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1.
Clin Epigenetics ; 13(1): 137, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215320

RESUMO

BACKGROUND: The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported. METHODS: We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients. RESULTS: All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients. CONCLUSIONS: We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.


Assuntos
Erros Inatos do Metabolismo/genética , Oxirredutases/análise , Peroxirredoxinas/análise , Vitamina B 12/metabolismo , Metilação de DNA/genética , Feminino , Humanos , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/etiologia , Triagem Neonatal/métodos
2.
J Inherit Metab Dis ; 44(4): 792-808, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33990986

RESUMO

Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD+ /NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox-dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3-phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation.


Assuntos
Aspartato Aminotransferases/deficiência , Ácido Aspártico/metabolismo , Malato Desidrogenase/deficiência , Malatos/metabolismo , Erros Inatos do Metabolismo/patologia , Mitocôndrias/patologia , Animais , Aspartato Aminotransferases/genética , Respiração Celular , Humanos , Lactente , Malato Desidrogenase/genética , Erros Inatos do Metabolismo/etiologia , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias/metabolismo , Espasmos Infantis/etiologia
3.
IUBMB Life ; 72(11): 2241-2259, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32916028

RESUMO

This article presents a personal and critical review of the history of the malate-aspartate shuttle (MAS), starting in 1962 and ending in 2020. The MAS was initially proposed as a route for the oxidation of cytosolic NADH by the mitochondria in Ehrlich ascites cell tumor lacking other routes, and to explain the need for a mitochondrial aspartate aminotransferase (glutamate oxaloacetate transaminase 2 [GOT2]). The MAS was soon adopted in the field as a major pathway for NADH oxidation in mammalian tissues, such as liver and heart, even though the energetics of the MAS remained a mystery. Only in the 1970s, LaNoue and coworkers discovered that the efflux of aspartate from mitochondria, an essential step in the MAS, is dependent on the proton-motive force generated by the respiratory chain: for every aspartate effluxed, mitochondria take up one glutamate and one proton. This makes the MAS in practice uni-directional toward oxidation of cytosolic NADH, and explains why the free NADH/NAD ratio is much higher in the mitochondria than in the cytosol. The MAS is still a very active field of research. Most recently, the focus has been on the role of the MAS in tumors, on cells with defects in mitochondria and on inborn errors in the MAS. The year 2019 saw the discovery of two new inborn errors in the MAS, deficiencies in malate dehydrogenase 1 and in aspartate transaminase 2 (GOT2). This illustrates the vitality of ongoing MAS research.


Assuntos
Aspartato Aminotransferases/deficiência , Ácido Aspártico/metabolismo , Malato Desidrogenase/deficiência , Malatos/metabolismo , Erros Inatos do Metabolismo/patologia , Mitocôndrias/patologia , Animais , Aspartato Aminotransferases/genética , Respiração Celular , Humanos , Malato Desidrogenase/genética , Erros Inatos do Metabolismo/etiologia , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias/metabolismo , Mutação
4.
J Appl Lab Med ; 5(2): 342-356, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32445384

RESUMO

BACKGROUND: The application of whole-exome sequencing for the diagnosis of genetic disease has paved the way for systems-based approaches in the clinical laboratory. Here, we describe a clinical metabolomics method for the screening of metabolic diseases through the analysis of a multi-pronged mass spectrometry platform. By simultaneously measuring hundreds of metabolites in a single sample, clinical metabolomics offers a comprehensive approach to identify metabolic perturbations across multiple biochemical pathways. METHODS: We conducted a single- and multi-day precision study on hundreds of metabolites in human plasma on 4, multi-arm, high-throughput metabolomics platforms. RESULTS: The average laboratory coefficient of variation (CV) on the 4 platforms was between 9.3 and 11.5% (median, 6.5-8.4%), average inter-assay CV on the 4 platforms ranged from 9.9 to 12.6% (median, 7.0-8.3%) and average intra-assay CV on the 4 platforms ranged from 5.7 to 6.9% (median, 3.5-4.4%). In relation to patient sample testing, the precision of multiple biomarkers associated with IEM disorders showed CVs that ranged from 0.2 to 11.0% across 4 analytical batches. CONCLUSIONS: This evaluation describes single and multi-day precision across 4 identical metabolomics platforms, comprised each of 4 independent method arms, and reproducibility of the method for the measurement of key IEM metabolites in patient samples across multiple analytical batches, providing evidence that the method is robust and reproducible for the screening of patients with inborn errors of metabolism.


Assuntos
Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/diagnóstico , Metaboloma , Metabolômica/métodos , Metabolômica/normas , Adolescente , Biomarcadores , Criança , Pré-Escolar , Cromatografia Líquida , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Redes e Vias Metabólicas , Erros Inatos do Metabolismo/etiologia , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Adulto Jovem
5.
Am J Med Genet A ; 182(7): 1608-1614, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32259399

RESUMO

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) deficiency is a very rare autosomal recessive inborn error of ketone body synthesis and presents with hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, and hepatomegaly with fatty liver precipitated by catabolic stress. We report acute presentation of two patients from unrelated two families with novel homozygous c.862C>T and c.725-2A>C mutations, respectively, in HMGCS2 gene. Affected patients had severe hypoketotic hypoglycemia, lethargy, encephalopathy, severe metabolic and lactic acidosis and hepatomegaly after infections. Surprisingly, molecular screening of the second family showed more affected patients without clinical findings. These cases expand the clinic spectrum of this extremely rare disease.


Assuntos
Hidroximetilglutaril-CoA Sintase/deficiência , Hipoglicemia/etiologia , Erros Inatos do Metabolismo/etiologia , Doenças Mitocondriais/etiologia , Mutação , Acidose/genética , Adolescente , Pré-Escolar , Feminino , Hepatomegalia/genética , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Hipoglicemia/genética , Lactente , Letargia/etiologia , Masculino , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Turquia
6.
J Am Soc Nephrol ; 31(4): 799-816, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32086278

RESUMO

BACKGROUND: Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. METHODS: Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies. RESULTS: Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy. CONCLUSIONS: Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.


Assuntos
Adenina Fosforribosiltransferase/deficiência , Adenina/análogos & derivados , Nefropatias/etiologia , Nefropatias/patologia , Erros Inatos do Metabolismo/etiologia , Erros Inatos do Metabolismo/patologia , Urolitíase/etiologia , Urolitíase/patologia , Adenina/fisiologia , Adenina Fosforribosiltransferase/metabolismo , Adulto , Animais , Estudos de Coortes , Dieta , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Masculino , Erros Inatos do Metabolismo/metabolismo , Camundongos , Pessoa de Meia-Idade , Urolitíase/metabolismo
7.
Mol Metab ; 38: 100924, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31974037

RESUMO

BACKGROUND: An organism's metabolic phenotype is primarily affected by its genotype, its lifestyle, and the nutritional composition of its food supply. In addition, it is now clear from studies in many different species that ancestral environments can also modulate metabolism in at least one to two generations of offspring. SCOPE OF REVIEW: We limit ourselves here to paternal effects in mammals, primarily focusing on studies performed in inbred rodent models. Although hundreds of studies link paternal diets and offspring metabolism, the mechanistic basis by which epigenetic information in sperm programs nutrient handling in the next generation remains mysterious. Our goal in this review is to provide a brief overview of paternal effect paradigms and the germline epigenome. We then pivot to exploring one key mystery in this literature: how do epigenetic changes in sperm, most of which are likely to act transiently in the early embryo, ultimately direct a long-lasting physiological response in offspring? MAJOR CONCLUSIONS: Several potential mechanisms exist by which transient epigenetic modifications, such as small RNAs or methylation states erased shortly after fertilization, could be transferred to more durable heritable information. A detailed mechanistic understanding of this process will provide deep insights into early development, and could be of great relevance for human health and disease.


Assuntos
Mutação em Linhagem Germinativa/genética , Erros Inatos do Metabolismo/genética , Animais , Metilação de DNA , Dieta , Epigênese Genética , Epigenômica , Células Germinativas/metabolismo , Humanos , Masculino , Mamíferos/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Erros Inatos do Metabolismo/etiologia , Exposição Paterna/efeitos adversos , Fenótipo , Espermatozoides/metabolismo
8.
Pediatr Blood Cancer ; 66(11): e27929, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31339233

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Adulto , Idade de Início , Criança , Ensaios Clínicos como Assunto/normas , Diagnóstico Diferencial , Gerenciamento Clínico , Toxidermias/etiologia , Doenças Fetais/diagnóstico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Falência Hepática/etiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Linfo-Histiocitose Hemofagocítica/terapia , Ativação de Macrófagos , Erros Inatos do Metabolismo/etiologia , Neoplasias/complicações , Fenótipo , Sepse/etiologia
9.
East Mediterr Health J ; 24(11): 1103-1111, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30701526

RESUMO

BACKGROUND: Although inborn errors of metabolism (IEM) are rare individually, collectively IEM cause substantial morbidity and mortality and the diagnosis is challenging. AIMS: To analyse epidemiological and clinical data, final diagnosis and clinical outcomes of patients with a suspected diagnosis of IEM (small molecule disorders type) admitted to a paediatric intensive care unit (PICU). METHODS: We collected and analysed medical records data of all patients admitted to the PICU at Alexandria University Children's Hospital, from January 2010 to December 2014, with a suspected or confirmed diagnosis of small molecule disorders, including clinical presentations, laboratory results and clinical outcomes. RESULTS: A total of 34 patients had a suspected or confirmed diagnosis of small molecule disorders at PICU admission. Diagnosis was confirmed in 22.7% of suspected cases at admission and in 25% of suspected cases during PICU stay. Consanguineous marriage was found in 50% of cases with confirmed small molecule disorders. CONCLUSIONS: A high index of suspicion is important for diagnosing and categorizing small molecule disorders in screening of high-risk individuals in low- and middle-income countries.


Assuntos
Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Erros Inatos do Metabolismo/epidemiologia , Criança , Pré-Escolar , Consanguinidade , Egito/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/etiologia , Erros Inatos do Metabolismo/mortalidade , Estudos Retrospectivos , Fatores de Risco
11.
Nat Commun ; 10(1): 62, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30622276

RESUMO

The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. However, a direct demonstration of the assembly of metabolite amyloid-like structures has so far been provided only in vitro. Here, we established an in vivo model of adenine self-assembly in yeast, in which toxicity is associated with intracellular accumulation of the metabolite. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.


Assuntos
Adenina/metabolismo , Amiloide/metabolismo , Erros Inatos do Metabolismo/etiologia , Saccharomyces cerevisiae/metabolismo , Adenina/toxicidade , Amiloide/toxicidade , Erros Inatos do Metabolismo/metabolismo
12.
Eur J Obstet Gynecol Reprod Biol ; 232: 87-96, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30502592

RESUMO

BACKGROUND: Consanguinity is the close union, sexual relationship or marriage between persons who have common biological ancestors usually up to about 2nd cousins. Contrary to general opinion consanguinity is quite common and is practiced worldwide. It is an important topic as while rates of consanguineous unions in certain society have decreased over time, rates have remained stable or increased in other societies with rates as high as 80.6% in some communities. Our aim was to conduct a review looking at general aspects of consanguinity and any published reproductive outcomes in literature. We also looked at possible future directions that could be relevant in the management of the consanguineous couple to help improve reproductive outcomes. METHOD: We conducted a PUBMED, CINAHL, Web of Knowledge and Google Scholar search looking at articles on consanguinity. Consanguinity articles related to pregnancy and reproduction were searched using additional filters looking at our specific areas of interest. All relevant publications up to March 2015 were reviewed. Additional search for relevant articles pertaining to pre implantation genetic diagnosis for future directions in the management of the consanguineous couple was done. Most publications were found in books, on line articles and journals. Most were retrospective, population or cohort studies. RESULT: Consanguinity is practiced by up to 10% of the world's population with rates ranging from 80.6% in certain provinces in the Middle East to less than 1% in western societies. It predates Islam and has been practiced since Old Testament times. The most commonly cited reason for consanguinity is sociocultural and socioeconomic although it is also more common in certain religions. In areas where rates of Consanguinity are reducing urban migration and increasing education rates are thought to be contributory. Congenital malformations have long been established to be higher in consanguineous couples above the background rate (4.5% Vs 1%).Due to "Founder effect" or a common ancestor, Consanguinity is most commonly associated with Inborn errors of metabolism most of which are autosomal recessive. Consanguinity increases the incidence of multifactorial disorders such as diabetes, cardiovascular disorders, obesity and certain types of cancers. These may in turn affect reproductive outcomes. It may also affect fertility rates. Pregnancy outcomes like increased pregnancy wastages and preterm labor have been reported with consanguinity. Other studies produced conflicting evidence on its effect regarding outcomes like hypertensive disorders of pregnancy and Intrauterine growth restriction. CONCLUSION: Consanguinity continues to be practiced worldwide and in some countries rates are increasing. The main reason for the practice appears to be sociocultural and socioeconomic although religious beliefs is a contributory factor. The most significant effects on reproductive outcomes are mostly due to autosomal recessive inherited conditions and inborn errors of metabolism. It also significantly increases the inheritance of certain multifactorial disorders like diabetes which may indirectly affect reproductive outcomes. In the future with the completion of the study of the whole human Genome and current advances in Pre implantation Genetic diagnosis and screening it may be possible to mitigate some of the adverse reproductive outcomes associated with consanguinity.


Assuntos
Consanguinidade , Fertilidade , Erros Inatos do Metabolismo/etiologia , Resultado da Gravidez , Feminino , Humanos , Incidência , Masculino , Idade Materna , Erros Inatos do Metabolismo/epidemiologia , Gravidez
14.
Cardiovasc Diabetol ; 17(1): 133, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301460

RESUMO

BACKGROUND: Gestational diabetes (GDM) and milder gestational impaired glucose tolerance (GIGT) identify women at risk of developing type 2 diabetes and cardiovascular disease later in life. Accordingly, the postpartum years after gestational dysglycemia can provide insight into early events in the natural history of these disorders. We thus sought to prospectively evaluate the relationship between gestational glucose tolerance and emerging cardiometabolic biomarkers [adiponectin, chemerin, retinol-binding protein-4 (RBP-4), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1)] at both 1- and 3-years postpartum in a cohort reflecting the full spectrum of gestational dysglycemia (from normal to GIGT to GDM). METHODS: Three-hundred-and-thirty-nine women completed a glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, which identified 4 gestational glucose tolerance groups: GDM (n = 105); GIGT (n = 59); abnormal GCT with normal OGTT (n = 99); and normal GCT with normal OGTT (n = 76). At 1- and 3-years postpartum, the women underwent repeat OGTT with measurement of biomarkers (adiponectin/chemerin/RBP-4/CRP/PAI-1). RESULTS: Serum adiponectin was lower in women with GDM and GIGT at both 1-year and 3-years (both P ≤ 0.002), whereas chemerin, RBP-4, CRP and PAI-1 showed no differences across the 4 groups. Importantly, the change in PAI-1 between 1- and 3-years progressively increased from the normal GCT group to the abnormal GCT group to GIGT to GDM (P = 0.03). Indeed, both GDM (t = 2.98, P = 0.003) and GIGT (t = 2.14, P = 0.03) independently predicted an increase in PAI-1 from 1- to 3-years postpartum. CONCLUSIONS: Hypoadiponectinemia and rising PAI-1 over time are early features of the cardiometabolic biomarker profile of women with recent gestational dysglycemia.


Assuntos
Adiponectina/deficiência , Glicemia/metabolismo , Diabetes Gestacional/sangue , Erros Inatos do Metabolismo/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Adiponectina/sangue , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Diabetes Gestacional/diagnóstico , Regulação para Baixo , Feminino , Humanos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/etiologia , Gravidez , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Regulação para Cima
16.
Mol Reprod Dev ; 85(8-9): 682-695, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30118583

RESUMO

Members of the solute carrier 26 (SLC26) family have emerged as important players in mediating anions fluxes across the plasma membrane of epithelial cells, in cooperation with the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Among them, SLC26A3 acts as a chloride/bicarbonate exchanger, highly expressed in the gastrointestinal, pancreatic and renal tissues. In humans, mutations in the SLC26A3 gene were shown to induce congenital chloride-losing diarrhea (CLD), a rare autosomal recessive disorder characterized by life-long secretory diarrhea. In view of some reports indicating subfertility in some male CLD patients together with SLC26-A3 and -A6 expression in the male genital tract and sperm cells, we analyzed the male reproductive parameters and functions of SLC26A3 deficient mice, which were previously reported to display CLD gastro-intestinal features. We show that in contrast to Slc26a6, deletion of Slc26a3 is associated with severe lesions and abnormal cytoarchitecture of the epididymis, together with sperm quantitative, morphological and functional defects, which altogether compromised male fertility. Overall, our work provides new insight into the pathophysiological mechanisms that may alter the reproductive functions and lead to male subfertility in CLD patients, with a phenotype reminiscent of that induced by CFTR deficiency in the male genital tract.


Assuntos
Antiporters/metabolismo , Epididimo/metabolismo , Epididimo/fisiopatologia , Fertilização , Infertilidade Masculina/metabolismo , Capacitação Espermática , Transportadores de Sulfato/metabolismo , Animais , Antiporters/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Diarreia/congênito , Diarreia/etiologia , Masculino , Erros Inatos do Metabolismo/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermatozoides/patologia , Transportadores de Sulfato/genética , Testículo/fisiopatologia
17.
Respir Physiol Neurobiol ; 256: 119-127, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29246449

RESUMO

Chronic intermittent hypoxia (CIH) occurs frequently in premature infants who have apnea of prematurity. Immaturity of the respiratory network from low central respiratory drive and the greater contribution of the carotid body on baseline breathing leads to respiratory instability in premature infants presenting as apnea and periodic breathing. During the 2nd week after birth, the smallest and the youngest premature infants have increased frequency of apnea and periodic breathing and associated oxygen desaturations that can persist for weeks after birth. CIH increases the production of reactive oxygen species that causes tissue damage. Premature infants have decreased capacity to scavenge reactive oxygen species. Oxidative injury is the cause of many of the co-morbidities that are seen in premature infants. In this review we discuss who low fat mass and the resulting relative deficiencies in leptin and adiponectin could contribute to the increase frequency of oxygen desaturations that occurs days after birth in the smallest and youngest premature infants. Leptin is a central respiratory stimulant and adiponectin protects the lung from vascular leak, oxidative injury and vascular remodeling.


Assuntos
Adiponectina/deficiência , Hipóxia/complicações , Recém-Nascido Prematuro/fisiologia , Leptina/deficiência , Erros Inatos do Metabolismo/etiologia , Animais , Humanos , Lactente
19.
J Infect ; 75(5): 455-463, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28851533

RESUMO

OBJECTIVES: Malaria in pregnancy (MiP) contributes to fetal undernutrition and adverse birth outcomes, and may constitute a developmental origin of metabolic diseases in the offspring. In a Ghanaian birth cohort, we examined the relationships between MiP-exposure and metabolic traits in adolescence. METHODS: MiP at delivery was assessed in 155 mother-child pairs. Among the now teenaged children (mean age, 14.8 years; 53% male), we measured fasting plasma glucose (FPG), body mass index (BMI), and systolic and diastolic blood pressure (BP). Associations of MiP with the adolescents' FPG, BMI, and BP were examined by linear regression. RESULTS: At delivery, 45% were MiP-exposed, which increased FPG in adolescence, adjusted for mother's age at delivery, parity and familial socio-economic status (infected vs. uninfected: mean ΔFPG = 0.20 mmol/L; 95% confidence interval (CI): 0.01, 0.39; p = 0.049). As a trend,this was discernible for BP, particularly for microscopic infections (mean Δsystolic BP = 5.43 mmHg; 95% CI: 0.00, 10.88; p = 0.050; mean Δdiastolic BP = 3.67 mmHg; 95% CI: -0.81, 8.14; p = 0.107). These associations were largely independent of birth weight, gestational age and teenage BMI. Adolescent BMI was not related to MiP. CONCLUSIONS: In rural Ghana, exposure to malaria during fetal development contributes to metabolic conditions in young adulthood.


Assuntos
Malária/embriologia , Erros Inatos do Metabolismo/etiologia , Complicações Infecciosas na Gravidez , Adolescente , Adulto , Estudos de Coortes , Feminino , Seguimentos , Gana , Humanos , Recém-Nascido , Malária/metabolismo , Masculino , Exposição Materna , Gravidez , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal
20.
J Am Soc Nephrol ; 28(11): 3175-3181, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28698271

RESUMO

IgA nephropathy (IgAN) is characterized by infections followed by episodic gross hematuria. Deficiency of mannose-binding lectin (MBL) is associated with recurrent infection in many diseases, but controversy exists regarding the role of MBL in IgAN. Here, we measured MBL2 variants and MBL levels in 749 patients with IgAN and 489 healthy controls. Overall, 5.2% (39 of 749) of patients with IgAN had MBL deficiency (MBL levels <100 ng/ml), among whom LYPB/LYPB and LXPA/LYPB were the predominant MBL2 haplotypes (82%; 32 of 39). We found a nonlinear association between MBL levels and renal outcome in IgAN. Patients with IgAN and MBL deficiency had a higher incidence of prodromic infections and gross hematuria than those with sufficient MBL levels (100-3540 ng/ml). Moreover, MBL deficiency independently associated with poor renal outcome in IgAN after multiple adjustments (hazard ratio, 5.18; 95% confidence interval, 2.50 to 10.72; P<0.001). Patients with high MBL levels (>3540 ng/ml) had more severe proteinuria and a higher proportion of crescents, although the association with IgAN progression did not reach statistical significance after adjustments. In conclusion, MBL deficiency and MBL excess may both have deleterious effects on IgAN progression, which suggests that MBL contributes to IgAN pathogenesis through multiple mechanisms.


Assuntos
Glomerulonefrite por IGA/sangue , Lectina de Ligação a Manose/sangue , Adulto , Feminino , Glomerulonefrite por IGA/complicações , Humanos , Masculino , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/etiologia , Prognóstico , Estudos Retrospectivos
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