Lignan polyphenols derived from plants are metabolized by bacteria in the gut to mammalian lignans, such as enterolactone (ENL) and enterodiol (END). Mammalian lignan intake has been reported to be ...associated with obesity and low blood glucose levels. However, the factors that are responsible for individual differences in the metabolic capacity for ENL and END are not well understood. In the present study, the effects of enterotypes of isoflavone metabolism, equol producers (EQP) and O-desmethylangolensin producers (O-DMAP), on lignan metabolism were examined. EQP was defined by urinary daidzein (DAI) and equol concentrations as log(equol/DAI) ≥ –1.42. O-DMAP was defined by urinary DAI and O-DMA concentrations as O-DMA/DAI > 0.018. Isoflavone and lignan concentrations in urine samples from 440 Japanese women were measured by gas chromatography-mass spectrometry. Metabolic enterotypes were determined from the urinary equol and O-DMA concentrations. Urinary END and ENL concentrations were compared in four groups, combinations of EQP (+/–) and O-DMAP (+/–). The urinary lignan concentration was significantly higher in the O-DMAP/EQP group (ENL: P<0.001, END: P<0.001), and this association remained significant after adjusting for several background variables (END: β = 0.138, P = 0.00607 for EQP and β = 0.147, P = 0.00328 for O-DMAP; ENL: β = 0.312, P<0.001 for EQP and β = 0.210, P<0.001 for O-DMAP). The ENL/END ratio was also highest in the O-DMAP/EQP group, indicating that equol and O-DMA metabolizing gut bacteria may be involved in lignan metabolism. In conclusion, urinary lignan concentrations were significantly higher in groups containing either EQP or O-DMAP than in the non-EQP/non-O-DMAP group. The variables and participants in this study were limited, which the possibility of confounding by other variables cannot be ruled out. However, there are no established determinants of lignan metabolism to date. Further research is needed to determine what factors should be considered, and to examine in different settings to confirm the external validity.
Over the last two decades, usage of neonicotinoid (NEO) insecticides has increased due to their high selectivity for insects versus mammals and their effectiveness for extermination of insects ...resistant to conventional pesticides such as pyrethroids and organophosphates (OPs). However, historical change of the NEO exposure level in humans is poorly understood. The aim of this study is to reveal changes in the levels of NEO and OP exposure in the human body over the last two decades using biomonitoring technique. We quantified urinary concentrations of 7 NEOs (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam) and 4 metabolites of OPs (dimethylphosphate, dimethylthiophosphate, diethylphosphate, and diethylthiophosphate) in 95 adult females aged 45–75 in 1994, 2000, 2003, 2009, and 2011 (n = 17–20 different individuals in each year). The results show that the detection rates of urinary NEOs in Japanese women increased significantly between 1994 and 2011, suggesting that intakes of NEOs into the human body rose during that period. In contrast, exposure to OPs having O,O-dimethyl moieties decreased steadily according to a finding that geometric means of urinary dimethylphosphate concentrations kept diminishing considerably. These changes may reflect the amounts of NEOs and OPs used as insecticides in Japan.
Isoflavones found in soy products are a promising class of nutrients that may have a positive effect on human health. In particular, the phytoestrogen metabolite equol is associated with a reduced ...risk of developing female hormone-related diseases. However, the effect of equol on estrogen remains unclear. Equol can modify blood and urinary estradiol (E2) levels. The aim of this cross-sectional study was to examine the associations between urinary estrogen levels, equol levels, and equol production status in Japanese women. We analyzed urine samples from 520 women by gas chromatography-mass spectrometry. Urinary E2 and 4-hydroxylated E2 levels were higher in equol producers (EQP) than in non-EQPs (P < 0.0001 and P=0.00112, respectively). After adjusting for age and tobacco use by analysis of covariance, the association remained significant (β = 0.299, P < 0.0001). Analysis of covariance demonstrated that equol levels in urine were also positively associated with urinary E2 (β = 0.597, P < 0.0001). The log equol concentration showed a significant, but moderate, negative association with the serum E2 concentration (β = - 0.0225, P = 0.0462). Our findings suggest that equol may promote urinary E2 excretion and modify blood E2 levels in women.
Perfluoroalkyl substances (PFASs) may contribute to causing breast cancer; however, associations between exposure to PFASs and risk of breast cancer are controversial.
In the present study, we newly ...distinguished branched isomers of PFASs from their linear isomers and aimed to investigate the association between serum PFAS concentrations and breast cancer risk in Japanese women.
We used a case-control design to study 405 eligible matched pairs attending four hospitals in Nagano Prefecture, Japan from May 2001 to September 2005. We used in-port arylation gas-chromatography mass spectrometry with negative chemical ionization to measure serum concentrations of 20 PFAS congeners. We calculated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer and its hormone-receptor subtypes by quartiles or tertiles of serum PFASs.
After multivariable adjustment for breast cancer risk factors, we found that serum concentrations of 20 PFAS congeners were significantly inversely associated with risk of breast cancer. Comparing the extreme quartiles of linear isomers of perfluorooctane sulfonate or perfluorooctanoic acid, ORs were 0.15 (95% CI: 0.07, 0.33 P for trend <0.0001) and 0.21 95% CI: 0.10, 0.44 P for trend <0.0001). Among postmenopausal women, whereas we found the linear isomer of perfluorotridecanoic acid to be inversely associated with breast cancer risk, a medium degree of exposure to the branched isomer of perfluorotridecanoic acid was associated with a marginally increased risk of breast cancer (OR 95% CI = 1.74 0.98, 3.09).
In our case-control study, we found overall no association between serum PFAS concentrations and increased risk of breast cancer. Many inverse associations between serum PFAS concentrations and breast cancer risk were found.
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•Perfluoroalkyl substances (PFASs) may contribute to causing breast cancer.•Associations between exposure to PFASs and risk of breast cancer are controversial.•We newly distinguish branched isomers of PFASs from their linear isomers.•We found many inverse associations between serum PFAS levels and breast cancer risk.
Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown.
...Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10(-4)). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10(-119)). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels.
We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.
Healthcare workers (HCWs) employed personal protective equipment (PPE) during the COVID-19 pandemic, crucial to protecting themselves from infection. To highlight the efficacy of PPE in preventing ...environmental infection among HCWs, a systematic review was conducted in line with PRISMA guidance.
A search of the PubMed and Web of Science databases was conducted from January 2019 to April 2021 using pre-defined search terms. Articles were screened by three researchers. The approved papers were read in full and included in this review if relevance was mutually agreed upon. Data were extracted by study design and types of PPEs.
47 of 108 identified studies met the inclusion criteria, with seven reviews and meta-analyses, seven cohort, nine case-control, fifteen cross-sectional studies, four before and after, four case series, and one modeling studies. Wearing PPE offered COVID-19 protection in HCWs but required adequate training. Wearing surgical masks provided improved protection over cloth masks, while the benefit of powered air-purifying respirators is less clear, as are individual gowns, gloves, and/or face shields.
Wearing PPE, especially facial masks, is necessary among HCWs, while training in proper use of PPE is also important to prevent COVID-19 infection.
Global DNA methylation levels in peripheral blood leukocytes can be a biomarker for cancer risk; however, levels can be changed by various factors such as environmental pollutants. We investigated ...the association between serum concentrations of perfluoroalkyl substances (PFASs) and global DNA methylation levels of leukocytes in a cross-sectional study using the control group of a Japanese breast cancer case-control study 397 women with a mean age of 54.1 (SD 10.1) years. Importantly, our analysis distinguished branched PFAS isomers as different from linear isomers. The serum concentrations of 20 PFASs were measured by in-port arylation gas-chromatography negative chemical ionization mass spectrometry. Global DNA methylation levels in peripheral blood leukocytes were measured using a luminometric methylation assay. Associations between log10-transformed serum PFAS concentrations and global DNA methylation levels were evaluated by regression coefficients in multivariable robust linear regression analyses. Serum concentrations of 13 PFASs were significantly associated with increased global DNA methylation levels in leukocytes. Global DNA methylation was significantly increased by 1.45 %–3.96 % per log10-unit increase of serum PFAS concentration. Our results indicate that exposure to PFASs may increase global DNA methylation levels in peripheral blood leukocytes of Japanese women.
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•We examined links between perfluoroalkyl substances (PFASs) and epigenetic changes.•Serum PFASs including their structural isomers were analyzed by gas chromatography.•Global DNA methylation levels in peripheral blood leukocytes were measured.•In the 2000s, perfluorooctane sulfonate dominated in the sera of Japanese women.•Many serum PFASs were positively associated with global DNA methylation levels.
Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed ...its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.
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