The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.

P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.

Anti-nanodisc antibodies specifically capture nanodiscs and facilitate molecular interaction kinetics studies for membrane protein.

Nanodisc technology has dramatically advanced the analysis of molecular interactions for membrane proteins. A nanodisc is designed as a vehicle for membrane proteins that provide a native-like phospholipid environment and better thermostability in a detergent-free buffer. This enables the determination of the thermodynamic and kinetic parameters of small molecule binding by surface plasmon resonance. In this study, we generated a nanodisc specific anti-MSP (membrane scaffold protein) monoclonal antibody biND5 for molecular interaction analysis of nanodiscs. The antibody, biND5 bound to various types of nanodiscs with sub-nanomolar to nanomolar affinity. Epitope mapping analysis revealed specific recognition of 8 amino acid residues in the exposed helix-4 structure of MSP. Further, we performed kinetics binding analysis between adenosine A2a receptor reconstituted nanodiscs and small molecule antagonist ZM241385 using biND5 immobilized sensor chips. These results show that biND5 facilitates the molecular interaction kinetics analysis of membrane proteins substituted in nanodiscs.

Changes in the association between the traditional Japanese diet score and suicide rates over 26 years: A global comparative study.

BACKGROUND: This study examined the global association between the Traditional Japanese Diet Score and suicide rate. METHODS: Average food supply and energy supply by country were obtained from the Food and Agriculture Organization of the United Nations Statistics Division database (FAOSTAT). Traditional Japanese Diet Score (TJDS) was calculated from food group classifications. Age-standardized suicide rates per 100,000 people by country were obtained from the Global Burden of Disease 2017 database. The 26-year associations between TJDS and suicide rates were examined controlling for covariates using a mixed-effects model in 138 countries with populations of 1 million or greater. RESULTS: A significant negative association was found in the analysis of the relationship between TJDS and the prevalence of suicide [ß (se) = -0.126 (0.031), p < 0.001]. The interaction term between TJDS and year was also significant [ß (se) = -0.011 (0.003), p < 0.001]. The change in the effect of TJDS on suicide rates by year was examined. The effect of TJDS was not significant from 1991 to 1999 but became significant after 2000; the slope of the TJDS to suicide rate in 2017 was -0.270 (95% confidence interval -0.382, -0.169, p < 0.001). LIMITATIONS: This was a national ecological study and did not consider individual differences in sex, age, and lifestyle. CONCLUSIONS: TJDS may be is a protective factor for depression, which may prevent suicide. The association between TJDS and suicide rates became stronger over time and was inversely associated with suicide rates after 2000.

Global relationship between Mediterranean diet and the incidence and mortality of ischaemic heart disease.

BACKGROUND: The purpose of this study was to clarify the global relationship between the Mediterranean diet score (MDS) and country-wise incidence and mortality of ischaemic heart disease (IHD) using an international database. METHODS: We used population data from a global longitudinal database covering 137 countries with a population of over one million. MDS were evaluated based on the total score of the nine foods that comprise the Mediterranean diet. The incidence and mortality of IHD by country was derived from the Global Burden of Disease (GBD) database. Average food (g/day/capita) and energy supply (kcal/day/capita) by country, excluding loss between production and household, were obtained from the Food and Agriculture Organization of the United Nations Statistics Division database. Data from the GBD database were used for body mass index, current smoking rates, physical activity, years of education and percentage of the Muslim population. We identified the percentage of the population over 65 years of age (aging rate) and gross domestic product per capita (US$/capita) using the World Bank database. A linear mixed-effect model was used for evaluating the effects of MDS on incidence and mortality of IHD controlled for socioeconomic and lifestyle variables. RESULTS: Analysis showed that MDS was significantly associated with IHD incidence after controlling for covariates (-1.01 ± 0.27, P < 0.001). Similarly, there was a significant association between MDS and IHD-related mortality after controlling for covariates (-0.73 ± 0.34, P < 0.05). CONCLUSION: Analysis of 27 years of data suggests that a Mediterranean diet might have a preventive effect on IHD.

Trends in age-standardised prevalence of type 2 diabetes mellitus according to country from 1990 to 2017 and their association with socioeconomic, lifestyle and health indicators: An ecological study.

BACKGROUND: There is a need for global public health strategies to effectively curb the ever-growing global diabetes population. This longitudinal ecological study was conducted to elucidate the country-specific trends of the age-standardised prevalence of type 2 diabetes mellitus (T2DM) and their association with socioeconomic, lifestyle and health indicators. METHODS: Data pertaining to the age-standardised prevalence of T2DM (rates per 100 000) and socioeconomic, lifestyle and health indicators were obtained from several international databases. Data available from 1990 to 2017 for 139 countries with populations of 1 million or greater were analysed, followed by estimation of slopes for T2DM prevalence in each country. The longitudinal association between T2DM and the standardised variables of socioeconomic, lifestyle and health indicators was fitted using a generalised linear mixed-effects model with random intercept for each country and random slope for year. RESULTS: The country-specific age-standardised prevalence of T2DM decreased significantly in 9 countries, remained unchanged in 11 countries and increased significantly in 119 countries. The estimated standardised effect of age-standardised education for T2DM was the largest at -524.5 (SE; 109.9), followed by -514.8 (SE; 95.6) for physical activity and 398.8 (SE; 45.8) for body mass index (BMI) (P < 0.0001 for all). CONCLUSIONS: The factors largely associated with global T2DM prevalence and trends were years of education, followed by physical activity and BMI. This study also provides basic resources for examining public health approaches to curb the increase in global T2DM prevalence.

Gut Microbiota Is Not Involved in the Induction of Acute Phase Protein Expression Caused by Vitamin C Deficiency.

Using rats, we previously found that vitamin C deficiency increases serum levels of interleukin-6 (IL-6) and glucocorticoid, and changes the gene expression of acute phase proteins (APP) in the liver. However, it remains unclear how vitamin C deficiency causes these inflammation-like responses. In this study, we investigated the possibility that changes in gut microbiota are involved in the induction of APP gene expression by vitamin C deficiency. ODS rats that cannot genetically synthesize vitamin C were divided into 4 groups based on the presence or absence of vitamin C or antibiotics and were raised for 15 d. Neomycin, vancomycin, and ampicillin were used as antibiotics, and 300 mg L-ascorbic acid/kg was added to the AIN93G diet. Vitamin C deficiency affected neither the wet tissue weights nor relative abundance of bacteria in the cecal contents. Antibiotic administration increased wet weights of the cecum, cecal contents, and colon, changed the relative abundance of some bacteria in the cecal contents, and decreased serum IL-6 level. However, antibiotic administration had no effect on serum concentrations of corticosterone and α1-acid glycoprotein (AGP), vitamin C concentration in the liver, and mRNA levels of haptoglobin and AGP in the liver. Therefore, disturbance of gut microbiota did not attenuate the increase in glucocorticoid level and induction of APP gene expression due to vitamin C deficiency. This suggests that gut microbiota is not involved in the inflammation-like responses caused by vitamin C deficiency.

Consumption of Polyphenols in Coffee and Green Tea Alleviates Skin Photoaging in Healthy Japanese Women.

PURPOSE: Hyperpigmentation of the skin can occur at any age depending on etiological factors but its intensity increases during adolescence in Japanese females and gradually develops further in adults. The purpose of this study was to characterize factors that influence skin hyperpigmentation, including age, skin type and dietary polyphenol sources. PATIENTS AND METHODS: A cross-sectional survey of healthy Japanese women aged from 30 to 60 years (n=244) was conducted using food and environmental questionnaires and a VISIA™ facial photoimage analyzer. RESULTS: UV Pigmented Spot (PS) scores correlated negatively with the consumption of total polyphenols (TPs) (R=-0.224, p<0.001) and the rate of hyperpigmented spot development (PS score/age after 18 years of age) was suppressed by the consumption of TPs. This trend was independent of the melanin index and the skin type, which indicates the ability of the skin to tan after sun exposure. Consumption of coffee, the largest source of TPs, suppressed the PS score (p<0.001). Consumption of green tea, the second largest source of TPs, also suppressed the PS score, which was weaker than coffee but was statistically significant (p=0.029). The PS score was suppressed the most in subjects with both a high consumption of coffee and green tea. CONCLUSION: Higher consumption of TPs may be beneficial to alleviate photoaging of the skin, and coffee as well as green tea contribute to suppress skin hyperpigmentation through adding large amounts of TPs in the diet.

Tissue Distribution of Menaquinone-7 and the Effect of α-Tocopherol Intake on Menaquinone-7 Concentration in Rats.

We have reported that vitamin E intake lowers phylloquinone (PK) concentration in extrahepatic tissues of rats. In this study, we aimed to clarify the characteristic of the distribution of menaquinone-7 (MK-7), a vitamin K contained in fermented foods, by comparison with other vitamin K distributions and to clarify the effect of vitamin E intake on MK-7 concentration in rats. Rats were fed a vitamin K-free diet (Free group), a diet containing 0.75 mg PK/kg (PK group), a 0.74 mg menaquinone-4 (MK-4)/kg diet (MK-4 group), a 1.08 mg MK-7/kg diet (MK-7 group), or a 0.29 mg menadione (MD)/kg diet (MD group) for 16 wk. MK-7 mainly accumulated in the liver, spleen, and adrenal gland of the MK-7 group, although PK accumulated in the serum and all tissues of the PK group. Conversely, MK-4 was present in all tissues of the PK, MK-4, MK-7, and MD groups. MK-4 concentration in the serum, liver, adipose tissue, and spleen was higher in the MK-4 group than in the other groups; however, MK-4 concentration in the kidney, testis, tibia, and brain was lower in the MK-4 group than in the PK, MK-7, and MD groups. Next, vitamin E- and K-deficient rats were orally administered MK-7 with or without α-tocopherol. α-Tocopherol did not affect MK-7 or MK-4 concentration in the serum and various tissues. These results suggested that MK-7 is particularly liable to accumulate in the liver, and MK-7 concentration is not affected by vitamin E intake.