Anathy, James D. Nolin, Amy S. Guala, Jos L. J. van der Velden, et al. "Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 6 (September 15, 2012): L528—L538. http://dx.doi.org/10.1152/ajplung.00167.2012.
Повний текст джерелаАнотація:
Protein- S-glutathionylation (PSSG) is an oxidative modification of reactive cysteines that has emerged as an important player in pathophysiological processes. Under physiological conditions, the thiol transferase, glutaredoxin-1 (Glrx1) catalyses deglutathionylation. Although we previously demonstrated that Glrx1 expression is increased in mice with allergic inflammation, the impact of Glrx1/PSSG in the development of allergic airways disease remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 in the pathogenesis of allergic inflammation and airway hyperresponsiveness (AHR) in mice. Glrx1 −/− or WT mice were subjected to the antigen, ovalbumin (OVA), and parameters of allergic airways disease were evaluated 48 h after three challenges, and 48 h or 7 days after six challenges with aerosolized antigen. Although no clear increases in PSSG were observed in WT mice in response to OVA, marked increases were detected in lung tissue of mice lacking Glrx1 48 h following six antigen challenges. Inflammation and expression of proinflammatory mediators were decreased in Glrx1 −/− mice, dependent on the time of analysis. WT and Glrx1 −/− mice demonstrated comparable increases in AHR 48 h after three or six challenges with OVA. However, 7 days postcessation of six challenges, parameters of AHR in Glrx1 −/− mice were resolved to control levels, accompanied by marked decreases in mucus metaplasia and expression of Muc5AC and GOB5. These results demonstrate that the Glrx1/ S-glutathionylation redox status in mice is a critical regulator of AHR, suggesting that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.
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Chung, Sangwoon, Isaac Kirubakaran Sundar, Hongwei Yao, Ye-Shih Ho та Irfan Rahman. "Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of IκB kinases in mice: impact on histone acetylation". American Journal of Physiology-Lung Cellular and Molecular Physiology 299, № 2 (серпень 2010): L192—L203. http://dx.doi.org/10.1152/ajplung.00426.2009.
Повний текст джерелаАнотація:
Glutaredoxin 1 (Glrx1) is a small dithiol protein that regulates the cellular redox state and redox-dependent signaling pathways via modulation of protein glutathionylation. IκB kinase (IKK), an essential enzyme for NF-κB activation, can be subjected to S-glutathionylation leading to alteration of its activity. However, the role of Glrx1 in cigarette smoke (CS)-induced lung inflammation and chromatin modifications are not known. We hypothesized that Glrx1 regulates the CS-induced lung inflammation and chromatin modifications via differential regulation of IKKs by S-glutathionylation in mouse lung. Glrx1 knockout (KO) and wild-type (WT) mice were exposed to CS for 3 days and determined the role of Glrx1 in regulation of proinflammatory response in the lung. Neutrophil influx in bronchoalveolar lavage fluid and proinflammatory cytokine release in lung were increased in Glrx1 KO mice compared with WT mice exposed to CS, which was associated with augmented nuclear translocation of RelA/p65 and its phospho-acetylation. Interestingly, phosphorylated and total levels of IKKα, but not total and phosphorylated IKKβ levels, were increased in lungs of Glrx1 KO mice compared with WT mice exposed to CS. Ablation of Glrx1 leads to increased CS-induced IKKβ glutathionylation rendering it inactive, whereas IKKα was activated resulting in increased phospho-acetylation of histone H3 in mouse lung. Thus, targeted disruption of Glrx1 regulates the lung proinflammatory response via histone acetylation specifically by activation of IKKα in response to CS exposure. Overall, our study suggests that S-glutathionylation and phosphorylation of IKKα plays an important role in histone acetylation on proinflammatory gene promoters and NF-κB-mediated abnormal and sustained lung inflammation in pathogenesis of chronic inflammatory lung diseases.
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Petry, Sebastian Friedrich, Axel Römer, Divya Rawat, Lara Brunner, Nina Lerch, Mengmeng Zhou, Rekha Grewal, et al. "Loss and Recovery of Glutaredoxin 5 Is Inducible by Diet in a Murine Model of Diabesity and Mediated by Free Fatty Acids In Vitro." Antioxidants 11, no. 4 (April 15, 2022): 788. http://dx.doi.org/10.3390/antiox11040788.
Повний текст джерелаАнотація:
Free fatty acids (FFA), hyperglycemia, and inflammatory cytokines are major mediators of β-cell toxicity in type 2 diabetes mellitus, impairing mitochondrial metabolism. Glutaredoxin 5 (Glrx5) is a mitochondrial protein involved in the assembly of iron–sulfur clusters required for complexes of the respiratory chain. We have provided evidence that islet cells are deprived of Glrx5, correlating with impaired insulin secretion during diabetes in genetically obese mice. In this study, we induced diabesity in C57BL/6J mice in vivo by feeding the mice a high-fat diet (HFD) and modelled the diabetic metabolism in MIN6 cells through exposure to FFA, glucose, or inflammatory cytokines in vitro. qRT-PCR, ELISA, immunohisto-/cytochemistry, bioluminescence, and respirometry were employed to study Glrx5, insulin secretion, and mitochondrial biomarkers. The HFD induced a depletion of islet Glrx5 concomitant with an obese phenotype, elevated FFA in serum and reactive oxygen species in islets, and impaired glucose tolerance. Exposure of MIN6 cells to FFA led to a loss of Glrx5 in vitro. The FFA-induced depletion of Glrx5 coincided with significantly altered mitochondrial biomarkers. In summary, we provide evidence that Glrx5 is regulated by FFA in type 2 diabetes mellitus and is linked to mitochondrial dysfunction and blunted insulin secretion.
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Choi, Yeon Joo, Dae Won Kim, Min Jea Shin, Hyeon Ji Yeo, Eun Ji Yeo, Lee Re Lee, Yejin Song, et al. "PEP-1-GLRX1 Reduces Dopaminergic Neuronal Cell Loss by Modulating MAPK and Apoptosis Signaling in Parkinson’s Disease." Molecules 26, no. 11 (June 1, 2021): 3329. http://dx.doi.org/10.3390/molecules26113329.
Повний текст джерелаАнотація:
Parkinson’s disease (PD) is characterized mainly by the loss of dopaminergic neurons in the substantia nigra (SN) mediated via oxidative stress. Although glutaredoxin-1 (GLRX1) is known as one of the antioxidants involved in cell survival, the effects of GLRX1 on PD are still unclear. In this study, we investigated whether cell-permeable PEP-1-GLRX1 inhibits dopaminergic neuronal cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We showed that PEP-1-GLRX1 protects cell death and DNA damage in MPP+-exposed SH-SY5Y cells via the inhibition of MAPK, Akt, and NF-κB activation and the regulation of apoptosis-related protein expression. Furthermore, we found that PEP-1-GLRX1 was delivered to the SN via the blood–brain barrier (BBB) and reduced the loss of dopaminergic neurons in the MPTP-induced PD model. These results indicate that PEP-1-GLRX1 markedly inhibited the loss of dopaminergic neurons in MPP+- and MPTP-induced cytotoxicity, suggesting that this fusion protein may represent a novel therapeutic agent against PD.
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Bousta, Abderrahmane, Sabrina Bondu, Alexandre Houy, Nicolas Cagnard, Carine Lefevre, Delphine Bernard, Marc-Henri Stern, Michaela Fontenay, and Olivier Kosmider. "Gene Expression and Alternative Splicing Datasets Analyses of MDS with Ring Sideroblasts Highlight Alternative Branchpoint Usage in Genes Involved in Iron Metabolism and Erythropoiesis." Blood 128, no. 22 (December 2, 2016): 1972. http://dx.doi.org/10.1182/blood.v128.22.1972.1972.
Повний текст джерелаАнотація:
Abstract Introduction SF3B1 hotspot mutations are associated with various cancers like uveal melanoma, chronic lymphocytic leukemia and myelodysplastic syndrome with ring sideroblasts (MDS-RS). These mutations affect RNA splicing by the use of alternative branchpoints resulting in an aberrant 3' splice site (ss) selection. RNA-sequencing (RNA-seq) analyzed to quantify exon-exon junctions identified aberrantly spliced transcripts in target genes, and half of them are predicted to be degraded by non-sense mediated decay. For this reason, target genes in SF3B1-mutated MDS remain partially characterized. In the present study, we performed deep RNA-seq analysis of bone marrow mononuclear cells in low/int-1 MDS with SF3B1 mutations to identify aberrant/cryptic splicing events among up or down-regulated gene sets. Methods SF3B1 MUT MDS (n=21) were compared to 6 SF3B1WT cases and 5 controls. Analysis of RNA-seq read count was performed using the Voom method associated with the Limma empirical Bayes analysis pipeline (https://genomebiology.biomedcentral.com/articles/10.1186/gb-2014-15-2-r29). Up or downregulated gene sets were identified using Gene Set Enrichment Analysis (GSEA, false discovery rate<0.1). Gene expression profiling data (Affymetrix Hu2.0) were also available for 26/27 patient samples. TopHat (v2.0.6) was used to align the reads against the human reference genome Hg19 RefSeq (RNA sequences, GRCh37) downloaded from the UCSC Genome Browser (http://genome.ucsc.edu). Read counts for splicing junctions from junctions.bed TopHat output were considered for a differential analysis using DESeq2. Only alternative acceptor splice sites (two or more 3′ss with junctions to the same 5′ss) and alternative donor splice sites (two or more 5′ss with junctions to the same 3′ss) with P-values ≤10−5 (Benjamini-Hochberg) and absolute Log2 (fold change) ≥1 were considered. Results Principal component analysis (PCA) nicely discriminated controls from patients, and patients according to the presence of a SF3B1 mutation. A set of 6971 genes was differently expressed (P- value<0.05) between SF3B1MUT and SF3B1WT cases and allows unsupervised clustering in two separated groups (Fig. 1). Distinct gene sets also discriminated SF3B1MUT or SF3B1WT from controls. Consistent with increased amount of erythroblasts in MDS-RS bone marrows, a set of erythroid genes including several genes involved in hemebiosynthesis pathway (ALAD, UROS, ALAS2, UROD) was significantly enriched in SF3B1MUT samples. Genes selected for their involvement in the core iron-sulfur cluster mitochondrial machinery (FXN, BOLA3, FDXR, GLRX5, ISCA2, NFS1, ISCU), the iron binding and trafficking (SLC25A38, ABCB10, TFR2, SLC25A37, ABCB6, FAM132B, SLC25A39, FTH1) and the cellular iron homeostasis (ACO1, ACO2, GLRX3) were also significantly enriched (FDR<10% and nominal P-value<0.05) when input in GSEA. Moreover, other enriched gene sets were G2M checkpoint, MYC targets, oxidative phosphorylation and E2F targets. All of these observations were similarly obtained when analyzing Affymetrix data. Furthermore SF3B1MUT samples with a K700E substitution harbored a specific pattern of deregulated genes, which allowed the ordering of SF3B1MUT samples according to the type of substitution. As previously reported by AlsafadiS et al (2016), analysis of splice junctions using DESeq2 revealed an overall high level of differences between SF3B1MUT and SF3B1WTsamples. Among more than 540 differentially spliced junctions, more than 80% involved an aberrant acceptor (3'ss) site. As determined by PCA, the top 50 genes associated with relevant aberrant junctions were linked to iron metabolism or erythropoiesis and differentially expressed between SF3B1MUT and SF3B1WTsamples. Conclusion In this study, we combined robust analyses of gene expression and aberrantly spliced transcript expression in MDS with SF3B1 mutation. By comparing SF3B1MUTversus SF3B1WT samples, we identified a set of deregulated genes in which both normally and aberrantly spliced transcripts were detected that could contribute to the physiopathology of MDS-RS. Figure 1 Hierarchical clustering and heatmapshowing differentially expressed genes (P-value<0.05) between SF3B1MUT (n=21, black) and SF3B1WT samples (n=6, grey) Ref. Alsafadi S et al. Nat Commun. 2016 Feb 4;7:10615. Figure 1. Hierarchical clustering and heatmapshowing differentially expressed genes (P-value<0.05) between SF3B1MUT (n=21, black) and SF3B1WT samples (n=6, grey) Ref. Alsafadi S et al. Nat Commun. 2016 Feb 4;7:10615. Disclosures No relevant conflicts of interest to declare.
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Murdoch, Colin E., Markus M. Bachschmid, and Reiko Matsui. "Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway." Biochemical Society Transactions 42, no. 6 (November 17, 2014): 1665–70. http://dx.doi.org/10.1042/bst20140213.
Повний текст джерелаАнотація:
S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating the activity of nuclear factor κB (NF-κB) and actin polymerization. Vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) migration is inhibited by Glrx overexpression. In mice overexpressing Glrx, blood flow recovery, exercise function and capillary density were significantly attenuated after hindlimb ischaemia (HLI). Wnt5a and soluble Fms-like tyrosine kinase-1 (sFlt-1) were enhanced in the ischaemic-limb muscle and plasma respectively from Glrx transgenic (TG) mice. A Wnt5a/sFlt-1 pathway had been described in myeloid cells controlling retinal blood vessel development. Interestingly, a Wnt5a/sFlt-1 pathway was found also to play a role in EC to inhibit network formation. S-glutathionylation of NF-κB components inhibits its activation. Up-regulated Glrx stimulated the Wnt5a/sFlt-1 pathway through enhancing NF-κB signalling. These studies show a novel role for Glrx in post-ischaemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in pathological conditions including diabetes.
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Li, Jing, Xuewen Tang, Xing Wen, Xiaoyuan Ren, Huihui Zhang, Yatao Du, and Jun Lu. "Mitochondrial Glrx2 Knockout Augments Acetaminophen-Induced Hepatotoxicity in Mice." Antioxidants 11, no. 9 (August 24, 2022): 1643. http://dx.doi.org/10.3390/antiox11091643.
Повний текст джерелаАнотація:
Acetaminophen (APAP) is one of the most widely used drugs with antipyretic and analgesic effects, and thus hepatotoxicity from the overdose of APAP becomes one of the most common forms of drug-induced liver injury. The reaction towards thiol molecules, such as GSH by APAP metabolite and N-acetyl-p-benzo-quinonimine (NAPQI), is the main cause of APAP-induced hepatotoxicity. However, the role of many other thiol-related regulators in toxicity caused by APAP is still unclear. Here we have found that knockout of the Glrx2 gene, which encodes mitochondrial glutaredoxin2 (Grx2), sensitized mice to APAP-caused hepatotoxicity. Glrx2 deletion hindered Nrf2-mediated compensatory recovery of thiol-dependent redox systems after acetaminophen challenge, resulting in a more oxidized cellular state with a further decrease in GSH level, thioredoxin reductase activity, and GSH/GSGG ratio. The weakened feedback regulation capacity of the liver led to higher levels of protein glutathionylation and thioredoxin (both Trx1 and Trx2) oxidation in Glrx2−/− mice. Following the cellular environment oxidation, nuclear translocation of apoptosis-inducing factor (AIF) was elevated in the liver of Glrx2−/− mice. Taken together, these results demonstrated that mitochondrial Grx2 deficiency deteriorated APAP-induced hepatotoxicity by interrupting thiol-redox compensatory response, enhancing the AIF pathway-mediated oxidative damage.
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Watanabe, Yosuke, Colin E. Murdoch, Soichi Sano, Yasuo Ido, Markus M. Bachschmid, Richard A. Cohen та Reiko Matsui. "Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization". Proceedings of the National Academy of Sciences 113, № 21 (9 травня 2016): 6011–16. http://dx.doi.org/10.1073/pnas.1524198113.
Повний текст джерелаАнотація:
Reactive oxygen species (ROS) are increased in ischemic tissues and necessary for revascularization; however, the mechanism remains unclear. Exposure of cysteine residues to ROS in the presence of glutathione (GSH) generates GSH-protein adducts that are specifically reversed by the cytosolic thioltransferase, glutaredoxin-1 (Glrx). Here, we show that a key angiogenic transcriptional factor hypoxia-inducible factor (HIF)-1α is stabilized by GSH adducts, and the genetic deletion of Glrx improves ischemic revascularization. In mouse muscle C2C12 cells, HIF-1α protein levels are increased by increasing GSH adducts with cell-permeable oxidized GSH (GSSG-ethyl ester) or 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanyl thiocarbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), an inhibitor of glutathione reductase. A biotin switch assay shows that GSSG-ester-induced HIF-1α contains reversibly modified thiols, and MS confirms GSH adducts on Cys520 (mouse Cys533). In addition, an HIF-1α Cys520 serine mutant is resistant to 2-AAPA–induced HIF-1α stabilization. Furthermore, Glrx overexpression prevents HIF-1α stabilization, whereas Glrx ablation by siRNA increases HIF-1α protein and expression of downstream angiogenic genes. Blood flow recovery after femoral artery ligation is significantly improved in Glrx KO mice, associated with increased levels of GSH-protein adducts, capillary density, vascular endothelial growth factor (VEGF)-A, and HIF-1α in the ischemic muscles. Therefore, Glrx ablation stabilizes HIF-1α by increasing GSH adducts on Cys520 promoting in vivo HIF-1α stabilization, VEGF-A production, and revascularization in the ischemic muscles.
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Hasim, Sahar, Nur Ahmad Hussin, Fadhel Alomar, Keshore R. Bidasee, Kenneth W. Nickerson, and Mark A. Wilson. "A Glutathione-independent Glyoxalase of the DJ-1 Superfamily Plays an Important Role in Managing Metabolically Generated Methylglyoxal in Candida albicans." Journal of Biological Chemistry 289, no. 3 (December 3, 2013): 1662–74. http://dx.doi.org/10.1074/jbc.m113.505784.
Повний текст джерелаАнотація:
Methylglyoxal is a cytotoxic reactive carbonyl compound produced by central metabolism. Dedicated glyoxalases convert methylglyoxal to d-lactate using multiple catalytic strategies. In this study, the DJ-1 superfamily member ORF 19.251/GLX3 from Candida albicans is shown to possess glyoxalase activity, making this the first demonstrated glutathione-independent glyoxalase in fungi. The crystal structure of Glx3p indicates that the protein is a monomer containing the catalytic triad Cys136-His137-Glu168. Purified Glx3p has an in vitro methylglyoxalase activity (Km = 5.5 mm and kcat = 7.8 s−1) that is significantly greater than that of more distantly related members of the DJ-1 superfamily. A close Glx3p homolog from Saccharomyces cerevisiae (YDR533C/Hsp31) also has glyoxalase activity, suggesting that fungal members of the Hsp31 clade of the DJ-1 superfamily are all probable glutathione-independent glyoxalases. A homozygous glx3 null mutant in C. albicans strain SC5314 displays greater sensitivity to millimolar levels of exogenous methylglyoxal, elevated levels of intracellular methylglyoxal, and carbon source-dependent growth defects, especially when grown on glycerol. These phenotypic defects are complemented by restoration of the wild-type GLX3 locus. The growth defect of Glx3-deficient cells in glycerol is also partially complemented by added inorganic phosphate, which is not observed for wild-type or glucose-grown cells. Therefore, C. albicans Glx3 and its fungal homologs are physiologically relevant glutathione-independent glyoxalases that are not redundant with the previously characterized glutathione-dependent GLO1/GLO2 system. In addition to its role in detoxifying glyoxals, Glx3 and its close homologs may have other important roles in stress response.
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Kumar, Priyadarsini, and Stanley Meizel. "Identification and spatial distribution of glycine receptor subunits in human sperm." REPRODUCTION 136, no. 4 (October 2008): 387–90. http://dx.doi.org/10.1530/rep-08-0223.
Повний текст джерелаАнотація:
The human sperm surface glycine receptor (GLR) plays a role in an important fertilization event, the sperm acrosome reaction. Here, by western blot analysis, we report the presence of GLRA1, GLRA2, GLRA3, and GLRB subunits in human sperm. Immunolocalization studies showed that the GLRA1 and GLRA2 subunits are present in the equatorial region, the GLRA3 subunit in the flagellar principal piece, and the GLRB subunit in the acrosomal region of sperm. This first demonstration of isoforms of the sperm GLRA subunit and of a differential spatial distribution of the α and β subunits on the surface of mammalian sperm suggests the possibility that human sperm GLRs have more than one function.
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Ye, Hong, and Tracey A. Rouault. "Erythropoiesis and Iron Sulfur Cluster Biogenesis." Advances in Hematology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/329394.
Повний текст джерелаАнотація:
Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. Heme synthesis depends on iron through its dependence on iron sulfur (Fe-S) cluster biogenesis. Here, we review the relationship between Fe-S biogenesis and heme synthesis in erythropoiesis, with emphasis on the proteins, GLRX5, ABCB7, ISCA, and C1orf69. These Fe-S biosynthesis proteins are highly expressed in erythroid tissues, and deficiency of each of these proteins has been shown to cause anemia in zebrafish model. GLRX5 is involved in the production and ABCB7 in the export of an unknown factor that may function as a gauge of mitochondrial iron status, which may indirectly modulate activity of iron regulatory proteins (IRPs). ALAS2, the enzyme catalyzing the first step in heme synthesis, is translationally controlled by IRPs. GLRX5 may also provide Fe-S cofactor for ferrochelatase, the last enzyme in heme synthesis. ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase, the enzyme producing lipoate for pyruvate dehydrogenase complex (PDC). PDC and aconitase are involved in the production of succinyl-CoA, a substrate for heme biosynthesis. Thus, many steps of heme synthesis depend on Fe-S cluster assembly.
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Camaschella, Clara, Alessandro Campanella, Luigia De Falco, Loredana Boschetto, Roberta Merlini, Laura Silvestri, Sonia Levi, and Achille Iolascon. "The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload." Blood 110, no. 4 (August 15, 2007): 1353–58. http://dx.doi.org/10.1182/blood-2007-02-072520.
Повний текст джерелаАнотація:
Abstract Inherited microcytic-hypochromic anemias in rodents and zebrafish suggest the existence of corresponding human disorders. The zebrafish mutant shiraz has severe anemia and is embryonically lethal because of glutaredoxin 5 (GRLX5) deletion, insufficient biogenesis of mitochondrial iron-sulfur (Fe/S) clusters, and deregulated iron-regulatory protein 1 (IRP1) activity. This leads to stabilization of transferrin receptor 1 (TfR) RNA, repression of ferritin, and ALA-synthase 2 (ALAS2) translation with impaired heme synthesis. We report the first case of GLRX5 deficiency in a middle-aged anemic male with iron overload and a low number of ringed sideroblasts. Anemia was worsened by blood transfusions but partially reversed by iron chelation. The patient had a homozygous (c.294A>G) mutation that interferes with intron 1 splicing and drastically reduces GLRX5 RNA. As in shiraz, aconitase and H-ferritin levels were low and TfR level was high in the patient's cells, compatible with increased IRP1 binding. Based on the biochemical and clinical phenotype, we hypothesize that IRP2, less degraded by low heme, contributes to the repression of the erythroblasts ferritin and ALAS2, increasing mitochondrial iron. Iron chelation, redistributing iron to the cytosol, might relieve IRP2 excess, improving heme synthesis and anemia. GLRX5 function is highly conserved, but at variance with zebrafish, its defect in humans leads to anemia and iron overload.
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Lee, Seung-Hwan, Saeedah Almutairi, and Alaa Kassim Ali. "Reactive oxygen species modulate immune cell effector function." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.20. http://dx.doi.org/10.4049/jimmunol.198.supp.222.20.
Повний текст джерелаАнотація:
Abstract During an infection or carcinogenesis, the stimulation of immune cells may lead to elevated intracellular levels of reactive oxygen species (ROS), and this oxidative stress can cause damage to the cell. Interestingly, previous reports have shown that ROS produced through cell activation play a critical role as signaling messengers in immune responses. Yet, little is known in regard to the role of ROS in natural killer (NK) cell effector functions. Our data suggest that the levels of ROS increase in NK cells upon stimulation. Therefore, we hypothesize that, upon stimulation of NK cells, ROS accumulate and provide positive signaling that leads to the upregulation of NK cell effector functions. To test this hypothesis, we examined NK cell function and proliferation in Glrx2-deficient mice in which the ROS levels are elevated in the mitochondrial matrix due to a defect in the redox system. We found that lack of Glrx2 in NK and T cells does not improve their cytotoxic potential or their ability to produce IFNg. However, Glrx2-deficient NK cells showed enhanced proliferation when stimulated with IL-2, indicating that during prolonged stress, the elevated levels of ROS drive NK cells to undergo robust cell division. This finding will elucidate a link between the levels of ROS and immune cell proliferation during viral infection and carcinogenesis.
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Zou, Xiaoyu, Muhammad Ijaz Ahmad, Di Zhao, Min Zhang, and Chunbao Li. "Glutaredoxin1 knockout promotes high-fat diet-induced obesity in male mice but not in female ones." Food & Function 12, no. 16 (2021): 7415–27. http://dx.doi.org/10.1039/d1fo01241j.
Повний текст джерелаАнотація:
Glrx1 deficiency aggravated high-fat-diet-induced hyperlipidemia, liver injury and oxidative stress. Diet altered the gut microbiota composition. The results provide a new insight into the susceptibilities to obesity between males and females.
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Sen, Sambuddha, Brian Rao, Christine Wachnowsky, and J. A. Cowan. "Cluster exchange reactivity of [2Fe–2S] cluster-bridged complexes of BOLA3 with monothiol glutaredoxins." Metallomics 10, no. 9 (2018): 1282–90. http://dx.doi.org/10.1039/c8mt00128f.
Повний текст джерелаАнотація:
Cluster exchange reactivity of a [2Fe–2S]-bridged BOLA3–GLRX5 heterodimer complex with mitochondrial partner proteins is quantitatively evaluated, and exchange rate constants and ITC-determined thermodynamic parameters contrasted with the corresponding BOLA3 heterocomplex with NFU1.
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Liu, Gang, Yongwei Wang, Gregory J. Anderson, Clara Camaschella, Yanzhong Chang, and Guangjun Nie. "Functional Analysis ofGLRX5Mutants Reveals Distinct Functionalities of GLRX5 Protein." Journal of Cellular Biochemistry 117, no. 1 (November 19, 2015): 207–17. http://dx.doi.org/10.1002/jcb.25267.
Повний текст джерела
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Tong, Wing-Hang, Nunziata Maio, De-Liang Zhang, Erika M. Palmieri, Hayden Ollivierre, Manik C. Ghosh, Daniel W. McVicar, and Tracey A. Rouault. "TLR-activated repression of Fe-S cluster biogenesis drives a metabolic shift and alters histone and tubulin acetylation." Blood Advances 2, no. 10 (May 21, 2018): 1146–56. http://dx.doi.org/10.1182/bloodadvances.2018015669.
Повний текст джерелаАнотація:
Key Points TLR activation suppresses expression of Fe-S cluster biogenesis factors NFS1, ISCU, HSC20, FXN, ISD11, GLRX5, CIAO1, FAM96A, and FAM96B. Restriction of Fe-S cluster biogenesis not only impairs oxidative metabolism but also modulates histone and tubulin acetylation profiles.
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Liu, Zhaoping, Yanyan Wang, Zhenru Xu, Shunling Yuan, Yanglin Ou, Zeyu Luo, Feng Wen, Jing Liu, and Ji Zhang. "Analysis of ceRNA networks and identification of potential drug targets for drug-resistant leukemia cell K562/ADR." PeerJ 9 (May 25, 2021): e11429. http://dx.doi.org/10.7717/peerj.11429.
Повний текст джерелаАнотація:
Background Drug resistance is the main obstacle in the treatment of leukemia. As a member of the competitive endogenous RNA (ceRNA) mechanism, underlying roles of lncRNA are rarely reported in drug-resistant leukemia cells. Methods The gene expression profiles of lncRNAs and mRNAs in doxorubicin-resistant K562/ADR and sensitive K562 cells were established by RNA sequencing (RNA-seq). Expression of differentially expressed lncRNAs (DElncRNAs) and DEmRNAs was validated by qRT-PCR. The potential biological functions of DElncRNAs targets were identified by GO and KEGG pathway enrichment analyses, and the lncRNA-miRNA-mRNA ceRNA network was further constructed. K562/ADR cells were transfected with CCDC26 and LINC01515 siRNAs to detect the mRNA levels of GLRX5 and DICER1, respectively. The cell survival rate after transfection was detected by CCK-8 assay. Results The ceRNA network was composed of 409 lncRNA-miRNA pairs and 306 miRNA-mRNA pairs based on 67 DElncRNAs, 58 DEmiRNAs and 192 DEmRNAs. Knockdown of CCDC26 and LINC01515 increased the sensitivity of K562/ADR cells to doxorubicin and significantly reduced the half-maximal inhibitory concentration (IC50) of doxorubicin. Furthermore, knockdown of GLRX5 and DICER1 increased the sensitivity of K562/ADR cells to doxorubicin and significantly reduced the IC50 of doxorubicin. Conclusions The ceRNA regulatory networks may play important roles in drug resistance of leukemia cells. CCDC26/miR-140-5p/GLRX5 and LINC01515/miR-425-5p/DICER1 may be potential targets for drug resistance in K562/ADR cells. This study provides a promising strategy to overcome drug resistance and deepens the understanding of the ceRNA regulatory mechanism related to drug resistance in CML cells.
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Weiler, Benjamin Dennis, Marie-Christin Brück, Isabell Kothe, Eckhard Bill, Roland Lill, and Ulrich Mühlenhoff. "Mitochondrial [4Fe-4S] protein assembly involves reductive [2Fe-2S] cluster fusion on ISCA1–ISCA2 by electron flow from ferredoxin FDX2." Proceedings of the National Academy of Sciences 117, no. 34 (August 12, 2020): 20555–65. http://dx.doi.org/10.1073/pnas.2003982117.
Повний текст джерелаАнотація:
The essential process of iron-sulfur (Fe/S) cluster assembly (ISC) in mitochondria occurs in three major phases. First, [2Fe-2S] clusters are synthesized on the scaffold protein ISCU2; second, these clusters are transferred to the monothiol glutaredoxin GLRX5 by an Hsp70 system followed by insertion into [2Fe-2S] apoproteins; third, [4Fe-4S] clusters are formed involving the ISC proteins ISCA1–ISCA2–IBA57 followed by target-specific apoprotein insertion. The third phase is poorly characterized biochemically, because previous in vitro assembly reactions involved artificial reductants and lacked at least one of the in vivo-identified ISC components. Here, we reconstituted the maturation of mitochondrial [4Fe-4S] aconitase without artificial reductants and verified the [2Fe-2S]-containing GLRX5 as cluster donor. The process required all components known from in vivo studies (i.e., ISCA1–ISCA2–IBA57), yet surprisingly also depended on mitochondrial ferredoxin FDX2 and its NADPH-coupled reductase FDXR. Electrons from FDX2 catalyze the reductive [2Fe-2S] cluster fusion on ISCA1–ISCA2 in an IBA57-dependent fashion. This previously unidentified electron transfer was occluded during previous in vivo studies due to the earlier FDX2 requirement for [2Fe-2S] cluster synthesis on ISCU2. The FDX2 function is specific, because neither FDX1, a mitochondrial ferredoxin involved in steroid production, nor other cellular reducing systems, supported maturation. In contrast to ISC factor-assisted [4Fe-4S] protein assembly, [2Fe-2S] cluster transfer from GLRX5 to [2Fe-2S] apoproteins occurred spontaneously within seconds, clearly distinguishing the mechanisms of [2Fe-2S] and [4Fe-4S] protein maturation. Our study defines the physiologically relevant mechanistic action of late-acting ISC factors in mitochondrial [4Fe-4S] cluster synthesis, trafficking, and apoprotein insertion.
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Ahmad, Muhammad Ijaz, Muhammad Umair Ijaz, Muzahir Hussain, Iftikhar Ali Khan, Noreen Mehmood, Sultan Mehmood Siddiqi, Congcong Liu, et al. "High fat diet incorporated with meat proteins changes biomarkers of lipid metabolism, antioxidant activities, and the serum metabolomic profile in Glrx1−/− mice." Food & Function 11, no. 1 (2020): 236–52. http://dx.doi.org/10.1039/c9fo02207d.
Повний текст джерелаАнотація:
High-fat mutton protein diet may alter lipid-, linoleic acid-, amino acid-, bile acid-, sphingolipid-, glycine-, serine- and glutathione-metabolism pathways in Glrx−/− mice whereas HFF diet ameliorated NAFLD by modifying these pathways.
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Neuwirth, Anke K., Dean R. Campagna, Mark D. Fleming, Sylvia S. Bottomley, and Ellis J. Neufeld. "Systematic Analysis of Known Candidate Genes in 58 Probands with Previously Uncharacterized Congenital Sideroblastic Anemia: Evidence for Genetic Heterogeneity and Identification of Novel Mutations in ALAS2 and PUS1." Blood 112, no. 11 (November 16, 2008): 484. http://dx.doi.org/10.1182/blood.v112.11.484.484.
Повний текст джерелаАнотація:
Abstract Sideroblastic anemias are a heterogeneous group of congenital and acquired bone marrow disorders characterized by pathologic iron accumulation in the mitochondria of erythroid precursors. Whereas the molecular ontology of acquired sideroblastic anemia is largely obscure, the genetic etiology is known for many patients with congenital sideroblastic anemia (CSA). Mutations in the heme biosynthetic enzyme 5-aminolevulinate synthase 2 gene (ALAS2)—associated with the classic, X-linked form of the disease—or mitochondrial DNA mutations/deletions (as in Pearson syndrome) have been reported in many cases. Rare cases are associated with mutations in the genes encoding a thiamine transporter (SLC11A2), pseudouridine synthase 1 (PUS1), a mitochondrial ATP-binding cassette transporter (ABCB7), and glutaredoxin 5 (GLRX5). Nonetheless, the molecular defect in a majority of cases of CSA remains unknown and there appears to be a significant bias in underreporting those cases that go genetically uncharacterized. Given this, we undertook a systematic genetic investigation of a large series of previously unreported CSA patients. METHODS AND RESULTS: 58 probands (26 female, 32 male) with CSA were studied. This cohort was comprised of 49 singleton patients and 10 families, including 8 families with at least 2 affected full siblings (1 set of monozygotic male twins, 1 each male or female sibling pairs, 2 male/female sibling pairs, 1 set each of 3 female or 3 male siblings, and one set of 3 siblings of unknown sex), and 2 families in which there was a history of CSA in a prior generation. In the great majority, CSA was the only clinical phenotype. We employed a sequential sequencing strategy to identify variants in ALAS2, PUS1, and GLRX5; ABCB7, SLC19A2, and mitochondrial DNA variants were not included in our analysis due to the absence of associated syndromic phenotypes in the cohort. To begin, ALAS2 was characterized by sequencing the coding region, intron-exon boundaries, proximal promoter, and intron 8, which contains an erythroid-specific enhancer, in all subjects. We detected 7 different missense mutations in 8 of the 58 probands, each of which was a singleton patient. No ALAS2 mutations were found in the promoter or intron 8. Two of the ALAS2 mutations were novel: V301A in a male patient and R517G in a female patient with a skewed X chromosome inactivation pattern in peripheral blood leukocytes as assessed by the human androgen receptor assay (HUMARA). The coding regions and intron-exon boundaries of PUS1 and GLRX5 were sequenced in all probands lacking ALAS2 mutations. Among these, a novel homozygous null (Q154X) PUS1 mutation was found in one familial case; only known polymorphisms in GLRX5 were detected. In 48 probands, including the 9 remaining familial cases, we did not identify a disease-causing mutation. However linkage studies in three families with affected males only were consistent with linkage to the ALAS2 locus in each case. CONCLUSIONS: These results demonstrate that: ALAS2 mutations are commonly associated with CSA, ALAS2 mutations and non-random X inactivation in affected females underscore the importance of ALAS2 analysis in women as well as in men with CSA, many potentially X-linked cases of CSA may have either ALAS2 mutations not detected by conventional sequencing approaches or mutations in other X-linked genes, PUS1 and GLRX5 variants are unusual causes of CSA, and there is strong genetic evidence that other, autosomal recessive forms of CSA exist.
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Cai, Hanfang, Mingxun Li, Wang Jian, Chengchuang Song, Yongzhen Huang, Xianyong Lan, Chuzhao Lei, and Hong Chen. "A novel lncRNA BADLNCR1 inhibits bovine adipogenesis by repressing GLRX5 expression." Journal of Cellular and Molecular Medicine 24, no. 13 (May 25, 2020): 7175–86. http://dx.doi.org/10.1111/jcmm.15181.
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Saudino, Giovanni, Dafne Suraci, Veronica Nasta, Simone Ciofi-Baffoni, and Lucia Banci. "Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation." International Journal of Molecular Sciences 22, no. 9 (May 3, 2021): 4848. http://dx.doi.org/10.3390/ijms22094848.
Повний текст джерелаАнотація:
Multiple mitochondrial dysfunctions syndrome (MMDS) is a rare neurodegenerative disorder associated with mutations in genes with a vital role in the biogenesis of mitochondrial [4Fe–4S] proteins. Mutations in one of these genes encoding for BOLA3 protein lead to MMDS type 2 (MMDS2). Recently, a novel phenotype for MMDS2 with complete clinical recovery was observed in a patient containing a novel variant (c.176G > A, p.Cys59Tyr) in compound heterozygosity. In this work, we aimed to rationalize this unique phenotype observed in MMDS2. To do so, we first investigated the structural impact of the Cys59Tyr mutation on BOLA3 by NMR, and then we analyzed how the mutation affects both the formation of a hetero-complex between BOLA3 and its protein partner GLRX5 and the iron–sulfur cluster-binding properties of the hetero-complex by various spectroscopic techniques and by experimentally driven molecular docking. We show that (1) the mutation structurally perturbed the iron–sulfur cluster-binding region of BOLA3, but without abolishing [2Fe–2S]2+ cluster-binding on the hetero-complex; (2) tyrosine 59 did not replace cysteine 59 as iron–sulfur cluster ligand; and (3) the mutation promoted the formation of an aberrant apo C59Y BOLA3–GLRX5 complex. All these aspects allowed us to rationalize the unique phenotype observed in MMDS2 caused by Cys59Tyr mutation.
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Key, Jana, Nesli Ece Sen, Aleksandar Arsović, Stella Krämer, Robert Hülse, Natasha Nadeem Khan, David Meierhofer, Suzana Gispert, Gabriele Koepf, and Georg Auburger. "Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence." Cells 9, no. 10 (October 2, 2020): 2229. http://dx.doi.org/10.3390/cells9102229.
Повний текст джерелаАнотація:
Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.
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Vaz, Catarina, Aida Pitarch, Emilia Gómez-Molero, Ahinara Amador-García, Michael Weig, Oliver Bader, Lucía Monteoliva, and Concha Gil. "Mass Spectrometry-Based Proteomic and Immunoproteomic Analyses of the Candida albicans Hyphal Secretome Reveal Diagnostic Biomarker Candidates for Invasive Candidiasis." Journal of Fungi 7, no. 7 (June 23, 2021): 501. http://dx.doi.org/10.3390/jof7070501.
Повний текст джерелаАнотація:
Invasive candidiasis (IC) is associated with high morbidity and mortality in hospitalized patients if not diagnosed early. Long-term use of central venous catheters is a predisposing factor for IC. Hyphal forms of Candida albicans (the major etiological agent of IC) are related to invasion of host tissues. The secreted proteins of hyphae are involved in virulence, host interaction, immune response, and immune evasion. To identify IC diagnostic biomarker candidates, we characterized the C. albicans hyphal secretome by gel-free proteomic analysis, and further assessed the antibody-reactivity patterns to this subproteome in serum pools from 12 patients with non-catheter-associated IC (ncIC), 11 patients with catheter-associated IC (cIC), and 11 non-IC patients. We identified 301 secreted hyphal proteins stratified to stem from the extracellular region, cell wall, cell surface, or intracellular compartments. ncIC and cIC patients had higher antibody levels to the hyphal secretome than non-IC patients. Seven secreted hyphal proteins were identified to be immunogenic (Bgl2, Eno1, Pgk1, Glx3, Sap5, Pra1 and Tdh3). Antibody-reactivity patterns to Bgl2, Eno1, Pgk1 and Glx3 discriminated IC patients from non-IC patients, while those to Sap5, Pra1 and Tdh3 differentiated between cIC and non-IC patients. These proteins may be useful for development of future IC diagnostic tests.
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Watanabe, Yosuke, Colin E. Murdoch, Markus M. Bachschmid, Richard A. Cohen, and Reiko Matsui. "Glrx Deletion Promotes Ischemic Revascularization by Hif1 Alpha Stabilization through S-Glutathionylation." Free Radical Biology and Medicine 87 (October 2015): S59. http://dx.doi.org/10.1016/j.freeradbiomed.2015.10.156.
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Padilla, C. Alicia, Svetlana Bajalica, Jacob Lagercrantz, and Arne Holmgren. "The Gene for Human Glutaredoxin (GLRX) Is Localized to Human Chromosome 5q14." Genomics 32, no. 3 (March 1996): 455–57. http://dx.doi.org/10.1006/geno.1996.0141.
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Liu, Gang, Shanshan Guo, Gregory J. Anderson, Clara Camaschella, Bing Han, and Guangjun Nie. "Heterozygous missense mutations in the GLRX5 gene cause sideroblastic anemia in a Chinese patient." Blood 124, no. 17 (October 23, 2014): 2750–51. http://dx.doi.org/10.1182/blood-2014-08-598508.
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Yang, Beimeng, Weibo Niu, Shiqing Chen, Fei Xu, Xingwang Li, Xi Wu, Yanfei Cao, et al. "Association study of the GLRX5 rs1007814 polymorphism with schizophrenia in the Han Chinese population." Psychiatric Genetics 27, no. 2 (April 2017): 76–77. http://dx.doi.org/10.1097/ypg.0000000000000160.
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Zhang, Kai, Xianyu Qin, Xianwu Zhou, Jianrong Zhou, Pengju Wen, Shaoxian Chen, Min Wu, Yueheng Wu, and Jian Zhuang. "Analysis of genes and underlying mechanisms involved in foam cells formation and atherosclerosis development." PeerJ 8 (November 17, 2020): e10336. http://dx.doi.org/10.7717/peerj.10336.
Повний текст джерелаАнотація:
Background Foam cells (FCs) play crucial roles in the process of all stages of atherosclerosis. Smooth muscle cells (SMCs) and macrophages are the major sources of FCs. This study aimed to identify the common molecular mechanism in these two types of FCs. Methods GSE28829, GSE43292, GSE68021, and GSE54666 were included to identify the differentially expressed genes (DEGs) associated with FCs derived from SMCs and macrophages. Gene Ontology biological process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by using the DAVID database. The co-regulated genes associated with the two origins of FCs were validated (GSE9874), and their expression in vulnerable atherosclerosis plaques (GSE120521 and GSE41571) was assessed. Results A total of 432 genes associated with FCs derived from SMCs (SMC-FCs) and 81 genes associated with FCs derived from macrophages (M-FCs) were identified, and they were mainly involved in lipid metabolism, inflammation, cell cycle/apoptosis. Furthermore, three co-regulated genes associated with FCs were identified: GLRX, RNF13, and ABCA1. These three common genes showed an increased tendency in unstable or ruptured plaques, although in some cases, no statistically significant difference was found. Conclusions DEGs related to FCs derived from SMCs and macrophages have contributed to the understanding of the molecular mechanism underlying the formation of FCs and atherosclerosis. GLRX, RNF13, and ABCA1 might be potential targets for atherosclerosis treatment.
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Malik, Gautam, Norbert Nagy, Ye-Shih Ho, Nilanjana Maulik, and Dipak K. Das. "RETRACTED: Role of glutaredoxin-1 in cardioprotection: An insight with Glrx1 transgenic and knockout animals." Journal of Molecular and Cellular Cardiology 44, no. 2 (February 2008): 261–69. http://dx.doi.org/10.1016/j.yjmcc.2007.08.022.
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Kose, Melis, Esra Isik, Ayça Aykut, Asude Durmaz, Engin Kose, Melike Ersoy, Gulden Diniz, et al. "The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum." Journal of Pediatric Endocrinology and Metabolism 34, no. 4 (February 24, 2021): 417–30. http://dx.doi.org/10.1515/jpem-2020-0410.
Повний текст джерелаАнотація:
Abstract Objectives Diagnostic process of mitochondrial disorders (MD) is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next-Generation Sequencing (NGS) technology offers a high-throughput platform for nuclear MD. Methods We included 59 of 72 patients that undergone WES and targeted exome sequencing panel suspected to have potential PMDs. Patients who were included in the analysis considering the possible PMD were reviewed retrospectively and scored according to the Mitochondrial Disease Criteria Scale. Results Sixty-one percent of the patients were diagnosed with whole-exome sequencing (WES) (36/59) and 15% with targeted exome sequencing (TES) (9/59). Patients with MD-related gene defects were included in the mito group, patients without MD-related gene defects were included in the nonmito group, and patients in whom no etiological cause could be identified were included in the unknown etiology group. In 11 out of 36 patients diagnosed with WES, a TES panel was applied prior to WES. In 47 probands in 39 genes (SURF1, SDHAF1, MTO1, FBXL4, SLC25A12, GLRX5, C19oRF12, NDUFAF6, DARS2, BOLA3, SLC19A3, SCO1, HIBCH, PDHA1, PDHAX, PC, ETFA, TRMU, TUFM, NDUFS6, WWOX, UBCD TREX1, ATL1, VAC14, GFAP, PLA2G6, TPRKB, ATP8A2, PEX13, IGHMBP2, LAMB2, LPIN1, GFPT1, CLN5, DOLK) (20 mito group, 19 nonmito group) 59 variants (31 mito group, 18 nonmito group) were detected. Seven novel variants in the mito group (SLC25A12, GLRX5, DARS2, SCO1, PC, ETFA, NDUFS6), nine novel variants in the nonmito group (IVD, GCDH, COG4, VAC14, GFAP, PLA2G6, ATP8A2, PEX13, LPIN1) were detected. Conclusions We explored the feasibility of identifying pathogenic alleles using WES and TES in MD. Our results show that WES is the primary method of choice in the diagnosis of MD until at least all genes responsible for PMD are found and are highly effective in facilitating the diagnosis process.
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Valdivieso, Ángel G., Mariángeles Clauzure, Macarena Massip-Copiz, and Tomás A. Santa-Coloma. "The Chloride Anion Acts as a Second Messenger in Mammalian Cells - Modifying the Expression of Specific Genes." Cellular Physiology and Biochemistry 38, no. 1 (2016): 49–64. http://dx.doi.org/10.1159/000438608.
Повний текст джерелаАнотація:
Background/Aims: Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, encoding a cAMP-activated chloride (Cl-) channel. We have previously demonstrated that the expression of several genes can be modulated by the CFTR activity; among them, SRC, MTND4, CISD1, and IL1B. However, the CFTR signalling mechanism involved in the expression of CFTR-dependent genes is unknown. The aim of this work was to determine if intracellular chloride (Cl-)i might function as a second messenger modulating the expression of specific genes. Methods: Differential display (DD) was applied to IB3-1 cells (CF cells), cultured under conditions that produce different intracellular Cl- concentrations ([Cl-]i), to analyse their expression profile. Results: Several differentially expressed gene products were observed by using DD, suggesting the presence of chloride-dependent gene expression. Two cDNA fragments, derived from differentially expressed mRNAs and showing opposed response to Cl-‚ were isolated, cloned, sequenced and its Cl- dependency validated by reverse transcription quantitative-PCR (RT-qPCR). We identified the gene RPS27, which encodes the multifunctional ribosomal protein RPS27, also known as metallopanstimulin-1 (MPS-1), and the gene GLRX5, encoding glutaredoxin-related protein 5, as chloride-dependent genes. RPS27 was negatively regulated with increased [Cl-]i, approximately from 25-75 mM Cl- (EC50 = 46 ± 7 mM), and positively regulated from 75-125 mM Cl- (EC50 = 110 ± 11 mM) (biphasic response). In contrast, GLRX5 was positively modulated by [Cl-]i, showing a typical sigmoidal dose-response curve from 0-50 mM Cl-, reaching a plateau after 50 mM Cl- (EC50 ∼ 34 mM). Conclusion: The results suggest the existence of chloride-dependent genes. The Cl- anion, therefore, might act as a second messenger for channels or receptors able to modulate the intracellular Cl- concentration, regulating in turn the expression of specific genes.
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Baker, Peter R., Marisa W. Friederich, Michael A. Swanson, Tamim Shaikh, Kaustuv Bhattacharya, Gunter H. Scharer, Joseph Aicher, et al. "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5." Brain 137, no. 2 (December 10, 2013): 366–79. http://dx.doi.org/10.1093/brain/awt328.
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Daher, Raêd, Abdellah Mansouri, Alain Martelli, Sophie Bayart, Hana Manceau, Isabelle Callebaut, Boualem Moulouel, et al. "GLRX5 mutations impair heme biosynthetic enzymes ALA synthase 2 and ferrochelatase in Human congenital sideroblastic anemia." Molecular Genetics and Metabolism 128, no. 3 (November 2019): 342–51. http://dx.doi.org/10.1016/j.ymgme.2018.12.012.
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Morgan, Kathleen L., Annette O. Estevez, Catherine L. Mueller, Briseida Cacho-Valadez, Antonio Miranda-Vizuete, Nathaniel J. Szewczyk, and Miguel Estevez. "The Glutaredoxin GLRX-21 Functions to Prevent Selenium-Induced Oxidative Stress in Caenorhabditis elegans." Toxicological Sciences 118, no. 2 (September 10, 2010): 530–43. http://dx.doi.org/10.1093/toxsci/kfq273.
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Alkattan, Abdullah, Ahmed Alkhalifah, Eman Alsalameen, Fatimah Alghanim, and Nashwa Radwan. "Polymorphisms of genes related to phase II metabolism and resistance to clopidogrel." Pharmacogenomics 23, no. 1 (January 2022): 61–79. http://dx.doi.org/10.2217/pgs-2021-0092.
Повний текст джерелаАнотація:
Clopidogrel is an antiplatelet drug commonly used to prevent coagulation. This review aimed to investigate the effect of polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK and GLRX genes on clopidogrel during phase II metabolism through exploring previous studies. The results revealed that low glutathione plasma levels caused by several alleles related to these genes could affect the bioactivation process of the clopidogrel prodrug, making it unable to inhibit platelet aggregation perfectly and thus leading to severe consequences in patients with a high risk of blood coagulation. However, the study recommends platelet reactivity tests to predict clopidogrel efficacy rather than studying gene mutations, as most of these mutations are rare and other nongenetic factors could affect the drug’s efficacy.