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1.
Anticancer Res ; 40(7): 4173-4182, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620667

RESUMO

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancers. Sorafenib, an oral multi-target TKI, improves the median overall survival time in patients with hepatocellular carcinoma (HCC). It also inhibits the absorption of carnitine by down-regulating the human organic cationic transporter OCTN2 located largely in the small intestinal mucosa and skeletal muscle. The aim of the study was to determine, by assessing carnitine metabolism, whether sarcopenia is induced in patients with HCC who are receiving sorafenib. PATIENTS AND METHODS: This retrospective study included 110 adult Japanese patients with liver cirrhosis and HCC who received sorafenib. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment, and serum carnitine fraction and myostatin levels were measured. Cross-sectional areas (cm2) of the skeletal muscles at the third lumbar vertebra level were determined by manually outlining computed tomography images before and after treatment. The cross-sectional areas were normalized for height [skeletal muscle index (SMI), cm2/m2]. RESULTS: Patients were allocated to two groups according to Child-Pugh (CP) class; 81 had CP-A liver function, and 29 had CP-B. SMI after treatment was significantly lower than that before treatment in both groups. Serum levels of total carnitine and free carnitine after treatment were significantly lower than those before treatment in both groups. There were no differences in serum levels of myostatin before and after treatment in either group. CONCLUSION: Sorafenib might decrease serum levels of carnitine by inhibiting carnitine absorption. Decreasing of serum levels of carnitine might lead to presarcopenia.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carnitina/sangue , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Sarcopenia/induzido quimicamente , Sorafenibe/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carnitina/metabolismo , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade
3.
Gan To Kagaku Ryoho ; 47(3): 490-492, 2020 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-32381925

RESUMO

AIM: Low serum carnitine levels have been reported in patients with cancer receiving chemotherapy and are considered one of the factors causing fatigue associated with chemotherapy. We evaluated the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with gastric cancer(GC). MATERIALS AND METHODS: We performed a randomized controlled trial between December 2013 and December 2018. Untreated patients with advanced GC were included in the study; 1 patient developed an allergy after receiving the first chemotherapy and was excluded from the study. The primary endpoint was brief fatigue inventory(BFI). Patients were categorized into 2 groups: those who received L-carnitine oral supplements(group C)and those who did not receive L-carnitine oral supplements(group N). RESULTS: The serum carnitine levels were improved significantly in group C compared with group N. BFIwas more aggravated in group N than group C; however, the difference was not significant. CONCLUSION: We could not demonstrate the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with GC.


Assuntos
Antineoplásicos/efeitos adversos , Fadiga/induzido quimicamente , Neoplasias Gástricas , Carnitina , Humanos , Neoplasias Gástricas/tratamento farmacológico
4.
Environ Sci Pollut Res Int ; 27(18): 23026-23034, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32329006

RESUMO

The present study aimed to investigate the possible mitigating effect of L-carnitine (LC) and/or α-tocopherol (Vit. E) administration against tilmicosin (TIL)-induced cardiotoxicity in rats. Fifty-six male albino rats were divided into seven groups according to LC, Vit. E, and/or TIL administration. Control, LC, and Vit. E groups were given saline, 150 mg LC/kg body weight (BW)/day and 100 mg Vit. E/kg BW/day, respectively, orally once daily for 15 days. The TIL group was administered saline orally once daily for 15 days and a single dose of TIL (75 mg/kg BW) subcutaneously (SC) on day 14 from the starting of the experimental period (15 days). The TIL-LC, TIL-Vit. E, and TIL-LC-Vit. E groups received 150 mg LC/kg BW/day, 100 mg Vit. E/kg BW/day, and 150 mg LC/kg BW pulse 100 mg Vit. E/kg BW, respectively, orally once daily for 15 days with TIL as described above. The results revealed that the administration of TIL significantly (P ≤ 0.05) raised serum activities of heart injury indicators, lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB with substantial increase (P ≤ 0.05) in the cardiac contents of malondialdehyde (MDA) and decreased in antioxidants. The pathological changes appeared in the form of necrotic muscle fibers and massive inflammatory cellular infiltrations in the cardiac muscle and increased the caspase-3 immunohistochemical expression in the heart tissues as well. These changes were ameliorated by LC and/or Vit. E administration. In conclusion, supplementation of LC and/or Vit. E ameliorated the cardiotoxicity of the TIL SC injection in the rat.


Assuntos
Carnitina , Vitamina E , Animais , Antioxidantes , Cardiotoxicidade , Masculino , Estresse Oxidativo , Ratos , Tilosina/análogos & derivados
5.
Artigo em Inglês | MEDLINE | ID: mdl-32220802

RESUMO

Metabolic profiling is commonly achieved by mass spectrometry (MS) following reversed-phase (RP) and hydrophilic interaction chromatography (HILIC) either performed independently, leading to overlapping datasets, or in a coupled configuration, requiring multiple liquid chromatography (LC) systems. To overcome these limitations, we developed a single, 20-minute chromatographic method using an in-line RP-ion-exchange (IEX) column arrangement and a single LC system. This configuration separates clinically significant polar and non-polar compounds without derivatization or ion-pairing reagents, allowing ionization in both polarities. An in-house library was created with 397 authentic standards, including acylcarnitines, amino acids, bile acids, nucleosides, organic acids, steroid hormones, and vitamins. Analysis of pooled plasma and urine samples revealed 5445 and 4111 ion features, leading to 88 and 82 confirmed metabolite identifications, respectively. Metabolites were detected at clinically relevant concentrations with good precision, and good chromatographic separation was demonstrated for clinically significant isomers including methylmalonic acid and succinic acid, as well as alloisoleucine and isoleucine/leucine. Evaluation of the samples by unsupervised principal component analysis showed excellent analytical quality.


Assuntos
Isoleucina/sangue , Isoleucina/urina , Metabolômica/métodos , Ácido Metilmalônico/sangue , Ácido Metilmalônico/urina , Ácido Succínico/sangue , Ácido Succínico/urina , Aminoácidos/química , Ácidos e Sais Biliares/química , Carnitina/análogos & derivados , Carnitina/química , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Cromatografia de Fase Reversa , Hormônios/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Metaboloma , Nucleosídeos/química , Bibliotecas de Moléculas Pequenas/química , Espectrometria de Massas em Tandem , Vitaminas/química
6.
Environ Sci Pollut Res Int ; 27(15): 18699-18707, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32207001

RESUMO

Neuro-schistosomiasis can induce neurological symptoms and severe disability. Since the resistance against the chemotherapy "praziquantel" was reported, the aim of the present study was investigating the anti-neuro-schistosomal effects of ZnO nanoparticles and/or L-carnitine (as free radicals scavenger) on schistosome-infected mice, where technology of nanoparticles has come to the forefront in the medical diagnosis and therapeutic drug delivery. In the human body, nanoscale-sized particles can move freely and reveal unique biological, mechanical, electrical, and chemical properties. In the present study, mice were divided into five groups. The first group served as the non-infected control group. Groups II, III, IV, and V were infected with cercariae of Schistosoma mansoni. Mice of groups III and IV were treated with ZnO nanoparticles (5.6 mg/kg b. wt.) and L-carnitine (500 mg/kg b. wt.), respectively, after 47 days post-infection. Finally, mice of the fifth group were injected with ZnO nanoparticles and after 1 h, the mice were intraperitoneally injected with L-carnitine once daily for 5 days. On day 52, post-infection mice of all groups were cervically decapitated. The treatment of ZnO nanoparticles and/or L-carnitine to schistosome-infected mice decreased brain oxidative stress parameters, where glutathione level and catalase activity were significantly increased as compared to schistosome-infected group. On the contrary, the treatment decreased nitrite/nitrate, malondialdehyde, and reactive oxygen species levels significantly. In addition, ZnO nanoparticles and/or L-carnitine treatment restored DNA laddering profile and improved the brain histopathological impairments resulting from neuro-schistosomiasis. Finally, the ZnO nanoparticle treatment and the co-treatment of ZnO nanoparticles and L-carnitine revealed anti-neuro-schistosomal effects on the infected mice.


Assuntos
Carnitina , Nanopartículas , Esquistossomose mansoni , Óxido de Zinco , Animais , Humanos , Camundongos , Schistosoma mansoni
7.
PLoS One ; 15(3): e0229772, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126131

RESUMO

BACKGROUND: Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS: This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS: Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS: Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cardiomiopatias/induzido quimicamente , Carnitina/deficiência , Fadiga/etiologia , Hiperamonemia/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/urina , Cardiomiopatias/sangue , Cardiomiopatias/complicações , Cardiomiopatias/dietoterapia , Carnitina/administração & dosagem , Carnitina/sangue , Carnitina/urina , Suplementos Nutricionais , Fadiga/sangue , Fadiga/diagnóstico , Fadiga/prevenção & controle , Feminino , Humanos , Hiperamonemia/sangue , Hiperamonemia/complicações , Hiperamonemia/dietoterapia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/urina , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doenças Musculares/sangue , Doenças Musculares/complicações , Doenças Musculares/dietoterapia , Estudos Prospectivos , Resultado do Tratamento
8.
Arch Med Res ; 51(1): 82-94, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113058

RESUMO

BACKGROUND AND AIM: Possible Hepato-protective effects of L-carnitine have been reported in previous studies. Present study was conducted to systematically review the efficacy of L-carnitine supplementation on liver enzymes. METHODS: The following databases were searched up to December 2018: PubMed, Scopus, ISI Web of Science, and the Cochrane library. Only randomized controlled trials (RCTs) evaluating the effects of L-carnitine supplementation on liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) were included. Pooled effect size measured using random effect model (Dersimonian-Liard). RESULTS: A total of 16 studies (including 1025 participants) were included in the present meta-analysis. Pooled analysis indicated that L-carnitine supplementation significantly decreased ALT (weighted mean difference (WMD): -10.729 IU/L, 95% CI: -13.787, -7.672, p <0.001; I2 = 95.9%), AST (WMD: -7.149 IU/L, 95% CI: -9.202, -5.096, p <0.001; I2 = 93.5%) and GGT (WMD: -7.395: IU/L, 95% CI: -9.171, -5.619, p <0.001; I2 = 80.1%). Subgroup analysis revealed that effect of L-carnitine supplementation on liver enzymes was not significant in normal weight and healthy subjects. Baseline BMI and health status were the potential source of heterogeneity. CONCLUSION: L-carnitine supplementation showed beneficial hepato-protective effects on circulating liver enzymes.


Assuntos
Carnitina/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Alanina Transaminase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Carnitina/administração & dosagem , Citoproteção/efeitos dos fármacos , Suplementos Nutricionais , Humanos , Fígado/metabolismo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , gama-Glutamiltransferase/efeitos dos fármacos , gama-Glutamiltransferase/metabolismo
9.
Clin Chim Acta ; 505: 92-97, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32070725

RESUMO

INTRODUCTION: Carnitine is essential for long-chain fatty acid oxidation in muscle and heart. Tissue stores are regulated by organic cation/Cn transporter plasmalemmal Octn2. We previously demonstrated low carnitine in quadriceps/gluteus and heart of adult mdx mice. METHODS: We studied protein and mRNA expression of Octn2, mitochondrial Octn1 and peroxisomal Octn3 in adult male C57BL/10ScSn-DMD mdx/J quadriceps, heart, and diaphragm compared to C57BL/10SnJ mice. RESULTS: We demonstrated reduction in mOctn2 expression on Western blot and similar expression of mOctn1 and mOctn3 in mdx quadriceps, heart and diaphragm. There was a significant upregulation of mOctn1 and mOctn2 mRNA by qRT-PCR in mdx quadriceps and of mOctn2 and mOctn3 mRNA in mdx heart. We showed upregulation of mdx mOctn1 and mOctn3 mRNA but no increase in protein expression. DISCUSSION: Dystrophin deficiency likely disrupts Octn2 expression decreasing muscle carnitine uptake thus contributing to membranotoxic long-chain acyl-CoAs with sarcolemmal and organellar membrane oxidative injury providing a treatment rationale for early L-carnitine in DMD.


Assuntos
Carnitina/química , Carnitina/uso terapêutico , Músculo Esquelético/química , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Miocárdio/química , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/genética , Membro 5 da Família 22 de Carreadores de Soluto/biossíntese , Membro 5 da Família 22 de Carreadores de Soluto/genética , Simportadores/biossíntese , Simportadores/genética , Animais , Carnitina/metabolismo , Diafragma/metabolismo , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
10.
Am J Physiol Endocrinol Metab ; 318(5): E701-E709, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101032

RESUMO

Little is known about xenometabolites in human metabolism, particularly under exercising conditions. Previously, an exercise-modifiable, likely xenometabolite derivative, cis-3,4-methylene-heptanoylcarnitine, was reported in human plasma. Here, we identified trans-3,4-methylene-heptanoylcarnitine, and its cis-isomer, in plasma and skeletal muscle by liquid chromatography-mass spectrometry. We analyzed the regulation by exercise and the arterial-to-venous differences of these cyclopropane ring-containing carnitine esters over the hepatosplanchnic bed and the exercising leg in plasma samples obtained in three separate studies from young, lean and healthy males. Compared with other medium-chain acylcarnitines, the plasma concentrations of the 3,4-methylene-heptanoylcarnitine isomers only marginally increased with exercise. Both isomers showed a more than twofold increase in the skeletal muscle tissue of the exercising leg; this may have been due to the net effect of fatty acid oxidation in the exercising muscle and uptake from blood. The latter idea is supported by a more than twofold increased net uptake in the exercising leg only. Both isomers showed a constant release from the hepatosplanchnic bed, with an increased release of the trans-isomer after exercise. The isomers differ in their plasma concentration, with a four times higher concentration of the cis-isomer regardless of the exercise state. This is the first approach studying kinetics and fluxes of xenolipid isomers from tissues under exercise conditions, supporting the hypothesis that hepatic metabolism of cyclopropane ring-containing fatty acids is one source of these acylcarnitines in plasma. The data also provide clear evidence for an exercise-dependent regulation of xenometabolites, opening perspectives for future studies about the physiological role of this largely unknown class of metabolites.


Assuntos
Carnitina/análogos & derivados , Carnitina/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Humanos , Masculino , Adulto Jovem
11.
Animal ; 14(S1): s165-s175, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32024571

RESUMO

Coordinated changes in energy metabolism develop to support gestation and lactation in the periparturient dairy cow. Maternal physiology involves the partitioning of nutrients (i.e. glucose, amino acids and fatty acids (FA)) for fetal growth and milk synthesis. However, the inability of the dairy cow to successfully adapt to a productive lactation may trigger metabolic stress characterized by uncontrolled adipose tissue lipolysis and reduced insulin sensitivity. A consequence is lipotoxicity and hepatic triglyceride deposition that favors the development of fatty liver disease (FLD) and ketosis. This review describes contemporary perspectives pertaining to FA surfeit and complex lipid metabolism in the transition dairy cow. The role of saturated and unsaturated FA as bioactive signaling molecules capable of modulating insulin secretion and sensitivity is explored. Moreover, the metabolic fate of FA as influenced by mitochondrial function is considered. This includes the influence of inadequate mitochondrial oxidation on acylcarnitine status and the use of FA for lipid mediator synthesis. Lipid mediators, including the sphingolipid ceramide and diacylglycerol, are evaluated considering their established ability to inhibit insulin signaling and glucose transport in non-ruminant diabetics. The mechanisms of FLD in the transition cow are revisited with attention centered on glycerophospholipid phosphatidylcholine and triglyceride secretion. The relationship between oxidative stress and oxylipids within the context of insulin antagonism, hepatic steatosis and inflammation is also reviewed. Lastly, peripartal hormonal involvement or lack thereof of adipokines (i.e. leptin, adiponectin) and hepatokines (i.e. fibroblast growth factor-21) is described. Similarities and differences in ruminant and non-ruminant physiology are routinely showcased. Unraveling the lipidome of the dairy cow has generated breakthroughs in our understanding of periparturient lipid biology. Therapeutic approaches that target FA and complex lipid metabolism holds promise to enhance cow health, well-being and productive lifespan.


Assuntos
Bovinos/fisiologia , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Leite/metabolismo , Transdução de Sinais , Animais , Carnitina/análogos & derivados , Carnitina/metabolismo , Ceramidas/metabolismo , Metabolismo Energético , Feminino , Glucose/metabolismo , Glicerofosfolipídeos/metabolismo , Insulina/metabolismo , Resistência à Insulina , Lactação , Lipólise , Fígado/metabolismo , Mitocôndrias/metabolismo , Esfingolipídeos/metabolismo , Triglicerídeos/metabolismo
12.
PLoS One ; 15(2): e0228568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027707

RESUMO

In human, OCTN2 (SLC22A5) and ATB0,+ (SLC6A14) transporters mediate the uptake of L-carnitine, essential for the transport of fatty acids into mitochondria and the subsequent degradation by ß-oxidation. Aim of the present study was to characterize L-carnitine transport in EpiAirway™, a 3D organotypic in vitro model of primary human tracheal-bronchial epithelial cells that form a fully differentiated, pseudostratified columnar epithelium at air-liquid interface (ALI) condition. In parallel, Calu-3 monolayers grown at ALI for different times (8d or 21d of culture) were used as comparison. OCTN2 transporter was equally expressed in both models and functional at the basolateral side. ATB0,+ was, instead, highly expressed and active on the apical membrane of EpiAirway™ and only in early-cultures of Calu-3 (8d but not 21d ALI). In both cell models, L-carnitine uptake on the apical side was significantly inhibited by the bronchodilators glycopyrrolate and tiotropium, that hence can be considered substrates of ATB0,+; ipratropium was instead effective on the basolateral side, indicating its interaction with OCTN2. Inflammatory stimuli, such as LPS or TNFα, caused an induction of SLC6A14/ATB0,+ expression in Calu-3 cells, along with a 2-fold increase of L-carnitine uptake only at the apical side; on the contrary SLC22A5/OCTN2 was not affected. As both OCTN2 and ATB0,+, beyond transporting L-carnitine, have a significant potential as delivery systems for drugs, the identification of these transporters in EpiAirway™ can open new fields of investigation in the study of drug inhalation and pulmonary delivery.


Assuntos
Sistema ASC de Transporte de Aminoácidos/fisiologia , Carnitina/metabolismo , Células Epiteliais/química , Sistema Respiratório/citologia , Membro 5 da Família 22 de Carreadores de Soluto/fisiologia , Sistema ASC de Transporte de Aminoácidos/análise , Transporte Biológico/efeitos dos fármacos , Broncodilatadores/farmacologia , Técnicas de Cultura de Células/métodos , Polaridade Celular , Glicopirrolato/farmacologia , Humanos , Membro 5 da Família 22 de Carreadores de Soluto/análise , Brometo de Tiotrópio/farmacologia
13.
Am J Clin Nutr ; 111(6): 1226-1234, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32055828

RESUMO

BACKGROUND: Trimethylamine N-oxide (TMAO), a compound derived from diet and metabolism by the gut microbiome, has been associated with several chronic diseases, although the mechanisms of action are not well understood and few human studies have investigated microbes involved in its production. OBJECTIVES: Our study aims were 1) to investigate associations of TMAO and its precursors (choline, carnitine, and betaine) with inflammatory and cardiometabolic risk biomarkers; and 2) to identify fecal microbiome profiles associated with TMAO. METHODS: We conducted a cross-sectional analysis using data collected from 1653 participants (826 men and 827 women, aged 60-77 y) in the Multiethnic Cohort Study. Plasma concentrations of TMAO and its precursors were measured by LC-tandem MS. We also analyzed fasting blood for markers of inflammation, glucose and insulin, cholesterol, and triglycerides (TGs), and further measured blood pressure. Fecal microbiome composition was evaluated by sequencing the 16S ribosomal RNA gene V1-V3 region. Associations of TMAO and its precursors with disease risk biomarkers were assessed by multivariable linear regression, whereas associations between TMAO and the fecal microbiome were assessed by permutational multivariate ANOVA and hurdle regression models using the negative binomial distribution. RESULTS: Median (IQR) concentration of plasma TMAO was 3.05 µmol/L (2.10-4.60 µmol/L). Higher concentrations of TMAO and carnitine, and lower concentrations of betaine, were associated with greater insulin resistance (all P < 0.02). Choline was associated with higher systolic blood pressure, TGs, lipopolysaccharide-binding protein, and lower HDL cholesterol (P ranging from <0.001 to 0.03), reflecting an adverse cardiometabolic risk profile. TMAO was associated with abundance of 13 genera (false discovery rate < 0.05), including Prevotella, Mitsuokella, Fusobacterium, Desulfovibrio, and bacteria belonging to the families Ruminococcaceae and Lachnospiraceae, as well as the methanogen Methanobrevibacter smithii. CONCLUSIONS: Plasma TMAO concentrations were associated with a number of trimethylamine-producing bacterial taxa, and, along with its precursors, may contribute to inflammatory and cardiometabolic risk pathways.


Assuntos
Betaína/sangue , Doenças Cardiovasculares/sangue , Carnitina/sangue , Colina/sangue , Microbioma Gastrointestinal , Metilaminas/sangue , Adiposidade , Idoso , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biomarcadores/sangue , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Metilaminas/metabolismo , Pessoa de Meia-Idade
14.
Int J Sports Med ; 41(7): 443-449, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32059242

RESUMO

This study aimed to investigate the effect of the menstrual cycle on serum carnitine and the endurance performance of healthy women. Fifteen eumenorrheic women underwent cycle ergometer exercise at 60% maximal oxygen uptake (V̇ O2max) for 45 min, followed by exercise at an intensity that was increased to 80% V̇ O 2max until exhaustion, during two menstrual cycle phases, including the early follicular phase (FP) and the midluteal phase (LP). The blood levels of estradiol, progesterone, total carnitine, free carnitine, and acylcarnitine were assessed. Compared with the FP, the LP had significantly lower serum total carnitine (p<0.05) and free carnitine (p<0.01). Moreover, the group with decreased endurance performance in the LP than in the FP showed a significantly higher change in serum free carnitine compared with the group that showed improved endurance performance in the LP than in the FP (p<0.05). The results of this study suggested that the changes in serum free carnitine during the menstrual cycle might influence endurance performance.


Assuntos
Carnitina/sangue , Exercício Físico/fisiologia , Fase Folicular/sangue , Fase Luteal/sangue , Resistência Física/fisiologia , Carnitina/análogos & derivados , Estradiol/sangue , Teste de Esforço , Feminino , Humanos , Progesterona/sangue , Adulto Jovem
15.
FASEB J ; 34(1): 1546-1557, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914600

RESUMO

G protein-coupled receptors (GPCRs) comprise the largest group of membrane receptors in eukaryotic genomes and collectively they regulate nearly all cellular processes. Despite the widely recognized importance of this class of proteins, many GPCRs remain understudied. G protein-coupled receptor 27 (Gpr27) is an orphan GPCR that displays high conservation during vertebrate evolution. Although, GPR27 is known to be expressed in tissues that regulate metabolism including the pancreas, skeletal muscle, and adipose tissue, its functions are poorly characterized. Therefore, to investigate the potential roles of Gpr27 in energy metabolism, we generated a whole body gpr27 knockout zebrafish line. Loss of gpr27 potentiated the elevation in glucose levels induced by pharmacological or nutritional perturbations. We next leveraged a mass spectrometry metabolite profiling platform to identify other potential metabolic functions of Gpr27. Notably, genetic deletion of gpr27 elevated medium-chain acylcarnitines, in particular C6-hexanoylcarnitine, C8-octanoylcarnitine, C9-nonanoylcarnitine, and C10-decanoylcarnitine, lipid species known to be associated with insulin resistance in humans. Concordantly, gpr27 deletion in zebrafish abrogated insulin-dependent Akt phosphorylation and glucose utilization. Finally, loss of gpr27 increased the expression of key enzymes in carnitine shuttle complex, in particular the homolog to the brain-specific isoform of CPT1C which functions as a hypothalamic energy senor. In summary, our findings shed light on the biochemical functions of Gpr27 by illuminating its role in lipid metabolism, insulin signaling, and glucose homeostasis.


Assuntos
Carnitina/análogos & derivados , Glucose/metabolismo , Homeostase/genética , Resistência à Insulina/genética , Receptores Acoplados a Proteínas-G/genética , Peixe-Zebra/genética , Animais , Carnitina/genética , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Deleção de Genes , Glucose/genética , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Peixe-Zebra/metabolismo
16.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906305

RESUMO

Lipid metabolism dysfunction and obesity are serious health issues to human beings. The current study investigated the effects of hyperbaric oxygen (HBO) against high fat diet (HFD)-induced lipid metabolism dysfunction and the roles of L-carnitine. C57/B6 mice were fed with HFD or normal chew diet, with or without HBO treatment. Histopathological methods were used to assess the adipose tissues, serum free fatty acid (FFA) levels were assessed with enzymatic methods, and the endogenous circulation and skeletal muscle L-carnitine levels were assessed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, western blotting was used to assess the expression levels of PPARα, CPT1b, pHSL/HSL, and UCP1. HFD treatment increased body/adipose tissue weight, serum FFA levels, circulation L-carnitines and decreased skeletal muscle L-carnitine levels, while HBO treatment alleviated such changes. Moreover, HFD treatment increased fatty acid deposition in adipose tissues and decreased the expression of HSL, while HBO treatment alleviated such changes. Additionally, HFD treatment decreased the expression levels of PPARα and increased those of CPT1b in skeletal muscle, while HBO treatment effectively reverted such changes as well. In brown adipose tissues, HFD increased the expression of UCP1 and the phosphorylation of HSL, which was abolished by HBO treatment as well. In summary, HBO treatment may alleviate HFD-induced fatty acid metabolism dysfunction in C57/B6 mice, which seems to be associated with circulation and skeletal muscle L-carnitine levels and PPARα expression.


Assuntos
Tecido Adiposo/metabolismo , Carnitina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Tecido Adiposo/citologia , Animais , Carnitina/sangue , Carnitina/química , Carnitina O-Palmitoiltransferase/metabolismo , Cromatografia Líquida , Oxigenação Hiperbárica , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Obesidade/tratamento farmacológico , PPAR alfa/metabolismo , Fosforilação , Esterol Esterase/química , Esterol Esterase/metabolismo , Espectrometria de Massas em Tandem , Proteína Desacopladora 1/metabolismo
17.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906370

RESUMO

l-Carnitine is an amino acid derivative widely known for its involvement in the transport of long-chain fatty acids into the mitochondrial matrix, where fatty acid oxidation occurs. Moreover, l-Carnitine protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Circulating carnitine is mainly supplied by animal-based food products and to a lesser extent by endogenous biosynthesis in the liver and kidney. Human muscle contains high amounts of carnitine but it depends on the uptake of this compound from the bloodstream, due to muscle inability to synthesize carnitine. Mitochondrial fatty acid oxidation represents an important energy source for muscle metabolism particularly during physical exercise. However, especially during high-intensity exercise, this process seems to be limited by the mitochondrial availability of free l-carnitine. Hence, fatty acid oxidation rapidly declines, increasing exercise intensity from moderate to high. Considering the important role of fatty acids in muscle bioenergetics, and the limiting effect of free carnitine in fatty acid oxidation during endurance exercise, l-carnitine supplementation has been hypothesized to improve exercise performance. So far, the question of the role of l-carnitine supplementation on muscle performance has not definitively been clarified. Differences in exercise intensity, training or conditioning of the subjects, amount of l-carnitine administered, route and timing of administration relative to the exercise led to different experimental results. In this review, we will describe the role of l-carnitine in muscle energetics and the main causes that led to conflicting data on the use of l-carnitine as a supplement.


Assuntos
Carnitina/análogos & derivados , Carnitina/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Carnitina/administração & dosagem , Carnitina/biossíntese , Carnitina/química , Carnitina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , Suplementos Nutricionais/efeitos adversos , Exercício Físico/fisiologia , Humanos , Metilaminas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Oxirredução
19.
PLoS One ; 15(1): e0226070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923252

RESUMO

Conjugated linoleic acid (CLA) is known for its multiple benefits including improvement of growth, increasing lean mass, and anti-carcinogenic effects. However, when used in long-term supplementations CLA does not improve semen parameters in boar and bull and reduces fertility in Japanese quails. The content of unsaturated fatty acids in dietary lipids plays a significant role in spermatogenesis owning the high proportion of unsaturated fatty acids in plasma membrane of sperms. Whether CLA plays a role in testicular tissue and epididymal fat is still unknown. Therefore, in this study we hypothesize that long-term supplementation of equal proportion of CLA isomer mix (c9,t11-CLA and t10,c12- CLA) in rabbit bucks might alter male reproductive potentials. Twelve V-Line weaned male rabbits were used in 26 weeks trial, rabbits were individually raised and randomly allocated into three dietary groups. Control group (CON) received a basal diet, a group received 0.5% CLA (CLA 0.5%), and a group received 1% CLA (CLA 1%). Rabbits were euthanized at the end of the trial and several parameters were evaluated related to growth, semen quality, and testicular and epididymal tissue histopathology and transcriptome. The long-term supplementation of CLA increased feed intake by 5% and body weight by 2-3%. CLA 1% decreased sperm progressive motility. In testicular tissue L-carnitine and α-tocopherol were decreased by CLA supplementation. In epididymal fat, CLA tended to decrease concentration of polyunsaturated fatty acids, the expression of SCD5 gene was upregulated by CLA 1% and CASP3 gene was upregulated by CLA 0.5%. Transcription of PPARG was downregulated by CLA. Feeding 1% CLA also decreased testicular epithelial thickness. Long-term supplementation of CLA modestly enhanced male rabbit growth, but negatively impacted male reproduction, especially at high dose of CLA.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Linoleicos Conjugados/farmacologia , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Carnitina/metabolismo , Suplementos Nutricionais , Regulação para Baixo/efeitos dos fármacos , Epididimo/metabolismo , Epididimo/patologia , Ácidos Graxos Insaturados/metabolismo , Masculino , PPAR gama/genética , PPAR gama/metabolismo , Coelhos , Análise do Sêmen , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
Chin J Integr Med ; 26(2): 146-151, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31997237

RESUMO

OBJECTIVE: To evaluate the clinical effectiveness and safety of the Chinese medicine (CM) Qixiong Zhongzi Decoction (, QZD) in the treatment of patients with idiopathic asthenozoospermia. METHODS: A total number of 66 patients with idiopathic asthenozoospermia were included and randomly divided into treatment and control groups by SAS-generated code from January 2015 to August 2016, 33 patients in each group. Patients in the treatment group were administered with 150 mL of QZD twice a day, whereas those in the control group were given 1 g of levocarnitine oral liquid twice a day. The two groups received the indicated medication for 12 weeks and were then followed up for 4 weeks. The primary outcome was sperm motility, and the secondary therapeutic indices were sperm volume, density, pregnancy probability, and CM syndrome score. The comparison between groups was carried out at 4, 8 and 12 weeks, respectively. The safety was determined before and after treatment. RESULTS: (1) Drop-off: 5 cases (7.58%) were lost after treatment (2 from the treatment group and 3 from the control group). (2) Primary outcomes: after 8- and 12-week treatment, the progressive sperms in the two groups were significantly higher than the baseline (all P<0.05); however, the treatment group showed greater improvement compared with the control group at 12-week treatment (22.7% ± 9.0% vs. 14.1% ±8.8%, P<0.05). The increasement of non-progressive grade sperms at both groups was observed at 8- and 12-week treatment with statistical difference (all P<0.05), however, the treatment group showed remarkable improvement compared with the control group at 12-week treatment (38.7% ±14.1% vs. 26.2% ±15.4%, P<0.05). (3) Secondary outcomes: no significant statistical differences were found in semen volume and density (4, 8, and 12-week treatment) and pregnancy probability of patients' wives (12-week treatment) between two groups (all P>0.05), however, the CM syndrome score of the treatment group significantly declined compared with baseline level at each time points (all P<0.05). (4) Safety: no obvious side reactions were found during the treatment in both groups. CONCLUSION: QZD could improve the progressive and non-progressive grade sperm in the treatment of idiopathic asthenozoospermia. It is safe with no obvious side effects.


Assuntos
Astenozoospermia/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Adulto , Carnitina/uso terapêutico , Humanos , Masculino , Medicina Tradicional Chinesa , Análise do Sêmen , Motilidade Espermática/efeitos dos fármacos , Resultado do Tratamento
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