Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

The role and mechanism of miR-425-3p regulating neuronal pyroptosis -mediated inorganic arsenic-induced generalized anxiety disorder.

Pyroptosis plays a critical role in the pathogenesis of mental disorders. However, its specific role and mechanism in arsenic (As)-induced generalized anxiety disorder (GAD) remain elusive. We utilized the data from CtdBbase, Phenopedia and DisGeNet to analyze genes that interact with arsenic poisoning and GAD. Subsequently KEGG and GO enrichment analysis were conducted to preliminatively predict the mechanism of inorganic arsenic-induced GAD. Male Wistar rats were administered water containing NaAsO2 (50, 100 µg/L) to evaluate GAD-like behavior through open field test and elevated plus maze. The expression of differential miRNAs including miR-425-3p, and pyroptosis in the prefrontal cortex of rats were detected. Furthermore, SKNSH cells were stimulated with NaAsO2 to examine the molecular changes, and then miR-425-3p mimic was transfected into SKNSH cells to detect pyroptosis in order to verify the function of miR-425-3p. Inorganic arsenic was confirmed to induce GAD-like behavior in rats, characterized by decreased locomotor activity and exploratory activities. Rats with inorganic arsenic-induced GAD exhibited reduced miR-425-3p expression levels in the prefrontal cortex and increased expression of pyroptosis-related proteins, including NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Treating with different concentrations of NaAsO2 showed that inorganic arsenic exposure downregulates miR-425-3p expression in SKNSH cells and upregulates the expression levels of pyroptosis-related proteins. Dual-luciferase reporter gene experiments demonstrated that miR-425-3p targets the NFKB1. Overexpressing miR-425-3p reversed the inorganic arsenic-induced pyroptosis in SKNSH cells by inhibiting the expression of NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Our findings suggest that inorganic arsenic exposure may induce GAD-like behavior in rats by downregulating miR-425-3p in prefrontal cortex, which targets NF-κB and regulates pyroptosis in neuronal cells.

Long-term outcome of children with acute promyelocytic leukemia: a randomized study of oral versus intravenous arsenic by SCCLG-APL group.

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

Efecto del plomo y del arsénico en condiciones de laboratorio sobre la rana africana de uñas (Xenopus laevis) y la rana leopardo (Lithobates berlandieri) / Effect of lead and arsenic under laboratory conditions on African clawed frog (Xenopus laevis) and leopard frog (Lithobates berlandieri)

Actualmente, existe una creciente preocupación ya que algunas especies de anfibios han mostrado un declive en sus poblaciones por causa de diversos factores, entre ellos los metales pesados; por esta razón, es importante realizar estudios sobre esta problemática ambiental. El objetivo de este estudio fue determinar la cantidad del plomo y arsénico que se concentra en los tejidos de la rana Africana de uñas (Xenopus laevis) en etapa juvenil y de la rana Leopardo (Lithobates berlandieri) en etapa larvaria y en el agua después de 16 semanas expuestas a placas de plomo y arseniato de sodio, con la finalidad de determinar si esta acumulación de metales provoca eventualmente anomalías morfológicas en su desarrollo. Los individuos fueron puestos en contacto con placas de plomo, arseniato de sodio, agua de la red de abastecimiento de agua de consumo público (grupos experimentales) y con agua potable (grupo control). Los organismos fueron inspeccionados de manera externa para identificar anomalías macroscópicas, además de realizarles análisis morfométricos. Los análisis espectroquímicos (espectrofotometría de absorción atómica, con la técnica de horno de grafito) mostraron que hay un proceso de bioconcentración y bioacumulación de metales cuando los organismos están en contacto con estos metales y con agua de la red de abastecimiento público, la cual está contaminada también, pues se detectaron cantidades altas de metales en los tejidos de las larvas. Respecto a la morfometría hubo diferencias significativas en algunas estructuras entre el grupo control y los grupos experimentales en X. laevis. En L. berlandieri fueron detectadas anomalías macroscópicas como curvatura de la cola, problemas de pigmentación, protuberancias en el abdomen e inadecuada posición de los intestinos en aquellos individuos que estuvieron en contacto con estos metales pesados. (AU)

Currently, there is growing concern as some amphibian species have shown a decline in their populations due to various factors, including heavy metals; for this reason, it is important to carry out studies on this environmental problem. The objective of this study was to determine the amount of lead and arsenic concentrated in the tissues of the African clawed frog (Xenopus laevis) in the juvenile stage and the Leopard frog (Lithobates berlandieri) in the larval stage and in the water after 16 weeks exposed to lead plates and sodium arsenate, in order to determine if this accumulation of metals eventually causes morphological abnormalities in their development. The individuals were placed in contact with lead plates, sodium arsenate, water from the public water supply network (experimental groups) and with drinking water (control group). The organisms were externally inspected to identify macroscopic anomalies, in addition to performing morphometric analysis. The spectrochemical analyzes (atomic absorption spectrophotometry, with the graphite furnace technique) showed that there is a process of bioconcentration and bioaccumulation of metals when the organisms are in contact with these metals and with water from the public supply network, which is also contaminated, since high amounts of metals were detected in the tissues of the larvae. Regarding morphometry, there were significant differences in some structures between the control group and the experimental groups in X. laevis. In L. berlandieri, macroscopic abnormalities such as curvature of the tail, pigmentation problems, protuberances in the abdomen and inappropriate position of the intestines were detected in those individuals that were in contact with these heavy metals. (AU)

Relationship between urinary biomarkers of early kidney damage and exposure to inorganic toxins in a pediatric population of Apizaco, Tlaxcala, Mexico.

BACKGROUND: In recent years, chronic kidney disease has increased in the pediatric population and has been related to environmental factors. In the diagnosis of kidney damage, in addition to the traditional parameters, early kidney damage biomarkers, such as kidney injury molecule 1, cystatin C, and osteopontin, among others, have been implemented as predictors of early pathological processes. OBJECTIVE: This study aimed to evaluate the relationship between exposure to environmental pollutants and early kidney damage biomarkers. METHODS: A cross-sectional pilot study was conducted in February 2016 and involved 115 apparently healthy children aged 6-15 residing in Apizaco, Tlaxcala. Participant selection was carried out randomly from among 16,472 children from the municipality of Apizaco. A socio-demographic questionnaire included  age, sex, education, duration of residence in the area, occupation, water consumption and dietary habits, pathological history, and some non-specific symptoms. Physical examination included blood pressure, weight, and height. The urine concentrations of urinary aluminum, total arsenic, boron, calcium, chromium, copper, mercury, potassium, sodium, magnesium, manganese, molybdenum, lead, selenium, silicon, thallium, vanadium, uranium, and zinc, were measured. Four of the 115 participants selected for the study were excluded due to an incomplete questionnaire or lack of a medical examination, leaving a final sample population of 111 participants. RESULTS: The results showed a mean estimated glomerular filtration rate of 89.1 ± 9.98 mL/min/1.73m2 and a mean albumin/creatinine ratio of 12.9 ± 16.7 mg/g urinary creatinine. We observed a positive and significant correlation between estimated glomerular filtration rate with fluoride, total arsenic and lead, and a correlation of albumin/creatinine ratio with fluoride, vanadium, and total arsenic. There was also a significant correlation between the early kidney damage biomarkers and fluoride, vanadium, and total arsenic, except for cystatin C. CONCLUSION: In conclusion, our results show that four urinary biomarkers: α1-microglobulin, cystatin C, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin are related to environmental exposure to urinary fluoride, vanadium, and total arsenic in our pediatric population.

The Association Between Arsenic Levels and Oxidative Stress in Myocardial Infarction: A Case-Control Study.

Cardiovascular diseases (CVDs) are known as the first causes of death throughout the world, and mainly myocardial infarction (MI), lead to 7.4 million deaths annually. Atherosclerosis is the major underlying cause of most CVDs. However, exposure to heavy metals, among other factors, deserves further attention as a risk factor for CVDs. This study was designed to evaluate the levels of arsenic (Ars) in myocardial infarction (MI) patients and healthy individuals as well as assess the association between the incidence of MI and Ars, total antioxidant capacity (TAC), and oxidative stress. This case-control study was conducted among patients with MI (n = 164) and normal individuals (n = 61) at Shafa Hospital in Kerman, Iran. Patients were classified into two groups, including coronary artery blocks above 50% (CAB > 50%, n = 83) and coronary artery blocks less than 50% (CAB < 50%, n = 83) based on their angiography findings. The demographic characteristics, clinical history, biochemical parameters, and serum Ars and TAC levels were evaluated. In the present study, both CAB groups had significantly reduced levels of TAC compared with the control. Furthermore, TAC was lower in the CAB > %50 group compared to the CAB < %50 group. Ars levels were significantly higher in both CAB groups compared with the control. There was a significant positive relationship between CAB and Ars, BG, HbA1c, urea, creatinine, TG, TC, and LDL-c, as well as a negative relationship between HDL-c and TAC. Moreover, TAC levels showed a significant inverse correlation with Ars, HbA1c, and creatinine, and a positive correlation with HDL-c. As risk factors, Ars, hs-CRP, TG, TC, and LDL-c enhance the severity of the disease, and HDL-c and TAC decrease the disease severity. Moreover, ROC curve analysis revealed that the highest AUC for the CAB > %50 (AUC = 78.29), and cytotoxic levels for both CAB groups (Ars ≥ 0.105 ppm), and no significant differences were found between the two groups. Our findings suggest that Ars at ≥ 0.105 ppm is able to increase the risk of MI through the increased OS and decreased TAC.

Docosahexaenoic Acid Effect on Prenatal Exposure to Arsenic and Atopic Dermatitis in Mexican Preschoolers.

Childhood atopic dermatitis (AD) is a chronic and recurrent health problem that involves multiple factors, particularly immunological and environmental. We evaluated the impact of docosahexaenoic acid (DHA) supplementation on prenatal arsenic exposure on the risk of atopic dermatitis in preschool children as part of the POSGRAD (Prenatal Omega-3 fatty acid Supplements, GRowth, And Development) clinical trial study in the city of Morelos, Mexico. Our study population included 300 healthy mother-child pairs. Of these, 146 were in the placebo group and 154 in the supplement group. Information on family history, health, and other variables was obtained through standardized questionnaires used during follow-up. Prenatal exposure to arsenic concentrations, which appear in maternal urine, was measured by inductively coupled plasma optical emission spectrometry. To assess the effect of prenatal arsenic exposure on AD risk, we ran a generalized estimating equation model for longitudinal data, adjusting for potential confounders, and testing for interaction by omega-3 fatty acid supplementation during pregnancy. The mean and SD (standard deviation) of arsenic concentration during pregnancy was 0.06 mg/L, SD (0.04 mg/L). We found a marginally significant association between prenatal arsenic exposure and AD (OR = 1.12, 95% CI: 0.99, 1.26); however, DHA supplementation during pregnancy modified the effect of arsenic on AD risk (p < 0.05). The results of this study strengthen the evidence that arsenic exposure during pregnancy increases the risk of atopic dermatitis early in life. However, supplementation with omega-e fatty acids during pregnancy could modify this association.

Assessment of cause-specific mortality and disability-adjusted life years (DALYs) induced by exposure to inorganic arsenic through drinking water and foodstuffs in Iran.

The health risk and burden of disease induced by exposure to inorganic arsenic (iAs) through drinking water and foodstuffs in Iran were assessed. The iAs levels in drinking water and foodstuffs (15 food groups) in the country were determined through systematic review of three international databases (PubMed, Scopus, and Web of Science) and meta-analysis. Based on the results of the systematic review and meta-analysis, the average iAs levels in drinking water and all the food groups at the national level were lower than the maximum permissible levels. The total average non-carcinogenic risk of dietary exposure to iAs in terms of hazard index (HI) was 3.4. The average incremental lifetime cancer risk (ILCR) values of dietary exposure to iAs were determined to be 1.5 × 10-3 for skin cancer, 1.0 × 10-3 for lung cancer, and 4.0 × 10-4 for bladder cancer. Over two-thirds of the non-carcinogenic and carcinogenic risk of dietary exposure to iAs was attributed to bread and cereals, drinking water, and rice. The total annual cancer incidence, deaths, disability-adjusted life years (DALYs), death rate, and DALY rate (per 100,000 people) were assessed to be 3347 (95 % uncertainty interval: 1791 to 5999), 1302 (697 to 2336), 72,606 (38,833 to 130,228), 1.6 (0.87 to 2.9), and 91 (49 to 160). The contribution of mortality in the attributable burden of disease was 95.1 %. The contributions of the causes in the attributable burden of disease were 72 % for lung cancer, 16 % for bladder cancer, and 12 % for skin cancer. Due to the significant attributable burden of disease, national and subnational action plans consisting of multi-disciplinary approaches for risk management of dietary exposure to iAs, especially for the higher arsenic-affected areas and high-risk population groups in the country are recommended.

Prenatal arsenic exposure stymies gut butyrate production and enhances gut permeability in post natal life even in absence of arsenic deftly through miR122-Occludin pathway.

This discourse attempts to capture a few important dimensions of gut physiology like microbial homeostasis, short chain fatty acid (SCFA) production, occludin expression, and gut permeability in post-natal life of mice those received arsenic only during pre-natal life. Adult Balb/c mice were fed with 4 ppm arsenic trioxide in drinking water during breeding and gestation. After the birth of the pups, the arsenic water was withdrawn and replaced with clean drinking water. The pups were allowed to grow for 28 days (pAs-mice) and age matched Balb/c mice which were never exposed to arsenic served as control The pAs-mice showed a striking reduction in Firmicutes to Bacteroidetes (F/B) ratio coupled with a decrease in tight junction protein, occludin resulting in an increase in gut permeability, increased infiltration of inflammatory cells in the colon and decrease in common SCFAs in which butyrate reduction was quite prominent in fecal samples as compared to normal control. The above phenotypes of pAs-mice were mostly reversed by supplementing 5% sodium butyrate (w/w) with food from 21st to 28th day. The ability of butyrate in enhancing occludin expression, in particular, was dissected further. As miR122 causes degradation of Occludin mRNA, we transiently overexpressed miR122 by injecting appropriate plasmids and showed reversal of butyrate effects in pAs-mice. Thus, pre-natal arsenic exposure orchestrates variety of effects by decreasing butyrate in pAs-mice leading to increased permeability due to reduced occludin expression. Our research adds a new dimension to our understanding that pre-natal arsenic exposure imprints in post-natal life while there was no further arsenic exposure.

Chronic Community Exposure to Environmental Metal Mixtures Is Associated with Selected Cytokines in the Navajo Birth Cohort Study (NBCS).

Many tribal populations are characterized by health disparities, including higher rates of infection, metabolic syndrome, and cancer-all of which are mediated by the immune system. Members of the Navajo Nation have suffered chronic low-level exposure to metal mixtures from uranium mine wastes for decades. We suspect that such metal and metalloid exposures lead to adverse health effects via their modulation of immune system function. We examined the relationships between nine key metal and metalloid exposures (in blood and urine) with 11 circulating biomarkers (cytokines and CRP in serum) in 231 pregnant Navajo women participating in the Navajo Birth Cohort Study. Biomonitored levels of uranium and arsenic species were considerably higher in participants than NHANES averages. Each biomarker was associated with a unique set of exposures, and arsenic species were generally immunosuppressive (decreased cellular and humoral stimulating cytokines). Overall, our results suggest that environmental metal and metalloid exposures modulate immune status in pregnant Navajo women, which may impact long-term health outcomes in mothers and their children.

Health risk assessment for human exposure to mercury species and arsenic via consumption of local food in a gold mining area in Colombia.

The risk to human health from exposure to certain pollutants through the consumption of fruits, tubers, and fish were evaluated in a settlement located in a Colombian area highly impacted by gold mining activities. The concentrations of mercury (Hg) and arsenic (As) in edible food tissues and methylmercury (MeHg) in fish were determined for risk assessment. A questionnaire-based dietary survey was answered by 178 residents of three population groups: children (CHD), women of childbearing age (WCBA), and the rest of the population (RP). The estimated weekly intake (EWI) of MeHg presented values of 1.9 and 2.4 times higher than the provisional tolerable weekly intake (1.6 µg/kg BW/week) recommended by the FAO/WHO for CH and WCBA, respectively. The results of the HQ values of As and Hg for different food were above the safety level (HQ < 1) for most of the groups. For Hg, the highest HQ values correspond to fish, whereas for As in most of the food, but specially in fruits. The total target hazard quotients (HI) were higher than 1, in all the groups (except for CHD that consume tubers) indicating potential non-carcinogenic health risks. The values of carcinogenic risk (CR) for As through exposure to food ranged from 1.2·10-4 to 7.7·10-4, well above than the safety level of US EPA risk (10-4-10-6), suggesting the probability of carcinogenic risk for the entire population via ingestion. Therefore, safety control mechanisms and environmental education strategies should be applied to address food intake, associated with good agricultural practices to provide solutions to protect the health of the residents in areas affected by gold mining activities.

Arsenic induces bronchial epithelial carcinogenesis with mitochondrial dysfunction through AKAP95-mediated cell cycle alterations.

Arsenic is a widely existing pollutant in the environment, but the mechanism of occurrence and development of lung cancer by long-term arsenic exposure needs to be elucidated further. How the high and low doses of arsenic induce human bronchial epithelial cell transformation is yet to be elucidated. In the present study, human bronchial epithelial cells were exposed to varying high-dose sodium arsenite (NaAsO2) for the short-term or treated with low dose for long-term. The data showed that both short- and long-term treatment promoted G1/S transition of Beas-2B cells, inducing a significant increase in the expression of AKAP95, cyclin D1, cyclin D2, and cyclin E1. However, silencing AKAP95 by treating cells with siAKAP95 exerted a protective function that inhibited G1/S transition, suggesting a regulatory mechanism of AKAP95 on the cell cycle during cell malignant transformation induced by NaAsO2. In addition, mitochondrial dysfunctions occurred during NaAsO2 exposure. Beas-2B cells exposed to low-dose NaAsO2 for long-term were subcultured for 20 generations, and the exposure time was positively proportional to the growth and migration rate of the cells. The exposed cells were used in a tumor-bearing transplantation experiment (mice), and the results showed that the longer the exposure time, the faster the tumor volume growth rate of As-Beas-2B cells. Tumor tissues were excised for hematoxylin-eosin staining, which showed altered cell morphology and increased volume.

Arsenic in Drinking Water and Incidences of Leukemia and Lymphoma: Implication for Its Dual Effects in Carcinogenicity.

Arsenic in drinking water has been recognized as carcinogenic to humans and can cause solid cancers of lung, urinary bladder, and skin. Positive associations have also been reported between arsenic ingestion and cancers of kidney, liver and prostate. Nevertheless, arsenic trioxide has been used successfully in the treatment of acute promyelocytic leukemia. Therefore, arsenic might play different roles in the carcinogenesis of solid cancers and hematologic malignancies. The relationship between arsenic in drinking water and the incidences of hematologic malignancies has not been fully investigated. We established a cohort of Taiwanese population and assorted 319 townships of Taiwan into two exposure categories using 0.05 mg/L as the cutoff. Then, we linked these data to the Taiwan Cancer Registry and computed standardized incidence ratios (SIRs) of lymphoma and leukemia by sex, exposure category and time period. The trend of changes in the SIRs over time was assessed, from 1981-1990 to 1991-2000 and then to 2001-2010. We found that in both lymphoma and leukemia, the higher exposure category was associated with lower SIRs in both men and women. In terms of time trends, the SIRs in both lymphoma and leukemia showed increasing trends in both sexes, while exposure to arsenic in drinking water decreased over time. The arsenic level in drinking water was negatively associated with the incidences of lymphoma and leukemia in both men and women. This study supports the dual effects of arsenic on carcinogenesis, with a potential protective effect against hematologic malignancies.

Intervention Study of Dictyophora Polysaccharides on Arsenic-Induced Liver Fibrosis in SD Rats.

Long-term arsenic (As) exposure can cause liver injury, hepatic cirrhosis, and cancer. Meanwhile, Dictyophora polysaccharides (DIP) have excellent antioxidation, anti-inflammation, and immune protection effects. There are currently few reports on the protection effects of DIP on As-induced hepatotoxicity and its pharmacological value. Therefore, this study was aimed at elucidating the protection of DIP on As-induced hepatotoxicity and exploring its preventive role in antifibrosis. In our study, the SD rat As poisoning model was established by the feeding method to explore the influence of As exposure on liver fibrosis. Then, DIP treatment was applied to the rats with As-induced liver fibrosis, and the changes of serum biochemical indexes and liver tissue pathology were observed. And the expression of fibrosis-related proteins TGF-ß1, CTGF, and α-SMA levels was then determined to explore the DIP intervention function. The results demonstrated that through reduced pathological changes of hepatic and increased serum AST, ALT, TP, ALB, and A/G levels, DIP ameliorated liver fibrosis induced by As as reflected. And the administration of DIP decreased the concentration of HA, LN, PCIII, CIV, TBIL, and DBIL. In addition, the synthesis of TGF-ß1 inhibited by DIP might regulate the expression of CTGF and decrease the proliferation of fibrinogen and fibroblasts, which reduced the synthesis of fibroblasts to transform into myofibroblasts. And a decrease of myofibroblasts downregulated the expression of α-SMA, which affected the synthesis and precipitation of ECM and alleviated the liver fibrosis caused by exposure to As. In conclusion, based on the pathological changes of liver tissue, serum biochemical indexes, and related protein expression, DIP can improve the As-induced liver fibrosis in rats and has strong medicinal value.

Quercetin attenuates the proliferation of arsenic-related lung cancer cells via a caspase-dependent DNA damage signaling.

Exposure to arsenic (As) mainly through contaminated drinking water enhances the lung tumor progression, invasion, and metastasis. The carcinogenic effect of As is due to the generation of reactive oxygen species (ROS) and DNA damage, and interference with DNA repair machinery. Herein, we investigated the potential therapeutic function of quercetin on As-treated lung cancer cells. Quercetin is a natural product with antioxidative, anti-inflammatory, and antiproliferative properties. We showed that quercetin induced cell death in the As-exposed lung cancer cells in a dose-dependent manner. Quercetin was able to significantly inhibit the proliferation of the As-treated cells over a period of 5 weeks. In addition, quercetin induced ROS-mediated DNA double-strand breaks in the As-treated lung cancer cells. We also showed that ROS generation induced by quercetin activated caspase-3 to a sufficient level to induce DNA damage but insufficient to induce death in As-treated lung cancer cells. Moreover, transient activation of caspase-2 was detected in quercetin- and As-cotreated cells. The flow cytometry-based cell cycle analysis showed that the antiproliferative function of quercetin was mediated by S-phase cell cycle arrest, which was associated with upregulation of the Ataxia Telangiectasia-mutated (ATM), but not ATM and RAD3-related. In conclusion, quercetin synergized the As-driven ROS generation and DNA damage, and induced the S-phase arrest, thus inhibiting the proliferation of As-exposed lung cancer cells. This data suggested that quercetin is an alternative reagent to chemo-drugs to prevent the growth of As-exposed lung cancer cells.

Effects of heavy metals in acute ischemic stroke patients: A cross-sectional study.

ABSTRACT: Cerebrovascular disease is the second commonest cause of mortality globally and among the commonest causes of disability. However, research executed to probe the heavy metal exposure-stroke incidence relationship is scarce. Accordingly, we executed our study to probe the relationship of heavy metal concentrations (ie, concentrations of lead [Pb], mercury [Hg], cadmium [Cd], and arsenic) in the serum and urine of acute ischemic stroke (AIS) patients with several patient variables.For enrollment, we chose patients who had a first AIS within 7 days after the onset of a stroke. Thus, 33 newly diagnosed patients with AIS were recruited. We determined the aforementioned metals' concentrations by executing inductively coupled plasma mass spectrometry. We also gauged the association between such metal concentrations and patient variables by employing Spearman correlation coefficient. To examine the differences in metal concentrations between the different variables, we implemented an independent Mann-Whitney U test.In our cohort analysis, we noted serum Pb and Cd concentrations to be positively correlated with serum creatinine and hemoglobin. Serum and urine Cd concentrations had a negative correlation with impaired HbA1c in AIS patients. Urine Hg had a positive correlation with C-reactive protein in the participants. Participants who smoked or consumed alcohol had significantly higher Pb and Cd levels in serum than did those who neither smoked nor drank. Patients with AIS who smoked or consumed alcohol had high levels of serum Pb and serum Cd than did those who did not. Patients with AIS who consumed alcohol had significantly higher Pb and Hg urine concentrations than did those who did not.Our study indicated that serum Cd and Pb elevation increased the AIS risk in southern Taiwan patients.

Urinary Metals, Arsenic, and Polycyclic Aromatic Hydrocarbon Exposure and Risk of Self-reported Emphysema in the US Adult Population.

PURPOSE: Metal and chemical exposure can cause acute and chronic respiratory diseases in humans. The purpose of this analysis was to analyze 14 types of urinary metals including mercury, uranium, tin, lead, antimony, barium, cadmium, cobalt, cesium, molybdenum, manganese, strontium, thallium, tungsten, six types of speciated arsenic, total arsenic and seven forms of polycyclic aromatic hydrocarbons (PAHs), and the link with self-reported emphysema in the US adult population. METHODS: A cross-sectional analysis using the 2011-2012, 2013-2014 and 2015-2016 National Health and Nutrition Examination Survey datasets was conducted. A specialized weighted complex survey design analysis package was used in analyzing the data. Multivariate logistic regression models were used to assess the association between urinary metals, arsenic, and PAHs and self-reported emphysema among all participants and among non-smokers only. Models were adjusted for lifestyle and demographic factors. RESULTS: A total of 4,181 adults were analyzed. 1-Hydroxynaphthalene, 2-hydroxynaphthalene, 3-hydroxyfluorene, 2-hydroxyfluorene, 1-hydroxypyrene, and 2 & 3-hydroxyphenanthrene were positively associated with self-reported emphysema. Positive associations were also observed in cadmium and cesium with self-reported emphysema. Among non-smokers, quantiles among 2-hydroxynaphthalene, arsenocholine, total urinary arsenic, cesium, and tin were associated with increased odds of self-reported emphysema. Quantiles among 1-hydroxyphenanthrene, cadmium, manganese, lead, antimony, thallium, and tungsten were associated with an inverse relationship with self-reported emphysema in non-smokers. CONCLUSION: The study determined that six types of urinary PAHs, cadmium, and cesium are positively associated with self-reported emphysema. Certain quantiles of 2-hydroxynaphthalene, arsenocholine, total urinary arsenic, cesium, and tin are positively associated with self-reported emphysema among non-smokers.

Association between Arsenic Level, Gene Expression in Asian Population, and In Vitro Carcinogenic Bladder Tumor.

The IARC classified arsenic (As) as "carcinogenic to humans." Despite the health consequences of arsenic exposure, there is no molecular signature available yet that can predict when exposure may lead to the development of disease. To understand the molecular processes underlying arsenic exposure and the risk of disease development, this study investigated the functional relationship between high arsenic exposure and disease risk using gene expression derived from human exposure. In this study, a three step analysis was employed: (1) the gene expression profiles obtained from two diverse arsenic-exposed Asian populations were utilized to identify differentially expressed genes associated with arsenic exposure in human subjects, (2) the gene expression profiles induced by arsenic exposure in four different myeloma cancer cell lines were used to define common genes and pathways altered by arsenic exposure, and (3) the genetic profiles of two publicly available human bladder cancer studies were used to test the significance of the common association of genes, identified in step 1 and step 2, to develop and validate a predictive model of primary bladder cancer risk associated with arsenic exposure. Our analysis shows that arsenic exposure to humans is mainly associated with organismal injury and abnormalities, immunological disease, inflammatory disease, gastrointestinal disease, and increased rates of a wide variety of cancers. In addition, arsenic exerts its toxicity by generating reactive oxygen species (ROS) and increasing ROS production causing the imbalance that leads to cell and tissue damage (oxidative stress). Oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell specifically; there is significant evidence of the advancing changes in oxidative/nitrative stress during the progression of bladder cancer. Therefore, we examined the relation of differentially expressed genes due to exposure of arsenic in human and bladder cancer and developed a bladder cancer risk prediction model. In this study, integrin-linked kinase (ILK) was one of the most significant pathways identified between both arsenic exposed population which plays a key role in eliciting a protective response to oxidative damage in epidermal cells. On the other hand, several studies showed that arsenic trioxide (ATO) is useful for anticancer therapy although the mechanisms underlying its paradoxical effects are still not well understood. ATO has shown remarkable efficacy for the treatment of multiple myeloma; therefore, it will be helpful to understand the underlying cancer biology by which ATO exerts its inhibitory effect on the myeloma cells. Our study found that MAPK is one of the most active network between arsenic gene and ATO cell line which is involved in indicative of oxidative/nitrosative damage and well associated with the development of bladder cancer. The study identified a unique set of 147 genes associated with arsenic exposure and linked to molecular mechanisms of cancer. The risk prediction model shows the highest prediction ability for recurrent bladder tumors based on a very small subset (NKIRAS2, AKTIP, and HLA-DQA1) of the 147 genes resulting in AUC of 0.94 (95% CI: 0.744-0.995) and 0.75 (95% CI: 0.343-0.933) on training and validation data, respectively.

Arsenic activates STAT3 signaling during the transformation of the human bronchial epithelial cells.

Arsenic (As3+), a metalloid abundant in environment, is classified as a group I carcinogen associated with several common human cancers, including cancers in lung, skin, bladder, liver, and prostate (Wei et al., 2019). The mechanisms of As3+-induced carcinogenesis had been extensively studied, and different mechanisms might be involved in different types of cancer (Wei et al., 2019). Recent studies showed that exposure to a high dose of arsenic is able to induce lung cancer. Meanwhile, prolonged exposure to a low concentration of arsenic can increase the risk of lung cancer also (Liao et al., 2009; Fernández et al., 2012). Emerging evidence indicated that prolonged exposure to arsenic promotes malignant transformation and some of the transformed cells have cancer-stem-like properties (Ngalame et al., 2014). In the present report, we revealed that exposure to As3+ for short time period inhibited tyrosine-705 phosphorylation of signal transducer and activator of transcription 3 (pSTAT3Y705) and induced Src homology region 2 domain-containing phosphatase-1 (SHP-1) in bronchial epithelial cell line, BEAS-2B. In addition, we found that long term exposure of the cells to As3+ activates phosphorylation of STAT3 at serine 727 (pSTAT3S727) as well as pSTAT3Y705. Moreover, As3+ is able to induce the expression of miRNA-21 (miR-21) and decrease the expression of PDCD4. Taken together, our data suggest that activation of STAT3 and induction of miR-21 are important contributing factors to the reduced expression of PDCD4, which may play significant role in As3+-induced transformation of BEAS-2B cells.

Synergy of arsenic with smoking in causing cardiovascular disease mortality: A cohort study with 27 follow-up years in China.

Background: To explore the patterns of the exposure-response relationship between arsenic exposure and cardiovascular disease (CVD) mortality and investigate the effect of cigarette smoking on the association. Methods: Seven thousand seven hundred thirty-five tin miners with at least 10 years of arsenic exposure were enrolled since 1992 and followed up for 27 years. Each individual's air arsenic exposure at workplace was calculated by time weighted average arsenic concentration × exposure months. Detailed information on smoking was collected at baseline, and information on smoking status was collected for five consecutive years from 1992 to 1996. Hazard ratio (HR) and 95% confidence interval (CI) for the risk of CVD were estimated using Cox proportional hazards models. Results: A total of 1,046 CVD deaths occurred in this cohort over 142,287.7 person-years of follow up. We firstly reported that for equal cumulative exposure, participants exposed to higher concentrations over shorter duration had a higher risk of CVD mortality than those exposed to lower concentration over longer duration. The HR and 95% CI were 1.38 (95%CI: 1.03-1.85) in participants exposed to arsenic concentration (45.5-99.5 mg/m3), 1.29 (95%CI: 1.02-1.67) in 99.5-361.0 mg/m3. Further, participants with age at first exposure <18 years had a significantly higher risk of morality from CVD, cerebrovascular and heart diseases than those with ≥18 years. Finally, all synergy indices were greater than 1 (range, 1.11-2.39), indicating that the joint effect of arsenic exposure and cigarette smoking on CVD mortality was greater than the sum of their individual effect. Conclusions: Exposure to air arsenic at workplace is adversely associated with mortality from CVD, especially among smokers younger than 18 years and smokers.