Leucine-Enriched Essential Amino Acids Enhance the Antiseizure Effects of the Ketogenic Diet in Rats.

The classic ketogenic diet (KD) can be used successfully to treat medically refractory epilepsy. However, the KD reduces seizures in 50-70% of patients with medically refractory epilepsy, and its antiseizure effect is limited. In the current study, we developed a new modified KD containing leucine (Leu)-enriched essential amino acids. Compared with a normal KD, the Leu-enriched essential amino acid-supplemented KD did not change the levels of ketosis and glucose but enhanced the inhibition of bicuculline-induced seizure-like bursting in extracellular recordings of acute hippocampal slices from rats. The enhancement of antiseizure effects induced by the addition of Leu-enriched essential amino acids to the KD was almost completely suppressed by a selective antagonist of adenosine A1 receptors or a selective dose of pannexin channel blocker. The addition of Leu-enriched essential amino acids to a normal diet did not induce any antiseizure effects. These findings indicate that the enhancement of the antiseizure effects of the KD is mediated by the pannexin channel-adenosine A1 receptor pathway. We also analyzed amino acid profiles in the plasma and hippocampus. A normal KD altered the levels of many amino acids in both the plasma and hippocampus. The addition of Leu-enriched essential amino acids to a KD further increased and decreased the levels of several amino acids, such as threonine, histidine, and serine, suggesting that altered metabolism and utilization of amino acids may play a role in its antiseizure effects. A KD supplemented with Leu-enriched essential amino acids may be a new therapeutic option for patients with epilepsy, including medically refractory epilepsy.

Use of plasma-free amino acids as biomarkers for detecting and predicting disease risk.

This paper reviews developments regarding the use of plasma-free amino acid (PFAA) profiles as biomarkers for detecting and predicting disease risk. This work was initiated and first published in 2006 and was subsequently developed by Ajinomoto Co., Inc. After commercialization in 2011, PFAA-based tests were adopted in over 1500 clinics and hospitals in Japan, and numerous clinician-led studies have been performed to validate these tests. Evidence is accumulating that PFAA profiles can be used for diabetes prediction and evaluation of frailty; in particular, decreased plasma essential amino acids could contribute to the pathophysiology of severe frailty. Integration of PFAA evaluation as a biomarker and effective essential amino acid supplementation, which improves physical and mental functions in the elderly, could facilitate the development of precision nutrition, including personalized solutions. This present review provides the background for the technology as well as more recent clinical findings, and offers future possibilities regarding the implementation of precision nutrition.

Intake of Seven Essential Amino Acids Improves Cognitive Function and Psychological and Social Function in Middle-Aged and Older Adults: A Double-Blind, Randomized, Placebo-Controlled Trial.

Background: To delay the onset of dementia, it is important for healthy adults to take preventive actions before the cognitive function clearly declines. Protein malnutrition is a potential risk factor for senile dementia, although the precise link between protein/amino acid nutrition and cognitive function is unknown. The purpose of this study was to examine the effect of the ingestion of seven selected essential amino acids as a granular powder, namely, leucine, phenylalanine, and lysine supplemented with isoleucine, histidine, valine, and tryptophan on cognitive and psychosocial functions in healthy adults. Methods: A double-blind, randomized, placebo-controlled trial was conducted. A total of 105 participants aged 55 years or older were randomly assigned to one of three groups: daily ingestion of 3 g (3gIG) or 6 g (6gIG) of the selected amino acids or daily ingestion of a placebo (PCG). Each group ingested the test powder for 12 weeks. As the main outcome, cognitive function was assessed before and after ingestion by a cognitive test battery. Psychosocial functions were also examined. Results: The numbers of participants excluding dropouts were 35 in PCG and 3gIG and 33 in 6gIG. Analysis of covariance revealed that the 6gIG showed significantly improved cognitive function (Trail Making Test B), social interaction and psychological health scores after ingestion compared to the PCG (multiplicity adjusted p < 0.05). Conclusions: Current findings suggested that ingestion of the seven essential amino acids led to improved attention and cognitive flexibility and psychosocial functioning, which is expected to prevent cognitive decline. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037779, Identifier: UMIN000033174).

Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice.

Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)-induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age-related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age-dependent decrease in slow-twitch muscle fiber function but reduced absolute fast-twitch muscle fiber function. DR-induced fast-twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum-fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2 S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet-restricted aged mice, which were accompanied by a recovery in H2 S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans-sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.

Glutamate Promotes Contraction of the Rat Ductus Arteriosus.

BACKGROUND: Extremely preterm infants frequently have patent ductus arteriosus (PDA). Recent recommendations include immediately beginning amino acid supplementation in extremely preterm infants. However, the effect of amino acids on closure of the ductus arteriosus (DA) remains unknown.Methods and Results:Aminogram results in human neonates at day 2 revealed that the plasma glutamate concentration was significantly lower in extremely preterm infants (<28 weeks' gestation) with PDA than in those without PDA and relatively mature preterm infants (28-29 weeks gestation). To investigate the effect of glutamate on DA closure, glutamate receptor expression in fetal rats was examined and it was found that the glutamate inotropic receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type subunit 1 (GluR1), mRNA was highly expressed in the DA compared to the aorta on gestational day 19 (preterm) and gestational day 21 (term). GluR1 proteins were co-localized with tyrosine hydroxylase-positive autonomic nerve terminals in the rat and human DA. Intraperitoneal administration of glutamate increased noradrenaline production in the rat DA. A whole-body freezing method demonstrated that glutamate administration induced DA contraction in both preterm (gestational day 20) and term rat fetuses. Glutamate-induced DA contraction was attenuated by the calcium-sensitive GluR receptor antagonist, NASPM, or the adrenergic receptor α1 blocker, prazosin. CONCLUSIONS: These data suggest that glutamate induces DA contraction through GluR-mediated noradrenaline production. Supplementation of glutamate might help to prevent PDA in extremely preterm infants. (Circ J 2016; 80: 2388-2396).

The seasonal fluctuation of plasma amino acids in aquarium-maintained bottlenose dolphins (Tursiops truncatus).

Although there has been extensive research on plasma amino acid profiles of mammals, there is currently a lack of information on seasonal differences in the concentrations of plasma amino acids specifically in cetaceans. The present study examined the response of the plasma amino acids to seasonal changes in the culture environment after controlling for the effect of sex and age. Significant seasonal changes in plasma carnosine (P=0.012), cystine (P=0.0014), isoleucine (P=0.0042), methionine (P=0.002), ornithine (P=0.0096), and taurine (P=0.032) were observed. These amino acids were mainly related to capacity for exercise, ammonia detoxification, thermoregulation, and osmoregulation. We proposed that optimizing plasma amino acids levels by supplementation of amino acids should be of considerable benefit for aquarium-maintained bottlenose dolphins. This study constitutes a first step towards improving our understanding of the metabolism of aquarium-maintained bottlenose dolphins. We also revealed that the ratio of tryptophan to large neutral amino acids significantly declined (P=0.0076), suggesting reduction in serotonin synthesis in winter and autumn. Although further studies are needed, this finding implied that bottlenose dolphins could produce behavioral changes seasonally by the alteration of serotonin activity. To better understand the metabolic machinery for amino acids that facilitate the adaptation of marine mammals to their environments, it is essential to continue monitoring of and further investigations into relationships between plasma amino acids and specific environmental factors.

Somatostatin is involved in anorexia in mice fed a valine-deficient diet.

The ingestion of a valine (Val)-deficient diet results in a significant reduction of food intake and body weight within 24 h, and this phenomenon continues throughout the period over which such a diet is supplied. Both microarray and real-time PCR analyses revealed that the expression of somatostatin mRNA was increased in the hypothalamus in anorectic mice that received a Val-deficient diet. On the other hand, when somatostatin was administered intracerebroventricularly to intact animals that were fed a control diet, their 24-h food intake decreased significantly. In addition, Val-deficient but not pair-fed mice or those fasted for 24 h showed a less than 0.5-fold decrease in the hypothalamic mRNA expression levels of Crym, Foxg1, Itpka and two unknown EST clone genes and a more than twofold increase in those of Slc6a3, Bdh1, Ptgr2 and one unknown EST clone gene. These results suggest that hypothalamic somatostatin and genes responsive to Val deficiency may be involved in the central mechanism of anorexia induced by a Val-deficient diet.

Alleviation of body weight loss by dietary methionine is independent of insulin-like growth factor-I in protein-starved young chickens.

It is well known that in protein-starved chickens, small amounts of amino acid supplement, especially methionine, reduces nitrogen excretion and thereby improves nitrogen balance. On the other hand, excess intake of methionine causes growth depression and the growth-depressive effect of excess methionine can be alleviated by consumption of dietary glycine. Insulin-like growth factor-I (IGF-I) is one of various growth-promoting factors relating to the efficiency of animal production and is known to be very sensitive to changes in nutritional status. In the present study, the interactive effect of glycine on nitrogen sparing effect of methionine in protein-starved chickens was examined. In addition, the relation of IGF-I and its specific binding protein to the nitrogen sparing effect of supplemented methionine was also investigated. Two-days refeeding of methionine supplemented to protein-free diet could promptly alleviate body weight loss in protein-starved chickens, and the alleviation of body weight loss by methionine was not improved by glycine supplements. Moreover, such acute alleviation of body weight loss by dietary methionine was independent of the change in plasma IGF-I concentration.

Weekly low-dose paclitaxel and carboplatin therapy in gynecological cancer patients with venous thrombosis.

BACKGROUND: To evaluate the safety and toxicity of weekly low-dose paclitaxel plus carboplatin therapy in gynecological cancer patients with venous thrombosis (VT). MATERIALS AND METHODS: Ovarian or endometrial cancer patients with VT who were scheduled to receive neoadjuvant or adjuvant chemotherapy were eligible. Each 21-day cycle of treatment consisted of carboplatin (AUC 2.0) and paclitaxel (80 mg/m2) on days 1, 8 and 15. At the end of chemotherapy, each patient's VT was checked by ultrasonography. RESULTS: Twenty-five gynecological cancer patients who received warfarin therapy with a target international normalized ratio (INR) of 1.5-2.5 were enrolled in this study. Neutropenia and peripheral neuropathy (grades 3 or 4) occurred in 26% and 4% of the patients, respectively. Chemotherapy did not cause any changes of the INR in any patient. After chemotherapy, the VT showed resolution in 19 patients (76%) and no patient developed fresh thrombosis. CONCLUSION: Weekly low-dose paclitaxel plus carboplatin therapy is a reasonable treatment option for gynecological cancer patients with VT.