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1.
JAMA Netw Open ; 5(5): e2213242, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35594043

RESUMO

Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population. Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US. Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021. Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models. Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality. Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.


Assuntos
Betaína , Doenças Cardiovasculares , Idoso , Doenças Cardiovasculares/epidemiologia , Carnitina , Colina , Estudos de Coortes , Feminino , Humanos , Masculino , Metilaminas , Estudos Prospectivos
2.
Food Funct ; 13(10): 5640-5653, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35506542

RESUMO

Nowadays, there is great interest in the discovery of food compounds that might inhibit gut microbial TMA production from its methylamine precursors. In this work, an innovative novel screening strategy capable of rapidly determining the differences in the metabolic response of Klebsiella pneumoniae, a bacteria producing TMA under aerobic conditions, to a library of extracts obtained from food and natural sources was developed. The proposed high-throughput screening (HTS) method combines resazurin reduction assay in 384-well plates and Gaussian Processes as a machine learning tool for data processing, allowing for a fast, cheap and highly standardized evaluation of any interfering effect of a given compound or extract on the microbial metabolism sustained by L-carnitine utilization. As a proof-of-concept of this strategy, a pilot screening of 39 extracts and 6 pure compounds was performed to search for potential candidates that could inhibit in vitro TMA formation from L-carnitine. Among all the extracts tested, three of them were selected as candidates to interfere with TMA formation. Subsequent in vitro assays confirmed the potential of oregano and red thyme hexane extracts (at 1 mg mL-1) to inhibit TMA formation in bacterial lysates. In such in vitro assay, the red thyme extract exerted comparable effects on TMA reduction (∼40%) as 7.5 mM meldonium (∼50% TMA decrease), a reported L-carnitine analogue. Our results show that metabolic activity could be used as a proxy of the capacity to produce TMA under controlled culture conditions using L-carnitine to sustain metabolism.


Assuntos
Doenças Cardiovasculares , Microbioma Gastrointestinal , Carnitina/metabolismo , Microbioma Gastrointestinal/fisiologia , Ensaios de Triagem em Larga Escala , Humanos , Metilaminas/metabolismo , Oxazinas , Compostos Fitoquímicos , Xantenos
3.
Front Immunol ; 13: 784046, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370999

RESUMO

In early lactation, an energy deficit leading to a negative energy balance (NEB) is associated with increased susceptibility to disease and has been shown to be an important factor during transition in dairy cows. L-carnitine as a key factor in the mitochondrial transport of fatty acids and subsequently for ß-oxidation and energy release is known to modulate mitochondrial biogenesis and thus influence metabolism and immune system. In the current study, we characterized hematological changes around parturition and investigated the potential effects of dietary L-carnitine supplementation on immune cell functions. For this approach, dairy cows were assigned either to a control (CON, n = 30) or an L-carnitine group [CAR, n = 29, 25 g rumen-protected L-carnitine per cow and day (d)]. Blood samples were taken from d 42 ante partum (ap) until d 110 post-partum (pp), with special focus and frequent sampling from 0.5 to72 h post-calving to clarify the impact of L-carnitine supplementation on leukocyte count, formation of reactive oxygen species (ROS) in polymorphonuclear cells (PMN) and peripheral mononuclear cells (PBMC) and their phagocytosis activity. Blood cortisol concentration and the capacity of PBMC proliferation was also investigated. All populations of leukocytes were changed during the peripartal period, especially granulocytes showed a characteristic increase up to 4 h pp. L-carnitine supplementation resulted in increased levels of eosinophils which was particularly pronounced one day before to 4 h pp, indicating a possible enhanced support for tissue repair and recovery. Non-supplemented cows showed a higher phagocytic activity in PBMC as well as a higher phagocytic capacity of PMN during the most demanding period around parturition, which may relate to a decrease in plasma levels of non-esterified fatty acids reported previously. L-carnitine, on the other hand, led to an increased efficiency to form ROS in stimulated PMN. Finally, a short period around calving proved to be a sensitive period in which L-carnitine administration was effective.


Assuntos
Carnitina , Leite , Animais , Carnitina/farmacologia , Bovinos , Suplementos Nutricionais , Feminino , Contagem de Leucócitos , Leucócitos Mononucleares , Parto/metabolismo , Gravidez , Espécies Reativas de Oxigênio
5.
Artigo em Russo | MEDLINE | ID: mdl-35485064

RESUMO

The presented material indicates that asthenia can be considered as a universal protective mechanism accompanying various psychophysiological processes and somatic diseases, which are based on the mechanisms of energy deficiency. The article discusses different etiological factors and clinical forms of asthenic syndrome (AS) depending on the causes of its development. The research specifies the main effects of carnitine, according to which a conclusion is made about the possibility of use of L-carnitine preparations for the correction of AS in mono- and polytherapy.


Assuntos
Astenia , Carnitina , Astenia/tratamento farmacológico , Astenia/etiologia , Carnitina/uso terapêutico , Humanos , Síndrome
6.
Sci Rep ; 12(1): 5845, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393499

RESUMO

The present study aimed to modulate the oxidative status-mediated polarity of the oocytes for sex-specific sperm fertilization to generate desired sex embryos. In vitro embryos were produced at different oxidative status, varying O2 concentrations, and without/with L-carnitine in maturation and culture media. The majority of the embryos produced at high oxidative stress were males whereas; low oxidative status favoured female embryos production. Low O2 doubled the proportion of female embryos (10.59 vs 21.95%); however, L-carnitine supplementation in media increased approximately seven-folds of the female embryos (12.26 vs. 77.62%) production. Oocytes matured at high oxidative status were in the repolarized state favouring positively charged Y sperm fertilization to produce significantly more male embryos. Low oxidative status favoured negatively charged X sperm fertilization to the oocytes in the depolarized state to produce more female embryos. Intracellular ROS was significantly low in female embryos than in males; however, female embryos were more stressful than males. The study concluded that the oxidative status-mediated alteration in pH of the medium to modulate the intracellular positive ions is the main critical factor to influence the sex of embryos through sex-specific sperms fertilization to the oocytes as per their polarity.


Assuntos
Fertilização In Vitro , Oócitos , Animais , Carnitina , Meios de Cultura , Feminino , Fertilização , Masculino , Ovinos , Carneiro Doméstico , Espermatozoides
7.
Biochim Biophys Acta Bioenerg ; 1863(5): 148557, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367451

RESUMO

We herein report the identification of the lantanide praseodymium trivalent ion Pr3+ as inhibitor of mitochondrial transporters for basic amino acids and phylogenetically related carriers belonging to the Slc25 family. The inhibitory effect of Pr3+ has been tested using mitochondrial transporters reconstituted into liposomes being effective in the micromolar range, acting as a competitive inhibitor of the human basic amino acids carrier (BAC, Slc25A29), the human carnitine/acylcarnitine carrier (CAC, Slc25A20). Furthermore, we provide computational evidence that the complete inhibition of the transport activity of the recombinant proteins is due to the Pr3+ coordination to key acidic residues of the matrix salt bridge network. Besides being used as a first choice stop inhibitor for functional studies in vitro of mitochondrial carriers reconstituted in proteoliposomes, Pr3+ might also represent a useful tool for structural studies of the mitochondrial carrier family.


Assuntos
Carnitina Aciltransferases , Praseodímio , Aminoácidos Básicos , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina Aciltransferases/química , Humanos , Proteínas de Transporte da Membrana Mitocondrial/química , Proteínas Mitocondriais/metabolismo
9.
Cells ; 11(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35455976

RESUMO

Statins, such as lovastatin, are lipid-lowering drugs (LLDs) that have been used to treat hypercholesterolaemia, defined as abnormally elevated cholesterol levels in the patient's blood. Although statins are considered relatively safe and well tolerated, recipients may suffer from adverse effects, including post-statin myopathies. Many studies have shown that supplementation with various compounds may be beneficial for the prevention or treatment of side effects in patients undergoing statin therapy. In our study, we investigated whether L-carnitine administered to zebrafish larvae treated with lovastatin alleviates post-statin muscle damage. We found that exposure of zebrafish larvae to lovastatin caused skeletal muscle disruption observed as a reduction of birefringence, changes in muscle ultrastructure, and an increase in atrogin-1. Lovastatin also affected heart performance and swimming behaviour of larvae. Our data indicated that the muscle-protective effect of L-carnitine is partial. Some observed myotoxic effects, such as disruption of skeletal muscle and increase in atrogin-1 expression, heart contraction could be rescued by the addition of L-carnitine. Others, such as slowed heart rate and reduced locomotion, could not be mitigated by L-carnitine supplementation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Carnitina/metabolismo , Carnitina/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Larva , Lovastatina/farmacologia , Músculo Esquelético , Peixe-Zebra/metabolismo
10.
J Affect Disord ; 307: 254-263, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35381295

RESUMO

BACKGROUND: Altered metabolism of acylcarnitines - transporting fatty acids to mitochondria - may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. METHODS: Summary statistics were obtained from large GWAS: the Fenland Study (N = 9363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression. RESULTS: In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (odds ratio [OR] 0.97, 95% confidence intervals [CIs] 0.95-1.00) and C3 (OR 0.97, 95%CIs 0.96-0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR = 1.05, 95%CIs = 1.02-1.07) and C10 (OR = 1.05, 95%CIs = 1.02-1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples. DISCUSSION: Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.


Assuntos
Carnitina , Depressão , Carnitina/análogos & derivados , Causalidade , Depressão/genética , Genômica , Humanos
11.
J Anim Sci ; 100(4)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365999

RESUMO

Spay and neuter surgeries are useful in controlling pet populations, but increase obesity risk due to increased appetite, decreased metabolic rate, and decreased energy expenditure. Dietary management may help limit post-spay weight gain, but few research studies have been conducted in cats. Therefore, the objective of this study was to evaluate the effects of a high-protein, high-fiber diet (HPHF) compared to a moderate-protein, moderate-fiber diet (MPMF) in female cats following spay surgery. Twenty healthy female cats (9.5 ±â€…0.1 mo) were used. After a 4-wk baseline phase with cats fed MPMF to maintain body weight (BW), 16 cats were spayed and allotted to MPMF (n = 8) or HPHF (n = 8), with the remaining cats being sham-operated and fed MPMF (n = 4). Cats were fed to maintain BW for 12 wk and then allowed to eat up to twice that amount for another 12 wk. Daily food intake, twice weekly BW, and twice weekly body condition scores (BCS) were assessed. Back fat thickness (BF) using ultrasound, body composition using dual-energy X-ray absorptiometry (DEXA), feline body mass index (fBMI), body fat percentage estimates using zoometry measurements, serum metabolites, and voluntary physical activity levels were measured prior to spay (week 0) and every 6 wk post-spay. A treatment*time effect was observed for food intake (g/d), but not caloric intake (kcal ME/d). Caloric intake was affected by time and treatment, being reduced over the first 12 wk and reduced at higher amounts in HPHF and MPMF cats vs. sham cats. BW, BCS, and body fat percentage were affected over time. Treatment*time effects were observed for blood urea nitrogen, alkaline phosphatase, and fructosamine, whereas blood triglycerides, total cholesterol, creatinine, total protein, phosphorus, and bicarbonate were affected by time. Physical activity was reduced over time. Our results demonstrate that spay surgery affects food intake, BW, metabolism, and physical activity of cats. Dietary intervention in this study, however, led to minor changes.


Spay surgery helps control pet populations, but increases obesity due to increased appetite, decreased metabolic rate, and decreased energy expenditure. Our objective was to evaluate the effects of high-protein, high-fiber diet (HPHF), and moderate-protein, moderate-fiber diets (MPMF) in female cats following spay surgery. Of the 20 cats used, 16 were spayed and fed MPMF (n = 8) or HPHF (n = 8) and four were sham-operated and fed MPMF. Cats were fed to maintain body weight (BW) for 12 wk and then allowed to overeat for 12 wk. Food intake, BW, body condition scores (BCS), back fat thickness, body composition, feline body mass index, body fat percentage estimates, serum metabolites, and physical activity levels were measured. Over the first 12 wk, caloric intake was reduced at higher amounts in spayed versus sham cats. BW, BCS, body fat percentage, and physical activity levels were altered over time. Our results demonstrate that the diets tested had minor effects, but spaying affected cat food intake, BW, metabolism, and physical activity.


Assuntos
Antioxidantes , Condicionamento Físico Animal , Ração Animal/análise , Animais , Composição Corporal , Peso Corporal , Carnitina , Gatos , Dieta/veterinária , Feminino
12.
Front Endocrinol (Lausanne) ; 13: 834205, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370967

RESUMO

Objective: Diabetic retinopathy is a common complication of type 2 diabetes mellitus (T2DM). Due to the limited effectiveness of current prevention and treatment methods, new biomarkers are urgently needed for the prevention and diagnosis of DR. This study aimed to explore the relationships between plasma acylcarnitine with DR in T2DM. Methods: From May 2015 to August 2016, data of 1032 T2DM patients were extracted from tertiary hospitals. Potential non-linear associations were tested by binary logistic regression models, and ORs and 95% CIs of the research variables were obtained. Correlation heat map was used to analyze the correlation between variables. The change of predictive ability was judged by the area under the receiver operating characteristic curve. Results: Of the 1032 patients with T2DM, 162 suffered from DR. After adjusting for several confounding variables, C2 (OR:0.55, 95%CI:0.39-0.76), C14DC (OR:0.64, 95%CI:0.49-0.84), C16 (OR:0.64, 95%CI:0.49-0.84), C18:1OH (OR:0.51, 95%CI:0.36-0.71) and C18:1 (OR:0.60, 95%CI:0.44-0.83) were negatively correlated with DR. The area under the curve increased from 0.794 (95% CI 0.745 to 0.842) to 0.840 (95% CI 0.797 to 0.833) when C2, C14DC, C18:1OH and C18:1 added to the traditional risk factor model. Conclusion: There was a negative correlation between C2, C14DC, C16, C18:1OH, and C18:1 and the risk of retinopathy in patients with T2DM. C2, C14DC, C18:1OH, and C18:1 may be new predictors and diagnostic markers of DR.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Biomarcadores , Carnitina/análogos & derivados , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Humanos , Curva ROC
13.
Medicine (Baltimore) ; 101(7): e28853, 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35363184

RESUMO

ABSTRACT: Carnitine is essential for the transport of long-chain fatty acids from the cytoplasm to the mitochondrial matrix. The carnitine shuttle transports long-chain fatty acylcarnitine to the mitochondrial matrix. Subsequently, long-chain fatty acyl CoA, which is split from long-chain fatty acylcarnitine by carnitine palmitoyltransferase II, undergoes fatty acid ß-oxidation. Acetyl CoA is produced from long-chain fatty acyl CoA via fatty acid ß-oxidation and aids in the synthesis of adenosine triphosphate via the tricarboxylic acid cycle and electron transport chain. In addition, in the fasting state, it leads to ketone body production in the liver and glucose production via gluconeogenesis. However, patients with compromised fatty acid ß-oxidation, owing to carnitine deficiency as well as defects in carnitine transport and the fatty acid ß-oxidation pathway, develop hypoglycemia, cardiomyopathy, arrhythmia, and hypotonia. These conditions are attributed to the accumulation of released fatty acids and acylcarnitine. This review aimed to shed light on the anesthetic management of patients with compromised fatty acid ß-oxidation undergoing various surgeries by assessing relevant case reports associated with fatty acid ß-oxidation disorder in PubMed. Pre-anesthetic and intraoperative evaluation should include monitoring of glucose and carnitine levels and specific cardiac tests, such as echocardiography. Considering that propofol is dissolved in 10% long-chain fatty acids, propofol infusion should be avoided because of increased long-chain fatty acid loading in patients with compromised fatty acid ß-oxidation. Thus, anesthesia using opioids (remifentanil and fentanyl), midazolam, dexmedetomidine, etomidate, and non-depolarizing neuromuscular blocking agents would be appropriate in such patients.


Assuntos
Anestésicos , Cardiomiopatias , Carnitina , Ácidos Graxos/metabolismo , Humanos , Oxirredução
14.
Front Endocrinol (Lausanne) ; 13: 810242, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35265037

RESUMO

Purpose: Male infertility is a global public health issue recognized by the WHO. Recently, antioxidants are increasingly used to treat idiopathic male infertility. However, the lack of available evidence has led to the inability to rank the effects of antioxidants on the sperm quality parameters and pregnancy rate of infertile men. This network meta-analysis studied the effects of different antioxidants on the sperm quality and pregnancy rate of idiopathic male infertility. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library databases for randomized controlled trials (RCTs). The weighted mean difference (WMD) and odds ratio (OR) were applied for the comparison of continuous and dichotomous variables, respectively, with 95% CIs. The outcomes were sperm motility, sperm concentration, sperm morphology, and pregnancy rate. Results: A total of 23 RCTs with 1,917 patients and 10 kids of antioxidants were included. l-Carnitine, l-carnitine+l-acetylcarnitine, coenzyme-Q10, ω-3 fatty acid, and selenium were more efficacious than placebo in sperm quality parameters. l-Carnitine was ranked first in sperm motility and sperm morphology (WMD 6.52% [95% CI: 2.55% to 10.05%], WMD 4.96% [0.20% to 9.73%]). ω-3 fatty acid was ranked first in sperm concentration (WMD 9.89 × 106/ml, [95% CI: 7.01 to 12.77 × 106/ml]). In terms of pregnancy rate, there was no significant effect as compared with placebo. Conclusions: l-Carnitine was ranked first in sperm motility and sperm morphology. ω-3 fatty acid was ranked first in sperm concentration. Coenzyme-Q10 had better effective treatment on sperm motility and concentration. Furthermore, high-quality RCTs with adequate sample sizes should be conducted to compare the outcomes of different antioxidants.


Assuntos
Ácidos Graxos Ômega-3 , Infertilidade Masculina , Antioxidantes/farmacologia , Carnitina , Coenzimas/farmacologia , Coenzimas/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Humanos , Infertilidade Masculina/tratamento farmacológico , Masculino , Metanálise em Rede , Gravidez , Taxa de Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Espermatozoides
15.
BMC Geriatr ; 22(1): 249, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35337292

RESUMO

BACKGROUND: Metabolic profiling may provide insights into the pathogenesis and identification of sarcopenia; however, data on the metabolic basis of sarcopenia and muscle-related parameters among older adults remain incompletely understood. This study aimed to identify the associations of metabolites with sarcopenia and its components, and to explore metabolic perturbations in older men, who have a higher prevalence of sarcopenia than women. METHODS: We simultaneously measured the concentrations of amino acids, carnitine, acylcarnitines, and lysophosphatidylcholines (LPCs) in serum samples from a cross-sectional study of 246 Chinese older men, using targeted metabolomics. Sarcopenia and its components, including skeletal muscle index (SMI), 6-m gait speed, and handgrip strength were assessed according to the algorithm of the Asian Working Group for Sarcopenia criteria. Associations were determined by univariate and multivariate analyses. RESULTS: Sixty-five (26.4%) older men with sarcopenia and 181 (73.6%) without sarcopenia were included in the study. The level of isovalerylcarnitine (C5) was associated with the presence of sarcopenia and SMI. Regarding the overlapped metabolites for muscle parameters, among ten metabolites associated with muscle mass, six metabolites including leucine, octanoyl-L-carnitine (C8), decanoyl-L-carnitine (C10), dodecanoyl-L-carnitine (C12) and tetradecanoyl-L-carnitine (C14), and LPC18:2 were associated with handgrip strength, and three of which (C12, C14, and LPC18:2) were also associated with gait speed. Specifically, tryptophan was positively associated and glycine was negatively associated with handgrip strength, while glutamate was positively correlated with gait speed. Isoleucine, branched chain amino acids, and LPC16:0 were positively associated with SMI. Moreover, the levels of LPC 16:0,18:2 and 18:0 contributed significantly to the model discriminating between older men with and without sarcopenia, whereas there were no significant associations for other amino acids, acylcarnitines, and LPC lipids. CONCLUSIONS: These results showed that specific and overlapped metabolites are associated with sarcopenic parameters in older men. This study highlights the potential roles of acylcarnitines and LPCs in sarcopenia and its components, which may provide valuable information regarding the pathogenesis and management of sarcopenia.


Assuntos
Sarcopenia , Idoso , Aminoácidos , Carnitina/análogos & derivados , Estudos Transversais , Feminino , Força da Mão , Humanos , Lisofosfatidilcolinas , Masculino , Músculo Esquelético , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/etiologia
16.
J Chromatogr A ; 1670: 462955, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35320751

RESUMO

In this study, new chiral ionic liquids based on the non-protein amino acid L-carnitine as cationic chiral counterpart and several anions (bis(trifluoromethane)sulfonimide (NTf2-), L-lactate- or Cl-) as counterions were synthesized. Moreover, three different salts based on L-carnitine were also synthesized and the other three were commercially acquired and used for comparison. The synthesized ionic liquids and salts were characterized by nuclear magnetic resonance, fourier transform infrared spectroscopy, high-performance liquid chromatography-mass spectrometry, and elemental analysis. Subsequently, they were used as additives to establish a γ-CD-based dual system for the enantiomeric separation of cysteine and homocysteine (previously derivatized with fluorenylmethoxycarbonyl chloride) by capillary electrokinetic chromatography. The effect of the nature of the anionic counterions and the presence of different substituents on the L-carnitine molecule on the chiral separation of both amino acids was investigated. The enantioseparations obtained with each dual system studied were compared in terms of the enantiomer effective mobilities (µeff) and the effective electrophoretic selectivity (αeff). Practically, all the dual systems evaluated exhibited substantially improved enantioseparations for the two amino acids compared with the single γ-CD system.


Assuntos
Ciclodextrinas , Líquidos Iônicos , Aminoácidos/química , Carnitina , Cromatografia , Ciclodextrinas/química , Eletroforese Capilar/métodos , Líquidos Iônicos/química , Sais , Estereoisomerismo , Compostos de Sulfidrila
17.
Sci Rep ; 12(1): 4673, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304586

RESUMO

We previously reported that perfluorooctanesulfonate (PFOS) causes autophagy-induced apoptosis in renal tubular cells (RTCs) through a mechanism dependent on reactive oxygen species (ROS)/extracellular signal-regulated kinase. This study extended our findings and determined the therapeutic potency of L-Carnitine in PFOS-treated RTCs. L-Carnitine (10 mM) reversed the effects of PFOS (100 µM) on autophagy induction and impaired autophagy flux. Furthermore, it downregulated the protein level of p47Phox, which is partly related to PFOS-induced increased cytosolic ROS in RTCs. Moreover, L-Carnitine reduced ROS production in mitochondria and restored PFOS-impeded mitochondrial function, leading to sustained normal adenosine triphosphate synthesis and oxygen consumption and reduced proton leakage in a Seahorse XF stress test. The increased inositol-requiring enzyme 1α expression by PFOS, which indicated endoplasmic reticulum (ER) stress activation, was associated with PFOS-mediated autophagy activation that could be attenuated through 4-phenylbutyrate (5 mM, an ER stress inhibitor) and L-Carnitine pretreatment. Therefore, by reducing the level of IRE1α, L-Carnitine reduced the levels of Beclin and LC3BII, consequently reducing the level of apoptotic biomarkers including Bax and cleaving PARP and caspase 3. Collectively, these results indicate that through the elimination of oxidative stress, extracellular signal-regulated kinase activation, and ER stress, L-Carnitine reduced cell autophagy/apoptosis and concomitantly increased cell viability in RTCs. This study clarified the potential mechanism of PFOS-mediated RTC apoptosis and provided a new strategy for using L-Carnitine to prevent and treat PFOS-induced RTC apoptosis.


Assuntos
Estresse do Retículo Endoplasmático , Endorribonucleases , Ácidos Alcanossulfônicos , Apoptose , Autofagia , Carnitina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular , Fluorcarbonetos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Biomolecules ; 12(3)2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35327546

RESUMO

Recent studies support that acylcarnitines exert a significant role in cardiovascular disease development and progression. The aim of this metabolomics-based study was to investigate the association of serum acylcarnitine levels with coronary artery disease (CAD) severity, as assessed via SYNTAX Score. Within the context of the prospective CorLipid trial (NCT04580173), the levels of 13 circulating acylcarnitines were accurately determined through a newly developed HILIC-MS/MS method in 958 patients undergoing coronary angiography in the AHEPA University Hospital of Thessaloniki, Greece. Patients presenting with acute coronary syndrome had significantly lower median acylcarnitine C8, C10, C16, C18:1 and C18:2 values, compared to patients with chronic coronary syndrome (p = 0.012, 0.007, 0.018, 0.011 and <0.001, respectively). Among CAD subgroups, median C5 levels were significantly decreased in unstable angina compared to STEMI (p = 0.026), while median C10, C16, C18:1 and C18:2 levels were higher in stable angina compared to STEMI (p = 0.019 p = 0.012, p = 0.013 and p < 0.001, respectively). Moreover, median C2, C3, C4 and C8 levels were significantly elevated in patients with diabetes mellitus (p < 0.001, <0.001, 0.029 and 0.011, respectively). Moreover, short-chain acylcarnitine C2, C4, C5 and C6 levels were elevated in patients with heavier calcification and lower left ventricular ejection fraction (LVEF) % (all p-values less than 0.05). With regard to CAD severity, median C4 and C5 levels were elevated and C16 and C18:2 levels were reduced in the high CAD complexity group with SYNTAX Score > 22 (p = 0.002, 0.024, 0.044 and 0.012, respectively), indicating a potential prognostic capability of those metabolites and of the ratio C4/C18:2 for the prediction of CAD severity. In conclusion, serum acylcarnitines could serve as clinically useful biomarkers leading to a more individualized management of patients with CAD, once further clinically oriented metabolomics-based studies provide similar evidence.


Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio com Supradesnível do Segmento ST , Biomarcadores , Carnitina/análogos & derivados , Doença da Artéria Coronariana/diagnóstico , Humanos , Estudos Prospectivos , Volume Sistólico , Espectrometria de Massas em Tandem/métodos , Função Ventricular Esquerda
19.
J Lipid Res ; 63(4): 100188, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35247455

RESUMO

Fatty acid beta-oxidation is a key process in mammalian lipid catabolism. Disturbance of this process results in severe clinical symptoms, including dysfunction of the liver, a major beta-oxidizing tissue. For a thorough understanding of this process, a comprehensive analysis of involved fatty acid and acyl-carnitine intermediates is desired, but capable methods are lacking. Here, we introduce oxaalkyne and alkyne fatty acids as novel tracers to study the beta-oxidation of long- and medium-chain fatty acids in liver lysates and primary hepatocytes. Combining these new tracer tools with highly sensitive chromatography and mass spectrometry analyses, this study confirms differences in metabolic handling of fatty acids of different chain length. Unlike longer chains, we found that medium-chain fatty acids that were activated inside or outside of mitochondria by different acyl-CoA synthetases could enter mitochondria in the form of free fatty acids or as carnitine esters. Upon mitochondrial beta-oxidation, shortened acyl-carnitine metabolites were then produced and released from mitochondria. In addition, we show that hepatocytes ultimately also secreted these shortened acyl chains into their surroundings. Furthermore, when mitochondrial beta-oxidation was hindered, we show that peroxisomal beta-oxidation likely acts as a salvage pathway, thereby maintaining the levels of shortened fatty acid secretion. Taken together, we conclude that this new method based on oxaalkyne and alkyne fatty acids allows for metabolic tracing of the beta-oxidation pathway in tissue lysate and in living cells with unique coverage of metabolic intermediates and at unprecedented detail.


Assuntos
Alcinos , Ácidos Graxos , Animais , Carnitina/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Mamíferos/metabolismo , Mitocôndrias/metabolismo , Oxirredução
20.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35269860

RESUMO

Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.


Assuntos
Doenças Neurodegenerativas , Carnitina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Micronutrientes/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo
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