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BACKGROUND: In the regeneration of waste oil, a strategical technological process for the European Union circular economy action plan, exhausted oils are regenerated to produce high performing oil bases. Aim of this work was to assess the exposure to benzene in plant workers during ordinary activities. METHODS: 59 workers, potentially exposed to benzene, and 9 administrative workers from an Italian plant were monitored for the whole work shift with personal air samplers; urinary benzene (BEN-U) and S-phenyl mercapturic acid (SPMA) were measured by mass spectrometry methods in end-shift urine samples. Different job tasks were identified among workers. RESULTS: Median (minimum-maximum) airborne exposures to benzene were <0.9 (<0.9-6.3) and <0.9 (<0.9-0.9) µg/m3, BEN-U and SPMA levels were 0.094 (<0.015-3.095) µg/L and 0.15 (<0.10-9.67) µg/g crt and 0.086 (0.034-0.712) µg/L and <0.10 (<0.10-3.19) µg/g creatinine in workers and administrative workers, respectively. No differences were found among job tasks and between workers and administrative workers, while higher levels were found in smokers than in non-smokers. For all job tasks, the exposure to benzene was always below occupational limit values. CONCLUSIONS: This study has investigated for the first time the exposure to benzene of workers employed in the re-refining of exhaust oil. The results showed that normal production activities in regenerating used oils do not pose a risk of exposure to benzene in workers.
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Contaminantes Ocupacionales del Aire , Benceno , Monitoreo Biológico , Exposición Profesional , Humanos , Benceno/análisis , Exposición Profesional/análisis , Adulto , Masculino , Persona de Mediana Edad , Contaminantes Ocupacionales del Aire/análisis , Italia , Femenino , Industria del Petróleo y Gas , Acetilcisteína/orina , Acetilcisteína/análogos & derivadosRESUMEN
The concentration in urine of N-acetyl-hydroxy-propyl-cisteine (3HPMA), an acrolein metabolite, has been employed as a marker of the risk of illness of smokers and the relative concentration of creatinine has been evaluated to verify the effect of moving from the practice of burning tobacco to nicotine vaping. From the results concerning the urine samples of 38 subjects, collected from 2021 to 2023 and analyzed by LC-MS/MS, corresponding to 5 active smokers, 13 previously heavy smokers who replaced traditional tobacco by vaping, and 20 non-smokers, a dramatic reduction was found in 3HPMA/creatinine in urine. 3HPMA varied from values of 2150-3100 µg gcreatinine-1 to levels of 225-625 µg gcreatinine-1 found for non-smokers, with the time decay described by the equation y = 0.3661x2 - 94.359x + 6246.4 (R2: 0.757), providing a time of approximately 10 years for tobacco memory after the cessation of the consumption of burned tobacco.
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Espectrometría de Masas en Tándem , Humanos , Nicotiana/química , Creatinina/orina , Cromatografía Liquida/métodos , Masculino , Adulto , Fumar/orina , Biomarcadores/orina , Fumar Tabaco/orina , Femenino , Vapeo , Fumadores , Acetilcisteína/análogos & derivadosRESUMEN
Objectives: To assess leukemia risk in occupational populations exposed to low levels of benzene. Methods: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model. Results: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6. Conclusion: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.
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Benceno , Leucemia , Exposición Profesional , Ácido Sórbico , Benceno/toxicidad , Humanos , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Medición de Riesgo , Leucemia/inducido químicamente , Leucemia/epidemiología , China/epidemiología , Masculino , Adulto , Ácido Sórbico/análogos & derivados , Ácido Sórbico/análisis , Persona de Mediana Edad , Acetilcisteína/orina , Acetilcisteína/análogos & derivados , Femenino , Estudios de Cohortes , IncidenciaRESUMEN
The urinary mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) are short-term biomarkers of exposure from acrylamide and its metabolite glycidamide, respectively. The medium-term exposure to acrylamide and glycidamide is monitored by the adducts N-(2-carbamoylethyl)-Val (AA-Val) and N-(2-carbamoyl-2-hydroxyethyl)-Val (GA-Val) in hemoglobin (Hb), respectively. Three questions were addressed by application of these biomarkers in two diet studies including 36 omnivores, 36 vegans and 16 strict raw food eaters (abstaining from any warmed or heated food for at least four months): first, what is the internal acrylamide exposure following a vegan or a raw food diet in comparison to that in omnivores? Second, did the exposure change between 2017 and 2021? And third, what is the stability over time of AAMA/GAMA excretion compared to that of AA-Val/GA-Val levels in Hb between both time points? Median urinary AAMA excretion per day in non-smoking omnivores, vegans and raw food eaters were 62.4, 85.4 and 15.4 µg/day, respectively; the corresponding median AA-Val levels were 27.7, 39.7 and 13.3 pmol/g Hb, respectively. Median levels in strict raw food eaters were about 25% (AAMA excretion) and 48% (AA-Val) of those in omnivores. In comparison to 2017, AAMA and GAMA excretion levels were hardly altered in 2021, however, levels of AA-Val and GA-Val in 2021 slightly increased. There was a weak correlation between AAMA excretion levels determined four years apart (rS = 0.30), and a moderate correlation between levels of AA-Val (rS = 0.55) in this timeframe. Our data in strict raw food eaters confirm a significant endogenous formation to acrylamide in a size range, which is-based on the levels of AA-Val-distinctly higher than reported previously based on levels of urinary AAMA excretion. The relatively lower AAMA excretion in raw food eaters likely represents a lower extent of glutathione conjugation due to missing hepatic first-pass metabolism in case of endogenous formation of acrylamide, which leads to a higher systemic exposure.
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Acetilcisteína , Acrilamida , Biomarcadores , Contaminación de Alimentos , Hemoglobinas , Calor , Acrilamida/toxicidad , Acrilamida/orina , Humanos , Biomarcadores/orina , Hemoglobinas/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/orina , Masculino , Adulto , Femenino , Persona de Mediana Edad , Veganos , Dieta , Compuestos Epoxi/orina , Compuestos Epoxi/toxicidad , Exposición Dietética , Adulto JovenRESUMEN
N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 µmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 µmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 µg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 µg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.
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Acetilcisteína/análogos & derivados , Lisina/análogos & derivados , Dependencia de Morfina , Síndrome de Abstinencia a Sustancias , Ratas , Masculino , Animales , Fentanilo/farmacología , Ratas Sprague-Dawley , Naloxona/farmacología , Antagonistas de Narcóticos/farmacologíaRESUMEN
Humans are chronically exposed to furan, a potent liver toxicant and carcinogen that occurs in a variety of heat-processed foods. Assessment of human exposure based on the furan content in foods is, however, subject to some uncertainty due to the high volatility of furan. Biomarker monitoring is thus considered an alternative or complementary approach to furan exposure assessment. Previous work suggested that urinary furan metabolites derived from the reaction of cis-2-butene-1,4-dial (BDA), the reactive intermediate of furan, with glutathione (GSH) or amino acids may serve as potential biomarkers of furan exposure. However, some metabolites were also reported to occur in urine of untreated animals, indicating either background contamination via animal feed or endogenous sources, which may limit their suitability as biomarkers of exposure. The overall aim of the present study was to accurately establish the correlation between external dose and concentration of furan metabolites in urine over time and to discriminate against endogenous formation and furan intake via feed. To this end, the furan metabolites GSH-BDA (N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine), NAcLys-BDA (R-2-(acetylamino)-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid), NAcCys-BDA-NAcLys (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine) and NAcCys-BDA-NAcLys sulfoxide (N-acetyl-S-[1-[5-(acetylamino)-5-carboxypentyl]-1H-pyrrol-3-yl]-L-cysteine sulfoxide) were simultaneously analyzed by stable isotope dilution ESI-LC-MS/MS as unlabeled and [13C4]-furan dependent metabolites following oral administration of a single oral dose of isotopically labelled [13C4]-furan (0.1, 1, 10, 100 and 1000 µg/kg bw) to male and female F344/DuCrl rats. Although a linear correlation between urinary excretion of [13C4]-furan-dependent metabolites was observed, analysis of unlabeled NAcLys-BDA, NAcCys-BDA-NAcLys and NAcCys-BDA-NAcLys sulfoxide revealed substantial, fairly constant urinary background levels throughout the course of the study. Analysis of furan in animal feed excluded feed as a source for these background levels. GSH-BDA was identified as the only furan metabolite without background occurrence, suggesting that it may present a specific biomarker to monitor external furan exposure. Studies in humans are now needed to establish if analysis of urinary GSH-BDA may provide reliable exposure estimates.
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Biomarcadores , Furanos , Glutatión , Ratas Endogámicas F344 , Furanos/orina , Animales , Biomarcadores/orina , Masculino , Glutatión/metabolismo , Glutatión/orina , Marcaje Isotópico , Ratas , Espectrometría de Masas en Tándem/métodos , Acetilcisteína/orina , Acetilcisteína/análogos & derivadosRESUMEN
The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson's disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.
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Acetilcisteína/análogos & derivados , Enfermedad de Parkinson , Sinucleinopatías , Humanos , Animales , Ratas , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , alfa-Sinucleína/genética , Chaperón BiP del Retículo Endoplásmico , Administración Intranasal , NeuroprotecciónRESUMEN
Benzene is a broadly used industrial chemicals which causes various hematologic abnormalities in human. Altered DNA methylation has been proposed as epigenetic biomarkers in health risk evaluation of benzene exposure, yet the role of methylation at specific CpG sites in predicting hematological effects remains unclear. In this study, we recruited 120 low-level benzene-exposed and 101 control male workers from a petrochemical factory in Maoming City, Guangdong Province, China. Urinary S-phenylmercapturic acid (SPMA) in benzene-exposed workers was 3.40-fold higher than that in control workers (P < 0.001). Benzene-induced hematotoxicity was characterized by reduced white blood cells counts and nuclear division index (NDI), along with an increased DNA damage and urinary 8-hydroxy-2'-deoxyguanosine (all P < 0.05). Methylation levels of TRIM36, MGMT and RASSF1a genes in peripheral blood lymphocytes (PBLCs) were quantified by pyrosequencing. CpG site 6 of TRIM36, CpG site 2, 4, 6 of RASSF1a and CpG site 1, 3 of MGMT methylation were recognized as hot CpG sites due to a strong correlation with both internal exposure and hematological effects. Notably, integrating hot CpG sites methylation of multiple genes reveal a higher efficiency in prediction of integrative damage compared to individual genes at hot CpG sites. The negative dose-response relationship between the combined methylation of hot CpG sites in three genes and integrative damage enabled the classification of benzene-exposed individuals into high-risk or low-risk groups using the median cut-off value of the integrative index. Subsequently, a prediction model for integrative damage in benzene-exposed populations was built based on the methylation status of the identified hot CpG sites in the three genes. Taken together, these findings provide a novel insight into application prospect of specific CpG site methylation as epi-biomarkers for health risk assessment of environmental pollutants.
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Acetilcisteína/análogos & derivados , Benceno , Islas de CpG , Metilación de ADN , Exposición Profesional , Humanos , Metilación de ADN/efectos de los fármacos , Masculino , Exposición Profesional/efectos adversos , Benceno/toxicidad , Adulto , China , Daño del ADN , Persona de Mediana Edad , Biomarcadores/orina , Acetilcisteína/orina , Proteínas Supresoras de Tumor/genética , Enzimas Reparadoras del ADN/genéticaRESUMEN
This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24â¯hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.
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Acetilcisteína/análogos & derivados , Aminobutiratos , Insuficiencia Cardíaca , Hipertensión , Prehipertensión , Ratas , Animales , Masculino , Sistema Renina-Angiotensina , Renina , Aldosterona , Tetrazoles/farmacología , Tetrazoles/uso terapéutico , Ratas Wistar , Valsartán/farmacología , Hipertensión/tratamiento farmacológico , Compuestos de Bifenilo/farmacología , Hipertrofia Ventricular Izquierda , Combinación de Medicamentos , Fibrosis , Volumen SistólicoRESUMEN
This study evaluated the use of the S-nitrosothiols, S-nitroso-N-acetylcysteine (NAC-SNO) and S-nitroso-N-acetylcysteine ethyl ester (NACET-SNO), at different concentrations (25-300 mg nitrite equivalent - NEq/kg) as sodium nitrite substitutes in restructured cooked hams. The pH value and instrumental cured color were not affected by the type or amount of curing agent used. Products with 25 and 50 mg/kg ingoing nitrite had lower thiobarbituric acid-reactive substance values than those with equimolar amounts of S-nitrosothiols. Products with >150 mg NEq/kg of S-nitrosothiols had residual nitrite similar to 50 mg/kg nitrite, and this resulted in the same volatile compound profile as nitrite added in equimolar amounts. A 300 mg NEq/kg of S-nitrosothiols was required to obtain a similar and minimally stable cured pink color perception as sliced samples with 50-150 mg/kg added nitrite. The results obtained reinforce the great potential of both alternative curing agents in the complete replacement of nitrite by equimolar amounts in restructured cooked products; however, differences in cured color stability should be considered.
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Acetilcisteína/análogos & derivados , Productos de la Carne , S-Nitrosotioles , Productos de la Carne/análisis , Nitrito de Sodio , S-Nitrosotioles/química , LípidosRESUMEN
BACKGROUND: Environmental exposure to benzene and toluene is a suspected risk factor for metabolic disorders among the general adult population. However, the effects of benzene and toluene on blood lipid profiles remain unclear. In this study, we investigated the association between urinary blood lipid profiles and metabolites of benzene and toluene in Korean adults. METHODS: We analyzed the data of 3,423 adults from the Korean National Environmental Health Survey Cycle 3 (2015-2017). We used urinary trans,trans-muconic acid (ttMA) as a biomarker of benzene exposure, and urinary benzylmercapturic acid (BMA) as an indicator of toluene exposure. Multivariate logistic regression analyses were performed to explore the association between blood lipid profiles and urinary metabolites of benzene and toluene. Additionally, we examined the linear relationship and urinary metabolites of benzene and toluene between lipoprotein ratios using multivariate regression analyses. RESULTS: After adjusting for covariates, the fourth quartile (Q4) of ttMA [odds ratio (OR) (95% confidence interval, CI = 1.599 (1.231, 2.077)] and Q3 of BMA [OR (95% CI) = 1.579 (1.129, 2.208)] were associated with an increased risk of hypertriglyceridemia. However, the Q4 of urinary ttMA [OR (95% CI) = 0.654 (0.446, 0.961)] and Q3 of urinary BMA [OR (95% CI) = 0.619 (0.430, 0.889)] decreased the risk of a high level of low-density lipoprotein cholesterol (LDL-C). Higher urinary ttMA levels were positively associated with the ratio of triglycerides to high-density lipoproteins [Q4 compared to Q1: ß = 0.11, 95% CI: (0.02, 0.20)]. Higher urinary metabolite levels were negatively associated with the ratio of low-density lipoprotein to high-density lipoprotein [Q4 of ttMA compared to reference: ß = -0.06, 95% CI: (-0.11, -0.01); Q4 of BMA compared to reference: ß = -0.13, 95% CI: (-0.19, -0.08)]. CONCLUSION: Benzene and toluene metabolites were significantly and positively associated with hypertriglyceridemia. However, urinary ttMA and BMA levels were negatively associated with high LDL-C levels. These findings suggest that environmental exposure to benzene and toluene disrupts lipid metabolism in humans.
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Benceno , Hipertrigliceridemia , Acetilcisteína/análogos & derivados , Adulto , Benceno/toxicidad , Biomarcadores/orina , LDL-Colesterol , Salud Ambiental , Humanos , Lipoproteínas HDL , República de Corea/epidemiología , Tolueno/análisis , TriglicéridosRESUMEN
There is an urgent need for development of drugs that are able to reverse the adverse effects of opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes the effects of bolus injections of N-acetyl-L-cysteine (L-NAC, 500 µmol/kg, IV) on ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) and analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion of fentanyl (1 µg/kg/min, IV). Fentanyl infusion elicited pronounced disturbances in (1) ventilatory parameters (e.g., decreases in frequency of breathing, tidal volume and minute ventilation), (2) ABG chemistry (decreases in pH, pO2, sO2 with increases in pCO2), (3) A-a gradient (increases that were consistent with reduced alveolar gas exchange), and (4) sedation and analgesia. Bolus injections of L-NAC given 60 and 90 min after start of fentanyl infusion elicited rapid and sustained reversal of the deleterious effects of fentanyl infusion on ventilatory parameters and ABG chemistry, whereas they did not affect the sedative or analgesic effects of fentanyl. Systemic L-NAC is approved for human use, and thus our findings raise the possibility that this biologically active thiol may be an effective compound to combat opioid-induced respiratory depression in human subjects.
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Analgésicos Opioides , Fentanilo , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacología , Analgésicos Opioides/efectos adversos , Animales , Fentanilo/efectos adversos , Humanos , Lisina/análogos & derivados , Masculino , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-DawleyRESUMEN
Oxidative stress is involved in the deterioration of bone quality and mechanical strength in both diabetic and aging adults. Therefore, we studied the ability of the antioxidant compound, S-allylmercapto-N-acetylcysteine (ASSNAC) to protect bone marrow stromal cells (BMSCs) from advanced glycation end-products (AGEs) cytotoxicity and improve bone microarchitecture of adult healthy and obese/diabetic (db/db) female mice. ASSNAC effect on AGEs-treated cultured rat BMSCs was evaluated by Neutral Red and XTT cell survival and reactive oxygen species (ROS) level assays. Its effect on healthy (C57BL/6) and obese/diabetic (C57BLKS/J Leprdb+/+; db/db) female mice femur parameters, such as (1) number of adherent BMSCs, (2) percentage of CD73+/CD45- cells in bone marrow (BM), (3) glutathione level in BM cells, and (4) femur microarchitecture parameters by microcomputed tomography, was studied. ASSNAC treatment protected BMSCs by significantly decreasing AGEs-induced ROS production and increasing their cellular resistance to the cytotoxic effect of AGEs. ASSNAC treatment of healthy female mice (50 mg/kg/day; i.p.; age 12-20 weeks) significantly increased the number of BMSCs (+60%), CD73+/CD45- cells (+134%), and glutathione level (+110%) in the femur bone marrow. Furthermore, it increased the femur length (+3%), cortical diameter (+3%), and cortical areal moment of inertia (Ct.MOI; +10%) a surrogate for biomechanical strength. In db/db mice that demonstrated a compromised trabecular bone and growth plate microarchitecture, ASSNAC treatment restored the trabecular number (Tb.N, +29%), bone volume fraction (Tb.BV/TV, +130%), and growth plate primary spongiosa volumetric bone mineral density (PS-vBMD, +7%) and thickness (PS-Th, +18%). In conclusion, this study demonstrates that ASSNAC protects bone marrow cells from oxidative stress and may improve bone microarchitecture in adult healthy and diabetic female mice.
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Antioxidantes , Diabetes Mellitus Experimental , Acetilcisteína/análogos & derivados , Compuestos Alílicos , Animales , Antioxidantes/farmacología , Densidad Ósea , Diabetes Mellitus Experimental/tratamiento farmacológico , Femenino , Fémur , Glutatión , Ratones , Ratones Endogámicos C57BL , Rojo Neutro/farmacología , Obesidad , Ratas , Especies Reactivas de Oxígeno , Microtomografía por Rayos X/métodosAsunto(s)
alfa-Clorhidrina , Acetilcisteína/análogos & derivados , Compuestos Epoxi , Ésteres , Glicerol , Humanos , PropanolesRESUMEN
OBJECTIVES: Oxidative stress produces neurotoxicity and has been associated with disorders of the nervous system. We observed the neuroprotective effects of N-acetylcysteine amide (NACA) against kainic acid (KA)-induced oxidative stress in aging organotypic hippocampal slice cultures (OHSCs). MATERIALS AND METHODS: We used 6-8-day-old rats for long-term cultured OHSCs (9 w). Cultured slices were injured by KA (5 µM) treatment for 18 h. OHSCs were treated with NACA dose-dependently in a medium for 24 h after KA treatment. The effects of NACA treatment were observed with propidium iodide (PI) uptake, western blotting, and optical imaging. RESULTS: Neuronal cell death, as assessed by PI uptake, was dose-dependently reduced by NACA treatment. Western blot analysis revealed that the 1 mM NACA-treated group exhibited significantly increased expression of superoxide dismutase compared with the KA-only group. In addition, NACA activated nuclear factor erythroid 2-related factor 2-dependent anti-inflammation signaling, which is well known to affect reactive oxygen species. Optical imaging revealed that NACA treatment reduced the latency and increased amplitude of the optical signals, which shows that synaptic activity and strength are associated with neuronal survival. CONCLUSION: Therefore, the neurons that survived due to the neuroprotective effects of NACA also showed enhanced functional activity in long-term cultured OHSCs using electrophysiological and biochemical assays.
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Fármacos Neuroprotectores , Acetilcisteína/análogos & derivados , Envejecimiento , Animales , Hipocampo/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , RatasRESUMEN
The widespread presence of 3-monochloropropane-1,2-diol (3-MCPD) and glycidol in refined edible oils have raised food industrial and public health concerns, but their specific biomarkers of exposure and urinary metabolic pathways indicating nephrotoxicity remain largely unknown. Here, we unraveled the in vivo biotransformation of these two contaminants and revealed how they affect metabolic pathways in rats. Urine metabolomes in rats administered with glycidol or 3-MCPD were investigated using ultra-high performance liquid chromatography combined with a quadrupole-orbitrap high-resolution mass spectrometry. Compared to the currently acknowledged metabolite which is only 2,3-dihydroxypropyl mercapturic acid, we identified 8 and 4 new specific exposure biomarkers of glycidol and 3-MCPD, respectively, via mapping the glyceryl polymerization and glutathione and sulfur conjugation. The changes of metabolites in the surrounding metabolic network were investigated to further gain insight into their metabolic fates. Exposure to glycidol up-regulated citrate, isocitrate, ketoglutarate, malate, and pyruvate in the tricarboxylic acid cycle and glycolysis pathways, while 3-MCPD intake down-regulated these signal molecules in both pathways. Nonetheless, L-cysteine, proline, and arginine were significantly decreased by the effect of either glycidol or 3-MCPD. Our findings first map the urinary metabolomics of both contaminants from edible oils and advance the omics-level recognition for their observational health hazards.
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alfa-Clorhidrina , Acetilcisteína/análogos & derivados , Animales , Compuestos Epoxi , Aceites de Plantas/química , Propanoles , Ratas , Toxicocinética , alfa-Clorhidrina/análisis , alfa-Clorhidrina/toxicidadRESUMEN
BACKGROUND: Most patients with epithelial ovarian cancer (EOC) relapse despite primary debulking surgery and chemotherapy (CT). Autologous dendritic cell immunotherapy (DCVAC) can present tumor antigens to elicit a durable immune response. We hypothesized that adding parallel or sequential DCVAC to CT stimulates antitumor immunity and improves clinical outcomes in patients with EOC. Based on the interim results of sequential DCVAC/OvCa administration and to accommodate the increased interest in maintenance treatment in EOC, the trial was amended by adding Part 2. METHODS: Patients with International Federation of Gynecology and Obstetrics stage III EOC (serous, endometrioid, or mucinous), who underwent cytoreductive surgery up to 3 weeks prior to randomization and were scheduled for first-line platinum-based CT were eligible. Patients, stratified by tumor residuum (0 or <1 cm), were randomized (1:1:1) to DCVAC/OvCa parallel to CT (Group A), DCVAC/OvCa sequential to CT (Group B), or CT alone (Group C) in Part 1, and to Groups B and C in Part 2. Autologous dendritic cells for DCVAC were differentiated from patients' CD14+ monocytes, pulsed with two allogenic OvCa cell lines (SK-OV-3, OV-90), and matured in the presence of polyinosinic:polycytidylic acid. We report the safety outcomes (safety analysis set, Parts 1 and 2 combined) along with the primary (progression-free survival (PFS)) and secondary (overall survival (OS)) efficacy endpoints. Efficacy endpoints were assessed in the modified intention-to-treat (mITT) analysis set in Part 1. RESULTS: Between November 2013 and March 2016, 99 patients were randomized. The mITT (Part 1) comprised 31, 29, and 30 patients in Groups A, B, and C, respectively. Baseline characteristics and DCVAC/OvCa exposure were comparable across the treatment arms. DCVAC/OvCa showed a good safety profile with treatment-emergent adverse events related to DCVAC/OvCa in 2 of 34 patients (5.9%) in Group A and 2 of 53 patients (3.8%) in Group B. Median PFS was 20.3, not reached, and 21.4 months in Groups A, B, and C, respectively. The HR (95% CI) for Group A versus Group C was 0.98 (0.48 to 2.00; p=0.9483) and the HR for Group B versus Group C was 0.39 (0.16 to 0.96; p=0.0336). This was accompanied by a non-significant trend of improved OS in Groups A and B. Median OS was not reached in any group after a median follow-up of 66 months (34% of events). CONCLUSIONS: DCVAC/OvCa and leukapheresis was not associated with significant safety concerns in this trial. DCVAC/OvCa sequential to CT was associated with a statistically significant improvement in PFS in patients undergoing first-line treatment of EOC. TRIAL REGISTRATION NUMBER: NCT02107937, EudraCT2010-021462-30.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Células Dendríticas/inmunología , Inmunoterapia/métodos , Paclitaxel/uso terapéutico , Acetilcisteína/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/farmacología , Femenino , Humanos , Ratones , Persona de Mediana Edad , Paclitaxel/farmacología , Adulto JovenRESUMEN
Metabolomics has been used to explore the molecular mechanism and screen biomarkers. However, the critical metabolic signatures associated with benzene-induced hematotoxicity remain elusive. Here, we performed a plasma metabolomics study in 86 benzene-exposed workers and 76 healthy controls, followed by a validation analysis in mice, to investigate the dynamical change of the metabolic profile. We found that 8 fatty acids were significantly altered in both benzene-exposed worker and benzene-exposed animal models. These metabolites were significantly associated with S-phenylmercapturic acid and WBC, and they mediated the benzene-induced WBC decline. Furthermore, in vivo results confirm that fatty acid levels were dynamically altered, characterized by a decrease at 15 days and then sharp increases at 30 and 45 days. Following these identified fatty acids, the potential metabolic pathways were investigated. Fatty acids, as precursors for fatty acid oxidation, may disturb the balance of fatty acid biosynthesis and degradation. Our results reveal that fatty acid metabolism was strongly reprogrammed after benzene exposure. This abnormal change of fatty acids might be the key metabolic signature associated with benzene-induced hematotoxicity.
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Acetilcisteína/análogos & derivados , Benceno/toxicidad , Ácidos Grasos , Leucemia , Metabolismo de los Lípidos/efectos de los fármacos , Metabolómica/métodos , Acetilcisteína/análisis , Acetilcisteína/metabolismo , Animales , Enfermedades Óseas Metabólicas/inducido químicamente , Enfermedades Óseas Metabólicas/metabolismo , Ácidos Grasos/biosíntesis , Ácidos Grasos/metabolismo , Humanos , Leucemia/inducido químicamente , Leucemia/metabolismo , Leucocitos/efectos de los fármacos , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Exposición Profesional/efectos adversos , Oxidación-Reducción/efectos de los fármacosRESUMEN
In this study, we investigated the association of 2,3-dihydroxypropyl mercapturic acid (DHPMA), a urinary biomarker of environmental and dietary exposure to 3-monochloropropane-1,2-diol and glycidol, with prevalent MetS in a Chinese middle-aged and elderly population. The urinary DHPMA concentrations were determined by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analysis and further calibrated by the urinary creatinine content. MetS cases were defined by the Adult Treatment Panel III criteria for Asian-Americans of National Cholesterol Education Program (NCEP/ATPIII). Multivariate-adjusted modified Poisson regression models were used to analyze the associations between the urinary DHPMA concentrations and MetS prevalence. Of the 1613 participants aged 45-75 years, we documented 552 (34.2%) MetS cases. After adjustment for potential risk factors, the relative risks (95% confidence intervals) of MetS prevalence across the increasing quartiles of DHPMA concentrations were 1.14 (0.93-1.39), 1.29 (1.06-1.56), and 1.50 (1.25-1.80), respectively, compared with the lowest quartile. We also observed strong positive association between urinary DHPMA concentrations and hypertriglyceridemia prevalence (P < 0.001 for trend). These positive associations remained unchanged in the subgroups stratified by general demographic, dietary and behavioral risk factors. These results suggested that urinary DHPMA was associated with higher prevalence of MetS among Chinese elderly people.
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Síndrome Metabólico , alfa-Clorhidrina , Acetilcisteína/análogos & derivados , Adulto , Anciano , Compuestos Epoxi , Humanos , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Prevalencia , Propanoles , Factores de Riesgo , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: Our prospective, open-label, single-arm phase II study investigated the safety and efficacy of DCVAC/LuCa (dendritic cell vaccines for lung cancer) combined with standard carboplatin/pemetrexed in advanced non-squamous (nsq) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients had stage IV nsq NSCLC without oncogenic drivers and had not received prior systemic cancer therapy. Treatment consisted of carboplatin/pemetrexed for up to 6 cycles followed by 21 cycles of pemetrexed maintenance or until progression or intolerance. Non-progression patients after two cycles of chemotherapy started to receive DCVAC/LuCa subcutaneously (s.c.) on day 15 of cycle 3, and thereafter q3w (day 15 of chemotherapy cycles) for up to 15 doses. Dosing of DCVAC/LuCa s.c. varied among patients depending on the baseline number of leucocytes but remained constant for each single patient. Safety was assessed by adverse events (AEs), treatment-related adverse events (TRAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). Efficacy was measured by overall survival (OS), progression-free survival (PFS), time to progression (TTP), and objective response rate (ORR). RESULTS: Sixty-one patients were enrolled. In the safety population (n = 60), eight patients (13.33%) had grade 3 or greater TRAEs, and six patients (10.0%) showed SAEs which were not related to leukapheresis or DC vaccination. Six grade 1 AEs were considered to be related to leukapheresis. No AESIs or DCVAC/LuCa-induced AEs were observed. The 2-year survival rate in the modified intention-to-treat population (n = 44) was 52.57%. Median OS was not reached. Median PFS was 8.0 months, median TTP was 10.2 months, and the ORR was 31.82%. CONCLUSION: In treatment-naïve stage IV nsq NSCLC patients without oncogenic drivers, the combination of carboplatin/pemetrexed and DCVAC/LuCa was well tolerated and showed promising efficacy. Therefore, a study to prove our immunotherapeutic concept in a randomized phase III trial is planned.