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.

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.

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.

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.

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.

Effect of Cigarette Constituent Messages With Engagement Text on Intention to Quit Smoking Among Adults Who Smoke Cigarettes: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) is required to communicate the risks of tobacco constituents to the public. Few studies have addressed how FDA media campaigns can effectively communicate about cigarette smoke constituents. Objective: To examine whether messages about cigarette smoke constituents are effective in reducing smoking intentions and behaviors among adults who smoke. Design, Setting, and Participants: This randomized clinical trial enrolled participants who were aged between 18 and 65 years, were English speakers, were living in the United States, and who smoked at least 100 cigarettes during their lifetime and now smoked every day or some days. Participants received daily messages via email for 15 days. Participants were randomized to 1 of 2 message conditions or a control group and reported their previous-day smoking behaviors daily. Follow-up surveys were conducted on days 16 and 32. Data were collected from June 2017 to April 2018 and analyzed from April to September 2018. Interventions: The 3 groups were (1) constituent plus engagement messages (eg, "Cigarette smoke contains arsenic. This causes heart damage.") that included the FDA as the source and engagement text (eg, "Within 3 months of quitting, your heart and lungs work better. Ready to be tobacco free? You can quit. For free nicotine replacement, call 1-800-QUIT-NOW"); (2) constituent-only messages that did not list the FDA as the source or include engagement text; and (3) a control condition with messages about littering cigarette butts. Main Outcomes and Measures: The primary outcome was the change in quit intentions (range, 1-4, with higher scores indicating stronger intentions) from pretest to day 16. Secondary outcome measures included daily smoking behaviors and quit attempts. Results: A total of 789 participants (mean [SD] age, 43.4 [12.9] years; 483 [61.2%] women; 578 [73.3%] White; 717 [90.9%] non-Hispanic) were included in the study. The mean (SD) quit intention score was 2.5 (0.9) at pretest. Mean (SE) change in quit intention score from pretest to day 16 was 0.19 (0.07) points higher in the constituent plus engagement condition than in the control condition (P = .005) and 0.23 (0.07) points higher in the constituent-only condition compared with the control condition (P = .001). Participant reports of cigarettes smoked, forgone, and butted out were similar across study conditions at baseline and did not differ significantly at days 16 and 32 across study conditions. Viewing more messages was associated with an estimated decrease of 0.15 (SE, 0.01) cigarettes smoked per day per message viewed overall across conditions. Conclusions and Relevance: To our knowledge, this is the first longitudinal test of cigarette constituent campaign messages in a national sample of adults who currently smoke. Messages about cigarette smoke constituents, with or without engagement text and source information, increased participants' intentions to quit, lending support to FDA efforts to educate consumers about such constituents. Trial Registration: ClinicalTrials.gov Identifier: NCT03339206.

Recent Advances in Arsenic Research: Significance of Differential Susceptibility and Sustainable Strategies for Mitigation.

Arsenic contamination in drinking water and associated adverse outcomes are one of the major health issues in more than 50 countries worldwide. The scenario is getting even more detrimental with increasing number of affected people and newer sites reported from all over the world. Apart from drinking water, the presence of arsenic has been found in various other dietary sources. Chronic arsenic toxicity affects multiple physiological systems and may cause malignancies leading to death. Exposed individuals, residing in the same area, developed differential dermatological lesion phenotypes and varied susceptibility toward various other arsenic-induced disease risk, even after consuming equivalent amount of arsenic from the similar source, over the same duration of time. Researches so far indicate that differential susceptibility plays an important role in arsenic-induced disease manifestation. In this comprehensive review, we have identified major population-based studies of the last 20 years, indicating possible causes of differential susceptibility emphasizing arsenic methylation capacity, variation in host genome (single nucleotide polymorphism), and individual epigenetic pattern (DNA methylation, histone modification, and miRNA expression). Holistic multidisciplinary strategies need to be implemented with few sustainable yet cost-effective solutions like alternative water source, treatment of arsenic-contaminated water, new adaptations in irrigation system, simple modifications in cooking strategy, and dietary supplementations to combat this menace. Our review focuses on the present perspectives of arsenic research with special emphasis on the probable causes of differential susceptibility toward chronic arsenic toxicity and sustainable remediation strategies.

Reversal of heavy metal-induced antibiotic resistance by dandelion root extracts and taraxasterol.

Introduction. Metal exposure is an important factor for inducing antibiotic resistance in bacteria. Dandelion extracts have been used for centuries in traditional Chinese and Native American medicine.Aim. We assessed the effects of dandelion water extracts and taraxasterol on heavy metal-induced antibiotic resistance in Escherichia coli as well as the underlying mechanisms.Methodology. Dandelion extracts were obtained through 4 h of boiling in distilled water. Bacterial growth was monitored with a spectrophotometer. Biochemical assays were performed to assess the activities and gene transcriptions of ß-lactamase and acetyltransferase. Oxidative stress was determined using an oxidation-sensitive probe, H2DCFDA.Results. The present study demonstrated that higher concentrations of nickel (>5 µg ml-1), cadmium (>0.1 µg ml-1), arsenic (>0.1 µg ml-1) and copper (>5 µg ml-1) significantly inhibited the growth of E. coli. Lower concentrations of nickel (0.5 µg ml-1), cadmium (0.05 µg ml-1) and arsenic (0.05 µg ml-1) had no effect on bacterial growth, but helped the bacteria become resistant to two antibiotics, kanamycin and ampicillin. The addition of dandelion root extracts and taraxasterol significantly reversed the antibiotic resistance induced by these heavy metals. The supplements of antibiotics and cadmium generated synergistic effects on the activities of ß-lactamase and acetyltransferase (two antibiotic resistance-related proteins), which were significantly blocked by either dandelion root extract or taraxasterol. In contrast, oxidative stress was not involved in the preventative roles of dandelion root extracts and taraxasterol in heavy metal-induced antibiotic resistance.Conclusion. This study suggests that heavy metals induce bacterial antibiotic resistance and dandelion root extracts and taraxasterol could be used to help reverse bacterial resistance to antibiotics.

Protective role of nitric oxide on nitrogen-thiol metabolism and amino acids profiling during arsenic exposure in Oryza sativa L.

Nitric oxide (NO) being a signaling molecule inside the plant cells, play significant role in signaling cascades and protection against environmental stresses. However, the protective role of NO in alleviating As toxicity in rice plants is currently not available. In the present study, the level of NO, nitrogen (N), inorganic N (nitrate, ammonium), thiols {TT (Total thiols), NPT (Nonprotein thiol)} and AAs contents along with N assimilating enzymes (NR, GDH, GOGAT) were analyzed after exposure of AsIII/NO treatment alone, and in combination. NO supplementation enhanced the content of N, inorganic N & thiol contents, NR, GOGAT activities, when compared with AsIII exposure alone. In AsIII exposed rice seedlings, content of AAs (except His, Arg, Met) reduced over the control, while supplementation of SNP improved AAs contents, compared to AsIII treatment alone. In conclusion, rice seedlings supplemented with NO tolerate the AsIII toxicity by reducing the N related parameters, thiol contents, altering the AA profile and enhanced the nutritional quality by increasing EAAs (essential amino acids) and NEAAs (non-essential amino acids).

Target lipidomics approach to reveal the resolution of inflammation induced by Chinese medicine combination in Liu-Shen-Wan against realgar overexposure to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Liu-Shen-Wan (LSW) is one of the popular over-the-counter drugs in Asia, which contains realgar (As4S4), used for the treatment of upper respiratory tract inflammation and skin infections. However, the safety and potential risk of this arsenic remain unknown. AIM OF THE STUDY: The aim of this study was to determine total arsenic in tissue and investigate effects of regular dose and overdose LSW exposure on rat liver. MATERIALS AND METHODS: We used a target lipidomics approach to quantify inflammatory eicosanoids and employed ICP-MS to determine total arsenic in tissue. RESULTS: The results showed that oral administration of 8 and 40 mg/kg LSW (1 and 5 fold human-equivalent dose) induced light changes of liver lipidomic profile in rats, which was associated with anti-inflammatory function of LSW. In our recent report, we observed that 41 and 134 mg/kg realgar (40 and 132 fold human-equivalent dose) stimulated rat liver inflammation through up-regulation of pro-inflammatory LOX-derived, CYP-derived HETEs and COX-derived PGs. However, we found that LSW in the form of drug combination, containing 41 and 134 mg/kg realger, could not stimulate these similar inflammatory responses in rats, although the liver total arsenic levels of the realger and LSW groups were same. CONCLUSION: The downregulation of pro-inflammatory response showed that the LSW containing realger is safer than realger alone administrated to rats. These results suggested that Chinese medicines combination could reduce realgar-derived arsenic toxicity in rats.

Comparative health risk assessment of realgar and NiuHuangJieDu tablets based on tissue arsenic levels after multiple oral administration to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar (As2S2), a mineral traditional Chinese medicine (TCM), is proved to have great therapeutic effects in clinic and has been widely used in China for hundreds of years. As one of the most popular realgar-containing TCMs, NiuHuangJieDu Tablets (NHJDT) is used as OTC (over-the-counter) drug in daily life for fever relieving, detoxicating, as well as cure of sore throat and gingival swelling. However, the safety of realgar and its-containing TCMs still remains unclear. AIM OF THE STUDY: This study was to investigate the accumulation of arsenic in rat body and evaluate the safety of realgar-containing TCMs in vivo. MATERIALS AND METHODS: The health risk of arsenic was evaluated in rats by tissue distribution and histopathology, as well as arsenic speciation in plasma after multiple oral gavage of low and high doses of realgar and NiuHuangJieDu Tablets (NHJDT), respectively. Total arsenic and arsenic speciation were determined by hydride generation-atomic fluorescence spectrometry (HG-AFS) and high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS), respectively. RESULTS: Arsenic accumulated in rat tissues especially in heart, liver, spleen, lung, kidney, uterus and ovary. Dimethylarsenic acid (DMA) was detected as the predominant species in rat plasma after dosing. In comparison of realgar, NHJDT with co-existing components significantly alleviated tissues injury, and reduced arsenic concentration in rat tissues and plasma. CONCLUSIONS: NHJDT with co-existing components combination was relatively safer than realgar, but the accumulation of arsenic was still significant after long-term medication. Therefore, great attentions should be paid to realgar-containing TCMs to avoid toxicity from arsenic accumulation. Moreover, the dose regimen of realgar-containing TCMs should be designed rationally for clinical application. These results may provide useful references for the application of realgar-containing TCMs and might be helpful for the understanding of TCM compound compatibility.

Oligomers of carrageenan regulate functional activities and artemisinin production in Artemisia annua L. exposed to arsenic stress.

Recently, a promising technique has come forward in field of radiation-agriculture in which the natural polysaccharides are modified into useful oligomers after depolymerization. Ionizing radiation technology is a simple, pioneering, eco-friendly, and single step degradation process which is used in exploiting the efficiency of the natural polysaccharides as plant growth promoters. Arsenic (As) is a noxious and toxic to growth and development of medicinal plants. Artemisinin is obtained from the leaves of Artemisia annua L., which is effective in the treatment of malaria. The present study was undertaken to find out possible role of oligomers of irradiated carrageenan (IC) on two varieties viz. 'CIM-Arogya' (As-tolerant) and 'Jeevan Raksha' (As-sensitive) of A. annua exposed to As. The treatments applied were 0 (control), 40 IC (40 mg L-1 IC), 80 IC (80 mg L-1 IC), 45 As (45 mg kg-1 soil As), 40 IC + 45 As (40 mg L-1 IC + 45 mg kg-1 soil As), and 80 IC + 45 As (80 mg L-1 IC + 45 mg kg-1 soil As). The present study was based on various parameters namely plant fresh weight (FW), dry weight (DW), leaf area index (LAI), leaf yield (LY), chlorophyll and carotenoid content, net photosynthetic rate (PN), stomatal conductance (Gs), carbonic anhydrase activity (CA), proline content (PRO), lipid peroxidation (TBARS), endogenous ROS production (H2O2 content), catalase activity (CAT), peroxidase activity (POX), superoxide dismutase activity (SOD), ascorbate peroxidase activity (APX), As content, and artemisinin content in leaves. Plant growth and other physiological and biochemical parameters including enzymatic activities, photosynthetic activity, and its related pigments were negatively affected under As stress. Leaf-applied IC overcame oxidative stress generated due to As in plants by activating antioxidant machinery. Interestingly, leaf-applied IC enhanced the production (content and yield) of artemisinin under high As stress regardless of varieties. The oligomers of IC and As were found to be responsible for the production of endogenous H2O2 which has a pivotal role in the biosynthesis of artemisinin in A. annua.

Arsenic and nutrient absorption characteristics and antioxidant response in different leaves of two ryegrass (Lolium perenne) species under arsenic stress.

Arsenic (As), a heavy metal element, causes soil environmental concerns in many parts of the world, and ryegrass has been considered as an effective plant species for bioremediation of heavy metal pollution including As. This study was designed to investigate As content, nutrient absorption and antioxidant enzyme activity associated with As tolerance in the mature leaves, expanded leaves and emerging leaves of perennial ryegrass (Lolium perenne) and annual ryegrass (Lolium multiflorum) under 100 mg·kg-1 As treatment. The contents of As, calcium (Ca), magnesium (Mg), manganese (Mn) in the leaves of both ryegrass species were greatest in the mature leaves and least in the emerging leaves. The nitrogen (N), phosphorus (P), potassium (K) contents of both ryegrass species were greatest in the emerging leaves and least in the mature leaves. The As treatment reduced biomass more in the mature leaves and expanded leaves relative to the emerging leaves for annual ryegrass and reduced more in emerging leaves relative to the mature and expanded leaves for perennial ryegrass. Perennial ryegrass had higher As content than annual ryegrass in all three kinds of leaves. The As treatment increased hydrogen peroxide (H2O2) in expanded leaves of two ryegrass species, relative to the control. The As treatment increased the ascorbate peroxidase (APX) activity in the expanded leaves of perennial ryegrass and the mature leaves of annual ryegrass, the catalase (CAT) activity in the mature and expanded leaves of perennial ryegrass and the emerging leaves of annual ryegrass, relative to the control. The As treatment reduced peroxidase (POD) activity in all three kinds of leaves of annual ryegrass and superoxide dismutase (SOD) activity in expanded leaves of perennial ryegrass, relative to the control. The results of this study suggest that As tolerance may vary among different ages of leaf and reactive oxygen species (ROS) and antioxidant enzyme activity may be associated with As tolerance in the ryegrass.

Early-Life Arsenic Exposure, Nutritional Status, and Adult Diabetes Risk.

PURPOSE OF REVIEW: In utero influences, including nutrition and environmental chemicals, may induce long-term metabolic changes and increase diabetes risk in adulthood. This review evaluates the experimental and epidemiological evidence on the association of early-life arsenic exposure on diabetes and diabetes-related outcomes, as well as the influence of maternal nutritional status on arsenic-related metabolic effects. RECENT FINDINGS: Five studies in rodents have evaluated the role of in utero arsenic exposure with diabetes in the offspring. In four of the studies, elevated post-natal fasting glucose was observed when comparing in utero arsenic exposure with no exposure. Rodent offspring exposed to arsenic in utero also showed elevated insulin resistance in the 4 studies evaluating it as well as microRNA changes related to glycemic control in 2 studies. Birth cohorts of arsenic-exposed pregnant mothers in New Hampshire, Mexico, and Taiwan have shown that increased prenatal arsenic exposure is related to altered cord blood gene expression, microRNA, and DNA methylation profiles in diabetes-related pathways. Thus far, no epidemiologic studies have evaluated early-life arsenic exposure with diabetes risk. Supplementation trials have shown B vitamins can reduce blood arsenic levels in highly exposed, undernourished populations. Animal evidence supports that adequate B vitamin status can rescue early-life arsenic-induced diabetes risk, although human data is lacking. Experimental animal studies and human evidence on the association of in utero arsenic exposure with alterations in gene expression pathways related to diabetes in newborns, support the potential role of early-life arsenic exposure in diabetes development, possibly through increased insulin resistance. Given pervasive arsenic exposure and the challenges to eliminate arsenic from the environment, research is needed to evaluate prevention interventions, including the possibility of low-cost, low-risk nutritional interventions that can modify arsenic-related disease risk.

Zinc alleviates arsenism in common carp: Varied change profiles of cytokines and tight junction proteins among two intestinal segments.

This study was designed to evaluate the effects of zinc on inflammation and tight junction (TJ) in different intestinal regions of common carp under sub-chronic arsenic insult. Fish were exposed to zinc (0, 1 mg/L) and arsenic trioxide (0, 2.83 mg/L) in individual or combination for a month. Inflammatory infiltration and TJ structure changes were displayed by H&E staining and transmission electron microscope. To further explore these changes, biochemical indicator (SOD), gene or protein expressions of inflammatory responses (NF-κB, IL-1ß, IL-6 and IL-8) and TJ proteins (Occludin, Claudins and ZOs) were determined. In the anterior intestine, arsenic decreased activity of SOD, mRNA levels of Occludin, Claudins and ZOs, increased mRNA levels of ILs. However, unlike the anterior intestine, arsenic has an upregulation effects of Occludin and Claudin-4 in the mid intestine. These anomalies induced by arsenic, except IL-8, were completely or partially recovered by zinc co-administration. Furthermore, transcription factor (NF-κB) nuclear translocation paralleled with its downstream genes in both intestinal regions. In conclusion, our results unambiguously suggested that under arsenic stress, zinc can partly relieve intestinal inflammation and disruption of tight junction segment-dependently.

Removing arsenic from water by coprecipitation with iron: Effect of arsenic and iron concentrations and adsorbent incorporation.

Arsenic (As) contamination of drinking water is a major cause of As toxicity in many parts of the world. A study was conducted to evaluate As removal from water containing 100-700 µg/L of As and As to Fe concentration ratios of 1:5-1:1000 using the coprecipitation process with and without As/Fe adsorption onto granular activated carbon (GAC). Fe concentration required to reduce As concentrations in order to achieve the WHO standard level of 10 µg/L increased exponentially with the increase in initial As concentration. When small amounts of GAC were added to the As/Fe solutions the Fe required to remove these As concentrations reduced drastically. This decline was due to the GAC adsorption of Fe and As, enhancing the removal of these metals through coprecipitation. Predictive regression equations were developed relating the GAC dose requirement to the initial As and Fe concentrations. Zeta potential data revealed that As was adsorbed on the GAC by outer-sphere complexation whereas Fe was adsorbed by inner-sphere complexation reversing the negative charge on GAC to positive values. X-ray diffraction of the GAC samples in the presence of Fe had an additional peak characteristic of ferrihydrite (Fe oxide) compared to that of the GAC sample without Fe. The study showed that incorporating an adsorbent into the coprecipitation process has the advantage of removing As from waters at all concentrations of Fe and As compared to coprecipitation alone which does not remove As to the required levels if Fe concentration is low.

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation.

Specific autoantibodies were assessed among residents of the Navajo Nation in New Mexico chronically exposed to metal mixtures from uranium mine wastes and in drinking water supplies. Age and the extent of exposure to legacy waste from 100 abandoned uranium mine and mill sites were associated with antibodies to denatured DNA, previously known to be an early indicator of medication-induced autoimmunity. Surprisingly, autoantibodies to native DNA and/or chromatin were also linked to environmental exposure, specifically uranium consumption through drinking water for both men and women, while urinary arsenic was negatively associated with these autoantibodies in women. These findings suggest that contaminants derived from uranium mine waste enhanced development of autoantibodies in some individuals, while arsenic may be globally immunosuppressive with gender-specific effects. Specific autoantibodies may be a sensitive indicator of immune perturbation by environmental toxicants, an adverse effect not considered in current drinking water standards or regulatory risk assessment evaluations.

Environmental and Genetic Factors Influencing Kidney Toxicity.

The kidneys are a frequent target organ for toxicity from exposures to various environmental chemicals and agents. To understand the risk to human health from such exposures, it is important to consider both the underlying chemical and pathologic mechanisms and factors that may modify susceptibility to injury. Choices of exemplary environmental agents to review are based on those with selective effects on the kidneys and for which significant amounts of mechanistic and human data are available. These include the heavy metals cadmium and arsenic, fluoride, the organic solvents trichloroethylene and perchloroethylene, drinking water disinfection by-products haloacids, food and herbal drug contaminants aristolochic acid and melamine, and heat stress. Some common mechanistic features of all these diverse exposures are highlighted, and include oxidative stress and mitochondrial damage. Two major genetic factors that are discussed include genetic polymorphisms in plasma membrane transporters that catalyze uptake and accumulation or efflux and elimination of environmental chemicals, and genetic polymorphisms in bioactivation enzymes that generate toxic and reactive metabolites. Identification of methods to prevent environmental toxicant-associated kidney damage and understanding the genetic factors that influence kidney function and the kidney's response to exposures can be applied to refine risk assessments.

Arsenic-induced inflammation in workers.

Occupational and environmental exposures to metal and metalloids can result in neurotoxicity and immunotoxicity. Selenium (Se) is essential for the proper functioning of neutrophils, macrophages, natural killer (NK) cells, T-lymphocytes and other immune mechanisms, while zinc (Zn) is a trace element essential for basic cell activities, including cell growth and differentiation. Arsenic (As) may lead to different types of immunosuppressive effects. This study consisted of 62 male workers, who had been exposed to arsenic for different durations and 73 non-exposed male workers (control group) with no history of occupational toxic metal exposure. Whole blood and serum samples were taken from each participant for immunological, toxicological and routine analysis during their annual periodical examination. Arsenic, selenium and zinc levels were determined by the ICP-MS and cytokines, IL-6, IL-10, TNF-α, sE-selectin and VCAM-1, were measured by ELISA. There were statistically significant differences (p < 0.001) between control and As-exposed group in As (1.37 ± 0.42 vs. 4.27 ± 1.54 µg/L) and Se levels (106.37 ± 48.04 vs. 74.70 ± 30.45 µg/L). The changing levels of As, Zn and Se seems to affect the severity of inflammatory reactions based on IL-6, IL-10 and TNF-α levels (r = 0.755, r = 0.679 and r = 0.617, respectively, for all p < 0.01). Selenium was found to have a suppressive effect on cytokines, as evidenced by Pearson correlations and regression analysis. These findings support the need to closely monitor Se levels in individuals exposed to arsenic and benefits for Se supplementation in the case of arsenic exposure, occupationally or environmentally.

Geochemical valuation and intake of F, As, and Se in coal wastes contaminated areas and their potential impacts on local inhabitants, Shaanxi China.

This study probe the human health risk of fluoride (F), arsenic (As), and selenium (Se) and their daily intake available quantity to human through different sources in different regions of Shaanxi, China. For this purpose, a number of samples, including coal and coal wastes, rocks, soil, and vegetables were collected from south Qinling Mountain stone-like coal (Geo type-I), Binxian-Jurassic (Geo type-II), Hancheng Permo-Carboniferous (Geo type-III), and countryside (Huanglong County) of Shaanxi province. All these samples were analyzed through atomic fluorescence spectroscopy and combustion hydrolysis methods. Results showed that Geo type-I was enriched with As, Se, and F, Geo type-II, III, and the countryside were slightly enriched with As and F and deficient in Se. The average daily intake (ADI) of Se in Geo type-I was 0.005-0.0045, Geo type-II 0.0005-0.0004, Geo type-III 0.0006-0.0005, and countryside 0.0002-0.001 in mg kg-1 day-1 adult-children, respectively, which was lower than the optimum level (0.06-0.075 mg kg-1day-1). ADI of As at Geo type-I was 0.0085-0.0075, Geo type-II 0.004-0.0037, Geo type-III 0.0008, and countryside 0.00022-0.00019 in mg kg-1 day-1 adult-children, respectively, which was above the acceptable range (10-6-10-4). ADI of F at Geo type-I was 0.0047-0.0041, Geo type-II 0.0098-0.0087, Geo type-III 0.002-0.0017 and countryside 0.0015-0.0013 in mg kg-1 day-1 adult-children, respectively. The toxicity level of Se and F at all the regions was lower than the NOAEL and LOAEL, while As was higher at Geo type-II and I. The extreme deficient of Se than the optimum range along with high F could deregulate the normal body growth especially causes bones and joint problems. However, the study found a rare patient with bone and joint disease (maybe Kashin-Beck disease) in the countryside. To find the exact cause of Kashin-Beck disease, the study needs further medical investigation in Se-deficient regions and their association with selenium deficiency and enriched fluoride.