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1.
Chemosphere ; 286(Pt 1): 131570, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34293559

RESUMO

The increase in pollution increased the threat level of living organisms in the environment. Municipal Solid Waste is one of the most important wastes which contribute to polluted sites affecting livelihood. They pollute the water stream, marine environment ecology, soil fertility, and agriculture production. This, in turn, reduces the microflora of the marine environment, agricultural soil, and fertility. This could be analyzed by setting up a Winogradsky column using dumpsite soil samples. The current work was designed to study the municipal solid wastes from different dumpsite soil. Soil characterization revealed that the pH of Kodungaiyur and Otteri was 7.3 and 6.4. The bulk density was 0.067 g/cm3 and 0.069 g/cm3. The Porosity resulted to be 0.511 particle/volume and 0.513 particle/volume for Kodungaiyur and Otteri. The Kodungaiyur soil containing contaminants supplied with natural sources showed a 100% germination index, and Otteri soil containing contaminants supplied with natural sources showed a maximum vigour index. The presence of medicinal strips in the collected soil samples led to the study on Acetaminophen degradation. HB1 showed to be 79 ± 0.005% at optimum pH 5 containing 100 mg/L of Acetaminophen at day four among the isolated bacterial strains. Further, the intermediate formation was determined using FTIR and GC-MS. The isolated HB1 bacterial strain was identified as Staphylococcus hominis, which is heterotroph.


Assuntos
Poluentes do Solo , Solo , Acetaminofen/toxicidade , Agricultura , Poluentes do Solo/análise , Poluentes do Solo/toxicidade , Resíduos Sólidos/análise
2.
Pol Merkur Lekarski ; 49(293): 346-351, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34800021

RESUMO

It is known that the violation of one or more functions of the liver, where the basic biochemical processes take place, is reflected in the functional state of many organs and systems, causing severe consequences. For the effective treatment of the hepatobiliary system diseases the drugs from fungi and plant materials are promising, the ingredients of which are close to natural metabolites, have different mechanisms of hepatoprotective action and, in general, can have a positive effect on liver function. AIM: The aim of the research was to investigate the hepatoprotective properties of the Maitake mushrooms thick extract in the experiment on rats with paracetamol (acetaminophen)-induced hepatitis. MATERIALS AND METHODS: The study was performed on 60 white male rats weighing 180-210 g and aged 6-6,5 months. Rats were divided into 10 groups, each of which included 6 animals. Acute hepatitis was simulated by acetaminophen intragastrically administering at a dose of 1250 mg/ kg of body weight 1 time per day as a suspension in 2% starch gel solution for 2 days. Correction of the toxic lesions was performed with a thick extract of Maitake mushrooms, which was administered intragastrically 2 hours before the introduction of acetaminophen and daily after the lesion at a dose of 150 mg/kg of body weight. "Silibor" (active basis - silymarin) was chosen as a comparison drug, which was administered according to the same scheme as Maitake extract at a dose of 20 mg/kg of animal body weight. On the 3rd, 7th and 10th days from the onset of the lesion, rats were euthanized using sodium barbamyl. Liver homogenate and blood serum were tested. Blood was taken from the hearts of animals. Endogenous intoxication of animals after the introduction of corrective factors was assessed by the activity of ALT, AST, GGTP, LF and the size of the thymol sample. All changes were confirmed by parametric and nonparametric methods of statistical analysis of the results of the study. RESULTS: The expressed cytolysis of hepatocytes, after administration to rats of toxicant, on the basis of research of the activity of aminotransferases, gamma-glutamyltranspeptidase, alkaline phosphatase and thymol sample size is proved. The results of the experiment were confirmed histologically. The introduction of a thick extract of Maitake mushrooms contributed to the normalization of the studied indicators. CONCLUSIONS: The application of the Maitake mushrooms thick extract as a corrective factor in the simulated acetaminophen hepatitis indicates its hepato-, cytoprotective and antioxidative properties.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Grifola , Hepatite , Doenças Metabólicas , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado , Masculino , Extratos Vegetais/uso terapêutico , Ratos
3.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639126

RESUMO

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 µmol/g tissue in WT mice vs. 0.85 ± 0.14 µmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas de Membrana/fisiologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
4.
Nanomedicine (Lond) ; 16(27): 2431-2448, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632809

RESUMO

Aim: To evaluate the feasibility of using dipotassium glycyrrhizinate (DG) as a nanocarrier-loading fisetin (FIT) with strengthened treatment efficacies against liver injury induced by acetaminophen overdose. Methods: DG-FIT was prepared, and its efficacy against liver injury induced by acetaminophen overdose was evaluated. Results: DG-FIT was successfully fabricated with excellent physicochemical properties. DG-FIT could be easily dissolved in water to form a clear micelle solution with high FIT encapsulation efficiency. FIT in DG-FIT exhibited a dramatically improved aqueous solubility. DG-FIT improved intestinal permeation. Regarding in vivo efficacies, DG-FIT exhibited significant effect against acetaminophen overdose by suppressing oxidative stress and proinflammatory cytokines involved. Conclusion: DG-FIT formulation possibly represents a promising method for strengthening the efficacy of FIT against acetaminophen-induced liver injury.


Assuntos
Acetaminofen , Doença Hepática Crônica Induzida por Substâncias e Drogas , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Flavonoides/metabolismo , Flavonóis , Humanos , Fígado/metabolismo , Estresse Oxidativo
5.
Bratisl Lek Listy ; 122(10): 732-738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34570575

RESUMO

BACKGROUND: The use of acetaminophen (APAP) is increasing recently, especially with COVID-19 outbreaks. APAP is safe at therapeutic levels, however, an overdose can cause severe liver injury. This study aims to explore possible mechanisms involved in APAP­induced hepatotoxicity and compare different hepatoprotective agents, namely vitamin E, hydrogen sulfide (H2S) and necrostatin-1 (NEC-1). METHODS: Adult male albino rats were divided into groups: Control group, APAP­induced hepatotoxicity group, Vitamin E­treated group, H2S­treated group and NEC-1­treated group. Serum levels for aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-33 (IL-33), tumor necrosis factor alpha (TNF-α), reduced glutathione (GSH) and lipid profile were measured. Histopathological examinations of liver tissue with H(et)E stain and immunohistochemistry for activated caspase-3 were also done. RESULTS: APAP­treated group showed elevated liver transaminases, hyperlipidemia, and deficient liver anti-oxidative response together with disturbed hepatic architecture and increased immune-expression of activated caspase-3 in hepatic tissue. Pretreatment with vitamin E, H2S or NEC-1 reversed the affected parameters. Vitamin E and H2S showed greater improvement when compared to NEC-1. CONCLUSION: Vitamin E, H2S and NEC-1 showed protective effects against APAP-induced hepatotoxicity, thus they may be used as an adjuvant therapy when APAP is indicated for long periods as is the case in COVID-19 patients (Tab. 2, Fig. 2, Ref. 45). Text in PDF www.elis.sk Keywords: acetaminophen, hepatotoxicity, apoptosis, necrostatin-1, vitamin E, H2S.


Assuntos
COVID-19 , Doença Hepática Induzida por Substâncias e Drogas , Sulfeto de Hidrogênio , Acetaminofen/toxicidade , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Humanos , Sulfeto de Hidrogênio/metabolismo , Imidazóis , Indóis , Fígado/metabolismo , Masculino , Estresse Oxidativo , Ratos , SARS-CoV-2 , Vitamina E/farmacologia
6.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575957

RESUMO

Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro-in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.


Assuntos
Cirrose Hepática/genética , MicroRNAs/genética , Acetaminofen/toxicidade , Actinas/genética , Caveolina 1/genética , Linhagem Celular , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Metotrexato/toxicidade
7.
J Hazard Mater ; 416: 126250, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492993

RESUMO

The research on the mechanisms and kinetics of radical oxidation in peracetic acid-based advanced oxidation processes was relatively limited. In this work, HO• and organic radicals mediated reactions of acetaminophen (ACT) were investigated, and the reactivities of important organic radicals (CH3COO• and CH3COOO•) were calculated. The results showed that initiated reaction rate constants of ACT are in the order: CH3COO• (5.44 × 1010 M-1 s-1) > HO• (7.07 × 109 M-1 s-1) > CH3O• (1.57 × 107 M-1 s-1) > CH3COOO• (3.65 × 105 M-1 s-1) >> •CH3 (5.17 × 102 M-1 s-1) > CH3C•O (1.17 × 102 M-1 s-1) > CH3OO• (11.80 M-1 s-1). HO•, CH3COO• and CH3COOO• play important roles in ACT degradation. CH3COO• is another important radical in the hydroxylation of aromatic compounds in addition to HO•. Reaction rate constants of CH3COO• and aromatic compounds are 1.40 × 106 - 6.25 × 1010 M-1 s-1 with addition as the dominant pathway. CH3COOO• has high reactivity to phenolate and aniline only among the studied aromatic compounds, and it was more selective than CH3COO•. CH3COO•-mediated hydroxylation of aromatic compounds could produce their hydroxylated products with higher toxicity.


Assuntos
Ácido Peracético , Poluentes Químicos da Água , Acetaminofen/toxicidade , Radical Hidroxila , Cinética , Oxirredução , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
8.
Nihon Shokakibyo Gakkai Zasshi ; 118(9): 840-850, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34511551

RESUMO

BACKGROUND & AIMS: Capsule endoscopy has revealed that nonsteroidal anti-inflammatory drugs may cause damage not only to the stomach but also to the small intestine, which has become one of the most serious issues in gastroenterology. However, few studies have reported the effect of ibuprofen (IBP), which is widely prescribed worldwide, on the small intestine, and it remains unclear whether IBP can cause small intestinal damage. We have previously shown that acetaminophen (APAP), which is used as an antipyretic/analgesic drug, inhibits IBP-induced gastric damage by suppressing matrix metalloprotease-13 (MMP-13) gene expression. In this study, we investigated the ability of IBP to induce small intestinal damage and the efficacy of APAP against IBP-induced small intestinal damage in rats. MAIN METHODS: Nonfasted male Sprague-Dawley rats were orally administered with IBP (200mg/kg) and then euthanized at various time points (0, 4, 8, 16, and 24h) after the administration. The small intestine, jejunum, and ileum were removed, and intestinal lesions were measured. To elucidate the efficacy of APAP against IBP-induced small intestinal damage, the rats were treated with IBP (200mg/kg) with or without APAP (200mg/kg), and small intestinal damage was evaluated 24h after the administration. Moreover, the expression levels of GAPDH, TNFα, iNOS, and MMP-13 genes were determined at various time points (8, 16, and 24h) by RT-qPCR. KEY FINDINGS: The oral administration of IBP induced obvious small intestinal damage, which was found to be significant at 24h (p<0.05 vs 0h, Dunnett's test). The coadministration of APAP significantly prevented IBP-induced damage (p<0.05, Student's t-test). In addition, the expression levels of TNFα and iNOS genes were significantly increased by IBP (p<0.01 and p<0.05 vs. vehicle, respectively, Tukey-Kramer test), whereas the cotreatment with APAP suppressed the increases at 8h. Moreover, compared with the vehicle, the IBP treatment significantly increased the expression level of the MMP-13 gene (p<0.01) at each time point (8, 16, and 24h, Tukey-Kramer test), whereas the APAP cotreatment significantly suppressed the increase (p<0.01 vs. IBP at 8h, p<0.05 vs. IBP at 16 and 24h, Tukey-Kramer test). CONCLUSIONS: This study suggested that a single administration of IBP was associated with the risk of inducing small intestinal ulcers in rats, and APAP could prevent IBP-induced small intestinal damage by suppressing the MMP-13 gene expression.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/toxicidade , Animais , Ibuprofeno/farmacologia , Intestino Delgado , Fígado , Masculino , Metaloproteinase 13 da Matriz/genética , Ratos , Ratos Sprague-Dawley
9.
Am J Physiol Lung Cell Mol Physiol ; 321(5): L941-L953, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34585971

RESUMO

Both preclinical and clinical studies have demonstrated that exposures to acetaminophen (APAP) at levels that cause hepatic injury cause pulmonary injury as well. However, whether exposures that do not result in hepatic injury have acute pulmonary implications is unknown. Thus, we sought to determine how APAP exposures at levels that do not result in significant hepatic injury impact the mature lung. Adult male ICR mice (8-12 wk) were exposed to a dose of APAP known to cause hepatotoxicity in adult mice [280 mg/kg, intraperitoneal (ip)], as well as a lower dose previously reported to not cause hepatic injury (140 mg/kg, ip). We confirm that the lower dose exposures did not result in significant hepatic injury. However, like high dose, lower exposure resulted in increased cellular content of the bronchoalveolar lavage fluid and induced a proinflammatory pulmonary transcriptome. Both the lower and higher dose exposures resulted in measurable changes in lung morphometrics, with the lower dose exposure causing alveolar wall thinning. Using RNAScope, we were able to detect dose-dependent, APAP-induced pulmonary Cyp2e1 expression. Finally, using FLIM we determined that both APAP exposures resulted in acute pulmonary metabolic changes consistent with mitochondrial overload in lower doses and a shift to glycolysis at a high dose. Our findings demonstrate that APAP exposures that do not cause significant hepatic injury result in acute inflammatory, morphometric, and metabolic changes in the mature lung. These previously unreported findings may help explain the potential relationship between APAP exposures and pulmonary-related morbidity.


Assuntos
Acetaminofen/toxicidade , Fígado/efeitos dos fármacos , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Acetaminofen/metabolismo , Animais , Citocromo P-450 CYP2E1/metabolismo , Modelos Animais de Doenças , Glicólise/efeitos dos fármacos , Fígado/metabolismo , Pulmão/metabolismo , Lesão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos ICR
10.
Free Radic Biol Med ; 172: 578-589, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34242792

RESUMO

Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), which is characterized by GSH depletion, oxidative stress and mitochondrial dysfunction. However, the specific mechanism of APAP-induced ALF remains to be clarified. In this study, we demonstrated that indoleamine 2,3-dioxygenase 1 (IDO1) aggravated APAP-induced ALF associated with excess lipid peroxidation, which was reversed by lipid peroxidation inhibitor (ferrostatin-1). Meanwhile, IDO1 deficiency effectively decreased the accumulation of reactive nitrogen species. Additionally, IDO1 deficiency prevented against APAP-induced liver injury through suppressing the activation of macrophages, thereby reduced their iron uptake and export, eventually reduced iron accumulation in hepatocytes through transferrin and transferrin receptor axis. In summary, our study confirmed that APAP-induced IDO1 aggravated ALF by triggering excess oxidative and nitrative stress and iron accumulation in liver. These results offer new insights for the clinical treatment of ALF or iron-dysregulated liver diseases in the future.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Dioxigenases , Falência Hepática Aguda , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dioxigenases/metabolismo , Hepatócitos , Ferro/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo
11.
J Nutr Sci Vitaminol (Tokyo) ; 67(3): 145-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193673

RESUMO

Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose causes hepatotoxicity, even liver failure, and oxidative stress plays pivotal role in its pathogenesis. Nicotinic acid (NA) is one form of vitamin B3, which has been used to treat a series of diseases in clinic for decades. To date, several studies have evidenced that NA has anti-oxidative property. Therefore, NA may have the hepatoprotective potential against APAP-induced toxicity. Here, our aim was to investigate the beneficial effect of NA against hepatotoxicity induced by APAP and its mechanism in vivo. BALB/c mice were intraperitoneally injected with NA (100 mg/kg) 3 times at 24, 12 and 1 h before APAP (600 mg/kg or 400 mg/kg) challenge. The results showed that pretreatment of NA markedly improved the survival rate, alleviated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and mitigated the histopathological injuries compared to APAP-exposed mice. Furthermore, NA significantly elevated the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) content, while reduced malondialdehyde (MDA) level. Finally, the signaling pathway was probed. The western blot revealed that NA up-regulated Sirtuin1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H quinone dehydrogenase-1 (NQO-1) expression and down-regulated Kelch-like ECH-associated protein 1 (Keap1) level in liver followed APAP exposure, implying Sirt1/Nrf2 axis exerted an essential role in the protective mechanism of NA on APAP toxicity. In brief, pretreatment of NA effectively protects liver against hepatotoxicity due to overdose of APAP through an antioxidant dependent manner modulated by Sirt1/Nrf2 signaling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Niacina , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Animais , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , Niacina/metabolismo , Estresse Oxidativo , Sirtuína 1/metabolismo
12.
Ecotoxicol Environ Saf ; 221: 112454, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34214917

RESUMO

Pharmaceuticals are emerging pollutants of concern for aquatic ecosystems where they are occurring in complex mixtures. In the present study, the chronic toxicity of an environmentally relevant pharmaceutical mixture on juvenile rainbow trout (Oncorhynchus mykiss) was investigated. Five pharmaceuticals (paracetamol, carbamazepine, diclofenac, naproxen and irbesartan) were selected based on their detection frequency and concentration levels in the Meuse river (Belgium). Fish were exposed for 42 days to three different concentrations of the mixture, the median one detected in the Meuse river, 10-times and 100-times this concentration. Effects on the nervous, immune, antioxidant, and detoxification systems were evaluated throughout the exposure period and their response standardized using the Integrated Biomarker Response (IBRv2) index. IBRv2 scores increased over time in the fish exposed to the highest concentration. After 42 days, fish exposed to the highest concentration displayed significantly higher levels in lysozyme activity (p < 0.01). The mixture also caused significant changes in brain serotonin turnover (p < 0.05). In short, our results indicate that the subchronic waterborne exposure to a pharmaceutical mixture commonly occurring in freshwater ecosystems may affect the neuroendocrine and immune systems of juvenile rainbow trout.


Assuntos
Oncorhynchus mykiss , Poluentes Químicos da Água/toxicidade , Acetaminofen/toxicidade , Animais , Bélgica , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carbamazepina/toxicidade , Diclofenaco/toxicidade , Irbesartana/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lisossomos/metabolismo , Naproxeno/toxicidade , Síndromes Neurotóxicas , Rios , Serotonina/metabolismo
13.
Langmuir ; 37(31): 9560-9570, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328747

RESUMO

Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.


Assuntos
Acetaminofen , Fosfolipídeos , Acetaminofen/toxicidade , Bicamadas Lipídicas , Fosfatidilcolinas , Espalhamento a Baixo Ângulo , Difração de Raios X
14.
Free Radic Biol Med ; 174: 57-65, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324981

RESUMO

Many studies have investigated the role of receptor-interacting protein 1 (RIP1) kinase in acetaminophen (APAP) overdose-induced acute liver injury. However, the results were not consistent and there still remain controversies. Importantly, in these previous studies, the usage of DMSO to dissolve the RIP1 kinase inhibitor Nec-1, resulted in misleading conclusion. Our study aimed to determine the role of RIP1 kinase in APAP-induced liver injury, via genetically or pharmaceutically inhibition of RIP1 kinase activity. Our results indicated that APAP-induced liver injury was significantly attenuated in RIP1 kinase-dead (Rip1K45A/K45A) mice compared to WT control. High dosage of APAP-induced mortality was also rescued by RIP1 kinase inactivation. In agreement, RIP1 kinase inhibitor, Nec-1 which was formulated with PEG400, could efficiently alleviate APAP-induced hepatotoxicity. For the underlying mechanism, our results suggested that RIP1 kinase inactivation did not influence the hepatic GSH depletion, but significantly reduced the hepatic cell death and inflammation induced by APAP treatment. Using bone marrow transplantation model, we also demonstrated that it was RIP1 kinase activity in tissue-resident hepatic cells other than hematopoietic-derived cells mainly responsible for APAP-induced liver injury. Our study confirmed the important role of RIP1 kinase activity in APAP-induced acute liver failure.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos , Fígado , Camundongos , Camundongos Endogâmicos C57BL
15.
ACS Appl Mater Interfaces ; 13(28): 32640-32652, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34225454

RESUMO

Although various liver chips have been developed using emerging organ-on-a-chip techniques, it remains an enormous challenge to replicate the liver lobules with self-assembled perfusable hepatic sinusoid networks. Herein we develop a lifelike bionic liver lobule chip (LLC), on which the perfusable hepatic sinusoid networks are achieved using a microflow-guided angiogenesis methodology; additionally, during and after self-assembly, oxygen concentration is regulated to mimic physiologically dissolved levels supplied by actual hepatic arterioles and venules. This liver lobule design thereby produces more bionic liver microstructures, higher metabolic abilities, and longer lasting hepatocyte function than other liver-on-a-chip techniques that are able to deliver. We found that the flow through the unique micropillar design in the cell coculture zone guides the radiating assembly of the hepatic sinusoid, the oxygen concentration affects the morphology of the sinusoid by proliferation, and the oxygen gradient plays a key role in prolonging hepatocyte function. The expected breadth of applications our LLC is suited to is demonstrated by means of preliminarily testing chronic and acute hepatotoxicity of drugs and replicating growth of tumors in situ. This work provides new insights into designing more extensive bionic vascularized liver chips, while achieving longer lasting ex-vivo hepatocyte function.


Assuntos
Células Endoteliais/metabolismo , Hepatócitos/metabolismo , Dispositivos Lab-On-A-Chip , Fígado/metabolismo , Acetaminofen/toxicidade , Animais , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Oxigênio/metabolismo , Testes de Toxicidade
16.
Med J Aust ; 215(6): 261-268, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34272737

RESUMO

OBJECTIVE: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements. DESIGN: Retrospective electronic medical record data analysis. SETTING, PARTICIPANTS: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020. MAIN OUTCOME MEASURES: 90-day transplant-free survival; drugs implicated as causal agents in DILI. RESULTS: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36). CONCLUSION: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.


Assuntos
Acetaminofen/toxicidade , Antipiréticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Suplementos Nutricionais/toxicidade , Doença Hepática Terminal/classificação , Adulto , Antibacterianos/toxicidade , Antineoplásicos/toxicidade , Antituberculosos/toxicidade , Austrália/epidemiologia , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/complicações , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/epidemiologia , Doença Hepática Terminal/mortalidade , Feminino , Hospitalização/estatística & dados numéricos , Hospitalização/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Análise de Sobrevida
17.
Life Sci ; 279: 119669, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081988

RESUMO

AIMS: Acetaminophen (APAP) toxicity is one of the leading causes of acute liver injury-related death and liver failure worldwide. In many studies, mitochondrial dysfunction has been identified as an important cause of damage in APAP toxicity. Therefore, our study aimed to investigate the possible effects of mitochondrial transplantation on liver damage due to APAP toxicity. MAIN METHODS: APAP toxicity model was implemented by administering a toxic dose of APAP. To demonstrate the efficiency of mitochondria transplantation, it was compared with N-acetylcysteine (NAC) application, which is now clinically accepted. Mitochondrial transplantation was carried out by delivering mitochondria to the liver via the portal circulation, which was injected into the spleen. In our study, the rats were randomly divided into 6 groups as Sham, APAP, Control 1, APAP+mito, Control 2, and APAP+NAC. In the end of the experiment, histological and biochemical analysis were performed and the biodistribution of the transplanted mitochondria to target cells were also shown. KEY FINDINGS: Successful mitochondrial transplantation was confirmed and mitochondrial transplantation improved the liver histological structure to a similar level with healthy rats. Moreover, plasma ALT levels, apoptotic cells, and total oxidant levels were decreased. It was also observed that NAC treatment increased GSH levels to the highest level among the groups. However, mitochondrial transplantation was more effective than NAC application in terms of histological and functional improvement. SIGNIFICANCE: It has been evaluated that mitochondrial transplantation can be used as an important alternative or adjunctive treatment method in liver damage caused by toxic dose APAP intake.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/terapia , Glutationa/metabolismo , Peroxidação de Lipídeos , Mitocôndrias/transplante , Analgésicos não Narcóticos/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
18.
Sci Transl Med ; 13(597)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108253

RESUMO

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatócitos , Interleucina-11 , Subunidade alfa de Receptor de Interleucina-11 , Fígado , Camundongos , Camundongos Endogâmicos C57BL
19.
Environ Sci Pollut Res Int ; 28(40): 57192-57206, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34086174

RESUMO

This experiment was to explore the possible defensive properties and potential molecular mechanisms of Camellia japonica (CJ) against APAP-stimulated acute liver failure (ALF) in mice. In this study, we investigated the effects of CJ on APAP-induced hepatotoxicity. Mice were orally treated with CJ before or after challenge with APAP. Both pretreatment and post-treatment with CJ attenuated APAP-induced hepatotoxicity, as confirmed by significantly reduced serum toxicity biomarkers and improved hepatic pathological damage. Pretreatment with CJ drastically decreased the rise of hepatic inflammatory cytokines levels and weakened neutrophil infiltration. Furthermore, pretreatment with CJ dramatically decreased the levels of hepatic oxidative stress markers such as hepatic malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE) expression and rescued the reduced hepatic level of GSH caused by APAP overdose. Additionally, CJ pretreatment markedly attenuated cyclooxygenase-2 (COX-2) activation, transcription factor nuclear factor-kappa B (NF-κB) phosphorylation, c-Jun-N-terminal kinase (JNK) phosphorylation, and activated AMP-activated protein kinase (AMPK) signaling pathway in the liver. The present study thus reveals that CJ attenuated APAP-induced ALF by inhibiting COX-2 activation, NF-κB, and JNK phosphorylation and activating the AMPK signaling pathway.


Assuntos
Camellia , Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Acetaminofen/toxicidade , Animais , Falência Hepática Aguda/induzido quimicamente , Camundongos , Estresse Oxidativo
20.
J Hazard Mater ; 418: 126180, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102367

RESUMO

The large consumption of acetaminophen (APAP) worldwide and unsatisfactory treatment efficiencies by conventional wastewater treatment processes give rise to the seeking of new technology for its effective removal. Herein, we proposed a facile one-step hydrothermal method to synthesize defective iron deposited titanate nanotubes (Fe/TNTs) for peroxymonosulfate (PMS) activation and APAP degradation. The retarded first-order reaction rate of APAP degradation by Fe/TNTs was 5.1 times higher than that of neat TNTs. Characterizations indicated iron deposition effectively induced oxygen vacancies and Ti3+, facilitating the electrical conductivity and PMS binding affinity of Fe/TNTs. Besides, oxygen vacancies could act as an electron mediator through PMS activation by iron. Moreover, the formation of Fe-O-Ti bond facilitated the synergistic redox coupling between Fe and Ti, further enhancing the PMS activation. SO4•- was the major radical, causing C-N bond cleavage and decreasing the overall toxicity. In contrast, APAP degradation by neat TNTs-PMS system mainly works through nonradical reaction. The Fe/TNTs activated PMS showed desired APAP removal under mild water chemistry conditions and good reusability. This work is expected to expand the potential application of titanate nanomaterials for PMS activation, and shed light on facile synthesis of oxygen defective materials for sulfate-radical-based advanced oxidation processes.


Assuntos
Acetaminofen , Nanotubos , Acetaminofen/toxicidade , Ferro , Oxigênio , Peróxidos , Água
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