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Arsenic is a human carcinogen widely distributed in the environment, and arsenic exposure from drinking water has received widespread attention as a global public health problem. Curcumin is a natural bioactive substance with high efficiency and low toxicity extracted from turmeric, which has a variety of biological properties such as antioxidation, anti-inflammation, anticancer, and immuno-modulatory activities. Curcumin is widely used in daily life as a food additive and dietary supplement. However, its protective effects in lung injuries by chronic arsenic exposure orally remain unexplored. In this study, curcumin treatment not only significantly accelerated arsenic elimination and improved lung tissue morphology, but also decreased arsenic-generated ROS by activating Nrf2 and its down-stream antioxidants. Further, curcumin alleviated inflammatory changes in mice exposed to arsenic for 6 and 12 weeks, as manifested by lung MPO levels, total protein and cellular levels in bronchoalveolar lavage fluid (BALF), serum IL-4 levels, and MAPK/NF-κB expression in lung tissue. Notably, our study also confirmed that curcumin could promote the expression and nuclear translocation of the transcription factor EB (TFEB), as well as activate TFEB-regulated autophagy in lung tissue of arsenic-treated mice, accompanied by inhibition of the AKT-mTOR signaling pathway. Overall, our study here suggests that natural bioactive compound curcumin could alleviate arsenic-induced pulmonary oxidative stress and inflammation in vivo, which is closely related to enhanced TFEB activity and induction of the autophagic process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Arsenic (As) is a prevalent and hazardous environmental toxicant associated with cancer and various health problems, which has been shown suppressive effects on dendritic cells (DCs). Autophagy is essential for the innate and adaptive immune responses of DCs, and the transcription factors TFEB and TFE3 are key regulators of autophagic and lysosomal target genes. However, the detrimental alterations of the autophagy-lysosome pathway in As-exposed DCs and the possible coordinating roles of TFEB and TFE3 in the immune dysfunction of this cell are less understood. In this paper, we found that As exposure significantly impaired lysosomal number, lysosomal acidic environment, and lysosomal membrane permeabilization, which might lead to blocked autophagic flux in cultured DCs. Furthermore, our results confirmed that TFEB or TFE3 knockdown exacerbated the disorders of lysosome and the blockade of autophagic flux in As-exposed DCs, and also enhanced the inhibitory expression of co-stimulatory molecules Cd80 and Cd83; adhesion molecule Icam1; cytokines TNF-α, IL-1β, and IL-6; chemokine receptor Ccr7; and antigen-presenting molecules MHC II and MHC I. By contrast, overexpression of TFEB or TFE3 partially alleviated the above-mentioned impairment of DCs by inorganic As exposure. In conclusion, these findings reveal a previously unappreciated inhibition of lysosome-mediated degradation and damage of lysosomal membrane integrity leading to dysregulated autophagy and impaired immune functions of DCs by arsenicals, and also suggest TFEB and TFE3 as potential therapeutic targets for ameliorating As toxicity., (© 2024. The Author(s).)

Numerous studies on arsenic-induced hepatonephric toxicity including cancer have been reported. Given that chronic inflammatory response and immune imbalance are associated with oncogenesis, we investigated whether arsenic could influence the hepatic and nephritic expression of inflammatory factors and the differentiation of T cells. Mice were exposed to NaAsO 2 (0, 25, and 50 mg/L) for 1 and 3 months. Our data showed the destruction of the structure and inflammatory infiltration in the liver. The arsenic markedly increased the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The myeloperoxidase (MPO) activities increased in the liver at 25 and 50 mg/L arsenic for 3 months as well as in the kidney at both 1 and 3 months. An increased expression of inflammatory indicators (IL-1 β , IL-12, and TNF- α ) at 25 and 50 mg/L arsenic for 1 and 3 months in the liver and kidney, as well as IL-1 β in the liver for 3 months and in the kidney at 50 mg/L for 1 and 3 months were demonstrated in our experiments. Besides, a definite tendency toward Th1/Th17 cytokines in the liver while Th2/Th17 cytokines in kidney was also observed by arsenic. Moreover, arsenic enhanced the expression of MAPK/Nrf2/NF- κ B signaling molecules. In conclusion, the results of the study suggested that arsenic induces continuous immune-inflammatory responses in the liver and kidney., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Xiaoxu Duan et al.)

Chronic arsenic exposure has been associated with various toxic effects, especially to the organs of liver and kidney. As a plant polyphenol, curcumin is the most vital bioactive ingredient of turmeric and has a wide range of pharmacological activities. In the present study, we investigated the potential roles of curcumin against arsenic-induced liver and kidney dysfunctions in mice. Curcumin treatment (200 mg/kg) not only decreased the deposition of arsenic in liver and kidney, but also relieved the hepatic and nephritic biochemical indexes (Glutamic oxaloacetic transaminase [AST], Alanine aminotransferase [ALT], albumin, and creatinine) altered by arsenic at doses of 10 and 25 mg/L via drinking water. What's more, curcumin exerted influences on the activities of myeloperoxidase and on the secretion of inflammatory cytokines in liver and kidney tissues. In addition, the levels of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) phosphorylation were declining while NRF2-signaling targets were increasing in mice liver and kidney by curcumin administration. In conclusion, our results here suggest that curcumin could exert both anti-inflammatory and antioxidant functions on arsenic-induced hepatic and kidney injury by inhibiting MAPKs/NF-κB and activating Nrf2 pathways cooperatively., (© 2021 Wiley Periodicals LLC.)

Arsenic is a toxic metalloid, which also compromises immunity and causes various immunological disorders. Exposure to arsenic exerts the immunosuppressive properties of dendritic cells (DCs). Autophagy is a self-renewal process of cells, which degrades damaged macromolecules and organelles through the lysosomal pathway. Thus, herein, we attempt to clarify the impacts of autophagy and the autophagy-lysosome pathway on arsenic-exposed DCs. Bone marrow-derived dendritic cells (BMDCs) were exposed to different concentrations of arsenic (0.25, 0.5 and 1 μM) with or without LPS stimulation. Initially, we observed that arsenic induced autophagosome accumulation, significantly enhanced the LC3 II and p62 expressions and down-regulated the p-mTOR protein levels. We also determined that arsenic-induced autophagy occurred via an mTOR pathway. The results further revealed that arsenic inhibited autophagic flux in LPS-stimulated BMDCs using the autophagy inhibitor chloroquine (CQ). Meanwhile, arsenic significantly decreased the number of lysosomes, protein expression of lysosomal-specific markers LAMP1 and LAMP2, and the protein levels of lysosomal cysteine cathepsins (CTSD and CTSL). Moreover, the overexpression of transcription factor EB (TFEB), the master transcriptional regulator of autophagy and lysosome biogenesis, partially relieved arsenic-inhibited lysosomal CTSD and CTSL expressions, recovered the disorder of autophagic flux, promoted the production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12, and reduced anti-inflammatory cytokine IL-10 secretion. In summary, our results support the idea that arsenic induces autophagy through an mTOR-dependent pathway in cultured BMDCs. Meanwhile, arsenic weakens the process of autophagic flux, which may be partially due to lysosomal dysfunction. Furthermore, we also suggest that TFEB can positively act on the autophagy-lysosome pathway and influence the expression of immunocytokines in DCs.

Arsenic is a ubiquitous metalloid element present in both inorganic and organic forms in the environment. The liver is considered to be a primary organ of arsenic biotransformation and methylation, as well as the main target of arsenic toxicity. Studies have confirmed that Chang human hepatocytes have an efficient arsenic methylating capacity. Our previous studies have proven that arsenite activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in hepatocytes. This study aimed to explore the activation of the Nrf2 pathway upon treatment of arsenic in various forms, including inorganic and organic arsenic. Our results showed that inorganic arsenic—both As 2 O 3 and Na 2 HAsO 4 significantly induced the expression of Nrf2 protein and mRNA, enhanced the transcription activity of Nrf2, and induced the expression of downstream target genes. These results confirmed the inorganic arsenic-induced Nrf2 pathway activation in hepatocytes. Although all arsenic chemicals used in the study induced Nrf2 protein accumulation, the organic arsenic C 2 H 7 AsO 2 did not affect the expression of Nrf2 downstream genes which were elevated by inorganic arsenic exposures. Through qRT-PCR and Nrf2 luciferase reporter assays, we further confirmed that C 2 H 7 AsO 2 neither increased Nrf2 mRNA level nor activated the Nrf2 transcription activity. Mechanistically, our results confirmed inorganic arsenic-induced both the nuclear import of Nrf2 and export of Bach1 (BTB and CNC homology 1), which is an Nrf2 transcriptional repressor, while organic arsenic only induced Nrf2 translocation. The unique pattern of Nrf2 regulation by organic arsenic underlines the critical role of Nrf2 and Bach1 in the arsenic toxicology. Unlabelled Image • The activation of the Nrf2 induced by inorganic and organic arsenic. • C 2 H 7 AsO 2 neither increased Nrf2 mRNA level nor activated the Nrf2 luciferase report. • C 2 H 7 AsO 2 did not affect Nrf2 downstream genes expression induced by inorganic arsenic. • The inorganic arsenic-induced both the nuclear import of Nrf2 and export of Bach1. • The organic arsenic only induced Nrf2 translocation. [ABSTRACT FROM AUTHOR]