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1.
Nat Commun ; 11(1): 3169, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576825

RESUMO

Understanding tumor metabolism holds the promise of new insights into cancer biology, diagnosis and treatment. To assess human cancer metabolism, here we report a method to collect intra-operative samples of blood from an artery directly upstream and a vein directly downstream of a brain tumor, as well as samples from dorsal pedal veins of the same patients. After performing targeted metabolomic analysis, we characterize the metabolites consumed and produced by gliomas in vivo by comparing the arterial supply and venous drainage. N-acetylornithine, D-glucose, putrescine, and L-acetylcarnitine are consumed in relatively large amounts by gliomas. Conversely, L-glutamine, agmatine, and uridine 5-monophosphate are produced in relatively large amounts by gliomas. Further we verify that D-2-hydroxyglutarate (D-2HG) is high in venous plasma from patients with isocitrate dehydrogenases1 (IDH1) mutations. Through these paired comparisons, we can exclude the interpatient variation that is present in plasma samples usually taken from the cubital vein.


Assuntos
Biomarcadores Tumorais/sangue , Vasos Sanguíneos/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Glioma/sangue , Glioma/metabolismo , Metabolômica , Acetilcarnitina/sangue , Adulto , Idoso , Agmatina/sangue , Sangue , Análise Química do Sangue , Glicemia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glucose , Glutamina/sangue , Glutaratos/sangue , Humanos , Isocitrato Desidrogenase/sangue , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Ornitina/análogos & derivados , Ornitina/sangue , Putrescina/sangue , Uridina Monofosfato/sangue , Adulto Jovem
2.
J Exp Clin Cancer Res ; 38(1): 464, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718684

RESUMO

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. METHODS: The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. RESULTS: We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. CONCLUSIONS: Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible "repurposed agent' for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.


Assuntos
Acetilcarnitina/farmacologia , Indutores da Angiogênese/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
EBioMedicine ; 49: 318-330, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676389

RESUMO

BACKGROUND: Type 2 diabetes patients and individuals at risk of developing diabetes are characterized by metabolic inflexibility and disturbed glucose homeostasis. Low carnitine availability may contribute to metabolic inflexibility and impaired glucose tolerance. Here, we investigated whether carnitine supplementation improves metabolic flexibility and insulin sensitivity in impaired glucose tolerant (IGT) volunteers. METHODS: Eleven IGT- volunteers followed a 36-day placebo- and L-carnitine treatment (2 g/day) in a randomised, placebo-controlled, double blind crossover design. A hyperinsulinemic-euglycemic clamp (40 mU/m2/min), combined with indirect calorimetry (ventilated hood) was performed to determine insulin sensitivity and metabolic flexibility. Furthermore, metabolic flexibility was assessed in response to a high-energy meal. Skeletal muscle acetylcarnitine concentrations were measured in vivo using long echo time proton magnetic resonance spectroscopy (1H-MRS, TE=500 ms) in the resting state (7:00AM and 5:00PM) and after a 30-min cycling exercise. Twelve normal glucose tolerant (NGT) volunteers were included without any intervention as control group. RESULTS: Metabolic flexibility of IGT-subjects completely restored towards NGT control values upon carnitine supplementation, measured during a hyperinsulinemic-euglycemic clamp and meal test. In muscle, carnitine supplementation enhanced the increase in resting acetylcarnitine concentrations over the day (delta 7:00 AM versus 5:00 PM) in IGT-subjects. Furthermore, carnitine supplementation increased post-exercise acetylcarnitine concentrations and reduced long-chain acylcarnitine species in IGT-subjects, suggesting the stimulation of a more complete fat oxidation in muscle. Whole-body insulin sensitivity was not affected. CONCLUSION: Carnitine supplementation improves acetylcarnitine formation and rescues metabolic flexibility in IGT-subjects. Future research should investigate the potential of carnitine in prevention/treatment of type 2 diabetes.


Assuntos
Acetilcarnitina/metabolismo , Carnitina/farmacologia , Suplementos Nutricionais , Voluntários Saudáveis , Músculo Esquelético/metabolismo , Acetilcarnitina/sangue , Composição Corporal/efeitos dos fármacos , Carnitina/sangue , Feminino , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Humanos , Hiperinsulinismo/sangue , Resistência à Insulina , Cinética , Masculino , Metaboloma , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos
4.
J Mass Spectrom ; 54(11): 878-884, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31652368

RESUMO

Overcoming the detrimental effects of sweet spots during crystallization is an important step to improve the quantitative abilities of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. In this study, we introduce MALDI targets, which exhibit a channel design to reduce sweet spot phenomena and improve reproducibility. The size of the channels was 3.0 mm in length, 0.35 mm in depth, and 0.40 mm in width, adjusted to the width of the implemented laser beam. For sample deposition, the matrix/sample mixture was homogenously deposited into the channels using capillary action. To demonstrate the proof-of-principle, the novel plates were used for the quantification of acetyl-L-carnitine in human blood plasma using a combined standard addition and isotope dilution method. The results showed that the reproducibility of acetyl-L-carnitine detection was highly improved over a conventional MALDI-MS assay, with RSD values of less than 5.9% in comparison with 15.6% using the regular MALDI method. The limits of quantification using the new plates were lowered approximately two-fold in comparison with a standard rastering approach on a smooth stainless-steel plate. Matrix effects were also assessed and shown to be negligible. The new assay was subsequently applied to the quantification of acetyl-L-carnitine in human plasma samples.


Assuntos
Acetilcarnitina/sangue , Cristalização , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Aço Inoxidável/química , Propriedades de Superfície
5.
Artigo em Russo | MEDLINE | ID: mdl-31626181

RESUMO

Acetyl-L-carnitine (ALA) is a biologically active form of L-carnitine, which is a readily available substrate for triggering energy-dependent metabolic processes in the mitochondria. The mechanism of the protective effect of ALA on brain tissue is a significant reduction in the amount of oxygen consumed for energy supply of the needs of the nervous system. ALA also has antioxidant and antiapoptotic activity. In addition, ALK plays a neuromodulating effect on both synaptic morphology and synaptic transmission. The similarity in structure with acetylcholine allows to have a cholinomimetic effect, as well as to show neuroprotective and neurotrophic properties. ALK has an antidepressant and analgesic effect in painful neuropathies. Therefore, ALA is a promising drug for the treatment of polyneuropathy of various origins. Compared with antidepressants efficacy and a minimum of side effects open up wide possibilities of using ALA in the treatment of depression with a low risk of developing NLR.


Assuntos
Acetilcarnitina , Carnitina , Depressão , Polineuropatias , Acetilcarnitina/uso terapêutico , Carnitina/uso terapêutico , Depressão/tratamento farmacológico , Humanos , Neurologia/tendências , Psiquiatria/tendências
7.
Urologiia ; (4): 62-68, 2019 Sep.
Artigo em Russo | MEDLINE | ID: mdl-31535807

RESUMO

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


Assuntos
Carnitina/uso terapêutico , Infertilidade Masculina/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Acetilcarnitina , Adulto , Método Duplo-Cego , Feminino , Fumaratos , Humanos , Masculino , Estresse Oxidativo , Gravidez , Estudos Prospectivos , Contagem de Espermatozoides , Motilidade Espermática , Espermatozoides
8.
Cochrane Database Syst Rev ; 6: CD011265, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201734

RESUMO

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of people with diabetes. A complete and comprehensive management strategy for the prevention and treatment of DPN, whether painful or not, has not yet been defined.Research into treatment for DPN has been characterised by a series of failed clinical trials, with few noteworthy advances. Strategies that support peripheral nerve regeneration and restore neurological function in people with painful or painless DPN are needed. The amino acid acetyl-L-carnitine (ALC) plays a role in the transfer of long-chain fatty acids into mitochondria for ß-oxidation. ALC supplementation also induces neuroprotective and neurotrophic effects in the peripheral nervous system. Therefore, ALC supplementation targets several mechanisms relevant to potential nerve repair and regeneration, and could have clinical therapeutic potential. There is a need for a systematic review of the evidence from clinical trials. OBJECTIVES: To assess the effects of ALC for the treatment of DPN. SEARCH METHODS: On 2 July 2018, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We checked references, searched citations, and contacted study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of ALC compared with placebo, other therapy, or no intervention in the treatment of DPN. Participants could be of any sex and age, and have type 1 or type 2 diabetes mellitus, of any severity, with painful or painless DPN. We accepted any definition of minimum criteria for DPN, in accordance with the Toronto Consensus. We imposed no language restriction.Pain was the primary outcome, measured as the proportion of participants with at least 30% (moderate) or 50% (substantial) decrease in pain over baseline, or as the score on a visual analogue scale (VAS) or Likert scale for pain. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: We included four studies with 907 participants, which were reported in three publications. Three trials studied ALC versus placebo (675 participants); in one trial the dose of ALC was 2000 mg/day, and in the other two trials, it was 1500 mg/day or 3000 mg/day. The fourth trial studied ALC 1500 mg/day versus methylcobalamin 1.5 mg/day (232 participants). The risk of bias was high in both trials of different ALC doses and low in the other two trials.No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief. ALC reduced pain more than placebo, measured on a 0- to 100-mm VAS (MD -9.16, 95% CI -16.76 to -1.57; three studies; 540 participants; P = 0.02; I² = 56%; random-effects; very low-certainty evidence; a higher score indicating more pain). At doses of 1500 mg/day or less, the VAS score after ALC treatment was little different from placebo (MD -0.05, 95% CI -10.00 to 9.89; two studies; 159 participants; P = 0.99; I² = 0%), but at doses greater than 1500 mg/day, ALC reduced pain more than placebo (MD -14.93, 95% CI -19.16 to -10.70; three studies; 381 participants; P < 0.00001; I² = 0%). This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.Two placebo-controlled studies reported that vibration perception improved after 12 months. We graded this evidence as very low certainty, due to inconsistency and a high risk of bias, as the trial authors did not provide any numerical data. The placebo-controlled studies did not measure functional impairment and disability scores. No study used validated symptom scales. One study performed sensory testing, but the evidence was very uncertain.The fourth included study compared ALC with methylcobalamin, but did not report effects on pain. There was a reduction from baseline to 24 weeks in functional impairment and disability, based on the change in mean Neuropathy Disability Score (NDS; scale from zero to 10), but there was no important difference between the ALC group (mean score 1.66 ± 1.90) and the methylcobalamin group (mean score 1.35 ± 1.65) groups (P = 0.23; low-certainty evidence).One placebo-controlled study reported that six of 147 participants in the ALC > 1500 mg/day group (4.1%) and two of 147 participants in the placebo group (1.4%) discontinued treatment because of adverse events (headache, facial paraesthesia, and gastrointestinal disorders) (P = 0.17). The other two placebo-controlled studies reported no dropouts due to adverse events, and more pain, paraesthesia, and hyperaesthesias in the placebo group than the 3000 mg/day ALC group, but provided no numerical data. The overall certainty of adverse event evidence for the comparison of ALC versus placebo was low.The study comparing ALC with methylcobalamin reported that 34/117 participants (29.1%) experienced adverse events in the ALC group versus 33/115 (28.7%) in the methylcobalamin group (P = 0.95). Nine participants discontinued treatment due to adverse events (ALC: 4 participants, methylcobalamin: 5 participants), which were most commonly gastrointestinal symptoms. The certainty of the adverse event evidence for ALC versus methylcobalamin was low.Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer. AUTHORS' CONCLUSIONS: We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months' treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty. Data on functional and sensory impairment and symptoms are lacking, or of very low certainty. The evidence on adverse events is too uncertain to make any judgements on safety.


Assuntos
Acetilcarnitina/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/tratamento farmacológico , Neuralgia/tratamento farmacológico , Acetilcarnitina/administração & dosagem , Acetilcarnitina/efeitos adversos , Adulto , Idoso , Neuropatias Diabéticas/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sensação/efeitos dos fármacos , Vibração , Vitamina B 12/administração & dosagem , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico
9.
Muscle Nerve ; 60(2): 124-136, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31074875

RESUMO

Complementary and alternative treatment modalities are commonly utilized by patients for neuropathy and neuropathic pain due to perceived lack of benefit from conventional medical treatment. As the association between metabolic syndrome and neuropathy is increasingly recognized, diet and lifestyle interventions are becoming important components in the management of neuropathy. Progress in the understanding of the gut-immune interaction highlights the role the gut microbiome and inflammation plays in the modulation of neuropathy and neuropathic pain. Evidence for nutritional interventions, exercise, supplements, acupuncture, and mindfulness-based practices in the treatment of neuropathic pain is encouraging. This article reviews the available evidence to support the safe use of complementary and alternative treatments for commonly encountered conditions associated with neuropathy and neuropathic pain. Muscle Nerve 60: 124-136, 2019.


Assuntos
Dietoterapia , Suplementos Nutricionais , Terapia por Exercício , Estilo de Vida , Neuralgia/terapia , Doenças do Sistema Nervoso Periférico/terapia , Complexo Vitamínico B/uso terapêutico , Acetilcarnitina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/uso terapêutico , Dieta , Disbiose/metabolismo , Exercício Físico , Ácidos Graxos Ômega-3/uso terapêutico , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Microbioma Gastrointestinal , Humanos , Medicina Integrativa , Síndrome Metabólica/metabolismo , Neuralgia/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Fosfato de Piridoxal/uso terapêutico , Ácido Tióctico/uso terapêutico , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/metabolismo , Deficiência de Vitaminas do Complexo B , Vitamina D/uso terapêutico
10.
Neurosci Lett ; 706: 36-42, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31078678

RESUMO

Ketamine, an anesthetic, is a non-competitive antagonist of the calcium-permeable N-methyl-d-aspartate (NMDA) receptor. High concentrations of ketamine have been implicated in cardiotoxicity and neurotoxicity. Often, these toxicities are thought to be mediated by reactive oxygen species (ROS). However, findings to the contrary showing ketamine reducing ROS in mammalian cells and neurons in vitro, are emerging. Here, we determined the effects of ketamine on ROS levels in zebrafish larvae in vivo. Based on our earlier studies demonstrating reduction in ATP levels by ketamine, we hypothesized that as a calcium antagonist, ketamine would also prevent ROS generation, which is a by-product of ATP synthesis. To confirm that the detected ROS in a whole organism, such as the zebrafish larva, is specific, we used diphenyleneiodonium (DPI) that blocks ROS production by inhibiting the NADPH Oxidases (NOX). Upon 20 h exposure, DPI (5 and 10 µM) and ketamine at (1 and 2 mM) reduced ROS in the zebrafish larvae in vivo. Using acetyl l-carnitine (ALCAR), a dietary supplement, that induces mitochondrial ATP synthesis, we show elevated ROS generation with increasing ALCAR concentrations. Combined, ketamine and ALCAR counter-balanced ROS generation in the larvae suggesting that ketamine and ALCAR have opposing effects on mitochondrial metabolism, which may be key to maintaining ROS homeostasis in the larvae and affords ALCAR the ability to prevent ketamine toxicity. These results for the first time show ketamine's antioxidative and ALCAR's prooxidative effects in a live vertebrate.


Assuntos
Acetilcarnitina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Microscopia de Fluorescência , Neurônios/metabolismo , Oniocompostos/farmacologia , Peixe-Zebra
11.
Neurochem Res ; 44(10): 2405-2412, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31041669

RESUMO

Neonatal hypoxia-ischemia (HI) is a common cause of brain injury in infants. Acute kidney injury frequently occurs after birth asphyxia and is associated with adverse outcome. Treatment with acetyl-L-carnitine (ALCAR) after HI protects brain and improves outcome. Rat pups underwent carotid ligation and 75 min hypoxia on postnatal day 7 to determine effects of HI on kidney which is understudied in this model. HI + ALCAR pups were treated at 0, 4 and 24 h after HI. The organic cation/carnitine transporter 2 (OCTN2), transports ALCAR and functions to reabsorb carnitine and acylcarnitines from urine. At 24 h after injury OCTN2 levels were significantly decreased in kidney from HI pups, 0.80 ± 0.04 (mean ± SEM, p < 0.01), compared to sham controls 1.03 ± 0.04, and HI + ALCAR pups 1.11 ± 0.06. The effect of HI on the level of pyruvate dehydrogenase (PDH) was determined since kidney has high energy requirements. At 24 h after HI, kidney PDH/ß-actin ratios were significantly lower in HI pups, 0.98 ± 0.05 (mean ± SEM, p < 0.05), compared to sham controls 1.16 ± 0.06, and HI + ALCAR pups 1.24 ± 0.03, p < 0.01. Treatment of pups with ALCAR after HI prevented the decrease in renal OCTN2 and PDH levels at 24 h after injury. Protection of PDH and OCTN2 after HI would improve energy metabolism in kidney, maintain tissue carnitine levels and overall carnitine homeostasis which is essential for neonatal health.


Assuntos
Acetilcarnitina/farmacologia , Lesões Encefálicas/tratamento farmacológico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Rim/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Transporte Biológico/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carnitina/análogos & derivados , Carnitina/farmacologia , Feminino , Hipóxia/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Ratos Sprague-Dawley
12.
Nat Commun ; 10(1): 1476, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931940

RESUMO

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1-5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.


Assuntos
Fibrose/metabolismo , Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Insuficiência Renal Crônica/metabolismo , Triptofano Hidroxilase/genética , Triptofano/análogos & derivados , Acetilcarnitina/metabolismo , Animais , Canavanina/análogos & derivados , Canavanina/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Estudos de Casos e Controles , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Introdução de Genes , Técnicas de Silenciamento de Genes , Humanos , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/citologia , Rim/efeitos dos fármacos , Rim/patologia , Metabolômica , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Taurina/metabolismo , Triptofano/metabolismo , Triptofano/farmacologia , Obstrução Ureteral
13.
Nutrients ; 11(4)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010169

RESUMO

The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (-81-66%, VIP = 1.43-3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (-45%, VIP = 1.83), sphingosine (-48%, VIP = 2.78), linoleamide (-45%, VIP = 1.51), and several lysophospholipids (-40-56%, VIP = 1.72-2.16). Moreover, lower AUC (-59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet-genes interactions by which PROX1 may promote T2DM development are needed.


Assuntos
Ácidos e Sais Biliares/sangue , Diabetes Mellitus Tipo 2/genética , Carboidratos da Dieta/metabolismo , Proteínas de Homeodomínio/genética , Inflamação/sangue , Metabolismo dos Lipídeos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , Acetilcarnitina/sangue , Adulto , Alelos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta , Interação Gene-Ambiente , Genótipo , Humanos , Ácidos Linoleicos/sangue , Masculino , Refeições , Metaboloma , Ornitina/sangue , Estresse Oxidativo , Período Pós-Prandial , Transdução de Sinais , Esfingosina/sangue
14.
Neuropharmacology ; 150: 145-152, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30917915

RESUMO

Stress-related psychiatric disorders are mental conditions that affect mood, cognition and behavior and arise because of the impact of prolonged stress on the central nervous system (CNS). Acetyl-L-carnitine (ALC) is an acetyl ester of L-carnitine that easily crosses the blood-brain barrier and was recently found to be decreased in patients with major depressive disorder. ALC plays a role in energy metabolism and is widely consumed as a nutritional supplement to improve physical performance. In this study, our objective was to evaluate the effects of ALC treatment (0.1 mg/L, 10 min) for 7 days on behavior and oxidative stress in zebrafish subjected to unpredictable chronic stress (UCS) protocol. Behavioral outcomes were assessed in the novel tank test, and parameters of oxidative status (lipid peroxidation and antioxidant defenses) were evaluated in the brain using colorimetric methods. According to our previous findings, UCS increased anxiety-like behavior and lipid peroxidation, while it decreased non-protein thiol levels and superoxide dismutase activity. However, ALC reversed the anxiety-like behavior and oxidative damage in stressed animals, while it was devoid of effect in control animals. Although our data reinforce the neuroprotective potential of ALC in the treatment of psychiatric disorders related to stress, further investigations are required to clarify its mechanisms of action and confirm its efficacy.


Assuntos
Acetilcarnitina/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acetilcarnitina/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Encéfalo/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Peixe-Zebra
15.
Andrologia ; 51(6): e13267, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30873633

RESUMO

Carnitine is essential for energy metabolism and spermatozoa maturation. Combining L-carnitine and L-acetylcarnitine with micronutrients has been investigated as a treatment for infertility in men. We evaluated the effects of a therapeutic formulation, Proxeed Plus, on sperm parameters in oligoasthenozoospermic men. This prospective, randomised, double-blind, placebo-controlled clinical trial involved 175 males (19-44 years) with idiopathic oligoasthenozoospermia who failed to impregnate their partners (12 months). Males received Proxeed Plus or placebo for 3 and 6 months. Sperm volume, progressive motility and vitality significantly (p < 0.001) improved after 6 months compared to baseline. Sperm DNA fragmentation index significantly decreased compared to baseline (p < 0.001) and the 3-month therapy (p = 0.014) in treated men. Increased seminal carnitine and α-glucosidase concentration also positively correlated with improved progressive motility. Decreased DNA fragmentation index was the good predictor of progressive sperm motility >10%, and simultaneous measurement of changes in sperm vitality and DNA fragmentation index gave the highest probability of sperm motility 10% (AUC = 0.924; 95% CI = 0.852-0.996; p < 0.001). Logistic regression analyses revealed DNA fragmentation index decrease as the only independent predictor of sperm motility 10% (OR = 1.106; p = 0.034). We have demonstrated the beneficial effects of carnitine derivatives on progressive motility, vitality and sperm DNA fragmentation. Combining metabolic and micronutritive factors is beneficial for male infertility.


Assuntos
Acetilcarnitina/administração & dosagem , Carnitina/administração & dosagem , Micronutrientes/administração & dosagem , Oligospermia/tratamento farmacológico , Espermatozoides/efeitos dos fármacos , Adulto , Fragmentação do DNA/efeitos dos fármacos , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Masculino , Placebos/administração & dosagem , Estudos Prospectivos , Contagem de Espermatozoides , Maturação do Esperma/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Resultado do Tratamento
16.
Neurosci Lett ; 703: 86-95, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30890473

RESUMO

Parkinson's disease (PD) is a progressive motor disease with clinical features emerging due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), which project to the caudate putamen (CPu) where they release dopamine (DA). The current study investigated whether acetyl-l-carnitine (ALC) could ameliorate the pathology seen in an in vivoin vivo chronic 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of PD. Four treatment groups were included: 1) CONTROL receiving probenecid (PROB; 250 mg/kg) only, 2) MPTP (25 mg/kg) + PROB, 3) MPTP + ALC (100 mg/kg), and 4) ALC alone. MPTP-induced losses in tyrosine hydroxylase and DA transporter immunoreactivity in the SNc and CPu were significantly reduced by ALC. HPLC data further suggests that decreases in CPu DA levels produced by MPTP were also attenuated by ALC. Additionally, microglial activation and astrocytic reactivity induced by MPTP were greatly reduced by ALC, indicating protection against neuroinflammation. Glucose transporter-1 and the tight junction proteins occludin and zonula occludins-1 were also protected from MPTP-induced down-regulation by ALC. Together, data suggest that in this model, ALC protects against MPTP-induced damage to endothelial cells and loss of DA neurons in the SNc and CPu, suggesting that ALC therapy may have the potential to slow or ameliorate the progression of PD pathology in a clinical setting.


Assuntos
Acetilcarnitina/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Probenecid , Putamen/efeitos dos fármacos , Putamen/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
17.
J Inherit Metab Dis ; 42(1): 128-139, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.


Assuntos
Homocistinúria/diagnóstico , Acetilcarnitina/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Feminino , Glicina N-Metiltransferase/deficiência , Glicina N-Metiltransferase/metabolismo , Homocisteína/metabolismo , Homocistinúria/metabolismo , Humanos , Recém-Nascido , Masculino , Metionina/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Ácido Metilmalônico/metabolismo , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/metabolismo , Triagem Neonatal/métodos , Fenilalanina/metabolismo , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/metabolismo
18.
J Eur Acad Dermatol Venereol ; 33(7): 1378-1385, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30803039

RESUMO

BACKGROUND: Global metabolomics analysis can provide substantial information on energy metabolism, physiology, possible diagnostic biomarkers and intervention strategies for pathogens. OBJECTIVE: To gain a better understanding of the mechanisms of syphilis and analysis of serum metabolite profiles in syphilis patients. METHODS: We conducted an untargeted metabolomics analysis of serum from 20 syphilis patients and 20 healthy controls. RESULTS: A total of 2890 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Distinct differential metabolites were identified by principal component analysis, partial least squares-discriminant analysis and hierarchical clustering analysis. Furthermore, five metabolites were identified as significantly different by Student's t-test, including trimethylamine N-oxide, l-arginine, lysoPC(18:0), betaine and acetylcarnitine. KEGG analysis showed that these differential metabolites were in various pathways, including Chagas disease, fatty acid biosynthesis, primary bile acid biosynthesis, Salmonella infection, ABC transporters, glycerophospholipid metabolism and choline metabolism. Among them, trimethylamine N-oxide was 3.922 times in patients with syphilis than healthy controls. CONCLUSION: Trimethylamine N-oxide may be used as an indicator to distinguish between syphilis patients and healthy controls. The changes in these metabolites suggest that Treponema pallidum affects the normal metabolic activity of host cells, providing some clues for elucidating the pathogenesis of T. pallidum.


Assuntos
Acetilcarnitina/sangue , Arginina/sangue , Betaína/sangue , Metilaminas/sangue , Sífilis/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Metabolômica , Pessoa de Meia-Idade , Análise de Componente Principal , Sífilis/microbiologia
19.
Cochrane Database Syst Rev ; 1: CD011451, 2019 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-30610762

RESUMO

BACKGROUND: Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. OBJECTIVES: To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites. SELECTION CRITERIA: We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms. DATA COLLECTION AND ANALYSIS: We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach. MAIN RESULTS: We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.


Assuntos
Acetilcarnitina/uso terapêutico , Quelantes/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Amônia/sangue , Fadiga/etiologia , Feminino , Encefalopatia Hepática/sangue , Encefalopatia Hepática/etiologia , Humanos , Cirrose Hepática/complicações , Masculino , Fadiga Mental/etiologia , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Nanotoxicology ; 13(2): 204-220, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30663479

RESUMO

Iron oxides nanoparticles (FeOX NPs), including α-Fe2O3, γ-Fe2O3, and Fe3O4, are employed in many technological applications. However, very few studies have investigated the embryonic developmental toxicity of FeOX NPs. In this study, metabolomics analysis were used to uncover the potential mechanisms of FeOX NPs developmental toxicity on embryo-larval zebrafish and mice. Our results indicated that γ-Fe2O3 NP treatment could cause increased mortality, dropped hatching rate, etc., while α-Fe2O3 and Fe3O4 NPs showed no obvious effect. Through metabolomics analysis, a total of 42 metabolites were found to be significantly changed between the γ-Fe2O3 NP-treated group and the control group (p < 0.05). Pathway enrichment analysis indicated the impairment of mitochondria function. γ-Fe2O3 NP treatment caused abnormal mitochondrion structure and a decrease in mitochondrial membrane potential in zebrafish embryos. Meanwhile, ATP synthesis was decreased while oxidative stress levels were affected. It is noteworthy that acetyl-l-carnitine (ALCAR) (p = 6.79E - 04) and l-carnitine (p = 1.43E - 03) were identified with minimal p values, the relationship between the two counter-balance was regulated by acetyltransferase (crata). Subsequently, we performed rescue experiments with ALCAR on zebrafish embryos, and found that the mortality rates reduced and hatching rates raised significantly in the γ-Fe2O3 NP-treated group. Additionally, γ-Fe2O3 exposure could lead to increased absorbed fetus rate, decreased placental weight, lower expression of acetyltransferase (Crat), reduced ATP synthesis as well as increased oxidative stress (p < 0.05). Our findings demonstrated that γ-Fe2O3 NP might affect the mitochondrial membrane potential and ATP synthesis by affecting the metabolism of ALCAR, thereby stimulating oxidative stress, cell apoptosis, and causing embryonic development toxicity.


Assuntos
Acetilcarnitina/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Compostos Férricos/toxicidade , Mitocôndrias/efeitos dos fármacos , Nanopartículas/toxicidade , Peixe-Zebra , Animais , Embrião não Mamífero/metabolismo , Feminino , Compostos Férricos/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metabolômica , Camundongos , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Gravidez
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