Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.034
Filtrar
1.
Medicine (Baltimore) ; 100(38): e27333, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559155

RESUMO

RATIONALE: Lipid storage myopathies (LSMs) are a series of genetic disorders of lipid metabolism predominantly affecting muscle. The low incidence and lethal properties of this disease make anesthesia experience limited in such patients. Among all etiologies of LSMs, primary carnitine deficiency (PCD) is now considered highly treatable by early administration of L-carnitine, though it remains unclear whether L-carnitine is effective enough to protect diseased muscle against conventionally used neuromuscular blocking agents (NMBAs) during general anesthesia. Currently, no data are available concerning possible prolonged muscle weakness in these cases. PATIENT CONCERNS: This case presents a 43-year-old female who was diagnosed with a PCD-induced LSM 3 years ago due to fatigability and exertional myalgias and has been treated with L-carnitine ever since. At the time of this report, she was admitted for uterine fibroids and scheduled for selective open gynecologic surgery under general anesthesia. DIAGNOSIS: The patient's diagnosis of PCD-induced LSM was based on the clinical features, muscle biopsy, and diminished organic cation/carnitine transporter 2 (OCTN2) transporter activity in the patient's skin fibroblasts. INTERVENTIONS: L-carnitine was taken by the patient until the morning of surgery. General anesthesia with cisatracurium and sevoflurane was selected as the anesthetic plan during the operation. The train-of-four (TOF) test was adopted as additional monitoring, particularly to track the recovery of neuromuscular function. OUTCOMES: The patient was extubated successfully following a spontaneously restored TOF ratio (TOFR) of 0.9. Nonetheless, we recorded a prolonged efficacy of cisatracurium in the clinical duration and the recovery time with TOFRs of 0.7 and 0.9, respectively. LESSONS: The conventional dose of cisatracurium combined with a low dose of sevoflurane can be safely used in patients with LSMs without additional anesthetic risks. Meanwhile, continuous TOF monitoring is recommended to perform high-quality anesthesia.


Assuntos
Anestesia Geral/métodos , Cardiomiopatias , Carnitina/deficiência , Carnitina/uso terapêutico , Hiperamonemia , Doenças Musculares , Adulto , Anestésicos Inalatórios , Atracúrio/análogos & derivados , Feminino , Humanos , Bloqueadores Neuromusculares , Sevoflurano
2.
Cells ; 10(9)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34571942

RESUMO

The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on plasma from acutely ill patients collected while in the emergency department, at admission, or during hospitalization. Lipidomics analyses were also performed on COVID-19-positive or -negative subjects with the lowest and highest body mass index (n = 60/group). Significant changes in amino acid and fatty acid/acylcarnitine metabolism emerged as highly relevant markers of disease severity, progression, and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half, yielding ~78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for mechanistic follow-up studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.


Assuntos
COVID-19/metabolismo , Prognóstico , Doença Aguda , Adulto , Aminoácidos/sangue , Índice de Massa Corporal , Carnitina/análogos & derivados , Carnitina/sangue , Estudos de Coortes , Ácidos Graxos/sangue , Feminino , Humanos , Cinurenina/sangue , Aprendizado de Máquina , Metabolômica , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Triptofano/sangue
3.
Anal Chem ; 93(38): 12973-12980, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34529423

RESUMO

Acylcarnitines (ACs) play important roles in the fatty acid ß-oxidation and are considered as diagnostic markers for many diseases. Accurate determination of ACs remains challenging due to their low abundance, high structure diversity, and limited availability of standard compounds. In this study, microwave-assisted Tmt-PP (p-[3,5-(dimethylamino)-2,4,6-triazine] benzene-1-sulfonyl piperazine) derivatization was utilized to facilitate the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) determination of ACs. The result indicated that Tmt-PP labeling enables the prediction of the retention time and MS response of ACs and enhances their MS response up to 4 times. The introduction of the microwave during the derivatization procedure greatly improved the reaction efficiency, demonstrated by the shortened reaction time from 90 to 1 min. Furthermore, we applied a strategy named quantitative analysis of multi-components by a single marker (QAMS) for the assay of 26 ACs with only 5 AC standards, solving the standard availability issue to a large extent. The established workflow was applied to discover dysregulated ACs in xenograft colon cancer mice, and the quantification results were highly comparable with traditional methods where there were the corresponding standards for each AC. Our study demonstrated that chemical derivatization-based LC-MS/MS integrated with the QAMS strategy is robust for the identification and quantification of ACs and has great potential in targeted metabolomics study.


Assuntos
Carnitina , Espectrometria de Massas em Tandem , Animais , Carnitina/análogos & derivados , Cromatografia Líquida , Metabolômica , Camundongos
4.
Curr Microbiol ; 78(11): 3945-3956, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34542662

RESUMO

The evolution of antimicrobial-resistant pathogens is a global health and development threat. Nanomedicine is rapidly becoming the main driving force behind ongoing changes in antimicrobial studies. Among nanoparticles, silver (AgNPs) have attracted attention due to their versatile properties. The study aimed to investigate the effects of AgNPs and L-carnitine (LC) on mixed Candida albicans and Staphylococcus aureus in the mice vaginitis model. Study of antimicrobial activity of AgNPs evaluated by Minimum Inhibitory Concentration (MIC) and Minimum Biocidal Concentration (MBC) assays. AgNPs inhibited biofilm formation of microbial strains, which was tested by using crystal violet staining. In the current study, we evaluated the effects of AgNPs and LC in NMRI mice infected intravaginally with C. albicans/ S. aureus for two weeks. The proportion of mice in each stage of the estrous cycle (proestrus, estrus, metestrus, and diestrus) was examined. Histological properties were assessed by hematoxylin/ eosin (H&E) staining of formalin-fixed, paraffin-embedded vaginal tissue sections. Based on the results, MICs of AgNPs against S. aureus, C. albicans, and their combination were 252.3, 124.8, and 501.8 ppm, and their minimum biofilm inhibitory concentration (MBIC) was 500, 250, and 1000 ppm, respectively. The estrous cycle in the treated group was similar to the control. Vaginal histology and cytology showed that LC can improve tissue damages caused by vaginitis and AgNPs. This study demonstrates the promising use of AgNPs as antimicrobial agents and the combination of AgNPs/ LC could be a great future alternative in the control of vaginitis.


Assuntos
Nanopartículas Metálicas , Vaginite , Animais , Candida albicans , Carnitina , Feminino , Humanos , Camundongos , Prata/farmacologia , Staphylococcus aureus
5.
Epilepsy Behav ; 122: 108220, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34371461

RESUMO

BACKGROUND: The benefits of carnitine supplementation in patients treated with valproate (VPA) are not clear. Therefore, we retrospectively explored the benefits of carnitine supplementation by analyzing laboratory data. METHODS: We measured the serum-free carnitine (FC), VPA, aspartate aminotransferase, alanine aminotransferase, amylase, and ammonia levels, and the platelet count, in 69 patients with childhood-onset epilepsy treated with VPA. Eight patients had received carnitine supplementation. The serum FC and acylcarnitine levels were measured using an enzyme cycling method. We compared laboratory values between patients with and without carnitine supplementation and analyzed the correlations between serum FC levels and laboratory values. RESULTS: The serum FC levels were normal (median, 48.8 µmol/L; range: 41.9-68.3 µmol/L) in all eight patients with carnitine supplementation, but below normal in 32 of 61 patients without supplementation. The median serum amylase levels were lower in the patients with carnitine supplementation (median, 48 U/L; range: 27-149 U/L) than in those without (median, 7 U/L; range: 14-234 U/L). The platelet count and serum ammonia levels did not differ significantly between patients with and without supplementation. There was no significant correlation between the serum FC level and the platelet count, serum amylase level, or ammonia level. CONCLUSIONS: Carnitine supplementation helps maintain serum FC levels in patients treated with VPA. The lower serum amylase levels in patients with carnitine supplementation may reflect protective effects of carnitine against latent pancreatic injury.


Assuntos
Epilepsia , Ácido Valproico , Carnitina , Criança , Suplementos Nutricionais , Epilepsia/tratamento farmacológico , Humanos , Estudos Retrospectivos , Ácido Valproico/uso terapêutico
6.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445174

RESUMO

In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.


Assuntos
Trifosfato de Adenosina/metabolismo , Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Cardiopatias/metabolismo , Mitocôndrias Cardíacas/metabolismo , Peixe-Zebra , Animais , Carnitina/metabolismo , Modelos Animais de Doenças , Coração/fisiopatologia , Cardiopatias/patologia , Humanos , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia
7.
Turk J Pediatr ; 63(4): 691-696, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34449152

RESUMO

BACKGROUND: Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare, autosomal recessive, and highly lethal fatty acid oxidation (FAO) disorder caused by defective acylcarnitine transport across the mitochondrial membrane. CACTD is characterized by severe episodes of hypoglycemia and hyperammonemia, seizures, cardiomyopathy, liver dysfunction, severe neurological damage, and muscle weakness. Herein, we described the clinical features, biochemical, and molecular findings of three patients with CACTD, presented with poor feeding, hypoglycemia, liver dysfunctions, and hyperammonemia, but died despite intensive treatment. CASES: All cases had similar signs and symptoms like poor feeding and respiratory failure associated with liver dysfunction. Urinary organic acid profiles in the presence of hypoglycemia and hyperammonemia led us to the possible diagnosis of one of fatty acid ß-oxidation defects. Results of the molecular analyses were compatible with CACTD. In addition to known mutation (c.270delC;p.Phe91Leufs*38) we detected a novel one (c.408C > A;p.Cys136*). CONCLUSIONS: All three cases died despite a very intensive therapy. Based on our experience with these three cases, it can be said that CACTD has a relatively poor prognosis, molecular studies are of most importance in suspected cases for the final diagnosis and such studies might be of help while giving genetic counselling and guidance to parents for future pregnancies.


Assuntos
Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Carnitina , Carnitina Aciltransferases/genética , Feminino , Humanos , Proteínas de Membrana Transportadoras , Mutação , Gravidez
9.
BMC Infect Dis ; 21(1): 808, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384363

RESUMO

BACKGROUND: Antiretroviral therapy (ART) can reduce opportunistic infections and mortality rates among individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals exhibit poor immune recovery after ART. Hence, we explored the association between metabolome profiles and immune recovery in HIV-infected individuals following ART. METHODS: An untargeted metabolomics approach was used to analyze plasma samples from 18 HIV-negative individuals and 20 HIV-infected individuals, including 10 immunological non-responders (INR, CD4+ T cell rise < 100 cells/µl) and 10 immunological responders (IR, CD4+ T cell rise > 300 cells/µl) after 2 years of ART. These individuals were followed for the next 6 years and viral loads and CD4+ T cell count were measured regularly. Orthogonal projection on latent structures discriminant analysis (OPLS-DA), ANOVA, correlation, receiver operating characteristic (ROC), and survival analyses were used for selection of discriminant metabolites. RESULTS: Eighteen lipid metabolites were identified which could distinguish among control, INR, and IR groups. Among them, myristoylcarnitine (MC), palmitoylcarnitine (PC), stearoylcarnitine (SC), and oleoylcarnitine (OC) were significantly elevated in INR plasma samples compared with those from the IR and control groups and were negatively associated with CD4+ T cell count. Additionally, ROC analysis using a combination of MC, PC, SC, and OC had high sensitivity and specificity for differentiating INR from IR (AUC = 0.94). Finally, survival analysis for the combination of MC, PC, SC, and OC demonstrated that it could predict CD4+ T cell count in patients undergoing long-term ART. CONCLUSIONS: High levels of lipid metabolites, MC, PC, SC, and OC are associated with poor immune recovery in patients receiving ART and these data provide potential new insights into immune recovery mechanisms.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Carnitina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Humanos , Carga Viral
10.
Biomed Khim ; 67(4): 338-346, 2021 Jul.
Artigo em Russo | MEDLINE | ID: mdl-34414892

RESUMO

Hyperhomocysteinemia is a risk factor for many diseases, including reproductive disorders in men. L-carnitine is used in medical practice to correct impaired bioenergetic conditions; in patients with idiopathic forms of infertility its effects are associated with improvement of the sperm parameters. However, the effect of exogenous L-carnitine on the level of homocysteine in the gonadal tissues, as a risk factor for impaired fertility, has not been investigated yet. The aim of this study was to investigate activity of bioenergetic enzymes in the epididymal mitochondrial fraction, the dynamics of changes in the cytoplasmic and mitochondrial lactate levels and LDH activity, the total carnitine content, as well as the oxidative status of these cells under conditions of oxidative stress caused by hyperhomocysteinemia, and to assess the effect of carnitine chloride on these parameters under conditions of methionine administration to male Wistar rats. Methionine administration to animals for three weeks at a dose of 3 g/kg, resulted in development of the severe forms of hyperhomocysteinemia with serum homocysteine concentrations exceeding 100 µmol/L. This was accompanied by a decrease in the activity of enzymes involved in the bioenergetic processes of the cell: tissue respiration (succinate dehydrogenase) and oxidative phosphorylation (H+-ATPase) in the epididymal head and tail. The change in lactate metabolism included an increase in its level in both the mitochondrial and cytoplasmic fractions of the epididymal head and mitochondria of the epididymal tail, and also simultaneous statistically significant decrease in LDH activity in the mitochondria and cytoplasm of the epididymal head. In male rats with severe hyperhomocysteinemia, an increase in the activity of mitochondrial SOD accompanied by an increase in the carbonylation of mitochondrial proteins in the head and tail of the epididymis was noted. Modeling of hyperhomocysteinemia under conditions of carnitine chloride of administration led to different reactions of the cells of the studied tissues assayed in the epididymal head and tail homogenate. In the epididymal head, carnitine chloride promoted an increase in the mitochondrial lactate concentration and a decrease in the cytoplasmic lactate concentration, as well as an increase in the LDH activity associated with the mitochondrial fraction. These changes were accompanied by an increase in the activity of H+-ATPase in the epididymal, thus suggesting that carnitine chloride stimulated lactate transport of into the mitochondria and its use as an energy substrate under conditions of oxidative stress caused by hyperhomocysteinemia. In the tail tissues, the changes were protective in nature and were associated with a decrease in the formation of oxidatively modified proteins.


Assuntos
Epididimo , Hiper-Homocisteinemia , Animais , Carnitina/metabolismo , Cloretos/metabolismo , Epididimo/metabolismo , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/metabolismo , Ácido Láctico/metabolismo , Masculino , Mitocôndrias , Ratos , Ratos Wistar
11.
Front Immunol ; 12: 649197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234772

RESUMO

Persistent antigen exposure during chronic hepatitis B infection leads to exhausted immune responses, thus impeding viral control. In recent years, immunometabolism opens new therapeutic possibilities for the modulation of immune responses. Herein, we investigated the immunomodulatory effect of L-carnitine (L-Cn) on immune cells in chronic HBV infection. In this study, 141 treatment-naïve patients with chronic HBV infection, 38 patients who achieved HBsAg loss following antiviral treatment, and 47 patients who suffered from HBV-related HCC from real-life clinical practice were recruited. The plasma L-Cn levels were measured by ELISA. RNA sequencing was conducted to define the transcriptional profiles of peripheral blood mononuclear cells after L-Cn stimulation. In vitro assays were performed to assess the effect of L-Cn on immune cells; the frequencies and function of immune cells were analyzed by flow cytometry. We found that compared with patients with HBsAg loss, patients with HBsAg positivity and patients who suffered from HBV-related HCC had higher levels of L-Cn, and the plasma levels of L-Cn in the HBeAg-positive chronic hepatitis patients who had elevated ALT were significantly higher than that of HBeAg-negative chronic infection and HBsAg loss groups. Moreover, a positive correlation between plasma levels of L-Cn and HBsAg levels was found. Additionally, RNA sequencing analysis demonstrated that L-Cn altered the transcriptional profiles related to immune response. In vitro assays revealed that L-Cn suppressed the proliferation of and IFN-γ production by CD4+ and CD8+ T cells. It also down-regulated the proliferation and IgG production of B cells. Notably, L-Cn enhanced IL-10 secretion from regulatory T cells and up-regulated the expression of inhibitory receptors on T cells. Moreover, a variant in CPT2 (rs1799821) was confirmed to be associated with L-Cn levels as well as complete response in CHB patients following Peg-IFNα antiviral therapy. Taken together, the immunosuppressive properties of L-Cn may hinder the control of HBV in chronic HBV infection, implicating that L-Cn manipulation might influence the prognosis of patients with HBV infection.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carnitina/sangue , Hepatite B Crônica/imunologia , Neoplasias Hepáticas/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proliferação de Células , Estudos Transversais , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
12.
J Dairy Sci ; 104(10): 11193-11209, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34253361

RESUMO

This study aimed at characterizing the effects of dietary l-carnitine supplementation on hepatic fatty acid (FA) metabolism during inflammation in mid-lactating cows. Fifty-three pluriparous Holstein dairy cows were randomly assigned to either a control (CON, n = 26) or an l-carnitine supplemented (CAR; n = 27) group. The CAR cows received 125 g of a rumen-protected l-carnitine product per cow per day (corresponding to 25 g of l-carnitine/cow per day) from d 42 antepartum (AP) until the end of the trial on d 126 postpartum (PP). Aside from the supplementation, the same basal diets were fed in the dry period and during lactation to all cows. In mid lactation, each cow was immune-challenged by a single intravenous injection of 0.5 µg of LPS/kg of BW at d 111 PP. Blood samples were collected before and after LPS administration. The mRNA abundance of in total 39 genes related to FA metabolism was assessed in liver biopsies taken at d -11, 1, and 14 relative to LPS (d 111 PP) and also on d 42 AP as an individual covariate using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). In addition to the concentrations of 3 selected proteins related to FA metabolism, acetyl-CoA carboxylase α (ACACA), 5' AMP-activated protein kinase (AMPK), and solute carrier family 25 member 20 (SLC25A20) were assessed by a capillary Western blot method in liver biopsies from d -11 and 1 relative to LPS from 11 cows each of CAR and CON. On d -11 relative to LPS, differences between the mRNA abundance in CON and CAR were limited to acyl-CoA dehydrogenase (ACAD) very-long-chain (ACADVL) with greater mRNA abundance in the CAR than in the CON group. The liver fat content decreased from d -11 to d 1 relative to the LPS injection and remained at the lower level until d 14 in both groups. One day after the LPS challenge, lower mRNA abundance of carnitine palmitoyltransferase 1 (CPT1), CPT2, ACADVL, ACAD short-chain (ACADS), and solute carrier family 22 member 5 (SLC22A5) were observed in the CAR group as compared with the CON group. However, the mRNA abundance of protein kinase AMP-activated noncatalytic subunit gamma 1 (PRKAG1), ACAD medium-chain (ACADM), ACACA, and FA binding protein 1 (FABP1) were greater in the CAR group than in the CON group on d 1 relative to LPS. Two weeks after the LPS challenge, differences between the groups were no longer detectable. The altered mRNA abundance before and 1 d after LPS pointed to increased transport of FA into hepatic mitochondria during systemic inflammation in both groups. The protein abundance of AMPK was lower in CAR than in CON before the LPS administration. The protein abundance of SLC25A20 was neither changing with time nor treatment and the ACACA protein abundance was only affected by time. In conclusion, l-carnitine supplementation temporally altered the hepatic mRNA abundance of some genes related to mitochondrial biogenesis and very-low-density lipoprotein export in response to an inflammatory challenge, but with largely lacking effects before and 2 wk after LPS.


Assuntos
Lactação , Leite , Animais , Carnitina , Bovinos , Suplementos Nutricionais , Ácidos Graxos , Feminino , Fígado , RNA Mensageiro
13.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R429-R440, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34318701

RESUMO

Lipopolysaccharides (LPS) challenge the metabolic integrity of high-yielding dairy cows, activating the immune system and altering energy metabolism. Fatty acid oxidation, a major energy-gaining pathway, can be improved by supplementary carnitine, facilitating the transport of fatty acids into mitochondria. The metabolic response to the LPS challenge could alter both the plasma and the milk metabolome. Plasma and milk samples collected from cows treated with (n = 27) or without (n = 27) dietary carnitine, before and after intravenous administration of LPS, were subjected to a targeted metabolomics analysis. Multivariate statistical analyses revealed that both plasma and milk metabolome changed in response to the LPS challenge in both the carnitine-supplemented and the control cows. Short-chain acylcarnitines (carbon chain length C2, C3, C4, and C5) and long-chain acylcarnitines (C14, C16, and C18) had the highest performance to indicate LPS response when testing the predictive power of single metabolites using receiver-operator characteristics (ROC) analysis. The maximum area under a ROC curve (AUC) was 0.93. Biogenic amines, including sarcosine, and amino acids such as glutamine and isoleucine had AUC > 0.80 indicating metabolic changes due to the LPS challenge. In summary, the metabolites involved in the LPS response were acylcarnitines C2 and C5, sarcosine, glutamine, and isoleucine in plasma, and acylcarnitines C4 and C5 in milk. The interrelationship of plasma and milk metabolome included correlation of acylcarnitines C2, C4, and C5 between plasma and milk.


Assuntos
Carnitina/análogos & derivados , Lactação/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Leite/metabolismo , Animais , Carnitina/sangue , Bovinos , Dieta/veterinária , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Metabolômica/métodos , Leite/efeitos dos fármacos
14.
BMJ Case Rep ; 14(7)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281938

RESUMO

Twelve years following gastric bypass surgery, a cachectic 69-year-old woman presented with both fasting and postprandial hypoglycaemia. Postprandial symptoms were relieved by dietary modification and acarbose, as is common in such cases. During a supervised fast, symptomatic hypoglycaemia occurred. Concurrent laboratory testing showed suppression of plasma insulin, c-peptide, proinsulin and insulin-like growth factor II. However, beta-hydroxybutyrate was also low, surprising given insulin deficiency. Elevated plasma free fatty acid (FFA) concentrations suggested that lipolysis was not impaired, making cachexia/malnutrition a less likely cause of hypoglycaemia. The apparent diagnosis was failure to counter-regulate-subsequent plasma carnitine measurements showed carnitine deficiency which presumably prevented FFA transport across mitochondrial membranes for ketogenesis. Repletion with high-dose oral carnitine supplements effected resolution of fasting hypoglycaemia.


Assuntos
Derivação Gástrica , Hipoglicemia , Desnutrição , Idoso , Peptídeo C , Carnitina/uso terapêutico , Jejum , Feminino , Derivação Gástrica/efeitos adversos , Humanos , Hipoglicemia/etiologia , Insulina
16.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208786

RESUMO

The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.


Assuntos
Carnitina/análogos & derivados , Fosforilação/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Tirosina/metabolismo , Animais , Células CHO , Carnitina/farmacologia , Cricetulus , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Insulina/metabolismo , Resistência à Insulina , Modelos Biológicos , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/química
17.
Arch Biochem Biophys ; 709: 108970, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34181873

RESUMO

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1ß, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of knockout mice (Gcdh-/-) and wild type (WT) mice submitted to a normal or a high Lys diet. The potential protective effects of L-car treatment on these parameters were also evaluated. Gcdh-/- mice showed behavioral changes, including lower motor activity (decreased number of crossings) and exploratory activity (reduced number of rearings). Also, Gcdh-/- mice had significantly higher concentrations of glutarylcarnitine (C5DC) in blood and cathepsin-D (CATD), interleukin IL-1ß and tumor factor necrosis alpha (TNF-α) in striatum than WT mice. Noteworthy, L-car treatment prevented most behavioral alterations, normalized CATD levels and attenuated IL-1ß levels in striatum of Gcdh-/- mice. Finally, IL-1ß was positively correlated with CATD and C5DC levels and L-car was negatively correlated with CATD. Our results demonstrate behavioral changes and a pro-inflammatory status in striatum of the animal model of GA1 and, most importantly, L-car showed important protective effects on these alterations.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Encefalopatias Metabólicas/tratamento farmacológico , Carnitina/uso terapêutico , Glutaril-CoA Desidrogenase/deficiência , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Animais , Encefalopatias Metabólicas/genética , Carnitina/análogos & derivados , Carnitina/metabolismo , Catepsina D/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Glutaril-CoA Desidrogenase/genética , Asseio Animal/efeitos dos fármacos , Inflamação/genética , Interleucina-1beta/metabolismo , Locomoção/efeitos dos fármacos , Lisina/farmacologia , Camundongos Knockout , Teste de Campo Aberto/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
18.
Nutrients ; 13(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073024

RESUMO

L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group (p < 0.001). Plasma BNP levels were significantly elevated in the placebo group (p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (ß = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.


Assuntos
Carnitina/sangue , Carnitina/farmacocinética , Suplementos Nutricionais , Insuficiência Cardíaca/prevenção & controle , Coração/efeitos dos fármacos , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Carnitina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Coração/fisiopatologia , Insuficiência Cardíaca/complicações , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego
19.
Commun Biol ; 4(1): 725, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117367

RESUMO

Methionine metabolism arises as a key target to elucidate the molecular adaptations underlying animal longevity due to the negative association between longevity and methionine content. The present study follows a comparative approach to analyse plasma methionine metabolic profile using a LC-MS/MS platform from 11 mammalian species with a longevity ranging from 3.5 to 120 years. Our findings demonstrate the existence of a species-specific plasma profile for methionine metabolism associated with longevity characterised by: i) reduced methionine, cystathionine and choline; ii) increased non-polar amino acids; iii) reduced succinate and malate; and iv) increased carnitine. Our results support the existence of plasma longevity features that might respond to an optimised energetic metabolism and intracellular structures found in long-lived species.


Assuntos
Longevidade/fisiologia , Metionina/sangue , Animais , Carnitina/metabolismo , Gatos , Bovinos , Colina/sangue , Colina/metabolismo , Colina/fisiologia , Cistationina/sangue , Cistationina/metabolismo , Cistationina/fisiologia , Cães , Cromatografia Gasosa-Espectrometria de Massas , Cobaias , Cavalos , Humanos , Malatos/sangue , Malatos/metabolismo , Metionina/metabolismo , Metionina/fisiologia , Camundongos , Filogenia , Coelhos , Ratos , Ovinos , Ácido Succínico/sangue , Ácido Succínico/metabolismo , Suínos
20.
Nutrients ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063417

RESUMO

Severe and long-term vitamin C deficiency can lead to fatal scurvy, which is fortunately considered rare today. However, a moderate state of vitamin C (vitC) deficiency (hypovitaminosis C)-defined as a plasma concentration below 23 µM-is estimated to affect up to 10% of the population in the Western world, albeit clinical hallmarks in addition to scurvy have not been linked to vitC deficiency. The brain maintains a high vitC content and uniquely high levels during deficiency, supporting vitC's importance in the brain. Actions include both antioxidant and co-factor functions, rendering vitamin C deficiency likely to affect several targets in the brain, and it could be particularly significant during development where a high cellular metabolism and an immature antioxidant system might increase sensitivity. However, investigations of a non-scorbutic state of vitC deficiency and effects on the developing young brain are scarce. This narrative review provides a comprehensive overview of the complex mechanisms that regulate vitC homeostasis in vivo and in the brain in particular. Functions of vitC in the brain and the potential consequences of deficiency during brain development are highlighted, based primarily on findings from experimental animal models. Perspectives for future investigations of vitC are outlined.


Assuntos
Deficiência de Ácido Ascórbico/sangue , Ácido Ascórbico/metabolismo , Encéfalo/metabolismo , Escorbuto/metabolismo , Animais , Antioxidantes/metabolismo , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacocinética , Deficiência de Ácido Ascórbico/genética , Encéfalo/crescimento & desenvolvimento , Carnitina , Ácidos Graxos Insaturados/metabolismo , Homeostase , Humanos , Camundongos Knockout , Modelos Animais , Neuroglia/metabolismo , Neurônios/metabolismo , Transportadores de Sódio Acoplados à Vitamina C/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...