No abstract

Arsenite is well established as a human carcinogen, but the molecular mechanisms leading to arsenite-induced carcinogenesis are complex and elusive. Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite is unknown. We have found that, with chronic exposure to arsenite, L-02 cells undergo a metabolic shift to glycolysis. In liver cells exposed to arsenite, hypoxia inducible factor-1α (HIF-1α) and monocarboxylate transporter-4 (MCT-4) are over-expressed. MCT-4, directly mediated by HIF-1α, maintains a high level of glycolysis, and the enhanced glycolysis promotes pro-inflammatory properties, which are involved in arsenite carcinogenesis. In addition, serum lactate and cytokines are higher in arsenite-exposed human populations, and there is a positive correlation between them. Moreover, there is a positive relationship between lactate and cytokines with arsenic in hair. In sum, these findings indicate that MCT-4, mediated by HIF-1α, enhances the glycolysis induced by arsenite. Lactate, the end product of glycolysis, is released into the extracellular environment. The acidic microenvironment promotes production of pro-inflammatory cytokines, which contribute to arsenite-induced liver carcinogenesis. These results provide a link between the induction of glycolysis and inflammation in liver cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

Endemic arsenicosis is a public health problem that affects thousands of people worldwide. However, the biological mechanism involved is not well characterized, and there is no specific treatment. Exposure to arsenic may be associated with immune-related problems. In the present work, we performed an investigation to determine whether the Th17/Treg balance was abnormal in peripheral blood mononuclear cells (PBMCs) of patients with arsenicosis caused by burning coal. Furthermore, we investigated the effect of Ginkgo biloba extract (GBE) on the Th17/Treg imbalance in patients with arsenicosis. In this trial, 81 arsenicosis patients and 37 controls were enrolled. The numbers of Th17 and Treg cells, as well as related transcription factors and serum cytokines, were determined at the beginning and end of the study. Patients with arsenicosis exhibited higher levels of Th17 cells, Th17-related cytokines (IL-17A and IL-6), and the transcription factor RORγt. There were lower levels of Treg cells, a Treg-related cytokine (IL-10), and the transcription factor Foxp3 as compared with controls. There was a positive correlation between the levels of Th17 cells and IL-17A and the levels of arsenic in hair. Arsenicosis patients were randomly assigned to a GBE treatment group or a placebo group. After 3 months of follow-up, 74 patients completed the study (39 cases in the GBE group and 35 in the placebo group). Administration of GBE to patient upregulated the numbers of Treg cells and the level of IL-10 and downregulated the numbers of Th17 cells and the levels of cytokines associated with Th17 cells. The mRNA levels of Foxp3 and RORγt were increased and decreased, respectively. These results indicated that exposure to arsenic is associated with immune-related problems. The present investigation describes a previously unknown mechanism showing that an imbalance of pro-and anti-inflammatory T cells is involved in the pathogenesis of arsenicosis and that a GBE exerts effects on arsenicosis through regulation of the pro-and anti-inflammatory T cell balance.

Arsenic is a well‐known environmental toxicant and carcinogen, which has been epidemiologically proved related to the increased hepatic disorders. Researches have shown that aseptic inflammation and abnormal immune response are associated with arsenic‐induced liver injury. However, the immunotoxic effects of liver have not been extensively characterized. Ginkgo biloba extract (GBE), a natural products of G. biloba leaves with proven anti‐inflammatory and potential immunoregulatory activities, was used as intervention agent to explore its protective effects on arsenic‐induced hepatotoxicity. Thus, the underlying mechanism of the immunotoxic effects on arsenic‐induced liver injury were investigated in 2.5, 5.0, and 10.0 mg/kg NaAsO2 of Wistar rats for 16 weeks. Subsequently, GBE was used as intervention agent in 50 mg/kg for 6 weeks after cessation of arsenic exposure. The ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL‐17A, IL‐6, TGF‐β1, and IL‐10 in serum and liver were detected. Meanwhile, the notable activation of aseptic inflammation‐related molecule TLR4 and its downstream targets MyD88 and NF‐κB in the liver were observed. In this work, we confirmed that subchronic exposed to arsenic triggered the infiltration of inflammatory cells in rat liver, coupled with obvious histopathological changes and aberrant hepatic serum biochemical parameters. Meanwhile, imbalanced immune response was verified by the notable abnormal ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL‐17A, IL‐6, TGF‐β1, and IL‐10 in serum and liver of arsenic exposed rats. Further, the level of TLR4, MyD88, and NF‐κB in liver both transcription and translation activity were raised. Subsequently, GBE markedly mitigated arsenic‐induced liver injury, most impressively, post treatment with GBE prominently suppressed the overactivated inflammatory‐related TLR4‐MyD88‐NF‐κB pathway and evidently decreased the secretion of inflammation cytokines. Meanwhile, the disturbance of pro‐ and anti‐inflammatory response was reversed. We concluded that the disruption of pro‐ and anti‐inflammatory T‐cells balance caused by cytokines mediated cell–cell interactions may be one of the mechanisms underlying arsenic‐induced liver injury and that GBE intervention exerts an evidence protective effects, which might be closely associated with the suppression of inflammatory‐related TLR4 pathway.

Endemic arsenism, caused by burning coal containing high levels of arsenic, is found only in the Guizhou and Shanxi Provinces of China. Dysregulated microRNAs (miRNAs), detected in the blood, are emerging as promising biomarkers. At present, little is known about the change and clinical efficacy of circulating miRNAs in patients with endemic arsenism produced by burning of coal. Here, we determined, by using TaqMan Human miRNA Array Chips, the differential expression of plasma miRNAs between patients with arsenism caused by coal-burning and a control group. Four increased miRNAs (miR-21, miR-145, miR-155, and miR-191) were verified in a larger sample by quantitative real-time PCR. Furthermore, bioinformatics and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to associate changes in plasma levels of the miRNAs with their functions and their effects on various pathways. The results of chip array assays show that the levels of miR-21, miR-141, miR-148a, miR-145, miR-155, miR-191, miR-218, and miR-491 were most prominently increased and that the levels of miR-200b, miR-200c, miR-26, and miR-34c were decreased. The qRT-PCR results confirm that the circulating levels of miR-21, miR-145, miR-155, and miR-191 are increased in patients with arsenism caused by coal-burning. KEGG analyses show that these miRNAs inhibit the target genes of pathways related to immune inflammation, oxidative stress, and DNA damage repair. Therefore, the four miRNAs may be biomarkers of endemic arsenism caused by coal-burning. Further studies with larger samples should be performed to confirm these findings and to elucidate the underlying mechanisms.