Elucidating the Mechanisms of Sodium Benzoate in Alzheimer Disease: Insights from Quantitative Proteomics Analysis of Serum Samples.

BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are crucial components of brain function involved in memory and neurotransmission. Sodium benzoate is a promising NMDAR enhancer and has been proven to be a novel, safe, and efficient therapy for patients with Alzheimer disease (AD). However, in addition to the role of sodium benzoate as an NMDA enhancer, other mechanisms of sodium benzoate in treating AD are still unclear. To elucidate the potential mechanisms of sodium benzoate in Alzheimer disease, this study employed label-free quantitative proteomics to analyze serum samples from AD cohorts with and without sodium benzoate treatment. METHODS: The serum proteins from each patient were separated into 24 fractions using an immobilized pH gradient, digested with trypsin, and then subjected to nanoLC‒MS/MS to analyze the proteome of all patients. The nanoLC‒MS/MS data were obtained with a label-free quantitative proteomic approach. Proteins with fold changes were analyzed with STRING and Cytoscape to find key protein networks/processes and hub proteins. RESULTS: Our analysis identified 861 and 927 protein groups in the benzoate treatment cohort and the placebo cohort, respectively. The results demonstrated that sodium benzoate had the most significant effect on the complement and coagulation cascade pathways, amyloidosis disease, immune responses, and lipid metabolic processes. Moreover, Transthyretin, Fibrinogen alpha chain, Haptoglobin, Apolipoprotein B-100, Fibrinogen beta chain, Apolipoprotein E, and Alpha-1-acid glycoprotein 1 were identified as hub proteins in the protein‒protein interaction networks. CONCLUSIONS: These findings suggest that sodium benzoate may exert its influence on important pathways associated with AD, thus contributing to the improvement in the pathogenesis of the disease.

Treatment and management for children with urea cycle disorder in chronic stage. / å°¿ç´ å¾ªçŽ¯éšœç¢æ‚£å„¿æ ¢æ€§æœŸæ²»ç–—å’Œç®¡ç†.

Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (N-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.

Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose-finding, randomized, double-blind, placebo-controlled trial for Alzheimer's disease.

AIM: Previous pilot studies suggest that sodium benzoate may be a potential cognitive enhancer for patients with Alzheimer's disease (AD), schizophrenia, or late-life depression. Especially for AD treatment, a confirmatory trial with predictive biomarkers is urgently needed. This study aimed to confirm benzoate as a novel treatment for AD and to discover its optimal dose and biomarkers. METHODS: A 24-week, dose-finding, randomized, double-blind, placebo-controlled trial, with clinical measurements at weeks 0, 8, 16, and 24, was conducted in three major medical centers in Taiwan. Among 154 patients screened for AD, 149 were eligible and randomized to one of the four treatments: (i) benzoate 500 group (fixed 500 mg/day); (ii) benzoate 750 (500 mg/day for the first 4 weeks, 750 mg/day from the 5th week); (iii) benzoate 1000 (500 mg/day for the first 4 weeks, 1000 mg/day from the 5th week); and (iv) placebo. The primary outcome measure was AD assessment scale-cognitive subscale (ADAS-cog). RESULTS: The benzoate 1000 group performed best in improving ADAS-cog (P = 0.026 at week 24), with female advantage. Higher plasma catalase at baseline predicted better outcome. Benzoate receivers tended to have higher catalase and glutathione than placebo recipients after treatment. The four intervention groups showed similar safety profiles. CONCLUSIONS: By enhancing two vital endogenous antioxidants, catalase and glutathione, sodium benzoate therapy improved cognition of patients with AD, with higher baseline catalase predicting better response. Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.

Survival and Neurologic Recovery After Prompt Diagnosis and Aggressive Management of Severe Idiopathic Hyperammonemic Encephalopathy in a Patient with Acute Myeloid Leukemia.

A case of a 19-year-old female with low-risk acute myeloid leukemia is presented who was diagnosed with idiopathic hyperammonemic encephalopathy following the development of abrupt neurologic decline, respiratory alkalosis, and elevated plasma ammonia levels of unknown etiology. Delayed symptom recognition of this exceedingly rare condition contributes to the often fatal outcomes of idiopathic hyperammonemic encephalopathy. As illustrated by this case, prompt diagnosis and utilization of a variety of ammonia-modulating treatment modalities can result in remarkable clinical recovery. This case provides guidance to clinicians in counseling families about the possibility of neurologic recovery in similar clinical scenarios.

Emerging trends in management of propionic acidemia / Tendências emergentes no manejo da academia propiônica

Objetivo : To evaluate the therapeutic agents used during metabolic crises and in long-term management of patients with propionic acidemia (PA).Materials and methods : The records of PA patients were retrospectively evaluated.Results : The study group consisted of 30 patients with 141 admissions. During metabolic crises, hyperammonemia was found in 130 (92%) admissions and almost all patients were managed with normal saline, ≥ 10% dextrose, and restriction of protein intake. In 56 (40%) admissions, management was done in intensive care unit, 31 (22%) with mechanical ventilation, 10 (7%) with haemodialysis, 16 (11%) with vasopressor agents, and 12 (9%) with insulin. In the rescue procedure, L-carnitine was used in 135 (96%) patients, sodium bicarbonate in 116 (82%), sodium benzoate in 76 (54%), and metronidazole in 10 (7%), biotin in about one-quarter, L-arginine in one third, and antibiotics in three-quarter of the admissions. Blood/packed RBCs were used in 28 (20%) patients, platelets in 26 (18%), fresh frozen plasma in 8 (6%), and granulocyte-colony stimulating factors in 10 (7%) admissions. All patients were managed completely/partially with medical nutrition formula plus amino acid mixture, vitamins and minerals. For long-term management 24 (80%) patients were on L-carnitine, 22 (73%) on sodium benzoate, 6 (20%) on biotin, one half on alkaline therapy and 4 (13%) on regular metronidazole use. Almost all patients were on medical formula and regular follow-up.Conclusion : Aggressive and adequate management of acute metabolic crises with restriction of protein intake, stabilization of patient, reversal of catabolism, and removal of toxic metabolites are essential steps. Concerted efforts to ensure adequate nutrition, to minimize the risk of acute decompensation and additional therapeutic advances are imperative to improve the outcome of PA patients. Arq Bras Endocrinol Metab. 2014;58(3):237-42.

Objetivo : Avaliar os agentes terapêuticos usados durante as crises metabólicas e para o manejo de longo prazo de pacientes com academia propiônica (AP).Materiais e métodos : Avaliação retrospectiva das fichas médicas de pacientes com AP.Resultados : O grupo estudado consistiu de 30 pacientes com 141 hospitalizações. Durante as crises metabólicas, a hiperamonemia foi observada em 130 (92%) pacientes hospitalizados e quase todos foram tratados com solução salina regular, ≥ 10% dextrose e restrição da ingestão de proteína. Em 56 (40%) das hospitalizações, o manejo foi feito na unidade de terapia intensiva, 31(22%) com ventilação mecânica, 10 (7%) com hemodiálise, 16 (11%) com vasopressores e 12 (9%) com insulina. Para o resgate, a L-carnitina foi usada em 135 (96%) pacientes, o bicarbonato de sódio em 116 (82%), o benzoato de sódio em 76 (54%), o metronidazole em 10 (7%), a biotina em cerca de um quarto, a L-arginina em um quarto e antibióticos em três quartos dos pacientes hospitalizados. Sangue/concentrado de hemácias foram usados em 28 (20%), plaquetas em 26 (18%), plasma fresco congelado em 8 (6%) e fatores estimulantes de colônias de granulócitos em 10 (7%) pacientes hospitalizados. Todos os pacientes foram manejados completamente/parcialmente com fórmula de nutrição hospitalar mais uma mistura de aminoácidos, vitaminas e minerais. Para o manejo de longo prazo, 24 (80%) dos pacientes foram tratados com L-carnitina, 22 (73%) com benzoato de sódio, 6 (20%) com biotina, a metade com tratamento alcalino e 4 (13%) com uso regular de metronidazole. Quase todos os pacientes foram tratados com fórmulas médicas e acompanhamento regular.Conclusão : O manejo adequado e agressivo de crises metabólicas com restrição da ingestão de proteína, ...

Hiperamonemia en niños: clasificación y opciones terapéuticas / Hyperammonaemia in children: classification and therapeutic options

La hiperamonemia se presenta en forma secundaria por aumento en la producción de amonio, como en la hemorragia gastrointestinal o disminución de la eliminación, como ocurre en errores innatos del metabolismo, principalmente en aquellos con defectos en el ciclo de la urea, insuficiencia hepática o fármacos. Clasificar la hiperamonemia y reportar las opciones terapéuticas en niños, su abordaje clínico y revisión de la literatura. Estudio prospectivo, descriptivo y transversal de niños con hiperamonemia. Variables: edad, género, etiología, niveles de amonio, clínica, tratamiento. 21 pacientes, 12 (57,12%) varones y 9 (42,88%) hembras. Edad promedio 3,91 años (rango:<1mes-14 años). Amonio promedio general 214,66 mmol/l (rango:110-980), clasificados según severidad: sin insuficiencia hepática 11/21 con promedio de amonio 99,44 y 201 mmol/l en hiperamonemia leve y moderada respectivamente. Clínica y laboratorio de insuficiencia hepática en 10/21 con promedio de amonio de 114,44, 287,51 y 756,66 en leve, moderada y severa hiperamonemia, con una diferencia significativa entre el nivel de amonio y la presencia o ausencia de insuficiencia hepática (p<0,0001); 5/10 con insuficiencia hepática ingresaron a terapia intensiva, 4 de ellos presentaron encefalopatía hepática, un paciente fallecido. Etiología: Error innato del metabolismo 33,33%, toxicidad por medicamentos 23,80%, hepatitis viral A fulminante 19,04% y otros virus 9,52%, hepatitis autoinmune 4,76% y urosepsis 4,76%. En los casos leves-moderados se administró lactulosa dosis respuesta vía oral 19/21 y por enema rectal 7/21 con L-carnitina en 15/21 y en Hiperamonemia severa adicionalmente Benzoato de sodio en 4/21 y hubo indicación de hemodiálisis en 3 pacientes. Restricción proteica en todos, vitaminoterapia y 6 niños tratados con ácido ursodeoxicólico. La hiperamonemia es multifactorial, requiere diagnóstico temprano, la clasificación de severidad permite el tratamiento oportuno para evitar complicaciones....

Hyperammonaemia occurs secondarily by increased production of ammonia, as gastrointestinal bleeding or decreased elimination, as occurs in inborn errors of metabolism, especially in those with defects in the urea cycle, liver failure or drugs. To classify the report hyperammonaemia and therapeutic options in children, its clinical approach and review of the literature. Prospective, descriptive and transversal children with hyperammonaemia. Variables: age, gender, etiology, ammonia levels, clinical treatment. 21 patients, 12 (57,12%) males and 9 (42,88%) females. Mean age 3,91 years (range: <1m-14a). ammonium 214,66 mmol / l (range :110-980), classified according to severity: no hepatic impairment 11/21 with 99,44 average ammonium and 201 mmol / l in Hyperammoanemia mild and moderate respectively. Clinical and laboratory liver failure 10/21 with ammonium averaging 114,44, 287,51 and 756,66 as mild, moderate and severe hyperammonemia, with a significant difference between the level of ammonia and the presence or absence of liver failure (p < 0,0001), 5/10 with liver failure admitted to intensive care, 4 of them had hepatic encephalopathy, a patient died. Etiology: An inborn error of metabolism 33,33%, 23,80% drug toxicity, fulminant viral hepatitis and other viruses 19,04% 9,52% 4,76% autoimmune hepatitis and urosepsis 4,76%. In mild-moderate cases were given oral lactulose Dose 19/21 and by enema rectal 7/21 with L-carnitine in 15/21 and further severe Hyperammonemia sodium benzoate 4/21 and was indication of hemodialysis in 3 patients. Protein restriction at all, vitamin therapy and 6 children treated with ácidoursodeoxicólico. Hyperammonemia is multifactorial, requires early diagnosis, classification of severity allows early treatment to avoid complications and development of irreversible neurological sequelae

Arginase deficiency with new phenotype and a novel mutation: contemporary summary.

In areas without expanded newborn screening, instead of presenting neonatally, patients with arginase deficiency typically present with spastic paraplegia in early childhood. Diagnosis of this rare neurometabolic disease poses the first challenge because it is often misdiagnosed as cerebral palsy during initial stages. We describe arginase deficiency in a 20-year-old woman with spastic paraplegia, progressive dystonia, dementia, peripheral neuropathy, epilepsy, liver cirrhosis, and non-B/non-C hepatocellular carcinoma. A novel homozygous mutation NM_000045.2 (ARG1):c.673del (p.Arg225GlyfsX5) was detected. We suggest that all children presenting with progressive neurodegeneration or spastic paraplegia in the absence of risk factors for cerebral palsy should be screened for inborn errors of metabolism, including arginase deficiency. For monitoring urea cycle defects, noninvasive imaging screening for liver fibrosis and hepatocellular carcinoma can help ensure early detection, with potential treatment implications.

Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn's disease.

BACKGROUND: Certain urinary metabolites are the product of gut microbial or mammalian metabolism; others, such as hippurate, are mammalian-microbial 'co-metabolites'. It has previously been observed that Crohn's disease (CD) patients excrete significantly less hippurate than controls. There are two stages in the biosynthesis of this metabolite: 1) gut microbial metabolism of dietary aromatic compounds to benzoate, and 2) subsequent hepatorenal conjugation of benzoate with glycine, forming hippurate. Differences in such urinary co-metabolites may therefore reflect systemic consequences of altered gut microbial metabolism, though altered host metabolic pathways may also be involved. METHODS: It was hypothesised that reduced hippurate excretion in CD patients was due to alterations in the gut microbiota, and not differences in dietary benzoate, nor defective host enzymatic conjugation of benzoate. 5 mg/kg sodium benzoate were administered orally to 16 CD patients and 16 healthy controls on a low-benzoate diet. Baseline and peak urinary hippurate excretion were measured. RESULTS: Baseline hippurate levels were significantly lower in the CD patients (p = 0.0009). After benzoate ingestion, peak urinary levels of hippurate did not differ significantly between the cohorts. Consequently the relative increase in excretion was significantly greater in CD (p = 0.0007). CONCLUSIONS: Lower urinary hippurate levels in CD are not due to differences in dietary benzoate. A defect in the enzymatic conjugation of benzoate in CD has been excluded, strongly implicating altered gut microbial metabolism as the cause of decreased hippurate levels in CD.

Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children.

4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate.

Ornithine transcarbamylase deficiency: a urea cycle defect.

The symptoms and signs of ornithine transcarbamylase deficiency are discussed. When the condition occurs among males in the neonatal period it is likely to be lethal. Pathological findings are non-specific. The diagnosis should be considered if coma with cerebral oedema and respiratory alkalosis occurs for no obvious reason. When hyperammonaemia is found, enzyme assay on a liver biopsy should be considered. A useful clue in an asymptomatic patient is a voluntary adoption of a vegetarian diet. Provocative tests, such as the allopurinol test can be used, but the method most frequently applied is mutation analysis. In the case of prenatal diagnosis this is possible on a chorionic villus sample. The prognosis of ornithine transcarbamylase deficiency is better for those with an onset after infancy, but morbidity from brain damage does not appear to be linked to the number of episodes of hyperammonaemia that have occurred. The syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase which catalyses the conversion of ornithine and carbamoyl phosphate to citrulline. The gene responsible for this enzyme is located on Xp21.1, and is expressed in the liver and gut. Mutations can be divided into two groups: those with neonatal onset with all enzyme activity abolished, and those with later onset with partial and varying enzyme deficiency. There can be a variety of precipitating causes, for example sodium valproate. Treatment can be given with a low protein diet, and with alternate pathway drugs such as sodium benzoate and phenylbutyrate. Liver transplant can be considered when symptoms are life-threatening, although there may be severe complications.Gene replacement therapy is the hope of the future.

Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations.

OBJECTIVE: To describe three female patients of one family with different phenotypes of the same mutation of the ornithine transcarbamylase gene. X-linked inherited ornithine transcarbamylase deficiency is the most frequent urea cycle disorder. Many of the hemizygous males die during the neonatal period. Women, who are mostly healthy carriers, can also develop symptomatic hyperammonemia. DESIGN: Case study. SETTING: Intensive care unit and internal medicine unit at a university hospital. PATIENTS: The 20-yr-old female propositus was hospitalized for unexplained coma. She had a history of headaches, recurrent vomiting, specific anorexia for high-protein foods, and an acute neurologic crisis with alleged food poisoning 8 yrs before. The present episode began with psychiatric symptoms and seizures treated by diazepam and valproate. This unexplained coma, associated with respiratory alkalosis and major brain swelling on brain computed tomography scan, revealed hyperammonemia leading to the diagnosis of ornithine transcarbamylase deficiency. Continuous venovenous hemodiafiltration and treatment with sodium benzoate and phenylbutyrate improved the situation. However, the patient had some neurologic sequelae. DNA studies have disclosed a pathogenic mutation in the ornithine transcarbamylase gene of the patient, her mother, and her sister. For the mother, the disease was overlooked despite the onset of unusual headaches and neurologic signs that mimicked a cerebral tumor 12 yrs before. The 28-yr-old sister of the propositus has always been asymptomatic, even during pregnancy. CONCLUSIONS: Diagnosis of urea cycle disorder should be considered in any patient with unexplained neurologic and psychiatric disorders with selective anorexia, even in adulthood. Unexplained coma with cerebral edema and respiratory alkalosis requires urgent measurement of ammonemia and metabolic work-up.