Search

Pituitary adenylate cyclase-activating polypeptide (PACAP) plays an essential role in the modulation of astrocyte functions. Although lactate secretion from astrocytes contributes to many forms of neuronal plasticity in the central nervous system, including fear learning and memory, the role of PACAP in lactate secretion from astrocytes is unclear. The amygdala and hippocampus of PACAP (+ / +) and PACAP (−/−) mice were acquired 1 h after memory acquisition and recall in the passive avoidance test. The concentration of glycogen and lactate in these regions was measured. The concentration of lactate in the hippocampus's extracellular fluid was also measured by microdialysis during memory acquisition or intracerebroventricular administration of PACAP. We observed that memory acquisition caused a significant decrease in glycogen concentration and increased lactate concentration in the PACAP (+ / +) mice's hippocampus. However, memory acquisition did not increase in the lactate concentration in PACAP (−/−) mice's hippocampus. Further, memory retrieval evoked lactate production in the amygdala and the hippocampus of PACAP (+ / +) mice. Still, there was no significant increase in lactate concentration in the same regions of PACAP (−/−) mice. In vivo microdialysis in rats revealed that the hippocampus's extracellular lactate concentration increased after a single PACAP intracerebroventricular injection. Additionally, the hippocampus's extracellular lactate concentration increased with the memory acquisition in PACAP (+ / +) mice, but not in PACAP (−/−) mice. PACAP may enhance lactate production and secretion in astrocytes during the acquisition and recall of fear memories.

IntroductionA diet high in saturated fat is well known to affect neuronal function and contribute to cognitive decline in experimental animals and humans. Fractalkine released from neurons acts on its receptor, CX3C chemokine receptor 1 (CX3CR1), in the microglia to regulate several brain functions. The present study addressed whether fractalkine-CX3CR1 signaling in the brain, especially the hippocampus, contributes to the cognitive deficits observed in diet-induced obese (DIO) mice.Research design and methodsMice were given 60% high-fat diet for 16 weeks. The expression of fractalkine and CX3CR1 in the hippocampus, amygdala and prefrontal cortex of DIO mice was analyzed. Cognitive ability in the Y-maze test and hippocampal glutamate receptors and synaptic markers were observed in DIO and CX3CR1 antagonist-treated mice. Regulation of fractalkine and CX3CR1 expression in the hippocampus was examined following administration of a selective insulin-like growth factor-1 (IGF-1) receptor inhibitor and a tyrosine receptor kinase B (TrkB) antagonist in normal mice.ResultsDIO mice exhibited significant cognitive deficits in the Y-maze test and decrease in fractalkine and CX3CR1 in the hippocampus and amygdala compared with mice fed a control diet (CD mice). Administration of the CX3CR1 antagonist 18a in normal mice induced significant cognitive deficits in the Y-maze test. DIO mice and CX3CR1 antagonist-treated mice exhibited significant decreases in protein levels of NMDA (N-methyl-D-aspartate) receptor subunit (NR2A), AMPA (α-amino-5-methyl-3-hydroxy-4-isoxazole propionate) receptor subunit (GluR1) and postsynaptic density protein 95 in the hippocampus compared with their respective controls. Furthermore, plasma IGF-1 and hippocampal brain-derived neurotrophic factor were significantly decreased in DIO mice compared with CD mice. Administration of a selective IGF-1 receptor inhibitor and a TrkB antagonist in normal mice significantly decreased fractalkine and CX3CR1 in the hippocampus.ConclusionsThese findings indicate that the cognitive decline observed in DIO mice is due, in part, to reduced fractalkine-CX3CR1 signaling in the corticolimbic system.

Pituitary adenylate cyclase-activating polypeptide (PACAP) plays an essential role in the modulation of astrocyte functions. Although lactate secretion from astrocytes contributes to many forms of neuronal plasticity in the central nervous system, including fear learning and memory, the role of PACAP in lactate secretion from astrocytes is unclear.The amygdala and hippocampus of PACAP (+ / +) and PACAP (-/-) mice were acquired 1 h after memory acquisition and recall in the passive avoidance test. The concentration of glycogen and lactate in these regions was measured. The concentration of lactate in the hippocampus's extracellular fluid was also measured by microdialysis during memory acquisition or intracerebroventricular administration of PACAP.We observed that memory acquisition caused a significant decrease in glycogen concentration and increased lactate concentration in the PACAP (+ / +) mice's hippocampus. However, memory acquisition did not increase in the lactate concentration in PACAP (-/-) mice's hippocampus. Further, memory retrieval evoked lactate production in the amygdala and the hippocampus of PACAP (+ / +) mice. Still, there was no significant increase in lactate concentration in the same regions of PACAP (-/-) mice. In vivo microdialysis in rats revealed that the hippocampus's extracellular lactate concentration increased after a single PACAP intracerebroventricular injection. Additionally, the hippocampus's extracellular lactate concentration increased with the memory acquisition in PACAP (+ / +) mice, but not in PACAP (-/-) mice.PACAP may enhance lactate production and secretion in astrocytes during the acquisition and recall of fear memories.

Atractylenolide-III (AIII), a sesquiterpene compound isolated from the rhizome of Atractylodes macrocephala, has been reported to have anti-inflammatory effects in the peripheral organs. However, its effects on brain inflammation remain elusive. The present study investigated the effects of AIII on the response to lipopolysaccharide (LPS) in mouse microglia and clarified the underlying mechanism. In this study, treatment of MG6 cells with AIII (100 μM) significantly decreased the mRNA expression and protein levels of toll-like receptor 4 (TLR4). In addition, pretreatment of MG6 cells and primary cultured microglia cells with AIII (100 μM) significantly decreased the mRNA expression and protein levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 induced by LPS (5 ng/mL) without cytotoxicity. Subsequently, pretreatment with AIII significantly suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) after LPS stimulation in MG6 cells. These results showed that AIII downregulated TLR4 expression, leading to suppression of the p38 MAPK and JNK pathways, which in turn inhibited the production of pro-inflammatory cytokines and enzymes in LPS-stimulated microglia. Our findings, therefore, suggest the potential for AIII as a therapeutic agent for the treatment of brain inflammation, particularly in microglia-associated inflammation., Atractylenolide-III, Mouse microglia, Cytokine, TLR4, p38 MAPK, JNK

The mesolimbic dopamine system is important for the rewarding and motivational aspects of consuming rewarding and palatable food. Nicotinic receptors are present in the mesolimbic dopamine system and enhance the reinforcement of drugs of abuse. In this study, we examined the involvement of nicotine receptor subtypes in sucrose addiction in a sucrose preference paradigm. Sucrose preference and intake in mice increased in proportion to stepwise increases in sucrose concentrations. Moreover, sucrose preference and intake following sucrose withdrawal in mice were increased in comparison with the first set of trials. In the present study, α7, but not α4 and β2, nicotinic receptor subunit mRNA was decreased in the nucleus accumbens, but not in the hypothalamus, after sucrose withdrawal and subsequent sucrose intake. Administration of an agonist for α7, but not α4 and β2, nicotinic receptors suppressed the enhancement of sucrose preference and intake following sucrose withdrawal. These findings indicate that α7 nicotinic receptor activation suppresses sucrose addiction in a sucrose preference test in mice.

The establishment process of high-producing Chinese hamster ovary (CHO) cells for therapeutic protein production is usually laborious and time consuming because of the low probability of obtaining stable, high-producing clones over a long term. Thus, development of an efficient approach is required to establish stable, high-producing cells. This study presents a novel method that can efficiently establish sustainably high-producing cell lines by acceleration of transgene amplification and suppression of transgene silencing. The effects of breast cancer 1 (BRCA1) downregulation on gene amplification efficiency and long-term productivity were investigated in CHO cells. Small interfering RNA expression vectors against BRCA1 were transfected into the CHO DG44-derived antibody-producing cell clone. Individual cell clones were obtained after induction of gene amplification in the presence of 400 nM methotrexate, which were cultured until passage 20. BRCA1-downregulated cell clones CHO B1Sa and B1Sb displayed 2.2- and 1.6-fold higher specific production rates than the S-Mock clone. Fluorescence in situ hybridization showed that transgene amplification occurred at a high frequency in B1Sa and B1Sb clones. Moreover, B1Sa and B1Sb clones at 20 passages had approximately 3.5- and 5.3-fold higher productivity than the S-Mock clone. Histone modification analysis revealed a decrease in an active mark for transcription, trimethylation of histone H3 at lysine 4 (H3K4), in the transgene locus of the S-Mock clone. However, H3K4 trimethylation levels were not decreased in B1Sa and B1Sb clones during long term culture. Our results suggest that high-producing cells, which maintain their productivity long-term, were efficiently established by BRCA1 downregulation.

Hesperidin, a flavanone glycoside consisting of the flavone hesperitin bound to the disaccharide rutinose, is found in highly nutritious foods, such as oranges, tangelos, tangerines, grapefruits, and other citrus fruits. Exogenous hesperidin has been shown to influence a wide variety of biological functions, including induction of apoptosis and suppression of proliferation in human cancer cells; inhibition of tumor development in various tissues; and expression of antibacterial, antiviral, and antifungal activities. Previous in vivo studies have revealed that hesperidin may play a role in ghrelin secretion from the stomach through antagonism of the serotonin receptors. Because ghrelin appears to be involved in the pathophysiological mechanisms of several human disorders, hesperidin could be a promising target for the treatment of various diseases. This review addresses studies focused on the orexigenic and prokinetic activities of hesperidin in the context of ghrelin secretion. This article also presents some promising patents of hesperidin.

The purpose of this study was to determine how a group of institutionalized elderly Japanese women perceived animal-assisted activity (AAA) and how their perceptions may be relevant to clinical nursing practices in the AAA context. The participants in this study, 8 elderly Japanese women residing in a nursing home in a northern Japanese city, had attended AAA sessions two times per month for 2 years prior to this study's data collection. Semi-structured interviews were conducted, and data were analyzed using phenomenological procedures. Six themes emerged concerning the interactive relationships between the participants and the animals; in addition, participants were able to develop interest in themselves, other residents, and their environment, due to feelings of ease and the development of one-on-one relationships with the AAA dogs. Volunteers from outside the nursing home made residents feel refreshed and gave them opportunities to broaden their contact with society.

Obesity is becoming a worldwide problem, as it is associated with serious comorbidities, including a high incidence of type II diabetes, cardiovascular disease and many forms of cancer. Obesity is defined as increased adipose mass resulting from chronic excess of energy intake over energy expenditure. Energy homeostasis including food intake and energy consumption has been demonstrated to be regulated predominantly by orexigenic and anorexigenic systems in the hypothalamus. The blood-born hormones, such as leptin, insulin and ghrelin, modulate activities of the orexigenic and anorexigenic neuropeptide-containing neurons in the hypothalamus. In addition, epidemiological studies have demonstrated that the incidence of depression and cognitive impairment is high in obese subjects compared to normal body weight subjects. Therefore, obese animal models that are pathophysiologically relevant to human obesity are very useful for understanding the mechanisms underlying the development of obesity and obesity-associated syndromes. This chapter shows representative animal obese models that are used to analyze pathophysiological properties of obesity.

Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Musclin possesses a region homologous to the natriuretic peptide family. Thus, musclin is found to bind with the natriuretic peptide clearance receptors. However, the role of musclin in vascular regulation remains unclear. In this study, we aim to investigate the direct effect of musclin on vascular tone and to analyze its role in hypertension using the spontaneously hypertensive rats (SHR). In aortic strips isolated from SHR, musclin induced contractions in a dose-dependent manner. We found that the musclin-induced vasoconstriction was more marked in SHR than in normal rats (WKY). Moreover, this contraction was reduced by blockade of natriuretic peptide receptor C using the ab14355 antibody. Therefore, mediation of the natriuretic peptide receptor in musclin-induced vasoconstriction can be considered. In addition, similar to the natriuretic peptide receptor, expression of the musclin gene in blood vessels was higher in SHR than in WKY. Injection of musclin markedly increased the blood pressure in rats that can be inhibited by anti-musclin antibodies. Musclin-induced vasoconstriction was more pronounced in SHR than in WKY as in its expression. Taken together, these results suggest that musclin is involved in blood pressure regulation. The higher expression of musclin in hypertension indicates that musclin could be used as a new target for the treatment of hypertension in the future.