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International Journal of Environmental... Jun 2020Osteoporosis is an age-related bone disease, affecting mainly postmenopausal women, characterized by decreased bone mineral density (BMD) and consequent risk of...
Hyperhomocysteinemia is Associated with Inflammation, Bone Resorption, Vitamin B12 and Folate Deficiency and MTHFR C677T Polymorphism in Postmenopausal Women with Decreased Bone Mineral Density.
Osteoporosis is an age-related bone disease, affecting mainly postmenopausal women, characterized by decreased bone mineral density (BMD) and consequent risk of fractures. Homocysteine (Hcy), a sulfur-aminoacid whose serum level is regulated by methylenetrahydrofolate reductase (MTHFR) activity and vitamin B12 and folate as cofactors, is a risk factor for inflammatory diseases. Literature data concerning the link between Hcy and osteoporosis are still debated. The aim of our study was to assess the relationship among Hcy and BMD, inflammation, vitamin status and bone turnover in postmenopausal osteoporosis. In 252 postmenopausal women, BMD was measured by dual-energy X-ray absorptiometry (DXA). In addition to serum Hcy, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and bone turnover markers (bone alkaline phosphatase-BAP, osteocalcin-OC, C-terminal telopeptide of type I collagen (CTX), vitamin deficiencies and MTHFR-C677T polymorphism were evaluated. Hcy, inflammation, bone resorption markers and prevalence of C677T polymorphism were higher, whereas vitamin D, B12, folate, and bone formation markers were lower in women with decreased BMD compared to those with normal BMD. Our results suggest a significant association between Hcy, BMD and inflammation in postmenopausal osteoporosis. The regulation of Hcy overproduction and the modulation of the inflammatory substrate could represent additional therapeutic approaches for osteoporosis prevention.
Topics: Bone Density; Female; Folic Acid; Folic Acid Deficiency; Homocysteine; Humans; Hyperhomocysteinemia; Inflammation; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Osteitis; Osteoporosis, Postmenopausal; Oxidoreductases; Polymorphism, Genetic; Postmenopause; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 32549258
DOI: 10.3390/ijerph17124260 -
Applied and Environmental Microbiology Oct 2020Cr(VI) is mutagenic and teratogenic and considered an environmental pollutant of increasing concern. The use of microbial enzymes that convert this ion into its less...
Cr(VI) is mutagenic and teratogenic and considered an environmental pollutant of increasing concern. The use of microbial enzymes that convert this ion into its less toxic reduced insoluble form, Cr(III), represents a valuable bioremediation strategy. In this study, we examined the YhdA enzyme, which belongs to the family of NADPH-dependent flavin mononucleotide oxide reductases and possesses azo-reductase activity as a factor that upon overexpression confers protection on from the cytotoxic effects promoted by Cr(VI) and counteracts the mutagenic effects of the reactive oxygen species (ROS)-promoted lesion 8-OxoG. Further, our assays unveiled catalytic and biochemical properties of biotechnological relevance in YhdA; a pure recombinant His-YhdA protein efficiently catalyzed the reduction of Cr(VI) employing NADPH as a cofactor. The activity of the pure oxidoreductase YhdA was optimal at 30°C and at pH 7.5 and displayed and values of 7.26 mM and 26.8 μmol·min·mg for Cr(VI), respectively. Therefore, YhdA can be used for efficient bioremediation of Cr(VI) and counteracts the cytotoxic and genotoxic effects of oxygen radicals induced by intracellular factors and those generated during reduction of hexavalent chromium. Here, we report that the bacterial flavin mononucleotide/NADPH-dependent oxidoreductase YhdA, widely distributed among Gram-positive bacilli, conferred protection to cells from the cytotoxic effects of Cr(VI) and prevented the hypermutagenesis exhibited by a MutT/MutM/MutY-deficient strain. Additionally, a purified recombinant His-YhdA protein displayed a strong NADPH-dependent chromate reductase activity. Therefore, we postulate that in bacterial cells, YhdA counteracts the cytotoxic and genotoxic effects of intracellular and extracellular inducers of oxygen radicals, including those caused by hexavalent chromium.
Topics: Bacillus subtilis; Bacterial Proteins; Chromium; FMN Reductase
PubMed: 32801174
DOI: 10.1128/AEM.01688-20 -
EMBO Molecular Medicine Jan 2019Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a AOX transgene...
Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a AOX transgene into RC complex III (cIII)-deficient knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.
Topics: Animals; Cardiomyopathies; Cell Respiration; Ciona intestinalis; Electron Transport Complex III; Gene Knock-In Techniques; Mice, Inbred C57BL; Mitochondrial Proteins; Oxidoreductases; Plant Proteins; Recombinant Proteins; Survival Analysis
PubMed: 30530468
DOI: 10.15252/emmm.201809456 -
The Journal of Nutrition Oct 2008l-Proline concentration is primarily related to the balance of enzymatic activities of proline dehydrogenase [proline oxidase (POX)] and Delta-1-pyrroline-5-carboxylate...
l-Proline concentration is primarily related to the balance of enzymatic activities of proline dehydrogenase [proline oxidase (POX)] and Delta-1-pyrroline-5-carboxylate (P5C) reductase. As a result, P5C plays a pivotal role in maintaining the concentration of proline in body fluids and inborn errors of P5C metabolism lead to disturbance of proline metabolism. Several inborn errors of proline metabolism have been described. Hyperprolinemia type I (HPI) is a result of a deficiency in POX. The POX gene (PRODH) is located on chromosome 22 (22q11.2) and this region is deleted in velo-cardio-facial syndrome, a congenital malformation syndrome. In addition, this gene locus is related to susceptibility to schizophrenia. The other type of hyperprolinemia is HPII. It is caused by a deficiency in P5C dehydrogenase activity. Hypoprolinemia, on the other hand, is found in the recently described deficiency of P5C synthetase. This enzyme defect leads to hyperammonemia associated with hypoornithinemia, hypocitrullinemia, and hypoargininemia other than hypoprolinemia. Hyperhydroxyprolinemia is an autosomal recessive inheritance disorder caused by the deficiency of hydroxyproline oxidase. There are no symptoms and it is believed to be a benign metabolic disorder. The deficiency of ornithine aminotransferase causes transient hyperammonemia during early infancy due to deficiency of ornithine in the urea cycle. In later life, gyrate atrophy of the retina occurs due to hyperornithinemia, a paradoxical phenomenon. Finally, prolidase deficiency is a rare autosomal recessive hereditary disease. Prolidase catalyzes hydrolysis of dipeptide or oligopeptide with a C-terminal proline or hydroxyproline and its deficiency can cause mental retardation and severe skin ulcers.
Topics: 1-Pyrroline-5-Carboxylate Dehydrogenase; Amino Acid Metabolism, Inborn Errors; Chromosome Mapping; Citric Acid Cycle; Dipeptidases; Gene Deletion; Humans; Mental Disorders; Nervous System Diseases; Proline; Proline Oxidase; Pyrroline Carboxylate Reductases; delta-1-Pyrroline-5-Carboxylate Reductase
PubMed: 18806117
DOI: 10.1093/jn/138.10.2016S -
The Journal of Biological Chemistry Nov 2019Oxidative modification of Cys residues by NO results in -nitrosylation, a ubiquitous post-translational modification and a primary mediator of redox-based cellular...
Oxidative modification of Cys residues by NO results in -nitrosylation, a ubiquitous post-translational modification and a primary mediator of redox-based cellular signaling. Steady-state levels of -nitrosylated proteins are largely determined by denitrosylase enzymes that couple NAD(P)H oxidation with reduction of -nitrosothiols, including protein and low-molecular-weight (LMW) -nitrosothiols (-nitroso-GSH (GSNO) and -nitroso-CoA (SNO-CoA)). SNO-CoA reductases require NADPH, whereas enzymatic reduction of GSNO can involve either NADH or NADPH. Notably, GSNO reductase (GSNOR, ) accounts for most NADH-dependent GSNOR activity, whereas NADPH-dependent GSNOR activity is largely unaccounted for (CBR1 mediates a minor portion). Here, we purified NADPH-coupled GSNOR activity from mammalian tissues and identified aldo-keto reductase family 1 member A1 (AKR1A1), the archetypal mammalian SNO-CoA reductase, as a primary mediator of NADPH-coupled GSNOR activity in these tissues. Kinetic analyses suggested an AKR1A1 substrate preference of SNO-CoA > GSNO. AKR1A1 deletion from murine tissues dramatically lowered NADPH-dependent GSNOR activity. Conversely, GSNOR-deficient mice had increased AKR1A1 activity, revealing potential cross-talk among GSNO-dependent denitrosylases. Molecular modeling and mutagenesis of AKR1A1 identified Arg-312 as a key residue mediating the specific interaction with GSNO; in contrast, substitution of the SNO-CoA-binding residue Lys-127 minimally affected the GSNO-reducing activity of AKR1A1. Together, these findings indicate that AKR1A1 is a multi-LMW-SNO reductase that can distinguish between and metabolize the two major LMW-SNO signaling molecules GSNO and SNO-CoA, allowing for wide-ranging control of protein -nitrosylation under both physiological and pathological conditions.
Topics: Aldehyde Oxidoreductases; Aldehyde Reductase; Animals; Coenzyme A; Humans; Kinetics; Mammals; Mice, Inbred C57BL; Mice, Knockout; NADP; Nitric Oxide; Oxidation-Reduction; S-Nitrosothiols; Signal Transduction
PubMed: 31649033
DOI: 10.1074/jbc.RA119.011067 -
Planta 1995Arabidopsis thaliana (L.) Heynh. Columbia wild type and a root hair-less mutant RM57 were grown on iron-containing and iron-deficient nutrient solutions. In both...
Arabidopsis thaliana (L.) Heynh. Columbia wild type and a root hair-less mutant RM57 were grown on iron-containing and iron-deficient nutrient solutions. In both genotypes, ferric chelate reductase (FCR) of intact roots was induced upon iron deficiency and followed a Michaelis-Menten kinetic with a Km of 45 and 54 microM FeIII-EDTA and a Vmax of 42 and 33 nmol Fe2+.(g FW)-1.min-1 for the wild type and the mutant, respectively. The pH optimum for the reaction was around pH 5.5. The approximately four fold stimulation of FCR activity was independent of formation of root hairs and/or transfer cells induced by iron deficiency. Iron-deficiency-induced chlorosis and the development of a rigid root habit disappeared when ferric chelate was applied to the leaves, while FCR activity remained unchanged. The time course of the responses to iron deficiency showed that morphological and physiological responses were controlled separately.
Topics: Arabidopsis; Cells, Cultured; Enzyme Induction; FMN Reductase; Hydrogen-Ion Concentration; Iron; Kinetics; Microscopy, Electron; NADH, NADPH Oxidoreductases; Plant Roots
PubMed: 7766049
DOI: 10.1007/BF00195707 -
PloS One 2013Thioredoxin reductase-1 (TRXR-1) is the sole selenoprotein in C. elegans, and selenite is a substrate for thioredoxin reductase, so TRXR-1 may play a role in metabolism...
Thioredoxin reductase-1 (TRXR-1) is the sole selenoprotein in C. elegans, and selenite is a substrate for thioredoxin reductase, so TRXR-1 may play a role in metabolism of selenium (Se) to toxic forms. To study the role of TRXR in Se toxicity, we cultured C. elegans with deletions of trxr-1, trxr-2, and both in axenic media with increasing concentrations of inorganic Se. Wild-type C. elegans cultured for 12 days in Se-deficient axenic media grow and reproduce equivalent to Se-supplemented media. Supplementation with 0-2 mM Se as selenite results in inverse, sigmoidal response curves with an LC50 of 0.20 mM Se, due to impaired growth rather than reproduction. Deletion of trxr-1, trxr-2 or both does not modulate growth or Se toxicity in C. elegans grown axenically, and (75)Se labeling showed that TRXR-1 arises from the trxr-1 gene and not from bacterial genes. Se response curves for selenide (LC50 0.23 mM Se) were identical to selenite, but selenate was 1/4(th) as toxic (LC50 0.95 mM Se) as selenite and not modulated by TRXR deletion. These nutritional and genetic studies in axenic media show that Se and TRXR are not essential for C. elegans, and that TRXR alone is not essential for metabolism of inorganic Se to toxic species.
Topics: Animals; Caenorhabditis elegans; Gene Knockout Techniques; Male; Selenic Acid; Selenious Acid; Thioredoxin Reductase 1; Thioredoxin Reductase 2; Thioredoxin-Disulfide Reductase
PubMed: 23936512
DOI: 10.1371/journal.pone.0071525 -
Plant Physiology and Biochemistry : PPB Sep 2020Low Fe availability affects plant production mainly by impairing the photosynthetic pathway, since Fe plays an essential role in chlorophyll synthesis as well as in the...
Low Fe availability affects plant production mainly by impairing the photosynthetic pathway, since Fe plays an essential role in chlorophyll synthesis as well as in the photosynthetic electron transport chain. Under these conditions, plant cells require the activation of protective mechanisms to prevent photo-inhibition. Among these mechanisms, photorespiration (PR) has been relatively little investigated in Fe-deficient plants. The aim of this work was to investigate the effect of Fe deficiency on photorespiration by performing in vivo analysis in leaves as well as biochemical characterization of some PR-related enzyme activities in a peroxisome-purified fraction from cucumber leaves. Modelling of light response curves at both 21 and 2% pO revealed a slowing down of PR under Fe deficiency. The activity of some PR-involving enzymes as well as the contents of glycine and serine were affected under Fe deficiency. Furthermore, nitrate reductase, the glutamine synthetase-glutamate synthase (GS-GOGAT) cycle and hydroxypyruvate dehydrogenase isoform activities were differentially altered under Fe deficiency. The dataset indicates that, in Fe-deficient cucumber leaves, the modulation of PR involves the induction of some PR-related pathways, such as the photorespiratory N recycling and cytosolic photorespiratory bypass processes.
Topics: Cucumis sativus; Glutamate-Ammonia Ligase; Iron Deficiencies; Nitrate Reductase; Nitrogen; Photosynthesis; Plant Leaves
PubMed: 32559518
DOI: 10.1016/j.plaphy.2020.05.032 -
Preventive Medicine Aug 2023Type 2 diabetes mellitus (T2DM) is a complex disease caused by multiple factors, which are often accompanied by the disorder of glucose and lipid metabolism and the lack...
Type 2 diabetes mellitus (T2DM) is a complex disease caused by multiple factors, which are often accompanied by the disorder of glucose and lipid metabolism and the lack of vitamin D.Over the years, researchers have conducted numerous studies into the pathogenesis and prevention strategies of diabetes. In this study, diabetic SD rats were randomly divided into type 2 diabetes group, vitamin D intervention group, 7-dehydrocholesterole reductase (DHCR7) inhibitor intervention group, simvastatin intervention group, and naive control group. Before and 12 weeks after intervention, liver tissue was extracted to isolate hepatocytes. Compared with naive control group, in the type 2 diabetic group without interference, the expression of DHCR7 increased, the level of 25(OH)D decreased, the level of cholesterol increased. In the primary cultured naive and type 2 diabetic hepatocytes, the expression of genes related to lipid metabolism and vitamin D metabolism were differently regulated in each of the 5 treatment groups. Overall, DHCR7 is an indicator for type 2 diabetic glycolipid metabolism disorder and vitamin D deficiency. Targeting DHCR7 will help with T2DM therapy.The management model of comprehensive health intervention can timely discover the disease problems of diabetes patients and high-risk groups and reduce the incidence of diabetes.
Topics: Animals; Rats; Diabetes Mellitus, Type 2; Hypercholesterolemia; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Rats, Sprague-Dawley; Vitamin D; Vitamin D Deficiency
PubMed: 37329988
DOI: 10.1016/j.ypmed.2023.107576 -
American Journal of Human Genetics Apr 2006Tetrahydrobiopterin (BH(4)) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, the three aromatic hydroxylases, and...
Tetrahydrobiopterin (BH(4)) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, the three aromatic hydroxylases, and glyceryl-ether mono-oxygenase. A proper level of BH(4) is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH(4) deficiency has been shown to be closely associated with diverse neurological psychiatric disorders. Sepiapterin reductase (SPR) is an enzyme that catalyzes the final step of BH(4) biosynthesis. Whereas the number of cases of neuropsychological disorders resulting from deficiencies of other catalytic enzymes involved in BH(4) biosynthesis and metabolism has been increasing, only a handful of cases of SPR deficiency have been reported, and the role of SPR in BH(4) biosynthesis in vivo has been poorly understood. Here, we report that mice deficient in the Spr gene (Spr(-/-)) display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH(4) and for the normal functions of BH(4)-dependent enzymes. The Spr(-/-) mice exhibit phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH(4) and neurotransmitter precursors completely rescued dwarfism and phenylalanine metabolism. The biochemical and behavioral characteristics of Spr(-/-) mice share striking similarities with the symptoms observed in SPR-deficient patients. This Spr mutant strain of mice will be an invaluable resource to elucidate many important issues regarding SPR and BH(4) deficiencies.
Topics: Alcohol Oxidoreductases; Animals; Base Sequence; Biopterins; Catecholamines; DNA Primers; Disease Models, Animal; Growth; Humans; Immunohistochemistry; Locomotion; Metabolism, Inborn Errors; Mice; Mice, Knockout; Phenotype; Phenylalanine; Serotonin
PubMed: 16532389
DOI: 10.1086/501372