Cognition and nutrition: the role of dietary protein and amino acids in cognitive health.

PURPOSE OF REVIEW: This review underscores recent advancements in the role of protein and amino acid nutrition on cognitive health. Given the escalating prevalence of neurodegenerative disorders, particularly Alzheimer's disease, it is essential to understand nonpharmaceutical interventions that could potentially counteract their development and progression. RECENT FINDINGS: Emerging research indicates that moderate protein intake may offer protective benefits against dementia. Studies also emphasize the importance of considering not just the quantity, but also the quality and source of dietary protein. The role of essential amino acids in nutrition is gaining attention in the field of cognitive health. Moreover, plasma-free amino acid concentrations, particularly branched-chain amino acids, are being explored as potential biomarkers for cognitive health and Alzheimer's disease. Mechanistic studies suggest that proteins and amino acids help maintain neuronal integrity, reduce inflammation, and support muscle retention, all essential factors for cognitive health. SUMMARY: Recent findings emphasize the complex relationship between protein, amino acids, and cognitive health, highlighting the potential of dietary interventions in warding off neurodegenerative diseases. Given the observational nature of these findings, further interventional and longitudinal studies are needed to ascertain causality and elucidate the mechanisms involved.

Modes of delivery and indications in women with COVID-19: a regional observational study in Japan.

BACKGROUND: During the coronavirus disease (COVID-19) pandemic, caesarean section (CS) has been the preferred deliver method for pregnant women with COVID-19 in order to limit the use of hospital beds and prevent morbidity among healthcare workers. METHODS: To evaluate delivery methods used during the COVID-19 pandemic as well as the rates of adverse events and healthcare worker morbidity associated with caesarean deliveries. METHODS: We investigated maternal and neonatal backgrounds, delivery methods, indications and complication rates among pregnant women with COVID-19 from December 2020 to August 2022 in Mie Prefecture, Japan. The predominant mutation period was classified as the pre-Delta, Delta and Omicron epoch. RESULTS: Of the 1291 pregnant women with COVID-19, 59 delivered; 23 had a vaginal delivery and 36 underwent CS. Thirteen underwent CS with no medical indications other than mild COVID-19, all during the Omicron epoch. Neonatal complications occurred significantly more often in CS than in vaginal delivery. COVID-19 in healthcare workers was not attributable to the delivery process. CONCLUSION: The number of CS with no medical indications and neonatal complications related to CS increased during the COVID-19 pandemic. Although this study included centres that performed vaginal deliveries during COVID-19, there were no cases of COVID-19 in healthcare workers. It is possible that the number of CS and neonatal complications could have been reduced by establishing a system for vaginal delivery in pregnant women with recent-onset COVID-19, given that there were no cases of COVID-19 among the healthcare workers included in the study.

We evaluated the incidence of adverse events associated with caesarean section (CS) deliveries and the morbidity of health care workers, which increased during the coronavirus infection pandemic. Maternal and neonatal background, delivery methods, indications and complication rates of pregnant women with COVID-19 from December 2020 to August 2022 in Mie Prefecture were investigated by time of onset. Of the 1291 pregnant women with COVID-19, 59 delivered while affected; 23 underwent vaginal delivery and 36 CS. Of these, 13 who underwent CS in the omicron epoch had no medical indication other than mild COVID-19. Neonatal complications were significantly more common with CS than with vaginal delivery, and there was no occurrence of COVID-19 in healthcare workers. In this study, there were no cases of COVID-19 among health care workers; establishing a system to perform vaginal delivery for pregnant women with COVID-19 could have reduced the number of CS and neonatal complications.

Paclitaxel-carboplatin plus bevacizumab therapy for advanced neuroendocrine carcinoma of the uterine cervix: A retrospective case series.

AIM: There is no conclusive data on the prognosis of patients who receive paclitaxel-carboplatin (TC) plus bevacizumab therapy for advanced neuroendocrine carcinoma (NEC) of the uterine cervix, a rare histological subtype of cervical cancer. Thus, the aim of this study was to determine the efficacy of TC chemotherapy plus bevacizumab and bevacizumab single maintenance therapy for advanced NEC of the cervix. METHODS: This was a retrospective review of patients who received TC plus bevacizumab therapy for metastatic, recurrent, or persistent NEC of the cervix at seven institutions between 2015 and 2020. Relevant data were extracted from the patients' medical records and analyzed. RESULTS: Seven patients, including six with small-cell NEC and one with large-cell NEC, were included for analysis. Three patients received bevacizumab single maintenance therapy following TC plus bevacizumab therapy, whereas four patients did not receive bevacizumab single maintenance therapy. The median overall survival and progression-free survival of the patients who received bevacizumab single maintenance therapy were longer than those of the patients who did not receive the therapy (34 months vs. 10.5 months and 19 months vs. 5 months, respectively). However, the patients who received bevacizumab single maintenance therapy had received cisplatin-based chemotherapy previously. CONCLUSIONS: On the premise that cisplatin-based chemotherapy is administered as the first-line treatment for advanced NEC of the cervix, bevacizumab single maintenance therapy following TC plus bevacizumab may be considered the second- or third-line treatment. However, the risk of adverse events, such as intestinal perforation, should be discussed with patients.

Blockade of the interaction between BMP9 and endoglin on erythroid progenitors promotes erythropoiesis in mice.

Bone morphogenetic protein-9 (BMP9), a member of the transforming growth factor ß (TGFß) superfamily, plays important roles in the development and maintenance of various cell lineages via complexes of type I and type II TGFß receptors. Endoglin is a coreceptor for several TGFß family members, including BMP9, which is highly expressed in a particular stage of differentiation in erythroid cells as well as in endothelial cells. Although the importance of the interaction between BMP9 and endoglin for endothelial development has been reported, the contribution of BMP9 to endoglin-expressing erythroid cells remains to be clarified. To address this point, we prepared an anti-BMP9 antibody that blocks the BMP9-endoglin interaction. Of note, challenge with the antibody promotes erythropoiesis in wild-type mice but not in a mouse model of renal anemia in which erythropoietin (EPO) production in the kidneys is genetically ablated. While endoglin-positive erythroid progenitors are mainly maintained as progenitors when bone marrow-derived lineage-negative and cKit-positive cells are cultured in the presence of EPO and stem cell factor, the erythroid-biased accumulation of progenitors is impeded by the presence of BMP9. Our findings uncover an unrecognized role for BMP9 in attenuating erythroid differentiation via its interaction with endoglin on erythroid progenitors.

l-Serine and EPA Relieve Chronic Low-Back and Knee Pain in Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Multisite pain, including low-back and knee pain, is a major health issue that greatly decreases quality of life. OBJECTIVES: This study analyzed the effects of l-serine, which provides necessary components for nerve function, and EPA, which exerts anti-inflammatory properties, on pain scores of adults with pain in at least the low back and knee for ≥3 mo. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study. The Japan Low Back Pain Evaluation Questionnaire (JLEQ) and Japanese Knee Osteoarthritis Measure (JKOM) were applied as primary outcomes. The Brief Pain Inventory (BPI) and safety evaluation were secondary outcomes. We enrolled 120 participants aged ≥20 y (36 men and 84 women: mean ± SD age = 40.8 ± 10.9 y). The participants were randomly allocated to either the active group (daily ingestion of 594 mg l-serine and 149 mg EPA) or placebo group. The study period consisted of 8-wk dosing and 4-wk posttreatment observation. ANCOVA between groups for each time point was conducted using the baseline scores as covariates. RESULTS: The JLEQ scores (active compared with placebo: 14.2 ± 11.2 compared with 19.0 ± 10.2) at week 8 were lower in the active group (P < 0.001). The JKOM scores at week 4 (11.7 ± 9.0 compared with 13.9 ± 7.9), week 8 (10.4 ± 7.9 compared with 13.1 ± 7.1), and week 12 (10.3 ± 7.4 compared with 13.8 ± 7.5) were lower in the active group (P ≤ 0.04). Additionally, the active group had 11-27% better scores compared with the placebo group for BPI1 (worst pain), BPI3 (average pain), and BPI5D (pain during moving) at week 4 (P ≤ 0.028) and week 8 (P ≤ 0.019), respectively, and BPI5D was 23% better in the active group at week 12 (P = 0.007). No adverse events were observed. CONCLUSIONS: l-Serine and EPA were effective for pain relief in adults with low-back and knee pain after multiplicity adjustment.This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000035056.

A ketogenic amino acid rich diet benefits mitochondrial homeostasis by altering the AKT/4EBP1 and autophagy signaling pathways in the gastrocnemius and soleus.

Muscle biology is important topic in diabetes research. We have reported that a diet with ketogenic amino acids rich replacement (KAAR) ameliorated high-fat diet (HFD)-induced hepatosteatosis via activation of the autophagy system. Here, we found that a KAAR ameliorated the mitochondrial morphological alterations and associated mitochondrial dysfunction induced by an HFD through induction of the AKT/4EBP1 and autophagy signaling pathways in both fast and slow muscles. The mice were fed with a standard HFD (30% fat in food) or an HFD with KAAR (HFDKAAR). In both the gastrocnemius and the soleus, HFDKAAR ameliorated HFD-impaired mitochondrial morphology and mitochondrial function, characterized by decreased mitofusin 2, optic atrophy 1, peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α and PPARα levels and increased dynamin-related protein 1 levels. The decreased levels of phosphorylated AKT and 4EBP1 in the gastrocnemius and soleus of HFD-fed mice were remediated by HFDKAAR. Furthermore, the HFDKAAR ameliorated the HFD-induced autophagy defects in the gastrocnemius and soleus. These findings suggest that KAAR may be a novel strategy to combat obesity-induced mitochondrial dysfunction, likely through induction of the AKT/4EBP1 and autophagy pathways in skeletal muscle.

The role of amino acid profiles in diabetes risk assessment.

PURPOSE OF REVIEW: The concentrations of plasma-free amino acids, such as branched-chain amino acids and aromatic amino acids, are associated with visceral obesity, insulin resistance, and the future development of diabetes and cardiovascular diseases. This review discusses recent progress in the early assessment of the risk of developing diabetes and the reversal of altered plasma-free amino acids through interventions. Additionally, recent developments that have increased the utility of amino acid profiling technology are also described. RECENT FINDINGS: Plasma-free amino acid alterations in the early stage of lifestyle-related diseases are because of obesity and insulin resistance-related inflammation, and these alterations are reversed by appropriate (nutritional, drug, or surgical) interventions that improve insulin sensitivity. For clinical applications, procedures for measuring amino acids are being standardized and automated. SUMMARY: Plasma-free amino acid profiles have potential as biomarkers for both assessing diabetes risk and monitoring the effects of strategies designed to lower that risk. In addition, the methodology for measuring amino acids has been refined, with the goal of routine clinical application.

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).

Ketogenic essential amino acids replacement diet ameliorated hepatosteatosis with altering autophagy-associated molecules.

Ketogenic amino acid (KAA) replacement diet has been shown to cure hepatic steatosis, a serious liver disease associated with diverse metabolic defects. In this study, we investigated the effects of KAA replacement diet on nutrition sensing signaling pathway and analyzed whether induction of hepatic autophagy was involved. Mice are fed with high fat diet (HFD) or KAA replacement in high-fat diet (30% fat in food; HFD)-fed (HFD(KAAR)) and sacrificed at 8, 12, 16 weeks after initiation of experimental food. Hepatic autophagy was analyzed in protein expression of several autophagy-associated molecules and in light chain-3 green fluorescent protein (LC-3 GFP) transgenic mice. HFD(KAAR) showed increased AMP-activated protein kinase (AMPK) phosphorylation and enhanced liver kinase B1 (LKB1) expression compared to control HFD-fed mice. The KAA-HFD-induced activation of AMPK was associated with an increased protein expression of sirtuin 1 (Sirt1), decreased forkhead box protein O3a (Foxo3a) level, and suppression of mammalian target of rapamycin (mTOR) phosphorylation compared with the HFD-fed mice. The intervention study revealed that a KAA-replacement diet also ameliorated all the established metabolic and autophagy defects in the HFD-fed mice, suggesting that a KAA-replacement diet can be used therapeutically in established diseases. These results indicate that KAA replacement in food could be a novel strategy to combat hepatic steatosis and metabolic abnormalities likely involvement of an induction of autophagy.

Detection of thalidomide embryotoxicity by in vitro embryotoxicity testing based on human iPS cells.

The mouse embryonic stem cell test (mEST) is used to assess the embryotoxicity of drug candidates by evaluating the effects on the cardiac differentiation of stem cells. However, thalidomide embryotoxicity has not yet been reported using the mEST. To detect the effects of thalidomide, we used human induced pluripotent stem cells (hiPSCs) instead of mouse embryonic stem cells, and assessed three endpoints: the inhibition of cardiac differentiation, the cytotoxicity to hiPSCs, and the cytotoxicity to human dermal fibroblasts, according to the mEST. From these data (IC50 values), the embryotoxicity was classified into one of three different classes based on the mEST and our criteria. Valproate was used as a positive control and ascorbic acid was used as a negative control, and their effects were assessed. Similar to valproate, thalidomide was classified as a Class 2 agent, with weak embryotoxicity, by the mEST criteria, and was classified as Category 3 embryotoxic based on our criteria. Ascorbic acid was classified as a Class 1 / Category 1, non-embryotoxic agent, based on both criteria. Thalidomide embryotoxicity was detected in the embryonic stem cell test based on hiPSCs. This test system is thus considered to have a much greater predictive ability than the mEST.

Pregnancy outcomes of gestational diabetes mellitus according to pre-gestational BMI in a retrospective multi-institutional study in Japan.

The aim of this study was to determine the effects of pre-gestational body mass index on pregnancy outcomes of women with gestational diabetes in Japan. A multi-institutional retrospective study was performed. We examined pregnant women who met the former criteria for gestational diabetes in Japan, receiving dietary intervention with self-monitoring of blood glucose with or without insulin therapy. Women with gestational diabetes were divided into three groups according to pre-gestational body mass index: body mass index <25 (control group), 25 ≤ body mass index <30 (overweight group), body mass index ≥30 (obese group). Data from a total of 1,758 eligible women were collected from 40 institutions. Participants included 960 controls, 426 overweight women, and 372 obese women with gestational diabetes. Gestational weight gain was highest in the control and lowest in the obese group. The prevalences of chronic hypertension and pregnancy induced hypertension were higher in the overweight and obese groups than in the control group. Multiple logistic regression analysis revealed pre-gestational body mass index, gestational weight gain, chronic hypertension, and nulliparity to be associated with the onset of pregnancy induced hypertension, while the 75-g OGTT results were unrelated to pregnancy induced hypertension. The prevalence of large-for-gestational age was lower in infants born to obese women than in those born to overweight or control women. The present results suggest that medical interventions for obese women with gestational diabetes may contribute to reducing the prevalence of large-for-gestational age but would not achieve marked reductions in maternal complications.

Analysis of the Association between Protein Intake and Disability-Adjusted Life Year Rates for Alzheimer's Disease in Japanese Aged over 60.

With advancements in medical technology, the structure of disease is shifting from acute illnesses to chronic conditions, such as Alzheimer's disease (AD). Consequently, there is an escalating need for evaluations that discourse on the potential effects on healthy life years, as well as disease onset. We aimed to evaluate the associations with AD disability-adjusted life year (AD-DALY) rates and protein intake by sex and age group. For the analysis, we used representative values for males and females in their 60s and aged over 70, extracted from the public dataset of the Global Burden of Disease Study and the National Health and Nutrition Survey in Japan, covering the years 1990 to 2019. In order to evaluate the association between AD-DALY rates and protein intake, we analyzed correlations and stratified multiple regression models. Additionally, we simulated alterations in AD-DALY rates associated with changes in protein intake by utilizing stratified multiple regression models. AD-DALY rates and protein intake indicated significant negative correlations across all sex and age groups. In stratified multiple regression models, significant associations were found between higher protein intake and lower AD-DALY rates in females. In the simulation, when protein intake was increased to 1.5 g/kg/day, AD-DALY rates decreased by 5-9 percent compared with 2019. However, the association between intake of animal and plant protein and AD-DALY rates were found to vary based on sex and age group. The present study suggests the possibility to improve AD-DALY rates by increasing population average protein intake levels in a recommended range.

Multivariable analysis of host amino acids in plasma and liver during infection of malaria parasite Plasmodium yoelii.

BACKGROUND: Malaria is the most significant human parasitic disease, and yet understanding of the energy metabolism of the principle pathogen, Plasmodium falciparum, remains to be fully elucidated. Amino acids were shown to be essential nutritional requirements since early times and much of the current knowledge of Plasmodium energy metabolism is based on early biochemical work, performed using basic analytical techniques, carried out almost exclusively on human plasma with considerable inter-individual variability. METHODS: In order to further characterize the fate of amino acid metabolism in malaria parasite, multivariate analysis using statistical modelling of amino acid concentrations (aminogram) of plasma and liver were determined in host infected with rodent malaria parasite, Plasmodium yoelii. RESULTS AND CONCLUSION: Comprehensive and statistical aminogram analysis revealed that P. yoelii infection caused drastic change of plasma and liver aminogram, and altered intra- and inter-correlation of amino acid concentration in plasma and liver. These findings of the interactions between amino acids and Plasmodium infection may provide insight to reveal the interaction between nutrients and parasites.

Development of a plasma-free amino acid-based risk score for the incidence of cardiovascular diseases in a general population: The Nagahama study.

BACKGROUND & AIMS: Levels of circulating amino acids (AAs) have been suggested to be associated with cardiovascular diseases (CVDs). This study aimed to develop a plasma-free amino acid (PFAA)-based CVD risk-prediction model in a general population. METHODS: The study participants consisted of 9220 community residents (mean age, 53.2 years; standard deviation, 13.3 years). Circulating levels of 19 PFAAs were measured via high-performance liquid chromatography/electrospray ionization mass spectrometry. The incidence of CVDs was determined by reviewing participants' clinical records. The prediction model was developed using the Cox proportional hazards model with the brute force variable selection and then cross-validated. RESULTS: During the 8.5-year follow-up, 220 CVD events were observed. Six AAs (alanine, citrulline, glycine, histidine, serine, and tyrosine) were identified as components of the prediction model, of which the C-index was 0.72. The association between the fourth quartile of the risk score calculated using the prediction model and the CVD events was independent of conventional risk factors (adjusted hazard ratio [HR], 1.9; 95 % confidence interval, 1.1-3.3). When examining crude relationships between conventional risk factors and the PFAA-based risk score by subgroup analyses, the association was significant for most subpopulations, men [crude HR = 6.4 (2.0-20.2)] and women [crude HR = 4.9 (2.6-9.3)], and individuals with [crude HR = 4.7 (2.5-8.9)] and without [crude HR = 7.2 (2.7-18.9)] lifestyle-related diseases, but not for older (≥70 years) participants [crude HR = 3.3 (0.8-13.5)]. The risk score successfully identified at-risk individuals [HR = 2.1 (1.2-3.5)] from participants who were classified as low risk by a conventional CVD risk score. CONCLUSIONS: The PFAA-based risk score predicted CVD events independently of conventional risk factors.

Positive Ascites Cytology, Postoperative Chemotherapy and Prognosis of Stage I Ovarian Clear Cell Carcinoma.

BACKGROUND/AIM: Ovarian clear cell carcinoma (CCC) is associated with a poor prognosis and is resistant to chemotherapy. The aim of this study was to investigate the prognosis of CCC in Mie prefecture and to identify poor prognostic factors. PATIENTS AND METHODS: In this multi-center retrospective study, we analyzed the data of patients with CCC between February 2012 and December 2020. Patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) 2014 system. Statistical analyses were performed using the Kaplan-Meier method and compared between the two groups using the log-rank test. RESULTS: A total of 112 patients were included and the median follow-up time was 48 months. There was no difference in the prognosis between stages IA, IC1, and IC2. For patients at stages IA, IC1, and IC2, there was no difference in progression-free survival (PFS) and overall survival between the adjuvant chemotherapy and no chemotherapy groups. Median postrecurrent survival was 18 and 20 months in the stages I-II and III-IV groups, respectively. Multivariate analysis revealed that positive ascites cytology (p=0.006) was associated with PFS for patients at stages I-II and that the stage (p=0.039) was associated with PFS for patients at stages III-IV. CONCLUSION: Positive ascites cytology was a poor prognostic factor for patients at an early stage of CCC. Postoperative chemotherapy could be omitted for patients in stages IA and IC1. Relapsed patients did not respond to the standard treatment and had a poor prognosis regardless of the primary stage.

Real-world efficacy and safety of bevacizumab single-maintenance therapy following platinum-paclitaxel chemotherapy plus bevacizumab in patients with advanced cervical cancer.

OBJECTIVE: Bevacizumab maintenance therapy following platinum-based combination chemotherapy for metastatic, recurrent, or persistent cervical cancer is not recommended as standard therapy. This pilot study aimed to evaluate the efficacy and safety of bevacizumab maintenance therapy and the contribution of the platinum-free interval to the efficacy of subsequent chemotherapy for advanced cervical cancer. METHODS: We retrospectively identified 115 patients with metastatic, recurrent, or persistent cervical cancer treated with platinum-paclitaxel chemotherapy plus bevacizumab at 7 institutions between 2015 and 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients who received bevacizumab maintenance therapy and those who did not. We also analyzed the adverse events associated with bevacizumab and survival time from the start of subsequent chemotherapy in both groups. RESULTS: Following platinum-paclitaxel plus bevacizumab chemotherapy, 34 patients received bevacizumab maintenance therapy and 81 patients did not. Of the 115 patients, 56 received chemotherapy for subsequent relapse. Although bevacizumab maintenance therapy prolonged PFS (median of 16.0 months vs. 9.0 months, p=0.041), significant differences were not observed in OS (p=0.374). Furthermore, bevacizumab maintenance therapy did not prolong OS and PFS after the start of subsequent chemotherapy (p=0.663 and p=0.136, respectively). Bevacizumab maintenance therapy significantly increased hypertension (p=0.035) and proteinuria (p=0.005) but did not cause complications leading to death. CONCLUSION: Bevacizumab single-maintenance therapy for advanced cervical cancer can be considered in selected cases, such as those with acceptable bevacizumab-related side effects. The outcomes of our study will likely contribute to decision-making regarding practical treatment strategies.

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.

Pharmacokinetics and cerebral distribution of glycine administered to rats.

High doses of glycine have been reported to improve negative schizophrenic symptoms, suggesting that ingested glycine activates glutamatergic transmission via N-methyl-D-aspartate (NMDA) receptors. However, the pharmacokinetics of administered glycine in the brain has not been evaluated. In the present study, the time- and dose-dependent distributions of administered glycine were investigated from a pharmacokinetic viewpoint. Whole-body autoradiography of radiolabeled glycine was performed, and time-concentration curves for glycine and serine in plasma, cerebrospinal fluid (CSF), and brain tissues were obtained. Furthermore, pharmacokinetic parameters were calculated. For a more detailed analysis, the amount of glycine uptake in the brain was evaluated using the brain uptake index method. Radiolabeled glycine was distributed among periventricular organs in the brain. Oral administration of 2 g/kg of glycine significantly elevated the CSF glycine concentration above the ED50 value for NMDA receptors. The glycine levels in CSF were 100 times lower than those in plasma. Glycine levels were elevated in brain tissue, but with a slower time-course than in CSF. Serine, a major metabolite of glycine, was elevated in plasma, CSF, and brain tissue. Glycine uptake in brain tissue increased in a dose-dependent manner. Time-concentration curves revealed that glycine was most likely transported via the blood-CSF barrier and activated NMDA receptors adjacent to the ventricles. The pharmacokinetic analysis and the brain uptake index for glycine suggested that glycine was transported into brain tissue by passive diffusion. These results provide further insight into the potential therapeutic applications of glycine.

"Nutrient-Repositioning"-Unexpected Amino Acid Functions.

Repositioning is usually used to indicate drug repositioning, or the finding of new disease applications for existing, approved drugs. Nutrients can be ingested for nutritional as well as therapeutic purposes, acting much the same as drugs. Amino acids are organic compounds that possess both amino and carboxy group functionalities and are best known as building blocks of proteins in living organisms. Recent studies of individual amino acids have revealed them to be functional ingredients of new therapeutics, promoting health in addition to nutrition. Here, we propose "nutrient-repositioning", the discovery of effects different from the existing effects of nutrients. This review summarizes some recent discoveries of unexpected amino acid functions, especially in BCAAs, histidine and serine.

Does Vaginal Cuff Creation and Avoidance of a Uterine Manipulator Improve the Prognosis of Total Laparoscopic Radical Hysterectomy for Early Cervical Cancer? A Retrospective Multicenter Study.

Our goal was to compare the treatment outcomes of open-abdominal radical hysterectomy (O-RH) and total laparoscopic hysterectomy (TLRH) with vaginal cuff creation and without using a uterine manipulator in stage IB1-B2 (tumor size < 4 cm) cervical cancer cases. In this retrospective multicenter analysis, 94 cervical cancer stage IB1-B2 patients who underwent O-RH or TLRH in six hospitals in Japan between September 2016 and July 2020 were included; 36 patients underwent TLRH. Propensity score matching was performed because the tumor diameter was large, and positive cases of lymph node metastases were included in the O-RH group due to selection bias. The primary endpoint was progression-free survival (PFS) and recurrence sites of TLRH and O-RH. PFS and OS (overall survival) were not significant in both the TLRH (n = 27) and O-RH (n = 27) groups; none required conversion to laparotomy. The maximum tumor size was <2 and ≥2 cm in 12 (44.4%) and 15 (55.6%) patients, respectively, in both groups. Reportedly, the TLRH group had lesser bleeding than the O-RH group (p < 0.001). Median follow-up was 33.5 (2−65) and 41.5 (6−75) months in the TLRH and O-RH groups, respectively. PFS and OS were not significantly different between the two groups (TLRH: 92.6%, O-RH: 92.6%; log-rank p = 0.985 and 97.2%, 100%; p = 0.317, respectively). The prognosis of early cervical cancer was not significantly different between TLRH and O-RH. Tumor spillage was prevented by creating a vaginal cuff and avoiding the use of a uterine manipulator. Therefore, TLRH might be considered efficient.