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      Utilizing methylglyoxal and D-lactate in urine to evaluate saikosaponin C treatment in mice with accelerated nephrotoxic serum nephritis

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          Abstract

          The relationship between methylglyoxal (MGO) and D-lactate during saikosaponin C (SSC) treatment of mice with accelerated nephrotoxic serum (NTS) nephritis was investigated. NTS nephritis was induced by administration of anti-basement membrane antibodies to C57BL/6 mice and three dosages of SSC were administered for 14 days. Proteinuria, blood urea nitrogen, serum creatinine, renal histology, urinary MGO and d-lactate changes were examined. Compared to the NTS control group, the middle dosage (10 mg/kg/day) of SSC significantly alleviated the development of nephritis based on urine protein measurements (34.40 ± 6.85 vs. 17.33 ± 4.79 mg/day, p<0.05). Pathological observation of the glomerular basement membrane (GBM) revealed monocyte infiltration, hypertrophy, and crescents were alleviated, and injury scoring also showed improved efficacy for the middle dose of SSC during nephritis (7.92 ± 1.37 vs. 3.50 ± 1.14, p<0.05). Moreover, the significant decreases in urinary levels of MGO (24.71 ± 3.46 vs. 16.72 ± 2.36 μg/mg, p<0.05) and D-lactate (0.31 ± 0.04 vs. 0.23 ± 0.02 μmol/mg, p<0.05) were consistent with the biochemical and pathological examinations. This study demonstrates that MGO and D-lactate may reflect the extent of damage and the efficacy of SSC in NTS nephritis; further studies are required to enable clinical application.

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          Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease.

          Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. Enzymes metabolising dicarbonyls, glyoxalase 1 and aldoketo reductases, provide an efficient and stress-response enzyme defence against dicarbonyl stress. Dicarbonyl stress is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites, and by exposure to exogenous dicarbonyls. It contributes to ageing, disease and activity of cytototoxic chemotherapeutic agents.
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            The glyoxalase pathway: the first hundred years... and beyond.

            The discovery of the enzymatic formation of lactic acid from methylglyoxal dates back to 1913 and was believed to be associated with one enzyme termed ketonaldehydemutase or glyoxalase, the latter designation prevailed. However, in 1951 it was shown that two enzymes were needed and that glutathione was the required catalytic co-factor. The concept of a metabolic pathway defined by two enzymes emerged at this time. Its association to detoxification and anti-glycation defence are its presently accepted roles, since methylglyoxal exerts irreversible effects on protein structure and function, associated with misfolding. This functional defence role has been the rationale behind the possible use of the glyoxalase pathway as a therapeutic target, since its inhibition might lead to an increased methylglyoxal concentration and cellular damage. However, metabolic pathway analysis showed that glyoxalase effects on methylglyoxal concentration are likely to be negligible and several organisms, from mammals to yeast and protozoan parasites, show no phenotype in the absence of one or both glyoxalase enzymes. The aim of the present review is to show the evolution of thought regarding the glyoxalase pathway since its discovery 100 years ago, the current knowledge on the glyoxalase enzymes and their recognized role in the control of glycation processes.
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              Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy.

              1. Methylglyoxal is a reactive alpha-oxoaldehyde and physiological metabolite formed by the fragmentation of triose-phosphates, and by the metabolism of acetone and aminoacetone. 2. Methylglyoxal modifies guanylate residues to form 6,7-dihydro-6,7-dihydroxy-6-methyl-imidazo[2,3-b]purine-9(8)one and N2-(1-carboxyethyl)guanylate residues and induces apoptosis. 3. Methylglyoxal modifies arginine residues in proteins to form N(delta)-(4,5-dihydroxy-4-methylimidazolidin-2-yl) ornithine, N(delta)-(5-hydro-5-methylimidazol-4-on-2-yl)ornithine and N(delta)-(5)methylimidazol-4-on-2-yl)ornithine residues. 4. Methylglyoxal-modified proteins undergo receptor-mediated endocytosis and lysosomal degradation in monocytes and macrophages, and induce cytokine synthesis and secretion. 5. Methylglyoxal is detoxified by the glyoxalase system. Decreased detoxification of methylglyoxal may be induced pharmacologically by glyoxalase I inhibitors which have anti-tumor and anti-malarial activities. 6. The modification of nucleic acids and protein by methylglyoxal is a signal for their degradation and may have a role in the development of diabetic complications, atherosclerosis, the immune response in starvation, aging and oxidative stress.
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                Author and article information

                Contributors
                Role: Formal analysisRole: Writing – original draft
                Role: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Methodology
                Role: Formal analysis
                Role: Formal analysisRole: Methodology
                Role: Formal analysis
                Role: Formal analysis
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 October 2020
                2020
                : 15
                : 10
                : e0241053
                Affiliations
                [1 ] School of Pharmacy, Taipei Medical University, Taipei, Taiwan
                [2 ] Department of Pharmacy, Taipei Medical University Hospital, Taipei, Taiwan
                [3 ] Department of Pharmacy, Cathay General Hospital, Taipei, Taiwan
                [4 ] Department of Pharmacy, WanFang Hospital, Taipei, Taiwan
                [5 ] Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan
                "INSERM", FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-0273-4847
                Article
                PONE-D-20-05825
                10.1371/journal.pone.0241053
                7588094
                33104740
                1215c2bc-44b0-42ec-b423-9e0205864c06
                © 2020 Lin et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 February 2020
                : 7 October 2020
                Page count
                Figures: 11, Tables: 1, Pages: 19
                Funding
                Funded by: Cathay General Hospital
                Award ID: 108CGH-TMU-06
                Award Recipient :
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was supported by Cathay General Hospital (108CGH-TMU-06).
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Nephritis
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Glomeruli
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Glomeruli
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Proteinuria
                Biology and Life Sciences
                Anatomy
                Histology
                Medicine and Health Sciences
                Anatomy
                Histology
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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