RESUMO
Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression. We examined putative biomarkers of neuropathy in blood and tissue and quantified levels of small fiber neuropathy, looking for associations between lowered 1-deoxySL and phenotypes. Toxic 1-deoxySLs were suppressed long-term in plasma and various tissue including the sciatic nerve, which is particularly targeted in DN. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease. However, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Hyperglycemia and dyslipidemia persisted during our study, and high levels of glutathione were seen in the spinal cord. Our results demonstrate that despite significant functional improvements, l-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia, that persist despite 1-deoxySL reduction.
Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Hiperglicemia , Camundongos , Animais , Serina/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Esfingolipídeos , Suplementos NutricionaisRESUMO
Chronic heart failure (CHF) is the end stage of many severe heart diseases. Fuzi decoction (FZD) originates from Zhang Zhongjing's Treatise on Febrile Diseases and is widely used in the treatment of CHF in the clinic, but the potential mechanism of FZD in CHF is unclear. In this study, an integrated approach combining network pharmacology and metabolomics was adopted to explore the mechanism of FZD in CHF. Network pharmacological studies indicated that the most significant signaling pathway was the HIF-1 signaling pathway. Untargeted metabolomics indicated abnormalities in serum metabolism in CHF rats, and FZD treatment significantly improved the metabolic abnormalities and altered the levels of 30 metabolites. A pathway enrichment analysis showed that FZD was mainly involved in glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis, ß-alanine metabolism, pantothenate and CoA biosynthesis, glyoxylate and dicarboxylate metabolism and other metabolic pathways. A correlation analysis showed that pyruvate and lactate were strongly correlated with the heart failure index, and a targeted metabolomics study showed that FZD restored the balance of the pyruvate-lactate axis that was disrupted due to CHF. Therefore, the mechanism of FZD against CHF may be related to regulate HIF-1 signaling pathway, pyruvate-lactate axis and glycine, serine and threonine metabolism.
Assuntos
Medicamentos de Ervas Chinesas , Insuficiência Cardíaca , Animais , Doença Crônica , Coenzima A/uso terapêutico , Diterpenos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Glicina , Glioxilatos , Insuficiência Cardíaca/tratamento farmacológico , Lactatos/uso terapêutico , Metabolômica , Farmacologia em Rede , Piruvatos/uso terapêutico , RNA de Transferência/uso terapêutico , Ratos , Serina/uso terapêutico , Treonina/uso terapêutico , beta-AlaninaRESUMO
Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Our previous study showed antimicrobial effects of anandamide (AEA) and arachidonoyl serine (AraS) against methicillin (MET)-resistant S. aureus (MRSA) strains, proposing the therapeutic potential of these endocannabinoid/endocannabinoid-like (EC/EC-like) agents for the treatment of MRSA. Here, we investigated the potential synergism of combinations of AEA and AraS with different types of antibiotics against MRSA grown under planktonic growth or biofilm formation. The most effective combinations under planktonic conditions were mixtures of AEA and ampicillin (AMP), and of AraS and gentamicin (GEN). The combination with the highest synergy in the biofilm formation against all tested bacterial strains was AEA and MET. Moreover, the combination of AraS and MET synergistically caused default of biofilm formation. Slime production of MRSA was also dramatically impaired by AEA or AraS combined with MET. Our data suggest the novel potential activity of combinations of EC/EC-like agents and antibiotics in the prevention of MRSA biofilm formation.
Assuntos
Antibacterianos/farmacologia , Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Ampicilina/farmacologia , Ampicilina/uso terapêutico , Antibacterianos/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Biofilmes/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Endocanabinoides/uso terapêutico , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Humanos , Resistência a Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Alcamidas Poli-Insaturadas/uso terapêutico , Serina/análogos & derivados , Serina/farmacologia , Serina/uso terapêutico , Infecções Estafilocócicas/microbiologiaRESUMO
BACKGROUND: Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder. METHODS: Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor. RESULTS: Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN. CONCLUSIONS: These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).
Assuntos
Antipsicóticos/uso terapêutico , Variação Contingente Negativa/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Esquizofrenia/tratamento farmacológico , Serina/uso terapêutico , Estimulação Acústica , Adolescente , Adulto , Transtornos Cognitivos/etiologia , Estudos Cross-Over , Método Duplo-Cego , Potenciais Evocados Auditivos/efeitos dos fármacos , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Esquizofrenia/fisiopatologia , Sulfonas/uso terapêutico , Fatores de Tempo , Adulto JovemRESUMO
Introdução: A Esclerose Lateral Amiotrófica (ELA) é definida como uma doença neurológica progressiva e inexorável, com cerca de 80% dos casos de etiologia desconhecida. Novos medicamentos têm emergido no tratamento de doenças neurodegenerativas, inclusive na ELA, redesenhando o modelo fisiopatológico. Dentre eles, destacam-se o uso da: Edaravone, Vitamina K2, Serina, Metilcobalamina, Pirroloquinolina quinona (PQQ), Ubiquinol e Glutationa. Especificamente na ELA, alguns já foram validados em estudos randomizados-controlados. Metodologia: Atualização da literatura (PUBMED, Medline) sobre a utilização desses fármacos em doenças neurológicas degenerativas, com enfoque para a Doença do Neurônio Motor (DNM-ELA), nos idiomas Português, Inglês, Espanhol e Francês, compreendidos entre os anos de (2010-2017). Discussão: A associação desses medicamentos tem mostrado resultados positivos em inúmeras doenças neurológicas. Alguns, como, por exemplo, a Metilcobalamina e o Edaravone,exerceriam mecanismos de ação capazes de interferir no processo de depleção dos neurônios motores da ponta anterior e do feixe piramidal em pacientes com ELA. Conclusão: Seria precipitado concluir que o uso associado desses fármacos poderia modificar ou mesmo restaurar os danos às unidades motoras; entretanto, faz-se necessário destacar seus mecanismos de ação e potencial capacidade de intervir na evolução da doença, principalmente, a partir de estudos em modelos fisiopatológico que culminam na degeneração dos neurônios motores.(AU)
Introduction: Amyotrophic Lateral Sclerosis (ALS) is defined as a progressive and inexorable neurological disease, with about 80% of cases of unknown etiology. New drugs have emerged in the treatment of neurodegenerative diseases, including ALS, redesigning the pathophysiological model. Among them, the use of: Edaravone, Vitamin K2, Serine, Methylcobalamin, Pyrroloquinoline quinone (PQQ), Ubiquinol and Glutathione are noteworthy. Specifically in ALS, some have been validated in randomized controlled trials. Methodology: Update of the literature (PUBMED, Medline) on the use of these drugs in degenerative neurological diseases, with a focus on Motor Neuron Disease (DNM-ELA) in the Portuguese, English, Spanish and French languages, of (2010-2017). Discussion: The association of these drugs has shown positive results in neurological diseases. Some, such as Methylcobalamin and Edaravone, would exert mechanisms of action capable of interfering in the process of depletion of the motor neurons of the anterior horn and pyramidal tracts in patients with ALS. Conclusion: It would be precipitate to conclude that the associated use of these drugs could modify or even restore damage to motor units; however, it is necessary to highlight its mechanisms of action and potential ability to intervene in the evolution of the disease, mainly from studies in pathophysiological models that culminate in the degeneration of motor neurons (AU)
Assuntos
Humanos , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Neurônios Motores/patologia , Serina/uso terapêutico , Vitamina K/uso terapêutico , Literatura de Revisão como Assunto , Preparações Farmacêuticas/administração & dosagem , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot-Marie-Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C.
Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/dietoterapia , Serina C-Palmitoiltransferase/genética , Serina/uso terapêutico , Adulto , Suplementos Nutricionais , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/metabolismo , Humanos , Mutação , Serina/metabolismo , Serina C-Palmitoiltransferase/sangue , Serina C-Palmitoiltransferase/metabolismo , Esfingolipídeos/sangueRESUMO
SCOPE: Serine lies at the central node linking biosynthetic flux from glycolysis to glutathione synthesis and one-carbon metabolic cycle which are closely related to antioxidant capacity. The present study was conducted to determine the effects of serine supplementation on oxidative stress and its relative mechanisms. METHODS AND RESULTS: Diquat treatment was performed to induce oxidative stress in mice and primary hepatocytes. The results showed that hepatic glutathione anti-oxidant systems were impaired and reactive oxygen species and homocysteine were increased in diquat-induced mice and hepatocytes, while such disadvantageous changes were diminished by serine supplementation both in vivo and in vitro. However, when cystathionine ß-synthase expression was inhibited by interference RNA in hepatocytes, the effects of serine supplementation on the improvement of glutathione synthesis and the alleviation of oxidative stress were diminished. Moreover, when hepatocytes were treated with cycloleucine, an inhibitor of methionine adenosyltransferase, the effects of serine supplementation on the improvement of methionine cycle and the alleviation of DNA hypomethylation and oxidative stress were also diminished. CONCLUSION: Our results indicated that serine supplementation alleviated oxidative stress via supporting glutathione synthesis and methionine cycle, mostly by condensing with homocysteine to synthesize cysteine and providing one-carbon units for homocysteine remethylation.
Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Glutationa/metabolismo , Hepatócitos/metabolismo , Metionina/metabolismo , Estresse Oxidativo , Serina/uso terapêutico , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cicloleucina/farmacologia , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Metilação de DNA/efeitos dos fármacos , Desfolhantes Químicos/antagonistas & inibidores , Desfolhantes Químicos/toxicidade , Diquat/antagonistas & inibidores , Diquat/toxicidade , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Homocisteína/metabolismo , Masculino , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Interferência de RNA , Distribuição Aleatória , Serina/antagonistas & inibidores , Serina/metabolismo , Organismos Livres de Patógenos EspecíficosRESUMO
To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.
Assuntos
Glutationa/metabolismo , Lipoproteínas/metabolismo , Metabolômica/métodos , NAD/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Serina/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Regulação Enzimológica da Expressão Gênica , Genoma , Glicina/sangue , Humanos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Modelagem Computacional Específica para o Paciente , Serina/sangue , Serina/uso terapêuticoRESUMO
1-Deoxysphingolipids (1-deoxySLs) are atypical neurotoxic sphingolipids that are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL concentrations cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), an axonal neuropathy associated with several missense mutations in SPT. Oral L-serine supplementation suppressed the formation of 1-deoxySLs in patients with HSAN1 and preserved nerve function in an HSAN1 mouse model. Because 1-deoxySLs also are elevated in patients with type 2 diabetes mellitus, L-serine supplementation could also be a therapeutic option for diabetic neuropathy (DN). This was tested in diabetic STZ rats in a preventive and therapeutic treatment scheme. Diabetic rats showed significantly increased plasma 1-deoxySL concentrations, and L-serine supplementation lowered 1-deoxySL concentrations in both treatment schemes (P < 0.0001). L-serine had no significant effect on hyperglycemia, body weight, or food intake. Mechanical sensitivity was significantly improved in the preventive (P < 0.01) and therapeutic schemes (P < 0.001). Nerve conduction velocity (NCV) significantly improved in only the preventive group (P < 0.05). Overall NCV showed a highly significant (P = 5.2E-12) inverse correlation with plasma 1-deoxySL concentrations. In summary, our data support the hypothesis that 1-deoxySLs are involved in the pathology of DN and that an oral L-serine supplementation could be a novel therapeutic option for treating DN.
Assuntos
Neuropatias Diabéticas/sangue , Esfingosina/análogos & derivados , Animais , Peso Corporal/efeitos dos fármacos , Neuropatias Diabéticas/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Eletrofisiologia , Neuropatias Hereditárias Sensoriais e Autônomas/sangue , Neuropatias Hereditárias Sensoriais e Autônomas/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-Dawley , Serina/uso terapêutico , Esfingosina/sangueRESUMO
The effects of dietary supplementation with 0.5% methionine, 2.5% serine, or both on hyperhomocysteinemia induced by deprivation of dietary choline or by dietary addition of 0.5% guanidinoacetic acid (GAA) were investigated in rats fed a 10% casein diet. Hyperhomocysteinemia induced by choline deprivation was not suppressed by methionine alone and was only partially suppressed by serine alone, whereas it was completely suppressed by a combination of methionine and serine, suggesting a synergistic effect of methionine and serine. Fatty liver was also completely prevented by the combination of methionine and serine. Compared with methionine alone, the combination of methionine and serine decreased hepatic S-adenosylhomocysteine and homocysteine concentrations and increased hepatic betaine and serine concentrations and betaine-homocysteine S-methyltransferase activity. GAA-induced hyperhomocysteinemia was partially suppressed by methionine alone, but no interacting effect of methionine and serine was detected. In contrast, GAA-induced fatty liver was completely prevented by the combination of methionine and serine. These results indicate that a combination of methionine and serine is effective in suppressing both hyperhomocysteinemia and fatty liver induced by choline deprivation, and that methionine alone is effective in suppressing GAA-induced hyperhomocysteinemia partially.
Assuntos
Caseínas/metabolismo , Colina/metabolismo , Dieta , Glicina/análogos & derivados , Hiper-Homocisteinemia/tratamento farmacológico , Metionina/farmacologia , Serina/farmacologia , Animais , Dieta/efeitos adversos , Suplementos Nutricionais , Sinergismo Farmacológico , Glicina/efeitos adversos , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/metabolismo , Masculino , Metionina/uso terapêutico , Ratos , Ratos Wistar , Serina/uso terapêuticoRESUMO
Angiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias/tratamento farmacológico , Serina/análogos & derivados , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Serina/farmacologia , Serina/uso terapêutico , Estilbenos/química , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismoRESUMO
Serine deficiency disorders are a new group of neurometabolic diseases resulting from a deficiency in one of the three enzymes in the biosynthetic pathway of L-serine. Deficiency of the enzyme 3-phosphoglycerate dehydrogenase (3-PGDH), which catalyzes the first step in the biosynthetic pathway, leads to congenital microcephaly, severe psychomotor retardation, and intractable seizures. We report a 4 1/2-year-old boy who presented with congenital microcephaly, psychomotor retardation, hypertonia, strabismus, and drug-resistant seizures due to 3-PGDH deficiency. His seizures responded to L-serine and glycine supplementation only. This potentially treatable disease should be borne in mind in patients with congenital microcephaly, psychomotor retardation and seizures. A timely diagnosis based on the detection of low cerebrospinal fluid levels of L-serine and glycine is expected to further increase the success of L-serine and glycine supplementation in these patients.
Assuntos
Deficiências Nutricionais/dietoterapia , Glicina/uso terapêutico , Fosfoglicerato Desidrogenase/deficiência , Convulsões/etiologia , Serina/uso terapêutico , Deficiências Nutricionais/complicações , Deficiências Nutricionais/enzimologia , Suplementos Nutricionais , Seguimentos , Humanos , Lactente , Masculino , Fosfoglicerato Desidrogenase/sangue , Convulsões/dietoterapia , Convulsões/enzimologiaRESUMO
We present the first two identified cases of phosphoserine aminotransferase deficiency. This disorder of serine biosynthesis has been identified in two siblings who showed low concentrations of serine and glycine in plasma and cerebrospinal fluid. Clinically, the index patient presented with intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation and died at age 7 mo despite supplementation with serine (500 mg/kg/d) and glycine (200 mg/kg/d) from age 11 wk. The younger sibling received treatment from birth, which led to a normal outcome at age 3 years. Measurement of phosphoserine aminotransferase activity in cultured fibroblasts in the index patient was inconclusive, but mutational analysis revealed compound heterozygosity for two mutations in the PSAT1 gene--one frameshift mutation (c.delG107) and one missense mutation (c.299A-->C [p.Asp100Ala])--in both siblings. Expression studies of the p.Asp100Ala mutant protein revealed a V(max) of only 15% of that of the wild-type protein.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Serina/biossíntese , Transaminases/deficiência , Transaminases/genética , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/patologia , Pré-Escolar , DNA/genética , Feminino , Mutação da Fase de Leitura , Glicina/deficiência , Glicina/uso terapêutico , Heterozigoto , Humanos , Técnicas In Vitro , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Serina/deficiência , Serina/uso terapêutico , Transaminases/química , Transaminases/metabolismoRESUMO
CONTEXT: Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. OBJECTIVE: To determine whether NMDA-glycine site agonists or glycine transporter-1 inhibitors have better efficacy and whether NMDA receptor-enhancing agents have beneficial effects for acute exacerbation of schizophrenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient units of 2 major medical centers in Taiwan. Patients Sixty-five schizophrenic inpatients with acute exacerbation. INTERVENTIONS: Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy. MAIN OUTCOME MEASURES: Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) (20 and 17 items) total scores. RESULTS: The sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P = .007) and SANS-17 (P = .003) scores and to D-serine in decreasing SANS-20 (P = .006) and SANS-17 (P = .002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS-blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P< or =.02 for all). Sarcosine adjunctive therapy also surpassed D-serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P< or =.04 for all). D-serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains. CONCLUSIONS: This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.
Assuntos
Sarcosina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Serina/uso terapêutico , Doença Aguda , Adulto , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Placebos , Escalas de Graduação Psiquiátrica , Risperidona/uso terapêutico , Sarcosina/farmacologia , Psicologia do Esquizofrênico , Serina/farmacologia , Estereoisomerismo , Resultado do TratamentoRESUMO
Six N-benzoylphenylisoserinates of Lactarius sesquiterpenoid alcohols, which previously showed antiviral activities, were tested for their biological properties. Their influence on the mitotic division of the cells and on selected immunological parameters, e. g., T and B lymphocyte proliferation and synthesis of the cytokines: interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) was assessed in vitro. All of the tested compounds significantly decreased the number of cell divisions. It appears that their influence on cellular divisions may be associated with anti-HSV activity. Moreover, one compound - isolactarorufin 8-epi-[N-benzoyl-(2' R,3' S)-3'-phenylisoserinate] significantly inhibited T lymphocyte proliferation and the synthesis of all tested cytokines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Agaricales , Proliferação de Células/efeitos dos fármacos , Mitose/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Álcoois/administração & dosagem , Álcoois/farmacologia , Álcoois/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Humanos , Leucócitos Mononucleares/citologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Serina/administração & dosagem , Serina/análogos & derivados , Serina/farmacologia , Serina/uso terapêutico , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêuticoRESUMO
Two amide synthetic derivatives of 3,4-di(OH)-hydrocinnamate (HC), 3,4-dihydroxyphenylpropionic (l-serine methyl ester) amide (E030) and 3,4-dihydroxyphenylpropionic (l-aspartic acid) amide (E076), were investigated to compare their lipid-lowering efficacy with HC. Male rats were fed a 1 g/100 g high-cholesterol diet for 6 weeks with supplements of either clofibrate (0.02%, w/w), HC (0.025%, w/w), E030 (0.039%, w/w) or E076 (0.041%, w/w). The clofibrate supplement was used as a positive control for the lipid-lowering efficacy. The food intakes and body weight gains were not significantly different among the groups. The plasma and hepatic cholesterol and triglyceride levels were lower in clofibrate, HC, E030, and E076-supplemented groups compared to the control group. The supplementation of HC and its amide derivatives was as effective as clofibrate in increasing the ratio of HDL-cholesterol to total plasma cholesterol and reducing the atherogenic index (AI). The hepatic cholesterol level in the HC and E076 groups was significantly lower than that in the clofibrate group. The hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA reductase) and acyl-CoA:cholesterol acyltransferase (ACAT) activities were significantly lower in the all test groups than in the control group. The excretion of neutral sterol was significantly higher in the HC, E030, and E076-supplemented groups compared to the control group. The plasma AST and ALT activities, indirect indexes of hepatic toxicity, were significantly lower in the HC, E030, and E076-supplemented groups than in the control group. Accordingly, the current results suggest that E030 and E076, two amide synthetic derivatives of HC, are effective in lowering lipid activity.
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácido Aspártico/análogos & derivados , Ácidos Cafeicos/uso terapêutico , Colesterol na Dieta/administração & dosagem , Hipercolesterolemia/prevenção & controle , Serina/análogos & derivados , Alanina Transaminase/sangue , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Aspartato Aminotransferases/sangue , Ácido Aspártico/síntese química , Ácido Aspártico/farmacologia , Ácido Aspártico/uso terapêutico , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/farmacologia , Colesterol/sangue , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Clofibrato/farmacologia , Clofibrato/uso terapêutico , Fezes/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipercolesterolemia/sangue , Hipercolesterolemia/induzido quimicamente , Lipídeos/biossíntese , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Serina/síntese química , Serina/farmacologia , Serina/uso terapêutico , Esterol O-Aciltransferase/metabolismo , Triglicerídeos/sangueRESUMO
Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.
Assuntos
Desidrogenases de Carboidrato/deficiência , Microcefalia/genética , Convulsões/genética , Serina/uso terapêutico , Criança , Pré-Escolar , Feminino , Glicina/sangue , Glicina/líquido cefalorraquidiano , Humanos , Lactente , Masculino , Fosfoglicerato Desidrogenase , Transtornos Psicomotores/genética , Convulsões/tratamento farmacológico , Serina/sangue , Serina/líquido cefalorraquidiano , Resultado do TratamentoAssuntos
Aminoácidos/uso terapêutico , Antineoplásicos , Leucemia Experimental/tratamento farmacológico , Paládio/uso terapêutico , Platina/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Glutamina/uso terapêutico , Glicina/uso terapêutico , Camundongos , Serina/uso terapêuticoAssuntos
Plaquetas/metabolismo , Esquizofrenia/tratamento farmacológico , Serina/análogos & derivados , Animais , Plaquetas/efeitos dos fármacos , Catecóis/farmacologia , Catecóis/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Lítio/farmacologia , Coelhos , Esquizofrenia/metabolismo , Serina/farmacologia , Serina/uso terapêutico , Serotonina/sangue , Fatores de Tempo , TrítioRESUMO
Salmonellosis pacifarin activity is detected by an increased survivorship of mice, doubly infected with avirulent and virulent Salmonella typhimurium, when heretofore unknown agents, found in certain natural foodstuffs and in the supernatants of certain bacterial cultures, are fed to the infected animals as dietary supplements. We now announce the identity of one of these agents: it is enterobactin, a cyclic trimer of 2,3-dihydroxy-N-benzoyl-L-serine. Basal diets enriched with as little as 2 mg of crystalline trimer per kg of diet show pacifarin activity to a statistically significant degree. Diets supplemented with as much as 100 mg of the monomer per kg of diet show no such activity.