Niemann–Pick disease type C (NPC) is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application.
In this study, we assessed a lifestyle in which occupants adjust the fittings based on climate, weather, and time, in terms of energy efficiency and thermal conditions. The proposed solution is a Zero Energy House (ZEH) with high thermal performance. The thermal performance of the building envelope can be adjusted by changing the operation of fittings based on the indoor and outdoor environments, as well as air conditioning usage. Many studies have achieved zero energy by increasing the thermal performance of an envelope and using highly efficient energy-saving facilities; however, uniquely, here we focus on occupant behavior to change the building envelope condition. In this paper, numerical analysis was used to investigate the effect of adjusting the fittings on buildings with different thermal performances of the envelope. The analysis demonstrates that, while more research into measures is needed in the summer, the adjustment of fittings and thermal storage properties in the winter season can reduce the heating load by 48–59% compared to the normal ZEH and improve the indoor environment. In terms of the heating and cooling load throughout the year, the results also showed that applying fittings adjustment and heat storage to an ordinary house can provide nearly the same energy-saving effect as a highly insulated house.
Childhood obesity is rapidly increasing worldwide and is largely the consequence of adoption of unhealthy diets excessive in calories and salt (NaCl) as well as devoid in pivotal micronutrients such as potassium (K) and magnesium (Mg). Education-based programs aiming to encourage healthy food knowledge and behaviors are crucial at a young age, and for this purpose, convenient ways to assess daily dietary intake are warranted. We therefore attempted to evaluate the dietary intake of Okinawan schoolchildren in Japan by analyzing a series of biomarkers in morning spot urine samples and explore whether these biomarkers correlate with body weight and a series of metabolic parameters. We enrolled 98 third-grade elementary schoolchildren in Okinawa, Japan. Morning spot urine samples were collected and analyzed using high-performance liquid chromatography (HPLC) to assess dietary intake. We found that estimated daily NaCl intake was higher in obese/overweight children as compared to healthy-weight children ( p = 0.0001). There was also a significant positive correlation between body mass index (BMI) and NaCl intake (Spearman) ( ρ = 0.45, p < 0.0001) and a negative correlation between BMI and Mg/Cr ( ρ = −0.27, p = 0.01). Furthermore, Na/K ratio was higher in samples collected on Monday (weekend) as compared to samples collected on Thursday or Friday (weekday) ( p < 0.0001). Conclusion : Via the use of morning spot urine analyses, our results show that NaCl intake was associated with obesity, and Mg excretion negatively correlated with BMI in Japanese schoolchildren, highlighting the potential role of these micronutrients in maintaining a healthy body weight. What is Known: •Overweight and obesity are largely due to excessive consumption of calories and positively correlated with salt (NaCl) intake. •Spot urine methods are convenient for assessing the nutritional needs and targeting prevention programs in children. What is New: •Utilizing morning spot urine analyses, estimated NaCl intake is positively correlated and Mg/Cr negatively correlated with BMI in Okinawan schoolchildren. •As estimated via morning spot urine samples, a greater proportion of children likely exceeds the recommended NaCl intake on the weekend as compared to weekday.
Palmitoylation is a lipid modification involving the attachment of palmitic acid to a cysteine residue, thereby affecting protein function. We investigated the effect of palmitoylation of tyrosinase, the rate-limiting enzyme in melanin synthesis, using a human 3-D skin model system and melanocyte culture. The palmitoylation inhibitor, 2-bromopalmitate (2-BP), increased melanin content and tyrosinase protein levels in melanogenic cells by suppressing tyrosinase degradation. The palmitoylation site was Cys⁵⁰⁰ in the C-terminal cytoplasmic tail of tyrosinase. The non-palmitoylatable mutant, tyrosinase(C500A), was slowly degraded and less ubiquitinated than wild-type tyrosinase. Screening for the DHHC (Asp-His-His-Cys) family of proteins for tyrosinase palmitoylation suggested that DHHC2, 3, 7, and 15 are involved in tyrosinase palmitoylation. Knockdown of DHHC2, 3, or 15 increased tyrosinase protein levels and melanin content. Determination of their subcellular localization in primary melanocytes revealed that DHHC2, 3, and 15 were localized in the ER, Golgi apparatus, and/or melanosomes, while only DHHC2 was localized in the melanosomes. Immunoprecipitation showed that DHHC2 and DHHC3 predominantly bind to mature and immature tyrosinase, respectively. Taken together, tyrosinase palmitoylation at Cys⁵⁰⁰ by DHHC2, 3, and/or 15, especially DHHC2 in trans-Golgi apparatus and melanosomes and DHHC3 in ER and cis-Golgi apparatus, regulate melanogenesis by modulating tyrosinase protein levels.
Niemann-Pick disease Type C (NPC) is a lysosomal storage disorder caused by mutation of the NPC1/NPC2 genes, which ultimately results in the accumulation of unesterified cholesterol (UEC) in lysosomes, thereby inducing symptoms such as progressive neurodegeneration and hepatosplenomegaly. This study determines the effects of 6-O-α-maltosyl-β cyclodextrin (Mal-βCD) on lipid levels and synthesis in Npc1-deficient (Npc1-KO cells) and vehicle CHO cells. Compared to vehicle cells, Npc1-KO cells exhibited high level of UEC, and low levels of esterified cholesterols (ECs) and long-chain fatty acids (LCFAs). The difference in lipid levels between Npc1-KO and CHO cells was largely ameliorated by Mal-βCD administration. Moreover, the effects of Mal-βCD were reproduced in the lysosomes prepared from Npc1-KO cells. Stable isotope tracer analysis with extracellular addition of D4-deuterated palmitic acid (D4-PA) to Npc1-KO cells increased the synthesis of D4-deuterated LCFAs (D4-LCFAs) and D4-deuterated ECs (D4-ECs) in a Mal-βCD-dependent manner. Simultaneous addition of D6-deuterated UEC (D6-UEC) and D4-PA promoted the Mal-βCD-dependent synthesis of D6-/D4-ECs, consisting of D6-UEC and D4-PA, D4-deuterated stearic acid, or D4-deuterated myristic acid, in Npc1-KO cells. These results suggest that Mal-βCD helps to maintain normal lipid metabolism by restoring balance among UEC, ECs, and LCFAs through acting on behalf of NPC1 in Npc1-KO cells and may therefore be useful in designing effective therapies for NPC.
• Warfarin is a common anticoagulant and has demonstrated interactions with several drugs. Among them, as a serious adverse event, a case of death due to the enhanced warfarin action owing to its combined use with a fluoropyrimidine anticancer drug has been reported, but the detailed mechanism has not been elucidated. • Some reports have advocated that fluorinated pyrimidine anticancer drugs reduce cytochrome P450 2C9 expression, leading to the enhanced pharmacological effects of warfarin. • The purpose of this study was to clarify the mechanisms of drug-drug interactions between warfarin and 5-fluorouracil (5-FU) and capecitabine in vivo using rats. Rats were administered warfarin in combination with 5-FU (15 mg/kg/day) or capecitabine (15 mg/kg/day) for 7 days. Prothrombin time and activated partial thromboplastin time were significantly prolonged in the warfarin plus 5-FU or capecitabine groups compared with those in the warfarin alone group. No significant difference was observed in the area under the plasma concentration-time curve of the warfarin alone group compared with the warfarin with 5-FU or capecitabine groups. • These data suggest that the enhancement of warfarin efficacy caused by the combination of 5-FU or capecitabine was due to a pharmacological interaction rather than a pharmacokinetic interaction.
Recently, oral hypoglycemic agents with newer glucose lowering mechanisms have been release. This is mostly to meet the diabetic patient’s need to avoid hypoglycemia, which is profoundly important for better long-term outcome of the treatment. In this study, we quantified the annual number of patients with type 2 diabetes who experienced hypoglycemia needed the third-party assistance who had random sample plasma glucose < 59.4 mg/dl (3.3 mmol/l) on one hand and analyzed the prescription trend of hypoglycemic agents all over Japan on the other. Analysis of the annual number of hypoglycemic patients visited ER was performed at Aizawa Hospital, a medical center located in the midst of a city having approximately 250000 residency and annual ER visitors of approximately 46000. The study duration was over the 10 years from 2008 to 2019. We found a clear-cut decreasing trend of hypoglycemia over the 10 years, ca. 61/year to 39/year. Immediately after the release of sodium-glucose co-transporter-2 inhibitors, since 2013 to 2017, the decrease was rather sharp as 81/year to 31/year, and the change of the national number of its prescription inversely correlated with the change of the number of the patients with hypoglycemia. This was not the case immediately after the introduction of dipeptidyl peptidase-4 inhibitors in the Japanese market since 2008 to 2012. These was no significant correlation between its prescription and the number of patients with hypoglycemia. The data strongly suggested there was a causal relationship exclusively between the introduction of sodium-glucose cotransporter-2 inhibitor, and the reduction of hypoglycemic events among patients with type 2 diabetes.
Moina macrocopa is a toxicologically less explored, yet widely distributed freshwater cladoceran found worldwide. The present study is aimed at determining the cadmium (Cd) uptake and Cd-induced molecular and biochemical biomarkers, including DNA damage and antioxidant enzyme (i.e., catalase (CAT) and glutathione S-transferase (GST)) responses, in M. macrocopa upon short-term (48 h) exposure assessments. The Cd uptake was determined using a Cd-sensitive fluorescence probe. The results indicated a concentration-dependent Cd internalization, statistically significant in neonates exposed to ≥ 5 Cd μg/L. DNA damage was detected by the randomly amplified polymorphic DNA (RAPD) technique. Significant DNA alterations were observed in individuals exposed to ≥ 10 Cd μg/L. Though there was an increasing trend of CAT activity induction with increasing Cd concentrations, it was not statistically significant among treatments with different Cd concentrations. In contrast, low Cd concentration (10 μg/L) significantly induced GST levels, and higher concentration (50 μg/L) significantly inhibited the GST levels. Moreover, a path analysis revealed that the internalization of Cd has a causal mechanism of induction of CAT activities which consequently cause DNA damage. Taken together, these results indicated that the internalization of Cd in M. macrocopa has the potential to cause oxidative stress even at sublethal concentrations, which may be one of the underlying causes of the observed DNA damage. Furthermore, our findings highlight the importance of utilizing molecular and biochemical biomarkers for toxicity assessment in cladocerans owing to their high sensitivity and rapid responses even under short-term exposure conditions with low concentrations.
Tofu is a promising candidate in the development of edible printable inks in food three-dimensional (3D) printing. In this study, a mixed ink was prepared by adding starch to tofu in various ratios. Our results showed that hardness, adhesiveness, and gumminess increased at an additive starch ratio greater than 30% but had no effect on the brittleness and cohesiveness. The number of layers in 3D printing also increased at that ratio and showed a high positive correlation with hardness, adhesiveness, and gumminess, but no correlation with brittleness and cohesiveness. The density at which water separation is controlled was 1.071 g/cm³, while the inflection point for physical properties was approximately 1.07 g/cm³. These results suggest that tofu containing more than 30% additive starch is a suitable material for 3D printing. However, based on the proportion of energy-providing macronutrients, tofu containing 15–25% additive starch is most nutritionally desirable. Our results indicate that tofu is a promising candidate for the development of an edible ink that promote a healthy lifestyle.
Background Patellar height, which decreases after open wedge high tibial osteotomy (OWHTO), has conventionally been assessed by tibial references using lateral radiographs of the knee; however, changes in the proximal tibia shape after OWHTO may affect this method. We aimed to evaluate the changes in patellar height position relative to the transepicondylar axis of the femur after OWHTO using in vivo three-dimensional (3D) computer models. Methods Fourteen patients who underwent 3D magnetic resonance imaging (MRI) at 30° and 50° knee flexion before OWHTO and after hardware removal were included. 3D computer models of the knee were created from the MRI scans and superimposed over the images taken in each position using voxel-based registration. For patellar height evaluation, a patellar reference point was established at each flexion angle and the femoral condylar planes (FCP) were set, including the transepicondylar axis. The patellar center angle was defined as the angle between an FCP that included the top of the intercondylar notch and an FCP that included the patellar reference point. The patellar center angle was evaluated at 30° and 50° knee flexion before and after OWHTO. Results The patellar center angle at 30° and 50° knee flexion did not significantly decrease after OWHTO, whereas the Caton-Deschamps index and Blackburne-Peel index based on tibia-referenced measurements significantly decreased postoperatively. Conclusion Patellar height position relative to the femur in the 3D computer model did not decrease after OWHTO, whereas tibia-referenced conventional radiographic measurements significantly decreased. When evaluating patellar height, characteristics of each parameter should be considered.
Tofu, a common part of the Asian diet, is soft, making it a good candidate for developing foods for people with dysphagia. Honey can coagulate soymilk proteins due to high levels of gluconic acid. In the present study, we aimed to investigate the soymilk-coagulating ability of 19 honey varieties to develop a soft sweet for people with dysphagia. We found that honey gathered from flora on Awaji Island had a higher coagulating ability than those of 18 other tested honey varieties. Based on the volume-to-weight ratio of honey, trial products were processed at honey concentrations of 20%, 25%, and 30% (w/w). The hardness, adhesiveness, and cohesiveness of products were examined according to the Consumer Affairs Agency's permissible criteria for foods for people with dysphagia. The hardness and adhesiveness of products at 25% and 30% honey concentrations were significantly higher than those at 20% honey concentration. Overall, the product evaluation was consistent with Permission Criteria II (can be swallowed after slight maceration). In terms of physical properties and product cost, the added honey concentration was determined to be 25% (w/w) for commercialization. The sweet was named “Tofun” and commercialized via collaboration with a local company as part of our community development efforts. The introduction of Tofun will encourage further innovation in the sugar confectionery industry.
Gold(I)-catalyzed heteroannulation affords the efficient and straightforward construction of heterocyclic compounds. Herein, we developed a gold(I)-catalyzed heteroannulation of salicylic amides with alkynes producing a broad range of 1,3-benzoxazin-4-ones. The utility of this protocol was highlighted by synthesizing variously substituted benzoxazinones containing quaternary carbon centers, showing a high functional group tolerance and excellent atom economy of the thus introduced reaction course.
This study presents a Japanese translation of the Goldsmiths Musical Sophistication Index (Gold-MSI). The index consists of 38 self-report questions and provides a general sophistication score as well as subscale scores for Active Engagement, Perceptual Abilities, Musical Training, Singing Abilities, and Emotions. The validation of the translation with 689 native Japanese speakers indicated excellent internal consistency and test–retest reliability. Confirmatory factor analysis revealed that the bifactor model structure formulated by the original study of Gold-MSI is maintained reasonably in our data. The strengths of the Gold-MSI self-report inventory are (1) it offers a multifaceted view of musical sophistication, (2) a subset of five subscales can be used to measure different aspects of musical sophistication independently, and (3) the ease of administration as it is a self-report questionnaire. In view of the fact that this inventory and its translations increasingly contribute to research on musical expertise, skills, and abilities, having a Japanese translation may enhance future research in these areas even further.
Limited expandability of subcutaneous adipose tissue may be characteristics of first-degree relatives of type 2 diabetes. We tested the hypothesis that family history of type 2 diabetes (FHD) may be associated with reduced peripheral fat mass. Body composition and metabolic variables were compared between 18 and 111 Japanese female collegiate athletes, and between 55 and 148 nonathletes with positive (FHD +) and negative FHD (FHD-), respectively. We had multivariate logistic regression analyses for FHD + as dependent variable in a total population.BMI averaged < 21 kg/m ² and did not differ between FHD + and FHD- nonathletes. Despite comparable BMI, body fat percentage and serum leptin were lower in FHD + nonathletes. This was due to lower arm and gluteofemoral fat percentage (both p = 0.02) whereas the difference in trunk fat percentage was not significant ( p = 0.08). These differences were not found between two groups of athletes. FHD + women had lower HDL cholesterol despite lower BMI in a total population. Fasting insulin, serum adiponectin and high-sensitivity C-reactive protein did not differ between FHD + and FHD- athletes or nonathletes. Multivariate logistic regression analyses revealed independent associations of FHD + with BMI (odds ratio, 0.869; 95% confidential interval, 0.768–0.984; p = 0.02) and HDL cholesterol (odds ratio, 0.977; 95% confidential interval, 0.957–0.997, p = 0.02). In c onclusion, FHD may be associated with reduced subcutaneous fat mass in young Japanese women, suggesting impaired adipose tissue expandability.
Protocadherin 9 (Pcdh9) is a member of the cadherin superfamily and is uniquely expressed in the vestibular and limbic systems; however, its physiological role remains unclear. Here, we studied the expression of Pcdh9 in the limbic system and phenotypes of Pcdh9 -knock-out mice ( Pcdh9 KO mice). Pcdh9 mRNA was expressed in the fear extinction neurons that express protein phosphatase 1 regulatory subunit 1 B (Ppp1r1b) in the posterior part of the basolateral amygdala (pBLA), as well as in the Cornu Ammonis (CA) and Dentate Gyrus (DG) neurons of the hippocampus. We show that the Pcdh9 protein was often localised at synapses. Phenotypic analysis of Pcdh9 KO mice revealed no apparent morphological abnormalities in the pBLA but a decrease in the spine number of CA neurons. Further, the Pcdh9 KO mice were related to features such as the abnormal optokinetic response, less approach to novel objects, and reduced fear extinction during recovery from the fear. These results suggest that Pcdh9 is involved in eliciting positive emotional behaviours, possibly via fear extinction neurons in the pBLA and/or synaptic activity in the hippocampal neurons, and normal optokinetic eye movement in brainstem optokinetic system-related neurons.
Excess body weight and hyperlipidaemia cause severe health problems and have social implications. Amycenone is an active substance extracted from Yamabushitake mushrooms with no reports of its activity against excess body weight and hyperlipidaemia. This research clarifies the effects and mechanisms of action of amycenone on the inhibition of body weight excess and hyperlipidaemia attenuation using KK- A y mice. Amycenone or water was administered to 8-week-old male KK- A y mice by gavage for 8 weeks. Their body weight and food intake were recorded during the experiment. At the end of the experimental period, the mice were dissected, and blood samples, lipid metabolism-related organs and tissues were collected and stored for further analysis. Amycenone treatment suppressed body weight gain and improved serum levels of fasting blood glucose and non-esterified fatty acids. Additionally, serum and hepatic cholesterol and triacylglycerol levels were reduced after this treatment, whereas the phosphorylation levels of AMPK, PKA and HSL increased and the expression level of FAS decreased. The protein level of C/EBPβ and gene expression level of Cpt1 were higher in the perirenal adipose tissue of amycenone-treated KK- A y mice. Furthermore, amycenone phosphorylated AMPK, PKA and ACC, and PPARγ expression was lower in the mesenteric adipose tissue. The phosphorylation levels of AMPK, LKB1, PKA and ACC were also induced, and FAS expression level was reduced in the liver of the amycenone-treated group. Amycenone could reduce excess body weight and attenuate hyperlipidaemia in KK- A y mice by inhibiting lipogenesis and promoting lipolysis through lipid metabolism pathway stimulation and fatty acid β-oxidation acceleration.
The purpose of this study was to investigate the level of preparedness among Japanese American older adults for life's end by examining their knowledge, preferences, and arrangements for end-of-life issues. A total of 248 community dwelling Japanese Americans aged 50 and older participated in the study. The cross-sectional survey results indicated that participants believed they were well-informed about end-of-life issues and well-prepared for their lives' end. While most participants were in favor of making end-of-life arrangements, particularly with regard to making a will/living trust, creating an advance health care directive, appointing a health care agent, and funeral planning, relatively few favored life-prolonging treatment or planning for organ donation. They placed a high value on natural death and family-centered decision-making processes. These findings highlight the importance of awareness and cultural humility for social workers when providing culturally informed services at life's end to diverse Americans, including Japanese American older adults and their families.
A lot of chiral stationary phases (CSPs) have been introduced for the purpose of analytical and preparative separations of enantiomers. CSPs based on proteins and glycoproteins have unique properties among those CSPs. This review article deals with the preparation of CSPs based on proteins and glycoproteins, their chiral recognition properties and mechanisms, focusing on the CSPs investigated in our group. The dealt proteins and glycoproteins are including bovine serum albumin, human serum albumin, lysozyme, pepsin, human α1-acid glycoprotein (AGP), chicken ovomucoid and chicken ovoglycoprotein (named chicken AGP).
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