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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 199-204, 2024 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-38311559

RESUMO

OBJECTIVE: To explore the clinical characteristics and genetic variants of two children with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD). METHODS: Two children with HMGCLD diagnosed at Henan Provincial Children's Hospital respectively in December 2019 and June 2022 were selected as the study subjects. Clinical data and results of laboratory testing were analyzed retrospectively. RESULTS: Both children had manifested with repeated convulsions, severe hypoglycemia, metabolic acidosis and liver dysfunction. Blood amino acids and acylcarnitine analysis showed increased 3-hydroxy-isovalyl carnitine (C5OH) and 3-hydroxy-isovalyl carnitine/capryloyl carnitine ratio (C5OH/C8), and urinary organic acid analysis showed increased 3-hydroxyl-3-methyl glutaric acid, 3-methyl glutaric acid, 3-methyl glutaconic acid, 3-hydroxyisoglycine and 3-methylprotarylglycine. Child 1 was found to harbor homozygous c.722C>T variants of the HMGCL gene, which was rated as uncertain significance (PM2_Supporting+PP3). Child 2 was found to harbor homozygous c.121C>T variants of the HMGCL gene, which was rated as pathogenic variant (PVS1+PM2_Supporting+PP4). CONCLUSION: Acute episode of HMGCLD is usually characterized by metabolic disorders such as hypoglycemia and metabolic acidosis, and elevated organic acids in urine may facilitate the differential diagnosis, though definite diagnosis will rely on genetic testing.


Assuntos
Acetil-CoA C-Acetiltransferase/deficiência , Acidose , Erros Inatos do Metabolismo dos Aminoácidos , Glutaratos , Hipoglicemia , Meglutol/análogos & derivados , Doenças Metabólicas , Criança , Humanos , Estudos Retrospectivos , Acidose/genética , Carnitina , Hipoglicemia/genética
2.
FASEB J ; 38(4): e23478, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38372965

RESUMO

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid ß-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.


Assuntos
Cardiomiopatias , Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Lipidômica , Doenças Mitocondriais , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional/deficiência , Doenças Musculares , Doenças do Sistema Nervoso , Rabdomiólise , Humanos , Doenças Mitocondriais/diagnóstico , Carnitina , Cisteamina , Lipídeos
3.
PLoS Negl Trop Dis ; 18(2): e0011923, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38306392

RESUMO

Dengue virus (DENV) infection causes dengue fever, the most prevalent arthropod-transmitted viral disease worldwide. Viruses are acellular parasites and obligately rely on host cell machinery for reproduction. Previous studies have indicated metabolomic changes in endothelial cell models and sera of animal models and patients with dengue fever. To probe the immunometabolic mechanism of DENV infection, here, we report the metabolomic landscape of a human macrophage cell model of DENV infection and its antibody-dependent enhancement. DENV infection of THP-1-derived macrophages caused 202 metabolic variants, of which amino acids occupied 23.7%, fatty acids 21.78%, carbohydrates 10.4%, organic acids 13.37%, and carnitines 10.4%. These metabolomic changes indicated an overall anabolic signature, which was characterized by the global exhaustion of amino acids, increases of cellular fatty acids, carbohydrates and pentoses, but decreases of acylcarnitine. Significant activation of metabolic pathways of glycolysis, pentose phosphate, amino acid metabolism, and tricarboxylic acid cycle collectively support the overall anabolism to meet metabolic demands of DENV replication and immune activation by viral infection. Totally 88 of 202 metabolic variants were significantly changed by DENV infection, 36 of which met the statistical standard (P<0.05, VIP>1.5) of differentially expressed metabolites, which were the predominantly decreased variants of acylcarnitine and the increased variants of fatty acids and carbohydrates. Remarkably, 11 differentially expressed metabolites were significantly distinct between DENV only infection and antibody-dependent enhancement of viral infection. Our data suggested that the anabolic activation by DENV infection integrates the viral replication and anti-viral immune activation.


Assuntos
Carnitina/análogos & derivados , Vírus da Dengue , Dengue , Viroses , Animais , Humanos , Vírus da Dengue/fisiologia , Anticorpos Facilitadores , Replicação Viral , Macrófagos , Carboidratos , Aminoácidos , Ácidos Graxos
4.
Nefrología (Madrid) ; 44(1): 40-49, ene.- feb. 2024. tab
Artigo em Espanhol | IBECS | ID: ibc-229420

RESUMO

Background/Aim The prevalence of cognitive impairment (CI) is high in hemodialysis patients. In this study, the relationship between CI and serum carnitine, plasma omega-3, omega-6 and omega-3/omega-6 fatty acid ratio was evaluated in hemodialysis patients. Materials and methods Sixty two patients [male: 40 (64.5%), mean age 51±13 years] were included in this cross-sectional study. Serum total and free-carnitine levels were determined by ELISA. Plasma omega-3 [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and omega-6 [arachidonic acid (AA), dihomo gamma linoleic acid (DGLA)] levels were measured using LC-ESI-MS/MS. According to the Montreal Cognitive Assessment (MoCA) scores, ≤24 points were considered as CI. MoCA score ≤24 and >24 were determined as Group 1 and Group 2, respectively. Results Group 1 had significantly higher AA+DGLA/EPA+DHA ratios and lower free-carnitine, DHA and EPA+DHA levels compared to Group 2 (P=0.008, P=0.040, P=0.032, P=0.032, respectively). Group 1 had a statistically lower education level (P<0.05). Negative correlation was found between MoCA scores and AA+DGLA/EPA+DHA ratios (rs=−0.284, P=0.026). Free-carnitine levels were positively correlated with EPA and EPA+DHA levels (rs=0.278, P=0.030 and rs=0.271, P=0.034, respectively), and negative correlated with AA+DGLA/EPA+DHA ratios (rs=−0.414, P=0.001). In multivariate logistic regression analysis, MoCA scores was associated with AA+DGLA/EPA+DHA ratio (P=0.009) and education level (P<0.001). Conclusion It was determined that high AA+DGLA/EPA+DHA ratio and low education level could be independent risk factors of the CI (AU)


Contexto/objetivo La prevalencia de deterioro cognitivo (CI) es alta en pacientes en hemodiálisis. En este estudio se evaluó la relación entre el CI y las proporciones de carnitina sérica, ácidos grasos omega-3, omega-6 y omega-3/omega-6 en plasma en pacientes en hemodiálisis. Materiales y métodos En este estudio transversal se incluyeron 62 pacientes (hombres: 40 [64,5%], edad media 51±13años). Los niveles séricos de carnitina total y libre se determinaron mediante ELISA. Los niveles plasmáticos de omega-3 (ácido eicosapentaenoico [EPA], ácido docosahexaenoico [DHA]) y omega-6 (ácido araquidónico [AA], ácido dihomo gamma linoleico [DGLA]) se midieron utilizando LC-ESI-MS/MS. Según las puntuaciones de la Evaluación Cognitiva de Montreal (MoCA), ≤24 indican CI. Las puntuaciones MoCA ≤24 y >24 se determinaron como grupo 1 y grupo 2, respectivamente. Resultados El grupo 1 tenía proporciones de AA + DGLA/EPA + DHA significativamente más altas y niveles más bajos de carnitina libre, DHA y EPA +DHA en comparación con el grupo2 (p=0,008, p=0,040, p=0,032 y p=0,032, respectivamente). El grupo1 tenía un nivel educativo estadísticamente más bajo (p<0,05). Se descubrió una correlación negativa entre las puntuaciones de MoCA y las proporciones AA + DGLA/EPA + DHA (rs=−0,284, p=0,026). Los niveles de carnitina libre se correlacionaron positivamente con los niveles de EPA y EPA + DHA (rs=0,278, p=0,030, y rs=0,271, p=0,034, respectivamente), y negativamente con las proporciones AA +DGLA/EPA +DHA (rs=−0,414, p=0,001). En el análisis de regresión logística multivariante las puntuaciones de MoCA se asociaron con las proporciones AA +DGLA/EPA + DHA (p=0,009) y con el nivel educativo (p<0,001). Conclusión Se determinó que una alta relación AA +DGLA/EPA +DHA y un bajo nivel educativo podrían ser factores de riesgo independientes del CI (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Ácidos Graxos/metabolismo , Carnitina/metabolismo , Diálise Renal , Estudos Transversais , Escolaridade , Fatores de Risco
5.
Aging Clin Exp Res ; 36(1): 36, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38345670

RESUMO

BACKGROUND: Intrinsic capacity is the combination of individual physical and mental abilities, reflecting the aging degree of the older adults. However, the mechanisms and metabolic characteristics of the decline in intrinsic capacity are still unclear. AIMS: To identify metabolic signatures and associated pathways of decline in intrinsic capacity based on the metabolite features. METHODS: We recruited 70 participants aged 77.19 ± 8.31 years. The five domains of intrinsic capacity were assessed by Short Physical Performance Battery (for mobility), Montreal cognition assessment (for cognition), 30-Item Geriatric Depression Scale (for psychology), self-reported hearing/visual impairment (for sensory) and Nutritional risk screening (for vitality), respectively. The serum samples of participants were analyzed by liquid chromatography-mass spectrometry-based metabolomics, followed by metabolite set enrichment analysis and metabolic pathway analysis. RESULTS: There were 50 participants with a decline in intrinsic capacity in at least one of the domains. A total of 349 metabolites were identified from their serum samples. Overall, 24 differential metabolites, 5 metabolite sets and 13 pathways were associated with the decline in intrinsic capacity. DISCUSSION: Our results indicated that decline in intrinsic capacity had unique metabolomic profiles. CONCLUSION: The specific change of acyl carnitines was observed to be a feature of decline in intrinsic capacity. Dysregulation of the pentose phosphate pathway and of arginine and ornithine metabolism was strongly associated with the decline in intrinsic capacity.


Assuntos
Arginina , Carnitina/análogos & derivados , Via de Pentose Fosfato , Humanos , Idoso , Metabolômica/métodos , China , Ornitina
6.
Metabolomics ; 20(2): 24, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393619

RESUMO

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Tiazolidinedionas , Humanos , Rosiglitazona/uso terapêutico , Pioglitazona , Miócitos Cardíacos , Cardiotoxicidade/complicações , Cardiotoxicidade/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Metabolômica , Tiazolidinedionas/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Aminoácidos , Biomarcadores , Carnitina , Valina
8.
Technol Cancer Res Treat ; 23: 15330338241233443, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38409962

RESUMO

Purpose: Treatment of triple-negative breast cancer (TNBC) remains challenging. Intermittent fasting (IF) has emerged as a promising approach to improve metabolic health of various metabolic disorders. Clinical studies indicate IF is essential for TNBC progression. However, the molecular mechanisms underlying metabolic remodeling in regulating IF and TNBC progression are still unclear. Methods: In this study, we utilized a robust mouse model of TNBC and exposed subjects to a high-fat diet (HFD) with IF to explore its impact on the metabolic reprogramming linked to cancer progression. To identify crucial serum metabolites and signaling events, we utilized targeted metabolomics and RNA sequencing (RNA-seq). Furthermore, we conducted immunoblotting, real-time quantitative polymerase chain reaction (RT-qPCR), cell migration assays, lentivirus-mediated Mmp9 overexpression, and Mmp9 inhibitor experiments to elucidate the role of decanoylcarnitine/Mmp9 in TNBC cell migration. Results: Our observations indicate that IF exerts notable inhibitory effects on both the proliferation and cancer metastasis. Utilizing targeted metabolomics and RNA-seq, we initially identified pivotal serum metabolites and signaling events in the progression of TNBC. Among the 349 serum metabolites identified, decanoylcarnitine was picked out to inhibit TNBC cell proliferation and migration. RNA-seq analysis of TNBC cells treated with decanoylcarnitine revealed its suppressive effects on extracellular matrix-related protein components, with a notable reduction observed in Mmp9. Further investigations confirmed that decanoylcarnitine could inhibit Mmp9 expression in TNBC cells, primary tumors, lung, and liver metastasis tissues. Mmp9 overexpression abolished the inhibitory effect of decanoylcarnitine on cell migration. Conclusion: This study pioneers the exploration of IF intervention and the role of decanoylcarnitine/Mmp9 in the progression of TNBC in obese mice, enhancing our comprehension of the potential roles of various dietary patterns in the process of cancer treatment.


Assuntos
Carnitina/análogos & derivados , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Camundongos Obesos , Linhagem Celular Tumoral , Jejum Intermitente , Obesidade/tratamento farmacológico , Obesidade/genética , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão Gênica
9.
J Ovarian Res ; 17(1): 9, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38191449

RESUMO

OBJECTIVE: To investigate the effect of L-carnitine supplementation during the controlled ovarian stimulation (COS) cycle with antagonist protocol in patients with polycystic ovary syndrome (PCOS) diagnosis undergoing IVF/ICSI treatment. METHODS AND MATERIALS: This was a double-blind clinical trial study including 110 patients with PCOS attended to Royan Institute between March 2020 and February 2023. At the beginning of the COS cycle, the eligible patients were allocated into two groups randomly according to the coding list of the drugs prepared by the statistical consultant. In the experimental group, patients received 3 tablets daily (L-carnitine 1000 mg) from the second day of menstruation of the previous cycle until the puncture day in the cases of freeze-all embryos (6 weeks) or until the day of the pregnancy test (8 weeks) in fresh embryo transfer cycle. In the control group, patients received 3 placebo tablets for the same period of time. Weight assessment and fasting blood sugar and insulin tests, as well as serum lipid profile were also measured at the baseline and ovum pick-up day. The results of the COS cycle as well as the implantation and pregnancy rates were compared between groups. RESULTS: Finally, 45 cases in L-carnitine group versus 47 cases in the placebo group were completed study per protocol. Data analysis showed that the two groups were homogeneous in terms of demographic characteristics and baseline laboratory tests and severity of PCOS. There is no statistically significant difference in terms of the oocyte recovery ratio and oocyte maturity rate, and the number and quality of embryos, as well as the rates of the fertilization, chemical and clinical pregnancy between groups. However, the means of weight (P < 0.001) and serum levels of fasting blood sugar (P = 0.021), fasting insulin (P = 0.004), triglyceride (P < 0.001) and cholesterol (P < 0.001), LDL (P < 0.001) have significantly decreased in women after consuming L-carnitine supplementation. CONCLUSION: The oral intake of L-carnitine during COS in PCOS women for 6 weeks had no effect on COS and pregnancy outcomes. However, taking this supplement for 6 weeks has been associated with weight loss and improved lipid profile and serum glucose. TRIAL REGISTRATION: The study was registered in the Clinicaltrials.gov site on December 17, 2020 (NCT04672720).


Assuntos
Insulinas , Síndrome do Ovário Policístico , Gravidez , Humanos , Feminino , Carnitina/farmacologia , Carnitina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Glicemia , Injeções de Esperma Intracitoplásmicas , Lipídeos
10.
BMC Cardiovasc Disord ; 24(1): 1, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166572

RESUMO

BACKGROUND: Primary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently. OBJECTIVE: We aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family. METHODS: We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies. RESULTS: Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development. CONCLUSIONS: The c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.


Assuntos
Cardiomiopatias , Cardiomiopatia Hipertrófica , Hiperamonemia , Doenças Musculares , Masculino , Humanos , Criança , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Carnitina/genética , Carnitina/metabolismo , Irã (Geográfico) , Membro 5 da Família 22 de Carreadores de Soluto/genética , Hiperamonemia/diagnóstico , Hiperamonemia/genética , Hiperamonemia/complicações , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cardiomiopatia Hipertrófica/complicações , Mutação
11.
Arch Pediatr ; 31(1): 85-88, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38168614

RESUMO

The cases were a pair of siblings with a carnitine palmitoyltransferase (CPT2) deficiency detected by tandem mass spectrometry. Their C16 and C18:1 levels were both within the normal range, while C0 was low, and the (C16+C18:1)/C2 ratio was high. Following genetic testing, a novel CPT2 gene mutation was identified in both patients. The male patient had a normal growth rate during 5 years of follow-up after treatment. By contrast, the female patient did not take l-carnitine supplements and died after an infectious disease-associated illness when she was 1 year old. These data emphasize the need to raise awareness about CPT2 deficiency so as to correctly diagnose and accurately manage the disease.


Assuntos
Carnitina O-Palmitoiltransferase , Erros Inatos do Metabolismo , Feminino , Humanos , Lactente , Masculino , Carnitina , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Mutação , Pré-Escolar
12.
Cell Metab ; 36(1): 193-208.e8, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38171333

RESUMO

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Mutações Sintéticas Letais , Glicólise , Carnitina
13.
Biol Pharm Bull ; 47(1): 23-27, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38171776

RESUMO

Mammalian type 2 carnitine parmitoyltransferase (EC 2.3.1.21), abbreviated as CPT2, is an enzyme involved in the translocation of fatty acid into the mitochondrial matrix space, and catalyzes the reaction acylcarnitine + CoA = acyl-CoA + carnitine. When rat CPT2 was expressed in Escherichia coli, its behavior was dependent on the presence or absence of i) its mitochondrial localization sequence and ii) a short amino acid sequence thought to anchor it to the mitochondrial inner membrane: CPT2 containing both sequences behaved as a hydrophobic protein, while recombinant CPT2 lacking both regions behaved as a water soluble protein; if only one region was present, the resultant proteins were observed in both fractions. Because relatively few protein species could be obtained from bacterial lysates as insoluble pellets under the experimental conditions used, selective enrichment of recombinant CPT2 protein containing both hydrophobic sequences was easily achieved. Furthermore, when CPT2 enriched in insoluble fraction was resuspended in an appropriate medium, it showed catalytic activity typical of CPT2: it was completely suppressed by the CPT2 inhibitor, ST1326, but not by the CPT1 inhibitor, malonyl-CoA. Therefore, we conclude that the bacterial expression system is an effective tool for characterization studies of mammalian CPT2.


Assuntos
Carnitina O-Palmitoiltransferase , Mitocôndrias , Ratos , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/química , Mitocôndrias/metabolismo , Malonil Coenzima A/metabolismo , Malonil Coenzima A/farmacologia , Ácidos Graxos/metabolismo , Proteínas Recombinantes/genética , Carnitina/metabolismo , Mamíferos/metabolismo
14.
Respir Res ; 25(1): 58, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273290

RESUMO

BACKGROUND: The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF. METHODS: We analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules. Linear regression was used to compare metabolite and clinical analyte levels between patients with IPF and controls and to determine associations between metabolite levels and measures of disease severity in patients with IPF. Unadjusted and adjusted univariable Cox regression models were used to evaluate associations between circulating metabolites and the risk of mortality or disease progression among patients with IPF. RESULTS: Levels of 64 metabolites and 5 clinical analytes were significantly different between patients with IPF and controls. Among analytes with greatest differences were non-esterified fatty acids, multiple long-chain acylcarnitines, and select ceramides, levels of which were higher among patients with IPF versus controls. Levels of the branched-chain amino acids valine and leucine/isoleucine were inversely correlated with measures of disease severity. After adjusting for clinical factors known to influence outcomes, higher levels of the acylcarnitine C:16-OH/C:14-DC were associated with all-cause mortality, lower levels of the acylcarnitine C16:1-OH/C14:1DC were associated with all-cause mortality, respiratory death, and respiratory death or lung transplant, and higher levels of the sphingomyelin d43:2 were associated with the risk of respiratory death or lung transplantation. CONCLUSIONS: IPF has a distinct circulating metabolic profile characterized by increased levels of non-esterified fatty acids, long-chain acylcarnitines, and ceramides, which may suggest a more catabolic environment that enhances lipid mobilization and metabolism. We identified select metabolites that were highly correlated with measures of disease severity or the risk of disease progression and that may be developed further as biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; URL: www. CLINICALTRIALS: gov .


Assuntos
Carnitina , Fibrose Pulmonar Idiopática , Humanos , Carnitina/análogos & derivados , Ceramidas , Progressão da Doença , Ácidos Graxos , Fibrose Pulmonar Idiopática/metabolismo , Metaboloma , Sistema de Registros
15.
Gene ; 901: 148128, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38181927

RESUMO

Cyclophosphamide (CP), as an anti-cancer drug, is frequently used to treat various types of cancer. A decreased number of ovarian follicles impaired normal ovarian function, and subsequent premature ovarian failure (POF) presented as a side effect of cyclophosphamide usage. These events may eventually affect the fertility rate of individuals. The present study showed the effect of cyclophosphamide on ovarian reserves and the protective effect of L-carnitine (LC) as an antioxidant to prevent POF. To design the study, six to eight-week-old NMRI female mice were divided into three groups: control, cyclophosphamide (CP), and cyclophosphamide + L-carnitine (CP + LC). Mice received drugs intraperitoneally (IP) for 21 days. In the following 24 h after the last injection, both ovaries were used to evaluate the expression of Sohlh1 and Lhx8 genes by Real-time PCR. Furthermore, the alteration of Lhx8 promoter methylation was examined by Methylation-sensitive high-resolution melting analysis (MS-HRM). The present data showed the negative effect of CP on regulator genes of oogenesis including Sohlh1 and Lhx8. In addition, an examination of the epigenetic status of the Lhx8 gene showed a change in promoter methylation of this gene following cyclophosphamide injection. Although, L-carnitine is an effective antioxidant in relieving oxidative stress caused by cyclophosphamide and its damage, in the present study, however, the use of L-carnitine failed to protect the ovaries from changes caused by CP injection. So, using cyclophosphamide can alter the expression of folliculogenesis genes through its effects on epigenetic changes and may cause POF. The results of the present study showed that L-carnitine consumption can't protect the ovaries against the adverse effects of CP.


Assuntos
Antioxidantes , Insuficiência Ovariana Primária , Humanos , Camundongos , Feminino , Animais , Antioxidantes/farmacologia , Fatores de Transcrição , Carnitina/farmacologia , Carnitina/uso terapêutico , Ciclofosfamida/efeitos adversos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/genética , Epigênese Genética , Reação em Cadeia da Polimerase em Tempo Real
16.
Food Chem ; 442: 138457, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38271903

RESUMO

This work presents a straightforward approach to the separation d/l-carnitine (d/l-Carn) using ion mobility-mass spectrometry (IM-MS) and theoretical calculations. Natamycin (Nat) was used as separation reagent to interact with the Carn, metal ions (G) were employed as ligand, the resultant ternary complexes [d/l-Carn + Nat + G]+ were observed experimentally. IM-MS results revealed that d/l-Carn could be baseline separated via complex formation using Li+, Na+, K+, Rb+, and Cs+, with a maximum peak separation resolution (Rp-p) of 2.91; Theoretical calculations were performed to determine the optimal conformations of [d/l-Carn + Nat + Li/K]+, and the predicted collisional cross section values were consistent with the experimental values. Conformational analysis was used to elucidate the enantiomeric separation of d/l-Carn at the molecular level via the formation of ternary complexes. Furthermore, quantitative analyses for the determination of the enantiomers were established with effective linearity and acceptable sensitivity. Finally, the proposed method was successfully applied in the determination of d/l-Carn in food samples.


Assuntos
Carnitina , Espectrometria de Mobilidade Iônica , Íons
17.
Free Radic Biol Med ; 213: 174-189, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38246515

RESUMO

Osteoporosis, which manifests as reduced bone mass and deteriorated bone quality, is common in the elderly population. It is characterized by persistent elevation of macrophage-associated inflammation and active osteoclast bone resorption. Currently, the roles of intracellular metabolism in regulating these processes remain unclear. In this study, we initially performed bioinformatics analysis and observed a significant increase in the proportion of M1 macrophages in bone marrow with aging. Further metabolomics analysis demonstrated a notable reduction in the expression of carnitine metabolites in aged macrophages, while carnitine was not detected in osteoclasts. During the differentiation process, osteoclasts took up carnitine synthesized by macrophages to regulate their own activity. Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. In this study, we found that the decrease in carnitine levels in aging macrophages causes overactivation of osteoclasts, ultimately leading to osteoporosis. A decrease in serum carnitine levels in patients with osteoporosis was found to have good diagnostic and predictive value. Moreover, supplementation with carnitine was shown to be effective in the treatment of osteoporosis.


Assuntos
Reabsorção Óssea , Osteoporose , Humanos , Idoso , Osteogênese/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Carnitina/metabolismo , Transdução de Sinais , Osteoclastos/metabolismo , Macrófagos/metabolismo , Reabsorção Óssea/complicações , Reabsorção Óssea/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/genética , Ligante RANK/farmacologia
18.
EBioMedicine ; 100: 104949, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199043

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome. METHODS: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules. FINDINGS: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms. INTERPRETATION: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life. FUNDING: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Carnitina/análogos & derivados , Lactente , Recém-Nascido , Humanos , Masculino , Feminino , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Estudos de Coortes , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Sangue Fetal , Estudos Prospectivos , Lipídeos
19.
Eur J Pharm Biopharm ; 196: 114185, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38280469

RESUMO

As a bioactive saponin derived from the seeds of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chow, jujuboside B (JuB) shows great potential in anti-anxiety, anti-depression and improving learning and memory function. However, its oral bioavailability is very poor. In this study, a novel drug-loading nanoparticles system was prepared with polyethylene glycol and polylactic-co-glycolic acid copolymer (PEG-PLGA), and further modified with L-carnitine (LC) to target intestinal organic cation/carnitine transporter 2 (OCTN2) to improve the oral absorption of JuB. Under the optimized preparation conditions, the particle sizes of obtained JuB-PEG-PLGA nanoparticles (B-NPs) and LC modified B-NPs (LC-B-NPs) were 110.67 ± 11.37 nm and 134.00 ± 2.00 nm with the entrapment efficiency (EE%) 73.46 ± 1.26 % and 76.01 ± 2.10 %, respectively. The pharmacokinetics in SD rats showed that B-NPs and LC-B-NPs increased the bioavailability of JuB to 134.33 % and 159.04 % respectively. In Caco-2 cell model, the prepared nanoparticles significantly increased cell uptake of JuB, which verified the pharmacokinetic results. The absorption of LC-B-NPs mainly depended on OCTN2 transporter, and Na+ played an important role. Caveolin and clathrin were involved in the endocytosis of the two nanoparticles. In conclusion, both B-NPs and LC-B-NPs can improve the oral absorption of JuB, and the modification of LC can effectively target the OCTN2 transporter.


Assuntos
Nanopartículas , Poliésteres , Polietilenoglicóis , Saponinas , Humanos , Ratos , Animais , Carnitina/farmacocinética , Células CACO-2 , Ratos Sprague-Dawley , Tamanho da Partícula
20.
Animal ; 18(2): 101049, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215677

RESUMO

Our understanding of metabolic alterations triggered by heat stress is incomplete, which limits the designing of nutritional strategies to mitigate negative productive and health effects. Thus, this study aimed to explore the metabolic responses of heat-stressed dairy cows to dietary supplementation with vitamin D3/Ca and vitamin E/Se. Twelve multiparous Holstein cows were enrolled in a split-plot Latin square design with two distinct vitamin E/Se supplementation levels, either at a low (ESe-, n = 6, 11.1 IU/kg vitamin E and 0.55 mg/kg Se) or a high dose (ESe+, n = 6 223 IU/kg vitamin E and 1.8 mg/kg Se) as the main plot. Treatment subplots, arranged in a replicated 3 × 3 Latin square design, comprised heat challenge (Temperature Humidity Index, THI: 72.0-82.0) supplemented with different levels of vitamin D3/Ca: either low (HS/DCa-, 1 012 IU/kg and 0.73%, respectively) or high (HS/DCa+, 3 764 IU/kg and 0.97%, respectively), and a pair-fed control group in thermoneutrality (THI = 61.0-64.0) receiving the low dose of vitamin D3/Ca (TN). The liquid chromatography-mass spectrometry-based metabolome profile was determined in blood plasma and milk sampled at the beginning (day 0) and end (day 14) of each experimental period. The results were analyzed for the effect of (1) TN vs. HS/ESe-/DCa-, and (2) the vitamin E/Se and vitamin D3/Ca supplementation. No group or group × day effects were detected in the plasma metabolome (false discovery rate, FDR > 0.05), except for triglyceride 52:2 being higher (FDR = 0.03) on day 0 than 14. Taurine, creatinine and butyryl-carnitine showed group × day interactions in the milk metabolome (FDR ≤ 0.05) as creatinine (+22%) and butyryl-carnitine (+190%) were increased (P < 0.01) on day 14, and taurine was decreased (-65%, P < 0.01) on day 14 in the heat stress (HS) cows, compared with day 0. Most compounds were unaffected by vitamin E/Se or vitamin D3/Ca supplementation level or their interaction (FDR > 0.05) in plasma and milk, except for milk alanine which was lower (-69%, FDR = 0.03) in the E/Se+ groups, compared with E/Se-. Our results indicated that HS triggered more prominent changes in the milk than in the plasma metabolome, with consistent results in milk suggesting increased muscle catabolism, as reflected by increased creatinine, alanine and citrulline levels. Supplementing with high levels of vitamin E/Se or vitamin D3/Ca or their combination did not appear to affect the metabolic remodeling triggered by HS.


Assuntos
Lactação , Leite , Feminino , Bovinos , Animais , Leite/metabolismo , Creatinina/análise , Creatinina/metabolismo , Creatinina/farmacologia , Dieta/veterinária , Temperatura Alta , Suplementos Nutricionais/análise , Resposta ao Choque Térmico , Vitamina E , Carnitina/metabolismo , Alanina/análise , Alanina/metabolismo , Alanina/farmacologia , Aminoácidos/metabolismo , Vitamina D/metabolismo
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