PMID: 

Medicine (Baltimore). 2019 May ;98(18):e15311. PMID: 31045767

Abstract Title: 

Progress in research on gold nanoparticles in cancer management.

Abstract: 

INTRODUCTION: The rapid advancement of nanotechnology in recent years has fuelled burgeoning interest in the field of nanoparticle research, particularly its application in cancer management. At present, there seems to be heightened interest in the application of gold nanoparticles (AuNPs) to the management of cancer, encompassing diagnosis, monitoring, and treatment. AuNPs could be used as drug delivery agents that target cancer cells or in gene therapy. These efforts are undertaken in the hope of revolutionizing current methods and strategies for cancer treatment. This review will focus on the current applications of AuNPs in cancer management. OBJECTIVES, DATA SOURCES, STUDY APPRAISAL AND SYNTHESIS METHODS, RESULTS:: objectives, data sources, study eligibility criteria, participants, and interventions, study appraisal and synthesis methods, results are not required, as the study will be a literature review. Just introduction, ethics and dissemination, and conclusion are applicable.ETHICS AND DISSEMINATION: Ethical approval and informed consent are not required, as the study is a literature review and does not involve direct contact with patients or alterations to patient care.CONCLUSION: AuNPs have many properties that are of great value for the diagnosis and treatment of tumors. AuNPs are small in size and can penetrate widely and deposit on the tumor site, bind to many proteins and drugs, target delivery drugs, and have good biocompatibility. The application of AuNPs in the diagnosis and treatment of tumors is very considerable. In the near future, AuNPs will certainly play an important role in the treatment of tumors.

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Environ Int. 2007 Jan ;33(1):108-21. Epub 2006 Aug 17. PMID: 16914205

Abstract Title: 

Environmental mercury contamination in China: sources and impacts.

Abstract: 

This review article focused on the current status of mercury (Hg) contamination in different ecological compartments in China, and their possible environmental and health impacts, focusing on some major cities. Mercury emission from non-ferrous metals smelting (especially zinc smelting), coal combustion and miscellaneous activities (of which battery and fluorescent lamp production and cement production are the largest), contributed about 45%, 38% and 17%, respectively, to the total Hg emission based on the data of 1999. Mercury contamination is widespread in different ecological compartments such as atmosphere, soil and water. There is evidence showing bioaccumulation and biomagnification of Hg in aquatic food chains, with higher concentrations detected in carnivorous fish. In terms of human exposure to Hg, fish consumption is the major exposure pathway for residents living in coastal cities such as Hong Kong, but inhalation may be another major source, affecting human health in areas with severe atmospheric Hg, such as Guiyang City (Guizhou Province). The first case study indicated that after closure of the acetic acid plant 20 years at Songyuan City (Jilin Province), 16.7% of residents' hair still contained Hg concentration in excess of 1 mg/kg (the reference dosage value, RfD set by USEPA). The second case study indicated that the male residents of Hong Kong who consumed more than four or more meals of fish per week tended to contain higher Hg in their hair, which was linked to their subfertility. There is also increasing evidence showing that skin disorders and autism in Hong Kong children are related to their high Hg body loadings (hair, blood and urine), through prenatal methyl Hg exposure. There seems to be an urgent need to identify the sources of Hg, speciation and concentrations in different ecological compartments, which may lead to high body loadings in human beings. Adverse health effects of residents living in places with a higher background level of Hg, due to long-term exposure to chronic levels of Hg through oral intake should not be overlooked.

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Bioconjug Chem. 2019 Jun 19 ;30(6):1724-1733. Epub 2019 May 22. PMID: 31067032

Abstract Title: 

Gold Nanoparticles Disrupt Tumor Microenvironment – Endothelial Cell Cross Talk To Inhibit Angiogenic Phenotypes in Vitro.

Abstract: 

It is currently recognized that perpetual cross talk among key players in tumor microenvironment such as cancer cells (CCs), cancer associated fibroblasts (CAFs), and endothelial cells (ECs) plays a critical role in tumor progression, metastasis, and therapy resistance. Disruption of the cross talk may be useful to improve the outcome of therapeutics for which limited options are available. In the current study we investigate the use of gold nanoparticles (AuNPs) as a therapeutic tool to disrupt the multicellular cross talk within the TME cells with an emphasis on inhibiting angiogenesis. We demonstrate here that AuNPs disrupt signal transduction from TME cells (CCs, CAFs, and ECs) to ECs and inhibit angiogenic phenotypes in vitro. We show that conditioned media (CM) from ovarian CCs, CAFs, or ECs themselves induce tube formation and migration of ECs in vitro. Migration of ECs is also induced when ECs are cocultured with CCs, CAFs, or ECs. In contrast, CM from the cells treated with AuNPs or cocultured cells pretreated with AuNPs demonstrate diminished effects on ECs tube formation and migration. Mechanistically, AuNPs deplete∼95% VEGF165 from VEGF single-protein solution and remove up to ∼45% of VEGF165 from CM, which is reflected on reduced activation of VEGF-Receptor 2 (VEGFR2) as compared to control CM. These results demonstrate that AuNPs inhibit angiogenesis via blockade of VEGF-VEGFR2 signaling from TME cellsto endothelial cells.

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PMID: 

Toxicology. 2007 Feb 28 ;231(1):40-57. Epub 2006 Nov 25. PMID: 17210217

Abstract Title: 

Cell death and cytotoxic effects in YAC-1 lymphoma cells following exposure to various forms of mercury.

Abstract: 

The effects of 1 min-4 h exposures to four Hg compounds (mercuric chloride [HgCl2], methyl mercuric chloride [CH3HgCl], p-chloromercuribenzoate [p-CMB] and thimerosal [TMS; ethylmercurithiosalicylate]) on cell death, microtubules, actin, CD3 receptor expression, protein tyrosine phosphorylation (PTyr-P) and intracellular calcium ([Ca2+]i) levels were investigated in YAC-1 lymphoma cells using flow cytometry. YOPRO-1 (YP) and propidium iodide (PI) dye uptake indicated all forms of Hg tested were toxic at concentrations ranging from 25.8-48.4 microM, with two distinct patterns of effects. Early apoptosis was prolonged for CH3HgCl- and TMS-treated cells, with more than 50% remaining YP+/PI- after 4h. Both CH3HgCl and TMS induced complete loss of beta-tubulin fluorescence, indicative of microtubule depolymerization and inhibition of tubulin synthesis and/or beta-tubulin degradation, while F-actin fluorescence diminished to a lesser degree and only after loss beta-tubulin. CH3HgCl and TMS induced an almost immediate two-fold increase in CD3 fluorescence, with levels returning to baseline within minutes. With continued exposure, CD3 fluorescence was reduced to approximately 50% of baseline values. Both compounds also increased PTyr-P two- to three-fold immediately, with levels returning to baseline at 4h. Similarly, two- to three-fold increases in [Ca2+]i were noted after 1 min exposure. [Ca2+]i increased progressively, reaching levels five- to eight-fold greater than control values. In contrast, dye uptake was delayed with HgCl2 and p-CMB, although cell death proceeded rapidly, with almost all non-viable cells being late apoptotic (YP+/PI+) by 4h. p-CMB produced early reductions in F-actin, and after 4h, complete loss of F-actin with only partial reduction of total beta-tubulin was seen with both p-CMB and HgCl2. HgCl2 reduced CD3 expression and PTyr-P slightly within minutes, while p-CMB produced similar effects on CD3 only at 4h, at which time PTyr-P was increased two- to three-fold. Both compounds increased [Ca2+]i within minutes, though levels remained under twice the baseline concentration after 15 min exposure. With continued exposure, [Ca2+]i increased to levels two- to five-fold greater than control values. These findings indicate the two groups of Hg compounds may induce cell death by distinct pathways, reflecting interactions with different cellular targets leading to cell death.

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PMID: 

Int J Nanomedicine. 2019 ;14:2705-2718. Epub 2019 May 1. PMID: 31118607

Abstract Title: 

Gold nanoparticle uptake is enhanced by estradiol in MCF-7 breast cancer cells.

Abstract: 

In the present study, we investigated the effects of 17β-estradiol (E) on membrane roughness and gold nanoparticle (AuNP) uptake in MCF-7 breast cancer cells.Estrogen receptor (ER)-positive breast cancer cells (MCF-7) were exposed to bare 20 nm AuNPs in the presence and absence of 1×10 M Efor different time intervals for up to 24 hrs. The effects of AuNP incorporation and Eincubation on the MCF-7 cell surface roughness were measured using atomic force microscopy (AFM). Endocytic vesicle formation was studied using confocal laser scanning microscopy (CLSM). Finally, the results were confirmed by hyperspectral optical microscopy.High-resolution AFM images of the surfaces of MCF-7 membranes (up to 250 nm) were obtained. The incubation of cells for 12 hrs with AuNP and Eincreased the cell membrane roughness by 95% and 30% compared with the groups treated with vehicle (ethanol) or AuNPs only, respectively. This effect was blocked by an ER antagonist (7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol [ICI] 182,780). Higher amounts of AuNPs were localized inside MCF-7 cells around the nucleus, even after 6 hrs of Eincubation, compared with vehicle-treated cells. Endolysosome formation was induced by E, which may be associated with an increase in AuNP-uptake.Eenhances AuNP incorporation in MCF-7 cells by modulating of plasma membrane roughness and inducing lysosomal endocytosis. These findings provide new insights into combined nanotherapies and hormone therapies for breast cancer.

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Graefes Arch Clin Exp Ophthalmol. 2012 Oct ;250(10):1459-66. Epub 2012 Jun 24. PMID: 22729468

Abstract Title: 

Cytoprotective effect of hyaluronic acid and hydroxypropyl methylcellulose against DNA damage induced by thimerosal in Chang conjunctival cells.

Abstract: 

BACKGROUND: To investigate genotoxicity of the preservative thimerosal (Thi), and the cytoprotective and antioxidant effects of hyaluronic Acid (HA) and hydroxypropyl methylcellulose (HPMC) on Chang conjunctival cells.METHOD: Cells were divided into three groups. One group was exposed to Thi at various concentrations (0.00001 %∼0.001 %) for 30 min; the other two groups were pretreated with 0.3 % HA or 0.3 % HPMC for 30 min before the Thi exposure. After cell viability was evaluated, alkaline comet assay and detection of the phosphorylated form of the histone variant H2AX (γH2AX) foci were used to determine DNAdamage. Reactive oxygen species (ROS) production was assessed by the fluorescent probe, 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA).RESULTS: A significant change of cell viability was observed after exposure to 0.001 % Thi for 30 min. DNA single- and double-strand breaks were significantly increased in a dose-dependent manner with Thi exposure. In addition, intracellular ROS induced by Thi was dose-dependent, except at 0.001 % less ROS was induced than at 0.0005 %. However, cells pretreated with 0.3 % HA or 0.3 % HPMC showed significantly increased cell survival, decreased DNA damage, and decreased ROS production compared to cells exposed to Thi alone. Pretreatment with 0.3 % HA was found to be even more protective than 0.3 % HPMC.CONCLUSION: Thi can induce DNA damage in human conjunctival epithelial cells, probably due to oxidative stress. HA and HPMC are protective agents that have antioxidant properties and can decrease DNA damage induced by Thi. Pretreatment of 0.3 % HA may be more protective of the ocular surface than 0.3 % HPMC.

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PMID: 

Int J Nanomedicine. 2019 ;14:3145-3154. Epub 2019 May 3. PMID: 31118628

Abstract Title: 

Effect of gold nanoparticles treatment on the testosterone-induced benign prostatic hyperplasia in rats.

Abstract: 

Gold nanoparticles (AuNps) are promising agents for prostate cancer therapy. Herein, the in vivo effects of 20 and 50 nm sized AuNps on experimentally induced benign prostatic hyperplasia (BPH) was examined.Adult male rats were divided into four groups (n=6-8 each). A negative control group and three groups were injected daily with testosterone (3 mg/kg/subcutaneously) to induce BPH. Animals receiving testosterone were randomized to untreated BPH group and two BPH groups which were treated intraperitoneally with 20 and 50 nm AuNps (5 mg/kg/daily) in addition to testosterone. After three weeks, histopathological changes and serum levels of testosterone and dihydrotestosterone (DHT) were analyzed. In addition, the prostate tissue levels of transforming growth factor-β(TGF-β), vascular endothelial growth factor-a (VEGF-A) and interleukin-6 (IL-6) were measured using ELISA.There were significant increases in the prostate weight/body weight ratio, serum testosterone and DHT and in the prostate tissue content of TGF-β, IL-6 and VEGF-A in the untreated BPH group. histological examination showed morphological abnormalities with more proliferation in the glandular epithelial and stromal area and with abundant epithelial papillary folds in the BPH group. Simultaneous administration of 50 nm AuNps with testosterone tended to increase the prostate weight/body weight ratio and increase the tissue level of IL-6 in compared to the BPH group. Conversely, treatment with 20 nm AuNps significantly reduced the elevated tissue content of TGF-β, IL-6, and VEGF-A. Histopathological examination also showed that 20 nm but not the 50 nm AuNps administration ameliorates testosterone-induced prostatic hyperplasia.In experimentally induced BPH, AuNps can inhibit the progression of BPH in a size-dependent manner. while 20 nm AuNps ameliorate BPH by its inhibitory effects on the prostatic cell proliferation, inflammation and angiogenesis, the 50 nm AuNps could potentially exacerbate the development of BPH in rats, mainly through enhancing the inflammatory process.

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PMID: 

Chem Res Toxicol. 2008 Feb ;21(2):483-93. Epub 2008 Jan 16. PMID: 18197631

Abstract Title: 

Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of DNA topoisomerase II alpha.

Abstract: 

Thimerosal is an organic mercury compound that is widely used as a preservative in vaccines and other solution formulations. The use of thimerosal has caused concern about its ability to cause neurological abnormalities due to mercury accumulation during a normal schedule of childhood vaccinations. While the chemistry and the biological effects of methylmercury have been well-studied, those of thimerosal have not. Thimerosal reacted rapidly with cysteine, GSH, human serum albumin, and single-stranded DNA to form ethylmercury adducts that were detectable by mass spectrometry. These results indicated that thimerosal would be quickly metabolized in vivo because of its reactions with protein and nonprotein thiols. Thimerosal also potently inhibited the decatenation activity of DNA topoisomerase II alpha, likely through reaction with critical free cysteine thiol groups. Thimerosal, however, did not act as a topoisomerase II poison and the lack of cross-resistance with a K562 cell line with a decreased level of topoisomerase II alpha (K/VP.5 cells) suggested that inhibition of topoisomerase II alpha was not a significant mechanism for the inhibition of cell growth. Depletion of intracellular GSH with buthionine sulfoximine treatment greatly increased the K562 cell growth inhibitory effects of thimerosal, which showed that intracellular glutathione had a major role in protecting cells from thimerosal. Pretreatment of thimerosal with glutathione did not, however, change its K562 cell growth inhibitory effects, a result consistent with the rapid exchange of the ethylmercury adduct among various thiol-containing cellular reactants. Thimerosal-induced single and double strand breaks in K562 cells were consistent with a rapid induction of apoptosis. In conclusion, these studies have elucidated some of the chemistry and biological activities of the interaction of thimerosal with topoisomerase II alpha and protein and nonprotein thiols and with DNA.

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PMID: 

Ann Allergy Asthma Immunol. 2005 Jan ;94(1):90-4. PMID: 15702823

Abstract Title: 

A generalized reaction to thimerosal from an influenza vaccine.

Abstract: 

BACKGROUND: Thimerosal is a preservative commonly used in ophthalmic solutions, otic drops, and vaccines because of its bactericidal property.OBJECTIVE: To report a case of a generalized reaction to thimerosal in a patient who received an influenza vaccine.METHODS: We describe a patient who developed a generalized maculopapular eruption after receiving a thimerosal-containing influenza vaccine. Patch testing was performed to determine if there was an allergy to thimerosal.RESULTS: Patch testing confirmed a T-cell-mediated sensitivity to thimerosal.CONCLUSIONS: Physicians need to be aware that thimerosal is found in many products, including vaccinations. Clinicians should also be aware that allergic reactions occur with exposure to thimerosal even in vaccines. To our knowledge, this is the first case report in the literature of a generalized reaction to thimerosalfrom an influenza vaccine.

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PMID: 

Oxid Med Cell Longev. 2016 ;2016:6143753. Epub 2016 Feb 18. PMID: 26989453

Abstract Title: 

Alternatively Spliced Methionine Synthase in SH-SY5Y Neuroblastoma Cells: Cobalamin and GSH Dependence and Inhibitory Effects of Neurotoxic Metals and Thimerosal.

Abstract: 

The folate and cobalamin (Cbl-) dependent enzyme methionine synthase (MS) is highly sensitive to oxidation and its activity affects all methylation reactions. Recent studies have revealed alternative splicing of MS mRNA in human brain and patient-derived fibroblasts. Here we show that MS mRNA in SH-SY5Y human neuroblastoma cells is alternatively spliced, resulting in three primary protein species, thus providing a useful model to examine cofactor dependence of these variant enzymes. MS activity was dependent upon methylcobalamin (MeCbl) or the combination of hydroxocobalamin (OHCbl) and S-adenosylmethionine (SAM). OHCbl-based activity was eliminated by depletion of the antioxidant glutathione (GSH) but could be rescued by provision of either glutathionylcobalamin (GSCbl) or MeCbl. Pretreatment of cells with lead, arsenic, aluminum, mercury, or the ethylmercury-containing preservative thimerosal lowered GSH levels and inhibited MS activity in association with decreased uptake of cysteine, which is rate-limiting for GSH synthesis. Thimerosal treatment decreased cellular levels of GSCbl and MeCbl. These findings indicate that the alternatively spliced form of MS expressed in SH-SY5Y human neuronal cells is sensitive to inhibition by thimerosal and neurotoxic metals, and lower GSH levels contribute to their inhibitory action.

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