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We designed formulations based on minoxidil (MXD) nanoparticles (N-MXD) and examined whether N-MXD can increase drug delivery into the follicles. In addition, we investigated the effect of N-MXD on hair growth in C57BL/6 mice. N-MXD (1%) was prepared as follows: methylcellulose, p-hydroxyalkylbenzoates, mannitol, and MXD were dispersed in purified water and milled using zirconia beads under refrigeration (5500 rpm, 30 s×15 times, intermittent milling). C57BL/6 mice were used to evaluate hair-growth effects. The expression levels of mRNA and protein for vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) were determined by real-time PCR and ELISA methods, respectively. The ratio of solid-MXD was approximately 60% in N-MXD, and the MXD nanoparticles (90-300 nm) were oblong in shape. For the design of nanomedicines, usability is important. Therefore, we measured the stability and toxicity after N-MXD treatment. No agglutination of MXD nanoparticles was detected for 2 weeks, and no redness or MXD powder residue was observed in the skin after repetitive applications of N-MXD. Next, we evaluated hair-growth effects by N-MXD treatment. MXD contents in the skin tissue from N-MXD were lower than for commercially available MXD formulations (CA-MXD). Conversely, MXD contents in the hair bulbs were higher for N-MXD than for CA-MXD, and the drug efficacy of N-MXD was also higher than that of CA-MXD. In addition, the mRNA and protein levels of IGF-1 and VEGF were enhanced by the repetitive application of N-MXD and CA-MXD, and the enhanced IGF-1 and VEGF levels were significantly higher for N-MXD than for CA-MXD. We designed a novel nanomedicine based on MXD nanoparticles and showed that N-MXD can deliver MXD into hair bulbs via hair follicles and that the therapeutic efficiency for hair growth is higher than for CA-MXD (solution type).

Background:Lactobacillus casei strain Shirota (LcS) has been found to exert antiallergic effects in animal experiments, but there is little information about its clinical effects in human patients with allergy. Methods: We performed a randomized double-blind, placebo-controlled study to investigate the effects of LcS in patients with allergic rhinitis triggered by Japanese cedar pollen (JCP). Participants were asked to drink fermented milk containing LcS (LcS group) or placebo (control group) for 8 weeks. Clinical symptoms and immunological parameters were compared between the two groups. Results: Symptom-medication scores (SMS) worsened in accordance with the increase in the amount of scattered JCP. In terms of the nasal and ocular SMS, there was no significant difference between the LcS group and the placebo group during the ingestion period. In the subgroup of patients with moderate-to-severe nasal symptom scores before starting the ingestion of test samples, supplementation with LcS tended to reduce nasal SMS. Conclusion: These results indicate that fermented milk containing LcS does not prevent allergic symptoms in patients sensitive to JCP, but may delay the occurrence of allergic symptoms in patients with moderate-to-severe nasal symptom scores.

Pancreatic cancer is one of the most fatal cancers without druggable molecular targets. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional factor that promotes malignancy in various cancers including pancreatic cancer. Herein, we found that HIF-1 is accumulated in normoxic or moderate hypoxic areas of pancreatic cancer xenografts in vivo and is active even during normoxia in pancreatic cancer cells in vitro. This prompted us to analyze whether the HIF-1 activator Mint3 contributes to malignant features of pancreatic cancer. Mint3 depletion by shRNAs attenuated HIF-1 activity during normoxia and cell proliferation concomitantly with accumulated p21 and p27 protein in pancreatic cancer cells. Further analyses revealed that Mint3 increased transcription of the oncogenic ubiquitin ligase SKP2 in pancreatic cancer cells via HIF-1. This Mint3-HIF-1-SKP2 axis also promoted partial epithelial-mesenchymal transition, stemness features, and chemoresistance in pancreatic cancer cells. Even in vivo, Mint3 depletion attenuated tumor growth of orthotopically inoculated human pancreatic cancer AsPC-1 cells. Database and tissue microarray analyses showed that Mint3 expression is correlated with SKP2 expression in human pancreatic cancer specimens and high Mint3 expression is correlated with poor prognosis of pancreatic cancer patients. Thus, targeting Mint3 may be useful for attenuating the malignant features of pancreatic cancer.

Objectives: This study aimed to evaluate, using wearable sensors, the impact of transitioning from an 8-hour to a 12-hour shift schedule on sleep patterns and well-being in intensive care unit (ICU) nurses with pre-existing sleep disturbances. We also examined differences in outcome based on chronotype.Methods: We conducted an observational study at a university hospital ICU between November 2020 and October 2023, before and after a hospital-wide shift schedule change. Nurses wore wearable sensors and completed daily surveys over 5 weeks under each shift system. Rotating-shift ICU nurses with a Pittsburgh Sleep Quality Index score >5 were eligible. Sleep metrics and subjective well-being were compared using linear mixed models, adjusting for age. Sleep episodes were categorized relative to shift timing, and chronotype-stratified subgroup analyses were performed.Results: Eighty nurses completed the study (12-hour shift: 37; 8-hour shift: 43). The interval between shifts was greater for the 12-hour shift group (36.12 vs 26.78 hours). Total sleep duration did not significantly differ between groups (12-hour shift: 418.5 minutes; 8-hour shift: 398 minutes); however, the 12-hour shift group had less fragmented sleep, higher subjective well-being scores, and lower reported stress and fatigue. Evening chronotypes appeared to benefit more from 12-hour shifts, with longer sleep duration and higher well-being scores, though these differences were not statistically significant.Conclusions: Transitioning to a 12-hour shift schedule was associated with reduced sleep fragmentation and improved well-being, particularly among evening chronotypes. These findings suggest that shift schedule structure and individual chronotype may influence adaptation to shift work in ICU settings.

IntroductionThe intestinal barrier plays a crucial role in distinguishing foods from toxins. Prostaglandin D2 (PGD2) is one of the lipid-derived autacoids synthesized from cell membrane-derived arachidonic acid. We previously reported that pharmacological stimulation of PGD2 receptor, D prostanoid 1 (DP1) attenuated the symptoms of azoxymethane/dextran sodium sulfate-induced colitis and ovalbumin-induced food allergy in mouse models. These observations suggested that DP1 stimulation protects the intestinal barrier. The present study aimed to uncover the effects of DP1 stimulation on intestinal barrier function and elucidate the underlying mechanisms.Materials and methodsIntestinal permeability was assessed in mice by measuring the transfer of orally administered fluorescein isothiocyanate-dextran (40 kDa) into the blood. The DP1 agonist BW245C (1 mg/kg) was administered 10 min prior to dextran administration. The intestinal permeability was confirmed using the ex vivo everted sac method. Tight junction integrity was evaluated in vitro by measuring the transepithelial electrical resistance (TER) in the human intestinal epithelial cell line Caco-2. Mucus secretion was assessed by observing Alcian Blue-stained intestinal sections.ResultsPharmacological DP1 stimulation reduced intestinal permeability both in vivo and ex vivo . Immunohistochemical staining showed that DP1 was strongly expressed on the apical side of the epithelial cells. DP1 stimulation did not affect TER in vitro but induced mucus secretion from goblet cells. Mucus removal by a mucolytic agent N-acetyl-l-cysteine canceled the inhibition of intestinal permeability by DP1 stimulation.ConclusionThese observations suggest that pharmacological DP1 stimulation decreases intestinal permeability by stimulating mucus secretion.

Cancer cells adapt to various stress conditions by optimizing gene expression profiles via transcriptional and translational regulation. However, whether and how EXOSC9, a component of the RNA exosome complex, regulates adaptation to stress conditions and tumorigenicity in cancer cells remain unclear. Here, we examined the effects of EXOSC9 depletion on cancer cell growth under various stress conditions. EXOSC9 depletion attenuated growth and survival under various stress conditions in cancer cells. Interestingly, this also decreased the number of P-bodies, which are messenger ribonucleoprotein particles (mRNPs) required for stress adaptation. Meanwhile, EXOSC2/EXOSC4 depletion also attenuated P-body formation and stress resistance with decreased EXOSC9 protein. EXOSC9-mediated stress resistance and P-body formation were found to depend on the intact RNA-binding motif of this protein. Further, RNA-seq analyses identified 343 EXOSC9-target genes, among which, APOBEC3G contributed to defects in stress resistance and P-body formation in MDA-MB-231 cells. Finally, EXOSC9 also promoted xenografted tumor growth of MDA-MB-231 cells in an intact RNA-binding motif-dependent manner. Database analyses further showed that higher EXOSC9 activity, estimated based on the expression of 343 target genes, was correlated with poorer prognosis in some cancer patients. Thus, drugs targeting activity of the RNA exosome complex or EXOSC9 might be useful for cancer treatment.

Oxygen isotope ratios (δ18O) of tree-ring cellulose are a novel proxy for summer hydroclimate in monsoonal Asia. In central Japan, we collected 67 conifer wood samples, mainly Chamaecyparis obtusa, with ages encompassing the past 2600 years. The samples were taken from living trees, archeological wood, architectural wood, and buried logs. We analyzed stable isotope ratios of oxygen (δ18O) and hydrogen (δ2H) in tree-ring cellulose in these samples (more than 15 000 rings in total) without using a pooling method and constructed a statistically reliable tree-ring cellulose δ18O time series for the past 2500 years. However, there were distinct age trends and level offsets in the δ18O record, and cellulose δ18O values showed a gradual decrease as an individual tree matures. This suggested it is difficult to establish a cellulose δ18O chronology for low-frequency signals by simple averaging of all the δ18O time series data. In addition, there were opposite age trends in the cellulose δ2H, and δ2H gradually increased with tree age. There were clear positive correlations in the short-periodicity variations between δ18O and δ2H, probably indicating a common climate signal. A comparison of the δ18O and δ2H time series in individual trees with tree-ring width suggested that the opposite age trends of δ18O and δ2H are caused by temporal changes in the degree of post-photosynthetic isotope exchange with xylem water (physiological effect), accompanied by changes in stem growth rate that are influenced by human activity in the forests of central Japan. Based on the assumptions that cellulose δ18O and δ2H vary positively and negatively with constant proportional coefficients due to climatological and physiological effects, respectively, we solved simultaneous equations for the climatological and physiological components of variations in tree-ring cellulose δ18O and δ2H in order to remove the age trend. This enabled us to evaluate the climatic record from cellulose δ18O variations. The extracted climatological component in the cellulose δ18O for the past 2600 years in central Japan was well correlated with numerous instrumental, historical, and paleoclimatological records of past summer climate at various spatial and temporal scales. This indicates that integration of tree-ring cellulose δ18O and δ2H data is a promising method to reconstruct past summer climate variations on annual to millennial timescales, irrespective of the growth environment. However, analytical and statistical methods need to be improved for further development of this climate proxy.

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague–Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.

We present an annual-resolution, millennium-long tree-ring chronology for northern Japan. The chronology is based on 5309 measurements of tree-ring δ18O from 37 samples of Hiba arbor-vitae (Thujopsis dolabrata var. hondae). Although the exact geographical origin of 27 of the samples is unknown because they were extracted from excavated archaeological material, pattern matching of the tree-ring δ18O variations was robust among all 37 samples. The floating chronology constructed using all samples was cross-dated against a previously published δ18O chronology from central Japan, yielding a correlation coefficient of 0.26 (t = 9.0; p < 0.01), resulting in a temporal coverage of 417–1595 CE (i.e., 1179 yrs). The global 14C spike event at 774–775 CE was clearly recorded in the annual 14C data, which provides independent support for the dating of tree rings using oxygen isotopes. Furthermore, this δ18O chronology from northern Japan was used to successfully cross-date a wood sample buried during the “Millennium Eruption” of Baitoushan, which is located on the border between China and North Korea.

Calcifying cystic odontogenic tumors (CCOTs) are benign cystic tumors that form abnormally keratinized ghost cells. Mutations in CTNNB1, which encodes beta-catenin, have been implicated in the development of these tumors, but a causal relationship has not been definitively established. Thus, mutational hot spots in 50 cancer genes were examined by targeted next-generation sequencing in 11 samples of CCOT. Mutations in CTNNB1, but not in other genes, were observed in 10 of 11 cases. These mutations constitutively activate beta-catenin signaling by abolishing the phosphorylation sites Asp32, Ser33, or Ser37, and are similar to those reported in pilomatrixoma and adamantinomatous craniopharyngioma. In contrast, BRAF or NRAS mutations were observed in 12 and two control samples of ameloblastoma, respectively. In HEK293 cells, overexpression of mutated CTNNB1 also upregulated hair keratin, a marker of ghost cells. Furthermore, ghost cells were present in two cases of ameloblastoma with BRAF and CTNNB1 mutations, indicating that ghost cells form due to mutations in CTNNB1. The data suggest that mutations in CTNNB1 are the major driver mutations of CCOT, and that CCOT is the genetic analog of pilomatrixoma and adamantinomatous craniopharyngioma in odontogenic tissue.