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.

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.

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.

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.

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.

In silico exploration of promising heterocyclic molecules against both acetylcholinesterase and butyrylcholinesterase enzymes.

We aimed to further explore the relationship between heterocyclic molecules and their associated biological activities for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. A dataset of 36 heterocycles was used to predict the activity of AChE and BChE inhibitors (the pIC50 values ranged from 7.84 to 12.49). A quantitative structure-activity relationship (QSAR) study was generated with the help of four different models (BMA, MNLR, MLR, and ANN). Four of the models were statistically acceptable based on both internal and external validation. The descriptors used in the models were similar to the X-ray structures of the target-ligand complexes, which made it possible to predict the pIC50 for AChE and BChE enzymes. Five selected molecules (compounds 6 (C21H21F3N4O), compound 7 (C22H23F3N4O), and compound 8 (C22H23F3N4O2) belong to the oxadiazole derivative group; compound 16 (C17H13ClN2O3) is classified into the chemical structures of different N, O, and S-based heterocycle groups; and compound 25 (C19H17NO2) pertains to the pyrimidine derivative group) possessed high pIC50 values for AChE and BChE enzymes (pIC50 values for AChE and BChE ranged from 9.01 to 10.32). The range of docking scores between the AChE and BChE receptors and their respective candidates was from -8.1 to -9.2 kcal/mol. The pharmacokinetics, biological activities, and physicochemical properties of five selected compounds supported their ability to protect against AD because they are not toxic, have a cholinergic effect, can cross the blood-brain barrier, and are well absorbed by the gastrointestinal tract.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.

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.

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.

Identification of promising inhibitory heterocyclic compounds against acetylcholinesterase using QSAR, ADMET, biological activity, and molecular docking.

Heterocyclic compounds exert diverse functions, especially acetylcholinesterase (AChE) inhibition. Thus, identifying the association between their detailed structures and biological activities is important to the development of novel medications for Alzheimer's disease (AD) treatment. In this study, diverse sets of 120 potent and selective heterocyclic compounds (-log[the half­maximal inhibitory concentration] (pIC50) values ranged from 8.01 to 12.50) were used to develop quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR), multiple nonlinear regression (MNLR), Bayesian model average (BMA), and artificial neural network (ANN) models. The models' robustness and stability have been assessed using both internal and external methodology. ANN outperforms MLR, MNLR, and BMA according to external validation. The molecular descriptors incorporated into the model were in satisfactory correlation with the AChE receptor-ligand complex X-ray structures, making the model interpretable and predictive. Three selected compounds exert drug-like characteristics (pIC50 values ranged from 11.01 to 11.17). The binding affinity between the optimal compounds and the AChE receptor (RCSB ID 3LII) ranged from - 7.4 to - 8.8 kcal/mol. Remarkably, the pharmacokinetics, physicochemical properties, and biological activities of compound 25 (C23H32N2O2, PubChem CID 118727071, pIC50 value = 11.17) were found to be consistent with its therapeutic effects in AD due to its cholinergic and non-toxic nature, non-P-glycoprotein, high gastrointestinal absorption, and capability to penetrate the blood-brain barrier.

In silico identification of molecular mechanisms for stroke risk caused by heavy metals and their mixtures: Sponges and drugs involved.

This study used various approaches and databases to evaluate the molecular processes and identify miRNA sponges and drugs associated with the pathophysiology of stroke caused by heavy metals and their combinations. We found that the genes ALB (albumin), IL1B (Interleukin-1ß), F2 (coagulation factor II), APOA1 (apolipoprotein A1), IL6 (Interleukin 6), and NOS2 (nitric oxide synthase 2) were linked to the development of strokes by 18 chemicals and a combination of cadmium, copper, and lead. These results may point to the significance of detoxification and neuroinflammation in stroke as well as the potential for targeting these genes in future stroke therapies. ALB and IL1B were the most common and significant genes. The "selenium micronutrient network," "vitamin B12 metabolism," and "folate metabolism" were shown to be the most significant pathways connected to the risk of stroke brought on by combined heavy metals. The two main cellular elements that may increase the risk of stroke caused by heavy metals were discovered to be "blood microparticle" and "endoplasmic reticulum lumen." We also observed an important chromosome (chr7p15.3), two transcription factors (NFKB2 [nuclear factor kappa B subunit 2] and NR1I2 [nuclear receptor subfamily 1 group, member 2]), and four microRNAs (hsa-miR-26a-5p, hsa-miR-9-5p, hsa-miR-124-3p, and hsa-miR-155-5p) associated with stroke caused by combined heavy metals. Additionally, for these miRNAs, we created and examined in silico microRNA sponge sequences. Triflusal and andrographolide have been identified as potential treatments for heavy metal-induced stroke. Taken together, heavy metals may be a significant contributor to the pathophysiology of stroke, but further investigation into the precise molecular pathways implicated in stroke pathophysiology is required to corroborate these findings.

Interactions between cadmium, lead, mercury, and arsenic and depression: A molecular mechanism involved.

BACKGROUND: We aimed to assess the interactions between mixed heavy metals, genes, and miRNAs implicated in depression development and to design and create miRNA sponges. METHODS: The key data-mining approaches in this study were the Comparative Toxicogenomics Database (CTD), MIENTURNET, GeneMania, Metascape, Webgestalt, miRNAsong, and Cytoscape software. RESULTS: A mixture of cadmium, lead, mercury, and arsenic was related to the development of depression. Even though the genes acquired from the heavy metals of depression studied were different, the "selenium micronutrient network", "vitamin B12 and folate metabolism", and "positive regulation of peptidyl-serine phosphorylation" pathways were highlighted. The heavy metal mixture altered the genes SOD1, IL6, PTGS2, PON1, BDNF, and ALB, highlighting the role of oxidative stress, pro-inflammatory cytokines, paraoxonase activity, neurotrophic factors, and antioxidants related to depression, as well as the possibility of targeting these genes in prospective depressive treatment. Chr1q31.1, five transcription factors (NR4A3, NR1H4, ATF3, CREB3L3, and NR1I3), the "endoplasmic reticulum lumen," "blood microparticle," and "myelin sheath", were found to be important chromosomal locations, transcription factors, and cellular parts linked to depression and affected by mixed heavy metals. Furthermore, we developed a network-based approach to detect significant genes, miRNA, pathways, and illnesses related to depression development. We also observed eight important miRNAs related to depression induced by mixed heavy metals (hsa-miR-16-5p, hsa-miR-132-3p, hsa-miR-1-3p, hsa-miR-204-5p, hsa-miR-206, hsa-miR-124-3p, hsa-miR-146a-5p, and hsa-miR-26a-5p). In addition, we created and evaluated miRNA sponge sequences for these miRNAs in silico. LIMITATIONS: A toxicogenomic design in silico was used. CONCLUSIONS: Our findings highlight the importance of oxidative stress, notably SOD1 and the selenium micronutrient network, in depression caused by heavy metal mixtures and provide additional insights into common molecular pathways implicated in depression pathogenesis.

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.

Risperidone ameliorated 1,2-Diacetylbenzene-induced cognitive impairments in mice via activating prolactin signaling pathways.

Cognitive impairment and organic solvent exposure have been becoming public health concerns due to an increasingly aging population, increased life expectancy, urbanization, and industrialization. Converging evidence indicates the link between 1,2-diacetylbenzene (DAB), prolactin (PRL), risperidone, and cognitive impairment. However, these relationships remain unclear. We investigated the therapeutic properties of risperidone in DAB-induced cognitive impairment using both in vivo and in silico methods. Risperidone alleviated DAB-induced cognitive impairment in hippocampal mice, possibly by inhibiting GSK-3ß, ß-amyloid, CDK5, BACE, and tau hyperphosphorylation. Risperidone also attenuated the activation of TREM-1/DAP12/NLRP3/caspase-1/IL-1ß, and TLR4/NF-κB pathways caused by DAB. Furthermore, risperidone inhibited DAB-induced oxidative stress, advanced glycation end products, and proinflammatory cytokines, as well as increased the expression of Nrf2, IL-10, Stat3, MDM2, and catalase activity. On the other hand, risperidone activated the expression of IRS1, PI3K, AKT, BDNF, Drd2, Scna5, and Trt as well as reduced the Bax/Bcl2 ratio and Caspase-3 levels. In silico analyses identified the prolactin signaling pathway, miR-155-5p, miR-34a-5p, and CEBPB as the main molecular mechanisms involved in the pathophysiology of DAB-induced cognitive impairment and targeted by risperidone. Our results suggest that risperidone could be used to treat cognitive impairment caused by organic solvents, especially DAB.

The Effects of a Mixture of Cadmium, Lead, and Mercury on Metabolic Syndrome and Its Components, as well as Cognitive Impairment: Genes, MicroRNAs, Transcription Factors, and Sponge Relationships : The Effects of a Mixture of Cadmium, Lead, and Mercury on Metabolic Syndrome and Its Components, as well as Cognitive Impairment: Genes, MicroRNAs, Transcription Factors, and Sponge Relationships.

Converging evidence indicates heavy metal-induced genes, transcription factors (TFs), and microRNAs (miRNAs) are critical pathological components of metabolic syndrome (MetS) and cognitive impairment. Thus, our goals are to identify the interaction of mixed heavy metals (cadmium + lead + mercury) with genes, TFs, and miRNAs involved in MetS and its components, as well as cognitive impairment development. The most commonly retrieved genes for each disease were different, but essential biological pathways such as oxidative stress, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, apoptosis, the IL-6 signaling pathway, and Alzheimer's disease were highlighted. The genes CASP3, BAX, BCL2, IL6, TNF, APOE, HMOX1, and IGF were found to be mutually affected by the heavy metal mixture studied, suggesting the importance of apoptosis, inflammation, lipid, heme, and glucose metabolism in MetS and cognitive impairment, as well as the potentiality of targeting these genes in prospective therapeutic intervention for these diseases. EGR2, ATF3, and NFE2L2 were noted as the most key TFs implicated in the etiology of MetS and its components, as well as cognitive impairment. We also found six miRNAs induced by studied heavy metals were the mutual miRNAs linked to MetS, its components, and cognitive impairment. In particular, we used miRNAsong to construct and verify a miRNA sponge sequence for these miRNAs. These sponges are promising molecules for the treatment of MetS and its components, as well as cognitive impairment.