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1.
The aim of this work is based in the premise that inorganic arsenic (As III) and trivalentmethylated metabolites monomethylarsonous (MMA III) and dimethylarsinous (DMA III) participate in DNA damage through the generation of reactive oxygen species (ROS). We have utilized two lymphoblastic lines,
Raji (B cells) and Jurkat (T cells), which were treated with the trivalent arsenic species (dose: 0–100 μ M) and analyzed by two assays (comet assay and flow cytometry) in the determination of DNA damage and ROS effects in vivo.
The results showed that the damage to the DNA and the generation of ROS are different in both cellular lines with respect
to the dose of organic arsenic, and the order of damage is MMA III>DMA III>As III. This fact suggests that the DMA III is not always the more cytotoxic intermediary xenobiotic, as has already been reported in another study. 相似文献
2.
Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells. Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA III), which accumulates in glial cells without compromising cell viability. MMA III LD 50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA III concentrations (50–1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA III concentrations that also induced TNF-α over-expression. Other effects of MMA III on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA III concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA III induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations. 相似文献
3.
Summary Arsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17β- D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA V), and dimethylarsinate (DMA V). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA V or DMA V. Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17β- D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport. 相似文献
4.
Arsenic is a well known carcinogenic environmental pollutant although its mechanism of action remains unknown. Since alterations in chromosome segregation have been observed in individuals exposed to high concentrations of arsenic in the drinking water, the aneuploidogenic potential of arsenic was evaluated in vitro. Whole blood cultures were incubated for 72 h and treated with various concentrations of sodium arsenite for the last 24 h. Cells were harvested and samples were processed specially for aneuploidy evaluation. The number of chromosomes in 200 metaphases of first and second division cells was scored. A dose-related effect was observed: the highest concentration (10 −2 μM) induces 28.33% and 22.4% hyperploid cells in first and second division respectively and 29% tetraploid cells. The colchicine-like effect of arsenic was also evaluated. Mitotic arrest was evaluated in cultures treated for the last 2 h. Sodium arsenite can produce 40.24% and 12.93% of the colcemid effect (mitotic arrestant effect at 10 −2 μM and 10 −10 μM respectively). A different individual susceptibility effect was observed in both parameters and confirmed with the chromosome aberrations levels induced by arsenic in the same donors. Data indicate that sodium arsenite has an aneuploidogenic and a mitotic arrestant effect. 相似文献
5.
Arsenic is the number one contaminant of concern with regard to human health according to the World Health Organization. Epidemiological studies on Asian and South American populations have linked arsenic exposure with an increased incidence of lung disease, including pneumonia, and chronic obstructive pulmonary disease, both of which are associated with bacterial infection. However, little is known about the effects of low dose arsenic exposure, or the contributions of organic arsenic to the innate immune response to bacterial infection. This study examined the effects on Pseudomonas aeruginosa ( P. aeruginosa) induced cytokine secretion by human bronchial epithelial cells (HBEC) by inorganic sodium arsenite (iAs III) and two major metabolites, monomethylarsonous acid (MMA III) and dimethylarsenic acid (DMA V), at concentrations relevant to the U.S. population. Neither iAs III nor DMA V altered P. aeruginosa induced cytokine secretion. By contrast, MMA III increased P. aeruginosa induced secretion of IL-8, IL-6 and CXCL2. A combination of iAs III, MMA III and DMA V (10 pbb total) reduced IL-8 and CXCL1 secretion. These data demonstrate for the first time that exposure to MMA III alone, and a combination of iAs III, MMA III and DMA V at levels relevant to the U.S. may have negative effects on the innate immune response of human bronchial epithelial cells to P. aeruginosa. 相似文献
6.
BackgroundChronic exposure to arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM) but the underlying molecular mechanism remains unclear. ObjectivesThis study evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes associated with diabetes and arsenic exposure in drinking water on the risk of developing T2DM. MethodsIn 2009–2011, we conducted a follow up study of 957 Bangladeshi adults who participated in a case-control study of arsenic-induced skin lesions in 2001–2003. Logistic regression models were used to evaluate the association between 38 SNPs in 18 genes and risk of T2DM measured at follow up. T2DM was defined as having a blood hemoglobin A1C level greater than or equal to 6.5% at follow-up. Arsenic exposure was characterized by drinking water samples collected from participants'' tubewells. False discovery rates were applied in the analysis to control for multiple comparisons. ResultsMedian arsenic levels in 2001–2003 were higher among diabetic participants compared with non-diabetic ones (71.6 µg/L vs. 12.5 µg/L, p-value <0.001). Three SNPs in ADAMTS9 were nominally associated with increased risk of T2DM (rs17070905, Odds Ratio (OR) = 2.30, 95% confidence interval (CI) 1.17–4.50; rs17070967, OR = 2.02, 95%CI 1.00–4.06; rs6766801, OR = 2.33, 95%CI 1.18–4.60), but these associations did not reach the statistical significance after adjusting for multiple comparisons. A significant interaction between arsenic and NOTCH2 (rs699780) was observed which significantly increased the risk of T2DM (p for interaction = 0.003; q-value = 0.021). Further restricted analysis among participants exposed to water arsenic of less than 148 µg/L showed consistent results for interaction between the NOTCH2 variant and arsenic exposure on T2DM (p for interaction = 0.048; q-value = 0.004). ConclusionsThese findings suggest that genetic variation in NOTCH2 increased susceptibility to T2DM among people exposed to inorganic arsenic. Additionally, genetic variants in ADAMTS9 may increase the risk of T2DM. 相似文献
7.
BackgroundIn several volcanic areas of Italy, arsenic levels exceed European regulatory limits (10 μg/L in drinking water). There is still uncertainty about health risks from arsenic at low-medium doses (<100 μg/L). ObjectivesA large population-based study using an administrative cohort of residents in the Viterbo province (Central Italy), chronically exposed to low-medium arsenic levels via drinking water, was investigated to evaluate the effects of a lifetime exposure to arsenic on mortality from cancers and chronic diseases. MethodsThe study population consisted of 165,609 residents of 17 municipalities, followed from 1990 until 2010. Average individual arsenic exposure at the first residence (As I) was estimated through a space-time modeling approach using residential history and arsenic concentrations from water supply. A time-dependent Cumulative Arsenic dose Indicator (CAI) was calculated, accounting for daily water intake and exposure duration. Mortality Hazard Ratios (HR) were estimated by gender for different diseases using Cox proportional models, adjusting for individual and area-level confounders. A flexible non-parametric approach was used to investigate dose-response relationships. ResultsMean As I exposure was 19.3 μg/L, and average exposure duration was 39.5 years. Associations of As I and CAI indicators with several diseases were found, with greatest risks found for lung cancer in both sexes (HR = 2.61 males; HR = 2.09 females), myocardial infarction, peripheral arterial disease and COPD in males (HR = 2.94; HR = 2.44; HR = 2.54 respectively) and diabetes in females (HR = 2.56). For lung cancer and cardiovascular diseases dose-response relationship is modelled by piecewise linear functions revealing effects even for doses lower than 10 μg/L, and no threshold dose value was identified as safe for health. ConclusionsResults provide new evidence for risk assessment of low-medium concentrations of arsenic and contribute to the ongoing debate about the threshold-dose of effect, suggesting that even concentrations below 10 μg/L carry a mortality risk. Policy actions are urgently needed in areas exposed to arsenic like in the Viterbo province, to comply with current EU regulations. 相似文献
8.
The present study was designed to investigate the effects of lithium treatment on red blood cells which were given arsenic exposure. Long-term lithium therapy is being extensively used for the treatment of bipolar disorders. Arsenic is a group I carcinogen and a major toxic pollutant in drinking water that affects millions of people worldwide. Male SD rats were segregated into four groups, viz. normal control, lithium treated, arsenic treated, and lithium + arsenic treated. Lithium was supplemented as lithium carbonate at a dose level of 1.1 g/kg diet for a period of 8 weeks. Arsenic was given in the form of sodium arsenite at a dose level of 100 ppm in drinking water, ad libitum, for the same period. Lysates of red blood cells were used to investigate the effects of lithium and arsenic treatments on anti-oxidant enzymes, reduced glutathione (GSH), and lipid peroxidation (LPO) levels. Various hematological parameters, activities of Na+ K+ ATPase and delta-aminolevulinic acid dehydratase (δ-ALAD) were also assessed. A significant reduction was observed in the activities of antioxidant enzymes, GSH levels, total erythrocyte counts, Na+ K+ ATPase, and ALAD enzyme activities in lysates of red blood cells when exposed either to lithium or arsenic. In addition, a significant increase in the levels of malondialdehyde (MDA), lymphocytes, neutrophils, and total leukocytes was also observed following lithium as well as arsenic treatments. However, when arsenic-treated rats were subjected to lithium treatment, a pronounced alteration was noticed in all the above parameters. Therefore, we conclude that lithium supplementation to the arsenic-treated rats enhances the adverse effects on red blood cells and therefore use of lithium may not be medicated to patients who are vulnerable to arsenic exposure through drinking water. It can also be inferred that adverse effects of lithium therapy may get aggravated in patients thriving in the arsenic-contaminated area. 相似文献
9.
Background Neuron specific enolase (ENO2, γ-enolase) has been used as a biomarker to help identify neuroendocrine differentiation in breast cancer. The goal of the present study was to determine if ENO2 expression in the breast epithelial cell is influenced by the environmental pollutants, arsenite and cadmium. Acute and chronic exposure of MCF-10A cells to As +3 and Cd +2 sufficient to allow colony formation in soft agar, was used to determine if ENO2 expression was altered by these pollutants. Results It was shown that both As +3 and Cd +2 exposure caused significant increases in ENO2 expression under conditions of both acute and chronic exposure. In contrast, ENO1, the major glycolytic enolase in non-muscle and neuronal cells, was largely unaffected by exposure to either As +3 or Cd +2. Localization studies showed that ENO2 in the MCF-10A cells transformed by As +3 or Cd +2 had both a cytoplasmic and nuclear localization. In contrast, ENO1 was localized to the cytoplasm. ENO2 localized to the cytoplasm was found to co-localized with ENO1. Conclusion The results are the first to show that ENO2 expression in breast epithelial cells is induced by acute and chronic exposure to As +3 or Cd +2. The findings also suggest a possible link between As +3 and Cd +2 exposure and neuroendocrine differentiation in tumors. Overall, the results suggest that ENO2 might be developed as a biomarker indicating acute and/or chronic environmental exposure of the breast epithelial cell to As +3 and Cd +2. 相似文献
10.
Elevated soil arsenic levels resulting from long-term use of arsenic contaminated ground for irrigation in Bangladesh may inhibit seed germination and seedling establishment of rice, the country's main food crop. A germination study on rice seeds and a short-term toxicity experiment with different concentrations of arsenite and arsenate on rice seedlings were conducted. Percent germination over control decreased significantly with increasing concentrations of arsenite and arsenate. Arsenite was found to be more toxic than arsenate for rice seed germination. There were varietal differences among the test varieties in response to arsenite and arsenate exposure. The performance of the dry season variety Purbachi was the best among the varieties. Germination of Purbachi was not inhibited at all up to 4 mg l –1 arsenite and 8 mg l –1 arsenate treatment. Root tolerance index (RTI) and relative shoot height (RSH) for rice seedlings decreased with increasing concentrations of arsenite and arsenate. Reduction of RTI caused by arsenate was higher than that of arsenite. In general, dry season varieties have more tolerance to arsenite or arsenate than the wet season varieties. 相似文献
11.
In the last decade arsenic metabolism has become an important matter of discussion. Methylation of inorganic arsenic (iAs)
to monomethylarsonic acid (MMA V) and dimethylarsinic acid (DMA V) is considered to decrease arsenic toxicity. However, in addition to these pentavalent metabolites, the trivalent metabolites
monomethylarsonous (MMA III) and dimethylarsinous acid (DMA III) have been identified recently as intermediates in the metabolic pathway of arsenic in cultured human cells. To examine the
role of oxidative damage in the generation of DNA strand breaks by methylated trivalent arsenic metabolites, we treated human
lymphocytes with both metabolites at non-cytotoxic concentrations. We further tested whether these effects are sensitive to
modulation by the antioxidants ascorbate (Vitamin C) and selenomethionine (Se-Met). Both trivalent metabolites produced oxidative
stress related DNA damage, consisting of single strand breaks and alkali-labile sites, with MMA III being more potent at low concentrations than DMA III. Neither MMA III nor DMA III induced DNA-double strand breaks. The oxidative stress response profiles of the metabolites were parallel as determined by
lipid peroxidation induction. MMA III induced peroxidation from the lowest concentration tested, while effects of DMA III were apparent only at concentrations above 10 μM. The antioxidant Se-Met exhibited a more pronounced inhibition of trivalent
arsenic metabolite-induced oxidative-DNA damage than did vitamin C. The present findings suggest that DNA damage by methylated
trivalent metabolites at non-cytotoxic concentrations may be mediated by a mix of reactive oxygen and nitrogen oxidized species. 相似文献
12.
We investigated the spindle inhibitory properties of six arsenicals differing in their methylation or oxidation state. Human
lymphoblasts were exposed for 6 h to either sodium arsenate (NaAs V), sodium arsenite (NaAs III), monomethylarsonic acid (MMA V), monomethylarsonous acid (MMA III), dimethylarsinic acid (DMA V), or dimethylarsinous acid (DMA III). After exposure slides were prepared, and the mitotic indices (MI) were assessed. We also exposed tubulin directly to each
arsenical and spectrophotometrically measured its effect on polymerization. NaAs V caused a small but significant increase in MI. MMA V also caused only a slight increase in MI that just reached statistical significance. In contrast, DMA V caused a significant increase in MI, producing ∼75% the MI of demecolcine and ∼4 times the MI of the control. NaAs III had no significant effect on MI and was quite toxic. MMA III induced more than a twofold increase in MI compared to the control, which was about 40% that caused by demecolcine. On a
micromolar basis, MMA III was the most potent of the arsenicals tested. DMA III gave inconsistent results. None of the pentavalent arsenicals had a substantial effect (either inhibition or enhancement)
on GTP-induced polymerization of tubulin. In contrast, NaAs III inhibited polymerization at concentrations of 1 mM and above and MMA III and DMA III at 10 μM and above. Taken together, these results present a complex picture of how arsenicals may affect cells. These studies
demonstrate that the metabolites of arsenic are active not only as chromosome breaking and DNA damaging agents but can also
interfere with cell division via tubulin disruption. 相似文献
13.
Since arsenic trioxide (As 3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution. Considering the good therapeutic potency and low toxicity of tetraarsenictetrasulfide (As 4S 4) in the treatment of APL, we investigated the effects of combining As 4S 4 and As 3+ on the apoptosis and differentiation of NB4 and primary APL cells. As 4S 4, acting similarly to As 3+, arrested the G 1/S transition, induced the accumulation of cellular reactive oxygen species, and promoted apoptosis. Additionally, low concentrations of As 4S 4 (0.1–0.4 μM) induced differentiation of NB4 and primary APL cells. Compared with the As 4S 4- or As 3+-treated groups, the combination of As 4S 4 and As 3+ obviously promoted apoptosis and differentiation of NB4 and primary APL cells. Mechanistic studies suggested that As 4S 4 acted synergistically with As 3+ to down-regulate Bcl-2 and nuclear factor-κB expression, up-regulate Bax and p53 expression, and induce activation of caspase-12 and caspase-3. Moreover, the combination of low concentrations of As 4S 4 and As 3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein. In summary, As 4S 4 and As 3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells. 相似文献
14.
High arsenic groundwater contamination causes serious health risks in many developing countries, particularly in India and Bangladesh. The arsenic fluxes in aquifers are primarily controlled by bacterial populations through biogeochemical cycle. In this present study, two gram-positive rod-shaped bacteria were isolated from shallow aquifers of Bhojpur district in Bihar during the early winter season, able to withstand arsenite (As 3+) concentration upto 70?mM and 1000?mM of arsenate (As 5+) concentration. They showed high resistance to heavy metals up to 30?mM and utilized some complex sugars along with different carbon sources. Growth at wide range of temperature, pH and salinity were observed. Both these isolates showed high efficiency in converting As 3+ into less toxic concentrations of As 5+ respectively from arsenic enriched culture media. Along with superior arsenic transformation and arsenic resistance abilities, the isolates showed a wide variety of metabolic capacity in terms of utilizing a variety of carbon sources under aerobic conditions, respectively. This study reports the potential As 3+-oxidizing bacteria that can play an important role in subsurface arsenic transformation that will aid in designing future bioremediation strategy for the arsenic affected areas. 相似文献
15.
The metalloregulatory protein ArsR, which offers high affinity and selectivity toward arsenite, was overexpressed in Escherichia coli in an attempt to increase the bioaccumulation of arsenic. Overproduction of ArsR resulted in elevated levels of arsenite bioaccumulation but also a severe reduction in cell growth. Incorporation of an elastin-like polypeptide as the fusion partner to ArsR (ELP153AR) improved cell growth by twofold without compromising the ability to accumulate arsenite. Resting cells overexpressing ELP153AR accumulated 5- and 60-fold-higher levels of arsenate and arsenite than control cells without ArsR overexpression. Conversely, no significant improvement in Cd 2+ or Zn 2+ accumulation was observed, validating the specificity of ArsR. The high affinity of ArsR allowed 100% removal of 50 ppb of arsenite from contaminated water with these engineered cells, providing a technology useful to comply with the newly approved U.S. Environmental Protection Agency limit of 10 ppb. These results open up the possibility of using cells overexpressing ArsR as an inexpensive, high-affinity ligand for arsenic removal from contaminated drinking and ground water. 相似文献
16.
The potential usefulness of an insect model to evaluate oxidative stress induced by environmental pollutants was examined with trivalent arsenic (As 3+, NaAsO 2) and pentavalent arsenic (As 5+, Na 2HAsO 4) in adult female house flies, Musca domestica, and fourth-instar cabbage loopers, Trichoplusia ni. M. domestica was highly susceptible to both forms of arsenic following 48 h exposure in the drinking water with LC 50s of 0.008 and 0.011% w/v for As 3+ and As 5+, respectively. T. ni larvae were susceptible to dietary As 3+ with an LC 50 of 0.032% w/w but seem to tolerate As 5+ well with an LC 50 of 0.794% concentration after 48 h exposure. The minimally acute LC 5 dose of both As 3+ and As 5+ varied considerably but averaged 0.005% for both insects. The potential of both valencies of arsenic for inducing oxidative stress in the insects exposed ad libitum to approximately LC 5 levels was assessed. The parameters examined were the alterations of the antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST), the peroxidase activity of glutathione transferase (GSTPX), and glutathione reductase (GR), and increases in lipid peroxidation and protein oxidation. SOD (1.3-fold), GST (1.6-fold), and GR (1.5-fold) were induced by As 3+ in M. domestica but CAT and GSTPX were not affected. As 5+ had no effect on M. domestica. In T. ni, the antioxidant enzyme activities were not affected by As 3+ except for SOD which was suppressed by 29.4% and GST which was induced by 1.4-fold. As 5+ had no effect except the suppression of SOD by 41.2%. Lipid peroxidation and protein oxidation, which represent stronger indices of oxidative stress, were elevated in both insects by up to 2.9-fold. However, based on the antioxidant enzyme response to the arsenic anions, the mode of action of arsenic induced oxidative stress may differ between the two insects. Until this aspect is further clarified, evidence at this time favors the prospect of As 3+ as a pro-oxidant, especially for M. domestica. © 1995 Wiley-Liss, Inc. 相似文献
17.
BackgroundLymphatic filariasis (LF) is known to be associated with an increased production of IL-10. The role of the other IL-10 family members in the pathogenesis of infection and/or disease is not known. Methodology/Principal FindingsWe examined the expression patterns of IL-10 family members – IL-19, IL-24 and IL-26 in LF. We demonstrate that both CD4 + and CD8 + T cells express IL-19, IL-24 and IL-26 and that the frequency of CD4 + T cells expressing IL-19 and IL-24 (as well as IL-10) is significantly increased at baseline and following filarial antigen stimulation in patients with LF in comparison to individuals with filarial lymphedema and uninfected individuals. This CD4 + T cell expression pattern was associated with increased production of IL-19 and IL-24 by filarial – antigen stimulated PBMC. Moreover, the frequency of CD4 + and CD8 + T cells expressing IL-26 was significantly increased following filarial antigen stimulation in filarial lymphedema individuals. Interestingly, IL-10 blockade resulted in diminished frequencies of IL-19 + and IL-24 + T cells, whereas the addition of recombinant IL-10 resulted in significantly increased frequency of IL-19 + and IL-24 + T cells as well as significantly up regulated IL-19 and IL-24 gene expression, suggesting that IL-10 regulates IL-19 and IL-24 expression in T cells. In addition, IL-1β and IL-23 blockade also induced a diminution in the frequency of IL-19 + and IL-24 + T cells, indicating a novel role for these cytokines in the induction of IL-19 and IL-24 expressing T cells. Finally, elimination of infection resulted in significantly decreased frequencies of antigen – specific CD4 + T cells expressing IL-10, IL-19 and IL-24. ConclusionsOur findings, therefore, suggest that IL-19 and IL-24 are associated with the regulation of immune responses in active filarial infection and potentially with protection against development of pathology, while IL-26 is predominantly associated with pathology in LF. 相似文献
18.
CD8 + T cells play an important role in vaccination and immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although numerous SARS-CoV-2 CD8 + T cell epitopes have been identified, the molecular basis underpinning T cell receptor (TCR) recognition of SARS-CoV-2-specific T cells remains unknown. The T cell response directed toward SARS-CoV-2 spike protein–derived S 269–277 peptide presented by the human leukocyte antigen (HLA)-A∗02:01 allomorph (hereafter the HLA-A2 S269–277 epitope) is, to date, the most immunodominant SARS-CoV-2 epitope found in individuals bearing this allele. As HLA-A2 S269–277-specific CD8 + T cells utilize biased TRAV12 gene usage within the TCR α-chain, we sought to understand the molecular basis underpinning this TRAV12 dominance. We expressed four TRAV12 + TCRs which bound the HLA-A2 S269–277 complex with low micromolar affinity and determined the crystal structure of the HLA-A2 S269–277 binary complex, and subsequently a ternary structure of the TRAV12 + TCR complexed to HLA-A2 S269–277. We found that the TCR made extensive contacts along the entire length of the S 269–277 peptide, suggesting that the TRAV12 + TCRs would be sensitive to sequence variation within this epitope. To examine this, we investigated cross-reactivity toward analogous peptides from existing SARS-CoV-2 variants and closely related coronaviruses. We show via surface plasmon resonance and tetramer studies that the TRAV12 + T cell repertoire cross-reacts poorly with these analogous epitopes. Overall, we defined the structural basis underpinning biased TCR recognition of CD8 + T cells directed at an immunodominant epitope and provide a framework for understanding TCR cross-reactivity toward viral variants within the S 269–277 peptide. 相似文献
19.
Arsenic is a carcinogenic compound widely distributed in the groundwater around the world. The fate of arsenic in groundwater
depends on the activity of microorganisms either by oxidizing arsenite (As III), or by reducing arsenate (As V). Because of the higher toxicity and mobility of As III compared to As V, microbial-catalyzed oxidation of As III to As V can lower the environmental impact of arsenic. Although aerobic As III-oxidizing bacteria are well known, anoxic oxidation of As III with nitrate as electron acceptor has also been shown to occur. In this study, three As III-oxidizing bacterial strains, Azoarcus sp. strain EC1-pb1, Azoarcus sp. strain EC3-pb1 and Diaphorobacter sp. strain MC-pb1, have been characterized. Each strain was tested for its ability to oxidize As III with four different electron acceptors, nitrate, nitrite, chlorate and oxygen. Complete As III oxidation was achieved with both nitrate and oxygen, demonstrating the novel ability of these bacterial strains to oxidize
As III in either anoxic or aerobic conditions. Nitrate was only reduced to nitrite. Different electron donors were used to study
their suitability in supporting nitrate reduction. Hydrogen and acetate were readily utilized by all the cultures. The flexibility
of these As III-oxidizing bacteria to use oxygen and nitrate to oxidize As III as well as organic and inorganic substrates as alternative electron donors explains their presence in non-arsenic-contaminated
environments. The findings suggest that at least some As III-oxidizing bacteria are flexible with respect to electron-acceptors and electron-donors and that they are potentially widespread
in low arsenic concentration environments. 相似文献
20.
To enhance the therapeutic effects and decrease the adverse effects of arsenic on the treatment of acute promyelocytic leukemia, we investigated the co-effects of selenite (Se 4+) and arsenite (As 3+) on the apoptosis and differentiation of NB4 cells and primary APL cells. A 1.0- μM concentration of Se 4+ prevented the cells from undergoing As 3+-induced apoptosis by inhibiting As 3+ uptake, eliminating As 3+-generated reactive oxygen species, and repressing the mitochondria-mediated intrinsic apoptosis pathway. However, 4.0 μM Se 4+ exerted synergistic effects with As 3+ on cell apoptosis by promoting As 3+ uptake, downregulating nuclear factor- кB, and activating caspase-3. In addition to apoptosis, 1.0 and 3.2 μM Se 4+ showed contrasting effects on As 3+-induced differentiation in NB4 cells and primary APL cells. The 3.2 μM Se 4+ enhanced As 3+-induced differentiation by promoting the degradation of promyelocytic leukemia protein–retinoic acid receptor- α (PML–RAR α) oncoprotein, but 1.0 μM Se 4+ did not have this effect. Based on mechanistic studies, Se 4+, which is similar to As 3+, might bind directly to Zn 2+-binding sites of the PML RING domain, thus controlling the fate of PML–RAR α oncoprotein.Acute promyelocytic leukemia (APL) is a subtype of human acute myeloid leukemia. 1 The promyelocytic leukemia protein–retinoic acid receptor- α (PML–RAR α) fusion protein, which is generated from a specific chromosome translocation t(15;17)(q22;q21), is the key driver of APL leukemogenesis. 2 Arsenic trioxide (ATO), which has been successfully used in the treatment of APL, induces the catabolism of PML–RAR α oncoprotein. 3 ATO is one of the primary therapeutic agents for APL, but organ toxicity, especially for the liver and kidney, causes excessive pain for patients. 4, 5 Studies on the toxicity of arsenic suggest that ATO metabolism increases its toxicity because of oxidative damage and generation of more toxic metabolites, including monomethylarsonous acid and dimethylarsinous acid. 6, 7, 8, 9 Thus, identifying new therapeutics to decrease the adverse effects of ATO is necessary.ATO induces both apoptosis and differentiation in human APL cells. 10 Apoptosis is an ordered cascade of enzymatic events. 11 Studies on the mechanism of ATO-induced apoptosis in APL cells suggest that ATO promotes apoptosis through the mitochondria-mediated intrinsic pathway that is induced by oxidative stress and regulated by Bcl-2 family members. 10, 12, 13 ATO can also induce apoptosis by inhibiting the nuclear factor- кB (NF- кB) pathway that regulates the expression of various survival proteins. 14, 15 In addition to apoptosis, ATO can induce the differentiation of APL cells by degrading the PML–RAR α fusion protein and activating the retinoic acid signaling pathway. 10, 16 Zhang et al.16 reported that ATO induced the degradations of PML and PML–RAR α oncoprotein by directly binding to PML. PML is a zinc-finger protein with a Cys-rich motif that contains a RING domain. The PML RING domain (PML-R) contains two Zn 2+-binding sites (ZFs) and requires Zn 2+ for autonomous folding. 17 The conserved Cys12, Cys29, and Cys32 residues in PML-R-ZF1, and Cys24, Cys40, and Cys43 residues in PML-R-ZF2 are the binding sites for trivalent arsenic. 16Selenium is an essential nutrient element that shows chemopreventive effect and anticancer potential. 18 Li et al.19 suggested that high dose (5.0–20 μM) of selenite (Se 4+) could induce the accumulation of reactive oxygen species (ROS) and the apoptosis of NB4 cells. Subsequently, Zuo et al.20 and Guan et al.21 confirmed that high concentrations of Se 4+ induced the apoptosis of NB4 cells through an ROS-mediated pathway. However, the accumulation of ROS could induce adverse effects to noncancer tissues by causing oxidative damages. 22 For cancer treatment, we attempt to increase the anticancer efficacy while decreasing the adverse effects. Thus far, few studies have investigated the effects of 2.0–4.0 μM Se 4+ on the apoptosis and differentiation of human APL cells. Selenium exerts its biological functions dose-dependently. 22 In addition, selenium has chemical properties and metabolic fates similar to those of arsenic. In consideration of the typical characteristics of ATO in the treatment of APL, we hypothesized that 2.0–4.0 μM Se 4+ might induce some interesting changes in APL cells, such as differentiation and the degradation of PML–RAR α.Combination therapy is widely used in cancer treatment. The relationship between selenium and arsenic is complex. Selenium and arsenic act as metabolic and toxic antagonists. 23 Combining a low concentration of Se 4+ with ATO might decrease the toxicity and increase the curative potency of ATO in the treatment of APL. Thus, it is of great significance to evaluate the effects of combining selenium with arsenic on the apoptosis and differentiation of human APL cells.In this study, we found dose-dependent contrasting effects of Se 4+ on arsenite (As 3+)-induced apoptosis and differentiation in NB4 cells and primary APL cells. A 4.0- μM concentration of Se 4+ enhanced As 3+-induced apoptosis through downregulation of NF -кB and activation of caspase-3, but 1.0 μM Se 4+ failed to elicit these effects. At 2.0–4.0 μM, Se 4+ induced cell differentiation and synergistically promoted As 3+-induced cell differentiation. Mechanistic studies suggested that Se 4+ might bind directly to PML-R in the form of divalent selenium (Se 2+) to promote the degradation of PML–RAR α oncoprotein. 相似文献
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