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Objective:To study the effects of arsenic exposure on necroptosis pathway and inflammatory response of mouse myocardial cells.Methods:Sixty male C57BL/6J mice were randomly divided into control group (group C) and low, medium, and high dose arsenic exposure groups (groups L, M, H) based on body weight using a random number table method. Each group had 15 mice, and they drank 0.00, 0.15, 1.50, and 15.00 mg/L arsenic trioxide (As 2O 3) solution prepared with deionized water. The exposure period was 12 weeks. Hematoxylin-eosin (HE) staining and Masson trichrome staining of paraffin-embedded heart tissues were used to observe the histopathology changes of the heart. Transmission electron microscopy (TEM) was used to evaluate the ultrastructural changes of myocardial cells. The quantitative real-time PCR (qRT-PCR) was used to detect the mRNA expression of inflammatory genes [tumor necrosis factor (TNF)-α and interleukin(IL)-6] and the genes involved in necroptosis pathway [receptor-interacting protein (RIP) 1, RIP3 and mixed-lineage kinase domain-like protein (MLKL)]. Protein expressions of RIP1 and RIP3 in the heart were assessed by western blotting. Results:Histopathological examination results showed there were myocardial necrosis, inflammatory cells infiltration and fibroblasts hyperplasia and other changes in groups M and H. TEM analysis revealed marked ultrastructural changes in groups M and H, including fractured myofibril, fractured Z lines of sarcomere, and swollen mitochondria with fractured cristae. Compared with group C (1.00 ± 0.00), the mRNA expression of RIP1 in group H was significantly up-regulated (1.41 ± 0.06, P < 0.05); the mRNA expressions of RIP3 (1.29 ± 0.14, 1.56 ± 0.08), MLKL (1.23 ± 0.05, 1.36 ± 0.07), TNF-α (2.20 ± 0.10, 2.23 ± 0.18) and IL-6 (1.87 ± 0.16, 1.63 ± 0.15) were significantly up-regulated in groups M and H ( P < 0.05). The protein expressions of RIP1 (0.43 ± 0.04, 0.50 ± 0.04) and RIP3 (0.68 ± 0.02, 0.84 ± 0.05) in groups M and H were higher than those in group C (0.25 ± 0.01, 0.45 ± 0.04, P < 0.05). Conclusion:Subchronic arsenic exposure induces histopathological changes such as myocardial necrosis and fibrosis in mice, inducing necroptosis and inflammatory reactions in myocardial cells.
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Objective:To learn about the progress of prevention and control of drinking-water-borne endemic arsenic poisoning in Henan Province, and provide scientific basis for achieving the goal of eliminating high arsenic hazards as scheduled.Methods:From July to August 2019, in accordance with the requirements of the National Monitoring Program for Drinking-water-borne Endemic Arsenic Poisoning, a general survey was carried out in 26 high-arsenic villages in 6 counties of Henan Province to investigate the water improvement situation and the operation of water improvement projects, and the arsenic content in drinking water of households was measured, meanwhile, the arsenic poisoning status of permanent residents in high-arsenic villages was investigated.Results:All 26 villages with high arsenic content in the province had undergone water improvement, with a water improvement rate of 100.00%. A total of 18 water improvement projects were investigated in 26 high-arsenic villages, all of which were operating normally. Twenty-six water samples were collected, and the arsenic content in the household water was < 0.01 mg/L, which met the sanitary standards for drinking water. No patient of endemic arsenic poisoning was found during the survey.Conclusion:In Henan Province, the drinking-water-borne endemic arsenic poisoning has been effectively controlled, and the prevention and control achievements should continue to be consolidated in the future.
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The accumulation effect of arsenic and low arsenic exposure can cause sustained health damage to people in arsenic poisoning areas. Early diagnosis and prevention of arsenic poisoning have become the focus of current prevention and control, and biomarkers have important application value in early diagnosis and prevention of diseases. Therefore, the screening and application of sensitive and specific biomarkers of arsenic poisoning are of great significance for the continuous elimination of arsenic poisoning. In this paper, the research progress of biomarkers of endemic arsenic poisoning is reviewed, in order to provide reference for the continuous prevention and control, early monitoring and early warning of endemic arsenic poisoning.
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Objective:To learn about the changes of the condition of coal-burning-borne endemic arsenism, the use of improved stoves and the formation of health-related behaviors in Shaanxi Province, and evaluate the effect of prevention and control measures.Methods:From 2015 to 2020, according to the "Implementation Plan for Monitoring Coal-burning-borne Endemic Arsenism in Shaanxi Province", regular field surveys were carried out in 4 natural villages, 2 counties in Ankang City and Hanzhong City, Shaanxi Province, to learn about the basic prevention and control situation in the monitoring village. Using the simple random sampling method, 10 families in each village were selected to investigate the use of stoves and the formation of health-related behaviors, and 5 of these families were selected to collect coal samples for arsenic content determination in accordance with the "Determination of Arsenic in Coal" (GB/T 3058-2008). According to the "Diagnosis of Endemic Arsenicosis" (WS/T 211-2015), the condition of the people exposed to high arsenic coal in the monitoring village was investigated. Urine samples of 30 adult patients (half males and half females) with arsenic poisoning were collected, the content of arsenic in urine was determined by the "Urine-Determination of Arsenic-Silver Diethyldithiocarbamate-Triethanolamine-Spectrophotometric Method" (WS/T 28-1996).Results:A total of 240 households were monitored in the past 6 years, and the quality conformance and correct utilization rates of improved stoves in the households monitored in the disease areas remained at 100.00% in 2018 - 2020. The utilization rate of clean energy increased from 75.00% (30/40) in 2015 to 100.00% (40/40) in 2018 - 2020 (χ 2trend = 25.5, P < 0.001). The 73.75% (177/240) of households using a variety of clean energy. From 2018 to 2020, the correct drying, storage and pre-processing washing rates of corn and pepper continued to reach 100.00% (40/40). The arsenic content of coal ( n = 120) in the disease areas was (118.09 ± 57.91) mg/kg, ranging from 16.70 to 280.94 mg/kg. The detection rate of arsenic poisoning decreased from 6.34% (231/3 646) in 2015 to 2.90% (109/3 754) in 2020 (χ 2trend = 121.8, P < 0.001), and no skin cancer or Bowen's disease was detected. The geometric mean of arsenic content in urine ( n = 720) was 0.038 1 mg/L, ranging from 0.000 5 to 0.312 9 mg/L. Conclusions:The condition of coal-burning-borne endemic arsenism areas in Shaanxi Province has reached the national elimination standard. The quality and correct utilization rate of improved stoves and the rate of using clean energy have increased. The healthy-related behaviors the people in the endemic areas have been basically formed. The prevention and control work has achieved good results.
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Objective:To observe the expression levels of Toll-like receptor 4 (TLR4) signaling pathway-related proteins and their phosphorylation in the liver tissues of rats with inorganic arsenic poisoning, and to explore the role of TLR4-mediated inflammatory signaling pathway in arsenic-induced liver fibrosis injury.Methods:Eighteen healthy weanling SD rats were divided into 3 groups according to their body weight (80 - 100 g) using a random number table (6 rats in each group, half males and half females). The control group was given 10 ml/kg of normal saline by gavage. The sodium arsenite (NaAsO 2) exposure group was given 10 mg/kg of NaAsO 2 by gavage. The TAK-242 intervention group was given 10 mg/kg of NaAsO 2 by gavage, and 0.5 mg/kg of TAK-242 was also administered intraperitoneally to inhibit TLR4 after 12 weeks. All rats were administered 6 days a week for 36 weeks. At the end of the treatment, the liver tissues and serum of the rats in each group were collected. HE and Masson staining were used to observe the pathological and fibrotic changes of the liver tissues. Automatic biochemical analyzer was used to detect serum liver function indexes of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Western blot was used to detect the expression changes of rat liver fibrosis protein α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), Vimentin and TLR4 signaling pathway-related proteins TLR4, nuclear factor κB (NF-κB)-p65 subunit (p65), NF-κB-p50 subunit (p50) and their phosphorylation p-p65 and p-p50 expression levels. Enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion levels of inflammatory related factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-10. Results:HE and Masson staining results showed that compared with the control group, the NaAsO 2 exposure group showed significant inflammatory cell infiltration, hepatocyte necrosis and collagen fibrous deposition, while the TAK-242 intervention group showed improvement of the inflammatory cell infiltration and reduction of collagen fibrous deposition compared with the NaAsO 2 exposure group. The results of serum liver function indexes showed that ALT, AST and ALP in NaAsO 2 exposure group were increased compared with the control group, but the TAK-242 intervention group was significantly decreased compared with the NaAsO 2 exposure group ( P < 0.05). Western bolt results showed that in NaAsO 2 exposure group, the expression levels of fibrosis protein α-SMA, TGF-β1 and Vimentin (1.04 ± 0.19, 0.92 ± 0.14, 1.20 ± 0.21) and TLR4 signaling pathway-related proteins and their phosphorylation TLR4, p50, p-p50 and p-p65 (1.16 ± 0.21, 0.95 ± 0.16, 1.24 ± 0.23, 1.56 ± 0.25) were higher than the control group (0.44 ± 0.08, 0.42 ± 0.08, 0.72 ± 0.07, 0.69 ± 0.15, 0.71 ± 0.11, 0.46 ± 0.07, 0.54 ± 0.11, P < 0.05), and the TAK-242 intervention group (0.60 ± 0.13, 0.59 ± 0.16, 0.49 ± 0.11, 0.47 ± 0.08, 0.86 ± 0.09, 0.79 ± 0.14, 1.02 ± 0.17) were lower than the NaAsO 2 exposure group ( P < 0.05). There was no significant difference in the expression level of TLR4 signal pathway-related protein p65 among the three groups ( F = 14.29, P = 0.053). ELISA results showed that the secretion levels of IL-6 and TNF-α [(98.89 ± 4.58), (83.25 ± 4.57) ng/g] in rats liver tissues of the NaAsO 2 exposure group were higher than the control group [(27.30 ± 3.92), (27.77 ± 1.83) ng/g, P < 0.05], while the secretion level of IL-10 [(36.88 ± 3.86) ng/g] was lower than the control group [(77.96 ± 7.87) ng/g, P < 0.05]. In TAK-242 intervention group, IL-6 and TNF-α secretion levels [(44.32 ± 3.60), (36.51 ± 2.93) ng/g] were lower and IL-10 secretion level [(60.40 ± 4.94) ng/g] was higher compared with the NaAsO 2 exposure group ( P < 0.05). Conclusion:TLR4-mediated inflammatory signaling pathway-related proteins and their phosphorylation are highly expressed in the liver tissues of rats with inorganic arsenic poisoning, and inhibition of TLR4 signaling pathway could significantly reduce the degree of liver fibrosis injury caused by inorganic arsenic in rats.
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Objective:To investigate epidemiological characteristics of arsenic poisoning-related skin lesions in an arsenic tailing area in Hunan Province.Methods:A cross-sectional study was conducted. From October 2016 to January 2017, all residents aged over 18 years (except pregnant women) were enrolled from 3 villages in Baiyun Town, Shimen County, Hunan Province by using a cluster-sampling method. Demographic information was collected through a face-to-face questionnaire interview. All residents received skin examination performed by professional dermatologists, and blood, urine, and hair samples were collected for the measurement of arsenic levels. Non-conditional logistic regression analysis was performed to analyze factors associated with arsenic poisoning-related skin lesions.Results:A total of 1 092 eligible residents in the arsenic tailing area were recruited in this study, and 756 (69.2%, 95% CI: 66.5%, 72.0%) presented with arsenic poisoning-related skin lesions, including hyperkeratosis, hypo- or hyper-pigmentation. The median ( Q1, Q3) arsenic levels were 0.31 (0.14, 0.74) μg/g in hair samples ( n = 1 079), 0.84 (0.67, 1.10) μg/L in blood samples ( n =1 091), and 60.31 (41.71, 91.52) μg/L in urine samples ( n =1 092). Multivariable analysis showed that the occurrence of arsenic poisoning-related skin lesions was associated with age, residential location, and occupational arsenic exposure history, but was not associated with gender, ethnicity, education levels, migration history, arsenic levels in hair, blood, or urine. Compared with the group aged 18 - 39 years, the group aged 40 - 59 years and the group aged over 60 years showed significantly higher risks of arsenic poisoning-related skin lesions (adjusted OR = 11.34, 95% CI: 5.98, 21.50, P < 0.001; adjusted OR = 71.82, 95% CI: 35.81, 144.05, P < 0.001, respectively). Compared with the residents in the Wangyangqiao village, residents in the Heshan village and Huangchang village showed significantly higher risks of arsenic poisoning-related skin lesions (adjusted OR = 2.89, 95% CI: 2.05, 4.08, P < 0.001; adjusted OR = 4.13, 95% CI: 1.94, 8.78, P < 0.001, respectively). The risk of arsenic poisoning-related skin lesions was significantly higher in residents with occupational exposure history than in those without (adjusted OR = 1.99, 95% CI: 1.04, 3.83, P = 0.039) . Conclusion:Nearly 70% of the residents presented with arsenic poisoning-related skin lesions in an arsenic tailing area in Hunan Province, and the duration and previous degree of arsenic exposure were associated with the risk of arsenic poisoning-related skin lesions.
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Arsenic is a non-metallic element, and the International Agency for Research on Cancer has identified arsenic and its compounds as carcinogens. Arsenic and its compounds can be absorbed through the respiratory tract, skin and digestive tract, distributed in the liver, kidney, lung and skin, and cause damage. Non-coding RNAs are closely related to arsenic-induced nervous system disorders, cell necrosis, reproductive toxicity, and carcinogenesis. In recent years, the network regulation of microRNAs (miRNAs) , long non-coding RNAs (lncRNAs) , and circular RNAs (circRNAs) among non-coding RNAs in various diseases induced by arsenic has become a new research field. This paper summarizes the existing scientific research results, and expounds the mechanism of miRNAs, lncRNAs and circRNAs in arsenic toxicity, and provides basic data and theoretical basis for the prevention and treatment of arsenic poisoning.
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Humans , Arsenic/toxicity , Arsenic Poisoning , MicroRNAs/genetics , RNA, Circular , RNA, Long Noncoding/geneticsABSTRACT
Objective:To study the effect of water improvement on urinary arsenic methylation metabolism in population exposed to arsenic through drinking water.Methods:A cluster sampling method was used to select drinking water type arsenism areas in Bayannur City, Inner Mongolia Autonomous Region. Permanent residents lived in the arsenism areas for more than 10 years were selected as the survey subjects. Urine samples ( n = 874, 111, 145) were collected in 2004 (before water improvement), 2014 (4 years after water improvement) and 2017 (7 years after water improvement), respectively, and some subjects were followed up in 2014 and 2017. High performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) was used to detect different forms of arsenic metabolites in urine [inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsenic acid (DMA)], and total arsenic (tAs), the iAs percentage (iAs%), MMA percentage (MMA%), DMA percentage (DMA%), monomethylation rate (PMI), dimethylation rate (SMI), and the ratio of MMA to DMA (MMA/DMA) were calculated. The content and distribution of urinary arsenic metabolites in people exposed to arsenic before and after water improvement were compared and analyzed. Results:Compared with 2004, the levels of iAs, MMA, DMA, tAs and iAs% in urine of arsenic exposed population in 2014 were lower ( Z =-14.12,-12.79,-14.27,-14.21,-6.90, P < 0.001), the levels of MMA%, DMA% and PMI were higher ( Z =-3.22,-2.91,-6.90, P < 0.05); in the same drinking water arsenic exposed population, compared with 2004, the levels of iAs, MMA, DMA, tAs and iAs% in urine ( n = 48) were lower ( Z =-5.57,-5.53,-5.54,-5.55,-2.86, P < 0.05) in 2014, and PMI level was higher ( Z =-2.86, P = 0.004). Compared with 2014, the levels of iAs% and MMA/DMA in urine of arsenic exposed population in 2017 were lower ( Z =-4.97,-2.25, P < 0.05), the levels of MMA, DMA, tAs, DMA%, PMI and SMI were higher ( Z =-4.01,-5.39,-4.77,-4.61,-4.97,-2.25, P < 0.05); in the same drinking water arsenic exposed population, compared with 2014, the level of iAs% in urine ( n = 28) was lower ( Z =-2.87, P = 0.004) in 2017, the levels of DMA% and PMI were higher ( Z =-2.32,-2.87, P < 0.05). Conclusion:Water improvement could significantly reduce the levels of urinary arsenic metabolites iAs, MMA, DMA and tAs and increase the level of DMA% in arsenic exposed population.
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Objective:To evaluate the effect of 2-aminoethoxydiphenyl-borate (2-APB) on cardiac dysfunction in arsenic poisoning rats by stratified strain technique.Methods:Thirty-two 12-week-old SD rats were randomly divided into control group ( n=8) and arsenic exposure group ( n=24). After 12 weeks of arsenic exposure, arsenic exposure group was divided into three groups: natural recovery group ( n=8), low-dose intervention group (n=8) and high-dose intervention group ( n=8). The rats were treated with 2-APB for 21 days. After the last administration, the routine parameters and the layered strain parameters were measured by ultrasonic instrument. Then the rats were killed and their blood and myocardial samples were obtained. The levels of serum creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) were tested, and the morphological changes of cardiomyocytes were observed by HE staining. Results:Left ventricular ejection fraction (LVEF), left ventricular short axis shortening (LVFS), global circumferential strain of subendocardial myocardium (GCS-endo), global circumferential strain of middle myocardium (GCS-mid), global circumferential strain of subepicardial myocardium (GCS-epi) and circumferential strain rate of left ventricular segments (SrC) in the natural recovery group were lower than those in the control group ( P<0.05), while serum CK-MB and LDH were higher than those in the control group ( P<0.05). Some ultrasonic parameters and biochemical indexes in the low and high dose intervention groups were improved in varying degrees compared with the natural recovery group ( P<0.05). The correlation between GCS-endo and CK-MB was the highest ( r=-0.931, P<0.05). Myocardial HE staining showed that the degree of myocardial cell swelling and necrosis were reduced, and erythrocyte exudation was reduced in the low and high dose intervention groups compared with the natural recovery group. Conclusions:The stratified strain technique can be used to evaluate the protective effect of 2-APB on cardiac dysfunction in arsenic poisoning rats, and GCS-endo may be one of its sensitive indexes.
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Arsenic is a kind of non-metallic substance with carcinogenic effect, which widely exists in the natural environment. Chronic arsenic exposure will cause a series of health damage involving multiple organs of the whole body. Because of its unclear pathogenesis, lack of specific drugs and early biomarkers, it has become the focus and hotspot of scientific and technological workers for a long time. Epigenetic modification not only correlates with arsenic exposure, but also participates in early arsenic-induced damage by regulating the expression of key molecules, which has become an important research direction of arsenic exposure mechanism. As one of the important modes of epigenetic modification, DNA methylation is expected to provide a new therapeutic target for endemic arsenism. However, how DNA methylation regulates the expression of key genes induced by arsenic and participates in the occurrence and development of arsenism and its relationship with the mechanism of arsenism need to be further studied. The research progress of DNA methylation in the pathogenesis of arsenism is reviewed.
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Objective:To evaluate the correlation between endemic arsenic poisoning and abnormal electrocardiogram (ECG).Methods:PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang data, VIP and other databases were used for literature retrieval, and epidemiological literatures related to abnormal ECG of endemic arsenic poisoning published in domestic and abroad were included in the study. The time limit was from the establishment of the database to December 1, 2020. RevMan 5.3 was used for Meta-analysis of binary variables. Random effect model was selected according to the results of heterogeneity, and odds ratio ( OR) was used as the effect index. Characteristic changes were found by subgroup analysis. Bias was published by funnel plot. Results:Nine articles were included in this Meta-analysis, with 6 articles in Chinese and 3 articles in English, respectively. The abnormal ECG changes included QTc prolongation, ST-T segment change, left axis deviation and arrhythmia. Finally, 1 975 cases were included in the exposure group, including 575 cases of abnormal ECG; 750 cases of control group, including 145 cases of abnormal ECG. Meta-analysis showed that the combined OR value [95% confidence interval ( CI)] of abnormal ECG changes was 4.41 (2.83 - 6.87), with statistical significance between the two groups ( Z = 6.56, P < 0.05); the results of subgroup analysis showed that the combined OR values (95% CI) of QTc prolongation, ST-T segment change, left axis deviation and arrhythmia were 12.30 (5.91 - 25.59), 2.74 (1.39 - 5.41), 2.93 (0.89 - 9.62) and 4.13 (2.38 - 7.17), respectively. Conclusions:Endemic arsenic poisoning may cause abnormal ECG. Prolongation of QTc caused by arsenic exposure may be the characteristic change of abnormal ECG.
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Objective:To understand the prevalence of depression in rural middle-aged and elderly people in Bayannur City, Inner Mongolia Autonomous Region, and to explore the relationship between arsenism and depression.Methods:In December 2016 and April 2018, a one-to-one interview questionnaire survey was conducted among middle-aged and elderly people aged 45 and above in rural areas of Bayannur City, and their depression and arsenism were analyzed. Multivariate logistic regression was used to analyze the relationship between arsenism and depression.Results:A total of 870 rural middle-aged and elderly people in Bayannur City were included, and the detection rate of depression was 15.3% (133/870). The detection rates of depression in arsenism and non-arsenism were 20.8% (37/178) and 13.9% (96/692), respectively, the difference was statistically significant (χ 2 = 4.67, P = 0.030). Multivariate logistic regression analysis after adjusting for factors associated with depression showed that people with arsenism were 1.8 times as likely to be depression compared to those without arsenism [adjusted odds ratio ( AOR) = 1.8, 95% confidence interval ( CI): 1.1 - 3.1, P < 0.05]. Conclusion:The detection rate of depression among rural middle-aged and elderly people in Bayannur City is relatively high, and arsenism may increase the risk of depression.
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Objective:To investigate the role of modification level of lysine trimethylation at position 27 of histone 3 (H3K27me3) on expression of anti-apoptotic protein B lymphocyte tumor-2 gene (BCL2) during arsenic-induced hepatocyte apoptosis.Methods:Rat liver BRL-3A cells were cultured in vitro. According to the arsenic treatment factor, the experiment was divided into two parts, in the first part arsenic was not added, the experiment was divided into normal, transfection reagent, negative transfection, H3K27me3 specific demethylase (JMJD3) small interfering RNA (siRNA) transfection and H3K27me3 methyltransferase (EZH2) siRNA transfection groups. In the second part arsenic was added, the experiment was divided into control, arsenic treatment, arsenic + negative transfection, arsenic + JMJD3siRNA transfection and arsenic + EZH2siRNA transfection groups. When arsenic was not added, the corresponding siRNA and transfection reagent was used to transfect cells at a ratio of 100 pmol : 7.5 μl for 6 h [the normal group was treated with phosphate buffer solution (PBS) of the same volume as transfection reagent], then the medium was changed and the cells were incubated for a total of 48 h. After 24 h of treatment with the above transfection and culture method in arsenic added group, a final concentration of 30 μmol/L sodium arsenite (NaAsO 2) was added and the cells were incubated for 24 h (the control group was treated with PBS with the same volume of NaAsO 2 for 24 h). Real-time cell analysis (RTCA) was used to measure the proliferation of BRL-3A cells in arsenic added group. Apoptosis of BRL-3A cells was analyzed by flow cytometry in arsenic added group. Western blotting was used to detect JMJD3, EZH2, H3K27me3 and BCL2 in no-arsenic and arsenic-added BRL-3A cells. The modification levels of H3K27me3 in BCL2 gene promoter regions were detected by chromatin immunoprecipitation of the cells exposed to arsenic. Results:There were statistically significant differences of the proliferation rates [control, arsenic treatment, arsenic + negative transfection, arsenic + JMJD3siRNA transfection and arsenic + EZH2siRNA transfection groups: (100.00 ± 10.43)%, (12.19 ± 3.37)%, (31.86 ± 1.95)%, (24.58 ± 3.64)%, (11.53 ± 1.11)%] and the apoptosis rates [(1.15 ± 0.04)%, (13.06 ± 1.33)%, (17.39 ± 0.22)%, (23.90 ± 1.66)%, (15.07 ± 0.88)%] between groups ( F = 146.50, 194.30, P < 0.001), correspondingly. The protein expression level of H3K27me3 in JMJD3siRNA transfection group was higher than that of normal, transfection reagent and negative transfection groups, while EZH2siRNA transfection group had an opposite result ( P < 0.05). The protein expression level of BCL2 in JMJD3siRNA transfection group was lower than that of normal, transfection reagent and negative transfection groups, while EZH2siRNA transfection group had an opposite result ( P < 0.05). The protein expression levels of H3K27me3 and BCL2 were not statistically significant differences between normal, transfection reagent and negative transfection groups ( P > 0.05). The protein expression levels of JMJD3, EZH2, H3K27me3 and BCL2 among control, arsenic treatment, arsenic + negative transfection, arsenic + JMJD3siRNA transfection and arsenic + EZH2siRNA transfection groups were compared, and the differences were statistically significant ( F = 26.56, 7.82, 9.81, 31.19, P < 0.05). Compared with control group, the protein expression levels of JMJD3 and EZH2 in arsenic treatment group were significantly reduced ( P < 0.05), and the protein expression level of H3K27me3 was higher ( P < 0.05), meanwhile the protein expression level of BCL2 was lower ( P < 0.05). Compared with arsenic + negative transfection group, the protein expression level of JMJD3 was significantly reduced in arsenic + JMJD3siRNA group, and the protein expression level of EZH2 was significantly reduced in arsenic + EZH2siRNA group ( P < 0.05). In addition, arsenic + JMJD3siRNA increased the level of H3K27me3 modification while reducing the protein expression of BCL2, while arsenic + EZH2siRNA had an opposite result ( P < 0.05). Compared with control group, the enrichment levels of H3K27me3 in BCL2 gene promoter regions (CHIP1 and CHIP2) in arsenic treatment group were significantly higher ( P < 0.05). Conclusion:Arsenic may inhibit the expression of BCL2 by increasing the enrichment level of H3K27me3 in the promoter regions of BCL2 gene, and promoting hepatocyte apoptosis.
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Objective:To investigate the role of DNA damage and repair inhibition in the effect of ginkgo biloba on liver injury in patients with coal-burning-borne arsenism.Methods:In March 2017, the investigation was conducted in Jiaole village arsenic poisoning area in Yuzhang Town, Xingren County, Guizhou Province. According to the "Diagnosis of Endemic Arsenicosis" (WS/T 211-2015) and the "Diagnostic Criteria of Occupational Toxic Hepatopathy" (GBZ 59-2010), 52 patients with arsenism were selected as the ginkgo biloba intervention group, and 49 cases of arsenism patients as intervention control group. Ginkgo biloba tablets were given orally for 3 months (1 tablet/time, 3 times/d) according to the commonly used clinical methods, and no other drugs were given to all subjects during the intervention period. The intervention control group was given placebo in the same way as that of ginkgo biloba intervention group. A total of 41 residents who did not burn high arsenic coal 12 km away with no abnormal liver function were selected as normal control group. Physical examinations were performed before the intervention and at the end of the intervention at 3 months. After receiving signed informed consent, morning urine and peripheral venous blood samples were collected to detect urinary arsenic content by inductively coupled plasma mass spectrometry (ICP-MS); liver function biochemical indexes [albumin (ALB), albumin/globulin (A/G), cholinesterase (CHE), total bile acid (TBA)] were determined by automatic biochemical analyzer, DNA damage by single-cell gel electrophoresis assay, and the expression of miR-145 (repair inhibition index) by qRT-PCR.Results:There were 116 subjects, 41 in normal control group, 39 in ginkgo biloba intervention group and 36 in intervention control group. In ginkgo biloba and intervention and intervention control groups, there was no significant difference in age, gender, smoking habits and drinking compared with normal control group ( P > 0.05). Urinary arsenic content, TBA level, DNA damage degree [comet tail DNA percentage (TailDNA%) and olive tail moment (OTM)] and plasma miR-145 expression level [(38.75 ± 19.09) μg/g Cr, (11.13 ± 1.55) μmol/L, 8.50 ± 0.88, 7.43 ± 0.68, 5.78 ± 0.75, respectively] in ginkgo biloba intervention group patients before intervention were higher than those in normal control group [(11.62 ± 5.33) μg/g Cr, (5.36 ± 0.87) μmol/L, 5.24 ± 0.33, 4.71 ± 0.29, 2.05 ± 0.27, respectively], the differences were statistically significant ( P < 0.05); the levels of ALB, A/G and CHE were significantly lower than those in normal control group ( P < 0.05). After the intervention of ginkgo biloba, urinary arsenic content, TBA level, DNA damage degree (TailDNA% and OTM) and plasma miR-145 expression level in patients were significantly lower than those before the intervention ( P < 0.05); the levels of ALB, A/G and CHE were significantly higher than those before the intervention ( P < 0.05). There was no significant difference in the above indexes before and after intervention in the intervention control group ( P > 0.05). The results of correlation analysis between DNA damage degree, miR-145 and liver function indexes after the intervention of ginkgo biloba showed that, DNA damage degree (TailDNA% and OTM) was negatively correlated with the levels of ALB, A/G and CHE ( r = - 0.34, - 0.33, - 0.48, - 0.31, - 0.31, - 0.42, P < 0.05), and positively correlated with the level of TBA ( r = 0.49, 0.48, P < 0.05); miR-145 was negatively correlated with the levels of ALB, A/G and CHE ( r = - 0.26, - 0.23, - 0.38, P < 0.05), which was positively correlated with the level of TBA ( r = 0.32, P < 0.05); and DNA damage degree was positively correlated with the expression of miR-145 ( r = 0.65, 0.52, P < 0.05). Conclusion:Ginkgo biloba tablets can alleviate the liver damage caused by arsenic through coal burning, and the mechanism of this process is related to its inhibition of miR-145 expression and reduction of DNA damage.
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With the aging and lifestyle changes of the residents in arsenicosis area, the disease spectrum has also undergone significant changes, and coexistence of chronic diseases in arsenicosis has become a primary threat to residents health. In the future, basic study from a new perspective should be deepen, to explore new pathways for integrated prevention and treatment of chronic diseases of arsenicosis, and build a whole management model of "screening, management, prevention, treatment and study" to guarantee the prevention and treatment of chronic diseases of arsenicosis.
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Objective:To investigate the antagonistic and therapeutic effects of Ginkgo biloba on arsenic-induced lung injury in rats and its mechanism.Methods:A total of 42 healthy clean grade Wistar rats, half male and half female, weighing 120 - 130 g, were randomly divided into 7 groups with 6 rats in each group. Two intervention models of Ginkgo biloba antagonism and treatment were established, respectively. The specific treatments were as follows: (1) Experimental study on the antagonism of Ginkgo biloba (4 groups): the control A group was given deionized water; the Ginkgo biloba control (GBE) group was given Ginkgo biloba solution (50 mg·kg -1·bw); the arsenic-treated (As) group was given sodium arsenite solution (10 mg·kg -1·bw); the Ginkgo biloba antagonistic (As + GBE) group was treated with sodium arsenite solution (10 mg·kg -1·bw) and Ginkgo biloba solution (50 mg·kg -1·bw), and the above administration was by gavage for 6 days/week, for 4 months. (2) Experimental study on the treatment of Ginkgo biloba (3 groups): the control B group was given deionized water for 5.5 months; in the arsenism natural recovery (recovery) group, sodium arsenite solution (10 mg·kg -1·bw) was administered by gavage for 4.0 months and deionized water for 1.5 months; the Ginkgo biloba treatment (treatment) group was given sodium arsenite solution (10 mg·kg -1·bw) by gavage for 4.0 months and Ginkgo biloba solution (50 mg·kg -1·bw) for 1.5 months, and the above administration was for 6 days/week. Masson staining was used to evaluate collagen fiber deposition in lung tissue. Western blotting was used to detect the expression level of related proteins in lung tissue homogenates, including inflammatory cytokines matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1β, IL-18; high mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) of the HMGB1/RAGE pathway; phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K), protein kinase B (AKT), phosphorylated AKT (p-AKT) of the PI3K/AKT pathway; transforming growth factor (TGF)-β1, SMAD2, p-SMAD2, SMAD3, p-SMAD3 and SMAD4 of the TGF-β1/SMAD pathway. Results:(1) Antagonistic effect of Ginkgo biloba: compared with the control A group, there was no significant change in protein expression and collagen fiber deposition in the lung tissue of GBE group ( P > 0.05); the levels of MMP-9, IL-1β and IL-18 protein expression and collagen fiber deposition in the lung tissue of As group were significantly increased ( P < 0.05); and the levels of HMGB1, RAGE, PI3K, p-AKT, TGF-β1, p-SMAD2, p-SMAD3 and SMAD4 protein expression were significantly increased ( P < 0.05). Compared with As group, the levels of MMP-9, IL-1β and IL-18 protein expression and collagen fiber deposition were significantly decreased in As + GBE group ( P < 0.05); and levels of HMGB1, RAGE, PI3K, p-AKT, TGF-β1, p-SMAD2, and p-SMAD3 protein expression were significantly decreased ( P < 0.05). (2) Therapeutic effect of Ginkgo biloba: compared with control B group, the levels of MMP-9, IL-1β, IL-18 protein expression and collagen fiber deposition were significantly increased in recovery group ( P < 0.05); and the levels of HMGB1, RAGE, PI3K, p-AKT, TGF-β1, p-SMAD2, p-SMAD3 and SMAD4 protein expression were significantly increased ( P < 0.05). Compared with recovery group, the levels of MMP-9, IL-1β, IL-18, HMGB1, RAGE, PI3K and p-AKT protein expression were significantly decreased in treatment group ( P < 0.05); and there was no significant change in collagen fiber deposition and TGF-β1, p-SMAD2, p-SMAD3 and SMAD4 protein expression levels in lung tissue ( P > 0.05). In both experiments, there was no significant difference in the protein expression levels of AKT, SMAD2 and SMAD3 between the groups ( P > 0.05). Conclusion:Ginkgo biloba intervention has ameliorated inflammatory injury and collagen fiber deposition in lung tissue of arsenic-treated rats possibly by inhibiting the expression levels of HMGB1/RAGE pathway-related proteins.
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Background Natural product sanguinarine chloride (SC) can significantly alleviate liver fibrosis and acute liver injury in mice, but whether it has a protective effect on mouse liver injury caused by sodium arsenite (SA) has not been studied. Objective To verify if SC may present preventive and therapeutic effects on SA-induced liver injury in mice. Methods A total of 140 SPF male Kunming mice were randomly divided into two sub-studies, which included a prevention sub-study and a treatment sub-study. In each sub-study, a blank group (normal saline), a model group (5 mg·kg−1 SA), and a positive control group (11.375 mg·kg−1 bicyclol and 182 mg·kg−1 glutathione), as well as SC low, medium, and high dose groups (25, 50, and 100 mg·kg−1) were arranged with 10 mice in each group. In the prevention sub-study, the blank group was given normal saline, the model group was given SA, and the other groups (the SC low, medium, and high dose groups and the positive control group) were given the corresponding treatment 30 min before gavage of SA, once a day, for 28 d. In the treatment sub-study, except for the blank group which was given normal saline, the other groups were given SA for 28 d, then the model group was given normal saline, and the other groups were given the corresponding treatment every day for 28 d. After the experiment, the mice were sacrificed to evaluate selected physiological and biochemical indicators in serum and liver tissue and to observe histopathological changes after HE staining. Results In either sub-study of preventive effect or treatment effect: compared with the blank group, body weight, liver weight, liver coefficient, as well as serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), malondialdehyde (MDA), glutathione peroxidase (GSH), and superoxide dismutase (SOD) among all SC groups were not significantly different (P>0.05); but compared with the model group, the SC groups showed increased body weight (P<0.01), decreased liver weight and liver coefficient (P<0.01), reduced ALT, AST, TBIL, and MDA (P<0.05 or P<0.01), and increased GSH and SOD with (P<0.05 or P<0.01) or without significance; compared with the positive control group, no differences were found in the above indicators (P＞0.05). The result of histopathological evaluation showed that the SC groups had a clear liver lobule structure, neatly arranged hepatic cords, and less infiltration of inflammatory cells. Conclusion SC has both preventive and therapeutic effects on SA-induced liver injury in mice.
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Objective:To investigate the arsenic content in internal and external environment of the people in drinking-water-borne endemic arsenic poisoning areas in Shaanxi Province, the status quo of the disease and the management and services of the existing patients, so as to provide a theoretical basis for evaluating the effect of prevention and control measures on drinking-water-borne endemic arsenic poisoning.Methods:From 2019 to 2020, in accordance with the requirements of the "Notice of Shaanxi Provincial Health Commission on Issuance of Monitoring Plans for Key Endemic Diseases such as Kashin-Beck Disease" and "Monitoring Plans for Drinking Water Arsenic Poisoning in Shaanxi Province", investigation was carried out in all villages of drinking-water-borne endemic arsenic poisoning in Mianxian County of Hanzhong City, Shanyang County and Zhen'an County of Shangluo City to understand the operation of water improvement project. One terminal water sample was collected to determine the content of arsenic in water, and permanent population of the whole village who are and/or had been exposed to excessive arsenic water in the past were examined for arsenic poisoning and the disease condition was determined according to the standard of "Diagnosis of Endemic Arsenicosis" (WS/T 211-2015). Five villages were randomly selected, and 50 people were selected from each village. Real-time urine sample was collected to determine the content of urinary arsenic. At the same time, management and services of the existing arsenic poisoning patients was investigated.Results:A total of 13 villages were investigated, all of which had been improved in water quality, and all 13 water improvement projects were operating normally, with arsenic content < 0.01 mg/L. A total of 12 577 people were examined, and 417 cases of arsenic poisoning were detected, with a detection rate of 3.32%. No new arsenic poisoning case and arsenic-related skin cancer case had been detected. A total of 260 urine samples were detected, and the geometric mean value of urinary arsenic (< 0.001 mg/L) was lower than the safety guideline value of human urinary arsenic (0.032 mg/L). The existing arsenic poisoning patients (417 cases) were included in health management and contracted services.Conclusions:Shaanxi Province has reached the elimination standard of drinking-water-borne endemic arsenic poisoning. In the future, more attention should be paid to the management of water improvement project, as well as to strengthen health promotion and management services for existing patients to consolidate the effects of prevention and control.
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Objective:To explore the effects of Ginkgo biloba on regulating NF-E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway in liver injury induced by coal-burning-borne endemic arsenic poisoning in rats.Methods:Group design method was adopted, according to body weight (80-100 g), a total of 30 Wistar rats were divided into 5 groups (6 rats in each group, half males and half females) by random number table method. The normal control group was fed with normal diet ad libitum for 4.5 months; the Ginkgo biloba control group was fed with Ginkgo biloba (25 mg/kg, 6 d/week) for 1.5 months after normal feeding for 3 months; the drinking water arsenic poisoning group and the arsenic contaminated grain group were fed respectively with 100 mg/L arsenic trioxide (As 2O 3) solution and 100 mg/kg arsenic-containing feed for 3 months, and then fed with normal diet for 1.5 months; the Ginkgo biloba treatment group was fed with 100 mg/kg arsenic-containing feed for 3 months, and then was given Ginkgo biloba (25 mg/kg, 6 d/week) for 1.5 months. After sacrificing the animals, the content of malondialdehyde (MDA), the activity of copper zinc superoxide dismutase (SOD1) and the activity of glutathione peroxidase (GPx) in serum were detected by thiobarbituric acid colorimetry, xanthine oxidase method and dimercaptodinitrobenzoic acid reduction method, respectively. The mRNA and protein expressions of indicator genes of Nrf2-Keap1-ARE signaling pathway in liver tissues were detected by quantitative real-time PCR, immunohistochemistry and Western blotting. Correlation between the indexes was analyzed by Pearson. Results:In drinking water arsenic poisoning group, arsenic contaminated grain group and Ginkgo biloba treatment group, the contents of MDA in serum were (3.54±0.51), (3.83±0.87) and (2.93±0.84) μmol/L, respectively, which were higher than that in normal control group [(1.85±0.36) μmol/L, P < 0.05]; and SOD1 activities [(68.21±4.37), (64.53±9.96), (73.09±5.43) U/ml] and GPx activities [(486.41±40.45), (458.24±42.25), (539.79±79.43) U/L] in serum were lower than those in normal control group [(81.47±5.73) U/ml, (747.86±80.33) U/L, P < 0.05]. Compared with the arsenic contaminated grain group, the content of MDA in serum in Ginkgo biloba treatment group was decreased, the activities of SOD1 and GPx in serum were increased ( P < 0.05). Compared with normal control group, the mRNA expressions of SOD1 and GPx1 in the liver tissues in drinking water arsenic poisoning group, arsenic contaminated grain group and Ginkgo biloba treatment group were significantly higher ( P < 0.05). Compared with arsenic contaminated grain group, the mRNA expressions of SOD1 and GPx1 in the liver tissue in Ginkgo biloba treatment group were increased ( P < 0.05). Compared with the normal control group, the protein expression of SOD1 in liver tissue in arsenic contaminated grain group was decreased ( P < 0.05), the protein expressions of GPx1 were decreased in the liver tissues in drinking water arsenic poisoning group, arsenic contaminated grain group and Ginkgo biloba treatment group ( P < 0.05). Compared with the arsenic contaminated grain group, the protein expressions of SOD1 and GPx1 were increased in the liver tissue in Ginkgo biloba treatment group ( P < 0.05). Compared with the normal control group and arsenic contaminated grain group, the protein expression of Keap1 was decreased in the liver tissue in Ginkgo biloba treatment group ( P < 0.05). Compared with the normal control group, the protein expressions of Nrf2 and phosphorylation of Nrf2 (pNrf2) were increased in the cytoplasm in drinking water arsenic poisoning group, arsenic contaminated grain group and Ginkgo biloba treatment group ( P < 0.05). Compared with the arsenic contaminated grain group, the protein expression of pNrf2 was decreased in the cytoplasm in Ginkgo biloba treatment group ( P < 0.05). The protein expressions of Nrf2 and pNrf2 in the nucleus in drinking water arsenic poisoning group, arsenic contaminated grain group and Ginkgo biloba treatment group were also higher than those in normal control group ( P < 0.05). Compared with the arsenic contaminated grain group, the protein expressions of Nrf2 and pNrf2 were increased in the nucleus in Ginkgo biloba treatment group ( P < 0.05). The results of correlation analysis revealed that the protein expressions of Nrf2 and pNrf2 in the nucleus were negatively correlated with Keap1 protein expression ( r=-0.523,-0.401, P < 0.05), and positively correlated with the mRNA expressions of SOD1 and GPx1 ( r=0.658, 0.530, 0.555, 0.603, P < 0.05). In addition, the protein expressions of SOD1 and GPx1 were positively correlated with their enzyme activities ( r=0.472, 0.629, P < 0.05). Conclusions:Arsenic could induce oxidative stress and liver injury. Ginkgo biloba could reduce the protein expression of Keap1, and promote nuclear translocation of Nrf2, which might induce the up-regulation of mRNA expressions of SOD1 and GPx1, and partially reverse the posttranscriptional regulation of arsenic on SOD1 and GPx1, and then increase their protein expressions and enzyme activities, thereby improve arsenic induced oxidative stress and liver injury.
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Objective To observe the change of T helper 17 (Th17),regulatory T cell (Treg) as a percentage of lymphocytes and the Th17/Treg ratio in peripheral blood of patients with coal-burning-borne arsenic poisoning,and to explore the role of Th17 cells and Treg cells balance in arsenic-induced immune injury.Methods A case-control study was conducted to investigate 149 cases of arsenic poisoning in Yuzhang arsenic poisoning area in the southwestern Gnizhou Province,and the age was (50.69 ± 6.14) years old,including 94 males and 55 females.The diagnosis was based on the "Diagnosis of Endemic Arsenicosis" (WS/T 211-2015),and the cases were divided into mild arsenic poisoning group (39 cases),moderate arsenic poisoning group (54 cases) and severe arsenic poisoning group (56 cases);forty--one residents of non-arsenic exposed villages about 12 km away from the diseased area were collected as control group,the age was (45.76 ± 7.88) years old,including 12 males and 29 females.Hair samples and peripheral blood were collected from the subjects.The content of hair arsenic was detected by inductively coupled plasma mass spectrometry (ICP-MS).The percentages of Th17 cells and Treg cells in peripheral blood lymphocytes were detected by flow cytometry,and changes in the ratio of Th17/Treg in each group were analyzed.Results The hair arsenic contents in control,mild,moderate,and severe arsenic poisoning groups [median (quartile)] were 0.12 (0.08-0.18),0.20 (0.16-0.33),0.25 (0.18-0.41),0.28 (0.21-0.50) μg/g,and the differences were statistically significant between groups (H =52.22,P ＜ 0.01),and the hair arsenic content in each arsenic poisoning group was higher than that of the control group (P ＜ 0.05).The percentages of Th17 cells in peripheral blood lymphocytes of moderate and severe arsenic poisoning groups [(0.42 ± 0.21)％,(0.41 ± 0.23)％] were higher than that of the control group [(0.29 ± 0.16)％,P ＜ 0.05].The percentages of Treg cells in peripheral blood lymphocytes of mild,moderate and severe arsenic poisoning groups [(0.37 ± 0.18)％,(0.31 ± 0.19)％,(0.27 ± 0.18)％] were lower than that of the control group [(0.71 ± 0.20)％,P ＜ 0.05];with respect to the mild arsenic poisoning group,the percentage of Treg cells in severe arsenic poisoning group was reduced (P ＜ 0.05).The ratios of Th17/Treg in mild,moderate and severe arsenic poisoning groups (1.17 ± 0.63,1.56 ± 0.69,1.83 ± 0.85) were higher than that of the control group (0.43 ± 0.22,P ＜ 0.05);compared with mild arsenic poisoning group,the ratio of Th17/Treg in severe arsenic poisoning group was elevated (P ＜ 0.05).Correlation analysis showed that the hair arsenic content was positively correlated with the percentage of Th17 cells in peripheral blood lymphocytes and the ratio of Th17/Treg (r =0.323,0.608,P ＜ 0.05),and negatively correlated with the percentage of Treg cells in peripheral blood lymphocytes (r =-0.486,P ＜ 0.05).Conclusion Coal-burning-borne arsenic poisoning can cause the proportion of Th17 cells in the peripheral blood of patients to increase in lymphocytes,and the proportion of Treg cells in lymphocytes to decrease,which in turn changes the balance of Th17/Treg,resulting in weakened immune tolerance and disorder the regulation of inflammatory response,thus participates in the occurrence and development of arsenic-induced immune damage.