A water channel closely related to rat brain aquaporin 4 is expressed in acid- and pepsinogen-secretory cells of human stomach

AbstractWe isolated a cDNA clone encoding a water channel protein, aquaporin (AQP), from human stomach. The encoded protein consisted of 323 amino acid residues, containing six putative transmembrane domains. The protein was designated human aquaporin 4 (hAQP4) because of its 94% sequence similarity to rat brain AQP4. Expression of hAQP4 cRNA in Xenopus oocytes resulted in a significant increase in osmotic water permeability, indicating that this protein functions as a water channel. Northern blot analysis demonstrated a strong signal of hAQP4 mRNA in brain, lung, and skeletal muscle as well as in stomach. Immunohistochemical experiments with human stomach tissues showed that hAQP4 as a protein is expressed mainly in cells located in the glandular portion of the fundic mucosa. These include chief cells which secrete pepsinogen and parietal cells which secrete hydrochloric acid. These results strongly indicate that hAQP4 is a principal factor involved in the osmotic regulation of pepsinogen and acid secretion in the stomach

Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders

The Impact of the COVID-19 Pandemic on the General Public in Urban and Rural Areas in Southern Japan

Urban and rural areas are situated in contrasting physical and social settings, which influence their levels of exposure as well as their preventive behaviors in response to the COVID-19 outbreak. The study investigated whether there were differences between the areas regarding the levels of difficulty and anxiety felt by the general public during the first wave of COVID-19 in April and May 2020. We conducted an online questionnaire in Fukuoka and Kumamoto Prefecture in southern Japan via a private research company and collected a total of 913 valid responses from individuals whose conditions of employment were affected by the coronavirus outbreak. Although urban areas experienced higher case rates compared to rural areas, ordinal logistic regression analysis revealed no significant differences between urban and rural respondents concerning the level of difficulty in routine life. The daily-life contents which made them feel difficult during the first wave also did not differ largely between the contrasting areas. Urban respondents appeared to have experienced a higher level of difficulty in finding an alternative job, but how respondents found one, if successful, did not differ between urban and rural areas. The area of residence played a role in explaining the level of anxiety toward being infected, especially when the anxiety-related questions involved relationships with neighbors. Rural respondents showed a significantly higher level of anxiety toward causing neighbors trouble and being criticized if infected. Respondents who were better embedded in their communities generally felt more anxious about being infected, regardless of whether they lived in urban or rural areas. Women and respondents with children were more likely affected by abnormal situations caused by the COVID-19 outbreak. Our study highlights the prevailing impact of the COVID-19 pandemic on the general public regardless of whether in urban or rural settings, as well as the potential contribution of social ties among people to protecting communities from infectious pathogens

Upregulation of lipoprotein receptors on brain endothelial cells and neurons in the early phase of ischemic stroke in mice

Current understanding on the mechanisms of acute stroke highlights the importance of targeting brain endothelial cells (ECs), which regulate blood–brain barrier (BBB) disruption, neuronal cell death, and immune cell infiltration. Because the transcellular pathway through ECs is activated immediately after stroke onset, understanding transporter expression should facilitate development of an efficient drug delivery system to ischemic ECs. Here, we examined BBB leakage profiles and expression of three lipoprotein receptors, lowdensity lipoprotein receptor (LDLR), scavenger receptor class B member 1 (SRB1), and LDLR-related protein 1 (LRP1), in a mouse model of permanent middle cerebral artery occlusion (MCAO). Evans blue staining showed a biphasic BBB disruption with one peak at 6 h and the other at 3 days after MCAO. The tight junction protein occludin in the ischemic cortex significantly decreased at 3 days, but not 6 h, after MCAO. LDLR, SRB1, and LRP1 mRNA levels were significantly up-regulated early after MCAO. LDLR and SRB1 proteins were colocalized predominantly in brain ECs, whereas LRP1 was localized in neurons in the ischemic cortex. The early overexpression of lipoprotein receptors after stroke suggests that lipoprotein-associated lipids could be suitable ligands for drug delivery into ECs and neurons in the acute ischemic brain

Bioinformatics Analysis of the Molecular Networks Associated with the Amelioration of Aberrant Gene Expression by a Tyr–Trp Dipeptide in Brains Treated with the Amyloid-β Peptide

Short-chain peptides derived from various protein sources have been shown to exhibit diverse bio-modulatory and health-promoting effects in animal experiments and human trials. We recently reported that the oral administration of the Tyr–Trp (YW) dipeptide to mice markedly enhances noradrenaline metabolism in the brain and ameliorates the working-memory deficits induced by the β-amyloid 25–35 peptide (Aβ25–35). In the current study, we performed multiple bioinformatics analyses of microarray data from Aβ25–35/YW-treated brains to determine the mechanism underlying the action of YW in the brain and to infer the molecular mechanisms and networks involved in the protective effect of YW in the brain. We found that YW not only reversed inflammation-related responses but also activated various molecular networks involving a transcriptional regulatory system, which is mediated by the CREB binding protein (CBP), EGR-family proteins, ELK1, and PPAR, and the calcium-signaling pathway, oxidative stress tolerance, and an enzyme involved in de novo l-serine synthesis in brains treated with Aβ25–35. This study revealed that YW has a neuroprotective effect against Aβ25–35 neuropathy, suggesting that YW is a new functional-food-material peptide

Tyr-Trp administration facilitates brain norepinephrine metabolism and ameliorates a short-term memory deficit in a mouse model of Alzheimer's disease.

The physiological actions of orally ingested peptides on the brain remain poorly understood. This study examined the effects of 39 orally administered synthetic Tyr-containing dipeptides on the enhancement of brain norepinephrine metabolism in mice by comparing the concentration of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Although Tyr-Tyr administration increased blood and cerebral cortex (Cx) Tyr concentrations the most, Tyr-Trp increased Cx MHPG concentration the most. The oral administration of Tyr-Trp ameliorated a short-term memory deficit of a mouse model of cognitive dysfunction induced by amyloid beta peptide 25-35. Gene expression profiling of mouse brain using a microarray indicated that Tyr-Trp administration led to a wide variety of changes in mRNA levels, including the upregulation of genes encoding molecules involved in catecholamine metabolism. A comparative metabolome analysis of the Cx of mice given Tyr-Trp or Tyr-Tyr demonstrated that Tyr-Trp administration yielded higher concentrations of Trp and kynurenine pathway metabolites than Tyr-Tyr administration, as well as higher L-dopa levels, which is the initial product of catecholamine metabolism. Catecholamines were not significantly increased in the Cx of the Tyr-Tyr group compared with the Tyr-Trp group, despite a marked increase in Tyr. Presumably, Tyr-Trp administration enhances catecholamine synthesis and metabolism via the upregulation of genes involved in Tyr and Trp metabolism as well as metabolites of Tyr and Trp. These findings strongly suggest that orally ingested Tyr-Trp modulates the brain metabolome involved in catecholamine metabolism and contributes to higher brain function

Atypical Cogan’s Syndrome Mimicking Giant Cell Arteritis Successfully Treated with Early Administration of Tocilizumab

A 49-year-old Japanese man with a 2-month history of a fever, headache, and bilateral conjunctival hyperemia was admitted. His condition fulfilled the giant cell arteritis classification criteria (new headache, temporal artery tenderness, elevated ESR) and atypical Cogan’s syndrome (CS) with scleritis and sensorineural hearing loss (SNHL). The interleukin (IL)-6 serum level was extremely high. Two weeks after his insufficient response of SNHL and scleritis to oral prednisolone, we administered tocilizumab (TCZ); rapid improvements in scleritis and SNHL occurred. Early IL-6 target therapy can help prevent irreversible CS-induced sensory organ damage