Dietary Flavonoids Consumption and Health: An Umbrella Review.

SCOPE: The current evidence between dietary flavonoids consumption and multiple health outcomes is inadequate and inconclusive. To summarize and evaluate the evidence for dietary flavonoids consumption and multiple health outcomes, an umbrella review of meta-analyses and systematic reviews is conducted. METHODS AND RESULTS: PubMed, Ovid-EMBASE, and the Cochrane Database of Systematic Reviews are searched up to January 2024. The study includes a total of 32 articles containing 24 unique health outcomes in this umbrella review. Meta-analyses are recalculated by using a random effects model. Separate analyses are performed based on the kind of different flavonoid subclasses. The study finds some unique associations such as flavonol and gastric cancer, isoflavone and uterine fibroids and endometrial cancer, total flavonoids consumption and lung cancer, ovarian cancer, and prostate cancer. Overall, the study confirms the negative associations between dietary flavonoids consumption and type 2 diabetes mellitus, cardiovascular diseases, breast cancer, colorectal cancer, lung cancer, and mortality, while positive associations are observed for prostate cancer and uterine fibroids. CONCLUSION: Although dietary flavonoids are significantly associated with many outcomes, firm generalizable conclusions about their beneficial or harmful effects cannot be drawn because of the low certainty of evidence for most of outcomes. More well-designed primary studies are needed.

Sex- and time-specific associations of obesity with glycaemic traits: A two-step multivariate Mendelian randomization study.

AIM: To assess the sex- and time-specific causal effects of obesity-related anthropometric traits on glycaemic traits. MATERIALS AND METHODS: We used univariate and multivariate Mendelian randomization to assess the causal associations of anthropometric traits (gestational variables, birth weight, childhood body mass index [BMI], BMI, waist-to-hip ratio [WHR], BMI-adjusted WHR [WHRadj BMI]) with fasting glucose and insulin in Europeans from the Early Growth Genetics Consortium (n ≤ 298 142), the UK Biobank, the Genetic Investigation of Anthropometric Traits Consortium (n ≤ 697 734; females: n ≤ 434 794; males: n ≤ 374 754) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (n ≤ 151 188; females: n ≤ 73 089; males: n ≤ 67 506), adjusting for maternal genetic effects, smoking, alcohol consumption, and age at menarche. RESULTS: We observed a null association for gestational variables, a negative association for birth weight, and positive associations for childhood BMI and adult traits (BMI, WHR, and WHRadj BMI). In female participants, increased birth weight causally decreased fasting insulin (betaIVW , -0.07, 95% confidence interval [CI] -0.11 to -0.03; p = 1.92 × 10-3 ), but not glucose levels, which was annulled by adjusting for age at menarche. In male participants, increased birth weight causally decreased fasting glucose (betainverse-variance-weighted (IVW) , -0.07, 95% CI -0.11 to -0.03; p = 3.22 × 10-4 ), but not insulin levels. In time-specific analyses, independent effects of birth weight were absent in female participants, and were more pronounced in male participants. Independent effects of childhood BMI were attenuated in both sexes; independent effects of adult traits differed by sex. CONCLUSIONS: Our findings provide evidence for causal and independent effects of sex- and time-specific anthropometric traits on glycaemic variables, and highlight the importance of considering multiple obesity exposures at different time points in the life course.

Systemic inflammation mediates the association between environmental tobacco smoke and depressive symptoms: A cross-sectional study of NHANES 2009-2018.

BACKGROUND: Depression is associated with both environmental tobacco smoke (ETS) and inflammation. However, whether systemic inflammation mediates the ETS-depression relationship is unclear. METHODS: We analyzed 19,612 participants from the 2009-2018 National Health and Nutrition Examination Survey (representing approximately 206,284,711 USA individuals), utilizing data of depressive symptoms (assessed by Patient Health Questionnaire-9), blood cotinine level (an ETS biomarker), dietary inflammatory index (DII, assessed by 24-h dietary recall) and inflammation, represented by immune-inflammation index (SII) and systemic inflammation response index (SIRI). RESULTS: Weighted multivariable logistic regression showed that a higher blood cotinine level is significantly associated with a higher depressive symptoms risk (OR = 1.79, 1.35-2.38). After adjusting for covariates, the effect in smokers (OR = 1.220, 95 % CI: 1.140-1.309) is larger than that in non-smokers (OR = 1.150, 95 % CI: 1.009-1.318). Compared to the lowest level, depressive symptoms risks in participants with the highest level of SII, SIRI and DII are 19 % (OR = 1.19, 1.05-1.35), 15 % (OR = 1.15, 1.01-1.31) and 88 % (OR = 1.88, 1.48-2.39) higher, respectively. Weighted linear regression demonstrated positive correlations of SII (ß = 0.004, 0.001-0.006), SIRI (ß = 0.009, 0.005-0.012) and DII (ß = 0.213, 0.187-0.240) with blood cotinine level. Restricted cubic splines model showed a linear dose-response relationship between blood cotinine and depressive symptoms (Pnon-linear = 0.410), with decreasing risk for lower DII. And SII and SIRI respectively mediate 0.21 % and 0.1 % of the association between blood cotinine and depressive symptoms. LIMITATION: Cross-sectional design, and lack of medication data for depression. CONCLUSIONS: Positive association of ETS (blood cotinine) with depressive symptoms risk is partly mediated by systemic inflammation, and anti-inflammatory diet could be beneficial.

Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease.

BACKGROUND: Comorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear. OBJECTIVE: We aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD. METHODS: Leveraging the largest genome-wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome-wide cross-trait analysis via Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association to identify specific single-nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome-wide association study via functional summary-based imputation and joint-tissue imputation to explore comorbid genes, followed by pathway enrichment analysis. RESULTS: We found that PD positively correlates with ALS (rg = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03-1.15, P = 3.00 × 10-3 ). We identified nine single-nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes (TMEM175, MAPT, NSF, LRRC37A2, ARHGAP27, GAK, and FGFRL1). In transcriptome-wide association study analysis, we showed six previously unreported pleiotropic genes (KANSL1, ARL17B, EFNA1, WNT3, ERCC8, and ADAM15), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977). CONCLUSIONS: Our work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society.

Derivation of copper water quality criteria in Bohai Bay for the protection of local aquatic life and the ecological risk assessment.

Developing effective marine water quality criteria (WQC) is crucial for controlling marine contamination and protecting marine life. The WQC for copper is urgently needed due to the toxicity and widespread of copper contamination. In this work, both short-term water quality criteria (SWQC) and long-term water quality criteria (LWQC) under 10 % effect endpoints were derived by using the model averaging of species sensitivity distribution (SSD10) method for Bohai Bay. The WQC values were obtained directly from the hazardous concentration for 5 % of species (HC5) values, which removes the influence of arbitrary assessment factor (AF). Modifications to the acute-chronic ratio (ACR) strategies and the inclusion of the test toxicity data of local species also improved the accuracy and applicability of the WQC values. The derived SWQC and LWQC were 2.21 and 0.45 µg/L, respectively. Furthermore, the overall risk level of copper in Bohai Bay was evaluated by using the risk quotient (RQ) method, and the results showed it was at a moderate-low level. This study provides a new approach for the derivation of the WQC for Cu and the risk assessment of Bohai Bay, which is essential for the protection of local aquatic life and provides guidance to the establishment of the national WQC.

Benzo[b]fluoranthene (B[b]F) affects apoptosis, oxidative stress, mitochondrial membrane potential and expressions of blood-brain barrier markers in microvascular endothelial cells.

Exposure to polycyclic aromatic hydrocarbons (PAHs) contributes to the damage of blood-brain barrier. While a number of studies were focused on benzo[a]pyrene, direct effects and mechanisms of benzo[b]fluoranthene (B[b]F), another main component of PAHs, on blood-brain barrier (BBB) are not documented. Here, we investigated if B[b]F at concentrations of environmental relevance could affect apoptosis, oxidative stress, mitochondrial membrane potential (MMP) and BBB marker expression in mouse brain microvascular endothelial (bEnd.3) cells, an in vitro model typically used to study BBB toxicology. Cells were treated with varying concentrations of B[b]F (0, 10, 20 and 40 µM) for 48 h. Cell proliferation, cell cycle, apoptosis, oxidative stress, MMP and BBB marker expressions were evaluated by label-free real-time cell analysis, flow cytometry, immunofluorescence and Western-blot. The proliferation of bEnd.3 cells was inhibited by B[b]F in a concentration dependent manner. B[b]F treatment significantly affected cell cycle, induced apoptosis, increased levels of reactive oxygen species (ROS) and disputed MMP. Expressions of BBB marker Occludin and Claudin-5 were decreased in the presence of 40 µM B[b]F. In conclusion, B[b]F might damage BBB by affecting proliferation, apoptosis, ROS level and Occludin and Claudin-5 expressions in microvascular endothelial cells.

Identification of 5 Potential Predictive Biomarkers for Alzheimer's Disease by Integrating the Unified Test for Molecular Signatures and Weighted Gene Coexpression Network Analysis.

BACKGROUND: Previous transcriptome-wide association study (TWAS) has documented 21 genes associated with Alzheimer's disease (AD) risk, but the predictive biomarkers remain unexplored. METHODS: TWAS leveraging the unified test for molecular signatures (UTMOST) was performed in 75,000 cases and 420,000 controls with 10 brain tissue gene expression references. Weighted gene coexpression network analysis (WGCNA) was conducted in GSE5281 and GSE48350 data sets containing 167 AD samples and 247 controls. Random forest (RF) analysis was applied to screen the potential predictive biomarkers based on overlapping genes identified by TWAS and WGCNA, followed by comprehensive bioinformatic analyses with differential gene expression, functional enrichment, and correlation with immune cells. A nomogram was established to verify the predictive power of the identified biomarkers. RESULTS: TWAS revealed 78 candidate genes (p < 2.89 × 10-6). In WGCNA turquoise module, 3 718 AD-related genes were screened. RF identified 5 predictive biomarkers (FAM71E1, DDB2, AP4M1, GPR4, DOC2A), which are enriched in the global genome nucleotide excision repair pathway and associated with immune cell designations "Natural.killer.T.cell," "Memory.B.cell," "T.follicular.helper.cell," "Neutrophil," and "MDSC." The nomogram based on the 5 markers showed a high predictive power. CONCLUSION: Five potential predictive biomarkers for AD were identified, providing new insights into the pathogenesis and etiology of AD.

Human antigen R affects the migration and invasion of human lung cancer A549 cells via regulating E-cadherin suppressor Snail.

Recent studies demonstrated that the progression and metastasis of lung cancer were associated with human antigen R (HuR), a post-transcriptional RNA-binding protein that stabilize and regulate the expression of many tumor-related genes. Although HuR was shown to affect the expressions of epithelial cadherin (E-cadherin), a tumor migration suppressor, in airway epithelial cells, esophageal squamous and colon cancer cells, direct evaluation for the effect and mechanism of HuR on the migration and invasion of lung cancer cells is not documented. In this study, HuR was knocked down via RNA interference and overexpressed using recombinant plasmid in adenocarcinomic human alveolar basal epithelial A549 cells. No apparent inhibition of cell viability was observed. HuR knocked down significantly suppressed A549 migration and invasion in scratch wound healing and transwell assays, with an increase in E-cadherin expression, while the overexpression of HuR notably facilitated A549 migration and invasion, with a decrease in E-cadherin level. In addition, immunoprecipitation study showed that HuR directly interacted with Snail, a repressor of E-cadherin, and upregulated the expression of Snail in A549 cells. These combined results suggested that the effect of HuR on A549 migration and invasion was realized by stabilizing and increasing the expression of Snail, which in-turn interfered with the expression of E-cadherin. The finding of this study revealed direct evidence that HuR affected the migration and invasion of lung cancer cells via regulating E-cadherin and Snail, providing an additional reference and mechanistic clue for further researches and therapeutic strategies in treating lung cancer.

Impact of Physiologically Relevant Genistein Exposure at Different Time Windows on Puberty Onset and Neuroendocrine Function in Female Rats.

SCOPE: Puberty timing, critical for adulthood wellbeing, is influenced by the environment, life-style, and diets. However, differential puberty-interfering effects of soy and soy isoflavone are observed in both epidemiological and toxicological studies. Additionally, their impact on neuroendocrine function at various pre-pubertal developmental windows is unclear. METHODS AND RESULTS: This study investigates the effect of genistein, a typical soy isoflavone, at neonatal, lactational, and post-weaning stages on the time of vaginal opening and determines the levels of neuroendocrine factors in female rats using immunofluorescence, immunochemistry, and enzyme-linked immunosorbent assays. A physiologically relevant dosage (10 mg kg-1 ) is used to resemble human exposure. The results show that genistein exposure at lactational stage significantly accelerates vaginal opening time, marginally increases hypothalamic gonadotropin-releasing hormone (GnRH) secretion, significantly enhances kisspeptin receptor expression, and markedly elevates blood levels of GnRH, luteinizing hormone, and follicle-stimulating hormone, while neonatal and post-weaning exposures do not induce significant alternations. CONCLUSION: Lactational stage may be an important window for genistein to impact reproductive development and neuroendocrine regulations.