Purpose
Dissipation of pharmaceutical compounds entered into the natural environment is an important process minimizing the adverse effects on the living organisms. The aim of the present study is to ...determine the effects of varying initial concentrations on the stability and degradation of three different pharmaceuticals in a chosen soil.
Methods
The behavior of three widely used pharmaceuticals (carbamazepine, metoprolol, and sertraline) in soil (Haplic Chernozem on loess) has been investigated using a tandem mass spectrometry (LC–MS/MS)-based analytical strategy.
Results
The stability of pharmaceuticals follows
carbamazepine
>
sertraline
>
metoprolol
except for the higher tested concentration, where sertraline exhibits an exceptionally faster dissipation. While the intermediate concentrations (~ 100 ng g
−1
) were generally shown to be the most stable, the fastest dissipation was observed with the highest tested concentration (~ 1000 ng g
−1
) for carbamazepine and sertraline, and for the lowest concentration (~ 10 ng g
−1
) for metoprolol. The fastest dissipation trends observed for carbamazepine and sertraline were likely explained by the higher nutritional values offered by the parent compounds to trigger the microbial growth, whereas the lowest load likely explains the fastest dissipation of metoprolol. The dissipation pattern was more or less similar irrespective of the mode of application (i.e., individually or as a mixture of all) of pharmaceuticals. Three carbamazepine metabolites are also identified, in which the concentrations of carbamazepine-10,11-epoxide mostly increased upon time, whereas the other two (rac trans-10,11-dihydro-10,11-dihydroxy carbamazepine, and 10,11-dihydro carbamazepine) did not increase much during the experiment timescale.
Conclusions
The present study clearly showed the influence of initial concentrations on the dissipations; however, it did not show any precise (i.e., either increasing or decreasing) trends. More experimental efforts involving much broader sample sizes are, therefore, necessary for a better understanding of this transformation mechanism and a possible description of the nonlinear trend.
Dicarbonyl stress plays an important role in the pathogenesis of microvascular complications that precede the formation of advanced glycation end products, and contributes to the development of renal ...dysfunction. In renal cells, toxic metabolites like methylglyoxal lead to mitochondrial dysfunction and protein structure modifications.In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in the model of metabolic syndrome.
Dicarbonyl stress was induced by intragastric administration of methylglyoxal (0.5 mg/kg bw for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats with insulin resistance and fatty liver.
Methylglyoxal administration aggravated glucose intolerance (AUC
< 0.05), and increased plasma glucose (
< 0.01) and insulin (
< 0.05). Compared to controls, methylglyoxal-treated rats exhibited microalbuminuria (
< 0.01). Targeted proteomic analysis revealed increases in urinary secretion of pro-inflammatory parameters (MCP-1, IL-6, IL-8), specific collagen IV fragments and extracellular matrix proteins. Urine metabolomic biomarkers in methylglyoxal-treated rats were mainly associated with impairment of membrane phospholipids (8-isoprostane, 4-hydroxynonenal).Decreased levels of glutathione (
< 0.01) together with diminished activity of glutathione-dependent antioxidant enzymes contributed to oxidative and dicarbonyl stress. Methylglyoxal administration elevated glyoxalase 1 expression (
< 0.05), involved in methylglyoxal degradation. Based on comparative transcriptomic analysis of the kidney cortex, 96 genes were identified as differentially expressed (FDR < 0.05). Network analysis revealed an over-representation of genes related to oxidative stress and pro-inflammatory signalling pathways as well as an inhibition of angiogenesis suggesting its contribution to renal fibrosis.
Our results support the hypothesis that dicarbonyl stress plays a key role in renal microvascular complications. At the transcriptome level, methylglyoxal activated oxidative and pro-inflammatory pathways and inhibited angiogenesis. These effects were further supported by the results of urinary proteomic and metabolomic analyses.
The present pilot study tested the efficiency of nanoTiO2 sunscreen to prevent the oxidative stress/inflammation caused by ultraviolet (UV) radiation using biomarkers in subjects’ blood, urine, and ...exhaled breath condensate (EBC). In addition, the skin absorption of nanoTiO2 was studied. Six identical subjects participated in three tests: (A) nanoTiO2 sunscreen, (B) UV radiation, and (C) sunscreen + UV. The first samples were collected before the test and the second after sunscreen application and/or UV exposure. On day 4, the third samples were collected, and the sunscreen was washed off, and the fourth samples were collected on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, aldehydes C6-C12, 8-iso-Prostaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes, using liquid chromatography-electrospray ionisation-tandem mass spectrometry. Titania was measured using inductively coupled plasma mass spectrometry and TiO2 nanoparticles by transmission and scanning electron microscopy. Sunscreen alone did not elevate the markers, but UV increased the biomarkers in the plasma, urine, and EBC. The sunscreen prevented skin redness, however it did not inhibit the elevation of oxidative stress/inflammatory markers. Titania and nanoTiO2 particles were found in the plasma and urine (but not in the EBC) in all sunscreen users, suggesting their skin absorption.
Improving medical implants with functional polymer coatings is an effective way to further improve the level of medical care. Antibacterial and biofilm-preventing properties are particularly ...desirable in the area of wound healing, since there is a generally high risk of infection, often with a chronic course in the case of biofilm formation. To prevent this we here report a polymeric design of polymer-bound N-acetyl-glucosamine-oligoethylene glycol residues that mimic a cationic, antibacterial, and biocompatible chitosan surface. The combination of easy to use, crosslinkable, thin, potentially 3D-printable polymethacrylate layering with antibacterial and biocompatible functional components will be particularly advantageous in the medical field to support a wide range of implants as well as wound dressings. Different polymers containing a N-acetylglucosamine-methacryloyl residue with oligoethylene glycol linkers and a methacryloyl benzophenone crosslinker were synthesized by free radical polymerization. The functional monomers and corresponding polymers were characterized by 1H, 13C NMR, and infrared (IR) spectroscopy. The polymers showed no cytotoxic or antiadhesive effects on fibroblasts as demonstrated by extract and direct contact cell culture methods. Biofilm formation was reduced by up to 70% and antibacterial growth by 1.2 log, particularly for the 5% GlcNAc-4EG polymer, as observed for Escherichia coli and Staphylococcus aureus as clinically relevant Gram-negative and Gram-positive model pathogens.
Introduction. The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic ...metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome—the hereditary hypertriglyceridemic rat (HHTg)—by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age. Results. Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%, P<0.01). HHTg animals exhibited qualitative changes in NEFA fatty acid composition, represented by an increased proportion of saturated fatty acids (P<0.05) and a decreased proportion of n-3 PUFA (P<0.01). Ectopic lipid deposition in the kidneys of HHTg rats—triglycerides (+30%) and cholesterol (+10%)—was associated with markedly elevated microalbuminuria as ageing increased, despite the absence of microalbuminuria at the young age of 3 months in these animals. According to targeted proteomic analysis, 3-month-old HHTg rats (in comparison to age-matched controls) exhibited increased urinary secretion of proinflammatory parameters (MCP-1, IL-6, IL-8, P<0.01) and decreased urinary secretion of epidermal growth factor (EGF, P<0.01) before manifestation of microalbuminuria. Elevation in the urinary secretion of inflammatory cytokines can be affected by increased relative expression of MCP-1 in the renal cortex (P<0.05). Conclusions. Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.
•Acute methyl alcohol intoxication leads to an inflammatory response in the brain.•Acute concentrations of IL-4, IL-5, IL-9, IL-10, IL-13, LxA4 and LxB4 were elevated.•The acute elevation did not ...persist suggesting against chronic neuroinflammation.•Association of the follow-up IL-5 concentration with abnormal optic nerve function.•Association of the follow-up IL-10 concentration with brain necrotic lesions.
Methyl alcohol intoxication is a global problem with high mortality and long-term visual sequelae and severe brain damage in survivors. The role of neuroinflammation in the mechanisms of methyl alcohol-induced toxic brain damage has not been well studied. We measured the acute concentrations and dynamics of lipoxins LxA4 and LxB4 and the interleukins IL-4, IL-5, IL-9, IL-10, and IL-13 in the serum of patients treated with methyl alcohol poisoning and the follow-up concentrations in survivors two years after discharge from the hospital. A series of acute measurements was performed in 28 hospitalized patients (mean age 54.2 ± 5.2 years, mean observation time 88 ± 20 h) and the follow-up measurements were performed in 36 subjects who survived poisoning (including 12/28 survivors from the acute group). Visual evoked potentials (VEP) and magnetic resonance imaging of the brain (MRI) were performed to detect long-term visual and brain sequelae of intoxication. The acute concentrations of inflammatory mediators were higher than the follow-up concentrations: LxA4, 62.0 ± 6.0 vs. 30.0 ± 5.0 pg/mL; LxB4, 64.0 ± 7.0 vs. 34.0 ± 4.0 pg/mL; IL-4, 29.0 ± 4.0 vs. 15.0 ± 1.0 pg/mL; IL-5, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-9, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-10, 38.0 ± 5.0 vs. 16.0 ± 1.0 pg/mL; IL-13, 35.0 ± 4.0 vs. 14.0 ± 1.0 pg/mL (all p < 0.001). The patients with higher follow-up IL-5 concentration had prolonged latency P1 (r = 0.413; p = 0.033) and lower amplitude N1P1 (r = −0.498; p = 0.010) of VEP. The higher follow-up IL-10 concentration was associated with MRI signs of brain necrotic damage (r = 0.533; p = 0.001) and brain hemorrhage (r = 0.396; p = 0.020). Our findings suggest that neuroinflammation plays an important role in the mechanisms of toxic brain damage in acute methyl alcohol intoxication.
2,3,7,8-Tetrachlorodibenzo-
p
-dioxin (TCDD) is highly toxic and affects the cardiovascular system, brain, and skin by AhR-dependent and other mechanisms, as well as causing metabolic impairments and ...cancer. The involvement of the respiratory system has not yet been studied. TCDD in the blood was measured and biomarkers of oxidative stress and inflammation were analysed in 2016 in the exhaled breath condensate (EBC) of the last eight male survivors (mean age 72.4 ± 1.3 years) from 80 workers intoxicated with TCDD during the production of herbicides from 1965 to 1968. The results were compared with their findings in 2010 to evaluate a trend. Malondialdehyde, 4-hydroxy-
trans
-nonenale, and 8-isoprostaglandin F2α (8-isoprostane), in addition to markers of the oxidation of nucleic acids and proteins 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-(hydroxymethyl)uracil,
o
-tyrosine, and 3-nitrotyrosine, as well as markers of inflammation leukotrienes and anti-inflammatory lipoxins, were analysed in EBC by liquid chromatography–electrospray ionisation–tandem mass spectrometry. In addition, the patients underwent chest X-ray, spirometry and fractional exhaled nitric oxide (FeNO) examinations. The control group included 7 men (66 ± 16 years) with comparable lifestyle factors. The median plasma TCDD level lowered from 155 (28–553) ng/kg fat in 2010 to 112 (46–390) ng/kg fat in 2016, i.e., 50 years after exposure. The mean TCDD body deposit was 5.0 ± 3.7 µg. Serum TCDD level in the pooled sample of the controls was 12 ng/kg fat. All markers of oxidative stress, LTB4 and LTC4, remained overexpressed in patients and anti-inflammatory lipoxins were under-expressed compared to controls (all
p
< 0.01). The mean FeNO and spirometry results were within the reference values. Borderline X-ray findings and combined lung function impairments were seen in the patients with the lower TCDD plasma levels. Differences in the expression of the biomolecular markers in EBC as compared to controls were not associated with lung impairments and the respiratory parameters measured. Therefore, these EBC markers can be used to evaluate systemic oxidative stress and inflammation in tissues and the endovascular, atherosclerotic, neurotoxic, and metabolic effects of TCDD.
Graphical abstract
Methyl alcohol intoxications are characterized by high lethality and high prevalence of serious visual and brain damage in survivors. The mechanisms of toxic brain damage are complex and the role of ...carbonyl stress has not been studied yet. We measured the acute and follow-up concentrations of reactive carbonyl compounds in patients with acute methyl alcohol intoxication. Blood samples were collected from 28 subjects hospitalized with confirmed methyl alcohol intoxication and from 36 subjects who survived poisoning 2 years after discharge. Serum concentrations of C
6–12
reactive aldehydes were measured by liquid chromatography–electrospray ionization–tandem mass spectrometry. The acute concentrations of all measured reactive aldehydes were higher than the follow-up concentrations: 36.4 ± 4.8 vs. 21.6 ± 5.2 ng cm
−3
for C
6
; 38.9 ± 5 vs. 17.0 ± 2.0 ng cm
−3
for C
7
; 18.8 ± 3.9 vs. 4 ± 0 cm
−3
for C
8
; 36.5 ± 3.9 vs. 19.0 ± 3.0 ng cm
−3
for C
9
; 6.1 ± 0.4 vs. 4.0 ± 0.5 ng cm
−3
for C
10
; 13.6 ± 3.0 vs. 3.7 ± 0.6 ng cm
−3
for C
11
; and 7.8 ± 0.4 vs. 4.7 ± 0.4 ng cm
−3
for C
12
(all
p
< 0.001). The patients who survived the intoxication had higher concentration of reactive carbonyl compounds than those who died: 38.6 ± 5.9 vs. 28.3 ± 1.7 ng cm
−3
for C
6
(
p
= 0.002); 20.7 ± 4.7 vs. 11.8 ± 1.2 ng cm
−3
for C
8
(
p
= 0.001); 37.7 ± 4.8 vs. 31.8 ± 3.8 ng cm
−3
for C
9
(
p
= 0.042); and 7.9 ± 0.6 vs. 7.3 ± 0.5 ng cm
−3
for C
12
(
p
= 0.022). A significant association was present between severity of metabolic acidosis, anion gap, and the acute concentration of measured biomarkers:
r
= − 0.39;
p
= 0.046 for C
6
;
r
= − 0.42;
p
= 0.035 for C
7
;
r
= − 0.48;
p
= 0.012 for C
8
;
r
= − 0.39;
p
= 0.046 for C
9
; and
r
= − 0.47;
p
= 0.015 for C
11
. The acute concentration of C
6
–C
12
reactive aldehydes positively correlated with the acute serum concentration of leukotrienes (all
p
< 0.05). Acute elevation of serum concentration of reactive carbonyl compounds suggests that carbonyl stress is involved in the mechanisms of leukotriene-mediated neuroinflammatory response to methyl alcohol-induced toxic brain damage.
Graphical abstract
The aim of the study is to measure serum concentrations of markers of nucleic acids and proteins oxidative damage in humans to study the dynamics and clinical determinants of oxidative stress caused ...by acute methanol poisoning. Acute blood serum samples for this study were collected from 28 patients with methanol poisoning and the follow-up samples from 36 survivors of poisoning were collected 2 years after discharge. Serum concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), 5-(hydroxymethyl)uracil (5-OHMU),
ortho
-tyrosine (
o
-Tyr), nitrotyrosine (NO-Tyr), and chlorotyrosine (Cl-Tyr) were measured by liquid chromatography-electrospray ionisation-tandem mass spectrometry. Acute concentrations of 8-OHdG and
o
-Tyr were significantly higher than the follow-up concentrations (94.4 ± 6.2 versus 78.0 ± 10.0 pg cm
−3
;
p
= 0.009 and 163.0 ± 11.0 versus 124.0 ± 17.0 pg cm
−3
;
p
< 0.001, correspondingly). Survivors of methanol poisoning had higher acute 8-OHdG and 8-OHG concentrations than those who died (97.3 ± 7.4 versus 50.0 ± 23.0 pg cm
−3
;
p
< 0.001 and 97.9 ± 7.2 versus 83.7 ± 6.7 pg cm
−3
;
p
= 0.047). Acute concentrations of 8-OHdG, 8-OHG, 5-OHMU, and
o
-Tyr were higher in the patients who survived without health sequelae than in those who survived with visual and CNS sequelae (all
p
< 0.05). Acute concentrations of markers of proteins and nucleic acids damage correlated with laboratory parameters of acidemia (anion gap) and serum ethanol concentration on admission (both
p
< 0.05). Acute elevation of the concentration of markers of nucleic acids and proteins oxidative damage in the patients with methanol poisoning suggest that mild-to-moderate oxidative stress may play an important role in the non-specific mechanisms of brain protection against direct neurotoxic effects of formic acid.
Graphical abstract
The present pilot study tested the efficiency of nanoTiO
sunscreen to prevent the oxidative stress/inflammation caused by ultraviolet (UV) radiation using biomarkers in subjects' blood, urine, and ...exhaled breath condensate (EBC). In addition, the skin absorption of nanoTiO
was studied. Six identical subjects participated in three tests: (A) nanoTiO
sunscreen, (B) UV radiation, and (C) sunscreen + UV. The first samples were collected before the test and the second after sunscreen application and/or UV exposure. On day 4, the third samples were collected, and the sunscreen was washed off, and the fourth samples were collected on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy-
-hexenal, 4-hydroxy-
-nonenal, aldehydes C6-C12, 8-
-Prostaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes, using liquid chromatography-electrospray ionisation-tandem mass spectrometry. Titania was measured using inductively coupled plasma mass spectrometry and TiO
nanoparticles by transmission and scanning electron microscopy. Sunscreen alone did not elevate the markers, but UV increased the biomarkers in the plasma, urine, and EBC. The sunscreen prevented skin redness, however it did not inhibit the elevation of oxidative stress/inflammatory markers. Titania and nanoTiO
particles were found in the plasma and urine (but not in the EBC) in all sunscreen users, suggesting their skin absorption.
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