A Case of Solid-Appearing Struma Ovarii: Pitfall in the Assessment Using Ovarian-Adnexal Reporting and Data System Magnetic Resonance Imaging Score.

Struma ovarii is a monodermal teratoma characterized by the presence of >50% thyroid tissue. It is mostly benign; therefore, preoperative diagnosis is important. It usually manifests as a multilocular cystic mass but rarely as a predominantly solid mass. On magnetic resonance imaging (MRI), solid-appearing struma ovarii showed early signal intensity enhancement on dynamic gadolinium-enhanced T1-weighted images, which histopathologically indicates the presence of thyroid tissue with abundant blood vessels. The Ovarian-Adnexal Reporting and Data System (O-RADS) MRI score is a validated classification worldwide for characterizing adnexal lesions. Based on the morphology, signal intensity, and enhancement of any solid tissue on the MRI, the scoring system can be used to classify adnexal lesions into five categories from score one (no adnexal mass) to score five (high risk of malignancy). An adnexal solid mass with a higher signal intensity than that of the myometrium 30-40 seconds after gadolinium (Gd) injection on non-dynamic contrast-enhanced (non-DCE) MRI was assigned a score of 5 (high risk of malignancy).  We present a case of solid-appearing struma ovarii with a higher signal intensity than that of the myometrium 30 seconds after Gd injection on non-DCE MRI, and it was classified as score five preoperatively. Therefore, a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed despite the presence of a benign ovarian mass. When an adnexal mass with a higher signal intensity than that of the myometrium 30-40 seconds after Gd injection on non-DCE MRI is encountered, struma ovarii should be included in the differential diagnosis, despite the O-RADS MRI score of five and management of the situation should be discussed.

Association of scan frequency with CGM-derived metrics and influential factors in adults with type 1 diabetes mellitus.

Introduction: This study aimed to investigate the association between scan frequency and intermittently scanned continuous glucose monitoring (isCGM) metrics and to clarify the factors affecting scan frequency in adults with type 1 diabetes mellitus (T1D). Methods: We enrolled adults with T1D who used FreeStyle® Libre. Scan and self-monitoring of blood glucose (SMBG) frequency and CGM metrics from the past 90-day glucose data were collected. The receiver operating characteristic curve was plotted to obtain the optimal cutoff values of scan frequency for the target values of time in range (TIR), time above range (TAR), and time below range (TBR). Results: The study was conducted on 211 adults with T1D (mean age, 50.9 ± 15.2 years; male, 40.8%; diabetes duration, 16.4 ± 11.9 years; duration of CGM use, 2.1 ± 1.0 years; and mean HbA1c, 7.6 ± 0.9%). The average scan frequency was 10.5 ± 3.3 scan/day. Scan frequency was positively correlated with TIR and negatively correlated with TAR, although it was not significantly correlated with TBR. Scan frequency was positively correlated with the hypoglycemia fear survey-behavior score, while it was negatively correlated with some glycemic variability metrics. Adult patients with T1D and good exercise habits had a higher scan frequency than those without exercise habits. The AUC for > 70% of the TIR was 0.653, with an optimal cutoff of 11 scan/day. Conclusions: In real-world conditions, frequent scans were linked to improved CGM metrics, including increased TIR, reduced TAR, and some glycemic variability metrics. Exercise habits and hypoglycemia fear-related behavior might affect scan frequency. Our findings could help healthcare professionals use isCGM to support adults with T1D.Clinical Trial Registry No. UMIN000039376.

Glucagon secretion and its association with glycaemic control and ketogenesis during sodium-glucose cotransporter 2 inhibition by ipragliflozin in people with type 1 diabetes: Results from the multicentre, open-label, prospective study.

AIM: Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin. METHODS: Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and ß-hydroxybutyrate. RESULTS: The area under the curve from fasting (0 min) to 120 min (AUC0-120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial ß-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0-120min) from baseline to 12 weeks were significantly correlated with those in ß-hydroxybutyrate levels. CONCLUSIONS: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied.

Advantages of sensor-augmented insulin pump therapy for pregnant women with type 1 diabetes mellitus.

AIMS/INTRODUCTION: To evaluate the efficacy of sensor-augmented pump (SAP) for improving obstetric and neonatal outcomes among pregnant women with type 1 diabetes mellitus by comparing it with continuous subcutaneous insulin infusion plus self-monitoring of blood glucose (continuous subcutaneous insulin infusion [CSII]/SMBG). MATERIALS AND METHODS: This retrospective cohort study included 40 cases of pregnancy complicated by type 1 diabetes mellitus treated with SAP (SAP group), and 29 cases of pregnancy complicated by type 1 diabetes mellitus treated with CSII/SMBG (CSII/SMBG group). The obstetric and neonatal outcomes were compared between the two groups. RESULTS: The median of the glycoalbumin levels in the first (18.8% vs 20.9%; P < 0.05) and second (15.4% vs 18.0%; P < 0.05) trimesters, the hemoglobin A1c levels in the peripartum period (6.1% vs 6.5%; P < 0.05) and the standard deviation score of birthweights (0.36 vs 1.52; P < 0.05) were significantly lower in the SAP group than in the CSII/SMBG group. The incidence rate of large for gestational age newborns was significantly lower in the SAP group than in the CSII/SMBG group (27.5% vs 65.5%; P < 0.05). No significant differences in the incidence rates of hypertensive disorders of pregnancy, small for gestational age, respiratory distress syndrome, neonatal hypoglycemia, hypervolemia and hyperbilirubinemia were observed between the groups. CONCLUSION: The present study showed that SAP therapy is more effective in preventing large for gestational age newborns in pregnant women with type 1 diabetes mellitus than CSII/SMBG.

A family study of compound variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found by urinary phenotyping for trimethylaminuria.

Phenotype-gene analyses and the increasing availability of mega-databases have revealed the impaired human flavin-containing monooxygenase 3 (FMO3) variants associated with the metabolic disorder trimethylaminuria. In this study, a novel compound variant of FMO3, p.[(Val58Ile; Tyr229His)], was identified in a 1-year-old Japanese girl who had impaired FMO3 metabolic capacity (70%) in terms of urinary trimethylamine N-oxide excretion levels divided by total levels of trimethylamine and its N-oxide. One cousin in the family had the same p.[(Val58Ile); (Tyr229His)]; [(Glu158Lys; Glu308Gly)] FMO3 haplotype and had a similar FMO3 metabolic capacity (69%). In a family study, the novel p.[(Val58Ile); (Tyr229His)] compound FMO3 variant was also detected in the proband 1's mother and aunt. Another novel compound FMO3 variant p.[(Glu158Lys; Met260Lys; Glu308Gly; Ile426Thr)] was identified in a 7-year-old girl, proband 2. This novel compound FMO3 variant was inherited from her mother. Recombinant FMO3 Val58Ile; Tyr229His variant and Glu158Lys; Met260Lys; Glu308Gly; Ile426Thr variant showed moderately decreased capacities for trimethylamine N-oxygenation compared to wild-type FMO3. Analysis of trimethylaminuria phenotypes in family studies has revealed compound missense FMO3 variants that impair FMO3-mediated N-oxygenation in Japanese subjects; moreover, these variants could result in modified drug clearances.

Factors associated with hemoglobin glycation index in adults with type 1 diabetes mellitus: The FGM-Japan study.

AIMS/INTRODUCTION: The discrepancy between HbA1c and glucose exposure may have significant clinical implications; however, the association between the hemoglobin glycation index (HGI) and clinical parameters in type 1 diabetes remains controversial. This study aimed to find the factors associated with HGI (laboratory HbA1c - predicted HbA1c derived from the continuous glucose monitoring [CGM]). MATERIALS AND METHODS: We conducted a cross-sectional study of adults with type 1 diabetes (n = 211, age 50.9 ± 15.2 years old, female sex = 59.2%, duration of CGM use = 2.1 ± 1.0 years). All subjects wore the CGM for 90 days before HbA1c measurement. Data derived from the FreeStyle Libre sensor were used to calculate the glucose management indicator (GMI) and glycemic variability (GV) parameters. HGI was defined as the difference between the GMI and the laboratory HbA1c levels. The participants were divided into three groups according to the HGI tertile (low, moderate, and high). Multivariate regression analyses were performed. RESULTS: The female sex ratio, HbA1c, and % coefficient of variation (%CV) significantly increased over the HGI tertile, while eGFR and Hb decreased over the HGI tertile. In multivariate analysis, the factors associated with HGI were %CV and eGFR, after adjusting for HbA1c level and sex (R2  = 0.44). CONCLUSIONS: This study demonstrated that HGI is associated with female sex, eGFR, and some glycemic variability indices, independently of HbA1c. Minimizing glycemic fluctuations might reduce HGI. This information provides diabetic health professionals and patients with personalized diabetes management for adults with type 1 diabetes.

To Use or Not to Use a Self-monitoring of Blood Glucose System? Real-world Flash Glucose Monitoring Patterns Using a Cluster Analysis of the FGM-Japan Study.

Objective This study investigated self-monitoring of blood glucose (SMBG) adherence and flash glucose monitoring patterns using a cluster analysis in Japanese type 1 diabetes (T1D) patients with intermittently scanned continuous glucose monitoring (isCGM). Methods We measured SMBG adherence and performed a data-driven cluster analysis using a hierarchical clustering in T1D patients from Japan using the FreeStyle Libre system. Clusters were based on three variables (testing glucose frequency and referred Libre data for hyperglycemia or hypoglycemia). Patients We enrolled 209 participants. Inclusion criteria were patients with T1D, duration of isCGM use ≥3 months, age ≥20 years old, and regular attendance at the collaborating center. Results The rate of good adherence to SMBG recommended by a doctor was 85.0%. We identified three clusters: cluster 1 (low SMBG test frequency but high reference to Libre data, 17.7%), cluster 2 (high SMBG test frequency but low reference to Libre data, 34.0%), and cluster 3 (high SMBG test frequency and high reference to Libra data, 48.3%). Compared with other clusters, individuals in cluster 1 were younger, those in cluster 2 had a shorter Libre duration, and individuals in cluster 3 had lower time-in-range, higher severe diabetic distress, and high intake of snacks and sweetened beverages. There were no marked differences in the incidence of diabetic complications and rate of wearing the Libre sensor among the clusters. Conclusion We stratified the patients into three subgroups with varied clinical characteristics and CGM metrics. This new substratification might help tailor diabetes management of patients with T1D using isCGM.

Glucocorticoid Receptor Expression Pattern in Very Low Birth Weight Infants Changes Drastically within the First Week of Life.

INTRODUCTION: We herein examined changes in expression levels of the glucocorticoid receptor subtypes GRα and GRß in very low birth weight (VLBW) and term infants to clarify time-dependent changes in glucocorticoid sensitivity after birth. METHODS: Whole blood samples were collected at birth and on postnatal days 4-7, and the mRNA expression levels of GRα and GRß were measured using RT-qPCR. The relative gene expression levels of GRα and GRß as the target genes normalized to actin beta as the endogenous control were calculated by the comparative cycle threshold method. RESULTS: The GRα/GRß expression ratio at birth was significantly lower in 32 VLBW cesarean section (CS) infants than in term planned CS infants (median [IQR], 1.5 [1.1-1.8]- and 1.1 [0.7-1.6]-fold change, p < 0.05). Furthermore, the GRα/GRß expression ratio increased from day 0 to days 4-7 (1.0 [0.6-1.4]- and 1.7 [0.6-1.4]-fold change, p < 0.01) in 43 VLBW infants. DISCUSSION/CONCLUSION: The present results suggest that glucocorticoid sensitivity in VLBW infants increases after birth and this rapid change may play a role in surviving critical postnatal events.

Elevated Blood Pressure (≥120/80 mmHg) Is Associated with Elevated Serum Plasminogen Activator Inhibitor-1, Low Birth Weight, and Family History of Diabetes in Young Normal Weight Japanese Women.

Objective: We examined whether elevated blood pressure (BP) (≥120/80 mmHg) was associated with several anthropometric, metabolic, and clinical variables, including the family history of type 2 diabetes (FHD) and low birth weight, in young normal weight Japanese women. Methods: BP, body composition, and fasting glucose, insulin, lipids, lipoproteins, apolipoproteins, and adipokines were measured in 332 young Japanese women. They received a questionnaire on birth weight and FHD. Results: The prevalence of low birth weight was 2.4% and that of positive FHD was 22.9%. Homeostasis model assessment-insulin resistance averaged <1.5 and did not differ cross-sectionally between 32 women with elevated BP and 300 women with normal BP although mean body mass index was higher in the former than in the latter (21.7 ± 2.9 kg/m2 vs. 20.8 ± 2.2 kg/m2, P = 0.02). Women with elevated BP had higher fat mass index (P = 0.02) and trunk fat percentage (P = 0.04). They had lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 (both P = 0.01) while fasting triglycerides and apolipoprotein B did not differ. In addition, they had higher plasminogen activator inhibitor-1 (PAI-1) (P = 0.001). Furthermore, the prevalence of low birth weight (9.4% vs. 1.7%, P = 0.03) and positive FHD (40.6% vs. 20.0%, P = 0.01) was higher in women with elevated BP. Multivariable logistic regression analyses revealed that elevated BP was independently associated with PAI-1 [odds ratio (OR); 1.05, 95% confidence interval (CI): 1.02-1.08, P = 0.001], low birth weight (OR: 12.3, 95% CI: 2.3-67.3, P = 0.04), and FHD (OR: 3.0, 95% CI: 1.3-7.9, P = 0.01). Conclusion: Elevated BP was associated with positive FHD, low birth weight, and elevated serum PAI-1 in young normal weight Japanese women.

Comparisons among populations and individuals to evaluate pollen-pistil interaction as a mechanism of reproductive interference in Taraxacum.

Reproductive interference (RI), an interspecific mating interaction that reduces the fitness of at least one of the species involved, can lead to exclusive distributions in closely related species. A hypothesis previously proposed is that RI in plants may occur by ovule usurpation, in which pistils lack interspecific incompatibility and mistakenly accept heterospecific pollen, thereby losing an opportunity for conspecific pollen fertilization. However, few comparative studies have evaluated the consistency of the inferred mechanism within and among individuals and populations. We conducted hand-pollination experiments in six populations of three native Taraxacum species that suffered from different levels of RI from an alien congener, T. officinale, and compared pollen-pistil interactions among populations. We also investigated the interactions for eight individual T. japonicum plants whose response to heterospecific pollen deposition had been previously measured. Our results revealed that pollen tubes often penetrated native ovaries following heterospecific pollination in populations suffering from strong RI, whereas they seldom did in populations suffering from marginal RI. However, the relative frequency of the pollen tube penetration was not significantly related to the strength of alien RI. Not all pistils on an individual plant showed the same pollen receptivity following heterospecific pollination; rather, some accepted and some refused the pollen tubes. The relationship between pollen tube penetration following heterospecific pollination and the strength of the alien RI was also not significant among individuals. Our present results generally support the ovule usurpation hypothesis, but suggest that other factors, such as competition for pollinator services, variation in the effects of heterospecific pollen donors, and condition of the native inflorescences, might also affect the observed RI strength.

Accuracy of a Professional Continuous Glucose Monitoring Device in Individuals with Type 2 Diabetes Mellitus.

Among continuous glucose monitoring (CGM) devices, which continuously measure glucose concentration in subcutaneous interstitial fluid for comprehensive monitoring of blood glucose profile, only FreeStyle Libre Pro® (Abbott Diabetes Care) is currently available in Japan as a professional system. FreeStyle Libre Pro® is easy to use because it does not require calibration by self-monitoring of blood glucose (SMBG), but information on its accuracy has been insufficient. To evaluate the measurement accuracy of FreeStyle Libre Pro®, we have now compared blood glucose levels determined by this device with those measured by SMBG in 40 individuals with type 2 diabetes mellitus. The mean absolute relative difference (MARD) for FreeStyle Libre Pro® measurements compared with SMBG measurements was calculated as an index of CGM accuracy. Overall blood glucose values measured by SMBG were 167.0 ± 60.1 mg/dL, and those determined by FreeStyle Libre Pro® were 155.0 ± 60.7 mg/dL, with this difference being statistically significant. The MARD for FreeStyle Libre Pro® relative to SMBG was 12.7 ± 9.3%. It was substantially higher in 2 of the 40 patients, at 49.2% and 47.5%, than in the other 38 individuals. MARD values did not differ significantly between before and 2 h after meals. However, the MARD was significantly higher for SMBG values of <100 mg/dL than for those of ≥250 mg/dL. Our results thus indicate that the measurement accuracy of FreeStyle Libre Pro® is relatively good, but that some cases in which values determined by the device deviate from SMBG values require caution in interpretation.

Accurate prediction of HbA1c by continuous glucose monitoring using a kinetic model with patient-specific parameters for red blood cell lifespan and glucose uptake.

BACKGROUND: A recent kinetic model proposed a new individualized glycaemic marker, calculated HbA1c (cHbA1c), based on kinetic parameters and glucose levels that are specific to each person. The aims of the current work were to validate the accuracy of this glucose metric for clinical use and evaluate data requirements for the estimation of personal kinetic factors. METHODS: We retrieved HbA1c and glucose data from a group of 51 Japanese T1D patients under sensor-augmented pump (SAP) therapy. Two patient-specific kinetic parameters were identified by data sections, defined as continuous glucose data between two laboratory HbA1c measurements. The cHbA1c was prospectively validated employing subsequent HbA1c data that were not originally used to determine personal kinetic parameters. RESULTS: Compared to estimated HbA1c (eHbA1c) and glucose management indicator (GMI), cHbA1c showed clinically relevant accuracy improvement, with 20% or more within ±0.5% (±5.5 mmol/mol) of laboratory HbA1c. The mean absolute deviation of the cHbA1c calculation was 0.11% (1.2 mmol/mol), substantially less than for eHbA1c and GMI at 0.54% (5.9 mmol/mol) and 0.47% (5.1 mmol/mol), respectively. CONCLUSION: Our study shows superior performance of cHbA1c compared with eHbA1c and GMI at reflecting laboratory HbA1c, making it a credible glucose metric for routine clinical use.

Adrenal Corticomedullary Mixed Tumor Associated With the FGFR4-G388R Variant.

Adrenal corticomedullary mixed tumors (CMMTs) are extremely rare; with only 20 cases being reported to date, the pathogenesis has remained elusive. A 31-year-old woman developed gestational hypertension with psychiatric disturbances persistent to postpartum and was diagnosed with pheochromocytoma, for which adrenalectomy was performed. Histological findings showed mixed adrenocortical adenoma and pheochromocytoma. Double immunostaining of inhibin and INSM1 (insulinoma-associated protein 1) showed that the 2 tumor components had distinct functional properties. Exome analysis of peripheral leukocytes and tumor (singular, as anatomically it is only 1 mass) revealed a homozygous germline FGFR4-G388R variant. As a readout of the variant, serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was detected only in the nucleus of adrenocortical adenoma component but not in the pheochromocytoma component. No tyrosine phosphorylation of STAT3 was detected. We report a case of CMMT with the germline FGFR4-G388R variant. Although additional studies are required, our immunohistochemical analysis suggests that the variant may play a role in the development of the adrenocortical component within the pheochromocytoma, leading to CMMT.

Response of preterm infants with transient hypothyroxinaemia of prematurity to the thyrotropin-releasing hormone stimulation test is characterized by a delayed decrease in thyroid-stimulating hormone after the peak.

OBJECTIVES: We evaluated the response to the thyrotropin-releasing hormone (TRH) stimulation test in very low-birth weight (VLBW) infants to elucidate the aetiology of transient hypothyroxinaemia of prematurity (THOP). DESIGN AND METHODS: We performed TRH stimulation tests on 43 VLBW infants. Subjects were divided into two groups; a THOP group (N = 11; basal TSH < 15 mU/L and basal FT4 ≤ 0.8 ng/dL) and a non-THOP group (N = 32; basal TSH < 15 mU/L and basal FT4 > 0.8 ng/dL). Basal FT4 and FT3 were measured before, and TSH (0, 30, 60, 90, 120 and 180 minutes) was measured after, the administration of TRH (7 µg/kg). We calculated the ratio of TSH 180 minutes to THS 0 minute as the primary outcome. We also collected data on T3 and rT3 in this study. RESULTS: In both groups, TSH 30 minutes values were the highest. However, the ratios of TSH 180 minutes to THS 0 minutes in the non-THOP group and the THOP group were (median [IQR]) 1.3 [1.0-1.7] and 3.0 [1.5-5.3] (P < .01). No significant differences were observed in T3 (1.0 [0.8-1.3] and 0.7 [0.4-0.7] ng/mL, P = .06). However, in the THOP group, rT3 was significantly lower than that of the non-THOP group (168.0 [148.1-197.0] and 92.9 [74.7-101.6] pg/mL, P < .01). CONCLUSIONS: The delayed decrease in the TSH concentration after the peak for the TRH tests and decreased levels of rT3 suggest that the main aetiology for THOP is suppression at the level of the hypothalamus, but not inactivation of peripheral thyroid hormone metabolism.

cis-Regulatory analysis for later phase of anterior neuroectoderm-specific foxQ2 expression in sea urchin embryos.

The specification of anterior neuroectoderm is controlled by a highly conserved molecular mechanism in bilaterians. A forkhead family gene, foxQ2, is known to be one of the pivotal regulators, which is zygotically expressed in this region during embryogenesis of a broad range of bilaterians. However, what controls the expression of this essential factor has remained unclear to date. To reveal the regulatory mechanism of foxQ2, we performed cis-regulatory analysis of two foxQ2 genes, foxQ2a and foxQ2b, in a sea urchin Hemicentrotus pulcherrimus. In sea urchin embryos, foxQ2 is initially expressed in the entire animal hemisphere and subsequently shows narrower expression restricted to the anterior pole region. In this study, as a first step to understand the foxQ2 regulation, we focused on the later restricted expression and analyzed the upstream cis-regulatory sequences of foxQ2a and foxQ2b by using the constructs fused to short half-life green fluorescent protein. Based on deletion and mutation analyses of both foxQ2, we identified each of the five regulatory sequences, which were 4-9 bp long. Neither of the regulatory sequences contains any motifs for ectopic activation or spatial repression, suggesting that later mRNA localization is regulated in situ. We also suggest that the three amino acid loop extension-class homeobox gene Meis is involved in the maintenance of foxQ2b, the expression of which is dominant during embryogenesis.

Characterization of soy-deprestatin, a novel orally active decapeptide that exerts antidepressant-like effects via gut-brain communication.

We found that the orally administered thermolysin digest of ß-conglycinin exhibits antidepressant-like effects in tail suspension and forced swim tests in mice. A comprehensive peptide analysis of the digest using liquid chromatography/mass spectrometry was performed, and LSSTQAQQSY emerged as a candidate antidepressant-like peptide. Orally administered synthetic LSSTQAQQSY exhibited antidepressant-like effects at a dose of 0.3 mg/kg; therefore, we named the decapeptide soy-deprestatin. In contrast, intraperitoneally administered soy-deprestatin was ineffective. We then hypothesized that it acted on the gut, and its signal was transferred to the brain. Indeed, orally administered soy-deprestatin exhibited antidepressant-like activity in sham-treated, but not vagotomized, mice. Oral administration of soy-deprestatin also increased the c-Fos expression in the nucleus of the solitary tract, which receives inputs from the vagus nerve. These results suggested that the antidepressant-like effects were mediated by the vagus nerve. Thermolysin digest- and soy-deprestatin-induced antidepressant-like effects were also blocked by antagonists of serotonin 5-HT1A, dopamine D1, or GABAA receptors. We also clarified the order of receptor activation as 5-HT1A, D1, and GABAA, using selective agonists and antagonists. Taken together, soy-deprestatin may exhibit antidepressant-like effects after oral administration via a novel pathway mediated by 5-HT1A, followed by D1 and GABAA systems. This is the first orally active peptide demonstrating antidepressant-like effects via gut-brain communication.-Mori, Y., Asakura, S., Yamamoto, A., Odagiri, S., Yamada, D., Sekiguchi, M., Wada, K., Sato, M., Kurabayashi, A., Suzuki, H., Kanamoto, R., Ohinata, K. Characterization of soy-deprestatin, a novel orally active decapeptide that exerts antidepressant-like effects via gut-brain communication.

Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation.

Free fatty acids not only play a role in cell membrane construction and energy production but also exert diverse cellular effects through receptor and non-receptor mechanisms. Moreover, epidemiological and clinical studies have so far suggested that polyunsaturated fatty acids (PUFAs) could have health benefits and the advantage as therapeutic use in cancer treatment. However, the underlying mechanisms of PUFA-induced cellular effects remained to be cleared. Here, we examined the effects of ω-3 and ω-6 PUFAs on cell death in ovarian cancer cell lines. ω-3 PUFA, docosahexaenoic acid (DHA) and ω-6 PUFA, γ-linolenic acid (γ-LNA) induced cell death in KF28 cells at the levels of physiological concentrations, but not HAC2 cells. Pharmacological and biochemical analyses demonstrated that cell death induced by DHA and γ-LNA was correlated with activation of JNK and p38 MAP kinases, and further an upstream MAP kinase kinase, apoptosis signal-regulating kinase 1, which is stimulated by reactive oxygen species (ROS). Furthermore, an antioxidant vitamin E attenuated PUFA-induced cell death and MAP kinase activation. These findings indicate that PUFA-induced cell death involves ROS-dependent MAP kinase activation and is a cell type-specific action. A further study of the underlying mechanisms for ROS-dependent cell death induced by PUFAs will lead to the discovery of a new target for cancer therapy or diagnosis.

Corticotrophin-releasing hormone stimulation tests for the infants with relative adrenal insufficiency.

BACKGROUND: Very low birthweight (VLBW) infants are considered to be vulnerable to relative adrenal insufficiency (RAI); however, diagnosis is difficult in some clinical settings. Considering this background, it is necessary to establish a diagnosis of RAI in preterm infants. OBJECTIVE: In this study, we attempted to clarify the difference in response to CRH stimulation tests for preterm infants with or without RAI. METHODS: Between June 2009 and December 2015, we performed CRH stimulation tests for preterm infants born at a gestational age of <30 weeks at around 2 weeks of age. Retrospectively, subjects were classified into two groups: infants with RAI (n = 9) or without RAI (n = 17) based on the clinical symptoms and responsiveness to hydrocortisone. RESULTS: We found no difference in base or peak serum cortisol levels related to CRH stimulation tests between the two groups; however, delta cortisol levels and responsive ratio (peak-to-base ratio) were significantly reduced in infants with RAI. 140 nmol/L for delta cortisol or 1.5 times for peak-to-base ratio may be cut-off levels in preterm infants. CONCLUSION: This study provides evidence that base cortisol levels of preterm infants with RAI were not different from those without RAI; however, CRH stimulation tests may be a useful tool for the diagnosis of RAI in preterm infants.

Rational identification of a novel soy-derived anxiolytic-like undecapeptide acting via gut-brain axis after oral administration.

Here we found that the chymotryptic digest of soy ß-conglycinin, a major storage protein, exhibited anxiolytic-like effects in mice. We then searched for anxiolytic-like peptides in the digest. Based on a comprehensive peptide analysis of the chymotryptic digest by high performance liquid chromatograph connected to an LTQ Orbitrap mass spectrometer and the structure-activity relationship of known peptides, we explored anxiolytic-like peptides present in the digest. FLSSTEAQQSY, which corresponds to 323-333 of the ß-conglycinin α subunit [ßCGα(323-333)] emerged as a candidate. Oral administration of synthetic ßCGα(323-333) exhibited anxiolytic-like effects in the elevated plus-maze and open-field test in male mice. Orally administered ßCGα(323-333) exhibited anxiolytic-like effects in sham-operated control mice but not in vagotomized mice. In addition, oral administration of ßCGα(323-333) increased the expression of c-Fos, a marker of neuronal activity, in the nucleus of the solitary tract, which receives inputs from the vagus nerve. These results suggest that the anxiolytic-like effects were mediated by the vagus nerve. The anxiolytic-like effects of ßCGα(323-333) were also blocked by antagonists of the serotonin 5-HT1A, dopamine D1 and GABAA receptors. However ßCGα(323-333) had no affinity for these receptors, suggesting it stimulates the release of endogenous neurotransmitters to activate the receptors. Taken together, a soy-derived undecapeptide, ßCGα(323-333), may exhibit anxiolytic-like effects after oral administration via the vagus nerve and 5-HT1A, D1 and GABAA systems.