Determination of Heavy Metal Concentrations in Normal and Pathological Human Endometrial Biopsies and In Vitro Regulation of Gene Expression by Metals in the Ishikawa and Hec-1b Endometrial Cell Line.
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ABSTRACT:
SUBMITTER: Guyot E
PROVIDER: S-EPMC4657954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although endometrial cancer is the most common type of gynecological malignancy in developed countries, its molecular etiology is not well understood. Leucine-rich repeat and immunoglobulin-like domain 2 (LRIG2) is an evolutionarily conserved gene, but its functions in the endometrium are unknown. In this study, we found that LRIG2 is highly downregulated in endometrial adenocarcinoma patients and that it functions as a tumor suppressor. LRIG2 induced the mitochondrion-mediated apoptotic pathways by regulating stoichiometric balance among BCL-2 family proteins, whereby pro-survival members, MCL-1 and BCL-xL, were downregulated and pro-apoptotic BAK and BAX were upregulated. LRIG2 also inhibited proliferation of the Hec-1A and Ishikawa endometrial adenocarcinoma cells by upregulating p21. LRIG2 induced BAX- and BAK-dependent cell death that was efficiently prevented by MCL-1 overexpression. Furthermore, we found that LRIG2 unexpectedly phosphor-activates phosphoinositide 3-kinase (PI3K)/AKT and epidermal growth factor receptor (EGFR), which are conventionally accepted as survival signaling cues in diverse types of cancer. We observed that PI3K/AKT and EGFR serve as key kinases that have roles as growth suppressors of Hec-1A endometrial cancer cells by mediating the LRIG2-induced modulation of the BCL-2 family of proteins and p21. In vivo delivery of antisense DNAs against LRIG2 promoted the Hec-1A endometrial tumor growth in a xenograft mouse model, and immunoblotting of these tumor extracts showed consistent modulation of AKT, EGFR, the BCL-2 family members, and p21. Thus, our results demonstrated that LRIG2 is a growth suppressor of endometrial adenocarcinoma cells.
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Project description:Hinokitiol is a natural tropolone derivative that is present in the heartwood of cupressaceous plants, and has been extensively investigated for its anti-inflammatory, antioxidant, and antitumor properties in the context of various diseases. To date, the effects of hinokitiol on endometrial cancer (EC) has not been explored. The purpose of our study was to investigate the anti-proliferative effects of hinokitiol on EC cells. Cell viability was determined with an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the quantification of apoptosis and reactive oxygen species (ROSs) was performed by using flow cytometry, while protein expression was measured with the Western blotting technique. Hinokitiol significantly suppressed cell proliferation through the inhibition of the expression of cell-cycle mediators, such as cyclin D1 and cyclin-dependent kinase 4 (CDK4), as well as the induction of the tumor suppressor protein p53. In addition, hinokitiol increased the number of apoptotic cells and increased the protein expression of cleaved-poly-ADP-ribose polymerase (PARP) and active cleaved-caspase-3, as well as the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2). Interestingly, except for KLE cells, hinokitiol induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and reducing the sequestosome-1 (p62/SQSTM1) protein level. Furthermore, hinokitiol triggered ROS production and upregulated the phosphorylation of extracellular-signal-regulated kinase (p-ERK1/2) in EC cells. These results demonstrate that hinokitiol has potential anti-proliferative and pro-apoptotic benefits in the treatment of endometrial cancer cell lines (Ishikawa, HEC-1A, and KLE).
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Project description:Background and purposeEndometriosis is a disorder in which the endometrium forms growths outside the uterus and is associated with chronic pain. Recent evidence suggests that endometrial motility plays a role in the aetiology of endometriosis. The endocannabinoid system regulates cellular migration. Given the growing involvement of the endocannabinoids in reproduction, we investigated the role of the endocannabinoid system in migration of endometrial cells.Experimental approachMigration of the human endometrial HEC-1B cells was assayed. Standard PCR techniques were used to determine the presence of the GPCR, GPR18, in HEC-1B cells, and p44/42 MAPK was assayed in stably transfected HEK293-GPR18 cells to determine receptor specificity for known cannabinoid agonists and antagonists. N-arachidonoyl ethanolamine (AEA) metabolism was measured, using HPLC/MS/MS for lipid analysis.Key resultsAEA, ?(9) -tetrahydrocannabinol (?(9) -THC) and N-arachidonoyl glycine (NAGly) induce migration of HEC-1B cells through cannabinoid CB(1) receptor-independent mechanisms. MAPK activation in HEK293-GPR18 cells revealed novel pharmacology for known CB(1) and CB(2) receptor ligands at GPR18 receptors, including ?(9) -THC, which activates MAPK at nanomolar concentrations, whereas WIN 55212-2, CP55940, JWH-133 and JWH-015, and arachidonyl-1-hydroxy-2-propylamide (R1-methanandamide) had no effect. Moreover, HEC-1B migration and MAPK activation by NAGly and ?(9) -THC were antagonized by Pertussis toxin, AM251 and cannabidiol.Conclusions and implicationsAn understanding of the function and regulation of GPR18 and its molecular interactions with endogenous ligands, and how phytocannabinoids play a role with GPR18 signalling is vital if we are to comprehensively assess the function of the cannabinoid signalling system in human health and disease.Linked articlesThis article is commented on by Alexander, pp. 2411-2413 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view Alexander visit http://dx.doi.org/10.1111/j.1476-5381.2011.01731.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
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Project description:Lead (Pb) and cadmium (Cd) are highly toxic and are widespread in agricultural soils, representing risks to plant and human health. In this study, Davidia involucrata was cultivated in soil with different concentrations of Pb and Cd and sampled after 90 days. We used ANOVA to analyse the photosynthesis of D. involucrata and the ability of Pb and Cd to enrich and migrate in roots, stems and leaves. Various results are described here. 1) Under individual and combined Pb and Cd stress, the accumulation factors in the roots were greater than 1, which was significantly greater than those in the stems and leaves (P < 0.05), and the translocation factors both were less than 1. The Pb and Cd enrichment ability of D. involucrata roots was significantly higher than that of stems and leaves, and the migration ability of the two heavy metals in D. involucrata was weak. 2) The Mg-dechelatase activities of chlorophyll degradation products increased under stress due to high concentrations of Pb and Cd. However, chlorophyllase activity was higher at relatively low concentrations of the two heavy metals (P < 0.05). δ-Aminolevulinic acid and porphobilinogen of chlorophyll synthesis products are easily converted to uroporphyrinogen III under low concentrations of Cd, which promotes the synthesis of chlorophyll. 3) The effect of Cd stress alone on the chlorophyll concentration was not significant. Under combined stress, concentrations of Pb and Cd in the range of 400~800 mg·kg-1 and 5~20 mg·kg-1 significantly promoted an increase in photosynthetic pigments (P < 0.05). 4) Inhibition of the net photosynthetic rate increased with increasing Pb and Cd concentrations under both individual and combined stress. In addition, the root of D. involucrata had a strong absorption and fixation effect on heavy metals, thereby reducing metal toxicity and improving the tolerance of D. involucrata to heavy metals.
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Project description:Soft drinks are consumed daily in Nigeria due to its affordability, characteristic taste, and thirst quenching potential. However, the high demand may compromise the quality of production with possible contamination of heavy metals which have shown to cause intoxication and death in humans. This study evaluated some constituents of twenty-six soft drinks in Nigeria and investigated the presence of some heavy metal contaminants. The soft drinks were screened for the presence of sugar, carbon dioxide, phosphate and alcohol as well as the pH and acidity determined. The level of cadmium, mercury and lead were determined using atomic absorption spectrophotometer. The study showed the presence of sugar, carbon dioxide, phosphate, and alcohol in the soft drinks. The soft drinks were acidic in nature, pH ranging from 3 to 5 with a mean of 3.6 and the acid concentration was relatively low between 3 and 12 g/L with a mean of 8.1 g/L. Lead was present in all the samples ranging from 0.17 to 3.39 mg/L with a mean of 0.8, mercury was present in 22 samples ranging from 0.29 to 11.32 mg/L with a mean of 2.08 mg/L while cadmium was present only in one sample (0.149 mg/L). When compared to EPA, WHO and NIS standards, the levels of the heavy metal contaminants were above the tolerated limits for good quality drinking water in most samples. These results suggest that soft drinks in Nigeria may be contaminated with heavy metals which constitute a major public health problem. Thus, quality control is recommended during the production process especially at the stages of sterilization and purification.
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Project description:Pet owners often don't acknowledge the need for home-prepared diet formulation by a trained professional and may use recipes from sources such as the internet. Macronutrient and mineral composition of home-prepared diets were analyzed and compared to NRC and FEDIAF recommendations, and heavy metal concentrations were analyzed and compared to FDA maximum tolerable levels (MTL) for dogs and cats. Recipes of home-prepared diets for adult dogs (n = 75) and cats (n = 25) were evaluated. Analyses of protein, fat, and fiber were performed according to AOAC, and mineral and heavy metal analyses were performed using inductively coupled plasma optical emission spectrometry (ICP-OES). None of the diets supplied recommended levels of all nutrients evaluated, and more than 84.0% of diets presented three or more nutrients below recommendations. Nutrients with most levels below recommendations were calcium and potassium in recipes for dogs and iron and zinc in recipes for cats. As for heavy metals, levels of lead, cobalt, mercury, uranium, and vanadium were above MTLs. Results suggest that home-prepared diets may be a health risk to dogs and cats if not properly formulated. Furthermore, the chronic heavy metal intake must be better elucidated in order to understand the full impact of results.
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Project description:Soil contamination with heavy metals due to the application of fertilizers and biocides in agricultural activities is a potential threat for human health through the food chain. The present work was designed to study the spatial distribution of heavy metals, pollution level and possible reasons for their contamination in agricultural soils of Aghili plain, Khuzestan, Iran. The median concentrations of As, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, V, Zn, and Hg were 2.90, 0.29, 8.10, 39.0, 17.75, 354.0, 0.97, 58.35, 5.90, 34.0, 42.0, and 0.01 mg/kg, respectively. The results revealed that average concentrations of all studied heavy metals with an exception of Co, Cu, and Ni, were lower than background values. Analysis of source identification showed that Zn, Pb, and Cu (P?<?0.01, r?>?0.9) and Co, Cr, Mn, Ni, and V (P?<?0.01, r?>?0.7) were mainly from anthropogenic. In addition, Cd probably was originated from agricultural activities (application of manure and phosphorous fertilizers). Enrichment factor values of all metals (except Ni), were in the range of non to moderate enrichment (EF?<?5). According to the degree of contamination (Cd) and ecological risk factor (ERF), all stations were categorized as low to moderate contaminated sites (4.5?<?Cd?<?17), and biological communities in some locations may be at risk (ERF >65). Results indicate that application of fertilizers, herbicides and pesticides in agricultural soils has led to soil contamination and special management and educational plans are needed for public and farmers to prevent further adverse effects.
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