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2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1167-1170, 2019 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-31813139

RESUMO

OBJECTIVE: To study the prevalence, clinical and genetic characteristics of primary carnitine deficiency (PCD). METHODS: From January 2013 to December 2017, 720 667 newborns and their mothers were tested for PCD by tandem mass spectrometry. Potential mutations of carnitine transporter gene SLC22A5 among suspected PCD patients were analyzed. Dietary guidance and L-carnitine supplementation were provided to the parents. Growth and intelligence development were surveyed during follow-up. RESULTS: In total 21 neonates and 6 mothers were diagnosed with PCD, which yielded an incidence of 1 in 34 317. Eighteen SLC22A5 mutations were detected, which included 4 novel mutations, namely c.1484T>C, c.394-1G>T, c.431T>C and c.265-266insGGCTCGCCACC. Eighteen patients were found to carry compound heterozygous mutations and 3 have carried homozygous SLC22A5 mutations. Three mothers carried compound heterozygous mutations and 2 carried homozygous mutations. Common mutations included c.1400C>G (42.3%), c.760C>T (11.5%) and c.51C>G (7.7%). During the 8-42 month follow-up, neonates with PCD showed no clinical symptoms but normal growth. Blood level of free carnitine was raised in all mothers after the treatment. CONCLUSION: The incidence of neonatal PCD in Henan is 1 in 34 317, with the most common mutation being c.1400C>G. Above finding has enriched the spectrum of SLC22A5 gene mutations.


Assuntos
Cardiomiopatias/genética , Carnitina/deficiência , Hiperamonemia/genética , Doenças Musculares/genética , Membro 5 da Família 22 de Carreadores de Soluto/genética , Cardiomiopatias/epidemiologia , Carnitina/administração & dosagem , Carnitina/genética , China , Feminino , Humanos , Hiperamonemia/epidemiologia , Recém-Nascido , Doenças Musculares/epidemiologia , Mutação , Triagem Neonatal
3.
Wei Sheng Yan Jiu ; 48(6): 988-992, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31875827

RESUMO

OBJECTIVE: To establish a method for simultaneous determination of L-carnitine, choline, taurin in infant by ultrafiltration tube cleaning and ultraperformance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS). METHODS: The sample was dissolved in water and acid hydrolyzed, then adjusted pH with a sodium hydroxide solution. After ultrafiltration tube cleaning and centrifugation, the sample solution was separated on an amide column ACQUITY UPLC BEH Amide(2. 1 mm × 100 mm, 1. 7 µm) and detected by MS/MS under multiple reaction monitoring(MRM) mode. The quantification was performed by the internal standard calibration method. RESULTS: The linear ranges were 1. 00-500 µg/L for L-carnitine and choline, 10-1000 µg/L for taurine with correlation coefficients of 0. 999. The mean recoveries were 89. 7%-107. 4% with relative standard deviations(RSD, n = 6) were2. 6%-8. 1%. The detection limits of the method were 0. 812 mg/kg for choline, 0. 623 mg/kg for L-carnitine and 9. 34 mg/kg for taurine, respectively. CONCLUSION: This method is simple, accurate, reproducible and sensitivity.


Assuntos
Espectrometria de Massas em Tandem , Animais , Carnitina , Colina , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Fórmulas Infantis , Leite , Taurina , Ultrafiltração
4.
J Agric Food Chem ; 67(47): 13082-13092, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31671940

RESUMO

Elevated circulating level of the intestinal microbiota-derived l-carnitine metabolite trimethylamine-N-oxide (TMAO) has recently been linked to many chronic diseases. The purpose of our study was to investigate the effects of omega-7-enriched Decaisnea insignis seed oil (DISO) on reducing TMAO formation to prevent the l-carnitine-induced hepatic damage in mice. Feeding of mice with 3% l-carnitine in drinking water clearly increased the serum and urinary levels of TMAO (p < 0.05 vs Normal), whereas the serum and urinary TMAO formation was sharply reduced by DISO administration (p < 0.05). Meanwhile, DISO resulted in strong inhibition against the elevation of hepatic injury marker (AST, ALT, and ALP) activities and dyslipidemia (TC, TG, LDL-C, and HDL-C), as well as liver inflammatory cytokine (IL-1, IL-6, TNF-α, and TNF-ß) release in l-carnitine-fed mice (p < 0.05). As revealed by 16S rDNA gene sequencing, DISO significantly inhibited the l-carnitine-induced elevations in the abundance of Firmicutes, Proteobacteria, and Erysipelotrichaceae and the increases in the proportion of Lactobacillus and Akkermansia, revealing that DISO attenuated the l-carnitine-caused gut dysbiosis. These findings suggested that DISO could alleviate liver dysfunction in l-carnitine-fed mice, which might be due to the protection against TMAO formation by modulating the gut microbiota.


Assuntos
Carnitina/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias/tratamento farmacológico , Magnoliopsida/química , Óleos Vegetais/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Masculino , Metilaminas/efeitos adversos , Camundongos , Sementes/química
5.
Chem Commun (Camb) ; 55(98): 14717-14720, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31702759

RESUMO

The final step in the biosynthesis of l-carnitine in humans is catalysed by the 2-oxoglutarate and ferrous iron dependent oxygenase, γ-butyrobetaine hydroxylase (BBOX). 1H and 19F NMR studies inform on the BBOX mechanism including by providing evidence for cooperativity between monomers in substrate/some inhibitor binding. The value of the 19F NMR methods is demonstrated by their use in the design of new BBOX inhibitors.


Assuntos
Inibidores Enzimáticos/química , Espectroscopia de Ressonância Magnética , gama-Butirobetaína Dioxigenase/metabolismo , Betaína/análogos & derivados , Betaína/síntese química , Betaína/química , Betaína/metabolismo , Carnitina/biossíntese , Carnitina/síntese química , Carnitina/química , Carnitina/metabolismo , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Flúor/química , gama-Butirobetaína Dioxigenase/antagonistas & inibidores
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1067-1072, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703127

RESUMO

OBJECTIVE: To determine the incidence and mutational types of fatty acid oxidation disorders (FAOD) in central-northern region of Guangxi. METHODS: A total of 62 953 neonates were screened for FAOD during December 2012 and December 2017. Acyl-carnitine profiling of neonatal blood sample was performed by tandem mass spectrometry using dry blood spots on a filter paper. The diagnosis of FAOD was confirmed by organic acid profiling of urea and genetic testing. RESULTS: Eighteen cases of FAOD were diagnosed among the 62 953 neonates. Among these, primary carnitine deficiency (PCD) was the most common type (n=13), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD) (n=2), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) (n=1), multiple acyl-CoA dehydrogenase deficiency (MADD) (n=1), and carnitine palmitoyltransferase II deficiency (CPT II D) (n=1). Genetic testing has revealed two previously unreported variants, i.e., c.337G to A (p.Gly113Arg) of ACADS gene and c.737G TO T (p.Gly246Val) of ETFA gene. CONCLUSION: PCD is the most common FAOD in central-northern Guangxi. Tandem mass spectrometry combined with genetic testing may facilitate early diagnosis of FAOD.


Assuntos
Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Carnitina/sangue , Carnitina O-Palmitoiltransferase/deficiência , China , Flavoproteínas Transferidoras de Elétrons/genética , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Triagem Neonatal , Espectrometria de Massas em Tandem
7.
An Acad Bras Cienc ; 91(4): e20180907, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31644644

RESUMO

A total number of 300 (225 ducks and 75 drakes) Sudani ducks, 28-wk-old were divided into five groups to investigate the effects of dietary L-carnitine (LC) supplementation on productive, hatching and physiological performance as well as nutrients digestibility coefficients. The results indicated that the productive performance and Semen quality parameters (ejaculate volume, sperms concentration and advanced motility) were significantly improved by LC supplementation (150-450 mg /kg diet) as compared to the control. Hatchability of fertile eggs (%) was significantly improved, while total embryonic mortality was significantly decreased by supplementing 300 and 450 mg LC/kg diet. Supplementing different dietary LC levels resulted in significantly high values of hemoglobin, red and white blood cells count and lymphocyte (L) cells percentage, while it decreased heterophils (H) cells and H/L ratio. Serum albumin, total cholesterol and AST enzyme values were significantly low in ducks fed diets supplemented with LC. Serum triglycerides were significantly the lowest by feeding 300 and 450 mg LC/kg diet. Nutrients digestibility coefficients were significantly improved in drakes fed diet supplemented with 450 mg LC/kg diet. Conclusively, dietary LC supplementation at 300 or 450 mg/kg for duck breeders in summer could improve productive, hatching and physiological performance and nutrients digestibility coefficients.


Assuntos
Ração Animal , Carnitina/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais , Patos/crescimento & desenvolvimento , Fenômenos Fisiológicos da Nutrição Animal , Animais , Análise Química do Sangue/veterinária , Digestão/fisiologia , Patos/fisiologia , Feminino , Masculino , Estações do Ano , Análise do Sêmen
8.
Zhonghua Er Ke Za Zhi ; 57(10): 797-801, 2019 Oct 02.
Artigo em Chinês | MEDLINE | ID: mdl-31594068

RESUMO

Objective: To investigate the profiles of blood amino acid and acylcarnitine in early neonates with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the sensitivity of newborn screening, and to explore potential biochemical metabolic markers for newborn screening program. Methods: Amino acid and acylcarnitine profiles in dried blood spots of newborn screening program were analyzed by tandem mass spectrometry (MS/MS). A total of 158 651 neonates born in Guangzhou from January 1, 2015 to June 30, 2019 were enrolled in this newborn screening program, and additionally 55 patients with NICCD confirmed by SLC25A13 gene analysis in Guangzhou Women and Children Medical Center were included in this study. NICCD screen-positive was defined as the cutoff value of citrulline (Cit) ≥ 30 µmol/L. The values of blood sampling time of the true positive group and those of the false negative group were compared by t-test. The levels of amino acid and acylcarnitine among different groups, including true positive group (Cit≥30 µmol/L), false negative group (Cit 21-<30 µmol/L and Cit<21 µmol/L) and the normal control group, were analyzed by F test, respectively. Results: Among 158 651 neonates, 39 neonates were positive for NICCD screening. Three of them were confirmed NICCD and 4 cases were found to be false negatives. The positive predictive value was 7.7% and the sensitivity was about 43.0%. Among 55 patients with NICCD, 18 cases (18/55, 32.7%) were true positives and 37 cases (37/55, 67.3%) were false negatives based on the cutoff value of citrulline in the dried blood spots for newborn screening. The blood sampling time was significantly different between true positive group and false negative group ((4.28±1.6) vs. (2.98±0.74) d, t=4.06, P<0.01). The increased levels of tyrosine((176.0±98.4) µmol/L), methionine ((37.0±26.9) µmol/L) and phenylalanine ((133.0±80.9)µmol/L) in Cit≥30 µmol/L group (n=18) were significantly different as compared with those in the other three groups, respectively (F=117.0, 58.5, 135.0, P<0.01). The levels of arginine ( (10.0±9.2) , (11.0±9.3) , (9.0±17.8) µmol/L), valine ( (119.0±29.8) , (107.6±14.1) , (102±68) µmol/L) and leucine ( (167.0±37.1) , (161.0±37.7) , (163.5±180.6) µmol/L) were not statistically significant among groups of Cit≥30 µmol/L(n=18), Cit21-<30 µmol/L(n=7) and Cit<21µmol/L(n=30,P>0.05), but they were significantly higher than those of the normal control group ((4±3), (78±21), (114.0±31.5) µmol/L, n=1 000), respectively(F=30.1, 23.0, 29.8, P<0.01). Alanine (Ala) ( (150±50) , (156.0±30.2), (168±105), (152±52) µmol/L) levels showed no significant difference (F=0.86, P>0.05) but the ratios of Ala/Cit (1.52±1.44, 6.82±1.56, 12.06±7.71, 19.42±6.27) decreased significantly among the four groups (F=69.0, P<0.05). The acylcarnitine levels showed no statistically significant results among the different groups (P>0.05). With Cit≥30 µmol/L and Ala/Cit<7.5 as cutoff values, the number of screen-positive cases reduced from 39 to 22 cases with no additional false negative case. With Cit≥21 µmol/L and Ala/Cit<7.5 as cutoff values the number of screen-positive cases increased to 117 cases with 1 additional true positive. Conclusions: The profiles of blood amino acid in early neonates with NICCD present the increased levels of multiple amino acids including citrulline, tyrosine, methionine and phenylalanine, and decreased ratio of Ala/Cit. Taking citrulline and ratio of Ala/Cit as screening markers can improve the positive predictive value appropriately. The limited sensitivity of NICCD newborn screening may be related to early blood sampling time.


Assuntos
Aminoácidos/sangue , Carnitina/análogos & derivados , Citrulinemia/diagnóstico , Triagem Neonatal/métodos , Carnitina/sangue , Criança , Citrulinemia/sangue , Feminino , Humanos , Recém-Nascido , Proteínas de Transporte da Membrana Mitocondrial , Espectrometria de Massas em Tandem
9.
Urologiia ; (4): 62-68, 2019 Sep.
Artigo em Russo | MEDLINE | ID: mdl-31535807

RESUMO

INTRODUCTION: Oxidative stress of sperm is a common pathologic condition, which can be detected in 30-80% infertile men. It is established that dietary consumption of antioxidants and microelements contributes to an increase of conception probability in subfertile couples, and also reduces the risk of reproductive losses. Drug complexes influencing various factors of spermatogenesis disturbance (oligo-, astheno-, teratozoospermia), oxidative stress and the level of sperm DNA fragmentation are of greatest and reasonable interest. AIM: To study the effects of complex acetyl-l-carnitine, l-carnitine fumarate and alpha-lipoic acid (SpermActin Forte) on oxidative stress, ejaculate quality and sperm DNA fragmentation in men with infertility. MATERIALS AND METHODS: A total of 80 infertile men aged 25-40 years with increased level of sperm DNA fragmentation and oxidative stress were included in open-label, prospective, randomized study. In Group A (n=20) patients received a placebo for 180 days, and in Group B patients were prescribed to SpermActin Forte, 1 sachet of 10 g once a day. The criteria for the efficiency of therapy included sperm analysis, the level of sperm DNA fragmentation, the level of sperm oxidative stress, as well as information about achievement of pregnancy, obtained by interviewing all participants. RESULTS: In patients taking antioxidant complex SpermActin Forte there were significant positive changes in the main parameters of sperm analysis, including sperm mobility and morphology starting from the third month of therapy. The level of free oxygen radicals (as indicator of oxidative stress) in Group B also significantly decreased (by 86%). A more profound decrease in DNA fragmentation was seen in Group B compared to Group A (21.5% vs. 3.6%). Pregnancy was achieved in 1 and 13 cases in Group A and B, respectively. CONCLUSION: The use of the SpermActin Forte antioxidant complex allowed to improve sperm analysis in most patients, and these changes were significant starting from the third month of therapy. Stimulation of spermatogenesis using the antioxidant complex SpermActin Forte is an effective and safe method of treating male infertility.


Assuntos
Carnitina/uso terapêutico , Infertilidade Masculina/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Acetilcarnitina , Adulto , Método Duplo-Cego , Feminino , Fumaratos , Humanos , Masculino , Estresse Oxidativo , Gravidez , Estudos Prospectivos , Contagem de Espermatozoides , Motilidade Espermática , Espermatozoides
10.
J Agric Food Chem ; 67(38): 10614-10623, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31483658

RESUMO

Type 2 diabetes (T2D) is a pandemic disease chiefly characterized by hyperglycemia. In this study, the combination of serum lipidomic and metabolomic approach was employed to investigate the effect of arabinoxylan on type 2 diabetic rats and identify the critical biomarkers of T2D. Metabolomics analysis revealed that branched-chain amino acids, 12α-hydroxylated bile acids, ketone bodies, and several short- and long-chain acylcarnitines were significantly increased in T2D, whereas lysophosphatidylcholines (LPCs) were significantly decreased. Lipidomics analysis indicated T2D-related dyslipidemia was mainly associated with the increased levels of acetylcarnitine, free fatty acids (FFA), diacylglycerols, triacylglycerols, and cholesteryl esters and the decreased levels of some unsaturated phosphatidylcholines (less than 22 carbons). These variations indicated the disturbed amino acid and lipid metabolism in T2D, and the accumulation of incompletely oxidized lipid species might eventually contribute to impaired insulin action and glucose homeostasis. Arabinoxylan treatment decreased the concentrations of 12α-hydroxylated bile acids, carnitines, and FFAs and increased the levels of LPCs. The improved bile acid and lipid metabolism by arabinoxylan might be involved in the alleviation of hypercholesterolemia and hyperlipidemia in T2D.


Assuntos
Anticolesterolemiantes/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Xilanos/administração & dosagem , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Carnitina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos , Lipídeos/química , Metabolômica , Ratos
11.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491949

RESUMO

Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for ß-oxidation and the TCA cycle, respectively. Ldlr -/-.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (-17%) and hepatic steatosis (-22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD.


Assuntos
Carnitina/farmacologia , Fígado Gorduroso/metabolismo , Niacinamida/análogos & derivados , Obesidade/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Niacinamida/farmacologia , Obesidade/tratamento farmacológico , Obesidade/genética , Estresse Oxidativo , Transdução de Sinais
12.
J Anim Sci ; 97(10): 4208-4218, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31410445

RESUMO

This study evaluated the effects of l-carnitine (CAR) and sugar beet pulp (SBP) inclusion in gilt gestation diets on gilt live weight, cortisol concentration, lactation feed intake, and lifetime growth of progeny. Eighty-four pregnant gilts (Large White × Landrace) were randomly assigned to a treatment at day 38 of gestation until parturition; Control (0% SBP, 0 g CAR), CAR (0.125 g/d CAR), SBP (40% SBP), and SBP plus CAR (40% SBP, 0.125 g/d CAR). Gilts were weighed and back-fat depth was recorded on day 38, day 90, and day 108 of gestation and at weaning. Gilt saliva samples were collected pre-farrowing and fecal consistency was scored from entry to the farrowing room until day 5 post-partum. The number of piglets born (total, live, and stillborn) and individual birth weight was recorded. Piglet blood glucose concentration was measured 24 h post-partum and pigs were weighed on day 1, day 6, day 14, day 26, day 76, day 110, and day 147 of life. Carcass data were collected at slaughter. There was no interaction between CAR and SBP for any variable measured. The SBP-fed gilts were heavier on day 90 and day 108 of gestation (P < 0.05) and lost more weight during lactation (P < 0.05) than control gilts. They also had a greater fecal consistency score (P < 0.01). Total farrowing duration, piglet birth interval, and lactation feed intakes were similar between treatments (P > 0.05). The number of piglets born (total, live, and stillborn) and piglet birth weight was likewise similar between treatments (P > 0.05). Piglets from CAR-fed gilts had lower blood glucose concentrations (P < 0.01), while piglets from SBP-fed gilts had greater blood glucose concentrations (P < 0.01). Piglets from CAR gilts had a lower average daily gain between day 1 and day 6 (P < 0.05) and day 14 and day 26 post-partum (P < 0.05) compared to piglets from control gilts. However, CAR gilts weaned a greater number of pigs (P = 0.07). Live weight and carcass weight at slaughter were heavier for pigs from CAR gilts (P < 0.05) and from SBP gilts (P < 0.05). Pigs from CAR gilts (P < 0.01) and SBP gilts (P < 0.05) had increased carcass muscle depth. In conclusion, no benefit was found from the combined feeding of CAR and SBP. Fed separately, CAR increased the live weight, carcass weight, and muscle depth of progeny at slaughter. Feeding a high SBP diet increased fecal consistency in gilts pre-farrowing and increased live weight and carcass muscle depth of progeny.


Assuntos
Suplementos Nutricionais/análise , Suínos/fisiologia , Ração Animal/análise , Animais , Beta vulgaris , Peso ao Nascer/efeitos dos fármacos , Carnitina/análise , Dieta/veterinária , Feminino , Lactação , Parto , Gravidez , Açúcares , Desmame , Ganho de Peso
13.
BMC Genomics ; 20(1): 652, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31416420

RESUMO

BACKGROUND: Genome-scale metabolic models (GSMM) integrating transcriptomics have been widely used to study cancer metabolism. This integration is achieved through logical rules that describe the association between genes, proteins, and reactions (GPRs). However, current gene-to-reaction formulation lacks the stoichiometry describing the transcript copies necessary to generate an active catalytic unit, which limits our understanding of how genes modulate metabolism. The present work introduces a new state-of-the-art GPR formulation that considers the stoichiometry of the transcripts (S-GPR). As case of concept, this novel gene-to-reaction formulation was applied to investigate the metabolic effects of the chronic exposure to Aldrin, an endocrine disruptor, on DU145 prostate cancer cells. To this aim we integrated the transcriptomic data from Aldrin-exposed and non-exposed DU145 cells through S-GPR or GPR into a human GSMM by applying different constraint-based-methods. RESULTS: Our study revealed a significant improvement of metabolite consumption/production predictions when S-GPRs are implemented. Furthermore, our computational analysis unveiled important alterations in carnitine shuttle and prostaglandine biosynthesis in Aldrin-exposed DU145 cells that is supported by bibliographic evidences of enhanced malignant phenotype. CONCLUSIONS: The method developed in this work enables a more accurate integration of gene expression data into model-driven methods. Thus, the presented approach is conceptually new and paves the way for more in-depth studies of aberrant cancer metabolism and other diseases with strong metabolic component with important environmental and clinical implications.


Assuntos
Aldrina/toxicidade , Disruptores Endócrinos/toxicidade , Neoplasias da Próstata/metabolismo , Carnitina/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Humanos , Masculino , Redes e Vias Metabólicas/genética , Modelos Biológicos , Prostaglandinas/biossíntese , Neoplasias da Próstata/química , Neoplasias da Próstata/genética , Transcriptoma
14.
Int J Mol Sci ; 20(16)2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31426571

RESUMO

Primary open-angle glaucoma (POAG) represents the leading cause of irreversible blindness worldwide and is a multifactorial, chronic neurodegenerative disease characterized by retinal ganglion cell and visual field loss. There are many factors that are associated with the risk of developing POAG, with increased intraocular pressure being one of the most prevalent. Due to the asymptomatic nature of the disease, the diagnosis of POAG often occurs too late, which necessitates development of new effective screening strategies for early diagnosis of the disease. However, this task still remains unfulfilled. In order to provide further insights into the pathophysiology of POAG, we applied a targeted metabolomics strategy based on a high-throughput screening method for the determination of tear amino acids, free carnitine, acylcarnitines, succinylacetone, nucleosides, and lysophospholipids in naïve to therapy glaucomatous patients and normal controls. Also, we conducted proteomic analyses of the whole lacrimal fluid and purified extracellular vesicles obtained from POAG patients and healthy subjects. This multi-omics approach allowed us to conclude that POAG patients had lower levels of certain tear amino acids and lysophospholipids compared with controls. These targeted analyses also highlighted the low amount of acetylcarnitine (C2) in POAG patient which correlated well with proteomics data. Moreover, POAG tear proteins seemed to derive from extracellular vesicles, which carried a specific pro-inflammatory protein cargo.


Assuntos
Glaucoma de Ângulo Aberto/metabolismo , Metaboloma , Proteoma/metabolismo , Lágrimas/metabolismo , Idoso , Biomarcadores/metabolismo , Carnitina/metabolismo , Feminino , Glaucoma de Ângulo Aberto/patologia , Heptanoatos/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Masculino , Pessoa de Meia-Idade
15.
Fish Shellfish Immunol ; 93: 1100-1110, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31422179

RESUMO

Nrf2/Keap1 pathway is associated with oxidative stress. l-carnitine is currently under preclinical evaluation as a antioxidant, but the use of l-carnitine in aquaculture has been poorly evaluated and so far no mechanism has been demonstrated. Here, we explored the effects of l-carnitine in vitro and in vivo and discussed the possible molecular mechanisms involved. Firstly, Nrf2-siRNA significantly knocked down the mRNA level of Nrf2 in FHM cells. Thus, the activities of antioxidant enzymes (T-SOD, CAT, GSH-PX) and the level of antioxidant substance (GSH) and the level of MDA showed that Nrf2-siRNA pretreatment weakened the protective effect of l-carnitine. Moreover, the mRNA levels of Keap1, Nrf2, Maf and HO-1 indicated that l-carnitine regulated Nrf2/Keap1 activation. Furthermore, oxidized fish oil remarkably suppressed growth in Rhynchocypris lagowski Dybowski, and the lower antioxidant capacity was also observed in liver. According to the results of immune related indexes (the levels of IL-1ß, TNF-α, LZM, AKP) in serum and the mRNA levels of immune related genes (NF-κB, IL-1ß, TNF-α, IL-8, IL-10 and TGF-ß) in liver, oxidized fish oil also induced inflammatory response in fish. Also, l-carnitine supplementation can relieve this bad condition. In conclusion, l-carnitine regulated Nrf2/Keap1 activation in vitro and in vivo and protected oxidized fish oil-induced inflammation response by inhibiting the NF-κB signaling pathway in Rhynchocypris lagowski Dybowski.


Assuntos
Carnitina/metabolismo , Cyprinidae/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/metabolismo , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Carnitina/administração & dosagem , Proteínas de Transporte/metabolismo , Linhagem Celular , Cyprinidae/genética , Cyprinidae/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Doenças dos Peixes/tratamento farmacológico , Óleos de Peixe/farmacologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/veterinária , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Oxirredução , Estresse Oxidativo , Substâncias Protetoras/administração & dosagem , Distribuição Aleatória
16.
Toxicol Lett ; 316: 183-193, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437515

RESUMO

Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic ß-hydroxybutyrate level (indicator of fatty acid ß-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 µM of IC50), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.


Assuntos
Antipsicóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Coenzima A Ligases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Olanzapina/toxicidade , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Adulto , Animais , Carnitina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coenzima A Ligases/genética , Cães , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Membro 5 da Família 22 de Carreadores de Soluto/genética , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Regulação para Cima
17.
Biochim Biophys Acta Bioenerg ; 1860(9): 708-716, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31340138

RESUMO

The mitochondrial carnitine/acylcarnitine carrier (CACT) catalyzes an antiport of carnitine and acylcarnitines and also a uniport reaction with a rate of about one tenth with respect to the antiport rate. The antiport process results from the coupling of the two uniport reactions in opposite directions. In this mechanism, the transition of the carrier from the outward open conformation to the inward open one (or vice versa) is much faster for the carrier-substrate complex than for the unbound carrier. To investigate the molecular determinants that couple the binding of the substrate with the conformational transitions, site directed mutagenesis has been employed. The antiport or the uniport reaction was followed as [3H]carnitine uptake in or efflux from proteoliposomes reconstituted with the WT or Trp mutants of the rat CACT. Substitution of each the three Trp residues led to different results. Nearly no variations were observed upon substitution of W192 and/or W296 with Ala. While, substantial alteration of the transport function was observed in the mutants W224A, W224Y and W224F. Mutation of W224 led to the loss of the antiport function while the uniport function was unaltered. In these mutants impairment of the substrate affinity on the external side was also observed. The data highlights that W224 is involved in the coupling of the substrate binding with the matrix gate opening. The experimental data are in line with predictions by homology modeling of the CACT in its cytosolic (c-state) or matrix (m-state) opened conformations.


Assuntos
Antiporters/metabolismo , Carnitina Aciltransferases/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Triptofano/metabolismo , Sequência de Aminoácidos , Animais , Aspergillus nidulans , Transporte Biológico , Carnitina Aciltransferases/química , Carnitina Aciltransferases/genética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Conformação Proteica , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência , Triptofano/química , Triptofano/genética
18.
Invest Ophthalmol Vis Sci ; 60(8): 3119-3126, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323682

RESUMO

Purpose: To determine plasma metabolite and metabolic pathway differences between patients with type 2 diabetes with diabetic retinopathy (DR) and without retinopathy (diabetic controls), and between patients with proliferative DR (PDR) and nonproliferative DR (NPDR). Methods: Using high-resolution mass spectrometry with liquid chromatography, untargeted metabolomics was performed on plasma samples from 83 DR patients and 90 diabetic controls. Discriminatory metabolic features were identified through partial least squares discriminant analysis, and linear regression was used to adjust for age, sex, diabetes duration, and hemoglobin A1c. Pathway analysis was performed using Mummichog 2.0. Results: In the adjusted analysis, 126 metabolic features differed significantly between DR patients and diabetic controls. Pathway analysis revealed alterations in the metabolism of amino acids, leukotrienes, niacin, pyrimidine, and purine. Arginine, citrulline, glutamic γ-semialdehyde, and dehydroxycarnitine were key contributors to these pathway differences. A total of 151 features distinguished PDR patients from NPDR patients, and pathway analysis revealed alterations in the ß-oxidation of saturated fatty acids, fatty acid metabolism, and vitamin D3 metabolism. Carnitine was a major contributor to the pathway differences. Conclusions: This study demonstrates that arginine and citrulline-related pathways are dysregulated in DR, and fatty acid metabolism is altered in PDR patients compared with NPDR patients.


Assuntos
Arginina/sangue , Carnitina/sangue , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Diabetes Mellitus Tipo 2/sangue , Retinopatia Diabética/etiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Acuidade Visual
19.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323921

RESUMO

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.


Assuntos
Raios gama/efeitos adversos , Radiação Ionizante , Animais , Biomarcadores/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Rim/efeitos dos fármacos , Rim/metabolismo , Macaca mulatta , Masculino , Metabolômica/métodos , Primatas
20.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349613

RESUMO

Treatment with all-trans retinoic acid (ATRA), the carboxylic form of vitamin A, lowers body weight in rodents by promoting oxidative metabolism in multiple tissues including white and brown adipose tissues. We aimed to identify novel markers of the metabolic impact of ATRA through targeted blood metabolomics analyses, with a focus on acylcarnitines and amino acids. Blood was obtained from mice treated with a high ATRA dose (50 mg/kg body weight/day, subcutaneous injection) or placebo (controls) during the 4 days preceding collection. LC-MS/MS analyses with a focus on acylcarnitines and amino acids were conducted on plasma and PBMC. Main results showed that, relative to controls, ATRA-treated mice had in plasma: increased levels of carnitine, acetylcarnitine, and longer acylcarnitine species; decreased levels of citrulline, and increased global arginine bioavailability ratio for nitric oxide synthesis; increased levels of creatine, taurine and docosahexaenoic acid; and a decreased n-6/n-3 polyunsaturated fatty acids ratio. While some of these features likely reflect the stimulation of lipid mobilization and oxidation promoted by ATRA treatment systemically, other may also play a causal role underlying ATRA actions. The results connect ATRA to specific nutrition-modulated biochemical pathways, and suggest novel mechanisms of action of vitamin A-derived retinoic acid on metabolic health.


Assuntos
Aminoácidos/sangue , Carnitina/análogos & derivados , Metaboloma/efeitos dos fármacos , Metabolômica , Tretinoína/farmacologia , Tecido Adiposo , Animais , Carnitina/sangue , Perfilação da Expressão Gênica , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Metabolômica/métodos , Camundongos , Modelos Biológicos , Oxirredução/efeitos dos fármacos
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