Slowly progressive cell death induced by GPx4-deficiency occurs via MEK1/ERK2 activation as a downstream signal after iron-independent lipid peroxidation.

Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme that reduces phospholipid hydroperoxide. Studies have reported that the loss of GPx4 activity through anticancer drugs leads to ferroptosis, an iron-dependent lipid peroxidation-induced cell death. In this study, we established Tamoxifen-inducible GPx4-deficient Mouse embryonic fibroblast (MEF) cells (ETK1 cells) and found that Tamoxifen-inducible gene disruption of GPx4 induces slow cell death at ~72 h. In contrast, RSL3- or erastin-induced ferroptosis occurred quickly within 24 h. Therefore, we investigated the differences in these mechanisms between GPx4 gene disruption-induced cell death and RSL3- or erastin-induced ferroptosis. We found that GPx4-deficiency induced lipid peroxidation at 24 h in Tamoxifen-treated ETK1 cells, which was not suppressed by iron chelators, although lipid peroxidation in RSL3- or erastin-treated cells induced ferroptosis that was inhibited by iron chelators. We revealed that GPx4-deficient cell death was MEK1-dependent but RSL3- or erastin-induced ferroptosis was not, although MEK1/2 inhibitors suppressed both GPx4-deficient cell death and RSL3- or erastin-induced ferroptosis. In GPx4-deficient cell death, the phosphorylation of MEK1/2 and ERK2 was observed 39 h after lipid peroxidation, but ERK1 was not phosphorylated. Selective inhibitors of ERK2 inhibited GPx4-deficient cell death but not in RSL3- or erastin-induced cell death. These findings suggest that iron-independent lipid peroxidation due to GPx4 disruption induced cell death via the activation of MEK1/ERK2 as a downstream signal of lipid peroxidation in Tamoxifen-treated ETK1 cells. This indicates that GPx4 gene disruption induces slow cell death and involves a different pathway from RSL3- and erastin-induced ferroptosis in ETK1 cells.

Associations Between Health Literacy and Underweight and Overweight Among Japanese Adults Aged 20 to 39 Years: A Cross-Sectional Study.

Background. Both underweight and overweight are public health concerns in Japan. Several studies examined the association between health literacy (HL) and obesity status in the general population; however, there is limited information on young adults. In addition, the association between HL and underweight status has not been extensively investigated. Aim. To examine the association between HL and underweight/overweight status among young Japanese adults aged 20 to 39 years. Method. This study was based on a cross-sectional survey of population-representative adults. HL was assessed using a questionnaire validated in Japanese adults. Body mass index (BMI) was calculated using self-reported weight and height. Participants were divided into two groups by HL score using the median score (lower vs. higher HL). The association between HL and underweight (BMI <18.5) or overweight (BMI ≥25.0) was examined using multinomial logistic regression analyses after adjusting for potential confounders. Results. In total, 476 women and 454 men were included in the analyses. Prevalence of underweight and overweight was 20.8% and 10.3% in women and 8.8% and 20.3% in men, respectively. In women, 45.1% of normal weight, 47.5% of underweight, and 30.6% of overweight had higher HL. Among men, 50.3% of normal weight, 35.0% of underweight, and 44.6% of overweight had higher HL. Bivariate analyses showed no statistically significant association between HL level and underweight/overweight status. Even after adjusting for potential confounders, these associations did not change. Discussion and Conclusion. This study suggests that HL scores may not be associated with underweight or overweight status in Japanese adults.

No association between fruits or vegetables and non-alcoholic fatty liver disease in middle-aged men and women.

OBJECTIVE: It has been hypothesized that fruit and vegetable intake is inversely associated with non-alcoholic fatty liver (NAFLD). However, some studies have speculated that fruit intake might be positively associated with NAFLD owing to the fructose content of the fruit. This might cause consumers to hesitate consuming fruit. The aim of this study was to assess the association between fruit and vegetable consumption and NAFLD. METHODS: This was a cross-sectional study of 977 men and 1467 women, 40 to 69 y of age without current liver disease other than NAFLD and who did not report excess alcohol intake (i.e., ≥30 g/d in men and ≥20 g/d in women). Dietary intake was assessed using a validated diet history questionnaire. NAFLD was diagnosed from abdominal ultrasonography results. The association between quartiles of fruit or vegetable consumption and NAFLD prevalence was assessed using logistic regression analysis, with lowest category as reference. RESULTS: The prevalence of NAFLD was 34.9% in men and 11.7% in women. Adjusted for age and lifestyle factors, fruit intake was inversely associated with NAFLD in both sexes. However, these associations disappeared after further adjustment for body mass index. Consumption of total vegetables was not associated with NAFLD. In women, a linear inverse association was demonstrated between green and yellow vegetable intake and NAFLD in the final model (Ptrend = 0.04), but odds ratios for any intake category did not reach significance. CONCLUSIONS: No obesity-independent association was found between fruit or vegetable intake and NAFLD. According to the findings of this study, Japanese do not need to restrict fruit consumption to limit fructose intake as a means of preventing NAFLD.

Association between rice, bread, and noodle intake and the prevalence of non-alcoholic fatty liver disease in Japanese middle-aged men and women.

BACKGROUND & AIMS: Prevention of non-alcoholic fatty liver disease (NAFLD) through lifestyle modification is an important public health issue. Carbohydrate intake from soft drinks has received particular interest. Owing to differences in dietary habits, however, major contributors to the intake of dietary carbohydrates, such as rice, bread, and noodles, might have more influence on NAFLD prevalence in East Asian countries than consumption of soft drinks. We examined the relationship of the intake of rice, bread, and noodles, as well as overall carbohydrate intake, with NAFLD prevalence in middle-aged Japanese. METHODS: This is a cross-sectional study of 977 men and 1467 women aged 40-69 y. Dietary information was obtained using a validated self-administered diet history questionnaire. Diagnosis of NAFLD was based on the following criteria: presence of steatosis on abdominal ultrasound, alcohol intake <20 g/day in women and <30 g/day in men, and exclusion of other liver diseases. Logistic regression was performed as multivariate analysis. RESULTS: The presence of NAFLD was 34.9% (n = 341) in men and 11.7% (n = 171) in women. Carbohydrate intake was positively associated with NAFLD prevalence in women (p for trend = 0.008). There was also a positive association between rice intake and NAFLD prevalence in women; the multi-adjusted odds ratio for the highest versus the lowest quartiles of rice intake was 1.87 (95% CI: 1.03, 3.41; p for trend = 0.006). These associations were not observed in men. No association was observed between bread and noodle intake and the prevalence of NAFLD in either sex. CONCLUSIONS: Consumption of carbohydrates and rice was positively associated with NAFLD prevalence in middle-aged Japanese women.

Amounts of Sr and Ca eluted from deciduous enamel to artificial saliva related to dental caries.

This study was performed to elucidate the relationship between dental caries and the levels of Sr and Ca eluted from enamel, and to examine whether these elements are useful as factors to assess caries risk. The available 103 (Sr) and 108 (Ca) samples were obtained among 111 collected deciduous teeth. The healthy regions of enamel were decalcified in artificial saliva at pH 6.2 and 5.5. The eluted levels of these elements from enamel were determined using atomic absorption spectrophotometry. Sr and Ca levels were not affected by the sex nor tooth type. Sr levels of the caries-experienced tooth (CE) group were 2.6-fold (pH 6.2) and 2.2-fold (pH 5.5) higher than those of the sound tooth (ST) group, respectively. Furthermore, the Sr levels were significantly higher in the teeth with treated than in those with untreated caries. Only at pH 6.2 was a significant difference found in Ca levels between the ST and CE groups. In the ST group, at pH 5.5, both the Sr and Ca levels significantly increased when the children had six or more carious teeth. The Sr and Ca elution levels were significantly inhibited in the teeth receiving fluoride application every 3 or 4 months compared to those that were not. These findings indicate that Sr can be an indicator of the acid resistance of teeth, and a useful factor to assess future caries risk.