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Alzheimer's disease (AD) has been considered as a metabolic dysfunction disease associated with impaired insulin signaling. Determining the mechanisms underlying insulin signaling dysfunction and resistance in AD will be important for its treatment. Impaired clearance of amyloid-β peptide (Aβ) significantly contributes to amyloid accumulation, which is typically observed in the brain of AD patients. Reduced expression of important Aβ-degrading enzymes in the brain, such as neprilysin (NEP) and insulin-degrading enzyme (IDE), can promote Aβ deposition in sporadic late-onset AD patients. Here, we investigated whether insulin regulates the degradation of Aβ by inducing expression of NEP and IDE in cultured astrocytes. Treatment of astrocytes with insulin significantly reduced cellular NEP levels, but increased IDE expression. The effects of insulin on the expression of NEP and IDE involved activation of an extracellular signal-regulated kinase (ERK)-mediated pathway. The reduction in cellular NEP levels was associated with NEP secretion into the culture medium, whereas IDE was increased in the cell membranes. Moreover, insulin-treated astrocytes significantly facilitated the degradation of exogenous Aβ within the culture medium. Interestingly, pretreatment of astrocytes with an ERK inhibitor prior to insulin exposure markedly inhibited insulin-induced degradation of Aβ. These results suggest that insulin exposure enhanced Aβ degradation via an increase in NEP secretion and IDE expression in astrocytes, via activation of the ERK-mediated pathway. The inhibition of insulin signaling pathways delayed Aβ degradation by attenuating alterations in NEP and IDE levels and competition with insulin and Aβ. Our results provide further insight into the pathological relevance of insulin resistance in AD development., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Infection with hepatitis E virus (HEV) genotypes 3 and 4 are usually asymptomatic but can occasionally result in life-threatening acute hepatitis. To date, only sporadic cases together with a few outbreaks have been documented. Seroprevalence studies with assays for the detection of HEV IgG antibodies, suggest that HEV is more prevalent than previously thought, even in non-endemic regions., Objectives: The aim of this study was to characterize an outbreak of hepatitis E (HE) in a nursing home for aged people between February and March 2016., Study Design: After the identification of two cases living in the same nursing home, the presence of antibodies against HEV and HEV RNA were examined in serum samples collected from the other residents and staff members to identify any additional cases. An epidemiological investigation was also carried out., Results: Only 4 patients showed mild symptoms such as anorexia, abdominal pain and fatigue. Among the 125 persons tested, 28 residents and one dietitian were confirmed positive for anti-HEV IgA or IgM antibodies, and/or HEV RNA. Eight samples had only IgG antibodies. Finally, 22 cases were notified with HE on the basis of the presence of IgA antibodies. All HEV isolates obtained were 99.8-100% identical and belonged to genotype 3., Conclusion: HEV infections seem to be under-reported or underestimated possibly due to cases being generally asymptomatic. Testing for the presence of both anti-HEV antibodies and HEV RNA would be beneficial for both the comprehensive diagnosis of HE infections and the prevention of further infections., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Amyloid-β (Aβ) production and clearance in the brain is a crucial focus of investigations into the pathogenesis of Alzheimer disease. Imbalance between production and clearance leads to accumulation of Aβ. The important Aβ-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), and defective enzyme expression may facilitate Aβ deposition in sporadic late-onset AD patients. It has been suggested that epigallocatechin gallate (EGCG), a member of the catechin family, might be an effective treatment for AD, because it has been shown to elevate NEP expression. Therefore, we examined whether catechins, which are functional components of common foods, could regulate the degradation of Aβ by inducing NEP and IDE expression. We also investigated the role of catechins in activating intracellular signal transduction in astrocytes. Treatment of cultured rat astrocytes with EGCG significantly reduced the expression of NEP, but not IDE, in a concentration- and time-dependent manner. NEP expression in cultured astrocytes was suppressed by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), and reduced NEP expression was accompanied by an increase of NEP release into the extracellular space (culture medium). Moreover, culture medium from EGCG-treated astrocytes facilitated the degradation of exogenous Aβ. These results suggest that EGCG may have a beneficial effect on AD by activating ERK-and PI3K-mediated pathways in astrocytes, thus increasing astrocyte secretion of NEP and facilitating degradation of Aβ., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Ingesting the amino acid l-ornithine effectively improves lipid metabolism in humans, although it is unknown whether it affects the activities of autonomic nerves that supply the peripheral organs related to lipid metabolism, such as adipose tissues. Thus, we investigated the effects of l-ornithine ingestion on autonomic nerves that innervate adipose tissues and the feeding behaviors of rats. Intragastric injection of l-ornithine (2.5%) in urethane-anesthetized rats activated sympathetic nerve activity to white adipose tissue (WAT-SNA), and stimulated sympathetic nerve activity to brown adipose tissue (BAT-SNA). In addition, WAT-SNA responses to l-ornithine were abolished in rats with ablated abdominal vagal nerves. l-ornithine ingestion for 9 weeks also significantly reduced rats' body weight, food intake, and abdominal fat weight. Proopiomelanocortin (POMC) levels in the hypothalamus and uncoupling protein 1 (UCP1) levels in brown adipose tissue were significantly increased in rats that ingested 2.5% l-ornithine for 9 weeks. These results suggested that ingested l-ornithine was taken up in the gastrointestinal organs and stimulated afferent vagal nerves and activated the central nervous system. Subsequently, increased hypothalamic POMC activated sympathetic neurotransmission to adipose tissues and accelerated energy expenditure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Anaphylactic shock is sometimes life-threatening, but the defense system against this circulatory failure was not fully understood. Ameliorating roles of angiotensin (ANG) II and vasopressin in anaphylactic hypotension were investigated in anesthetized ovalbumin-sensitized Sprague-Dawley rats. The sensitized rats were randomly allocated to the following pretreatment groups (n=7/group): (1) control (non-pretreatment), (2) ANG II synthesis inhibitor captopril, (3) ANG II receptor antagonist losartan, and (4) V1a vasopressin receptor antagonist. Anaphylactic shock was induced by an intravenous injection of the antigen. The systemic arterial pressure (SAP), central venous pressure (CVP), portal venous pressure (PVP) and portal venous blood flow (PBF) were measured, and splanchnic vascular resistance (Rspl: (SAP-PVP)/PBF) was determined. In the control group, SAP markedly decreased, followed by a gradual recovery toward baseline. Rspl transiently decreased immediately after antigen, and then increased 1.5-fold at 15 min and thereafter. The pretreatment with either losartan, captopril or V1a receptor antagonist augmented the initial fall of SAP and attenuated the SAP recovery along with augmentation of the late increase in Rspl. The 2-h survival rate was significantly smaller in either pretreatment group than in the control group (100%). Plasma levels of ANG II and vasopressin increased to 3.8- and 9.8-fold, respectively, at 30 min after antigen in the control group, whereas captopril pretreatment inhibited the increase in ANG II. In conclusion, inhibition of ANG II or vasopressin exacerbates anaphylaxis-induced hypotension in anesthetized rats., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We previously demonstrated that the peptidergic neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP) affects the autonomic system and contributes to the control of metabolic and cardiovascular functions. Previous studies have demonstrated the importance of centrally-mediated sympathetic effects of leptin for obesity-related hypertension. Here we tested whether PACAP signaling in the brain is implicated in leptin-induced sympathetic excitation and appetite suppression. In anesthetized mice, intracerebroventricular (ICV) pre-treatment with PACAP6-38, an antagonist of the PACAP receptors (PAC1-R and VPAC2), inhibited the increase in white adipose tissue sympathetic nerve activity (WAT-SNA) produced by ICV leptin (2μg). In contrast, leptin-induced stimulation of renal sympathetic nerve activity (RSNA) was not affected by ICV pre-treatment with PACAP6-38. Moreover, in PACAP-deficient (Adcyap1-/-) mice, ICV leptin-induced WAT-SNA increase was impaired, whereas RSNA response was preserved. The reductions in food intake and body weight evoked by ICV leptin were attenuated in Adcyap1-/- mice. Our data suggest that hypothalamic PACAP signaling plays a key role in the control by leptin of feeding behavior and lipocatabolic sympathetic outflow, but spares the renal sympathetic traffic., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Previous studies have demonstrated that neuromedin U (NMU) affects cardiovascular functions such as blood pressure (BP) or heart rate (HR) in rats. Here, we examined the effects of the lateral cerebral ventricular (ICV) injection of various doses of NMU on renal sympathetic nerve activity (RSNA) and BP in urethane-anesthetized rats. ICV injection of NMU elevated RSNA, BP and HR in a dose-dependent manner. Moreover, neither ICV pretreatment of thioperamide, an antagonist of histaminergic H3-receptor, or of diphenhydramine, an antagonist of histaminergic H1-receptor, abolished increasing effects of NMU on RSNA, BP and HR In addition, ICV injection of NMU suppressed gastric vagal nerve activity (GVNA) and activated brown adipose tissue sympathetic nerve activity (BAT-SNA) of anesthetized rats, and elevated brown adipose tissue temperature (BAT-T) of conscious rats. Thus, these evidence suggest that NMU affects neural activities of autonomic nerves containing RSNA, GVNA or BAT-SNA, and BP by mediating central mechanism.

The effect on the pentobarbital sleep time by olfactory stimulation with various odorants was investigated using mice to appraise the physiological or psychological significance of olfactory information. The sleep time was determined as the time elapsed between intraperitoneal pentobarbital administration and the first time that the animal was able to spontaneously right itself. The sleep time was affected by inhalation of some odorants compared to pure air controls, but not by others. The sleep time was prolonged by terpinyl acetate and phenethyl alcohol, and was shortened by lemon oil and jasmin oil. However, neither potentiation nor attenuation of pentobarbital action by odorant inhalation was observed when using anosmic mice produced by intranasal zinc sulphate treatment. In conclusion, olfactory stimulation associated with odorant inhalation influences the pentobarbital sleep time, suggesting that olfactory information may have a more potent influence on the physiological and psychological status than has previously been thought.