Exploring the association of metal mixture in blood to the kidney function and tumor necrosis factor alpha using machine learning methods.

This research aimed to approach relationships between metal mixture in blood and kidney function, tumor necrosis factor alpha (TNF-α) by machine learning. Metals levels were measured by Inductively Couple Plasma Mass Spectrometry in blood from 421 participants. We applied K Nearest Neighbor (KNN), Naive Bayes classifier (NB), Support Vector Machines (SVM), random forest (RF), Gradient Boosting Decision Tree (GBDT), Categorical boosting (CatBoost), eXtreme Gradient Boosting (XGBoost), Whale Optimization-based XGBoost (WXGBoost) to identify the effect of plasma metals, TNF-α, and estimated glomerular filtration rate (eGFR by CKD-EPI equation). We conducted not only toxic metals, lead (Pb), arsenic (As), cadmium (Cd) but also included trace essential metals, selenium (Se), copper (Cu), zinc (Zn), cobalt (Co), to predict the interaction of TNF-α, TNF-α/white blood count, and eGFR. The high average TNF-α level group was observed among subjects with higher Pb, As, Cd, Cu, and Zn levels in blood. No associations were shown between the low and high TNF-α level group in blood Se and Co levels. Those with lower eGFR group had high Pb, As, Cd, Co, Cu, and Zn levels. The crucial predictor of TNF-α level in metals was blood Pb, and then Cd, As, Cu, Se, Zn and Co. The machine learning revealed that As was the major role among predictors of eGFR after feature selection. The levels of kidney function and TNF-α were modified by co-exposure metals. We were able to acquire highest accuracy of over 85% in the multi-metals exposure model. The higher Pb and Zn levels had strongest interaction with declined eGFR. In addition, As and Cd had synergistic with prediction model of TNF-α. We explored the potential of machine learning approaches for predicting health outcomes with multi-metal exposure. XGBoost model added SHAP could give an explicit explanation of individualized and precision risk prediction and insight of the interaction of key features in the multi-metal exposure.

Suppressive Effects of Siegesbeckia orientalis Ethanolic Extract on Proliferation and Migration of Hepatocellular Carcinoma Cells through Promoting Oxidative Stress, Apoptosis and Inflammatory Responses.

Previous studies have demonstrated that Siegesbeckia orientalis (SO) has a suppressive effect on the growth and migration of endometrial and cervical cancer cells. The present study examined the effect of SO ethanolic extract (SOE) on the proliferation and migration of hepatocellular carcinoma (HCC) and examined the effects of SOE on non-cancerous cells using HaCaT keratinocytes as a model. The SOE effectively inhibited the proliferation of Hepa1-6 (IC50 = 282.4 µg/mL) and HepG2 (IC50 = 344.3 µg/mL) hepatoma cells, whereas it has less cytotoxic effect on HaCaT cells (IC50 = 892.4 µg/mL). The SOE treatment increased the generation of ROS in HCC, but decreased the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase. In contrast, it reduced intracellular ROS formation and upregulated the expression of the related antioxidant enzymes in the H2O2-stimulated HaCaT cells. The SOE intervention also down-regulated the anti-apoptotic Bcl-2 and the migration-related proteins including matrix metalloproteinases (MMPs) and ß-catenin in the HCC, suggesting that SOE could promote HCC apoptosis and inhibit HCC migration. On the contrary, it reduced apoptosis and promoted the migration of the keratinocytes. Additionally, the SOE treatment significantly up-regulated the pro-inflammatory cytokines, including TNF-α, IL-6 and IL-1ß, in Hepa1-6 and HepG2 cells. Conversely, it significantly decreased the expression of these cytokines in the H2O2-induced HaCaT cells. These findings indicated that SOE treatment can delay the progression of HCC by increasing oxidative stress, promoting inflammatory response, inducing cancer cell apoptosis and inhibiting their migration. It also has protective effects from pro-oxidant H2O2 in non-cancerous cells. Therefore, SOE may provide a potential treatment for liver cancer.

Use of Generalized Weighted Quantile Sum Regressions of Tumor Necrosis Factor Alpha and Kidney Function to Explore Joint Effects of Multiple Metals in Blood.

Exposure to heavy metals could lead to adverse health effects by oxidative reactions or inflammation. Some essential elements are known as reactors of anti-inflammatory enzymes or coenzymes. The relationship between tumor necrosis factor alpha (TNF-α) and heavy metal exposures was reported. However, the interaction between toxic metals and essential elements in the inflammatory response remains unclear. This study aimed to explore the association between arsenic (As), cadmium (Cd), lead (Pb), cobalt (Co), copper (Cu), selenium (Se), and zinc (Zn) in blood and TNF-α as well as kidney function. We enrolled 421 workers and measured the levels of these seven metals/metalloids and TNF-α in blood; kidney function was calculated by CKD-EPI equation. We applied weighted quantile sum (WQS) regression and group WQS regression to assess the effects of metal/metalloid mixtures to TNF-α and kidney function. We also approached the relationship between metals/metalloids and TNF-α by generalized additive models (GAM). The relationship of the exposure−response curve between Pb level and TNF-α in serum was found significantly non-linear after adjusting covariates (p < 0.001). Within the multiple-metal model, Pb, As, and Zn were associated with increased TNF-α levels with effects dedicated to the mixture of 50%, 31%, and 15%, respectively. Grouped WQS revealed that the essential metal group showed a significantly negative association with TNF-α and kidney function. The toxic metal group found significantly positive associations with TNF-α, serum creatinine, and WBC but not for eGFR. These results suggested Pb, As, Zn, Se, and mixtures may act on TNF-α even through interactive mechanisms. Our findings offer insights into what primary components of metal mixtures affect inflammation and kidney function during co-exposure to metals; however, the mechanisms still need further research.

Interaction between Single Nucleotide Polymorphisms (SNP) of Tumor Necrosis Factor-Alpha (TNF-α) Gene and Plasma Arsenic and the Effect on Estimated Glomerular Filtration Rate (eGFR).

When poisons enter the human body, tumor necrosis factor (TNF-α) will increase and cause damage to tissues through oxidative stress or inflammatory reaction. In previous studies, arsenic (As) has known to cause many health problems. Some studies have shown that As exposure is negatively correlated with estimated glomerular filtration rate (eGFR), or with the prevalence of proteinuria. At present, there are few studies focusing on the effects of As exposure and TNF-α single nucleotide polymorphism (SNP) to eGFR; thus, this study was intended to explore the interactions between TNF-α SNPs and plasma As and their effects on eGFR. A cohort of 500 adults, aged 30 to 70 years, was randomly selected from Taiwan Biobank (TWB). We used the gene chip to screen out seven SNPs of the TNF-α gene and used the results, combined with questionnaires, biochemical tests, and stored plasma samples from the TWB, for the analysis of As by inductively coupled plasma mass spectrometry (ICP-MS). After adjustments for BMI, hypertension, hyperlipidemia, kidney stones, and smoking habits, multiple regression statistics were performed to explore the interaction between SNPs and plasma As with eGFR. In this sample of the general population, plasma As had a significant association with the decline of eGFR (ß (SE) = −7.92 (1.70), p < 0.0001). TNF-α gene SNP rs1800629 had the property of regulating TNF-α, which interacts with plasma As; individuals with the AG type had a significantly lower eGFR than those with the GG type, by 9.59 mL/min/1.73 m2 (p < 0.05), which, regarding the dominant model, could infer that the A allele is a risk allele. SNP rs769177 had no interaction with plasma As; however, participants with the TT or TC type had significantly higher eGFR levels than the CC carriers, by 4.02 mL/min/1.73 m2 (p < 0.05). While rs769176 interacted with plasma As, if a person with the TC type had a higher plasma As concentration, that would sustain higher eGFR. This study found that certain SNPs of the TNF-α gene would be robust to the decline of eGFR caused by As exposure. Still, we need further research to confirm the protective regulation mechanism of these SNPs.

Epidermal Growth Factor Receptor (EGFR) Gene Polymorphism May be a Modifier for Cadmium Kidney Toxicity.

The results of many studies indicate that cadmium (Cd) exposure is harmful to humans, with the proximal tubule of the kidney being the main target of Cd accumulation and toxicity. Studies have also shown that Cd has the effect of activating the pathway of epidermal growth factor receptor (EGFR) signaling and cell growth. The EGFR is a family of transmembrane receptors, which are widely expressed in the human kidney. The aim of this study was to investigate the kidney function estimated glomerular filtration rate (eGFR), and its relationship with plasma Cd level and EGFR gene polymorphism. Using data from Academia Sinica Taiwan biobank, 489 subjects aged 30-70 years were analyzed. The demographic characteristics was determined from questionnaires, and biological sampling of urine and blood was determined from physical examination. Kidney function was assessed by the eGFR with CKD-EPI formula. Plasma Cd (ug/L) was measured by inductively coupled plasma mass spectrometry. A total of 97 single-nucleotide polymorphisms (SNPs) were identified in the EGFR on the Taiwan biobank chip, however 4 SNPs did not pass the quality control. Multiple regression analyses were performed to achieve the study aim. The mean (±SD) plasma Cd level of the study subjects was 0.02 (±0.008) ug/L. After adjusting for confounding variables, rs13244925 AA, rs6948867 AA, rs35891645 TT and rs6593214 AA types had higher eGFR (4.89 mL/min/1.73 m2 (p = 0.035), 5.54 mL/min/1.73 m2 (p = 0.03), 4.96 mL/min/1.73 m2 (p = 0.048) and 5.16 mL/min/1.73 m2 (p = 0.048), respectively). Plasma cadmium and rs845555 had an interactive effect on eGFR. In conclusion, EGFR polymorphisms could be modifiers of Cd kidney toxicity, in which rs13244925 AA, rs6948867 AA, rs35891645 TT and rs6593214 AA may be protective, and Cd interacting with rs845555 may affect kidney function.

The Association of Renal Function and Plasma Metals Modified by EGFR and TNF-α Gene Polymorphisms in Metal Industrial Workers and General Population.

Exposure to metals may be associated with renal function impairment, but the effect modified by genetic polymorphisms was not considered in most studies. Epidermal growth factor receptor (EGFR) and tumor necrotic factor-α (TNF-α) play important roles in renal hemodynamics, and they have been reported to be associated with some renal diseases. The aim of our research is to explore whether genetic variations in EGFR and TNF-α have influence on renal function under exposure to various metals. This cross-sectional study consisted of 376 metal industrial workers, 396 participants of Taiwan Biobank, and 231 volunteers of health examinations. We identified 23 single nucleotide polymorphisms (SNPs) on the EGFR gene and 6 SNPs on the TNF-α gene, and we also measured their plasma concentration of cobalt, copper, zinc, selenium, arsenic, and lead. Multiple regression analysis was applied to investigate the association between various SNPs, metals, and renal function. Our results revealed some protective and susceptible genotypes under occupational or environmental exposure to metals. The individuals carrying EGFR rs2280653 GG might have declined renal function under excessive exposure to selenium, and those with EGFR rs3823585 CC, rs12671550 CC, and rs4947986 GG genotypes might be susceptible to lead nephrotoxicity. We suggest the high-risk population to prevent renal diseases.

The Relationship between Metabolic Syndrome and Plasma Metals Modified by EGFR and TNF-α Gene Polymorphisms.

With the escalating global prevalence of metabolic syndrome (MetS), it is crucial to detect the high-risk population early and to prevent chronic diseases. Exposure to various metals has been indicated to promote MetS, but the findings were controversial, and the effect of genetic modification was not considered. Epidermal growth factor receptor (EGFR) was proposed to be involved in the pathway of metabolic disorders, and tumor necrotic factor-α (TNF-α) was regarded as an early inflammatory biomarker for MetS. This research aimed to analyze the impact of EGFR and TNF-α gene polymorphisms on the prevalence of MetS under environmental or occupational exposure to metals. We gathered data from 376 metal industrial workers and 639 non-metal workers, including physical parameters, biochemical data, and plasma concentrations of six metals. According to the genomic database of Taiwan Biobank, 23 single nucleotide polymorphisms (SNPs) on EGFR gene and 6 SNPs on TNF-α gene were incorporated in our research. We applied multivariable logistic regression to analyze the probability of MetS with various SNPs and metals. Our study revealed some susceptible and protective EGFR and TNF-α genotypes under excessive exposure to cobalt, zinc, selenium, and lead. Thus, we remind the high-risk population of taking measures to prevent MetS.

Interaction of Smoking and Lead Exposure among Carriers of Genetic Variants Associated with a Higher Level of Oxidative Stress Indicators.

Smoking and lead (Pb) exposure increased oxidative stress in human body, and people with some gene variants may be susceptible to Pb and smoking via oxidative stress. The aim of this study is to evaluate oxidative stress by measuring thiobarbituric acid reactive substances (TBARS) and the relationship of lipid peroxidation markers in Pb workers with different gene polymorphisms (rs4673 and rs1050450) in both smokers and nonsmokers. Blood samples were collected from 267 Pb workers who received their annual health examination in the Kaohsiung Medical University Hospital. Glutathione peroxidase 1 (GPx-1) rs1050450 and cytochrome B-245 Alpha Chain (CYBA) rs4673 single-nucleotide polymorphisms (SNP) were analyzed by specific primer-probes using Real-Time PCR methods. The interaction between blood Pb and smoking increased serum levels of TBARS and the ratio of oxidative low-density lipoprotein and low-density lipoprotein (oxLDL/LDL). Analysis of workers with rs1050450 SNPs showed higher blood Pb levels in the workers with CC genotype than those with CT genotype. Smokers had significantly higher blood Pb, alanine transaminase (ALT), TBARS, and OxLDL levels than nonsmokers. TBARS increased 0.009 nmol/mL when blood Pb increased one µg/dL in smokers compared to nonsmokers. The ratio of OxLDL/LDL increased 0.223 when blood Pb increased one µg/dL in smokers compared to nonsmokers. TBARS levels and the ratio of OxLDL/LDL were positively correlated and interacted between blood Pb and smoking after the adjustment of confounders, suggesting that smoking cessation is an important issue in the Pb-exposed working environment.

The Association of Serum TNF-α Levels and Blood Multi-Elements Modified by TNF-α Gene Polymorphisms in Metal Industrial Workers.

Health of the metal industrial workers should be a noteworthy issue due to the hazard ofchronic exposure to metals or toxic elements. The interactions among multiple elements aresophisticated and may differ from person to person. Tumor necrosis factor-α (TNF-α) genepolymorphisms were supposed to be involved with the interactions because TNF-α plays animportant role in inflammation, a mechanism by which toxic elements cause threats to humanhealth. This research aimed to analyze the influence of TNF-αgene polymorphisms and multielementson serum TNF-α level. Blood multi-elements concentrations (lead, cadmium, arsenic,selenium, cobalt, copper, and zinc), serum TNF-α level, and TNF-α single nucleotidepolymorphisms (SNPs), including -238G > A (rs361525), -308G > A (rs1800629), -857C > T(rs1799724), -863C > A (rs1800630), and -1031T > C (rs1799964), were measured in 462 metalindustrial workers. We applied mixed-effect models to analyze the interactions among multielementsand TNF-α SNPs. Blood concentration of all elements were positively associated withserum TNF-α level, and the effects may be modified by TNF-α gene polymorphisms. Our studyrevealed that TNF-α -308A/A and -1031C/C may be susceptible genotypes, and thus we suggestthat those workers should take preventive measures against metal toxicity.

Factors affecting therapeutic response to Rivastigmine in Alzheimer's disease patients in Taiwan.

Rivastigmine has been widely used in mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A dose-dependent effect has been suggested, but the plasma concentration of rivastigmine and its metabolite, NAP 226-90, were not measured in previous studies. The influencing factors of therapeutic response are complicated and discordant in various studies among different ethnic groups. Hence, we analyzed the therapeutic responses of rivastigmine, measured by neuropsychological assessments, among 63 clinically diagnosed AD patients taking a daily dosage of 6-9 mg in relation to their plasma concentration of rivastigmine and NAP 226-90, apolipoprotein E (APOE) genotype and demographic characteristics. Our reports revealed that 41.3% of recruited AD patients had improvement in cognition, measured by Mini-Mental Status Examination (MMSE), and 63.5% in global status, by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. In cognition, the clinically improving group had a significantly higher rivastigmine concentration [p = 0.049, odds ratio (OR) = 1.029, 95%CI = 1.000-1.058], lower initial MMSE score (p = 0.010, OR = 0.708, 95%CI = 0.546-0.920), and lower initial CDR-SB score (p = 0.003, OR = 0.552, 95%CI = 0.372-0.817). The patients with APOE ε4 allele had worsening cognition (p = 0.037, OR = 3.870, 95%CI = 1.082-13.840). In global status, only higher education (p = 0.043, OR = 1.222, 95%CI = 1.007-1.484) was significantly associated with clinical improvement. In conclusion, high concentrations of rivastigmine may benefit cognitive function of AD patients, especially in APOE ε4 (-) carriers.

Effect of Workplace Counseling Interventions Launched by Workplace Health Promotion and Tobacco Control Centers in Taiwan: An Evaluation Based on the Ottawa Charter.

Workplace health promotion (WHP) is important to prevent work-related diseases, reduce workplace hazards, and improve personal health of the workers. Health promotion projects were launched through the centers of WHP funded by the Taiwan Bureau of Health Promotion since 2003. Hence, the aim of this study is to evaluate the impact of WHP programs intervention from 2003 to 2007. The intervention group consisted of 838 business entities which had ever undergone counseling of the three centers in northern, central, and southern Taiwan from 2003 to 2007. The control group was composed of 1000 business entities randomly selected from the business directories of the Ministry of Economic Affairs, Taiwan. The questionnaire survey included general company profiles and the assessment of workplace health according to the five action areas of the Ottawa Charter for Health Promotion. We have received 447 (53.3%) questionnaires from the intervention group and 97 questionnaires from the control group. The intervention group was more effective in using the external resources and medical consultation, and they had better follow-up rates of the abnormal results of annual health examinations. Compared to the control group, the intervention group had a significantly decreased smoking rate in 246 companies (61.2%) and a reduced second-hand smoke exposure in 323 companies (78.6%) (p<0.001). By means of the intervention of WHP programs, we can enhance the awareness of the enterprises and the employees to improve worksite health and to create a healthy work environment.

Use of Fomepizole in Pediatric Methanol Exposure: The First Case Report in Taiwan and a Literature Review.

Methanol poisoning is rare in the pediatric population, but a delay in diagnosis and intervention may cause severe morbidity and mortality. The current therapy for methanol poisoning is ethanol or fomepizole, which acts as a competitive inhibitor of hepatic alcohol dehydrogenase to inhibit the production of toxic metabolites derived from the oxidation of methanol. However, clinical experience in pediatric methanol poisoning is limited, and the safety profiles of the antidotes have not been established in children, especially in Asian populations. This is the first case to describe the use of fomepizole in a child with methanol exposure in Taiwan.

Maternal diabetes or hypertension and lifestyle factors may be associated with metabolic syndrome: a population-based study in Taiwan.

Early detection and interventions for metabolic syndrome (MetS) are the most cost-effective methods for preventing many chronic diseases. There have been discordant findings in various countries due to different genetics and lifestyles. The goal of this study was to investigate the association of MetS with parental diseases, a Chinese-style diet, and rural-urban regional differences with a large-scale epidemiological survey in Taiwan. Data were obtained from the Taiwanese Survey on Hypertension, Hyperglycemia, and Hyperlipidemia (TwSHHH), a cross-sectional population-based study with multistage stratified random sampling conducted by the Taiwan Bureau of Health Promotion in 2002. Public health nurses visited homes to conduct the survey, including blood drawing and an interview. Multiple logistic regression analysis was used for exploring the factors associated with MetS. A total of 6591 people completed data for analysis. Our results revealed that older age, male sex, and maternal diabetes or hypertension, were significantly associated with MetS. Eating poultry with skin and fat and eating a bean-free diet may be associated with a higher risk of MetS. People who exercised regularly and the residents of the Taipei metropolitan area had a lower prevalence of MetS. As a result, people with maternal diabetes or hypertension should pay attention to their cardiovascular health and prevention of MetS. We suggest that eating skinless and low-fat poultry, eating more beans, and exercising regularly, may decrease the risk of MetS. We should make an effort to advocate for health promotion, including lifestyle modification, especially among the high-risk population and among residents in rural areas with limited medical resources.