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1.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202683

RESUMO

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.


Assuntos
Metabolismo dos Carboidratos , Inositol/deficiência , Inositol/metabolismo , Animais , Transporte Biológico , Vias Biossintéticas , Suplementos Nutricionais , Absorção Gastrointestinal , Microbioma Gastrointestinal , Humanos , Inositol/administração & dosagem , Rim/metabolismo
2.
Nutrients ; 12(11)2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33153126

RESUMO

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.


Assuntos
Suplementos Nutricionais , Inositol/análogos & derivados , Inositol/deficiência , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Animais , Colesterol/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Inositol/administração & dosagem , Resistência à Insulina , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Período Pós-Prandial , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triglicerídeos/metabolismo
3.
Sci Data ; 5: 180184, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30251996

RESUMO

Mycothiol (MSH) and ergothioneine (ERG) are thiols able to compensate for each other to protect mycobacteria against oxidative stress. Gamma-glutamylcysteine (GGC), another thiol and an intermediate in ERG biosynthesis has detoxification abilities. Five enzymes are involved in ERG biosynthesis, namely EgtA, EgtB, EgtC, EgtD and EgtE. The role of these enzymes in the production of ERG had been unclear. On the other hand, the enzyme MshA is known to be essential for MSH biosynthesis. In this manuscript, we describe the raw data of the generation and characterization of Mycobacterium tuberculosis (M.tb) mutants harbouring a deletion of the gene coding for each of these enzymes, and the raw data of the phenotypic characterization of the obtained thiol-deficient M.tb mutants. High throughput screening (HTS) of off-patent drugs and natural compounds revealed few compounds that displayed a higher activity against the thiol-deficient mutants relative to the wild-type strain. The mode of action of these drugs was further investigated. Raw data displaying these results are described here.


Assuntos
Cisteína/deficiência , Cisteína/genética , Dipeptídeos/deficiência , Dipeptídeos/genética , Ergotioneína/deficiência , Ergotioneína/genética , Glicopeptídeos/deficiência , Glicopeptídeos/genética , Inositol/deficiência , Inositol/genética , Mycobacterium tuberculosis , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Mutação , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Estresse Oxidativo/genética , Compostos de Sulfidrila
4.
Fish Shellfish Immunol ; 76: 333-346, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29544771

RESUMO

In this study, we investigated the effects of dietary myo-inositol on the intestinal immune barrier function and related signaling pathway in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.33 ±â€¯0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila. The results indicated that compared with the optimal dietary myo-inositol level, myo-inositol deficiency (27.0 mg/kg diet): (1) decreased lysozyme (LZ) and acid phosphatase (ACP) activities, as well as complement 3 (C3), C4 and immunoglobulin M (IgM) contents in the proximal intestine (PI), middle intestine (MI) and distal intestine (DI) of young grass carp (P < 0.05). (2) down-regulated the mRNA levels of anti-microbial substance: liver expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin, ß-defensin-1 and mucin2 in the PI, MI and DI of young grass carp (P < 0.05). (3) up-regulated pro-inflammatory cytokines [IL-1ß (not in DI), TNF-α and IL-8], nuclear factor kappa B P65 (not NF-κB P52), c-Rel, IκB kinaseα (IKKα), IKKß and IKKγ mRNA levels in the PI, MI and DI of young grass carp (P < 0.05); and down-regulated pro-inflammatory cytokines IL-15 (not in DI) and inhibitor of κBα (IκBα) mRNA levels (P < 0.05). (4) down-regulated the mRNA levels of anti-inflammatory cytokines [IL-10 (not in DI), IL-11, IL-4/13B (not IL-4/13A), TGF-ß1 and TGF-ß2], target of rapamycin (TOR), eIF4E-binding proteins 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6k1) in the PI, MI and DI of young grass carp (P < 0.05). All data indicated that myo-inositol deficiency could decrease fish intestine immunity and cause inflammation under infection of A. hydrophila. Finally, the optimal dietary myo-inositol levels for the ACP and LZ activities in the DI were estimated to be 415.1 and 296.9 mg/kg diet, respectively.


Assuntos
Carpas/genética , Carpas/imunologia , Inositol/deficiência , Intestinos/imunologia , Transdução de Sinais/imunologia , Complexo Vitamínico B/análise , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , NF-kappa B/metabolismo , Serina-Treonina Quinases TOR/metabolismo
5.
Int J Mol Sci ; 18(10)2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29053604

RESUMO

Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components-as phytates and inositols-for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability.


Assuntos
Inositol/deficiência , Doenças Metabólicas/induzido quimicamente , Disponibilidade Biológica , Humanos , Inositol/farmacocinética , Estado Nutricional
6.
Fish Shellfish Immunol ; 67: 475-492, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28610850

RESUMO

In this study, we investigated the effects of dietary myo-inositol on the growth and intestinal physical barrier functions of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.83 ± 0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila for 14 days. The results indicated that compared with optimal myo-inositol levels, myo-inositol deficiency (27.0 mg/kg diet): (1) decreased glutathione (GSH) contents and antioxidant enzymes activities, and down-regulated the mRNA levels of antioxidant enzymes [not glutathione-S-transferase (gst) p1 and gstp2] and NF-E2-related factor 2 (nrf2), whereas up-regulated the reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC) contents, and the mRNA levels of Kelch-like-ECH-associated protein 1 (keap1) in three intestinal segments of young grass carp (P < 0.05). (2) Up-regulated cysteinyl aspartic acid-protease (caspase)-2, -3, -7, -8, -9, apoptotic protease activating factor-1 (apaf-1), Bcl2-associated X protein (bax), fas ligand (fasl), gen-activated protein kinase (p38mapk) and c-Jun N-terminal protein kinase (jnk) mRNA levels, whereas down-regulated B-cell lymphoma-2 (bcl-2), inhibitor of apoptosis proteins (iap) and myeloid cell leukemia-1 (mcl-1) mRNA levels in three intestinal segments of young grass carp (P < 0.05). (3) Down-regulated mRNA levels of cell cycle proteins cyclin b, cyclin d, cyclin e and E2F transcription factor 4 (e2f4) in three intestinal segments of young grass carp (P < 0.05). (4) Down-regulated the mRNA levels of zonula occludens (zo) 1, zo-2, occludin, claudin-b, -c, -f, -3c, -7a, -7b as well as -11, and up-regulated the mRNA levels of claudin-12, -15a (not -15b) and myosin light chain kinase (mlck) in three intestinal segments of young grass carp (P < 0.05). All above data indicated that dietary myo-inositol deficiency could damage physical barrier function in three intestinal segments of fish. Finally, the myo-inositol requirements based on the percent weight gain (PWG), reactive oxygen species (ROS) contents in the proximal intestine (PI), relative mRNA levels of caspase-2 (PI), cyclin b (MI) as well as claudin-b (PI) were estimated to be 276.7, 304.1, 327.9, 416.7 and 313.2 mg/kg diet, respectively.


Assuntos
Antioxidantes/metabolismo , Carpas/fisiologia , Carboidratos da Dieta/metabolismo , Proteínas de Peixes/metabolismo , Inositol/deficiência , Transdução de Sinais , Ração Animal/análise , Animais , Apoptose/efeitos dos fármacos , Carpas/genética , Carpas/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Dieta/veterinária , Suplementos Nutricionais/análise , Intestinos/efeitos dos fármacos , Distribuição Aleatória , Junções Íntimas/efeitos dos fármacos
7.
Gynecol Endocrinol ; 32(9): 690-695, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27595157

RESUMO

Inositol is an organic compound of high biological importance that is widely distributed in nature. It belongs to the sugar family and is mainly represented by its two dominant stereoisomers: myo-inositol and D-chiro-inositol that are found in the organism in the physiological serum ratio 40:1. Inositol and its derivatives are important components of the structural phospholipids of the cell membranes and are precursors of the second messengers of many metabolic pathways. A high concentration of myoinositol is found in the follicular fluid and in semen. Inositol deficiency and the impairment of the inositol-dependent pathways may play an important role in the pathogenesis of insulin resistance and hypothyroidism. The results of the research also point out the potential beneficial role of inositol supplementation in polycystic ovarian syndrome and in the context of assisted reproduction technologies and in vitro fertilization. The main aim of the article is to overview the major inositol-dependent metabolic pathways and to discuss its importance for reproduction.


Assuntos
Inositol/fisiologia , Resistência à Insulina/fisiologia , Ovulação/metabolismo , Síndrome do Ovário Policístico/metabolismo , Técnicas de Reprodução Assistida , Feminino , Humanos , Inositol/deficiência , Inositol/metabolismo , Inositol/uso terapêutico
8.
Clin Chim Acta ; 460: 88-92, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27342997

RESUMO

BACKGROUND: Myo-inositol (MI) deficiency is associated with an increased risk for neural tube defects (NTDs), mental disorders and metabolic diseases. We developed a gas chromatography-mass spectrometry (GC-MS) method to detect MI in human plasma, which was accurate, relatively efficient and convenient for clinical application. METHODS: An external standard method was used for determination of plasma MI. Samples were analyzed by GC-MS after derivatization. The stable-isotope labeled internal standard approach was used to validate the method's accuracy. Alpha fetal protein (AFP) was detected by chemiluminescence immunoassay. RESULTS: The method was validated by determining the linearity, sensitivity and recovery rate. There was a good agreement between the internal standard approach and the present method. The NTD-affected pregnancies showed lower plasma MI (P=0.024) and higher AFP levels (P=0.001) than control. Maternal MI level showed a better discrimination in spina bifida subgroup, while AFP level showed a better discrimination in anencephaly subgroup after stratification analysis. CONCLUSIONS: We developed a sensitive and reliable method for the detection of clinical plasma MI, which might be a marker for NTDs screening, and established fundamental knowledge for clinical diagnosis and prevention for the diseases related to disturbed MI metabolism.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Inositol/sangue , Anencefalia/sangue , Anencefalia/diagnóstico , Feminino , Humanos , Inositol/deficiência , Masculino , Programas de Rastreamento/métodos , Defeitos do Tubo Neural/diagnóstico , Gravidez , Diagnóstico Pré-Natal , Padrões de Referência , Sensibilidade e Especificidade , Disrafismo Espinal/diagnóstico
9.
J Biol Chem ; 290(46): 27460-72, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26324718

RESUMO

Depletion of inositol has profound effects on cell function and has been implicated in the therapeutic effects of drugs used to treat epilepsy and bipolar disorder. We have previously shown that the anticonvulsant drug valproate (VPA) depletes inositol by inhibiting myo-inositol-3-phosphate synthase, the enzyme that catalyzes the first and rate-limiting step of inositol biosynthesis. To elucidate the cellular consequences of inositol depletion, we screened the yeast deletion collection for VPA-sensitive mutants and identified mutants in vacuolar sorting and the vacuolar ATPase (V-ATPase). Inositol depletion caused by starvation of ino1Δ cells perturbed the vacuolar structure and decreased V-ATPase activity and proton pumping in isolated vacuolar vesicles. VPA compromised the dynamics of phosphatidylinositol 3,5-bisphosphate (PI3,5P2) and greatly reduced V-ATPase proton transport in inositol-deprived wild-type cells. Osmotic stress, known to increase PI3,5P2 levels, did not restore PI3,5P2 homeostasis nor did it induce vacuolar fragmentation in VPA-treated cells, suggesting that perturbation of the V-ATPase is a consequence of altered PI3,5P2 homeostasis under inositol-limiting conditions. This study is the first to demonstrate that inositol depletion caused by starvation of an inositol synthesis mutant or by the inositol-depleting drug VPA leads to perturbation of the V-ATPase.


Assuntos
Anticonvulsivantes/farmacologia , Inositol/deficiência , Liases Intramoleculares/antagonistas & inibidores , ATPases Vacuolares Próton-Translocadoras/metabolismo , Vacúolos/enzimologia , Ácido Valproico/farmacologia , Farmacorresistência Fúngica/genética , Deleção de Genes , Homeostase , Inositol/genética , Mio-Inositol-1-Fosfato Sintase/genética , Pressão Osmótica , Fosfatos de Fosfatidilinositol/metabolismo , Transporte Proteico , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , ATPases Vacuolares Próton-Translocadoras/genética
10.
Am J Physiol Renal Physiol ; 309(9): F755-63, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26311112

RESUMO

Renal depletion of myo-inositol (MI) is associated with the pathogenesis of diabetic nephropathy in animal models, but the underlying mechanisms involved are unclear. We hypothesized that MI depletion was due to changes in inositol metabolism and therefore examined the expression of genes regulating de novo biosynthesis, reabsorption, and catabolism of MI. We also extended the analyses from diabetes mellitus to animal models of dietary-induced obesity and hypertension. We found that renal MI depletion was pervasive across these three distinct disease states in the relative order: hypertension (-51%)>diabetes mellitus (-35%)>dietary-induced obesity (-19%). In 4-wk diabetic kidneys and in kidneys derived from insulin-resistant and hypertensive rats, MI depletion was correlated with activity of the MI-degrading enzyme myo-inositol oxygenase (MIOX). By contrast, there was decreased MIOX expression in 8-wk diabetic kidneys. Immunohistochemistry localized the MI-degrading pathway comprising MIOX and the glucuronate-xylulose (GX) pathway to the proximal tubules within the renal cortex. These findings indicate that MI depletion could reflect increased catabolism through MIOX and the GX pathway and implicate a common pathological mechanism contributing to renal oxidative stress in metabolic disease.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Hipertensão/metabolismo , Inositol/metabolismo , Túbulos Renais Proximais/metabolismo , Obesidade/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Hipertensão/complicações , Hipertensão/genética , Inositol/deficiência , Inositol Oxigenase/genética , Inositol Oxigenase/metabolismo , Resistência à Insulina , Túbulos Renais Proximais/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/genética , Proteínas/genética , Proteínas/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar , Xilulose/genética , Xilulose/metabolismo
11.
Br J Nutr ; 113(12): 1862-75, 2015 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-25990651

RESUMO

We previously reported that a chronic supplementation with myo-inositol (MI) improved insulin sensitivity and reduced fat accretion in mice. We then tested the potency of such dietary intervention in the prevention of insulin resistance in C57BL/6 male mouse fed a high-fat diet (HFD). In addition, some abnormalities in inositol metabolism were reported to be associated with insulin resistance in several animal and human studies. We then investigated the presence of such anomalies (i.e. inosituria and an inositol intra-tissue depletion) in this diet-induced obesity (DIO) mouse model, as well as the potential benefit of a MI supplementation for inositol intra-tissue deficiency correction. HFD (60 % energy from fat) feeding was associated with inosituria and inositol intra-tissue depletion in the liver and kidneys. MI supplementation (0·58 mg/g per d) restored inositol pools in kidneys (partially) and liver (fully). HFD feeding for 4 months induced ectopic lipid redistribution to liver and muscles, fasting hyperglycaemia and hyperinsulinaemia, insulin resistance and obesity that were not prevented by MI supplementation, despite a significant improvement in insulin sensitivity parameter K insulin tolerance test and a reduction in white adipose tissue (WAT) mass ( - 17 %, P< 0·05). MI supplementation significantly reduced fatty acid synthase activity in epididymal WAT, which might explain its beneficial, but modest, effect on WAT accretion in HFD-fed mice. Finally, we found some abnormalities in inositol metabolism in association with a diabetic phenotype (i.e. insulin resistance and fasting hyperglycaemia) in a DIO mouse model. Dietary MI supplementation was efficient in the prevention of inositol intra-tissue depletion, but did not prevent insulin resistance or obesity efficiently in this mouse model.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Inositol/administração & dosagem , Inositol/metabolismo , Adipocinas/sangue , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/metabolismo , Animais , Suplementos Nutricionais , Ácido Graxo Sintases/metabolismo , Hiperglicemia/metabolismo , Inositol/análise , Inositol/deficiência , Inositol/urina , Resistência à Insulina , Rim/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/prevenção & controle
12.
PLoS One ; 10(3): e0120108, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25781026

RESUMO

In eukaryotic cells, type 4 P-type ATPases function as phospholipid flippases, which translocate phospholipids from the exoplasmic leaflet to the cytoplasmic leaflet of the lipid bilayer. Flippases function in the formation of transport vesicles, but the mechanism remains unknown. Here, we isolate an arrestin-related trafficking adaptor, ART5, as a multicopy suppressor of the growth and endocytic recycling defects of flippase mutants in budding yeast. Consistent with a previous report that Art5p downregulates the inositol transporter Itr1p by endocytosis, we found that flippase mutations were also suppressed by the disruption of ITR1, as well as by depletion of inositol from the culture medium. Interestingly, inositol depletion suppressed the defects in all five flippase mutants. Inositol depletion also partially restored the formation of secretory vesicles in a flippase mutant. Inositol depletion caused changes in lipid composition, including a decrease in phosphatidylinositol and an increase in phosphatidylserine. A reduction in phosphatidylinositol levels caused by partially depleting the phosphatidylinositol synthase Pis1p also suppressed a flippase mutation. These results suggest that inositol depletion changes the lipid composition of the endosomal/TGN membranes, which results in vesicle formation from these membranes in the absence of flippases.


Assuntos
Inositol/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Endocitose , Endossomos/metabolismo , Inositol/deficiência , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Fosfatidilinositóis/metabolismo , Fosfatidilserinas/metabolismo , Proteínas de Transferência de Fosfolipídeos/genética , Transporte Proteico , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
13.
J Biosci Bioeng ; 120(3): 294-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25683449

RESUMO

Thiol compounds with low-molecular weight, such as glutathione, mycothiol (MSH), bacillithiol, and ergothioneine (ERG), are known to protect microorganisms from oxidative stresses. Mycobacteria and actinobacteria utilize both MSH and ERG. The biological functions of MSH in mycobacteria have been extensively studied by genetic and biochemical studies, which have suggested it has critical roles for detoxification in cells. In contrast, the biological functions of ERG remain ambiguous because its biosynthetic genes were only recently identified in Mycobacterium avium. In this study, we constructed mutants of Streptomyces coelicolor A3(2), in which either the MSH or ERG biosynthetic gene was disrupted, and examined their phenotypes. A mshC (SCO1663)-disruptant completely lost MSH productivity. In contrast, a disruptant of the egtA gene (SCO0910) encoding γ-glutamyl-cysteine synthetase unexpectedly retained reduced productivity of ERG, probably because of the use of l-cysteine instead of γ-glutamyl-cysteine. Both disruptants showed delayed growth at the late logarithmic phase and were more susceptible to hydrogen peroxide and cumene hydroperoxide than the parental strain. Interestingly, the ERG-disruptant, which still kept reduced ERG productivity, was more susceptible. Furthermore, the ERG-disruptant accumulated 5-fold more MSH than the parental strain. In contrast, the amount of ERG was almost the same between the MSH-disruptant and the parental strain. Taken together, our results suggest that ERG is more important than MSH in S. coelicolor A3(2).


Assuntos
Ergotioneína/metabolismo , Estresse Oxidativo , Streptomyces coelicolor/metabolismo , Cisteína/análogos & derivados , Cisteína/biossíntese , Cisteína/deficiência , Cisteína/metabolismo , Ergotioneína/biossíntese , Ergotioneína/deficiência , Glutamato-Cisteína Ligase/deficiência , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glicopeptídeos/biossíntese , Glicopeptídeos/deficiência , Glicopeptídeos/metabolismo , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Inositol/biossíntese , Inositol/deficiência , Inositol/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Streptomyces coelicolor/efeitos dos fármacos , Streptomyces coelicolor/enzimologia , Streptomyces coelicolor/genética
14.
J Clin Psychopharmacol ; 35(2): 175-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25679134

RESUMO

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.


Assuntos
Antimaníacos/uso terapêutico , Comportamento/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Inositol/deficiência , Compostos de Lítio/uso terapêutico , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Deficiência de Vitaminas do Complexo B/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/psicologia , Dieta , Inibidores Enzimáticos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Pilocarpina
15.
Ginekol Pol ; 85(1): 54-7, 2014 Jan.
Artigo em Polonês | MEDLINE | ID: mdl-24505965

RESUMO

Inositol acts as a second messenger in insulin signaling pathway Literature data suggest inositol deficiency in insulin-resistant women with the polycystic ovary syndrome. Supplementation of myo-inisitol decreases insulin resistance as it works as an insulin sensitizing agent. The positive role of myo-inositol in the treatment of polycystic ovary syndrome has been of increased evidence recently The present review presents the effects of myo-inositol on the ovarian, hormonal and metabolic parameters in women with PCOS.


Assuntos
Inositol/deficiência , Inositol/uso terapêutico , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Complexo Vitamínico B/uso terapêutico , Glicemia/efeitos dos fármacos , Feminino , Ácido Fólico/uso terapêutico , Fase Folicular/efeitos dos fármacos , Humanos , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Saúde da Mulher
16.
Neuropsychopharmacology ; 39(2): 319-28, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23924600

RESUMO

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.


Assuntos
Técnicas de Inativação de Genes/métodos , Inositol/deficiência , Inositol/genética , Lítio/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Animais , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética
17.
Nat Commun ; 4: 1881, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23695675

RESUMO

Drugs that kill tuberculosis more quickly could shorten chemotherapy significantly. In Escherichia coli, a common mechanism of cell death by bactericidal antibiotics involves the generation of highly reactive hydroxyl radicals via the Fenton reaction. Here we show that vitamin C, a compound known to drive the Fenton reaction, sterilizes cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis. While M. tuberculosis is highly susceptible to killing by vitamin C, other Gram-positive and Gram-negative pathogens are not. The bactericidal activity of vitamin C against M. tuberculosis is dependent on high ferrous ion levels and reactive oxygen species production, and causes a pleiotropic effect affecting several biological processes. This study enlightens the possible benefits of adding vitamin C to an anti-tuberculosis regimen and suggests that the development of drugs that generate high oxidative burst could be of great use in tuberculosis treatment.


Assuntos
Ácido Ascórbico/farmacologia , Peróxido de Hidrogênio/metabolismo , Ferro/metabolismo , Viabilidade Microbiana/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Cisteína/deficiência , Dano ao DNA , Farmacorresistência Bacteriana/efeitos dos fármacos , Glicopeptídeos/deficiência , Inositol/deficiência , Lipídeos/biossíntese , Testes de Sensibilidade Microbiana , Modelos Biológicos , Mycobacterium tuberculosis/genética , Oxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Esterilização , Transcrição Gênica/efeitos dos fármacos
18.
Ann Neurol ; 74(2): 301-5, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23553900

RESUMO

Astrocytic necrosis is a prominent pathological feature of neuromyelitis optica (NMO) lesions and is clinically relevant. We report 5 NMO-related cases, all with longitudinally extensive lesions in the upper cervical cord, who underwent cervical cord (1) H-magnetic resonance spectroscopy. Lower myo-inositol/creatine values, suggesting astrocytic damage, were consistently found within the NMO lesions when compared with healthy controls and patients with multiple sclerosis (MS), who showed at least 1 demyelinating lesion at the same cord level. Therefore, the in vivo quantification of myo-inositol may distinguish NMO from MS. This is an important step toward developing imaging markers for clinical trials in NMO.


Assuntos
Astrócitos/patologia , Inositol/metabolismo , Neuromielite Óptica/patologia , Medula Espinal/patologia , Adulto , Astrócitos/metabolismo , Biomarcadores , Vértebras Cervicais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Inositol/deficiência , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/metabolismo , Medula Espinal/metabolismo
19.
Genes Cells ; 18(4): 288-301, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23387983

RESUMO

In eukaryotic cells under nonstressed conditions, the endoplasmic reticulum (ER)-located molecular chaperone BiP is associated with an ER-membrane protein Ire1 to inhibit its self-association. While ER stress leads Ire1 to form transiently BiP-unbound clusters, which strongly evoke the unfolded protein response (UPR), here we propose an alternative activation status of Ire1. When yeast cells are physiologically ER-stressed by inositol depletion for a prolonged time, the UPR is weakly activated in a sustained manner after a transient peak of activation. During persistent stress, Ire1 foci disappear, while Ire1 continues to be self-associated. Under these conditions, Ire1 may be activated as a homo-dimer, as it shows considerable activity even when carrying the W426A mutation, which allows Ire1 to form homo-dimers but not clusters. Unlike the Ire1 clusters, the nonclustered active form seems to be associated with BiP. An Ire1 mutant not carrying the BiP-association site continued to form clusters and to be activated strongly even after long-term stress. Similar observations were obtained when cells were ER-stressed by dithiothreitol. We thus propose that upon persistent ER stress, Ire1 is weakly and continuously activated in a nonclustered form through its (re)association with BiP, which disperses the Ire1 clusters.


Assuntos
Proteínas Fúngicas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Resposta a Proteínas não Dobradas , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Proteínas Fúngicas/genética , Proteínas de Choque Térmico HSP70/genética , Inositol/deficiência , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Ligação Proteica , Multimerização Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Desdobramento de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética
20.
Nat Commun ; 4: 1332, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23299882

RESUMO

Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, therapeutic target of lithium remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Lítio/uso terapêutico , Mimetismo Molecular , Animais , Azóis/química , Azóis/farmacologia , Azóis/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/enzimologia , Transtorno Bipolar/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/enzimologia , Barreira Hematoencefálica/patologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Inositol/deficiência , Inositol/farmacologia , Isoindóis , Lítio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/metabolismo
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