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1.
Appl Microbiol Biotechnol ; 105(16-17): 6123-6132, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34331556

RESUMO

Global consumption of smokeless tobacco (SLT) reached 300 million users worldwide majorly from middle-income countries. More than 4000 chemical compounds represent it as one of the noxious consumable products by humans. Besides toxicants/carcinogens, the heavy microbial load on smokeless tobacco further keeps human health at higher risk. Several of these inhabitant microbes participate in biofilm formation and secrete endotoxin/mycotoxins and proinflammatory-like molecules, leading to several oral diseases. Tobacco-associated bacteria exhibit their role in tobacco-specific nitrosamines (TSNAs) formation and acetaldehyde production; both are well-documented carcinogens. Moreover, tobacco exhibits the potential to alter the oral microbiome and induce dysbiotic conditions that lead to the onset of several oral and systemic diseases. Traditional cultivation approaches of microbiology provide partial information of microbial communities of a habitat; therefore, microbiomics has now been employed to study the metagenomes of entire microbial communities. In the past 5 years, few NGS-based investigations have revealed that SLT harbors four dominant phyla (Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes) dominating Bacillus spp. and/or Pseudomonas spp. However, functional characterization of their genetic elements will be a more informative attribute to understand the correlation between inhabitant microbial diversity and their relatedness concerning abundance and diseases. This review provides an update on the microbial diversity of SLT and its associated attributes in human health. KEY POINTS: • Heavy microbial load on smokeless tobacco alarms for poor oral hygiene. • Inhabitant microorganisms of SLT participate in TSNA and biofilm formation. • SLTs alter the oral microbiome and causes oral dysbiosis.


Assuntos
Microbiota , Nitrosaminas , Tabaco sem Fumaça , Carcinógenos , Humanos , Tabaco
2.
Chem Commun (Camb) ; 57(61): 7581-7584, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34250986

RESUMO

A pharmacophore integration strategy was utilized to develop the first co-donor of formaldehyde and nitric oxide (FANO), composed of urotropine derived nitramine/nitrosamine. FANO simultaneously generated formaldehyde and nitric oxide on-demand, resulting in synergistic anticancer effects. Importantly, liposomal formulation of FANO effectively inhibited tumor growth with minimal side-effects, providing a potent combined nitric oxide therapy for malignancy.


Assuntos
Antineoplásicos/uso terapêutico , Formaldeído/metabolismo , Neoplasias/tratamento farmacológico , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico/metabolismo , Poliaminas/uso terapêutico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Lipossomos/química , Metenamina/química , Camundongos , Doadores de Óxido Nítrico/síntese química , Nitrosaminas/síntese química , Nitrosaminas/uso terapêutico , Poliaminas/síntese química
3.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299067

RESUMO

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D4 (LTD4), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4-CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.


Assuntos
Acetatos/farmacologia , Antiasmáticos/farmacologia , Proliferação de Células , Ciclopropanos/farmacologia , Leucotrieno D4/metabolismo , Nitrosaminas/toxicidade , Neoplasias Pancreáticas/tratamento farmacológico , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Sulfetos/farmacologia , Animais , Carcinógenos/toxicidade , Cricetinae , Humanos , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
4.
Sci Total Environ ; 798: 149210, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34315055

RESUMO

The contribution of two algae species, Microcystis aeruginosa (M. aeruginosa) and Cyclotella meneghiniana (C. meneghiniana), to the formation of nitrosamines (NAs) during chloramination in drinking water treatment was investigated. A variety of factors including contact time, algae cell concentration, chloramine dosages, and algal cell components (cell debris (CD), intracellular organic matter (IOM), and extracellular organic matter (EOM)) were evaluated for influencing the formation of different NAs, such as N-Nitrosodiethylamine (NDMA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodibutylamine (NDBA), N-Nitrosodi-n-propylamine (NDPA), and N-nitrosopyridine (NPyr). In addition, NAs formation from Chlorophyll-a and Microcystin-LR (MC-LR) after chloramination was studied. These results showed that the increase of reaction time and algae cell concentration enhanced the formation potential of five types of NAs from both algae species, except for the NDMA formation from C. meneghiniana, which increased first and then decreased with increased reaction time. The generation of NDMA was detected as the dominated type of NAs. The formation of total NAs from both algae species followed same pattern of increasing first and then decreasing with the increase of chloramine dosage. The largest NAs formation potential (NAsFP) of M. aeruginosa and C. meneghiniana showed at 1.5 mM and 1.0 mM monochloramine, respectively. Moreover, the impacts of algae cellular components on the formation potential of NAs followed the order of IOM > EOM ≫ CD and IOM ≫ CD > EOM for M. aeruginosa and C. meneghiniana, respectively, indicating that IOM was the main source of NAs precursors for both algae. Furthermore, EEM analysis before and after chloramination confirmed that the soluble microbial products (SMPs) and protein-like substances were the main cellular components that contributed to NAs formation for both algae. The NAs formation potential of Microcystin-LR was much higher than that of Chlorophyll-a chloramination.


Assuntos
Microcystis , Nitrosaminas , Purificação da Água , Halogenação , Água
5.
Artigo em Inglês | MEDLINE | ID: mdl-34299799

RESUMO

Biomarkers of tobacco exposure are known to be associated with disease risk but previous studies are limited in number and restricted to certain regions. We conducted a nested case-control study examining baseline levels and subsequent lung cancer incidence among current male exclusive cigarette smokers in the Golestan Cohort Study in Iran. We calculated geometric mean biomarker concentrations for 28 matched cases and 52 controls for the correlation of biomarker levels among controls and for adjusted odds' ratios (ORs) for lung cancer incidence by biomarker concentration, accounting for demographic characteristics, smoking quantity and duration, and opium use. Lung cancer cases had higher average levels of most biomarkers including total nicotine equivalents (TNE-2), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and 3-hydroxyfluorene (3-FLU). Many biomarkers correlated highly with one another including TNE-2 with NNAL and N-Acetyl-S-(2-cyanoethyl)-L-cysteine (2CYEMA), and N-Acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (t4HBEMA) with N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (3HMPMA) and N-Acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (4HMBEMA). Lung cancer risk increased with concentration for several biomarkers, including TNE-2 (OR = 2.22, 95% CI = 1.03, 4.78) and NNN (OR = 2.44, 95% CI = 1.13, 5.27), and estimates were significant after further adjustment for demographic and smoking characteristics for 2CYEMA (OR = 2.17, 95% CI = 1.03, 4.55), N-Acetyl-S-(2-carbamoylethyl)-L-cysteine (2CAEMA) (OR = 2.14, 95% CI = 1.01, 4.55), and N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (2HPMA) (OR = 2.85, 95% CI = 1.04, 7.81). Estimates were not significant with adjustment for opium use. Concentrations of many biomarkers were higher at the baseline for participants who subsequently developed lung cancer than among the matched controls. Odds of lung cancer were higher for several biomarkers including with adjustment for smoking exposure for some but not with adjustment for opium use.


Assuntos
Neoplasias Pulmonares , Nitrosaminas , Produtos do Tabaco , Biomarcadores , Carcinógenos , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Fumantes
6.
Appl Microbiol Biotechnol ; 105(13): 5607-5616, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34228183

RESUMO

Nitrosamine compounds, represented by N-nitrosodimethylamine, are regarded as potentially genotoxic impurities (PGIs) due to their hazard warning structure, which has attracted great attention of pharmaceutical companies and regulatory authorities. At present, great research gaps exist in genotoxicity assessment and carcinogenicity comparison of nitrosamine compounds. In this work, a collection of GFP-fused yeast cells representing DNA damage repair pathways were used to evaluate the genotoxicity of eight nitrosamine compounds (10-6-105 µg/mL). The high-resolution expression profiles of GFP-fused protein revealed the details of the DNA damage repair of nitrosamines. Studies have shown that nitrosamine compounds can cause extensive DNA damage and activate multiple repair pathways. The evaluation criteria based on the total expression level of protein show a good correlation with the mammalian carcinogenicity data TD50, and the yeast cell collection can be used as a potential reliable criterion for evaluating the carcinogenicity of compounds. The assay based on DNA damage pathway integration has high sensitivity and can be used as a supplementary method for the evaluation of trace PGIs in actual production. KEY POINTS: • The genotoxicity mechanism of nitrosamines was systematically studied. • The influence of compound structure on the efficacy of genotoxicity was explored. • GFP-fused yeast cells have the potential to evaluate impurities in production.


Assuntos
Técnicas Biossensoriais , Nitrosaminas , Animais , Dano ao DNA , Mutagênicos/toxicidade , Nitrosaminas/toxicidade , Saccharomyces cerevisiae/genética
7.
Se Pu ; 39(1): 96-103, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-34227363

RESUMO

In this study, a comprehensive analytical method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) was developed for the determination of nine N-nitrosamines in animal derived foods. There are many kinds of N-nitrosamines in foods that are harmful to human health. However, the national standard GB 5009.26-2016 pertains only to the detection of N-dimethylnitrosamine; there are many drawbacks of this method, such as complicated sample preparation, low recovery rate, and poor reproducibility. Hence, it is of practical significance to establish a method for the simultaneous determination of a variety of N-nitrosamines. The optimal extraction conditions for the developed method were as follows: 10.0 g aliquots of the sample were placed in a 50 mL centrifuge tube, followed by the addition of 10 mL acetonitrile and 200 µL internal working standard solutions. After 30 min of freezing treatment, 4 g magnesium sulfate and 1 g sodium chloride were added for dehydration, and the tube was centrifuged at 9000 r/min for 5 min. After vortex centrifugation, 5 mL of the clear supernatant was purified using 150 mg polystyrene divinylbenzene (PLS-A). The purified extracts were dewatered using 1.6 g MgSO4 and 0.4 g NaCl, and then filtered through a 0.22 µm membrane filter unit prior to GC-MS/MS analysis. Temperature-programmed was applied at an initial temperature of 50 ℃. After 0.16 min, the temperature was raised to 220 ℃ at the rate of 900 ℃/min for 5 min. N-Nitrosamines were separated on an HP-Innowax column (30 m×0.25 mm×0.25 µm). Identification and quantification were achieved using an electron impact ion (EI) source in positive ion mode with multiple reaction monitoring (MRM). The internal standard method was used to quantify the N-nitrosamines. Under the optimal conditions, the correlation coefficients of the standard calibration curves were not less than 0.99 in the range of 0.1-50.0 µg/L. The limits of detection were 0.03-0.30 µg/kg (S/N=3), and limits of quantification were 0.15-1.00 µg/kg (S/N=10). At spiked levels of 0.5, 1.0, and 3.0 µg/kg, the average recoveries of N-nitrosamines in spiked samples ranged from 80.4% to 98.5%, with relative standard deviations between 2.41% and 12.50%. This method was used to determine animal derived food products, except N-itrosomethylethylamine and N-nitrosomorpholine, others were founded. The results showed that N-nitrosamines levels in salted aquatic products were generally higher than those of the other samples. The method established in this study is simple to operate, and it does not require any time-consuming distillation extraction. Furthermore, there is minimal consumption of samples and reagents; consequently, the experiment cost is reduced, and the method is environmentally friendly. This method has theoretical and practical significance for the control of N-nitrosamines residues in animal derived foods, establishment of detection standards, and corresponding management measures.


Assuntos
Análise de Alimentos/métodos , Nitrosaminas , Animais , Cromatografia Gasosa-Espectrometria de Massas , Isótopos , Nitrosaminas/análise , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
8.
Artigo em Inglês | MEDLINE | ID: mdl-34300133

RESUMO

Home smoking bans can reduce tobacco smoke exposure, but little is known about the impact for Chinese American household pairs. In this study of 202 household pairs with low acculturation, 53.9% reported a home smoking ban, 31.7% had inconsistent reports, and 14.4% reported no ban. With decreasing home smoking ban enforcement, more nonsmokers had tobacco smoke exposure (66.1%-86.2%) as measured by the tobacco-specific nitrosamine biomarker urine NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol). Despite reported bans, about one-quarter of nonsmokers still reported tobacco smoke exposure at home (23.6%-30%) within the past 2 months and three-quarters reported outdoor exposure. In adjusted regression analyses of geometric mean NNAL ratios, nonsmokers in households with no ban had over two times higher levels than nonsmokers in households with a ban: adjusted log NNAL ratio = 2.70 (95% CI 1.21, 6.03). Higher smoker NNAL level and nonsmoker English fluency were also significantly associated with nonsmoker NNAL levels. Nonsmoker levels in households with an inconsistent ban were not significantly different compared to those with a ban. Although home smoking bans were generally associated with lower NNAL levels, tobacco smoke exposure in this immigrant population with low English proficiency was higher than that of the general population. From a health equity standpoint, there is a need for broader implementation and enforcement of comprehensive smoke-free policies.


Assuntos
Nitrosaminas , Política Antifumo , Poluição por Fumaça de Tabaco , Americanos Asiáticos , Humanos , não Fumantes
9.
Expert Rev Clin Pharmacol ; 14(9): 1075-1080, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34085580

RESUMO

Introduction: The known connections between the terms 'sartans' and 'melanoma' has grown recently in the clinical field, suggesting that the relationship between these concepts is very likely to be significant, rather than hypothetical or unfeasible. This is because: 1) the presence of angiotensin receptors in melanoma tissue, melanocytes and skin is a known fact; 2) the influence of sartans on the processes of melanogenesis has already been presented in recent published scientific papers; 3) key in vitro studies have shown that angiotensin receptor blockers (sartans) could potentiate carcinogenesis in the direction of melanoma and metastases; and 4) clinical examples of the occurrence of melanoma after starting therapy with sartans have become numerous and difficult to ignore.Areas covered: We report the first case of occult melanoma in an 87-year-old Bulgarian patient, this manifested in the form of a solitary metastasis on the left arm, which occurred after long-term therapy with telmisartan.Expert opinion: The fact that nitrosamines have a proven carcinogenic effect and are the cause of heterogeneous neoplasms shows that they have the potential to be possible melanoma triggers. The multifactorial pathogenesis of melanoma could certainly be clarified after the 'crystallization' of this currently serious issue.


Assuntos
Melanoma/induzido quimicamente , Neoplasias Cutâneas/induzido quimicamente , Telmisartan/efeitos adversos , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Humanos , Melanoma/diagnóstico , Melanoma/patologia , Nitrosaminas/administração & dosagem , Nitrosaminas/efeitos adversos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Telmisartan/administração & dosagem
10.
J Pharm Biomed Anal ; 203: 114205, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34130010

RESUMO

Upon emergence of nitrosamines in various drugs, e.g in valsartan, metformin and ranitidine, 4-methyl-1-nitrosopiperazine (MeNP) was found in rifampicin in August 2020. Rifampicin is used, amongst others, for post-exposure prophylaxis of leprosy. The occurrence of MeNP can be explained by the synthesis, because 1-amino-4-methylpiperazine is concomitantly used with the organic oxidizing reagent isoamyl nitrite. According to a method reported by the FDA, the quantification of MeNP in rifampicin capsules was performed by LC-MS/HRMS. A significant contamination with MeNP was found in all samples, ranging from 0.7 to 5.1 ppm and exceeding the acceptable intake limit proposed by the FDA up to 32-fold. However, the severity of a possible leprosy infection outweighs the risks, which are concomitant with the intake of a single dose of rifampicin for post-exposure prophylaxis. Nevertheless, the extent of contamination is alarming, and countermeasures are needed to minimize public health risks. The presence of nitrosamines in rifampicin illustrates the need for better strategies in impurity profiling and compendial testing once again.


Assuntos
Nitrosaminas , Rifampina , Cápsulas , Cromatografia Líquida , Espectrometria de Massas em Tandem
11.
Toxicol Sci ; 182(1): 10-28, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-33944952

RESUMO

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10-5, 5 × 10-3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 h. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal injection (IP) and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated time points and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 h post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the TK and genotoxicity of NNK.


Assuntos
Nitrosaminas , Espectrometria de Massas em Tandem , Animais , Carcinógenos , Cromatografia Líquida de Alta Pressão , Dano ao DNA , Exposição por Inalação , Injeções Intraperitoneais , Masculino , Nitrosaminas/toxicidade , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Toxicocinética
12.
J Plant Physiol ; 261: 153429, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33932764

RESUMO

Tobacco-specific nitrosamines (TSNAs) are carcinogens that accumulate in tobacco leaves during curing, storage, and processing, and their amounts in processed tobacco vary dependent on several intrinsic and extrinsic factors. Here, we assessed the hypothesis that there is a link between reactive oxygen species levels in leaves and TSNA formation during curing. First, we show that burley varieties KT 204LC and NCBH 129LC accumulate TSNAs to different levels but not as a result of a variety-specific abundance of TSNA precursors. Next, we measured the levels of reactive oxygen species, and we show that the variety that accumulates more TSNAs, NCBH 129LC, had significantly higher levels of hydrogen peroxide than KT 204LC. The NCBH 129LC also has more oxidatively damaged and glutathionylated proteins. Finally, we analyzed the antioxidant levels in KT 204LC and NCBH 129LC and their tolerance to oxidative stress. NCBH 129LC contained more of the essential antioxidant glutathione and was more tolerant to the oxidative stress-generating compound paraquat. Collectively, our data suggest that there is indeed a link between foliar oxidative stress parameters and the extent to which TSNAs accumulate in cured tobacco leaves.


Assuntos
Nitrosaminas/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Tabaco/metabolismo , Carcinógenos/metabolismo , Folhas de Planta/metabolismo
13.
Environ Sci Technol ; 55(12): 7841-7849, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34041906

RESUMO

Seven nitrosamines and three nitramines in particulate matter with an aerodynamic diameter of less than or equal to 2.5 µm (PM2.5) collected in 2018 in Seoul, South Korea, were quantified. Annual mean concentrations of the sum of nitrosamines and nitramines were 9.81 ± 18.51 and 1.12 ± 0.70 ng/m3, respectively, and nitrosodi-methylamine (NDMA) and dimethyl-nitramine (DMN) comprised the largest portion of nitrosamines and nitramines, respectively. Statistical analyses such as non-parametric correlation analysis, positive matrix factorization, analysis of covariance, and orthogonal partial least squared discrimination analysis were carried out to identify contribution of the atmospheric reactions in producing NDMA and DMN. In addition, kinetic calculation using reaction information obtained from the previous chamber studies was performed to estimate concentrations of NDMA and DMN that might be produced from the atmospheric reactions. It was concluded that (1) the atmospheric reactions contributed to the concentrations of NDMA more than they did for those of DMN, (2) the contribution of atmospheric reactions to the concentrations of NDMA and DMN was significant due to high NO2 concentrations in winter, and (3) primary emissions predominantly affected the ambient concentrations of NDMA and DMN in spring, summer, and autumn.


Assuntos
Poluentes Atmosféricos , Nitrosaminas , Poluentes Atmosféricos/análise , Compostos de Anilina , Monitoramento Ambiental , Nitrobenzenos , Nitrosaminas/análise , Material Particulado/análise , República da Coreia , Seul
14.
Chem Biol Interact ; 344: 109496, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33939976

RESUMO

An increased risk of developing lung cancer has been associated with exposure to cigarette smoke carcinogens and alteration in the gut microbiota. However, there is limited understanding about the impact of exposure to NNK and BaP, the two important components of cigarette smoke carcinogens, on gut microbiota in lung cancer. The present study characterized the influence of exposure to a mixture of NNK plus BaP on lung cancer, feces metabolite composition, and gut microbiota in the A/J mice. The A/J mice were administered NNK plus BaP, and the changes in gut microbiota and feces metabolic profiles were characterized using 16S rRNA gene sequencing and metabolomics, respectively. Results presented here illustrated that a mixture of NNK plus BaP exposure triggered lung carcinogenesis as shown by light microscopy and histopathological evaluation. 16S rRNA sequencing of gut microbiota indicated that exposure to NNK plus BaP could modified fecal bacterial composition. Elevated levels of Actinobacteria, Bifidobacterium, and Intestinimonas and reduced levels of Alistipes, Odoribacter, and Acetatifactor are associated with NNK plus BaP triggered lung cancer. In addition, metabolomics profile revealed the regulation of metabolism including purine metabolism, phenylalanine metabolism, primary bile acid biosynthesis, steroid hormone biosynthesis, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and others. In conclusion, the results provide some guidance for using gut microbes as biomarkers to assess the progression of lung cancer, and lead to interventional targets to control the development of the disease in the future.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Benzo(a)pireno/farmacologia , Carcinógenos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Nitrosaminas/farmacologia , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/patologia , Animais , Bactérias/metabolismo , Disbiose/etiologia , Disbiose/metabolismo , Fezes/química , Fezes/microbiologia , Feminino , Pulmão/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metabolômica , Camundongos Endogâmicos
15.
Toxicol Lett ; 346: 34-46, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33872747

RESUMO

Tobacco exposure is well known to induce genetic and epigenetic changes that contribute to the pathogenesis of lung cancer. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a significant tobacco-specific carcinogen, but the oncogenic mechanisms of NNK have not been thoroughly elucidated. In this study we found that DNA methyltransferase 1 (DNMT1) was overexpressed in malignantly transformed human bronchial epithelial Beas-2B cells induced by NNK (2B-NNK cells), by treatment with NNK (400 µg/mL) for 7 days. An Arraystar Human noncoding RNA Promoter Microarray was used to detect the DNA methylation status of the promoter region of long noncoding RNAs (lncRNAs). The result showed that 1010 differentially methylated fragments were present in the lncRNA promoter region. QRT-PCR revealed that the expression of lncRNA AC007255.8 was remarkably downregulated in 2B-NNK cells and lung cancer tissues. Furthermore, Methylation-specific PCR showed that the methylation of the lncRNA AC007255.8 promoter was increased in 2B-NNK cells and lung cancer tissues. The reduced expression of lncRNA AC007255.8 was significantly associated with hypermethylation of lncRNA AC007255.8 promoter region. LncRNA AC007255.8 overexpression could result in decreased cell proliferation and increased cell apoptosis in 2B-NNK cells. In conclusion, NNK induced lncRNA AC007255.8 promoter hypermethylation via upregulation of DNMT1 in Beas-2B cells, leading to downregulation of lncRNA AC007255.8, and ultimately the enhancement of cell proliferation and the inhibition of apoptosis. This research affords novel insights into the epigenetic mechanisms of lung cancer, and will stimulate further research into the involvement of aberrant DNA methylation of non-coding regions of the genome in the pathogenesis of lung cancer.


Assuntos
Butanonas/toxicidade , DNA/metabolismo , Nitrosaminas/toxicidade , RNA Longo não Codificante/metabolismo , Brônquios/citologia , Linhagem Celular , Transformação Celular Neoplásica , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Células Epiteliais , Regulação da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/metabolismo , Metilação , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Mucosa Respiratória/citologia , Regulação para Cima
16.
Molecules ; 26(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33923004

RESUMO

The wide range and complexity of cosmetic formulations currently available on the market poses a challenge from an analytical point of view. In addition, during cosmetics manufacture, impurities coming from raw materials or formed by reaction of different organic compounds present in the formulation may be present. Their identification is mandatory to assure product quality and consumer health. In this work, micro-matrix solid-phase dispersion (µMSPD) is proposed as a multi-target sample preparation strategy to analyze a wide number of unexpected families of compounds including polycyclic aromatic hydrocarbons (PAHs), pesticides, plasticizers, nitrosamines, alkylphenols (APs), and alkylphenol ethoxylates (APEOs). Analytical determination was performed by gas chromatography-mass spectrometry (GC-MS) for the determination of 51 target compounds in a single run, whereas liquid chromatography tandem mass spectrometry (LC-MS/MS) was employed for the analysis of six APs and APEOs. Both methodologies were successfully validated in terms of linearity, accuracy, and precision in leave-on and rinse-off cosmetics. Limits of detection (LODs) were calculated in the low ng g-1, showing their suitability to determine trace levels of impurities and banned compounds with different chemical natures, providing useful tools to cosmetic control laboratories and companies.


Assuntos
Cosméticos , Nitrosaminas/química , Hidrocarbonetos Policíclicos Aromáticos/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limite de Detecção , Nitrosaminas/isolamento & purificação , Praguicidas/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Extração em Fase Sólida
17.
Sci Total Environ ; 783: 146982, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-33866170

RESUMO

The occurrence of mutagenic and carcinogenic N-nitrosamines in drinking water is of great concern. In this study, dynamics and removal of nine N-nitrosamines in three drinking water treatment systems of a southern city of China are monitored during one year of sampling. The impacts of physicochemical treatment units on the removal and generation of N-nitrosamines were evaluated. The O3 and KMnO4 based pre-oxidation units have caused an increase in N-nitrosamines concentration, with O3 showing the substantial generation of N-nitrosamines. The carbon filter and ultrafiltration membrane units were found effective in removing N-nitrosamine precursors. These drinking water treatment systems have been useful in removing N-nitrosamine precursors; meanwhile, a slight decrease was found in already formed N-nitrosamines concentration. However, N-nitrosomorpholine (NMOR) and N-nitrosodiphenylamine (NDPhA) were found resistant toward all kinds of physicochemical treatments, and negligible changes in concentration were noted in all drinking water treatment systems. The distribution networks in the city provided an effective contact period to residual chlorine and precursors, which caused an increase in N-nitrosamines concentration. Overall, N-nitrosodimethylamine (NDMA) and N-nitroso-diethylamine (NDEA) have been found near the cancer risk threshold (10-6) in all of the drinking water treatment systems, while the remaining seven N-nitrosamines were found below the risk level.


Assuntos
Água Potável , Nitrosaminas , Poluentes Químicos da Água , Purificação da Água , China , Água Potável/análise , Nitrosaminas/análise , Diálise Renal , Poluentes Químicos da Água/análise
18.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916743

RESUMO

Active and passive smoking are serious public health concerns Assessment of tobacco smoke exposure using effective biomarkers is needed. In this study, we developed a simultaneous determination method of five tobacco-specific nitrosamines (TSNAs) in hair by online in-tube solid-phase microextraction (SPME) coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS). TSNAs were extracted and concentrated on Supel-Q PLOT capillary by in-tube SPME and separated and detected within 5 min by LC-MS/MS using Capcell Pak C18 MGIII column and positive ion mode multiple reaction monitoring systems. These operations were fully automated by an online program. The calibration curves of TSNAs showed good linearity in the range of 0.5-1000 pg mL-1 using their stable isotope-labeled internal standards. Moreover, the limits of detection (S/N = 3) of TSNAs were in the range of 0.02-1.14 pg mL-1, and intra-day and inter-day precisions were below 7.3% and 9.2% (n = 5), respectively. The developed method is highly sensitive and specific and can easily measure TSNA levels using 5 mg hair samples. This method was used to assess long-term exposure levels to tobacco smoke in smokers and non-smokers.


Assuntos
Cabelo/química , Nitrosaminas/análise , Microextração em Fase Sólida , Espectrometria de Massas em Tandem , Tabaco/química , Adulto , Idoso , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
19.
Lancet Respir Med ; 9(8): 840-850, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33857436

RESUMO

BACKGROUND: Electronic nicotine delivery systems (ENDSs) are used by some smokers to reduce cigarette consumption, but their effectiveness is uncertain. We aimed to examine the extent to which ENDSs or a non-nicotine cigarette substitute influence tobacco-related toxicant exposure and cigarette consumption in smokers interested in smoking reduction. METHODS: We did a four-arm, parallel-group, randomised controlled trial at two sites in the USA (Penn State University, Hershey, PA, and Virginia Commonwealth University, Richmond, VA). We enrolled adults aged 21-65 years who smoked more than nine cigarettes per day (for at least the past year), with exhaled CO of more than 9 parts per million at screening, who were not currently using an ENDS, and who were interested in reducing smoking but not quitting. Participants were randomised (site-specific with allocation concealment; 1:1:1:1) to receive either a cartomiser-based, pen-style ENDS (eGo-style) paired with 0, 8, or 36 mg/mL liquid nicotine (participants and researchers masked to concentration) or a non-ENDS cigarette-shaped plastic tube that delivered no nicotine or aerosol (cigarette substitute; unmasked) for 24 weeks. Conditions were chosen to reflect a range of nicotine delivery including none (cigarette substitute and 0 mg/mL ENDS), low (8 mg/mL), and cigarette-like (36 mg/mL), and all conditions were paired with smoking reduction instructions. The primary outcome was concentration of the tobacco-specific carcinogen metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; urinary total) collected at randomisation and at 4, 12, and 24 weeks. Multiple imputation with and without covariate adjustment was used in addition to sensitivity analyses. This trial is registered with ClinicalTrials.gov, NCT02342795. FINDINGS: Between July 22, 2015, and Nov 16, 2017, 684 individuals were screened and 520 (76%) were enrolled and randomised. 188 (36%) of 520 participants were lost to follow-up by week 24; attrition did not differ by study group (39 [30%] of 130 in the cigarette substitute group, 56 [43%] of 130 in the ENDS with 0 mg/mL nicotine group, 49 [38%] of 130 in the ENDS 8 mg/mL group, and 44 [34%] of 130 in the ENDS 36 mg/mL group). Urinary total NNAL at 24 weeks in the ENDS with 36 mg/mL nicotine group was 210·80 pg/mg creatinine (95% CI 163·03-274·42) compared with 346·09 pg/mg creatinine (265·00-455·32) in the cigarette substitute group (p=0·0061). No other significant differences between groups were observed for any time point for urinary total NNAL. Serious adverse event frequency was similar across groups (12 events in 12 participants [9%] in the ENDS with 36 mg/mL nicotine group, seven events in six participants [5%] in the 8 mg/mL group, 11 events in ten participants [8%] in the 0 mg/mL group, and 13 events in 13 participants [10%] in the cigarette substitute group), and all of these were deemed unrelated or unlikely to be related to study product use. There was one death between randomisation and 24 weeks (suicide; in the ENDS with 0 mg/mL nicotine group). INTERPRETATION: Use of an ENDS with cigarette-like nicotine delivery can reduce exposure to a major pulmonary carcinogen, NNAL, even with concurrent smoking. Future ENDS trials should involve products with well characterised nicotine delivery, including those with nicotine delivery approaching that of a cigarette. FUNDING: National Institutes of Health, US Food and Drug Administration.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Nicotina/administração & dosagem , Abandono do Hábito de Fumar/métodos , Adulto , Carcinógenos/análise , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrosaminas/urina
20.
J Pharm Sci ; 110(6): 2311-2328, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33705731

RESUMO

For decades, regulators have grappled with different approaches to address the issue of control of impurities. Safety-based limits, such as permissible daily exposure (PDE), acceptable intake (AI), threshold of toxicological concern (TTC) and less than lifetime limits (LTL) have all been used. For many years these safety-based limits have been recognized as virtually safe doses (VSDs). Recently, however, many regulatory agencies are seeking to impose limits for N-nitrosamine impurities, which are significantly below the VSD. This commentary will discuss the evolution of safety-based limits for impurities, provide an overview of the valsartan N-nitrosamine contamination issue and review the toxicology of N-nitrosamines. The outcome of a lessons-learned exercise on sartan medications undertaken by the European Medicines Agency (EMA) will also be discussed. The review will also highlight the many analytical challenges inherent with controlling impurities to ppb-based limits. The use of highly sensitive, low ppb limits, methods may lead to future issues of batch rejection, based on false positives. Regulators initially viewed the N-nitrosamine risk as being insufficient to prompt immediate product discontinuation and patients were specifically advised to continue using their affected medication. Patients were also informed that exposure to N-nitrosamines is extremely common via food and drinking water.


Assuntos
Nitrosaminas , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Contaminação de Medicamentos , Humanos , Nitrosaminas/toxicidade , Medição de Risco , Valsartana
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