Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

Nasal Drug Absorption from Powder Formulations: Effect of Fluid Volume Changes on the Mucosal Surface.

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.

DNA methylation-dependent modulator of Gsg2/Haspin gene expression.

The Gsg2 (Haspin) gene encodes a serine/threonine protein kinase and is predominantly expressed in haploid germ cells. In proliferating somatic cells, Gsg2 is shown to be expressed weakly but plays an essential role in mitosis. Although the Gsg2 minimal promoter recognized by the spermatogenic cell-specific nuclear factor(s) has been found, to date, the molecular mechanism that differentially controls Gsg2 expression levels in germ and somatic cells remains to be sufficiently clarified. In this study, we analyzed the DNA methylation status of the upstream region containing the Gsg2 promoter. We found a tissue-dependent and differentially methylated region (T-DMR) upstream (-641 to -517) of the authentic promoter that is hypomethylated in germ cells but hypermethylated in other somatic tissues. Profiling of Gsg2 expression and DNA methylation status at the T-DMR in spermatogenic cells indicated that the hypomethylation of the T-DMR is maintained during spermatogenesis. Using the reporter assay, we also demonstrated that DNA methylation at the T-DMR of Gsg2 reduced the promoter activity by 60-80%, but did not fully suppress it. Therefore, the T-DMR functions as a modulator in a DNA methylation-dependent manner. In conclusion, Gsg2 is under epigenetic control.

Brain microstructural properties related to subjective well-being: diffusion tensor imaging analysis.

Although it is known that health is not merely the absence of disease, the positive aspects of mental health have been less comprehensively researched compared with its negative aspects. Subjective well-being (SWB) is one of the indicators of positive psychology, and high SWB is considered to benefit individuals in multiple ways. However, the neural mechanisms underlying individual differences in SWB remain unclear, particularly in terms of brain microstructural properties as detected by diffusion tensor imaging. The present study aimed to investigate the relationship between measurements of diffusion tensor imaging [mean diffusivity (MD) and fractional anisotropy] and the degree of SWB as measured using a questionnaire. Voxel-based analysis was used to investigate the association between MD and SWB scores in healthy young adults (age, 20.7 ± 1.8 years; 695 males and 514 females). Higher levels of SWB were found to be associated with lower MD in areas surrounding the right putamen, insula, globus pallidus, thalamus and caudate. These results indicated that individual SWB is associated with variability in brain microstructural properties.

[Effect of withdrawal of 5-fluorouracil bolus administration on recovery from neutropenia in colorectal cancer patients treated with mFOLFOX6 chemotherapy-comparison with total dosage reduction].

A combination of oxaliplatin(L-OHP), folinic acid and 5-fluorouracil(5-FU)(mFOLFOX6)has been widely administered to treat advanced or recurrent colorectal cancer. In this regimen, a bolus of 5-FU is administered intravenously, followed by its 46-hr continuous intravenous infusion. For 12 patients who showed neutropenia during mFOLFOX6 chemotherapy at Itami City Hospital, we investigated neutrophil recovery by comparing a patient group treated by the withdrawal of the 5-FU bolus administration(n=6)with a patient group treated by total dose reduction of L-OHP, as well as both the bolus and continuous 5-FU administration(n=6). After two weeks, the neutrophil numbers in the bolus withdrawal group showed a relatively higher value than that in the total dose reduction group[p= 0.032]. For patients showing neutropenia related to mFOLFOX6 chemotherapy, withdrawal of 5-FU bolus administration is suggested to be an effective method of promoting the recovery of neutrophil numbers.

DNA hypomethylation circuit of the mouse oocyte-specific histone H1foo gene in female germ cell lineage.

The oocyte-specific subtype of the linker histone H1 is H1FOO, which constitutes a major part of oocyte chromatin. H1foo is expressed in growing oocytes, through fertilization, up until the two-cell embryo stage, when it is subsequently replaced by somatic H1 subtypes. To elucidate whether an epigenetic mechanism is involved in the limited expression of H1foo, we analyzed the dynamics of the DNA methylation status of the H1foo locus in germ and somatic cells. We identified a tissue-dependent and differentially methylated region (T-DMR) upstream of the H1foo gene, which was hypermethylated in sperm, somatic cells, and stem cell lines. This region was specifically unmethylated in the ovulated oocyte, where H1foo is expressed. 5-Aza-2'-deoxycytidine treatments and luciferase assays provided in vitro evidence that DNA methylation plays a role in repressing H1foo in nonexpressing cells. DNA methylation analyses of fetal germ cells revealed the T-DMR to be hypomethylated in female and male germ cells at Embryonic Day 9.5 (E9.5), whereas it was highly methylated in somatic cells at this stage. Intriguingly, the unmethylated status was continuously observed throughout oogenesis at E9.5, E12.5, E15.5, E18.5, in mature oocytes, and after fertilization, in E3.5 blastocysts. In comparison, male germ cells acquired methylation beyond E18.5. These data demonstrate a continuously unmethylated circuit at the H1foo locus in the female germline.