Regular ArticleRole of Tumor Necrosis Factor-α in Cadmium-Induced Hepatotoxicity
Abstract
Liver and kidney injury following acute or chronic exposure to cadmium is well characterized. While hepatocytes and endothelial cells of the sinusoids are thought to be the primary cellular targets in the liver, ultrastructural changes may vary depending upon the exposure regimen and the time following administration. Since acute and chronic liver disease is often associated with the presence of cytokines, we investigated the role of proinflammatory cytokines in cadmium-induced hepatotoxicity. Supernatants from cultured liver slices obtained from acute or subchronic cadmium-exposed rats and mice were collected and cytokine secretion was examined. In addition, mRNA transcripts for IL-1α, IL-1β, IL-6, TNF-α, MIP-2, IFN-γ, and ICAM-1 from livers of treated mice were quantitated by reverse transcription-polymerase chain reaction. Modest increases in secretion of TNF-α, IL-1α, and IL-6 were observed in response to cadmium which were enhanced in LPS-primed mice. Additionally, cadmium exposure increased IL-1α, IL-1β, TNF-α, MIP-2, IL-6, and ICAM-1 mRNA transcripts in the liver. Immunohistochemical analysis revealed that TNF-α was associated with nonparenchymal cells in livers of cadmium-treated mice. Cadmium exposure produced a marked increase in plasma hepatocellular enzyme levels (i.e., AST, LDH, SDH), acute phase proteins (i.e., serum amyloid A), and foci formation in the liver, while focal inflammation and serum amyloid A (SAA) secretion, but not plasma enzymes, were further increased in cadmium-exposed mice primed with LPS. SAA secretion and focal inflammation were prevented by pretreatment with antibodies to TNF-α, indicating that these pathological manifestations are cytokine dependent. These data indicate that TNF-α, released from nonparenchymal cells as well as associated cytokines, are responsible for certain manifestations observed with cadmium-induced hepatotoxicity.
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Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis
2023, Free Radical Biology and MedicineChronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells (RWPE-1). The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1 cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1 cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.
Therapeutic perspective of thiosemicarbazones derivatives in inflammatory pathologies: A summary of in vitro/in vivo studies
2021, International ImmunopharmacologyFollowing induction of inflammation, the nuclear factor kappa B (NF-κB) in activated macrophages induces the transcription of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase (COX), an inflammatory enzyme implicated in the synthesis of prostaglandins (PGs). The latter are involved in the transition and the maintenance of chronic inflammation underling various chronic disorders that require treatment. Concerning this, many anti-inflammatory drugs are available to treat the inflammatory disorders, but their therapeutic use is associated with a variety of side effects. Therefore, the discovery of new safer and potential anti-inflammatory drugs is necessary. In this regard, thiosemicarbazones (TSC) compounds and their metals complexes attracted high interest due to their wide range of biological activities, interestingly, the anti-inflammatory activity. They are formed by the action of thiosemicarbazide on an aldehyde or ketone, and contain a sulfur atom in place of the oxygen atom. Their ability to form a stable complex with transition metal is known to enhances the biological activity and reduces the side effects of the parent compound. Thus, this review article describes the inflammatory response mediated by NF-κB-COX-PGs and summarizes the anti-inflammatory activity of different thiosemicarbazones derivatives synthesized in research area.
Immunotoxicology of cadmium: Cells of the immune system as targets and effectors of cadmium toxicity
2021, Food and Chemical ToxicologyCadmium (Cd) has been listed as one of the most toxic substances affecting numerous tissues/organs, including the immune system. Due to variations in studies examining Cd effects on the immune system (exposure regime, experimental systems, immune endpoint measured), data on Cd immunotoxicity in humans and experimental animals are inconsistent. However, it is clear that Cd can affect cells of the immune system and can modulate some immune responses. Due to the complex nature of the immune system and its activities which are determined by multiple interactions, the underlying mechanisms involved in the immunotoxicity of this metal are still vague. Here, the current knowledge regarding the interaction of Cd with cells of the immune system, which may affect immune responses as well as potential mechanisms of consequent biological effects of such activities, is reviewed. Tissue injury caused by Cd-induced effects on innate cell activities depicts components of the immune system as mediators/effectors of Cd tissue toxicity. Cd-induced immune alterations, which may compromise host defense against pathogenic microorganisms and homeostatic reparative activities, stress this metal as an important health hazard.
Cadmium neurotoxicity: From its analytical aspects to neuronal impairment
2021, Advances in NeurotoxicologyCadmium has several toxic effects to human health, including carcinogenicity, nephrotoxicity, hepatotoxicity, cardiovascular, reproductive toxicities, neurotoxicity, among others. This chapter will focus mainly on cadmium toxicity: from its analytical aspects to neuronal impairment. In this context, the knowledge of analytical methods to quantify cadmium is extremely needed. The normal range of cadmium in different biological samples, and the treatment that is necessary to measure cadmium on them will be presented. In addition, the literature data about cadmium neurotoxicity bringing parameters of the cholinergic system, purinergic system, Na+,K+-ATPase activity, oxidative stress, neurotransmitter imbalance and histological brain changes will be discussed. Cd acts as a neurotoxin; a scientific fact. However, the findings underline the need for further research in the field of Cd-induced neurotoxicity, as a deeper understanding of the mechanisms underlying the neurobehavioral impairment could shed more light on the causes of its well-established cognitive implications. It is necessary to look at gender and age differences in Cd susceptibility and the role of epigenetics in determining long-term and late-onset health effects from Cd. Finally, measures should be taken to reduce Cd exposure in the general population in order to minimize the risk of health damage.
Subchronic Oral Cadmium Exposure Exerts both Stimulatory and Suppressive Effects on Pulmonary Inflammation/Immune Reactivity in Rats
2019, Biomedical and Environmental SciencesThe aim of this study is to investigate the effects of oral cadmium (Cd) ingestion on the pulmonary immune response.
Determination of Cd content in lungs and histopathological evaluation of the tissue was performed in rats following 30-day oral Cd administration (5 and 50 mg/L). Antioxidant enzyme defense (superoxide dismutase and catalase), cell infiltration, and production of tumor necrosis factor (TNF) and interferon (IFN)-γ, as well as the activity of myeloperoxidase (MPO), nitric oxide (NO), and various cytokines [interleukin (IL)-1β, IL-6, IL-10, and IL-17] were investigated.
Cd caused tissue damage and cell infiltration in the lungs, and this damage was more pronounced at higher doses. Cd deposition resulted in lung inflammation characterized by a dose-dependent IL-1β increase in lung homogenates, increased TNF levels at both doses, and IL-6 stimulation at low doses with inhibition observed at higher doses. Cd exerted differential effects on lung leukocytes isolated by enzyme digestion, and these effects were characterized by a lack of change in the production of reactive oxygen and nitrogen species, an inhibition of IL-1β and TNF, and stimulation of MPO and IFN-γ. The higher capacity of Cd-exposed lung cells to respond to the opportunistic pathogen Staphylococcus epidermidis was demonstrated in vitro.
The potential of ingested Cd to exert both proinflammatory and immunosuppressive effects on pulmonary tissue inflammation and immune reactivity highlights the complex immunomodulatory actions of this metal.
A protective role of Heme-regulated eIF2Α kinase in cadmium-induced liver and kidney injuries
2017, ChemosphereCitation Excerpt :However, we here found that hepatic injuries were more severe in Hri−/− mice, particularly with the observation of atrophy of central vein. While liver is the most affected organ upon Cd exposure, kidney is considered to be the following damaged organ (Kayama et al., 1995b). In our study, Cd administration was also shown to induce renal injury, similar to previous reports (Dudley et al., 1985; Pari et al., 2007; Satarug et al., 2011).
A number of studies have reported that cadmium (Cd) can incur liver and kidney injuries. The recruitment and activation of leukocytes have been demonstrated to be involved in Cd-induced biological effects. Ironically, activated leukocytes and secreted cytokines are also reported to be required for the later recovery of the damaged tissues. Yet, the mechanisms driving the production of leukocytes have not been fully elucidated. Heme-regulated eIF2α kinase (HRI) is essential for translational regulation and stressed erythropoiesis in iron deficiency. Meanwhile, HRI is important in the maturation and function of macrophages, indicating that HRI might be indispensable for the development and function of other myeloid lineages. Apart from macrophages, whether HRI regulates the production of leukocytes and further affects Cd-induced tissue injuries is still elusive. In this study, we aimed to elucidate the role of HRI in liver and kidney injuries and the associated mechanisms upon Cd exposure. We found that Cd-exposed mice showed impaired production of leukocytes and developed morphological disorders in liver and kidney. Furthermore, Hri null mice exhibited a reduced number of monocytes and neutrophils and compromised cytokine production, relative to wild-type mice. Absence of Hri also exacerbated the impairments of liver and kidney upon Cd treatment. Together, these results highlighted a crucial role of HRI in protecting liver and kidney against Cd-induced injuries through inducing the development of monocytes and neutrophils. Our results further extended the understanding of HRI on the regulation of non-erythroid lineages and might provide new aspects for preventing and treating Cd-induced detrimental effects.