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1.
Biomarkers ; 24(5): 415-422, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050554

RESUMO

The quantitative determination of sarcosine is of great importance in clinical chemistry, food and fermentation industries. Elevated sarcosine levels are associated with Alzheimer, dementia, prostate cancer, colorectal cancer, stomach cancer and sarcosinemia. This review summarizes the various methods for quantitative analysis of sarcosine with special emphasis on various strategies of biosensors and their analytical performance. The current bio sensing methods have overcome the drawbacks of conventional methods. Sarcosine biosensors work optimally at pH 7.0 to 8.0 in the linear range of 0.1 to 100 µM within 2 to 17 s and between 25 and 37 °C, within a limit of detection (LOD) between 0.008 and 500 mM. The formulated biosensors can be reused within a stability period of 3-180 days. Future research could be focused to modify existing sarcosine biosensors, leading to simple, reliable, and economical sensors ideally suited for point-of-care treatment. Clinical significance Elevated sarcosine levels are associated with prostate and colorectal cancer, Alzheimer, dementia, stomach cancer and sarcosinemia. Quantitative determination of sarcosine is of great importance in clinical chemistry as well as food and fermentation industries. Attempts made in development of sarcosine biosensors have been reviewed with their advantages and disadvantages, so that scientist and clinicians can improvise the methods of developing more potent sarcosine biosensor applicable in multitudinous fields. This is the first comprehensive review which compares the various immobilization methods, sensing principles, strategies used in biosensors and their analytical performance in detail.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Técnicas Biossensoriais/métodos , Doenças Mitocondriais/sangue , Neoplasias da Próstata/sangue , Sarcosina Desidrogenase/deficiência , Sarcosina/sangue , Doença de Alzheimer/sangue , Biomarcadores/sangue , Neoplasias Colorretais/sangue , Humanos , Masculino , Sarcosina Desidrogenase/sangue , Neoplasias Gástricas/sangue
2.
Clin Biochem ; 72: 71-80, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30954436

RESUMO

OBJECTIVES: Altered amyloid metabolism and mitochondrial dysfunction play key roles in the development of Alzheimer's disease (AD). We asked whether an association exists between disturbed platelet mitochondrial respiration and the plasma concentrations of Aß40 and Aß42 in patients with AD. DESIGN AND METHODS: Plasma Aß40 and Aß42 concentrations and mitochondrial respiration in intact and permeabilized platelets were measured in 50 patients with AD, 15 patients with vascular dementia and 25 control subjects. A pilot longitudinal study was performed to monitor the progression of AD in a subgroup 11 patients with AD. RESULTS: The mean Aß40, Aß42 and Aß42/Aß40 levels were not significantly altered in patients with AD compared with controls. The mitochondrial respiratory rate in intact platelets was significantly reduced in patients with AD compared to controls, particularly the basal respiratory rate, maximum respiratory capacity, and respiratory reserve; however, the flux control ratio for basal respiration was increased. A correlation between the plasma Aß42 concentration and mitochondrial respiration in both intact and permeabilized platelets differs in controls and patients with AD. CONCLUSIONS: Based on our data, (1) mitochondrial respiration in intact platelets, but not the Aß level itself, may be included in a panel of biomarkers for AD; (2) dysfunctional mitochondrial respiration in platelets is not explained by changes in plasma Aß concentrations; and (3) the association between mitochondrial respiration in platelets and plasma Aß levels differs in patients with AD and controls. The results supported the hypothesis that mitochondrial dysfunction is the primary factor contributing to the development of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Fragmentos de Peptídeos/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Biomarcadores/sangue , Respiração Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/sangue , Doenças Mitocondriais/complicações , Consumo de Oxigênio
3.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897730

RESUMO

Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency.


Assuntos
Carnitina O-Palmitoiltransferase/sangue , Carnitina O-Palmitoiltransferase/deficiência , Fatores de Crescimento de Fibroblastos/sangue , Erros Inatos do Metabolismo/sangue , Doenças Mitocondriais/sangue , Adulto , Animais , Biomarcadores/sangue , Carnitina O-Palmitoiltransferase/genética , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Malonil Coenzima A/genética , Malonil Coenzima A/metabolismo , Erros Inatos do Metabolismo/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Doenças Mitocondriais/genética
4.
Dis Markers ; 2019: 2984747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881520

RESUMO

Because tandem mass spectrometry- (MS/MS-) based newborn screening identifies many suspicious cases of fatty acid oxidation and carnitine cycle disorders, a simple, noninvasive test is required to confirm the diagnosis. We have developed a novel method to evaluate the metabolic defects in peripheral blood mononuclear cells loaded with deuterium-labeled fatty acids directly using the ratios of acylcarnitines determined by flow injection MS/MS. We have identified diagnostic indices for the disorders as follows: decreased ratios of d27-C14-acylcarnitine/d31-C16-acylcarnitine and d23-C12-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-II (CPT-II) deficiency, decreased ratios of d23-C12-acylcarnitine/d27-C14-acylcarnitine for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and increased ratios of d29-C16-OH-acylcarnitine/d31-C16-acylcarnitine for trifunctional protein (TFP) deficiency, together with increased ratios of d7-C4-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-I deficiency. The decreased ratios of d1-acetylcarnitine/d31-C16-acylcarnitine could be indicative of ß-oxidation ability in patients with CPT-II, VLCAD, and TFP deficiencies. Overall, our data showed that the present method was valuable for establishing a rapid diagnosis of fatty acid oxidation disorders and carnitine cycle disorders and for complementing gene analysis because our diagnostic indices may overcome the weaknesses of conventional enzyme activity measurements using fibroblasts or mononuclear cells with assumedly uncertain viability.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Cardiomiopatias/sangue , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/sangue , Espectrometria de Massas/métodos , Doenças Mitocondriais/sangue , Miopatias Mitocondriais/sangue , Proteína Mitocondrial Trifuncional/deficiência , Técnicas de Diagnóstico Molecular/métodos , Monócitos/química , Doenças Musculares/sangue , Doenças do Sistema Nervoso/sangue , Rabdomiólise/sangue , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Adulto , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/química , Carnitina O-Palmitoiltransferase/deficiência , Deutério/química , Humanos , Lactente , Proteína Mitocondrial Trifuncional/sangue , Monócitos/metabolismo , Oxirredução
5.
Eur J Hum Genet ; 27(2): 331-335, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30315213

RESUMO

Mitochondrial myopathies are a heterogeneous group of disorders associated with a wide range of clinical phenotypes. We present a 16-year-old girl with a history of exercise intolerance since childhood. Acylcarnitine species suggestive of multiple acyl-CoA dehydrogenase deficiency were found in serum, however genetic analysis did not reveal variants in genes associated with this disorder. Biochemical analyses of skeletal muscle mitochondria revealed an isolated and extremely low activity of cytochrome c oxidase (COX). This finding was confirmed by enzyme histochemistry, which demonstrated an almost complete absence of fibers with normal COX activity. Whole-exome sequencing revealed a single base-pair deletion (m.8088delT) in MT-CO2, which encodes subunit 2 of COX, resulting in a premature stop codon. Restriction fragment length polymorphism-analysis confirmed mtDNA heteroplasmy with high mutant load in skeletal muscle, the only clinically affected tissue, but low levels in other investigated tissues. Single muscle fiber analysis showed segregation of the mutant genotype with respiratory chain dysfunction. Immuno-histochemical studies indicated that the truncating variant in COX2 has an inhibitory effect on the assembly of the COX holoenzyme.


Assuntos
Carnitina/análogos & derivados , Complexo IV da Cadeia de Transporte de Elétrons/genética , Mutação da Fase de Leitura , Doenças Mitocondriais/genética , Doenças Musculares/genética , Adolescente , Carnitina/sangue , Códon de Terminação , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Mitocôndrias Musculares/metabolismo , Doenças Mitocondriais/sangue , Doenças Mitocondriais/patologia , Doenças Musculares/sangue , Doenças Musculares/patologia
6.
Invest Ophthalmol Vis Sci ; 59(11): 4355-4361, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30193307

RESUMO

Purpose: To determine the plasma metabolomic signature of primary open-angle glaucoma (POAG). Methods: We compared the metabolomic profiles of plasma from individuals with POAG (n = 36) with age- and sex-matched controls with cataract (n = 27). A targeted metabolomics study was performed using the standardized p180 Biocrates Absolute IDQ p180 kit with a QTRAP 5500 mass spectrometer. Multivariate analyses were performed using principal component analysis (PCA) and the least absolute shrinkage and selection operator (LASSO) method. Results: Among the 151 metabolites accurately measured, combined univariate and multivariate analyses revealed 18 discriminant metabolites belonging to the carbohydrate, acyl-carnitine, phosphatidylcholine, amino acids, and polyamine families. The metabolomic signature of POAG points to three closely interdependent pathophysiologic conditions; that is, defective mitochondrial oxidation of energetic substrates, altered metabolism resembling that observed in senescence, and a deficiency in spermidine and spermine, both polyamines being involved in the protection of retinal ganglion cells. Conclusions: Our results highlight a systemic and age-related mitochondrial defect in the pathogenesis of POAG.


Assuntos
Envelhecimento , Proteínas do Olho/sangue , Glaucoma de Ângulo Aberto/sangue , Metaboloma , Metabolômica/métodos , Doenças Mitocondriais/sangue , Espermidina/sangue , Espermina/sangue , Idoso , Feminino , Humanos , Masculino , Espectrometria de Massas , Análise de Componente Principal
7.
Environ Sci Pollut Res Int ; 25(32): 32506-32514, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30238259

RESUMO

Benzene is an environmental and occupational contaminant. Health hazards associated with occupational benzene exposure is a major public health problem in China. In this study, we analyzed metabolite profiles among plasma samples collected from benzene-exposed workers with low white blood cell count (BLWs) and healthy controls using high-performance liquid chromatography-time-of-flight mass spectrometry. To screen potential benzene hematotoxicity biomarkers and metabolic pathways, principal component analysis was used to examine metabolite profile changes in plasma samples. The alterations in fatty acid oxidation (FAO) pathway were consistent with our previous findings in a mouse model; hence, two key genes were selected and verified in WBC samples. A total of nine identified metabolites were significantly changed in BLWs, which were involved in glutathione metabolism, porphyrin metabolism, lipid metabolism pathway, and FAO metabolism. Furthermore, compared with healthy controls, the mRNA expressions of carnitine acyltransferase (CRAT) and ACADVL were significantly increased in BLWs. Particularly, WBC counts was negatively correlated with the expression of AVADVL in BLWs. These aberrant metabolites could act as potential biomarkers for benzene hematotoxicity. In addition, fatty acid oxidation pathway may play a critical role in the development of hematotoxicity caused by benzene.


Assuntos
Benzeno/toxicidade , Ácidos Graxos/sangue , Contagem de Leucócitos , Exposição Ocupacional/efeitos adversos , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Adulto , Animais , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Carnitina Aciltransferases/sangue , China , Feminino , Glutationa/sangue , Hemolíticos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Erros Inatos do Metabolismo Lipídico/sangue , Masculino , Espectrometria de Massas , Metaboloma , Metabolômica/métodos , Camundongos , Doenças Mitocondriais/sangue , Doenças Musculares/sangue , Exposição Ocupacional/análise , Oxirredução , Porfirinas/sangue , RNA Mensageiro/metabolismo
9.
J Inherit Metab Dis ; 41(6): 1179-1187, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30159853

RESUMO

BACKGROUND: There is increasing evidence that long-term complications in organic acidemias are caused by impaired mitochondrial metabolism. Currently, there is no specific biomarker to monitor mitochondrial dysfunction in organic acidemias. Serum fibroblast growth factor 21 (FGF-21) is a biomarker for mitochondrial disease and could be a candidate to monitor mitochondrial function in the deleterious course of disease. METHODS: Data of 17 patients with classical organic acidemias (11 propionic acidemia (PA), four methylmalonic acidemia (MMA) and two isovaleric acidemia (IVA) patients) were included. The clinical course was evaluated; metabolic decompensations and long-term complications were correlated with plasma FGF-21 levels. Cardiomyopathy, prolonged QT interval, renal failure, and optic neuropathy were defined as long-term complications. RESULTS: Patients ages ranged from 16 months up to 32 years. Serious long-term complications occurred in eight patients (five PA and three MMA patients). In MMA and PA patients plasma FGF-21 levels during stable metabolic periods were significantly higher in patients with long-term complications (Mdn = 2556.0 pg/ml) compared to patients without (Mdn = 287.0 pg/ml). A median plasma FGF-21 level above 1500 pg/ml during a stable metabolic period, measured before the occurrence of long-term complications, had a positive predictive value of 0.83 and a negative predictive value of 1.00 on long-term complications in MMA and PA patients. CONCLUSION: This study demonstrates the potential role of FGF-21 as a biomarker for long-term complications in classical organic acidemias, attributed to mitochondrial dysfunction.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Fatores de Crescimento de Fibroblastos/sangue , Isovaleril-CoA Desidrogenase/deficiência , Doenças Mitocondriais/sangue , Acidemia Propiônica/complicações , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Doenças Mitocondriais/complicações , Adulto Jovem
10.
Essays Biochem ; 62(3): 443-454, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29980631

RESUMO

Biomarkers are an indicator of biologic or pathogenic processes, whose function is indicating the presence/absence of disease or monitoring disease course and its response to treatment. Since mitochondrial disorders (MDs) can represent a diagnostic challenge for clinicians, due to their clinical and genetic heterogeneity, the identification of easily measurable biomarkers becomes a high priority. Given the complexity of MD, in particular the primary mitochondrial respiratory chain (MRC) diseases due to oxidative phosphorylation (OXPHOS) dysfunction, a reliable single biomarker, relevant for the whole disease group, could be extremely difficult to find, most of times leading the physicians to better consider a 'biosignature' for the diagnosis, rather than a single biochemical marker. Serum biomarkers like lactate and pyruvate are largely determined in the diagnostic algorithm of MD, but they are not specific to this group of disorders. The concomitant determination of creatine (Cr), plasma amino acids, and urine organic acids might be helpful to reinforce the biosignature in some cases. In recent studies, serum fibroblast growth factor 21 (sFGF21) and serum growth differentiation factor 15 (sGDF15) appear to be promising molecules in identifying MD. Moreover, new different approaches have been developed to discover new MD biomarkers. This work discusses the most important biomarkers currently used in the diagnosis of MRC diseases, and some approaches under evaluation, discussing both their utility and weaknesses.


Assuntos
Metabolismo Energético , Doenças Mitocondriais/sangue , Aminoácidos/sangue , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Creatina Quinase/sangue , Fatores de Crescimento de Fibroblastos/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Ácido Láctico/sangue , Doenças Mitocondriais/metabolismo , Fosforilação Oxidativa , Ácido Pirúvico/sangue
11.
Psychiatry Clin Neurosci ; 72(8): 546-555, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29726068

RESUMO

Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.


Assuntos
Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Ácido Láctico/metabolismo , Doenças Mitocondriais/metabolismo , Transtorno Bipolar/sangue , Transtorno Bipolar/líquido cefalorraquidiano , Transtorno Bipolar/diagnóstico , Encéfalo/diagnóstico por imagem , Humanos , Ácido Láctico/sangue , Ácido Láctico/líquido cefalorraquidiano , Doenças Mitocondriais/sangue , Doenças Mitocondriais/líquido cefalorraquidiano , Doenças Mitocondriais/diagnóstico
12.
Biochem Biophys Res Commun ; 500(2): 124-131, 2018 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-29627572

RESUMO

Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD.


Assuntos
Lipídeos/sangue , Metabolômica/métodos , Doenças Mitocondriais/sangue , Área Sob a Curva , Biomarcadores/sangue , Análise Discriminante , Humanos , Análise dos Mínimos Quadrados , Metaboloma , Análise de Componente Principal , Curva ROC
13.
Med Hypotheses ; 113: 52-53, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29523294

RESUMO

Mitochondrial dysfunction (MD) is a complex pathophysiological phenomenon, linked with many inherited and acquired diseases. A clinical evaluation of MD requires rather extensive approach, while no gold-standard circulating biomarker has been established so far. Partly produced in mitochondria, creatine thus might be considered as a sensible compound of mitochondrial bioenergetics. Increased plasma creatine perhaps is linked with MD, illustrating disturbances in its utilization in the stressed organelle.


Assuntos
Biomarcadores/sangue , Creatina/sangue , Mitocôndrias/patologia , Doenças Mitocondriais/sangue , Trifosfato de Adenosina/metabolismo , Creatina Quinase Mitocondrial/metabolismo , Transporte de Elétrons , Metabolismo Energético , Humanos , Mitocôndrias/metabolismo , Modelos Teóricos , Músculos/fisiologia
15.
Pediatr Res ; 83(2): 455-465, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28981487

RESUMO

BackgroundDiagnosing mitochondrial disease (MD) is a challenge. In addition to genetic analyses, clinical practice is to perform invasive procedures such as muscle biopsy for biochemical and histochemical analyses. Blood cell respirometry is rapid and noninvasive. Our aim was to explore its possible role in diagnosing MD.MethodsBlood samples were collected from 113 pediatric patients, for whom MD was a differential diagnosis. A respiratory analysis model based on ratios (independent of mitochondrial specific content) was derived from a group of healthy controls and tested on the patients. The diagnostic accuracy of platelet respirometry was evaluated against routine diagnostic investigation.ResultsMD prevalence in the cohort was 16%. A ratio based on the respiratory response to adenosine diphosphate in the presence of complex I substrates had 96% specificity for disease and a positive likelihood ratio of 5.3. None of the individual ratios had sensitivity above 50%, but a combined model had 72% sensitivity.ConclusionNormal findings of platelet respirometry are not able to rule out MD, but pathological results make the diagnosis more likely and could strengthen the clinical decision to perform further invasive analyses. Our results encourage further study into the role of blood respirometry as an adjunct diagnostic tool for MD.


Assuntos
Plaquetas/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Consumo de Oxigênio , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Ácido Láctico/sangue , Masculino , Oxigênio/química , Prevalência , Sensibilidade e Especificidade
16.
Hum Reprod Update ; 24(1): 86-105, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29136166

RESUMO

BACKGROUND: Hyperglycemia can result from a loss of pancreatic beta-cells or a decline in their function leading to decreased insulin secretion or may arise from insulin resistance and variable degrees of inadequate insulin secretion resulting in diabetes and related comorbidities. To date several reviews have addressed the issue of diabetes-related male infertility but most have focused on how metabolic syndrome causes the decline in male fertility. However, a comprehensive overview as to how diabetes-induced hyperglycemia impairs male fertility is missing. Impaired regulation of glucose and the resultant hyperglycemia are major threats to the health of individuals in modern societies especially given the rapidly rising prevalence affecting an increasing number of men in their reproductive years. Consequently, diabetes-induced hyperglycemia is likely to contribute to a decline in global birth rates especially in those societies with a high diabetic prevalence. OBJECTIVE AND RATIONALE: This systematic review addresses and summarizes the impact of hyperglycemia on male reproductive health with a particular emphasis on the molecular mechanisms that influence the testis and other parts of the male reproductive tract. SEARCH METHODS: A systematic search of the literature published in the MEDLINE-Pubmed database (http://www.ncbi.nlm.nih.gov/pubmed) and Cochrane Library (http://www.cochranelibrary.com) was performed, as well as hand searching reference lists, from the earliest available online indexing year until May 2017, using diabetes- and male fertility-related keywords in combination with other search phrases relevant to the topic of hyperglycemia. Inclusion criteria were: clinical studies on type 1 diabetic (T1D) men and studies on T1D animal models with a focus on reproductive parameters. Case reports/series, observational studies and clinical trials were included. Studies on patients with type 2 diabetes (T2D) or animal models of T2D were excluded to distinguish hyperglycemia from other metabolic effects. OUTCOMES: A total of 890 articles were identified of which 197 (32 clinical, 165 animal studies) were selected for qualitative analysis. While the clinical data from men with hyperglycemia-induced reproductive dysfunction were reported in most studies on T1D, the study designs were variable and lacked complete information on patients. Moreover, only a few studies (and mostly animal studies) addressed the underlying mechanisms of how hyperglycemia induces infertility. Potential causes included impaired function of the hypothalamic-pituitary-gonadal axis, increased DNA damage, perturbations in the system of advanced glycation endproducts and their receptor, oxidative stress, increased endoplasmatic reticulum stress, modulation of cellular pathways, impaired mitochondrial function and disrupted sympathetic innervation. However, intervention studies to identify and confirm the pathological mechanisms were missing: data that are essential in understanding these interactions. WIDER IMPLICATIONS: While the effects of regulating the hyperglycemia by the use of insulin and other modulators of glucose metabolism have been reported, more clinical trials providing high quality evidence and specifically addressing the beneficial effects on male reproduction are required. We conclude that interventions using insulin to restore normoglycemia should be a feasible approach to assess the proposed underlying mechanisms of infertility.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Hiperglicemia/complicações , Infertilidade Masculina/etiologia , Reprodução/fisiologia , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/fisiopatologia , Infertilidade Masculina/sangue , Infertilidade Masculina/prevenção & controle , Insulina/uso terapêutico , Masculino , Doenças Mitocondriais/sangue , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/prevenção & controle
17.
J Pediatr ; 182: 217-222.e3, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28088395

RESUMO

OBJECTIVES: To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate ≥ 2.5 mmol/L or L:P ≥ 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days. STUDY DESIGN: Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. RESULTS: Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days. CONCLUSIONS: A serum lactate ≥ 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00986648.


Assuntos
Ácido Láctico/sangue , Falência Hepática Aguda/diagnóstico , Doenças Mitocondriais/diagnóstico , Ácido Pirúvico/sangue , Sistema de Registros , Adolescente , Fatores Etários , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Modelos Logísticos , Masculino , Doenças Mitocondriais/sangue , Doenças Mitocondriais/mortalidade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento
18.
J Diabetes Complications ; 31(1): 253-259, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27422531

RESUMO

Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations in both nuclear and mitochondrial DNA. In fact, mitochondrial DNA (mtDNA) defects are known to be associated with a large spectrum of human diseases and patients might present wide range of clinical features with various combinations. Our study reported a Tunisian family with clinical features of maternally inherited diabetes and deafness (MIDD). Accordingly, we performed a whole mitochondrial genome mutational analysis, results revealed a haplotype composed by "A750G, A1438G, G8860A, T12705, T14766C and T16519C", in homoplasmic state, in the mother and transmitted to her daughter and her son. The patient with MIDD2 and retinopathy presented, in addition to this haplotype associated to the MIDD, two de novo variations including a novel one m.8241T>G (p. F219C) in MT-CO2 gene and a known one m.13276G>A (p. M314V) in MT-ND5 gene. The coexistence of these two mutations could explain the retinopathy observed in this patient.


Assuntos
DNA Mitocondrial , Surdez/genética , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Modelos Moleculares , Mutação Puntual , Adulto , Substituição de Aminoácidos , Análise Mutacional de DNA , Bases de Dados de Proteínas , Surdez/sangue , Surdez/complicações , Surdez/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética/sangue , Retinopatia Diabética/complicações , Retinopatia Diabética/metabolismo , Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/química , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Saúde da Família , Feminino , Humanos , Masculino , Doenças Mitocondriais/sangue , Doenças Mitocondriais/complicações , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Obesidade/sangue , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Linhagem , Conformação Proteica , Homologia Estrutural de Proteína , Tunísia
19.
Muscle Nerve ; 55(4): 564-569, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27489983

RESUMO

INTRODUCTION: Human fibroblast growth factor 21 (FGF21) is a regulator of lipid and glucose metabolism. It is expressed in skeletal muscle and may be a sensitive and specific marker for mitochondrial diseases and other neuromuscular disorders. METHODS: Serum FGF21 levels were determined in 71 human samples. Thirty patients with mitochondrial disease, 16 patients with myotonic dystrophy type 1 (DM1), 5 patients with facioscapulohumeral dystrophy, and 20 healthy controls were enrolled. Results Serum FGF21 levels were significantly elevated in patients with progressive external ophthalmoplegia and DM1 compared with patients with facioscapulohumeral dystrophy, other types of mitochondrial diseases, and controls. In the mitochondrial disorder group, serum FGF21 levels were related to the number of ragged blue fibers. Significant insulin resistance was found in DM1 that might be responsible for FGF21 elevation. Conclusions FGF21 elevation may be associated with certain types of mitochondrial disease, and it is influenced by insulin resistance. Muscle Nerve 55: 564-569, 2017.


Assuntos
Creatina Quinase/sangue , Fatores de Crescimento de Fibroblastos/sangue , Doenças Mitocondriais/sangue , Doenças Mitocondriais/etiologia , Distrofia Miotônica/sangue , Distrofia Miotônica/complicações , Adulto , Idoso , DNA Mitocondrial/genética , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Distrofia Muscular Facioescapuloumeral/sangue , Distrofia Muscular Facioescapuloumeral/complicações , Distrofia Miotônica/genética , Oftalmoplegia/sangue , Oftalmoplegia/fisiopatologia , Estatística como Assunto , Tireotropina/sangue
20.
Mol Neurobiol ; 54(10): 8110-8116, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27889897

RESUMO

The present study aimed to investigate whether serum growth differentiation factor 15 concentration is a valuable and reliable diagnostic biomarker of mitochondrial diseases. We examined consecutive patients with mitochondrial diseases, in comparison with patients with non-mitochondrial disease neuromuscular disorders and healthy controls. The serum concentrations of growth differentiation factor 15 were measured by ELISA, and compared with those of FGF21, lactate, and creatine kinase. We also evaluated the correlations between growth differentiation factor 15 concentrations and the Newcastle Mitochondrial Disease Adult Scale, numbers of ragged-red fibers, and COX-negative fibers in the biopsied muscles. The median serum growth differentiation factor 15 concentration was significantly elevated in 42 patients with mitochondrial diseases, compared with 20 patients with non-mitochondrial disease neuromuscular disorders and 50 healthy controls. The area under the curve of growth differentiation factor 15 for the diagnosis of muscle-manifesting mitochondrial diseases was 0.999, in comparison with those area under the curves of the other biomarkers including fibroblast growth factor 21 (0.935, p < 0.01), lactate (0.845 for p < 0.001), and creatine kinase (0.575, p < 0.001). Growth differentiation factor 15 was significantly correlated with mitochondrial disease severity and the proportion of ragged-red fibers identified in the biopsied muscles. Circulating growth differentiation factor 15 measurement is a superior biomarker with high sensitivity and specificity, which can be used as a non-invasive test to screen for primary mitochondrial diseases and dysmetabolic myopathy with associated mitochondrial dysfunction in susceptible individuals.


Assuntos
Fator 15 de Diferenciação de Crescimento/sangue , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos Transversais , Feminino , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Adulto Jovem
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