Cd Cytotoxicity Research Articles

Modulation of Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters.

Zinc (Zn) is the second most abundant metal in the human body and is essential for the function of 10% of all proteins. As metals cannot be synthesized or degraded, they must be assimilated from the diet by specialized transport proteins, which unfortunately also provide an entry route for the toxic metal pollutant cadmium (Cd). The intestinal absorption of Zn depends on the composition of food that is consumed, firstly the amount of Zn itself and then the quantity of other food constituents such as phytate, protein, and calcium (Ca). In cells, Zn is involved in the regulation of intermediary metabolism, gene expression, cell growth, differentiation, apoptosis, and antioxidant defense mechanisms. The cellular influx, efflux, subcellular compartmentalization, and trafficking of Zn are coordinated by transporter proteins, solute-linked carriers 30A and 39A (SLC30A and SLC39A), known as the ZnT and Zrt/Irt-like protein (ZIP). Because of its chemical similarity with Zn and Ca, Cd disrupts the physiological functions of both. The concurrent induction of a Zn efflux transporter ZnT1 (SLC30A1) and metallothionein by Cd disrupts the homeostasis and reduces the bioavailability of Zn. The present review highlights the increased mortality and the severity of various diseases among Cd-exposed persons and the roles of Zn and other transport proteins in the manifestation of Cd cytotoxicity. Special emphasis is given to Zn intake levels that may lower the risk of vision loss and bone fracture associated with Cd exposure. The difficult challenge of determining a permissible intake level of Cd is discussed in relation to the recommended dietary Zn intake levels.

Growth and metabolic differences in the potential of phytoremediation between two hybrid bermudagrasses in roots, stems, and leaves under cadmium stress

Bermudagrass (Cynodon) species has been identified as a dominant plant species in cadmium (Cd)-contaminated soils. Objectives of current study were to evaluate Cd tolerance of two hybrid bermudagrass (Cynodon transvaalensis × Cynodon dactylon) cultivars Tifdwarf and Chuannong-3 for urban greening and slope ecological restoration and further to explore the difference in Cd tolerance associated with changes in ion absorption and distribution, antioxidant metabolism, and accumulations of phytochelatins (PCs) and metallothioneins (MTs) in roots, stems, and leaves. After exposure to equal concentration and duration of Cd stress, growth, chlorophyll content, and photochemical efficiency of both cultivars reduced significantly, but Cd-induced these inhibitory effects were more pronounced in Chuannong-3. As compared to Chuannong-3, Tifdwarf maintained significantly higher Cd concentration in roots and lower Cd concentration, bioconcentration factor, and translocation factor in aboveground parts in response to Cd stress. Each plant of Tifdwarf also accumulated more Cd in leaves, stems, and roots than each plant of Chuannong-3 due to larger biomass under Cd stress. Cd stress also significantly inhibited uptake and partitioning of iron, sodium, and potassium in two cultivars. In addition, Tifdwarf exhibited better antioxidant defense for reactive oxygen species (ROS) scavenging than Chuannong-3 under Cd stress, as reflected by higher antioxidant enzyme activities and antioxidant metabolites involved in ascorbic acid (ASA)-glutathione (GSH) cycle. Tifdwarf also accumulated more PCs in leaves, stems, and roots and more MTs in leaves and stems than Chuannong-3, which could help to chelate Cd to reduce cytotoxicity of Cd. Moreover, strong antioxidant property of MTs was beneficial for maintaining ROS homeostasis in plants. Therefore, better Cd tolerance of Tifdwarf could be mainly due to the inhibition of Cd uptake and partitioning, enhanced ASA-GSH cycle, and more accumulations of PCs and MTs. Tifdwarf showed better potential for Cd remediation or urban greening in Cd-polluted soils.

Toxicity Tolerance in the Carcinogenesis of Environmental Cadmium.

Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted.

Saturated fatty acids synergizes cadmium to induce macrophages M1 polarization and hepatic inflammation

Exposure to the toxic metal cadmium (Cd) is a well-established risk factor for hepatic inflammation, but it remains unclear how metabolic components, such as different fatty acids (FAs), interact with Cd to influence this process. Understanding these interactions is essential for identifying potential preventative and therapeutic targets for this disorder. To address this question, we conducted in vitro and in vivo studies to investigate the combinatorial effect of Cd and saturated FAs on hepatic inflammation. Specifically, we assessed the cytotoxicity of Cd on macrophages and their polarization and inflammatory activation upon co-exposure to Cd and saturated FAs. Our results showed that while saturated FAs had minimal impact on the cytotoxicity of Cd on macrophages, they significantly collaborated with Cd in predisposing macrophages towards a pro-inflammatory M1 polarization, thereby promoting inflammatory activation. This joint effect of Cd and saturated FAs resulted in persistent inflammation and hepatic steatohepatitis in vivo. In summary, our study identified macrophage polarization as a novel mechanism by which co-exposure to Cd and saturated lipids induces hepatic inflammation. Our findings suggest that intervening in macrophage polarization may be a potential approach for mitigating the adverse hepatic effects of Cd.

Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.

Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington's disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 µM CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin-proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.

Polystyrene exacerbates cadmium-induced mitochondrial damage to lung by blocking autophagy in mice.

Cadmium (Cd) is an environmental heavy metal, and its accumulation is harmful to animal and human health. The cytotoxicity of Cd includes oxidative stress, apoptosis, and mitochondrial histopathological changes. Furthermore, polystyrene (PS) is a kind of microplastic piece derived from biotic and abiotic weathering courses, and has toxicity in various aspects. However, the potential mechanism of action of Cd co-treated with PS is still poorly unclear. The objective of this study was to investigate the effects of PS on Cd-induced histopathological injury of mitochondria in the lung of mice. In this study, the results have showed that Cd could induce the activity of oxidative enzymes of the lung cells in mice, increasing the content of partial microelement and the phosphorylation of inflammatory factor NF-κB p65. Cd further destroys the integrity of mitochondria by increasing the expression of apoptotic protein and blocking the autophagy. In addition, PS solely group aggravated the lung damage in mice, especially mitochondrial toxicity, and played a synergistic effect with Cd in lung injury. However, how PS can augment mitochondrial damage and synergism with Cd in lung of mice requiring further exploration. Therefore, PS was able to exacerbate Cd-induced mitochondrial damage to the lung in mice by blocking autophagy, and was associated with the apoptosis.

Amelioration of cadmium cytotoxicity to human cells by nutrient cation contents and the building of a biotic ligand model

A variety of important major and trace elements may competitively inhibit cadmium (Cd) absorption in human cells and reduce Cd toxicity. However, the impact of essential elements on the cytotoxicity of metals can be difficult to quantify and anticipate. Cd acute toxicity to Caco-2 cell viability was studied in culture solutions and modeled by a biotic ligand model (BLM). The individual effects of the cations potassium (K+), calcium (Ca2+), magnesium (Mg2+), ferrous ion(Fe2+), zinc (Zn2+) and manganese (Mn2+) on Cd toxicity were also investigated. The results indicated that the toxicity of Cd in culture solutions to cell viability declined with increasing concentrations of Zn2+ and Mn2+ in the solutions, while K+, Ca2 +, Mg2 + and Fe2+ had no significant effect. Using the BLM, the stability constants for the binding of Cd2 +, Zn2+, and Mn2+ to biotic ligands were determined to be logKCdBL = 5.76, logKZnBL = 4.39 and logKMnBL = 5.31, respectively. Moreover, it was calculated that 51% occupancy of the biotic ligand sites for Cd by Cd was required to cause a 50% reduction in Caco-2 cell viability. A BLM was successfully established using the estimated constants to predict the Cd cytotoxicity to Caco-2 cell viability as a function of solution characteristics, so that the effective concentrations that reduced cell viability by 50% (EC50) could be predicted by the BLM within 1.6 fold changes of the observed EC50. The application's viability and precision for foretelling Cd toxicity in Caco-2 cells are discussed.

Potential of Miscanthus floridulus associated with endophytic bacterium Bacillus cereus BL4 to remediate cadmium contaminated soil.

Phytoremediation assisted by endophytic bacteria is promising to efficiently remediate cadmium (Cd) contaminated soil. Bacillus cereus BL4, isolated from Miscanthus floridulus growing around a pyrite mine, exhibited high Cd tolerance and plant growth-promoting traits and could improve Cd bioavailability in soil. As a result of the pot experiment, after inoculation with strain BL4, the fresh weight, height, and Cd accumulation of Miscanthus floridulus shoots increased by 19.08-32.26 %, 6.02-16.60 %, and 23.67 %-24.88 %, respectively, and roots increased by 49.38-56.41 %, 22.87-33.93 %, and 28.51 %-42.37 %, respectively. Under Cd stress, the chlorophyll content, photosynthetic rate, and root activity of Miscanthus floridulus increased, while the membrane permeability and malonaldehyde (MDA) content significantly decreased after the inoculation of BL4, which indicated the alleviation of the cytotoxicity of Cd. Accordingly, the glutathione (GSH) content increased, and the activities of antioxidant enzymes presented downward trends after BL4 inoculation. Cd bioavailability in soil increased after BL4 inoculation, accompanied by increases in the activities of soil enzymes (invertase, urease, alkaline phosphatase, dehydrogenase, FDA hydrolase, and catalase) as well as the richness and diversity of soil bacteria. Our findings revealed that strain BL4 might strengthen the phytoremediation of Cd by Miscanthus floridulus through its effects on plant physio-biochemistry and soil microecology, which provided a basis for the relative application to Cd-contaminated soil.

Mitigation of Cadmium Toxicity through Modulation of the Frontline Cellular Stress Response

Cadmium (Cd) is an environmental toxicant of public health significance worldwide. Diet is the main Cd exposure source in the non-occupationally exposed and non-smoking populations. Metal transporters for iron (Fe), zinc (Zn), calcium (Ca), and manganese (Mn) are involved in the assimilation and distribution of Cd to cells throughout the body. Due to an extremely slow elimination rate, most Cd is retained by cells, where it exerts toxicity through its interaction with sulfur-containing ligands, notably the thiol (-SH) functional group of cysteine, glutathione, and many Zn-dependent enzymes and transcription factors. The simultaneous induction of heme oxygenase-1 and the metal-binding protein metallothionein by Cd adversely affected the cellular redox state and caused the dysregulation of Fe, Zn, and copper. Experimental data indicate that Cd causes mitochondrial dysfunction via disrupting the metal homeostasis of this organelle. The present review focuses on the adverse metabolic outcomes of chronic exposure to low-dose Cd. Current epidemiologic data indicate that chronic exposure to Cd raises the risk of type 2 diabetes by several mechanisms, such as increased oxidative stress, inflammation, adipose tissue dysfunction, increased insulin resistance, and dysregulated cellular intermediary metabolism. The cellular stress response mechanisms involving the catabolism of heme, mediated by heme oxygenase-1 and -2 (HO-1 and HO-2), may mitigate the cytotoxicity of Cd. The products of their physiologic heme degradation, bilirubin and carbon monoxide, have antioxidative, anti-inflammatory, and anti-apoptotic properties.

Astilbin attenuates apoptosis induced by cadmium through oxidative stress in carp (Cyprinus carpio L.) head kidney lymphocyte

As a kind of environmental pollutant, heavy metal Cadmium (Cd) exists widely in the environment. It is well known that Cd can accumulate and cause damage in liver, kidney and other organs. However, there are few studies on the immune cytotoxicity of Cd to fish. In particular, there are few studies on the toxicity of Cd to the head kidney lymphocytes of common carp. In order to further explore these mechanisms, we established an Cd exposure model in vitro. At the same time, we used the natural antioxidant astilbin (AST) to treat the cells to study its antagonistic effect on the toxicity of Cd. After exposure to Cd, the level of oxidative stress in head kidney lymphocytes increased, and the mRNA and protein expression of apoptosis-related markers Fas, FADD, Caspase8 and Caspase3 increased significantly (P < 0.05), which led to lymphocytes apoptosis. Hoechst staining and AO/EB staining also showed that the level of apoptosis increased after exposure to Cd. This is consistent with our previous research results. AST treatment reduced oxidative stress and apoptosis induced by Cd. In addition, oxidative stress inhibitor NAC could also reduce head kidney lymphocytes apoptosis induced by Cd, indicating that oxidative stress was involved in this process. Our results suggested that AST can alleviate the apoptosis of carp head kidney lymphocytes induced by Cd through oxidative stress. This study enriches the theoretical mechanism of Cd toxicity to fish head kidney lymphocytes, and puts forward a method to solve the toxicity of Cd, which provides a theoretical and research basis for the in vivo study of animal models in the future.

The role of autophagy in cadmium-induced acute toxicity in glomerular mesangial cells and tracking polyubiquitination of cytoplasmic p53 as a biomarker

Cadmium (Cd) is a highly toxic environmental pollutant that can severely damage the kidneys. Here, we show that Cd-induced apoptosis is promoted by the cytoplasmic polyubiquitination of p53 (polyUb-p53), which is regulated by the polyubiquitination of SQSTM1/p62 (polyUb-p62) and autophagy in mouse kidney mesangial cells (MES13E cells). p53 was detected in monomeric and different high-molecular-weight (HMW) forms after Cd exposure. Monomeric p53 levels decreased in a concentration- and time-dependent manner. HMW-p53 transiently accumulated in the cytoplasm independent of proteasome inhibition. The expression patterns of p53 were similar to those of p62 upon Cd exposure, and the interactions between polyUb-p53 and polyUb-p62 were observed using immunoprecipitation. P62 knockdown reduced polyUb-p53 and upregulated nuclear monomeric p53, whereas p53 knockdown reduced polyUb-p62. Autophagy inhibition induced by ATG5 knockdown reduced Cd-induced polyUb-p62 and polyUb-p53 but upregulated the levels of nuclear p53. Pharmacological inhibition of autophagy by bafilomycin A1 increased polyUb-p62 and polyUb-p53 in the cytoplasm, indicating that p53 protein levels and subcellular localization were regulated by polyUb-p62 and autophagy. Immunoprecipitation and immunofluorescence revealed an interaction between p53 and LC3B, indicating that p53 was taken up by autophagosomes. Cd-resistant RMES13E cells and kidney tissues from mice continuously injected with Cd had reduced polyUb-p53, polyUb-p62, and autophagy levels. Similar results were observed in renal cell carcinoma cell lines. These results indicate that cytoplasmic polyUb-p53 is a potential biomarker for Cd-induced acute toxicity in mesangial cells. In addition, upregulation of nuclear p53 may protect cells against Cd cytotoxicity, but abnormal p53 accumulation may contribute to tumor development.

Cadmium exposure suppresses insulin secretion through mtROS-mediated mitochondrial dysfunction and inflammatory response in pancreatic beta cells

BackgroundCadmium (Cd) exposure is a worldwide environmental threat to the public health and participates in the pathogenesis of multiple diseases. Epidemiologic research have established a direct relation between Cd exposure and diabetes development in humans. Although pancreatic β-cell dysfunction has been considered as the major culprit in the pathogenesis of diabetes, there is a paucity of studies to elucidate the molecular mechanism of Cd toxicity on β-cells. MethodsTo unveil the toxic effect and its underlying mechanism of Cd exposure on β-cells, we used an in vitro MIN6 cell model of environment-relevant Cd exposure to elucidate the crucial role of mtROS-mediated mitochondrial dysfunction and inflammatory response in suppression of pancreatic β-cell insulin secretion. ResultsWe uncovered that Cd treatment suppresses cell viability and induces insulin secretion dysfunction in a dose-dependent manner. Moreover, Cd exposure elicits the inflammatory response, as indicated by increased IL-1β, IL-6 and TNF-α expressions. Significant elevations of intracellular ROS and mitochondrial ROS levels were detected as early as 3 h after Cd treatment. In mitochondrial function analysis, we demonstrated that Cd treatment induced mitochondrial dysfunction and disorder of mitochondrial fission indicated by the significant decline in ATP production, the marked depolarization of mitochondrial membrane potential, the decrease in mtDNA copy numbers, the suppressions of mitochondrial transcription factor A (Tfam) and mitochondrial fission-related gene Drp1 expressions. Pretreatment with TEMPO, a specific mitochondrial ROS (mtROS) scavenger, efficiently antagonizes Cd cytotoxicity, which is indicated by attenuating Cd-induced mitochondrial dysfunction, suppressing IL-1β, IL-6 and TNF-α expressions, ameliorating insulin production dysfunction and preserving cell viability in MIN6 cells. ConclusionOur study demonstrates that Cd exposure induces an inflammatory response through mtROS-mediated mitochondrial dysfunction. Antagonism of mtROS production might be an effective strategy to prevent pancreatic toxicity from environment-relevant Cd exposure.

Selenite Ameliorates Cadmium-induced Cytotoxicity Through Downregulation of ROS Levels and Upregulation of Selenoprotein Thioredoxin Reductase 1 in SH-SY5Y Cells.

Cadmium (Cd) as a ubiquitous toxic heavy metal in the environment, causes severe hazards to human health, such as cellular stress and organ injury. Selenium (Se) was reported to reduce Cd toxicity and the mechanisms have been intensively studied so far. However, it is not yet crystal clear whether the protective effect of Se against Cd-induced cytotoxicity is related to selenoproteins in nerve cells or not. In this study, we found that Cd inhibited selenoprotein thioredoxin reductase 1 (TrxR1; TXNRD1) and decreased the expression level of TrxR1, resulting in cellular oxidative stress, and Se supplements ameliorated Cd-induced cytotoxicity in SH-SY5Y cells. Mechanistically, the detoxification of Se against Cd is attributed to the increase of the cellular TrxR activity and upregulated TrxR1 protein level, culminating in strengthened antioxidant capacity. Results showed that Se supplements attenuated the ROS production and apoptosis in SH-SY5Y cells, and significantly mitigated Cd-induced SH-SY5Y cell death. This study may be a valuable reference for shedding light on the mechanism of Cd-induced cytotoxicity and the role of TrxR1 in Se-mitigated cytotoxicity of Cd in neuroblast cells, which may be helpful for understanding the therapeutic potential of Cd and Se in treating or preventing neurodegenerative diseases, like Alzheimer's disease (AD) and Parkinson's disease (PD).

Evidence for Ovarian and Testicular Toxicities of Cadmium and Detoxification by Natural Substances

Cadmium (Cd) is an environmental toxicant, capable of reducing mitochondrial ATP production and promoting the formation of reactive oxygen species (ROS) with resultant oxidative stress conditions. The ovary and testis are the primary gonads in which female gametes (oocytes) and male gametes (spermatozoa), estrogen and testosterone are produced. These organs are particularly susceptible to Cd cytotoxicity due to their high metabolic activities and high energy demands. In this review, epidemiological and experimental studies examining Cd toxicities in gonads are highlighted together with studies using zinc (Zn), selenium (Se), and natural substances to reduce the effects of Cd on follicular genesis and spermatogenesis. Higher blood concentrations of Cd ([Cd]b) were associated with longer time-to-pregnancy in a prospective cohort study. Cd excretion rate (ECd) as low as 0.8 μg/g creatinine was associated with reduced spermatozoa vitality, while Zn and Se may protect against spermatozoa quality decline accompanying Cd exposure. ECd &gt; 0.68 µg/g creatinine were associated with an increased risk of premature ovarian failure by 2.5-fold, while [Cd]b ≥ 0.34 µg/L were associated with a 2.5-fold increase in the risk of infertility in women. Of concern, urinary excretion of Cd at 0.68 and 0.8 μg/g creatinine found to be associated with fecundity are respectively 13% and 15% of the conventional threshold limit for Cd-induced kidney tubular effects of 5.24 μg/g creatinine. These findings suggest that toxicity of Cd in primary reproductive organs occurs at relatively low body burden, thereby arguing for minimization of exposure and environmental pollution by Cd and its transfer to the food web.

The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization.

The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its role in human health and cancer risk, may also be transported by the ZIP8 protein. Several mutations in the ZIP8 gene are associated with the aberrant ion homeostasis of cells and can lead to human diseases. However, the intricate relationships between ZIP8 mutations, cellular Se homeostasis, and human diseases (including cancers and illnesses associated with Cd exposure) have not been explored. To further verify if ZIP8 is involved in cellular Se transportation, we first knockout (KO) the endogenous expression of ZIP8 in the HeLa cells using the CRISPR/Cas9 system. The elimination of ZIP8 expression was examined by PCR, DNA sequencing, immunoblot, and immunofluorescence analyses. Inductively coupled plasma mass spectrometry indicated that reduced uptake of Se, along with other micronutrients and Cd, was observed in the ZIP8-KO cells. In contrast, when ZIP8 was overexpressed, increased Se uptake could be detected in the ZIP8-overexpressing cells. Additionally, we found that ZIP8 with disease-associated single-point mutations G38R, G204C, and S335T, but not C113S, showed reduced Se transport ability. We then evaluated the potential of Se on Cd cytotoxicity prevention and therapy of cancers. Results indicated that Se could suppress Cd-induced cytotoxicity via decreasing the intracellular Cd transported by ZIP8, and Se exhibited excellent anticancer activity against not all but only selected cancer cell lines, under restricted experimental conditions. Moreover, clinical-based bioinformatic analyses revealed that up-regulated ZIP8 gene expression was common across multiple cancer types, and selenoproteins that were significantly co-expressed with ZIP8 in these cancers had been identified. Taken together, this study concludes that ZIP8 is an important protein in modulating cellular Se levels and provides insights into the roles of ZIP8 and Se in disease prevention and therapy.

Anti-leukemia properties of cadmium nanoparticles in the in vitro and in vivo condition: A chemobiological study

IntroductionThe present study investigated the anti-acute myeloid leukemia effects of Ziziphora clinopodides Lam leaf aqueous extract conjugated cadmium nanoparticles.Material and methodsTo synthesize CdNPs, Z. clinopodides aqueous extract was mixed with Cd(NO3)2 .4H2O. The characterization of the biosynthesized cadmium nanoparticles was carried out using many various techniques such as UV-Vis. and FT-IR spectroscopy, XRD, FE-SEM, and EDS.ResultsThe uniform spherical morphology of NPs was proved by FE-SEM images with NPs the average size of 26.78cnm. For investigating the antioxidant properties of Cd(NO3)2, Z. clinopodides, CdNPs, and Daunorubicin, the DPPH test was used. The cadmium nanoparticles inhibited half of the DPPH molecules in a concentration of 196 µg/mL. To survey the cytotoxicity and anti-acute myeloid leukemia effects of Cd(NO3)2, Z. clinopodides, CdNPs, and Daunorubicin, MTT assay was used on the human acute myeloid leukemia cell lines i.e., Murine C1498, 32D-FLT3-ITD, and Human HL-60/vcr. The IC50 of the cadmium nanoparticles was 168, 205, and 210 µg/mL against Murine C1498, 32D-FLT3-ITD, and Human HL-60/vcr cell lines, respectively. In the part of in vivo study, DMBA was used for inducing acute myeloid leukemia in mice. CdNPs similar to daunorubicin ameliorated significantly (p≤0.01) the biochemical, inflammatory, RBC, WBC, platelet, stereological, histopathological, and cellular-molecular parameters compared to the other groups.ConclusionsAs mentioned, the cadmium nanoparticles had significant anti-acute myeloid leukemia effects. After approving the above results in the clinical trial studies, these cadmium nanoparticles can be used as a chemotherapeutic drug to treat acute myeloid leukemia in humans.

Soluble curcumin ameliorates motility, adhesiveness and abrogate parthanatos in cadmium-exposed retinal pigment epithelial cells

Cadmium (Cd) is a nonessential transition metal and one of the most toxic environmental pollutants. Industrial, agricultural and urban activities are the main sources of Cd environmental contamination. Multiple deleterious effects of Cd exposure were reported for different cell types and living organisms in a great number of research papers. Cd bioaccumulation hazard is mediated by the relatively long half-life of this metal in an organism. For example, in mammals its half-life lasts for about 10–30 years. Cd exposure affects many tissues. However, some of them, including the central nervous system and sensory organs, are most susceptible to its toxicity. The harmful effects of Cd could be linked to oxidative stress generation and consequently intracellular signalling disruption. Since Cd induces redox imbalance the antioxidants could be a prospective tool to ameliorate Cd cytotoxicity. In present work, we have studied the protective efficacy of soluble curcumin on Cd-caused retinal pigment epithelium (RPE) cells viability, reactive oxygen species production, adhesive and extracellular matrix proteins expression, cell migration and parthanatos level. Low dose (5 µM) of soluble curcumin ameliorated all aforementioned indices of Cd-induced cytotoxicity. Curcumin has restored the RPE cells motility as well as fibronectin and E-cadherin expression. Therefore, the modulation of RPE adhesiveness could be regarded as a cytoprotective effect of curcumin. Furthermore, Cd-caused poly(ADP-ribose) polymerase-1 (PARP-1) suppression and cleaved PARP-1 upregulation were ameliorated by curcumin exposure. Therefore, the protective effect of soluble curcumin could be related, at least partially, to the modulation of PARP activity and inhibition of parthanatos flux. The observed results have demonstrated that low doses of soluble curcumin are a promising tool to protect RPE cells against Cd-caused retinal injury.

The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer

Cadmium (Cd) is an environmental toxicant with serious public health consequences due to its persistence within arable soils, and the ease with which it enters food chains and then, accumulates in human tissues to induce a broad range of adverse health effects. The present review focuses on the role of zinc (Zn), a nutritionally essential metal, to protect against the cytotoxicity and carcinogenicity of Cd in urinary bladder epithelial cells. The stress responses and defense mechanisms involving the low-molecular-weight metal binding protein, metallothionein (MT), are highlighted. The efflux and influx transporters of the ZnT and Zrt-/Irt-like protein (ZIP) gene families are discussed with respect to their putative role in retaining cellular Zn homeostasis. Among fourteen ZIP family members, ZIP8 and ZIP14 mediate Cd uptake by cells, while ZnT1 is among ten ZnT family members solely responsible for efflux of Zn (Cd), representing cellular defense against toxicity from excessively high Zn (Cd) intake. In theory, upregulation of the efflux transporter ZnT1 concomitant with the downregulation of influx transporters such as ZIP8 and ZIP14 can prevent Cd accumulation by cells, thereby increasing tolerance to Cd toxicity. To link the perturbation of Zn homeostasis, reflected by the aberrant expression of ZnT1, ZIP1, ZIP6, and ZIP10, with malignancy, tolerance to Cd toxicity acquired during Cd-induced transformation of a cell model of human urothelium, UROtsa, is discussed as a particular example.

Zinc, Zinc Transporters, and Cadmium Cytotoxicity in a Cell Culture Model of Human Urothelium.

We explored the potential role of zinc (Zn) and zinc transporters in protection against cytotoxicity of cadmium (Cd) in a cell culture model of human urothelium, named UROtsa. We used real-time qRT-PCR to quantify transcript levels of 19 Zn transporters of the Zrt-/Irt-like protein (ZIP) and ZnT gene families that were expressed in UROtsa cells and were altered by Cd exposure. Cd as low as 0.1 µM induced expression of ZnT1, known to mediate efflux of Zn and Cd. Loss of cell viability by 57% was seen 24 h after exposure to 2.5 µM Cd. Exposure to 2.5 µM Cd together with 10–50 µM Zn prevented loss of cell viability by 66%. Pretreatment of the UROtsa cells with an inhibitor of glutathione biosynthesis (buthionine sulfoximine) diminished ZnT1 induction by Cd with a resultant increase in sensitivity to Cd cytotoxicity. Conversely, pretreatment of UROtsa cells with an inhibitor of DNA methylation, 5-aza-2’-deoxycytidine (aza-dC) did not change the extent of ZnT1 induction by Cd. The induced expression of ZnT1 that remained impervious in cells treated with aza-dC coincided with resistance to Cd cytotoxicity. Therefore, expression of ZnT1 efflux transporter and Cd toxicity in UROtsa cells could be modulated, in part, by DNA methylation and glutathione biosynthesis. Induced expression of ZnT1 may be a viable mechanistic approach to mitigating cytotoxicity of Cd.

Individual and combined hepatocytotoxicity of DDT and cadmium in vitro.

The organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) and heavy metal cadmium (Cd) are widespread environmental pollutants. They are persistent in the environment and can accumulate in organisms. Although the individual toxicity of DDT and Cd has been well documented, their combined toxicity is still not clear. Since liver is their common target, in this study, the individual and combined toxicity of DDT and Cd in human liver carcinoma HepG2 and human normal liver THLE-3 cell lines were investigated. The results showed that DDT and Cd inhibited the viability of HepG2 and THLE-3 cells dose-dependently and altered lysosomal morphology and function. Intracellular reactive oxygen species and lipid peroxidation levels were induced by DDT and Cd treatment. The combined cytotoxicity of DDT and Cd was greater than their individual cytotoxicity, and the interaction between Cd and DDT was additive on the inhibition of cell viability and lysosomal function of HepG2 cells. The interaction was antagonistic on the inhibition of cell viability of THLE-3 cells. These results may facilitate the evaluation of the cumulative risk of pesticides and heavy metal residues in the environment.