Search

Abstract Background We recently examined the distribution of abdominal fat, dietary intake and biochemical data in patients with nonalcoholic fatty liver disease (NAFLD) and found that non-obese NAFLD patients did not necessarily exhibit insulin resistance and/or dysregulated secretion of adipocytokines. However, dietary cholesterol intake was superabundant in non-obese patients compared with obese patients, although total energy and carbohydrate intake was not excessive. Therefore, excess cholesterol intake appears to be one of the main factors associated with NAFLD development and liver injury. Methods We reviewed a year of follow-up data of non-obese NAFLD patients treated with Niemann-Pick C1 like 1 inhibitor ezetimibe to evaluate its therapeutic effect on clinical parameters related to NAFLD. Without any dietary or exercise modification, 10 mg/day of ezetimibe was given to 8 patients. In 4 of 8 patients, ezetimibe was administered initially. In the remaining 4 patients, medication was switched from ursodeoxycholic acid to ezetimibe. Results In each patient, body mass index was maintained under 25 kg/m2 during the observation period. Serum ALT levels significantly decreased within 6 months and in 4 patients levels reached the normal range ( Conclusion We conclude that the cholesterol absorption inhibitor ezetimibe can suppress hepatic injury in non-obese patients with NAFLD and that ezetimibe may offer a novel treatment for NAFLD.

Chronic psychosocial stress stands as a significant heterogeneous risk factor for psychiatric disorders. The brain's physiological response to such stress varies based on the frequency and intensity of stress episodes. However, whether stress episodes divergently could affect hippocampal cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling remains unclear, a key regulator of psychiatric symptoms. We aimed to assess how two distinct patterns of social defeat stress exposure impact anxiety- and depression-like behaviors, fear, and hippocampal CREB-BDNF signaling in adult male rats. To explore this, adult male Sprague-Dawley rats were subjected to psychosocial stress using a Resident/Intruder paradigm for ten consecutive days (continuous social defeat stress: [CS]) or ten social defeat stress over the course of 21 days (intermittent social defeat stress [IS]). Behavioral tests (including novelty-suppressed feeding test, forced swimming test, and contextually conditioned fear) were conducted. Protein expression levels of phosphorylated CREB and BDNF in the dorsal and ventral hippocampi were examined. CS led to heightened anxiety-like behavior, fear, and increased levels of phosphorylated CREB in both the dorsal and ventral hippocampi. Conversely, IS resulted in increased anxiety-like behavior and behavioral despair alongside decreased levels of phosphorylated CREB and BDNF, particularly in the dorsal hippocampus. These findings indicate that chronic psychosocial stress divergently affects hippocampal CREB-BDNF signaling and emotional regulation depending on the stress episode. Such insights could enhance our understanding of the molecular basis of the heterogeneity of psychiatric disorders and facilitate the development of innovative treatment approaches to patients with psychiatric disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Sleep disturbances are not only frequent symptoms, but also risk factors for major depressive disorder. We previously reported that depressed patients who experienced "Hypersomnia" showed a higher and more rapid response rate under paroxetine treatment, but the underlying mechanism remains unclear. The present study was conducted to clarify the beneficial effects of sleep rebound through an experimental "Hypersomnia" rat model on glucocorticoid and hippocampal neuroplasticity associated with antidepressive potency., Methods: Thirty-four male Sprague-Dawley rats were subjected to sham treatment, 72-h sleep deprivation, or sleep deprivation and subsequent follow-up for one week. Approximately half of the animals were sacrificed to evaluate adrenal weight, plasma corticosterone level, hippocampal content of mRNA isoforms, and protein of the brain-derived neurotrophic factor (Bdnf) gene. In the other half of the rats, Ki-67- and doublecortin (DCX)-positive cells in the hippocampus were counted via immunostaining to quantify adult neurogenesis., Results: Prolonged sleep deprivation led to adrenal hypertrophy and an increase in the plasma corticosterone level, which had returned to normal after one week follow-up. Of note, sleep deprivation-induced decreases in hippocampal Bdnf transcripts containing exons II, IV, VI, and IX and BDNF protein levels, Ki-67-(+)-proliferating cells, and DCX-(+)-newly-born neurons were not merely reversed, but overshot their normal levels with sleep rebound., Limitations: The present study did not record electroencephalogram or assess behavioral changes of the sleep-deprived rats., Conclusions: The present study demonstrated that prolonged sleep deprivation-induced adversities are reversed or recovered by sleep rebound, which supports "Hypersomnia" in depressed patients as having a beneficial pharmacological effect., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anorexia nervosa (AN) is a chronic, life-threatening disease with mental and physical components that include excessive weight loss, persistent food restriction, and altered body image. It is sometimes accompanied by hyperactivity, day-night reversal, and amenorrhea. No medications have been approved specific to the treatment of AN, partially due to its unclear etiopathogenesis. Because adiponectin is an appetite-regulating cytokine released by adipose tissue, we hypothesized that it could be useful as a specific biomarker that reflects the disease state of AN, so we developed a modified AN mouse model to test this hypothesis. Twenty-eight 3-week-old female C57BL/6J mice were randomly assigned to the following groups: 1) no intervention; 2) running wheel access; 3) food restriction (FR); and 4) activity-based anorexia (ABA) that included running wheel access plus FR. After a 10-day cage adaptation period, the mice of the FR and ABA groups were given 40% of their baseline food intake until 30% weight reduction (acute FR), then the body weight was maintained for 2.5 weeks (chronic FR). Running wheel activity and the incidence of the estrous cycle were assessed. Spontaneous food restriction and the plasma adiponectin level were evaluated at the end of the acute and chronic FR phases. An increase in running wheel activity was found in the light phase, and amenorrhea was found solely in the ABA group, which indicates that this is a good model of AN. This group showed a slight decrease in spontaneous food intake accompanied with an attenuated level of normally induced plasma adiponectin at the end of the chronic FR phase. These results indicate that the plasma adiponectin level may be a useful candidate biomarker for the status or stage of AN., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kuriyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Psychosocial stress factors, such as threat and defeat, are major risk factors for the development of depression. The precise mechanisms underlying stress-induced depression are not clearly understood because the stress response in the brain varies in a stress-frequency-dependent manner. In the current research milieu on the pathogenesis of depression, the focus is on depression-like behavioral phenotype, hypothalamic-pituitary-adrenal (HPA) axis, and hippocampal neurogenesis. However, most studies have evaluated the symptomatic features of depression at certain time points after exposure to psychosocial stress. Here, we examined the frequency-dependent effects of psychosocial stress on depression-related features in rats., Methods: In the present study, different frequencies (one, two, three, or four times) of psychosocial stress were applied to 19 male Sprague-Dawley rats using a resident/intruder paradigm. Subsequently, the rats were subjected to a stress reactivity test to evaluate HPA axis activity, following which assessments of immobility behavior in the forced swimming test (FST) and adult neurogenesis were conducted., Results: One-time stressed rats showed a decrease in immobility behavior in the FST and the amount of doublecortin (DCX)-positive cells. Two-time stress caused hypoactivity of the HPA axis. In contrast, immobility behavior and HPA axis activity were increased after four-time stress exposure, but the number of DCX-positive cells was decreased., Conclusions: Our findings suggest that psychosocial stress produces a biphasic effect on the symptoms of depression in a stress-frequency-dependent manner, which could provide insights to facilitate further pathogenesis research on depression., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Early-life social isolation induces emotional and cognitive dysregulation, such as increased aggression and anxiety, and decreases neuron excitability in the medial prefrontal cortex (mPFC). The noradrenergic system in the mPFC regulates emotion and cognitive function via α 1 or α 2A adrenergic receptors, depending on noradrenaline levels. However, social isolation-induced changes in the mPFC noradrenergic system have not been reported. Here, male Wistar rats received post-weaning social isolation for nine consecutive weeks and were administered behavioral tests (novel object recognition, elevated plus maze, aggression, and forced swimming, sequentially). Protein expression levels in the mPFC noradrenergic system (α 1 and α 2A adrenergic receptors, tyrosine hydroxylase, and dopamine-β-hydroxylase used as indices of noradrenaline synthesis and release) were examined through western blotting. Social isolation caused cognitive dysfunction, anxiety-like behavior, and aggression, but not behavioral despair. Socially-isolated rats exhibited increased protein levels of the α 1 adrenergic receptor, tyrosine hydroxylase, and dopamine-β-hydroxylase in the mPFC; there was no significant difference between the groups in the α 2A adrenergic receptor expression levels. Preferential activation of the α 1 adrenergic receptor caused by high noradrenaline concentration in the mPFC may be involved in social isolation-induced emotional and cognitive regulation impairments. Targeting the α 1 adrenergic receptor signaling pathway is a potential therapeutic strategy for psychiatric disorders with symptomatic features such as emotional and cognitive dysregulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients undergoing chemotherapy for cancer frequently experience fatigue, which can significantly lower their quality of life and interfere with treatment. However, the risk factors for the occurrence of chemotherapy-induced fatigue (CIF) are unclear. In this study, we investigated the occurrence of CIF in 415 patients newly treated with chemotherapy at Fukuoka University Hospital between December 2020 and July 2022, and analyzed the factors that influence the occurrence of fatigue. The observation period was defined as the two-week period starting from the day after the induction of chemotherapy, and we collected data retrospectively from medical records. Fatigue was assessed based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 by pharmacists who interviewed patients. The prevalence of fatigue was 56.4% (234/415). Nausea and vomiting, anorexia, hypoalbuminemia, and a high blood urea nitrogen/creatinine (BUN/Cr) ratio were extracted as risk factors for CIF. The prevalence of fatigue in 95 patients with nausea and vomiting was 83.2% (79/95), of whom 74.7% (59/79) had concomitant anorexia. Patients with nausea and vomiting had a high prevalence of both fatigue and anorexia, indicating that control for nausea and vomiting is crucial for the prevention of CIF. The serum albumin level reflects the nutritional status of patients approximately three weeks before chemotherapy, and BUN/Cr ≥20 indicates dehydration. Patients with a poor nutritional status or dehydration should be closely monitored for fatigue before and during treatment. These findings offer new prospects for healthcare providers to avoid or reduce CIF and improve patients' quality of life by early control of CIF risk factors.

An 82-year-old male with jaundice was referred to our hospital for a detailed examination. The computed tomography (CT) examination detected an enhanced mass lesion of the distal bile duct. Endoscopic retrograde cholangiography showed a filling defect corresponding to the CT findings. Simultaneously, a forceps biopsy and an endoscopic retrograde biliary drainage were performed. We performed pancreatoduodenectomy, and adenocarcinoma was pathologically proven. The histopathological finding of the resected specimen was a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) composed of large cell neuroendocrine carcinoma and well-differentiated adenocarcinoma. Although pathological R0 resection was achieved, liver metastasis was observed 6 months after the operation. Although neuroendocrine carcinoma (NEC) rarely develops in the bile duct, it manifests a higher degree of malignancy than other ordinary bile duct adenocarcinomas. Further investigation is needed to choose an appropriate treatment.

Sleep loss induces performance impairment and fatigue. The reactivation of human herpesvirus-6, which is related to the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), is one candidate for use as an objective biomarker of fatigue. Phosphorylated eIF2α is a key regulator in integrated stress response (ISR), an intracellular stress response system. However, the relation between sleep/sleep loss and ISR is unclear. The purpose of the current study was to evaluate the effect of prolonged sleep deprivation and recovery sleep on ISR-related gene expression in rat liver. Eight-week-old male Sprague-Dawley rats were subjected to a 96-hour sleep deprivation using a flowerpot technique. The rats were sacrificed, and the liver was collected immediately or 6 or 72 h after the end of the sleep deprivation. RT-qPCR was used to analyze the expression levels of ISR-related gene transcripts in the rat liver. The transcript levels of the Atf3 , Ddit3 , Hmox-1 , and Ppp15a1r genes were markedly increased early in the recovery sleep period after the termination of sleep deprivation. These results indicate that both activation and inactivation of ISRs in the rat liver occur simultaneously in the early phase of recovery sleep.

Aims: Chronic stress and glucocorticoid exposure are risk factors for depression. Oxytocin (OT) has been shown to have antistress and antidepressant-like effects in male rodents. However, depression is twice as common in women than in men, and it remains unclear whether OT exerts antidepressant-like effects in women with depression. Therefore, in this study, we investigated the therapeutic effect of chronic OT administration in a female mouse model of dexamethasone (DEX)-induced depression., Methods: Female C57BL/6J mice were administered saline (vehicle, s.c.), DEX (s.c.), or OT (i.p.) + DEX (s.c.) daily for 8 weeks, and then assessed for anxiety- and depression-like behaviors. We also examined the hippocampal levels of phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF), which are important mediators of the response to antidepressants., Results: Simultaneous OT treatment blocked the adverse effects of DEX on emotional behaviors. Furthermore, it upregulated p-CREB and BDNF in the hippocampus., Conclusion: OT may exert antidepressant-like effects by activating hippocampal CREB-BDNF signaling in a female mouse model of depression., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Context: Mutations in the NR0B1 gene, also well-known as the DAX1 gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to NR0B1 mutations may be compensated by inducing loss of function of NR5A1 protein., Patient: A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel NR0B1 mutation, c.1222C>T(p.Gln408Ter)., Methods: NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter., Results: TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor., Conclusion: The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

A 69-year-old man on hemodialysis for chronic renal failure was diagnosed with ascending colon cancer, and received surgical resection. Multiple liver metastases were detected after surgery. He was administered modified FOLFOX6 therapy (reducing the dose to 50%), and showed severe disturbance of consciousness due to hyperammonemia on treatment day 6. After treatment with daily hemodialysis, branched-chain amino acid solutions, lactulose and rifaximin, his conscious level improved on day 9. Intensive chemotherapy in dialysis patients should be carefully performed considering the serious adverse events including hyperammonemia.

Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1 G71A mutant protein under the control of Thy1 promoter. These mice exhibited apathy-like behavior and parkinsonism. However, it is possible that this phenotype was due to a gene-dosage imbalance or transgene insertion position. To circumvent these potential caveats, we have generated a knock-in mouse model carrying a p.G71A mutation in Dctn1. Heterozygous Dctn1 G71A and wild-type littermates were subjected to a battery of behavioral analyses. Furthermore, immunohistochemistry for tyrosine hydroxylase (TH) was performed on brain sections of these mice, and TH signal intensity in substantia nigral neurons was quantified. Dctn1 G71A mice were immobile for longer than wild-type mice of the same age and sex in the tail-suspension test, revealing depressive characteristics. In addition, the beam-walking test and pole test detected motor deficits in Dctn1 G71A female mice. Finally, immunostaining revealed a decrease in TH immunoreactivity in neurons of the substantia nigra in the Dctn1 G71A mice. Collectively, heterozygous Dctn1 G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, as judged by TH immunostaining, thereby exhibiting multiple features of Perry disease. Hence, this mouse model will be useful in elucidating pathological mechanisms of Perry disease and for developing novel therapeutic strategies against it., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Urinary sodium-to-potassium ratios are known to be high in preschoolers, but there are no reports comparing these ratios with those of the children's mothers. The aim of this study was to investigate the association between the urinary sodium-to-potassium ratios of mothers and their preschool children under the hypothesis that the ratio is equivalent between the two. We evaluated 297 preschoolers aged four to five attending six kindergartens (four in northern Japan, two in southern Japan), and we also evaluated the children's mothers. We asked the participants to take morning first urine samples for 2 consecutive days in the spring and autumn of the same year (four samples per participant) and to fill out a dietary questionnaire. There was a correlation between the urinary sodium-to-potassium ratios of preschoolers and those of their mothers. However, in a comparison between the preschoolers and their mothers overall, higher values were found in the preschoolers [preschoolers: 4.6 (3.5-6.3) mmol/L/g·Cr; mothers: 4.3 (3.9-4.7) mmol/L/g·Cr, p = 0.003]. These results correlated with the urinary sodium-to-potassium ratios estimated from the dietary questionnaire. The preschoolers showed high sodium and low potassium intake consumption compared to the mothers. Interestingly, these were found to differ by region and gender. In conclusion, the urinary sodium-to-potassium ratio in Japanese preschoolers is related to and higher than that of their mothers. It is important to educate children, their parents, childcare professionals, and society as a whole about proper salt restriction and potassium supplementation, as well as to improve the food environment., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

The patient was a woman in her early 60s with type 4 advanced cancer which spread throughout the entire stomach. Total gastrectomy with regional lymphadenectomy was performed. She was diagnosed as Stage Ⅳ scirrhous gastric cancer with positive lavage cytology pathologically without any macroscopic peritoneal metastasis(P0CY1). S-1 plus cisplatin therapy was carried out as first-line therapy, but must be stopped after 2 courses because of appetite loss. As the second-line, ramucirumab monotherapy was administered, due to the patient's denial of alopecia and numbness as side effects of paclitaxel. Tumor marker value of CA19-9 remained high 24 months after ramucirumab chemotherapy, but gradually decreased near the normal level with no proof of distant metastasis or peritoneal dissemination. However, after 74 courses, CA19-9 value was elevated and peritoneal dissemination was detected from CT scan. Nivolumab therapy was started as third-line, but only for 5 courses because of indefinite complaints. Afterwards, no chemotherapy has been performed as the patient's request until almost 5 years after surgery. The prognosis of patients with P0CY1 gastric cancer is generally poor, but in our case long-term survival was obtained from ramucirumab therapy only. Recently, ramucirumab monotherapy is administered for advanced HCC patients and expect to be effective in AFP producing gastric cancer. There is an urgent need to elucidate potential predictive biomarkers of ramucirumab efficacy.

A 77-year-old man was given a diagnosis of pT4aN0M1a(PUL2), stage Ⅳ, RAS mutant type, after the operation for advanced ascending colon cancer. He was administered mFOLFOX6 plus Bmab as first-line chemotherapy. He showed consciousness disturbance on the 2nd day during the 6 cycles. Because of head computed tomography and magnetic resonance imaging showing no abnormal findings, we diagnosed convulsive seizure. His consciousness level gradually improved after intravenous infusion. He showed consciousness disturbance on the 2nd day during the 7 cycles again. Because blood ammonia level were high at 400μg/dL, he was diagnosed as hyperammonemic encephalopathy. His consciousness level rapidly recovered after branched chain amino acid(BCAA)infusion. SOX plus Bmab therapy was started as a post-treatment, he developed hyperammonemia(NH3 288μg/dL)again, on the 4th day during the 3 cycles. After taking of oral administration of BCAA and lactulose, the recurrence of hyperammonemic encephalopathy was not found. Therefore, 3 cycles of SOX plus Bmab therapy and 12 cycles of IRIS plus Bmab therapy were administered.

Bone morphogenetic protein (BMP) signaling in the hippocampus regulates psychiatric behaviors and hippocampal neurogenesis in non-stress conditions; however, stress-induced changes in hippocampal BMP signaling have not yet been reported. Therefore, we sought to examine whether psychosocial stress, which induces psychiatric symptoms, affects hippocampal BMP signaling. A total of 32 male Sprague-Dawley rats were exposed to a psychosocial stress using a Resident/Intruder paradigm for ten consecutive days. Subsequently, rats were subjected to a battery of behavioral tests (novelty-suppressed feeding test, sucrose preference test, and forced swimming test) for the evaluation of adult neurogenesis and activity of BMP signaling in the dorsal and ventral hippocampus. Repeated social defeat promoted anxiety-like behaviors, but neither anhedonia nor behavioral despair. Socially defeated rats exhibited an increase in the number of Ki-67-positive cells, decrease in the number of doublecortin (DCX)-positive cells, and decrease only in the dorsal hippocampus of the ratio of DCX-positive to Ki-67-positive cells, a proxy for newly-born cell maturation speed and survival. In contrast, no differences were observed in the number of 5-Bromo-2'-deoxyuridine (BrdU)-positive cells, indicating survival of newly-born cells both in the dorsal and ventral hippocampus. Furthermore, psychosocial stress significantly increased the BMP-4 and phosphorylated Smad1/5/9 expression levels specifically in the dorsal hippocampus. Our findings suggest that repeated psychosocial stress activates BMP signaling and differently affects cell proliferation and neurogenesis exclusively in the dorsal hippocampus, potentially exacerbating anxiety-related symptoms. Targeting BMP signaling is a potential therapeutic strategy for psychiatric disorders., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

To prevent and treat hypertension, it is important to restrict salt in one's diet since adolescence. However, an effective salt-reduction education system has yet to be established. Besides accurate evaluation, we believe that the frequent usage of a measurement device may motivate individuals to avoid high salt intake. The present study evaluated the use of a urinary salt excretion measurement device for salt-reduction education in a parallel randomized trial of two groups. The sample comprised 100 university students who provided consent to participate. A survey with 24-hour home urine collection and blood pressure measurement was conducted. Participants in the self-monitoring group measured their own urinary salt excretion level for 4 weeks, using the self-measurement device. Analyses were conducted on 51 participants in the control group and 49 in the self-monitoring group. At baseline, there was no significant difference between the two groups in terms of their characteristics and 24-hour urinary salt excretion levels. After intervention, 24-hour urinary sodium/potassium ratio showed no change in the control group [baseline score: 4.1 ± 1.5; endline score: 4.2 ± 2.0; P = 0.723], but it decreased significantly in the self-monitoring group [baseline score: 4.0 ± 1.7; endline score: 3.5 ± 1.4; P = 0.044]. This change was significant even after adjusting for baseline and endline differences between groups using analysis of covariance (P = 0.045). The self-monitoring urinary salt excretion measurement device improved the 24-hour urinary sodium/potassium ratio. The device is a useful and practical tool for educating young individuals about dietary salt reduction., (©2019 Wiley Periodicals, Inc.)

The recently discovered circular RNAs (circRNAs) are mostly formed by back-splicing where the downstream 5' splice site splices to the upstream 3' splice site by conventional pre-mRNA splicing. These circRNAs regulate gene expression by acting as sponges for micro-RNAs or RNA-binding proteins. Here we show that the NR5A1 (previously called Ad4BP or SF-1) gene which is exclusively expressed in the adrenal cortex and steroidogenic tissue can form atypical circRNAs by unconventional splicing. Two stem loops with inositol-requiring protein-1α (IRE1α) cleavage sites are connected by an IRE1α cleavage site to form a circRNA (circIRE RNA). From total RNA of normal human adrenal cortex, we detected a circIRE RNA with connected ends by IRE1α cleavage sites in exon 6 and exon 1 (circIRE NR5A1 ex6-1 RNA). circIRE NR5A1 ex6-1 RNA was not detected in the adrenocortical cancer cell line, H295R. When IRE1α was expressed in H295R cells a different circIRE NR5A1 RNA connecting IRE1-cleavage sites in exon 7 and exon 1 was detected (circIRE NR5A1 ex7-1 RNA). The expression of this circIRE RNA was inhibited by the IRE1 inhibitor 1, STF-083010, implicating that it was formed via the ER stress pathway, where IRE1α is a major factor. This is the first report of this type of circular RNA connected by IRE1-cleavage sites found to be expressed in mammalian cells in a tissue-specific manner. To our surprise, the concomitant expression of NR5A1 was increased by IRE1α implicating that NR5A1 was not subjected to IRE1-dependent decay of mRNA (RIDD) but rather activating a transcriptional regulatory network to cope with ER stress in steroidogenic tissue reminiscent to XBP1 in other tissue. We believe this is the first report of such tissue-specific transcriptional cascade responding to ER stress as well as the novel finding of circular RNAs connected by IRE1α cleavage sites expressed in mammalian tissue., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Quetiapine, an atypical antipsychotic, has been used for the treatment of several neuropsychiatric disorders. However, the underlying mechanism of the broad therapeutic range of quetiapine remains unknown. We previously reported that several aversive conditions affect dorsal/ventral hippocampal neurogenesis differentially. This study was aimed to elucidate the positive effects of chronic treatment with quetiapine on regional differences in hippocampal proliferation and immature neurons and behavioral changes under psychosocial stress using the Resident-Intruder paradigm. Twenty-three male Sprague-Dawley rats were intraperitoneally administered a vehicle or quetiapine (10 mg/kg) once daily for 28 days. Two weeks after starting the injections, animals were exposed to intermittent social defeat (four times over two weeks). The behavioral effects of stress and quetiapine were evaluated by the Novelty-Suppressed Feeding (NSF) test. The stereological quantification of hippocampal neurogenesis was estimated using immunostaining with Ki-67 and doublecortin (DCX). Chronic quetiapine treatment stimulated the Ki-67- and DCX-positive cells in the dorsal hippocampus, but not in the ventral subregion. The stress-induced changes in neurogenesis and hyponeophagic behavior were not reversed by repeated administration of quetiapine. Future study with additional behavioral tests is needed to elucidate the functional significance of the quetiapine-induced increase in dorsal hippocampal neurogenesis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The present study aimed to evaluate salt-reduction education using a self-monitoring urinary salt-excretion device., Design: Parallel, randomized trial involving two groups. The following parameters were checked at baseline and endline of the intervention: salt check sheet, eating behaviour questionnaire, 24 h home urine collection, blood pressure before and after urine collection., Setting: The intervention group self-monitored urine salt excretion using a self-measuring device for 4 weeks. In the control group, urine salt excretion was measured, but the individuals were not informed of the result., Subjects: Seventy-eight individuals (control group, n 36; intervention group, n 42) collected two 24 h urine samples from a target population of 123 local resident volunteers. The samples were then analysed., Results: There were no differences in clinical background or related parameters between the two groups. The 24 h urinary Na:K ratio showed a significant decrease in the intervention group (-1·1) compared with the control group (-0·0; P=0·033). Blood pressure did not change in either group. The results of the salt check sheet did not change in the control group but were significantly lower in the intervention group. The score of the eating behaviour questionnaire did not change in the control group, but the intervention group showed a significant increase in eating behaviour stage., Conclusions: Self-monitoring of urinary salt excretion helps to improve 24 h urinary Na:K, salt check sheet scores and stage of eating behaviour. Thus, usage of self-monitoring tools has an educational potential in salt intake reduction.

Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K₂) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent.

Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2'-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA . In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5' splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5' splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5' splice site of exon 1 offers novel insight on 5' splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

Previous studies have indicated that sleep deprivation negatively affects hippocampal neurogenesis, which may explain the reason for the relation between sleep loss and depression. Increasing evidence indicates that the hippocampus is anatomically and functionally segregated along a dorsolateral (cognitive function)/ventromedial (control for mood and stress response) axis. Thus, the present study was conducted to elucidate regional differences in the adverse effects of sleep deprivation on hippocampal neurogenesis. Male Sprague-Dawley rats were subjected to sleep deprivation using the "platform on the water" method for 24- or 72-h. Quantification of hippocampal cell proliferation and immature newborn neurons was stereologically estimated using immunostaining with Ki-67 and doublecortin (DCX), respectively, by optical fractionator method. A consecutive three days of sleep deprivation significantly reduced the density of Ki-67- and DCX-immunopositive cells both in the dorsal and ventral hippocampal subgranular zone and the decrease in DCX-labeled cells was more pronounced in the ventral hippocampus than in dorsal region. Our results indicate that prolonged sleep deprivation decreases hippocampal cell proliferation and neurogenesis in both the dorsal and ventral dentate gyrus. Future studies will be needed to clarify the impact of sleep deprivation-induced decreases in hippocampal neurogenesis on the development of depression., (Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)

Obesity causes hyperleptinemia. We have previously shown that D 2 receptor-mediated inhibition of ventral tegmental area (VTA) dopaminergic neurons is attenuated in diet-induced mice with obesity. Consequently, we hypothesized that high concentrations of serum leptin during obesity might modulate D 2 receptor-mediated effects on VTA dopaminergic neurons. To investigate our hypothesis, we examined leptin effects on D 2 receptor-mediated inhibition of putative VTA dopaminergic neurons from lean mice using electrophysiological techniques. Leptin (100 nmol/L) directly inhibited spontaneous firing in 71% of putative VTA dopaminergic neurons (leptin-responsive), whereas the remaining 29% of neurons were leptin-nonresponsive. In 41% of leptin-responsive neurons, leptin attenuated the reduced firing rate produced by quinpirole (100 nmol/L), whereas the remaining 59% of neurons exhibited no effect of leptin. In leptin-nonresponsive neurons, no significant leptin-induced effect was observed on reduced firing rate produced by quinpirole. In leptin-responsive neurons with positive leptin-induced attenuation of quinpirole effects, leptin-induced attenuation persisted for >20 min, whereas no such persistent attenuation was observed in other types of neurons. In conclusion, leptin attenuates D 2 receptor-mediated inhibition in a subpopulation of putative VTA dopaminergic neurons. We suggest that leptin directly decreases, and indirectly increases, excitability of VTA dopaminergic neurons. In turn, this may contribute to a change in feeding behavior through the mesolimbic dopaminergic system during the development of obesity., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background and Objectives: Malnutrition is an important prognostic factor for patients with liver disease and a novel nutritional assessment tool is required for these patients. The aim of this study was to validate the Mini Nutritional Assessment (MNA) as a nutritional screening tool for patients with liver disease, by comparing MNA scores with other nutrition-related parameters., Methods and Study Design: Patients who were hospitalized at the gastroenterology division of Kyushu and Beppu Medical Center were enrolled. The study included 77 patients with liver disease (male/female, 46/31; mean±SD age, 68.5±10.7 years; liver cirrhosis, 64.9%; liver cancer, 61.0%). Correlations of MNA score at hospital admission with anthropometric parameters and blood test data were evaluated., Results: In patients with liver disease, MNA scores demonstrated that 18 (23.4%) had normal nutritional status, 41 (53.2%) were at risk of malnutrition, and 18 (23.4%) were malnourished, indicating that up to 76.6% of the liver disease group were malnourished. Especially, patients with liver cirrhosis had lower scores of nutritional markers and MNA. The MNA score in liver cirrhotic patients correlated with the following parameters: % arm circumference, % triceps skinfolds, ratio of % maximum grasp strength and arm circumference, maximum grasp strength, arm muscle circumference, calf circumference, serum albumin levels, the controlling nutritional status score, and Onodera's prognostic index, while patients without liver cirrhosis did not show such correlation., Conclusions: MNA scores correlated with nutrition-related data in patients with liver cirrhosis. The MNA is an appropriate tool for nutritional screening assessment in these cirrhotic patients of any etiology.

BACKGROUND Psoriasis is known as the most frequent disease treated by long-term topical steroids. It is also known that patients with thick, chronic plaques require the highest potency topical steroids. However, the treatment is limited to up to four weeks due to risk of systemic absorption. CASE REPORT An 80-year-old man was diagnosed with type 2 diabetes 16 years before, and was being administered insulin combined with alpha glucosidase inhibitor. He was diagnosed with plaque psoriasis and his oral steroid treatment was switched to topical steroid treatment due to lack of improvement and poorly controlled blood glucose level. The hypoglycemic events improved after the psoriatic lesions improved. CONCLUSIONS Control of blood glucose level is difficult at the very beginning of topical steroid treatment for psoriasis especially if a patient is receiving insulin treatment. Intense monitoring of blood glucose level during initiation of topical steroid treatment is necessary to prevent unfavorable complications.

The authors investigated interannual differences in the sodium excretion levels of young healthy Japanese women as estimated from spot urine analysis at Nakamura Gakuen University from 1995 to 2015. Participants included 4931 women aged 18 to 20 years who were classified into three time periods according to year of health check: first (1995-2001), second (2002-2007), and third (2008-2015). Estimated daily urinary sodium and potassium excretion levels and the sodium to potassium ratio were 120.6±31.9 mmol, 35.2±8.1 mmol, and 3.5±0.9, respectively. Adjusted for body weight, sodium excretion, and potassium excretion significantly decreased in the second and third period compared with the first period (P<.001). Systolic blood pressure also decreased in the same way between time periods (P<.001). Estimated urinary excretion levels of sodium and potassium in young Japanese women have decreased over the past 20 years independently of body weight., (©2017 Wiley Periodicals, Inc.)

In this study, the authors measured sodium and potassium concentrations in spot urine samples of preschool children on multiple days, and evaluated individual, daily, and seasonal effects. A total of 104 healthy preschool children aged 4 to 5 years were studied. Urine samples were collected from the first urine of the day after waking for three consecutive days (Monday-Wednesday) four times a year (spring, summer, autumn, winter). The authors estimated the daily urine volume as 500 mL and daily creatinine excretion as 300 mg, and used these to calculate daily sodium and potassium excretion levels. Daily sodium and potassium excretion levels and sodium to potassium ratios were highly variable. The coefficient variant in the children's excretion levels were also high within and between individuals. Sodium excretion levels and sodium to potassium ratios were higher on Monday (weekend sodium intakes) than Tuesday. Season had no effect on sodium or potassium excretion levels, but the sodium to potassium ratio was higher in summer than in winter. In conclusion, levels of urinary sodium excretion are comparatively high and those of potassium are low in preschool students, with high variability within and between individuals., (©2017 Wiley Periodicals, Inc.)

Background: Obese persons have a higher incidence of depression than healthy-weight persons. Several studies indicated that the exposure to a high fat diet (HFD) results in a decrease in hippocampal neurogenesis, which leads to higher stress response and stress-induced depression. Although stress is a risk factor for obesity and depression, no studies to date have investigated the effect of stress on the hippocampal neurogenesis of HFD-induced obese animals. The aim of this study was to elucidate whether or not obese HFD-fed mice are vulnerable to stress-induced depression by investigating hippocampal neurogenesis., Methods: Sixty-four male ICR mice (four weeks of age) were fed a control (N=24) or 45%HFD (N=40) for seven weeks. Of the HFD-fed group, twenty-four mice met the criteria for "diet-induced obesity". The animals were then exposed to three consecutive days of psychological stress using a Communication Box. Half were sacrificed to evaluate the physiological changes, and the other half were perfused to quantify hippocampal neuroblasts/immature neurons by the estimation of doublecortin-immunopositive cells., Results: In the HFD-fed mice, psychological stress resulted in increases in caloric intake and visceral adipose tissue and a significant decrease in doublecortin-positive cells in the dentate gyrus; however, no such differences were found in the control diet-fed group. Limitations Further study using other neurogenic markers to assess the stage-specific changes in hippocampal neurogenesis will be required CONCLUSIONS: Our findings suggest that an HFD-induced decrease in hippocampal newly-born neurons leads to stress vulnerability, which may contribute to a high risk of stress-induced depression for obese persons., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The salt check sheet developed by Tsuchihashi et al. is widely used in general practice to assess salt intake and the associated diets. However, its appropriateness for the general population has not been assessed alongside 24-h urinary salt excretion monitoring. Therefore, in local residents, we analyzed the correlation between check-sheet scores and 24-h urinary salt excretion levels to determine the appropriateness of the check sheet. We asked 176 local residents to complete the salt check sheet and provide urinary samples; the latter were obtained using a proportional sampling method over a 24-h period. One hundred and forty subjects completed the study (men/women: 23/117, mean±s.d. age: 52.7±19.6 years, blood pressure: 122.3±18.0/74.3±11.1 mm Hg), of whom 51 (36.4%) had hypertension. The total salt check-sheet scores were widely distributed (mean±s.d.: 11.1±4.2 points, range: 0-22 points), and the subjects were divided into the following groups on the basis of salt levels: 29.3% were 'low' (0-8 points), 42.8% were 'medium' (9-13 points), 23.6% were 'high' (14-19 points) and 4.3% were 'very high' (>20 points). The mean 24-h urinary salt excretion level was 8.5±3.3 g. The subjects with higher salt-intake levels tended to have increased 24-h urinary salt excretion levels, with significant differences between the three groups ('low' vs. 'medium' vs. 'high to very high' salt levels: 7.6±2.9 g vs. 8.4±2.8 g vs. 9.6±4.2 g, respectively; P=0.03). The total salt check-sheet scores significantly correlated with the 24-h urinary salt excretion levels (r=0.27; P<0.01). Thus, the salt check sheet is applicable for the general population.

Background and study aims: We previously reported our discovery of a white opaque substance (WOS) that is opaque to endoscopic light inside the epithelium while using magnifying endoscopy (ME) to examine gastric epithelial neoplasia. Histopathologic analysis revealed that the WOS comprises minute lipid droplets (LDs) accumulated within the neoplastic epithelium. In addition, the WOS was found in colorectal epithelial neoplasia, although it was unclear whether this WOS corresponded to an accumulation of LDs, as in the stomach. Therefore, the aim of the current study was to elucidate whether the WOS observed in colorectal epithelial tumors comprises LDs. Patients and methods: A consecutive series of 40 WOS-positive and 40 WOS-negative colorectal epithelial tumors was analyzed. One biopsy specimen was taken from each neoplasm. Cryostat sections were stained with oil red O for LD, and sections after formalin-fixation for LD were immunostained with anti-adipophilin antibody. Results: The prevalence of LDs stained with oil red O in WOS-positive vs. WOS-negative lesions was 47.5 % (19/40) vs. 5 % (2/40), respectively ( P  < 0.001). Furthermore, the WOS coincided with the expression of adipophilin; the prevalence of LDs stained by anti-adipophilin antibody in WOS-positive vs. WOS-negative lesions was 100 % (40/40) vs. 62.5 % (25/40), respectively ( P  < 0.001). Conclusions: This study elucidated for the first time that endoscopically visualized WOS in colorectal epithelial neoplasia may be composed of LDs accumulated in the neoplastic epithelium.

Sorbitol polyglycidyl ether (SPE) which is a bio-based water-soluble epoxy resin was cured with chitosan (CS) and/or a commercial water-soluble polyamidoamine- or polyetheramine-type epoxy hardener (PAA or PEA). Furthermore, biocomposites of the CS-cured SPE (CS-SPE) and CS/PAA- or CS/PEA-cured SPE (SPE-CA or SPE-CE) biocomposites with chitin nanofiber (CNF) were prepared by casting and compression molding methods, respectively. The curing reaction of epoxy and amino groups of the reactants was confirmed by the FT-IR spectral analysis. SPE-CS and SPE-CA were almost transparent films, while SPE-CE was opaque. Transparency of SPE-CS/CNF and SPE-CA/CNF became a little worse with increasing CNF content. The tanδ peak temperature of SPE-CS was higher than those of SPE-PAA and SPE-PEA. SPE-CA or SPE-CE exhibited two tanδ peak temperatures related to glass transitions of the CS-rich and PAA-rich or PEA-rich moieties. The tanδ peak temperatures related to the CS-rich and PAA-rich moieties increased with increasing CNF content. A higher order of tensile strengths and moduli of the cured resins was SPE-CS≫SPE-CA>SPE-CE. The tensile strength and modulus of each sample were much improved by the addition of 3wt% CNF, while further addition of CNF caused a lowering of the strength and modulus., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β 2 -microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate.

Background and Aim: White opaque substance (WOS) is a novel endoscopic finding in gastric neoplasms, indicating the intracellular accumulation of lipid droplets (LDs). However, gastric lipid metabolism has not been extensively investigated, even in normal mucosa. We investigated the expression profiles of lipid-metabolism-associated genes in gastric neoplasms., Methods: Thirty-four patients with early gastric cancer or adenoma were enrolled in this study. Paired biopsy samples from tumor and adjacent non-tumor areas were obtained and analyzed by real-time polymerase chain reaction. Endoscopically resected specimens were evaluated histopathologically., Results: Genes associated with β-oxidation (peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1A, and hydroxyacyl-CoA dehydrogenase), lipoprotein excretion (apolipoprotein B, microsomal triglyceride transfer protein, and acyl-CoA:cholesterol acyltransferase 2), fatty acid transport (fatty acid-binding protein), construction of triglycerides in the endoplasmic reticulum (acyl-CoA:diacylglycerol acyltransferase 1), and LD degradation/lipolysis (comparative gene identification-58, adipose triglyceride lipase) were significantly downregulated in neoplasms compared with non-tumor areas. Pyruvate dehydrogenase lipoamide kinase isozyme 4 (negative regulator of glycolysis) and adipophilin (LD surface component) were also repressed. Conversely, expression levels of genes associated with de novo lipogenesis (sterol regulatory element-binding protein 1c, acyl-CoA:diacylglycerol acyltransferase 2) were significantly enhanced in neoplasms. There was no significant difference in gene expression levels between carcinomas and adenomas, or between WOS-positive and WOS-negative neoplasms., Conclusion: Gene expression profiles in neoplasms suggest a predominance of lipid storage (lipogenesis/LD formation) over consumption (β-oxidation/excretion/lipolysis). Lipid accumulation and WOS in gastric epithelial neoplasms may be caused by impaired mitochondrial oxidation, lipoprotein excretion, and LD degradation., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Self-measured salt excretion from overnight urine samples shows significant correlation with 24-h-urinary salt excretion, but it is not known whether a self-measuring method can monitor daily fluctuations in individual salt consumption. In this study, we measured salt excretion from 24-h urine samples (24-h salt) in 50 volunteers over 3 test days (2 weekdays and 1 holiday), and examined to what extent the values correlated with estimates of 24-h salt excretion from overnight urine samples obtained using a self-monitoring device (ON salt). Urine collection was considered successful when the difference between the predicted and actual 24-h-urinary creatinine excretion was within 30%. Thirty-three (M/F=7/26; 39.6±16.7 years) out of 50 participants completed their urine collections successfully and their samples were used in the analysis. Twenty-four-hour salt and ON salt did not significantly differ between test days and between the weekdays and the holiday. Moreover, there was a significant positive correlation between 24-h salt and ON salt for each test day. The coefficients of variation (CVs) for 24-h salt among test days and among subjects were 24.7% and 21.3%, respectively. The CVs for ON salt were lower than those for 24-h salt (13.3% and 17.7%, respectively). In conclusion, self-measurement of salt excretion from overnight urine samples allows estimation of daily salt intake; thus, the use of a self-monitoring device may be a useful motivational tool for personal salt restriction.

Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis- N,N -dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo . The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article.

Background: The 5-hydroxytryptamine (5-HT) 1A receptors are considered a potential target for the treatment of mental and neuropsychiatric disorders. Several studies have indicated that 5-HT1A receptor agonists increase hippocampal neurogenesis, which is implicated in the action mechanism of antidepressants. However, these agents have not been applied to humans due to intolerable side effects. We recently showed that chronic administration of tandospirone, a clinically available 5-HT1A receptor partial agonist, increased hippocampal neurogenesis dose-dependently. The present study was done to determine if chronic tandospirone treatment has antidepressant potential from the standpoint of hippocampal neurogenesis and behavior., Methods: Male Sprague-Dawley rats were intraperitoneally administered a vehicle or tandospirone (10mg/kg) once daily for 28 days. Two weeks after starting the injections, animals were exposed to intermittent social defeat (four times over two weeks). The effects of stress and tandospirone on the rodents׳ behavior were evaluated by the Novelty-Suppressed Feeding (NSF) test. The quantification of hippocampal neurogenesis was estimated using immunostaining with Ki-67 and doublecortin (DCX)., Results: Chronic tandospirone treatment reversed the psychosocial stress-induced increase in the latency in the NSF test and decrease in the density of DCX-positive cells in the dentate gyrus of the dorsal and ventral hippocampus. However, no difference in the density of Ki-67-positive cells was observed between the vehicle- and tandospirone-administered groups., Limitations: To clarify the antidepressant potential of TDS, the other behavioral tests for depression will be required., Conclusions: Our findings suggest that tandospirone has antidepressant potential through an inhibiting effect on stress-induced changes in hippocampal neurogenesis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aim: To investigate the relationship between the iron-metabolism-related gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients., Methods: The hepatic expression profile of iron-metabolism-related genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolism-related genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry., Results: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes., Conclusion: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.

Background & Aims: Injury to biliary epithelial cells caused by disorders in bile composition may be the initial step in the pathogenesis of primary biliary cirrhosis (PBC). We therefore examined choline/phospholipid metabolism in livers of patients with PBC., Methods: Hepatic levels of mRNA encoded by choline metabolism-related genes in early stage PBC patients were quantified by real-time RT-PCR. Serum cholesterol and triglyceride concentrations in each lipoprotein compartment and serum/tissue choline levels were also measured. OCT1 expression was quantified by genotype (rs683369 and rs622342)., Results: Serum choline concentrations were significantly higher in PBC patients than in normal individuals, with the concentrations in the former lowered by treatment with fibrates. Hepatic choline levels were markedly lower in PBC patients than in controls. The levels of expression of genes associated with choline uptake (OCT1 and CTL1), phosphatidylcholine synthesis (PEMT and BHMT), and phosphatidylcholine transport (MDR3) were significantly upregulated in PBC compared with control livers. Serum cholesterol concentrations and the cholesterol/triglyceride ratio in serum very low density lipoprotein were markedly higher in PBC patients than in controls. In PBC liver, OCT1 protein levels were lower in patients with minor (CG/GG at rs683369 and/or CC at rs622342) than major (CC at rs683369 and AA at rs622342) genotypes of the OCT1 gene., Conclusion: During early stage PBC, hepatocellular choline uptake and PC synthesis become dysregulated. OCT1 genotypes may influence the pathogenesis of PBC., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)