An in silico investigation of the toxicological effects and biological activities of 3-phenoxybenzoic acid and its metabolite products.

We aimed to elucidate the toxic effects and biological activities of 3-phenoxybenzoic acid (3PBA) and its metabolite products.Numerous in silico methods were used to identify the toxic effects and biological activities of 3PBA, including PASS online, molecular docking, ADMETlab 2.0, ADMESWISS, MetaTox, and molecular dynamic simulation.Ten metabolite products were identified via Phase II reactions (O-glucuronidation, O-sulfation, and methylation).All of the investigated compounds were followed by Lipinski's rule, indicating that they were stimulants or inducers of hazardous processes.Because of their high gastrointestinal absorption and ability to reach the blood-brain barrier, the studied compounds' physicochemical and pharmacokinetic properties matched existing evidence of harmful effects, including haematemesis, reproductive dysfunction, allergic dermatitis, toxic respiration, and neurotoxicity.The studied compounds have been linked to the apoptotic pathway, the reproductivity system, neuroendocrine disruptors, phospholipid-translocating ATPase inhibitors, and JAK2 expression.An O-glucuronidation metabolite product demonstrated higher binding affinity and interaction with CYP2C9, CYP3A4, caspase 3, and caspase 8 than 3PBA and other metabolite products, whereas metabolite products from methylation were predominant and more toxic.Our in silico findings partly meet the 3Rs principle by minimizing animal testing before more study is needed to identify the detrimental effects of 3PBA on other organs (liver, kidneys).Future research directions may involve experimental validation of in silico predictions, elucidation of molecular mechanisms, and exploration of therapeutic interventions.These findings contribute to our understanding of the toxicological profile of 3PBA and its metabolites, which has implications for risk assessment and regulatory decisions.

Key properties & pharmacokinetics of 3PBA & its metabolites were reportedMetabolite products from methylation were predominant and more toxicMain toxics: haematemesis, reproductive dysfunction, toxic respiration, dermatitis.

Prognostic biomarker prediction for glioma induced by heavy metals and their mixtures: An in-silico study.

Although there is an association between heavy metals and glioma, the molecular mechanisms involved in glioma development remain unclear. Therefore, this study aimed to assess the molecular mechanisms implicated in glioma development induced by heavy metals and their mixtures using various methodologies and databases (CTD, Google Scholar, PubMed, ScienceDirect, SpringerLink, miRNAsong, GeneMANIA, Metascape, MIENTURNET, UALCAN). I found that heavy metals, particularly arsenic, mercury, lead, and cadmium, as well as their mixtures, have substantial influences on the etiology of gliomas. "glioblastoma signaling pathways," "integrated cancer pathway," "central carbon metabolism in cancer," "microRNAs in cancer," "p53 signaling pathway," "chemical carcinogenesis-DNA adducts," "glioma," "TP53 network," and "MAPK signaling pathway" were the predominant molecular pathways implicated in the glioma development induced by the studied heavy metals and their mixtures. Five genes (SOD1, CAT, GSTP1, PTGS2, TNF), two miRNAs (hsa-miR-26b-5p and hsa-miR-143-3p), and transcription factors (DR1 and HNF4) were identified as key components related to combined heavy metal and glioma development. Physical interactions were found to be the most common among the heavy metals and their mixtures studied (ranging from 45.2% to 77.6%). The expression level of SOD1 was significantly lower in glioblastoma multiforma samples compared to normal samples, whereas GSTP1 and TP53 expression levels were significantly higher. Brain lower and grade glioma patients who had higher levels of TP53, hsa-miR-25, hsa-miR-34, hsa-miR-222, and hsa-miR-143 had a reduced likelihood of survival. Our findings suggest that further priority should be given to investigating the impact of specific heavy metals or their mixtures on these molecular processes.

Resveratrol, Endocrine Disrupting Chemicals, Neurodegenerative Diseases and Depression: Genes, Transcription Factors, microRNAs, and Sponges Involved.

We aimed to examine the molecular basis of the positive effect of resveratrol against amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), cognitive impairment (CI), and depression induced by a mixture of bisphenol A (BPA), BPS, and BPF. The CTD, GeneMania, Metascape, SwissADME, Cytoscape, MIENTURNET, miRNAsong, and Autodock Vina were the fundamental tools for analysis. Resveratrol exerts its protective effects on selected diseases induced by a mixture of BPA, BPS, and BPF through the following genes: PTGS2 and GSR for ALS; INS, IL6, BDNF, and SOD1 for PD; BDNF, CASP3, TNF, INS, IGF1, IL1B for CI; and BDNF, PTGS2, and IL6 for depression. Detoxification was noted as the most important for ALS, dopamine metabolism for PD, apoptosis for CI, and the selenium micronutrient network for depression. hsa-miR-377-3p, hsa-miR-1-3p, hsa-miR-128-3p, and hsa-miR-204-5p were highlighted. We created and tested in silico sponges that inhibited these miRNAs. NFE2L2, BACH1, PPARG, and NR4A3 were listed as the key transcription factors implicated in resveratrol's protective effect against harmful studied chemicals. Furthermore, resveratrol's physicochemical properties and pharmacokinetics are consistent with its therapeutic benefits in ALS, PD, CI, and depression, owing to its high gastrointestinal absorption, drug-likeness, non-P-glycoprotein substrate, and capacity to penetrate the blood-brain barrier.

Effects of mixed heavy metals on obstructive lung function: findings from epidemiological and toxicogenomic data.

The molecular mechanisms and associations of mixed heavy metals (lead, mercury, and cadmium) on obstructive lung function (OLF) in males and females remain unknown. Here, we evaluated the interaction between the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio and three common heavy metals in males and females (n = 6221). Molecular processes involved in OLF development caused by mixed heavy metals were also identified to corroborate the earlier findings. In both males and females, as well as across the entire population, we found that serum cadmium levels were inversely related to the FEV1/FVC ratio. Interactions between serum cadmium and lead, as well as cadmium and mercury, were observed in relation to the FEV1/FVC ratio. Additionally, we observed negative correlations between the FEV1/FVC ratio and mixed serum cadmium, lead, and mercury in both men and women as well as in the overall population. Seven genes were identified as contributing to the etiology of OLF and targeted by combined heavy metals in silico analysis (CYP1A1, CRP, CXCL8, HMOX1, IL6, NOS2, and TNF). The primary relationships between these genes were co-expression interactions. The significant transcription factors and miRNAs associated with OLF and a combination of the examined heavy metals were identified as NFKB2, hsa-miR-155-5p, and hsa-miR-203a-3p. The main biological processes involved in the emergence of OLF induced by mixed heavy metals were listed as inflammatory and oxidative stress pathways, lung fibrosis, chronic obstructive pulmonary disease, as well as cytokine activity, monooxygenase activity, oxidoreductase activity, and interleukin-8 production. Threshold estimations and miRNA sponge patterns for heavy metal exposure levels associated with OLF were evaluated for both males and females. This study found that cadmium plays the most important role in the mixture of cadmium, lead, and mercury in the pathogenesis of OLF. Future studies are required to verify our findings and uncover the molecular mechanisms of long-term exposure to a variety of heavy metals, especially cadmium, in other populations, including children, adolescents, and the elderly.

The protective effects of curcumin on metabolic syndrome and its components: In-silico analysis for genes, transcription factors, and microRNAs involved.

BACKGROUND: We aimed to identify the molecular mechanisms behind curcumin's therapeutic benefits for metabolic syndrome (MetS) and its components. METHODS: The Comparative Toxicogenomics Database, MIENTURNET, Metascape, GeneMania, and Cytoscape software were critical analytic tools. RESULTS: Curcumin may have therapeutic effects on MetS and its components via the following genes: NOS3, IL6, INS, and ADIPOQ, particularly PPARG. Curcumin has higher docking scores than other genes with INS and PPARG (docking scores: -8.3 and -5.8, respectively). Physical interactions (56%) were found to be the most prevalent for dyslipidemia, co-expression for hypertension, obesity, T2DM, and MetS. "Galanin receptor pathway", "lipid particles composition", "IL-18 signaling pathway", "response to extracellular stimulus", and "insulin resistance" were listed in the first of the key pathways for MetS, dyslipidemia, hypertension, obesity, and diabetes, respectively. The protein-protein interaction enrichment analysis study also identified "vitamin B12 metabolism," "folate metabolism," and "selenium micronutrient network" as three major molecular pathways linked to MetS targeted by curcumin. PPARG was the key transcription factor that regulated practically all curcumin-targeted genes linked to MetS and its components. Curcumin targeted hsa-miR-155-5p, which has been linked to T2DM, hypertension, and MetS, as well as hsa-miR-130b-3p and hsa-miR-22-3p, which have been linked to dyslipidemia and obesity, respectively. In silico, sponges that regulated hsa-miR-155-5p were developed and evaluated. Curcumin, MetS, and its components have been found to target adipocytes, cardiac myocytes, smooth muscle, the liver, and pancreas. Curcumin's physicochemical properties and pharmacokinetics are closely connected with its therapeutic advantages in MetS and its components due to its high gastrointestinal absorption, drug-likeness, water solubility, and lipophilic nature. Curcumin is a CYP1A9 and CYP3A4 inhibitor. Although curcumin has a low bioavailability, it can be synthesized and administered to increase its pharmacokinetic features. CONCLUSIONS: Curcumin needs to undergo therapeutic optimization and further study into its pharmacological structure before it can be used to treat MetS and its components.

The association between the metabolic syndrome and iron status in pre- and postmenopausal women: Korean National Health and Nutrition Examination Survey (KNHANES) in 2012.

We aim to determine the association between Fe status and the metabolic syndrome (MetS) during menopause. Records of 1069 premenopausal and 703 postmenopausal Korean women were retrieved from the database of the fifth Korean National Health and Nutrition Examination Survey (KNHANES V 2012) and analysed. The association between the MetS and Fe status was performed using multivariable-adjusted analyses, subsequently develop a prediction model for the MetS by margin effects. We found that the risk of Fe depletion among postmenopausal women was lower than premenopausal women (PR = 0·813, 95 % CI 0·668, 0·998, P = 0·038). The risk of the MetS was 2·562-fold lower among premenopausal women with than without Fe depletion (PR = 0·390, 95 % CI 0·266, 0·571, P < 0·001). In contrast, the risk of the MetS tended to be higher among postmenopausal women with than without Fe depletion (PR = 1·849, 95 % CI 1·406, 2·432, P < 0·001). When the serum ferritin levels increased, the risk of the MetS increased in both premenopausal women and postmenopausal women. The margin effects showed that an increase in serum Hb and ferritin was associated with an increase in the risk of the MetS according to menopausal status and age group. Therefore, ferritin is the most validated and widely used Fe marker, could be a potential clinical value in predicting and monitoring the MetS during menopause. Further prospective or longitudinal studies, especially, clinically related studies on menopause and Fe status, are needed to clarify the causality between serum ferritin levels and the MetS that could offer novel treatments for the MetS.

Transmission and serotype features of hand foot mouth disease in household contacts in Dong Thap, Vietnam.

BACKGROUND: Hand, foot and mouth disease (HFMD) has emerged as a major public health issue in Vietnam since 2003. We aimed to investigate the household transmission of HFMD and its causative viruses from 150 households in a high incidence province in Vietnam. METHODS: A longitudinal study was conducted in patients presenting to the provincial hospital with a HFMD-like syndrome, along with their household members between April and August 2014 in Dong Thap Province. Each participant was followed up for 2 weeks. We enrolled 150 patients aged under 15 who were clinically diagnosed with HFMD in Dong Thap Hospital, 600 household members, and 581/600 household members completed the study. All participants were interviewed using a standard questionnaire. Throat swabs and blood samples were taken for molecular detection of viruses and assessment of neutralizing antibodies, respectively. Index cases were defined using a clinical case definition, household contact cases were defined using a similar definition applied to the 2 weeks before admission and 2 weeks after discharge of the index case. Characteristics of index cases, household contacts, the attack rate, serotype features and related factors of HFMD were reported. RESULT: Among 150 index cases, 113 were laboratory confirmed: 90/150 were RT-PCR-positive, 101/142 had a ≥ 4-fold increase of neutralizing antibody against Enterovirus A71 (EV-A71), Coxsackievirus (CV) A6 or CV-A16 across the two samples collected. 80/150 (53%) were males, and 45/150 (30%) were under the age of 1. The predominant serotype was CV-A6, identified in 57/87 (65.5%) of the specimens. No deaths were reported. Among 581 household contacts, 148 were laboratory confirmed: 12/581 were RT-PCR-positive, 142/545 had a ≥ 4-fold increase of neutralizing antibodies against EV-A71, CV-A6 or CV-A16; 4 cases experienced HFMD in the past 4 weeks. Attack rate among household contacts was 148/581 (25.5%). In 7/12 (58%) instances, the index and secondary cases were infected with the same serotype. Having a relationship to index case was significantly associated with EV infection. CONCLUSION: The attack rate among household contacts was relatively high (25.5%) in this study and it seems justified to also consider the household setting as an additional target for intervention programs.

Molecular mechanisms implicated in protein changes in the Alzheimer's disease human hippocampus.

This study aimed to elucidate the specific biochemical pathways linked to changes in proteins in the Alzheimer's disease (AD) human hippocampus. Our data demonstrate a constant rise in the expression of four proteins (VGF, GFAP, HSPB1, and APP) across all eleven studies. Notably, UBC was the most centrally involved and had increased expression in the hippocampus tissue of individuals with AD. Modified proteins in the hippocampal tissue were found to activate the innate immune system and disrupt communication across chemical synapses. Four hub proteins (CD44, APP, ITGB2, and APOE) are connected to amyloid plaques, whereas two hub proteins (RPL24 and RPS23) are related to neurofibrillary tangles (NFTs). The presence of modified proteins was discovered to trigger the activation of microglia and decrease the functioning of ribosomes and mitochondria in the hippocampus. Three significant microRNAs (hsa-miR-106b-5p, hsa-miR-17-5p, and hsa-miR-16-5p) and transcription factors (MYT1L, PIN1, and CSRNP3) have been discovered to improve our understanding of the alterations in proteins within the hippocampal tissues that lead to the progression of AD. These findings establish a path for possible treatments for AD to employ therapeutic strategies that specifically focus on the proteins or processes linked to the illness.

Role of prolactin in the protective effect of amisulpride against 1,2-Diacetylbenzene's neurotoxicity.

Exposure to organic solvents is associated with various health problems, including neurodegenerative diseases. Among these solvents, 1,2-diethylbenzene is notable for its ability to produce a toxic metabolite, 1,2-Diacetylbenzene (DAB), which can cause memory impairment. Prolactin (PRL) is theorized to protect the central nervous system. Certain antipsychotic drugs, known for increasing PRL secretion, have shown to improve cognitive performance in psychotic Alzheimer's patients. Among these, amisulpride stands out for its high efficacy, limited side effects, and high selectivity for dopamine D2 receptors. In our study, we explored the potential of amisulpride to inhibit DAB-induced neurotoxicity via PRL activation. Our results show that amisulpride enhances the PRL/JAK/STAT, PI3K/AKT, and BDNF/ERK/CREB pathways, playing critical roles in PRL's neuroprotection pathways and memory formation. Additionally, amisulpride inhibited DAB-triggered NLRP3 inflammasome activation and apoptosis. Collectively, these findings suggest that amisulpride may be a promising therapeutic intervention for DAB-induced neurotoxicity, partly through activating the PRL pathway.

The first two case reports of confirmed Mpox in patients with syphilis in a dense urban setting, Can Tho, Vietnam: From clinical presentation, treatment, and epidemiological surveillance to prevention.

This report elucidated the first two noteworthy cases of Mpox that manifested as an emerging concern in a densely populated city in Vietnam. Two male patients (22 and 27 years old) were admitted to the hospital due to the presence of small pustules on their faces, accompanied by symptoms of fatigue, drowsiness, and muscle pain. Reverse transcription-polymerase chain reaction confirmed the presence of Mpox. The patients possessed a medical history involving four previous treatments for syphilis, a continuous antiretroviral regimen for over 3 years, no previous history of chickenpox, a lack of vaccination against chickenpox, and engagement in intimate contact with other men. Following a 14-day isolation period coupled with appropriate medical interventions, both patients exhibited stable health conditions, marked by the absence of fever and the desiccation of skin blisters. Subsequently, they were discharged with instructions for ongoing health monitoring. Comprehensive surveillance and monitoring approaches have been implemented for all individuals in close contact with the affected patients, adhering to established guidelines. Notably, no suspected cases have been identified during the current surveillance efforts. The collective findings underscore the significance of robust surveillance, continuous monitoring, and strategic vaccination initiatives, particularly in densely populated urban centers, to effectively manage and mitigate the impact of Mpox outbreaks.

Elucidation of the effects of 2,5-hexandione as a metabolite of n-hexane on cognitive impairment in leptin-knockout mice (C57BL/6-Lepem1Shwl/Korl).

Exposure to n-hexane and its metabolite 2,5-hexandione (HD) is a well-known cause of neurotoxicity, particularly in the peripheral nervous system. To date, few studies have focused on the neurotoxic effects of HD on cognitive impairment. Exposure to HD and diabetes mellitus can exacerbate neurotoxicity. There are links among HD, diabetes mellitus, and cognitive impairment; however, the specific mechanisms underlying them remain unclear. Therefore, we aimed to elucidate the neurotoxic effects of HD on cognitive impairment in ob/ob (C57BL/6-Lepem1Shwl/Korl) mice. We found that HD induced cognitive impairment by altering the expression of genes (FN1, AGT, ACTA2, MYH11, MKI67, MET, CTGF, and CD44), miRNAs (mmu-miR15a-5p, mmu-miR-17-5p, and mmu-miR-29a-3p), transcription factors (transcription factor AP-2 alpha [TFAP2A], serum response factor [Srf], and paired box gene 4 [PAX4]), and signaling pathways (ERK/CERB, PI3K/AKT, GSK-3ß/p-tau/amyloid-ß), as well as by causing neuroinflammation (TREM1/DAP12/NF-κB), oxidative stress, and apoptosis. The prevalent use of n-hexane in various industrial applications (for instance, shoe manufacturing, printing inks, paints, and varnishes) suggests that individuals with elevated body weight and glucose levels and those employed in high-risk workplaces have greater probability of cognitive impairment. Therefore, implementing screening strategies for HD-induced cognitive dysfunction is crucial. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00228-1.

Effects of mixed heavy metals on kidney function in premenopausal and postmenopausal women.

OBJECTIVE: To evaluate the relationships between heavy metals (cadmium, lead, and mercury) and their mixtures and estimated glomerular filtration rate (eGFR) in premenopausal and postmenopausal women. METHODS: Using data from the Korean National Health and Nutrition Examination Survey (2009-2017), multivariate linear regression models, marginal effects, and weighted quantile sum regression, we assessed the associations between single heavy metals and their mixtures and eGFR among 5,372 women. RESULTS: Risks of reduced eGFR, comorbidities, and heavy metal exposure were found to be higher in postmenopausal women than in premenopausal women. A negative association of cadmium ( ß = -2.97; 95% CI, -5.10 to -0.85) and a positive association of mercury ( ß = 2.97; 95% CI, 1.49 to 4.44), with eGFR in postmenopausal women. Inverse associations of lead with eGFR in both premenopausal women ( ß = -4.75; 95% CI, -6.04 to -3.46) and postmenopausal women ( ß = -4.54; 95% CI, -6.96 to -2.13). Interactions were identified between lead and mercury, as well as cadmium and lead for eGFR among premenopausal women ( ß = -2.04; 95% CI, -2.98 to -1.10) and postmenopausal women ( ß = -3.52; 95% CI, -6.04 to -1.01), respectively. There was a negative association between mixed heavy metals and eGFR in both premenopausal women ( ß = -2.23; 95% CI, -3.51 to -0.96) and postmenopausal women ( ß = -3.86; 95% CI, -6.89 to -0.83). Lead was found as a key chemical related to reduced eGFR. Cutoff values for each heavy metal concentration related to eGFR were provided. CONCLUSION: Postmenopausal women were more influenced by mixed heavy metals' effects on kidney function than premenopausal women. Early interventions (eg, water filtering, heavy metal yearly screening) in women, especially postmenopausal women, are needed to reduce the incidence of chronic kidney disease.

Interactions between heavy metals and sleep duration among pre-and postmenopausal women: A current approach to molecular mechanisms involved.

The effects of heavy metals (cadmium, lead, and mercury) and their mixtures on sleep duration in pre-and postmenopausal women, particularly the molecular mechanisms, remain unknown. Here, we assessed the interaction between heavy metals and sleep duration among pre-and postmenopausal women (n = 1134). Furthermore, molecular mechanisms related to sleep disorders induced by studied heavy metals were further analyzed to support the previous findings. We found that serum lead levels were positively related to weekend and weekday sleep duration in premenopausal women. There were interactions between serum lead and mercury and menopausal status for sleep duration. Serum lead and mercury levels were shown to be inversely related to sleep duration in postmenopausal women. Despite the lack of statistically significant associations between mixed heavy metals and sleep duration, there were increasing trends in premenopausal women's sleeping patterns and decreasing trends in postmenopausal women's sleeping patterns. In silico analysis, IL1B, hsa-21-5p, hsa-887-3p, hsa-877-3p, and NR4A1 were identified as the most relevant genes, miRNAs, and transcription factors linked with sleep disorders induced by combined heavy metals (cadmium, lead, and mercury). Furthermore, "type 1 melanocortin receptor binding," "endocrine hormone secretion," "interleukin-1 receptor antagonist activity," "altered melanocortin system," and "sleep wake disorders" were identified as the predominant molecular mechanisms involved in the pathophysiology of sleep disorders induced by the studied heavy metals. Cut off point values and miRNA sponge templates for heavy metal exposure levels relevant to sleep disorders in pre- and postmenopausal women were reported. Future research is needed to verify our findings and provide insight into the molecular processes of long-term mixed heavy metal exposure in various populations, such as children and the elderly.

An evaluation of the effects of mixed heavy metals on prediabetes and type 2 diabetes: epidemiological and toxicogenomic analysis.

The link between mixed heavy metals (mercury, lead, and cadmium), prediabetes, and type 2 diabetes mellitus (T2DM), especially molecular mechanisms, is poorly understood. Thus, we aimed to identify the association between mixed heavy metals and T2DM and its components using a data set from the Korean National Health and Nutrition Examination Survey. We further analyzed the main molecular mechanisms implicated in T2DM development induced by mixed heavy metals using in-silico analysis. Our findings observed that serum mercury was associated with prediabetes, elevated glucose, and ln2-transformed glucose when using different statistical methods. "AGE-RAGE signaling pathway in diabetic complications", "non-alcoholic fatty liver disease", "metabolic Syndrome X", and three miRNAs (hsa-miR-98-5p, hsa-let-7a-5p, and hsa-miR-34a-5p) were listed as the most important molecular mechanisms related to T2DM development caused by mixed heavy metals. These miRNA sponge structures were created and examined, and they may be beneficial in the treatment of T2DM. The predicted cutoff values for three heavy metal levels linked to T2DM and its components were specifically identified. Our results imply that chronic exposure to heavy metals, particularly mercury, may contribute to the development of T2DM. To understand the changes in the pathophysiology of T2DM brought on by a combination of heavy metals, more research is required.

In silico identification of novel heterocyclic compounds combats Alzheimer's disease through inhibition of butyrylcholinesterase enzymatic activity.

Increasing evidence indicates that heterocyclic molecules possess properties against butyrylcholinesterase (BChE) enzymatic activity, which is a potential therapeutic target for Alzheimer's disease (AD). Thus, this study aimed to further evaluate the relationship between heterocyclic molecules and their biological activities. A dataset of 38 selective and potent heterocyclic compounds (-log[the half­maximal inhibitory concentration (pIC50)]) values ranging from 8.02 to 10.05) was applied to construct a quantitative structure-activity relationship (QSAR) study, including Bayesian model average (BMA), artificial neural network (ANN), multiple nonlinear regression (MNLR), and multiple linear regression (MLR) models. Four models met statistical acceptance in internal and external validation. The ANN model was superior to other models in predicting the pIC50 of the outcome. The descriptors put into the models were found to be comparable with the target-ligand complex X-ray structures, making these models interpretable. Three selected molecules possess drug-like properties (pIC50 values ranged from 9.19 to 9.54). The docking score between candidates and the BChE receptor (RCSB ID 6EYF) ranged from -8.4 to -9.0 kcal/mol. Remarkably, the pharmacokinetics, biological activities, molecular dynamics, and physicochemical properties of compound 18 (C20H22N4O, pIC50 value = 9.33, oxadiazole derivative group) support its protective effects on AD treatment due to its non-toxic nature, non-carcinogen, cholinergic nature, capability to penetrate the blood-brain barrier, and high gastrointestinal absorption.Communicated by Ramaswamy H. Sarma.

Exposure to mixed chemicals elevated triiodothyronine (T3) and follicle-stimulating hormone (FSH) levels: epidemiology and in silico toxicogenomic involvement.

There is a dearth of evidence on the effects of a mixture of numerous different types of chemicals on hormone functions. We hypothesized that exposure to mixed chemicals may alter hormone levels. Thus, this study was to identify an association between the mixed chemicals (25 chemicals) and hormone levels (thyroxine (T4) and triiodothyronine (T3), thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH)) among 5687 Korean adults using four different statistical approaches. Furthermore, we elucidate the effects of the key chemicals on thyroid disease and infertility based on the findings from epidemiology data. The positive associations between mixed chemicals and T3 and between mixed chemicals and FSH were observed across different methods after adjusting for all possible confounders. In the weighted quantile sum regression models, there were positive associations between mixed chemicals and T3 (ß = 4.43, 95%CI: 2.81-5.88) and ln-transformed FSH (lnFSH) (ß = 0.15, 95%CI: 0.10-0.20). In the quantile g-computation models, positive associations were found between mixed chemicals and T3 (ß=2.15, 95%CI: 0.17-4.14) and lnFSH (ß=0.15, 95%CI: 0.07-0.22). In the Bayesian kernel machine regression models, culminative effects of mixed chemicals showed positive associations with T3 and lnFSH; mercury (group posterior inclusion probabilities (PIPs) = 0.557 and conditional PPI = 0.556) and lead (group PIP group = 0.815 and conditional PPI = 0.951) were the most important chemicals for T3 and FSH, respectively. The results obtained were partially robust when subjected to in silico toxicogenomic data. We identified several molecular mechanisms that were implicated in Hg-induced thyroid disease, including the selenium micronutrient network, oxidative stress response, IL-17 signaling pathway, poorly differentiated thyroid carcinoma, and primary hyperthyroidism. The molecular processes implicated in Pb-induced infertility were "response to nutrient levels," "gonad development," "male infertility," "female infertility," and "intrinsic pathway for apoptosis," with a particular focus on FSH. The present study investigated the threshold levels of the studied chemicals and their potential impact on the disruption of T3 and FSH hormones. Future research is warranted to determine the effects of mixed chemicals on various hormones because there have been few studies on the disruption of hormones caused by such mixed chemicals.

Roles of mixed nutrient intakes on metabolic syndrome among korean adults 19-80 years old: molecular mechanisms involved.

Purpose: We aim to identify the association between nutrient intake mixtures (22 micro-macro nutrients) and metabolic syndrome (MetS) or its components, including molecular mechanisms involved, among 16,807 Korean adults aged 19-80. Methods: The associations of mixed nutrient intakes on MetS or its components were identified using linear regression models, WQS regression, qgcomp, and BKMR regression. Genes, transcription factors, miRNA, biological processes, and pathways were assessed using GeneMania, CHEA3, MIENTURNET, and ToppFun functions. Results: We found that the overall effect of mixed nutrient intakes was also related to MetS and its components. In silico analysis, we found that a mixture of nutrients interacted with the IL6 gene and was linked with MetS. Physical interactions were the key interactions (77%) involved in the mutual genes and MetS targeted by a mixture of nutrients. IL6 related pathways, "positive regulation of type B pancreatic cell apoptotic process", "regulation of glucagon secretion", "LDL pathway during atherogenesis", and "IL-10 anti-inflammatory signaling pathway" were identified as key molecular mechanisms that may be targeted by mixed nutrients implicated in MetS. The key miRNAs and transcription factors involved in the process of MetS targeted by a mixture of nutrients were also described. The cutoff levels for nutrient intake levels associated with MetS and its components were also described. Conclusion: Our findings will pave the way for further research to evaluate the interactions between a mixture of nutrients and non-communicable diseases. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01158-1.

Higher intakes of nutrients and regular drinking are associated with habitual sleep duration in pre- and postmenopausal women with comorbidities.

OBJECTIVES: We aimed to assess the association between nutrient intake, health-related behaviors, and habitual sleep duration in pre- and postmenopausal women. DESIGN: A cross-sectional study. PARTICIPANTS: 2084 pre- and postmenopausal women aged 18-80 years old. MEASUREMENTS: Nutrient intake and sleep duration were measured by a 24-hour recall approach and self-reports, respectively. We examined the association and interaction between comorbidities, nutrient intake, and sleep duration groups among 2084 women using data from KNHASES (2016-2018) and multinomial logistic regression. RESULTS: In premenopausal women, we observed negative associations between very short (<5 hours)/short (5-6 hours)/long (≥9 hours) sleep duration and 12 nutrients (vitamin B1, B3, vitamin C, PUFA, n-6 fatty acid, iron, potassium, phosphorus, calcium, fiber, carbohydrate) and a positive association between retinol and short sleep duration (prevalence ratio (PR), 1.08; 95% CI, 1.01-1.15). In premenopausal women, interactions were found between comorbidities and PUFA (PR, 3.83; 95% CI, 1.56-9.41), n-3 fatty acid (PR, 2.43; 95% CI, 1.17-5.05), n-6 fatty acid (PR, 3.45; 95% CI, 1.46-8.13), fat (PR, 2.77; 95% CI, 1.15-6.64), and retinol (PR, 1.28; 95% CI, 1.06-1.53) for very short and short sleep duration, respectively. Interactions between comorbidities, vitamin C (PR, 0.41; 95% CI, 0.24-0.72), and carbohydrates (PR, 1.67; 95% CI, 1.05-2.70) for very short and short sleep duration in postmenopausal women, respectively. Regular drinking was positively associated with a risk of short sleep duration in postmenopausal women (PR, 2.74, 95% CI: 1.11-6.74). CONCLUSIONS: Dietary intake and alcohol use were found to be involved in sleep duration, so healthcare staff should encourage women to maintain a healthy diet and reduce alcohol use to improve sleep duration.

Cadmium, lead, and mercury interactions on obstructive lung function in pre- and postmenopausal women.

There was a dearth of information on how heavy metals affect women's lung function. To assess the effects of cadmium, lead, and mercury and their interactions on obstructive lung function in pre- and postmenopausal women. The associations between an individual heavy metal and its mixtures and the first second of forced expiration (FEV1)/forced vital capacity (FVC) were studied using multivariate non-linear, linear, and logistic regression models, Bayesian kernel machine regression (BKMR), and marginal effects in 1821 women. Serum cadmium and lead levels and the percentage of FEV1/FVC < 70% were substantially higher in postmenopausal women than in premenopausal women. Cadmium (ß = - 0.84, 95%, - 1.63 to - 0.05) and lead (ß = - 0.43, 95%CI, - 1.62 to - 0.04) were found to be inversely associated with the FEV1/FVC ratio in premenopausal women, while a combination of cadmium and mercury showed a negative association with the FEV1/FVC ratio in postmenopausal women (ß = - 0.65, 95%CI, - 1.27 to - 0.03). In the non-linear regression model, an inverted U-shape association of mercury with FEV1/FVC indicator was found in postmenopausal women (ß = - 0.78, 95%CI, - 1.41 to - 0.15). In BKMR model, a mixture of three heavy metals was negatively associated with the FEV1/FVC ratio. Cadmium was identified as an important substance associated with lung function decline (posterior inclusion probabilities (PIPs) = 0.731 in premenopausal and PIPs = 0.514 in postmenopausal women). Cadmium appeared linear; an inverted U-shape association of mercury with the FEV1/FVC indicator and slightly positive associations of lead with the FEV1/FVC indicator in postmenopausal women were found. Threshold cutoff values for the studied substances related to clinical lung function decline were established. In conclusion, the presence of mixed heavy metals (cadmium, lead, and mercury) and their association with obstructive lung function showed worse results than separate associations. These findings have important implications for policy and future research about how heavy metals affect women's lungs.