Effect of the chaotropic anions thiocyanate and perchlorate on the entry of ricin into Vero cells.
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ABSTRACT:
SUBMITTER: Sandvig K
PROVIDER: S-EPMC1145012 | biostudies-other | 1985 Jun
REPOSITORIES: biostudies-other
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Project description:Understanding the mechanism of rabies virus (RABV) infection is vital for prevention and therapy of virulent rabies. However, the infection mechanism remains largely uncharacterized due to the limited methods and viral models. Herein, we utilized a powerful single-virus tracking technique to dynamically and globally visualize the infection process of the live attenuated rabies vaccine strain-SRV9 in living Vero cells. Firstly, it was found that the actin-enriched filopodia is in favor of virus reaching to the cell body. Furthermore, by carrying out drug perturbation experiments, we confirmed that RABV internalization into Vero cells proceeds via classical dynamin-dependent clathrin-mediated endocytosis with requirement for intact actin, but caveolae-dependent endocytosis is not involved. Then, our real-time imaging results unambiguously uncover the characteristics of viral internalization and cellular transport dynamics. In addition, our results directly and quantitatively reveal that the intracellular motility of internalized RABV particles is largely microtubule-dependent. Collectively, our work is crucial for understanding the initial steps of RABV infection, and elucidating the mechanisms of post-infection. Significantly, the results provide profound insight into development of novel and effective antiviral targets.
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Project description:BackgroundIt is known that perchlorate, nitrate and thiocyanate have the property of inhibiting sodium iodide symporter. Animal studies have suggested that these compounds, especially perchlorate, might also interfere with insulin secretion. However, the association between their exposure and diabetes risk is largely unknown in humans.MethodsAmong 11 443 participants (mean age 42.3 years) from the National Health and Nutritional Examination Survey 2001-14, urinary perchlorate, nitrate and thiocyanate were measured by using ion chromatography coupled with electrospray tandem mass spectrometry. Diabetes was defined as self-reported doctor diagnosis, use of oral hypoglycaemic medication or insulin, fasting plasma glucose ≥ 126 mg/dl or glycated haemoglobin A1c (HbA1c) ≥ 6.5%.ResultsThe median (interquartile range) levels of urinary perchlorate, nitrate and thiocyanate were 3.32 (1.84, 5.70) μg/l, 46.4 (27.9, 72.0) mg/l and 1.23 (0.59, 2.78) mg/l, respectively. Higher levels of urinary perchlorate were associated with elevated levels of fasting glucose, HbA1c, insulin and homeostatic model assessment of insulin resistance (all Ptrend < 0.001). After multivariate adjustment including urinary creatinine, smoking status and body mass index (BMI), higher urinary perchlorate, but not nitrate or thiocyanate, was associated with an increased prevalence of diabetes mellitus. Comparing extreme quintiles, the odds ratio (95% confidence interval) of diabetes was 1.53 (1.21, 1.93; Ptrend < 0.001) for perchlorate, 1.01 (0.77, 1.32; Ptrend = 0.44) for nitrate and 0.98 (0.73, 1.31; Ptrend = 0.64) for thiocyanate. When urinary perchlorate, nitrate and thiocyanate were further mutually adjusted, the results did not materially change. Similar results were observed when analyses were stratified by smoking status, as well as by age, gender, kidney function and BMI.ConclusionsHigher urinary perchlorate levels are associated with an increased prevalence of diabetes mellitus, independent of traditional risk factors. Future prospective studies are needed to confirm these findings.
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Project description:A large number of plant and bacterial toxins with enzymatic activity on intracellular targets are now known. These toxins enter cells by first binding to cell surface receptors, then they are endocytosed and finally they become translocated into the cytosol from an intracellular compartment. In the case of the plant toxin ricin and the bacterial toxin Shiga toxin, this happens after retrograde transport through the Golgi apparatus and to the endoplasmic reticulum. The toxins are powerful tools to reveal new pathways in intracellular transport. Furthermore, knowledge about their action on cells can be used to combat infectious diseases where such toxins are involved, and a whole new field of research takes advantage of their ability to enter the cytosol for therapeutic purposes in connection with a variety of diseases. This review deals with the mechanisms of entry of ricin and Shiga toxin, and the attempts to use such toxins in medicine are discussed.
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Project description:Perchlorate is a commonly occurring environmental toxicant that may be transported across the placental barrier by the sodium-iodide symporter (NIS), possibly resulting in both increased perchlorate exposure and decreased iodide uptake by the fetus. Therefore, we measured levels of three physiologically relevant NIS-inhibitors (perchlorate, nitrate, and thiocyanate) and iodide in maternal and fetal fluids collected during cesarean-section surgeries on 150 U.S. women. Geometric means of perchlorate, thiocyanate, and nitrate levels in maternal urine (2.90, 947, and 47900 microg/L, respectively) were similar to previously published results, while urinary iodide levels (1420 microg/L) were significantly higher (p < 0.0001), likely because of prevalent prenatal vitamin use in the study population (74%). Thiocyanate levels were higher in the maternal serum, cord serum, and amniotic fluid of smokers compared to women with environmental tobacco smoke exposure and nonsmokers (p-values of 0.0006, 0.0011, and 0.0026, respectively). Perchlorate was detected in most samples: urine (100%), maternal serum (94%), cord serum (67%), and amniotic fluid (97%). Maternal urinary perchlorate levels were positively correlated with perchlorate levels in amniotic fluid (r = 0.57), indicating that maternal urine perchlorate is an effective biomarker of fetal perchlorate exposure. Maternal serum perchlorate was generally higher than cord serum perchlorate (median ratio 2.4:1 for paired samples), and maternal urine perchlorate was always higher than fetal amniotic fluid perchlorate levels (mean ratio 22:1); conversely, iodide levels were typically higher in fetal fluids compared to maternal fluids. We found no evidence of either disproportionate perchlorate accumulation or lack of iodide in the fetal compartment. In this panel of healthy infants, we found no association between cord blood levels of these anions and newborn weight length, and head circumference.
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Project description:Nitazoxanide (NTZ) is effective against helminths and numerous microorganisms, including bacteria and viruses. In vivo, NTZ is metabolized into Tizoxanide (TIZ), which is the active circulating metabolite. With the emergence of SARS-Cov-2 as a Pandemic agent, NTZ became one of the molecules already approved for human use to engage clinical trials, due to results in vitro showing that NTZ was highly effective against the SARS-Cov-2, agent of COVID-19. There are currently several ongoing clinical trials mainly in the USA and Brazil involving NTZ due not only to the in vitro results, but also for its long-known safety. Here, we study the response of Vero cells to TIZ treatment and unveil possible mechanisms for its antimicrobial effect, using a label-free proteomic approach (LC/MS/MS) analysis to compare the proteomic profile between untreated- and TIZ-treated cells. Fifteen differentially expressed proteins were observed related to various biological processes, including translation, intracellular trafficking, RNA processing and modification, and signal transduction. The broad antimicrobial range of TIZ points towards its overall effect in lowering cell metabolism and RNA processing and modification. The decreased levels of FASN, HNRNPH and HNRNPK with the treatment appear to be important for antiviral activity.
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Project description:Supramolecular approaches for the quantitative anion analysis in water remain scarce due to the lack of receptors that effectively bind anions in this medium. Herein, we present a novel, fast and easy, supramolecular approach for a selective and quantitative analysis of perchlorate anions in water, coupling the UV-Vis spectroscopic method and phase-transfer extraction of anions by a water-insoluble anion receptor.
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Project description:BackgroundAdequate maternal thyroid function during pregnancy is necessary for normal fetal brain development, making pregnancy a critical window of vulnerability to thyroid disrupting insults. Sodium/iodide symporter (NIS) inhibitors, namely perchlorate, nitrate, and thiocyanate, have been shown individually to competitively inhibit uptake of iodine by the thyroid. Several epidemiologic studies examined the association between these individual exposures and thyroid function. Few studies have examined the effect of this chemical mixture on thyroid function during pregnancyObjectivesWe examined the cross sectional association between urinary perchlorate, thiocyanate and nitrate concentrations and thyroid function among healthy pregnant women living in New York City using weighted quantile sum (WQS) regression.MethodsWe measured thyroid stimulating hormone (TSH) and free thyroxine (FreeT4) in blood samples; perchlorate, thiocyanate, nitrate and iodide in urine samples collected from 284 pregnant women at 12 (±2.8) weeks gestation. We examined associations between urinary analyte concentrations and TSH or FreeT4 using linear regression or WQS adjusting for gestational age, urinary iodide and creatinine.ResultsIndividual analyte concentrations in urine were significantly correlated (Spearman's r 0.4-0.5, p<0.001). Linear regression analyses did not suggest associations between individual concentrations and thyroid function. The WQS revealed a significant positive association between the weighted sum of urinary concentrations of the three analytes and increased TSH. Perchlorate had the largest weight in the index, indicating the largest contribution to the WQS.ConclusionsCo-exposure to perchlorate, nitrate and thiocyanate may alter maternal thyroid function, specifically TSH, during pregnancy.
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Project description:Vero cells are highly susceptible to many viruses in humans and animals, and its membrane proteins (MPs) are responsible for virus entry. In our study, the MP proteome of the Vero cells was investigated using a shotgun LC-MS/MS approach. Six hundred twenty-seven proteins, including a total of 1839 peptides, were identified in MP samples of the Vero cells. In 627 proteins, 307 proteins (48.96%) were annotated in terms of biological process of gene ontology (GO) categories; 356 proteins (56.78%) were annotated in terms of molecular function of GO categories; 414 proteins (66.03%) were annotated in terms of cellular components of GO categories. Of 627 identified proteins, seventeen proteins had been revealed to be virus receptor proteins. The resulting protein lists and highlighted proteins may provide valuable information to increase understanding of virus infection of Vero cells.
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Project description:BackgroundPerchlorate, thiocyanate, and nitrate are sodium/iodide symporter (NIS) inhibitors that block iodide uptake into the thyroid, thus affecting thyroid function. Thyroid dysfunction can adversely affect somatic growth and development in children. To our knowledge, no studies have examined effects of NIS inhibitors on body size measures.ObjectiveWe investigated associations between NIS inhibitors and childhood growth in 940 girls from the Puberty Study of the Breast Cancer and Environment Research Program.MethodsUrine samples collected from girls 6-8 years of age at enrollment (2004-2007) from New York City, greater Cincinnati, Ohio, and the Bay Area in California were analyzed for NIS inhibitors and creatinine (C). The longitudinal association between NIS inhibitors and anthropometric measures [height, waist circumference, and body mass index (BMI)] during at least three visits was examined using mixed effects linear models, adjusted for race and site.ResultsCompared with girls in the low-exposure group (3.6, 626, and 500 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) girls with the highest NIS inhibitor exposure (9.6, 2,343, and 955 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) had slower growth in waist circumference and BMI but not height. Significant differences in the predicted mean waist circumference and BMI between the low- and high-exposure groups were observed beginning at 11 years of age.ConclusionsHigher NIS inhibitor exposure biomarkers were associated with reductions in waist circumference and BMI. These findings underscore the need to assess exposure to NIS inhibitors with respect to their influence on childhood growth.CitationMervish NA, Pajak A, Teitelbaum SL, Pinney SM, Windham GC, Kushi LH, Biro FM, Valentin-Blasini L, Blount BC, Wolff MS, for the Breast Cancer and Environment Research Project (BCERP). 2016. Thyroid antagonists (perchlorate, thiocyanate, and nitrate) and childhood growth in a longitudinal study of U.S. girls. Environ Health Perspect 124:542-549; http://dx.doi.org/10.1289/ehp.1409309.
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