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1.
Chemosphere ; 240: 124970, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726584

RESUMO

Measurement of specific biomarkers identified by proteomics provides a potential alternative method for risk assessment, which is required to discriminate between hepatotoxicity and endocrine disruption. In this study, adult zebrafish (Danio rerio) were exposed to the hepatotoxic substance acetaminophen (APAP) for 21 days, in a fish short-term reproduction assay (FSTRA). The molecular changes induced by APAP exposure were studied in liver and gonads by applying a previously developed combined FSTRA and proteomics approach. We observed a significant decrease in egg numbers, an increase in plasma hyaluronic acid, and the presence of single cell necrosis in liver tissue. Furthermore, nine common biomarkers (atp5f1b, etfa, uqcrc2a, cahz, c3a.1, rab11ba, mettl7a, khdrbs1a and si:dkey-108k21.24) for assessing hepatotoxicity were detected in both male and female liver, indicating hepatic damage. In comparison with exposure to fadrozole, an endocrine disrupting chemical (EDC), three potential biomarkers for liver injury, i.e. cahz, c3a.1 and atp5f1b, were differentially expressed. The zebrafish proteome response to fadrozole exposure indicated a significant regulation in estrogen synthesis and perturbed binding of sperm to zona pellucida in the ovary. This study demonstrates that biomarkers identified and quantified by proteomics can serve as additional weight-of-evidence for the discrimination of hepatotoxicity and endocrine disruption, which is necessary for hazard identification in EU legislation and to decide upon the option for risk assessment.


Assuntos
Biomarcadores/análise , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Disruptores Endócrinos/toxicidade , Monitoramento Ambiental/métodos , Proteômica/métodos , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Animais , Biomarcadores/metabolismo , Diagnóstico Diferencial , Fadrozol/toxicidade , Feminino , Gônadas/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
2.
Chemosphere ; 238: 124589, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31437630

RESUMO

Vitellogenin (VTG), a well-established biomarker for the diagnosis of endocrine activity in fish, is used in multiple OECD test guidelines (TG) to identify activities of chemicals on hormonal pathways. However, the synthesis of VTG may not only be modified by typical endocrine-related pathways, but also through non-endocrine-mediated processes. In particular, hepatotoxicity, i.e. toxicant-induced impairment of liver structure and function, might influence VTG as a biomarker, since VTG is synthesized in hepatocytes. An intimate understanding of the interplay between endocrine-related and non-endocrine-related pathways influencing VTG production is crucial for the avoidance of erroneous diagnoses in hazard assessment for regulatory purposes of chemical compounds. In order to investigate whether hepatotoxicity may interfere with hepatic VTG synthesis, adult zebrafish (Danio rerio) were exposed to three well-known hepatotoxicants, acetaminophen, isoniazid and acetylsalicylic acid, according to OECD TG 230. Various hepatotoxicity- and endocrine system-related endpoints were recorded: mRNA expression of selected endocrine- and hepatotoxicity-related marker genes in the liver; VTG levels in head/tail homogenates; and liver histopathology. All three test compounds induced significant, but mild single cell necrosis of hepatocytes and transcriptional changes of hepatotoxicity-related marker genes, thus confirming hepatotoxic effects. A positive correlation between hepatotoxicity and reduced hepatic VTG synthesis was not observed, with the single exception of a weak increase in female zebrafish exposed to APAP. This suggests that - in studies conducted according to OECD TG 229 or 230 - it is unlikely that hepatotoxic chemicals will interfere with the hepatic capacity for VTG synthesis.


Assuntos
Acetaminofen/toxicidade , Aspirina/toxicidade , Hepatócitos/metabolismo , Isoniazida/toxicidade , Vitelogeninas/biossíntese , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas , Sistema Endócrino/efeitos dos fármacos , Feminino , Hepatócitos/efeitos dos fármacos , Masculino , Proteínas de Peixe-Zebra/biossíntese
3.
Arq Gastroenterol ; 56(4): 333-338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721967

RESUMO

BACKGROUND: Indigofera suffruticosa Mill (Fabaceae) is abundant in northeastern Brazil and popularly used in the treatment of infectious and inflammatory processes. Several biological properties, such as anti-inflammatory, anticancer, antitumor, hepatoprotective and low toxicity, are reported for this plant. OBJECTIVE: This study investigated hepatoprotective activity and the antioxidant effect of methanolic extract of I. suffruticosa leaves (MEIS) on Swiss albino mice submitted to experimental models of acetaminophen-induced liver injury. METHODS: MEIS (50 mg/kg; p.o.) was standardized according to the LD50 and its hepatoprotective property on Swiss albino mice evaluated during a 7-day period. On the eighth day, the acetaminophen-induced hepatic injury was performed. Histomorphometric analysis of liver tissue, antioxidant activity and serum levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT) and bilirubin were measured. RESULTS: MEIS (50 mg/kg; p.o.) restored serum enzyme levels and results were close to those of positive control (silymarin) when compared to the negative control. Histopathological and histomorphometric analyzes confirmed MEIS hepatoprotective activity, showing reorganization of structural units of cells, nuclei and sinusoidal capillaries of hepatocytes, reducing the damage on liver tissue and increasing organ regeneration rate. MEIS showed high antioxidant potential at concentrations of 1000 and 500 µg/mL. CONCLUSION: This study suggests that MEIS has hepatoprotective activity and high antioxidant potential.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Indigofera/química , Extratos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Masculino , Camundongos
4.
Life Sci ; 236: 116939, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593705

RESUMO

Taxifolin (TAX) reportedly exerts protective and therapeutic effects in liver. Herein, the effects of TAX against acetaminophen (APAP)-induced hepatotoxicity were investigated. Pharmacodynamics, pharmacology and metabolomics analyses of TAX were assessed on C57 mice and L-02 cells. TAX was administered for 7 days, and APAP was given on the last day to establish an acute liver injury model. ALT and AST levels were determined, and liver ROS, MDA, GST, GSH and GPX1 were analysed. The expression and protein abundance of GPX1, GPS-Pi, GCLC and GCLM were assessed by PCR and western blotting, and metabolic changes in cells and serum were investigated by UPLC-Q-Orbitrap-MS. Serum ALT and AST, and liver ROS, MDA, GST, GSH and GPX1 levels confirmed the protective effects of TAX. Besides, we found Only treating with TAX decreased the expression of CYP2E1 in mice liver tissue. TAX reversed the APAP-induced decrease in cell viability in L-02 cells, and reduced cellular ROS levels. Furthermore, TAX reversed the APAP-induced decrease in antioxidant enzymes at both mRNA and protein levels. Metabolomics analysis identified metabolites mainly related to glutathione metabolism (36 in vivo and 23 in vitro). The concentration of glutathione, oxidized glutathione, carnitine, succinic acid, pyroglutamic acid, citrulline, taurine, palmitoleic acid, phytoshingosine-1-P and sphingosine-1-P were close to normal levels after treating with TAX. These results indicate that TAX prevents APAP-induced liver injury by inhibiting APAP metabolic activation mediated by CYP450 enzymes, modulating glutathione metabolism, and expression of related antioxidative signals. These properties could be harnessed to prevent or treat hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glutationa/metabolismo , Metaboloma , Substâncias Protetoras/farmacologia , Quercetina/análogos & derivados , Analgésicos não Entorpecentes/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
6.
Environ Pollut ; 254(Pt B): 113092, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472453

RESUMO

Because of its analgesic properties, acetaminophen (AAP) is widely used to relieve headache. AAP is generally considered safe for humans, but its effects on aquatic organisms are not well known. Here, we have hypothesis that effects of AAP on aquatic organisms would be environmental temperature dependent, because their physiological function depend on the temperature. To test this hypothesis, we used medaka (Oryzias latipes) as a model, because they can live at a wide range of temperatures (0-40 °C). We exposed medaka larvae to 0 (control), 50, or 150 mg/L of AAP at 15, 25 (optimal temperature), or 30 °C for 4 days. Egg yolk absorption was accelerated with raising temperature at any AAP dose. AAP exposure did not have biologically significant effects on survival ratio and body length of larvae at any tested temperature or dose, but heart rate decreased as the dose of AAP and environmental temperature increased. In addition, as the temperature increased, amount of ATP in individual larvae increased in control group, but decreased in AAP exposed group. Subsequently, exposure to 150 mg/L of AAP at 30 °C decreased the number of red blood cells in the gills; we used 150 mg/L of AAP in subsequent hematological and histological analyses. Hematological analysis showed that rising temperature increased the proportion of morphologically abnormal red blood cells in AAP-exposed larvae, suggesting that AAP induced anemia-like signs in larvae. Histological observation of the kidney, which is a hematopoietic organ in fish, revealed no abnormalities. However, in the liver, which is responsible for drug metabolism, the proportion of vacuoles increased with increasing temperature. Although the exposure concentration we tested was higher than environmentally relevant concentrations, our data indicated that rising temperature enhances the toxicity of AAP to medaka larvae, suggesting an ecological risk of AAP due to global warming.


Assuntos
Acetaminofen/toxicidade , Larva/efeitos dos fármacos , Temperatura Ambiente , Poluentes Químicos da Água/toxicidade , Acetaminofen/química , Animais , Aquecimento Global , Oryzias/fisiologia , Testes de Toxicidade , Poluentes Químicos da Água/química
7.
Crit Care Resusc ; 21(3): 188-199, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31462206

RESUMO

OBJECTIVE: Acute liver failure (ALF) leads to severe illness and usually requires admission to the intensive care unit (ICU). Despite its importance, little is known about patients with ALF in Australia and New Zealand. DESIGN: Binational observational study to evaluate the aetiology, baseline characteristics, patterns of illness, management, and outcomes for patients with ALF admitted to Australian and New Zealand ICUs. SETTING: All six Australian and New Zealand ICUs in liver transplant centres submitted de-identified data for ten or more consecutive patients with ALF. Data were obtained from the clinical record and included baseline characteristics, aetiology, mode of presentation, illness severity, markers of liver failure, critical care interventions, utilisation of transplantation, and hospital outcome. RESULTS: We studied 62 patients with ALF. Paracetamol overdose (POD) was the underlying cause of ALF in 53% of patients (33/62), with staggered ingestion in 42% of patients (14/33). Among patients with POD, 70% (23/33) were young women, most had psychiatric diagnoses, and most presented relatively early with overt liver failure. This group were transplanted in only 6% of cases (2/33) and had an overall mortality of 24% (8/33). The remaining patients with ALF had less common conditions, such as hepatitis B and non-paracetamol drug-induced ALF. These patients presented later and exhibited less extreme evidence of acute hepatic necrosis. Transplantation was performed in 38% of patients (11/29) in this subgroup. The mortality of nontransplanted non-POD patients was 56% (10/18). Illness severity at ICU admission, initial requirement for organ support therapies and length of hospital stay were similar between patients with POD and non-POD ALF. CONCLUSION: POD is the major cause of ALF in Australian and New Zealand liver transplant centres and is a unique and separate form of ALF. It has a much lower associated mortality and treatment with liver transplantation than non-POD ALF. Non-POD patients have a poor prognosis in the absence of transplantation.


Assuntos
Acetaminofen/administração & dosagem , Acetaminofen/toxicidade , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/toxicidade , Overdose de Drogas/epidemiologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/cirurgia , Transplante de Fígado/métodos , Adolescente , Adulto , Austrália/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/etiologia , Transtornos Mentais/complicações , Transtornos Mentais/epidemiologia , Nova Zelândia/epidemiologia , Resultado do Tratamento , Adulto Jovem
8.
Ecotoxicol Environ Saf ; 182: 109438, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31310901

RESUMO

The nonsteroidal anti-inflammatory drugs (NSAIDs) are amongst the most commonly detected classes of pharmaceuticals in freshwater environments, with paracetamol being the most abundant. The aim of this study was to evaluate the possible toxic effects of environmentally relevant concentrations (0.25, 2.5 and 25 µg.L-1) of paracetamol in Rhamdia quelen fish exposed for 14 days using different biomarkers. The total count of leukocytes and thrombocytes was reduced at the highest concentration. In the gills, all concentrations of paracetamol reduced the glutathione S-transferase (GST) activity and the reduced glutathione (GSH) levels compared to the control group. The activity of catalase (CAT) was not altered and glutathione peroxidase (GPx) activity increased at the highest concentrations. The superoxide dismutase (SOD) activity decreased at 25 µg.L-1 and the LPO levels increased at 2.5 µg.L-1 when compared to the control group. The concentration of ROS was not different among the groups. In the posterior kidney the activities of GST (2.5 µg.L-1), CAT (2.5 µg.L-1 and at 25 µg. L-1) and GPx and GSH levels increased at all concentrations when compared to the control group. The SOD activity and LPO levels did not change. Paracetamol caused genotoxicity in the blood and gills at concentrations of 2.5 µg.L-1 and in the posterior kidney at 2.5 and 25 µg.L-1. An osmoregulatory imbalance in plasma ions and a reduction in the carbonic anhydrase activity in the gills at 0.25 µg.L-1 were observed. Histopathological alterations occurred in the gills of fish exposed to 25 µg.L-1 and in the posterior kidney at 0.25 and 25 µg.L-1 of paracetamol. The integrated biomarker index showed that the stress caused by the concentration of 25 µg.L-1 was the highest one. These results demonstrated toxic effects of paracetamol on the gills and posterior kidneys of fish, compromising their physiological functions and evidencing the need for monitoring the residues of pharmaceuticals released into aquatic environment.


Assuntos
Acetaminofen/toxicidade , Peixes-Gato/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Anti-Inflamatórios não Esteroides , Biomarcadores/metabolismo , Catalase , Dano ao DNA , Brânquias/efeitos dos fármacos , Glutationa/farmacologia , Glutationa Peroxidase , Glutationa Transferase
9.
Gene ; 712: 143966, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279711

RESUMO

BACKGROUND: Acute paracetamol (PCM) toxicity is a clinical problem; can result in a serious liver injury that finally may progress to acute liver failure. Curcumin (CUR) is a prevalent natural compound that can maintain prooxidant/antioxidant balance and thus can help in liver protection; also, Silymarin (SL) is a traditional antioxidant herb, used to treat liver disorders through scavenging free radicals. This study aimed to illustrate the histological, biochemical and molecular changes induced by acute PCM overdose on rats' liver to elucidate the effectiveness of CUR compared to SL in alleviating such changes. MATERIALS AND METHODS: Male Wister Albino rats were divided into 6 groups each comprising 23 rats: control group, curcumin (CUR) treated group received (100 mg CUR/ kg), silymarin treated group received (100 mg SL/kg) for 7 successive days. Paracetamol (PCM) exposed group administered a single dose of PCM (200 mg/kg orally on 8th day). PCM + CUR group and PCM + SL group pretreated with CUR and SL respectively for 7 days then received single PCM dose (200 mg/kg) on the 8th day. Blood and liver tissues were collected for biochemical, histopathological and immunohistochemical analyses using anti-p53 antibody. In addition, real time polymerase chain reaction (RT- PCR) was used to measure Bax, bcl2 and Peroxisome proliferator-activated receptor-gamma (PPAR γ) mRNA expression levels. RESULTS: In the paracetamol overdose group, the liver architecture showed necrotic changes, hydropic degeneration, congestion and dilatation of central veins. This hepatocellular damage was confirmed by a significant increase of AST, ALT levels and by an apparent increase in the number of p53 stained cells. PCM toxicity showed significant elevation of total oxidant status (TOS), oxidant status index (OSI) and decreased total antioxidant capacity (TAC) compared to controls (p < 0.001). Gene expression analysis showed that PCM caused an elevation of bcl2 and a reduction of both Bax and PPARγ mRNA expression. The histological alternation in the liver architecture was markedly improved in (PCM + CUR) group compared to (PCM+ SL) group, with an obvious decrease in the number of P53 stained cells. CUR pretreatment inhibited the elevation of TOS and OSI as well as the reduction of TAC caused by PCM toxicity compared to (PCM + SL) group. CONCLUSION: Both SL and CUR pretreatment prevented the toxic effects of PCM, but CUR is more effective than SL in ameliorating acute PCM induced hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Curcumina/farmacologia , Falência Hepática Aguda/induzido quimicamente , Fígado/efeitos dos fármacos , Silimarina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose , Sinergismo Farmacológico , Imuno-Histoquímica , Masculino , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo
10.
Environ Sci Pollut Res Int ; 26(24): 25301-25311, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31256398

RESUMO

Cisplatin is considered one of the best anticancer medications often used for the treatment of various cancers even with its adverse effects. Acetaminophen (paracetamol) is a widely used analgesic-antipyretic drug that causes hepatotoxicity at higher than the effective doses. The present study assesses the nephroprotective and hepatoprotective effects of two seaweeds against cisplatin and acetaminophen toxicity in rats. Damage to the liver and kidney was induced by administering a single intraperitoneal dose of acetaminophen (600 mg/kg) or cisplatin (7 mg/kg) to groups of rats. The damage to the liver and kidney was assessed by the elevated liver (ALT, AST, ALP, LDH, electrolytes) and kidney (urea, creatinine) biomarkers. The ethanol extract of brown seaweed reversed the elevated levels of kidney and liver biomarkers along with triglycerides, cholesterol, and glucose. Among the two seaweeds, Sargassum ilicifolium showed better nephroprotective and hepatoprotective effects than the standard drug N-Acetyl-cysteine, Halymenia porphyroides showed only limited protection. Findings of this study provide evidence of nephroprotective and hepatoprotective effects of S. ilicifolium. Seaweed could be a beneficial dietary supplement to attenuate nephrotoxicity and hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Alga Marinha/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Creatinina , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Ratos
11.
Environ Toxicol ; 34(11): 1177-1190, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322327

RESUMO

For several years, the scientific community has been concerned about the presence of pharmaceuticals in the wild, since these compounds may have unpredictable deleterious effects on living organisms. Two examples of widely used pharmaceuticals that are present in the environment are paracetamol and ciprofloxacin. Despite their common presence in the aquatic environment due to their poor removal by sewage treatment plants, knowledge concerning their putative toxic effects is still scarce. This work aimed to characterize the effects of paracetamol (0.005, 0.025, 0.125, 0.625, and 3.125 mg/L) and ciprofloxacin (0.005, 0.013, 0.031, 0.078, 0.195, and 0.488 µg/L) in zebrafish embryos and larvae, exposed to environmentally relevant levels, close to the real concentrations of these pharmaceuticals in surface waters and effluents. The adopted toxic end points were developmental, a behavioral parameter (total swimming time), and a biomarker-based approach (quantification of the activities of catalase, glutathione-S-transferase, cholinesterases, glutathione peroxidase, and lipid peroxidation levels) combined with epigenetic analysis (immunohistochemical detection of 5-methylcytidine). Exposure to paracetamol had effects on all of the adopted toxic end points; however, ciprofloxacin only caused effects on behavioral tests and alterations in biomarkers. It is possible to ascertain the occurrence of oxidative stress following exposure to both drugs, which was more evident regarding paracetamol, an effect that may be related to the observed epigenetic modifications.


Assuntos
Acetaminofen/toxicidade , Ciprofloxacino/toxicidade , Epigênese Genética , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Biomarcadores/metabolismo , Catalase/metabolismo , Metilação de DNA , Desenvolvimento Embrionário/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Larva/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento
12.
Toxicol Lett ; 312: 34-44, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31059760

RESUMO

Inflammation is one of the factors that may increase the sensitivity of hepatic cells to acetaminophen (APAP) induced toxicity. To investigate the mechanisms, we exposed 3-dimensional (3D) Human Liver Microtissues, a co-culture of primary human hepatocytes (PHH) and Kupffer cells (KCs), to 0, 0.5 (low), 5 (median) and 10 mM (high dose) APAP for 24 h, with/without lipopolysaccharide (LPS). Microarray-technology was used to evaluate the transcriptome changes. In the presence of LPS, the median-dose of APAP is sufficient to inhibit the expression of respiratory chain- and antioxidant-related genes, suggesting the involvement of reactive oxygen species (ROS) and oxidative stress. Furthermore, the median- and high-dose of APAP inhibited the expression of Fc fragment receptor (FcγR)-coding genes, regardless of the presence of LPS. The toll-like receptor 4 (TLR4) expression, however, was continuously elevated after the LPS/APAP co-exposures, which may result in reduced KC-phagocytosis and unbalanced cytokine patterns. Compared to the treatment with LPS only, LPS/APAP co-exposures induced the production of interleukin (IL)-8, a pro-inflammatory cytokine, but suppressed the secretion of IL-6, a cytokine regulating hepatic regeneration, along with the increase in APAP dosages. In addition to the disrupted mitochondrial functions, the presence of LPS exacerbated APAP toxicity. These findings suggest that 3D Microtissues are a suitable model for the mechanistic exploration of inflammation-associated drug toxicity.


Assuntos
Citocinas/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Técnicas de Cultura de Tecidos/métodos , Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Técnicas de Cocultura , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Macrófagos do Fígado/efeitos dos fármacos , Receptores de IgG/genética , Receptores de IgG/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Transcriptoma/efeitos dos fármacos
13.
Pak J Pharm Sci ; 32(2 (Supplementary)): 817-823, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31103977

RESUMO

The beneficial effects of Pistacia integerrima (PI) fruit methanol extract on some liver and kidney related parameters and blood cells count of paracetamol (PCM) intoxicated male rabbits were studied. Paracetamol intoxication caused remarkable increase in the serum ALT, AST and ALP levels. The PCM intoxicated rabbits that received PI extract orally at doses of 200 mg and 400 mg/kg b.w. /oral/day for 16 days showed significant reduction in serum ALT, AST and ALP levels (P<0.05). Liver microsections from PCM intoxicated rabbits treated with PI fruit methanol extract showed improvement in the liver histoarchitecture. The urine output of PCM intoxicated control rabbits group was significantly lower (P<0.05). The PCM intoxicated rabbits that received PI extract showed significant increase in urine output (P<0.05). The PCM intoxicated rabbits treated with PI extract also showed significant reduction in the levels of serum urea and creatinine (P<0.05). The renal creatinine clearance of PCM rabbits treated with PI extract improved significantly (P<0.05). Microsections of kidneys from PCM intoxicated rabbits treated with PI fruit methanol extract showed improvement in renal histoarchitecture. During this study, PI extract caused no improvement in the RBC count of PCM intoxicated rabbits. However, the extract caused significant increase in WBC and platelets count (P < 0.05) of PCM intoxicated rabbits. From the findings of the present research, it was concluded that oral administration of P. integerrima fruit methanol extract is beneficial for the liver and kidney related biochemical parameters and blood cells count of paracetamol intoxicated male rabbits.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Rim/efeitos dos fármacos , Pistacia/química , Extratos Vegetais/farmacologia , Acetaminofen/efeitos adversos , Animais , Contagem de Células Sanguíneas , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Frutas , Rim/patologia , Masculino , Metanol/química , Coelhos
14.
Environ Sci Pollut Res Int ; 26(21): 21858-21870, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31134547

RESUMO

Over time, the consumption of pharmaceutical drugs has highly augmented, directly contributing for an increase of the discharges of these substances into sewage water due to excretion, and their direct release to the environment, with or without adequate treatment. Considering that part of the sewage water is dumped into rivers and seas, this is the major source of contamination of the aquatic environment. Paracetamol and acetylsalicylic acid are among the most worldwide consumed pharmaceutical drugs, frequently found in wastewater discharges and consequently in the aquatic environment in considerable amounts, posing ecotoxicity concerns especially towards aquatic non-target species. Thus, it is important to study the ecotoxicological implications that these drugs might pose to organisms from aquatic environments. The objective of this study was to assess the toxic effects of these two compounds on key biochemical features (antioxidant defenses and damage, metabolism, and cholinergic neurotoxicity) of the marine snail species Gibbula umbilicalis after an acute (96 h) exposure, simulating pulses of contamination. In order to understand the effects that those drugs have on this species, the biochemical biomarkers analyzed were the activities of catalase (CAT), glutathione-S-transferases (GSTs), cholinesterases (ChEs), and the levels of lipid peroxidation (TBARS). After acute exposure to paracetamol, catalase activity decreased significantly in organisms exposed to both highest concentrations; no significant alterations were observed for glutathione-S-transferases activity; TBARS concentration decreased significantly in organisms exposed to the intermediate and both highest concentrations, and cholinesterase activity increased significantly in animals exposed to the lowest concentration. However, after acute exposure to acetylsalicylic acid, catalase activity increased significantly; no significant alterations were observed for glutathione-S-transferases activity, and TBARS concentrations and cholinesterase activity increased. This set of data shows that G. umbilicalis is highly responsive to the presence of the tested drugs, and may thus be a promising species to serve as test organism in future marine ecotoxicological testing. The adoption of this species may broaden the offer of highly ecologically representative test organisms to be included in biomonitoring projects of the coastal and marine environment. Furthermore, it is possible to suggest that both drugs may pose significant deleterious effects of pro-oxidative origin to the physiology of the selected species, with potential adverse ecological consequences, even after short periods of exposure. The absence of neurotoxicity showed that despite being able to trigger antioxidant mechanisms, both drugs did not affect neurotransmission.


Assuntos
Acetaminofen/toxicidade , Aspirina/toxicidade , Caramujos/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Organismos Aquáticos , Ecotoxicologia/métodos , Biomarcadores Ambientais/efeitos dos fármacos , Monitoramento Ambiental , Enzimas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Caramujos/metabolismo
15.
Life Sci ; 230: 97-103, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129139

RESUMO

AIM: Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver damage. Magnolia officinalis is a traditional hepatoprotective Chinese medicine and Honokiol (HO) is the major active constituent. The present study was to investigate the effect of HO on APAP-induced hepatotoxicity and related mechanisms. MAIN METHODS: Four groups of mice were subjected to treatment as vehicle, APAP, APAP + HO and APAP + HO + NRF2 inhibitor. The morphological and biochemical assessments were used to evaluate the hepatoprotective effects. The extent of APAP-protein adducts was determined through evaluate the hepatic content 3­(cystein­S­yl)acetaminophen (APAP-Cys), the hydrolysis products of APAP-protein adducts. The activities of CYP2E1, CYP1A2 and CYP3A4 were evaluated by cocktail incubation, and the protein expression levels of NRF2, GCLC, GCLM, GS and GST were evaluated by western blot analysis. KEY FINDINGS: Morphological and biochemical assessments clearly demonstrated that HO could alleviate APAP-induced liver damage. The hepatoprotective effect of HO was positively associated with the reduction of APAP-protein adducts. Further investigation suggested that HO induced inhibition of CYP 2E1 and CYP2A1 as well as upregulation of GSH co-contributed to the reduction of APAP-protein adducts. Furthermore, HO induced activations of NRF2 and its target enzymes, such as GCLC, GCLM and GST, gave rise to the upregulation of GSH. SIGNIFICANCE: Our results suggested that HO could alleviate APAP-induced liver damage through reducing the generation of APAP-protein adducts, which might be mediated by inhibiting the activity of CYP 2E1 and CYP2A1 as well as enhancing the generation of GSH via NRF2 pathway.


Assuntos
Acetaminofen/toxicidade , Compostos de Bifenilo/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Lignanas/farmacologia , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Animais , Compostos de Bifenilo/metabolismo , Glutationa/metabolismo , Lignanas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(5): 1031-1039, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31007174

RESUMO

Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It is also one of the most common reasons for termination of new drugs during pre-clinical testing and withdrawal of new drugs post-marketing. DILI is generally divided into two forms: intrinsic and idiosyncratic. Many of the challenges with DILI are due in large part to poor understanding of the mechanisms of toxicity. Although useful models of intrinsic DILI are available, they are frequently misused. Modeling idiosyncratic DILI presents greater challenges, but promising new models have recently been developed. The purpose of this manuscript is to provide a critical review of the most popular animal models of DILI, and to discuss the future of DILI research.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Acetaminofen/toxicidade , Animais , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Humanos , Tolerância Imunológica
17.
Sci Total Environ ; 673: 102-109, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30986672

RESUMO

This work aims to assess, individually and in mixtures, possible phytotoxic effects of three pharmaceuticals (paracetamol, ibuprofen and amoxicillin) on germination and early growth of Lactuca sativa seeds. Pharmaceuticals are an important group of emerging contaminants, whose presence has been described in several environmental compartments, including soils. However, knowledge on their possible impact in terrestrial organisms is still sparse and even more when mixtures are considered. Germination tests are important to evaluate the quality of soil and the toxic effects that contaminants can pose to plants. The acute effects of individual pharmaceuticals as well as binary and ternary mixtures were assessed using different endpoints, namely: percentage of seed germination, root elongation, shoot and leaf length, after an exposure time of five days. Overall, in the exposure of L. sativa seeds to individual pharmaceuticals there are indications of acute toxicity in the early plant growth. However, this inhibitory effect tends to be cancelled in the acute exposure to mixtures. This study shows the importance of evaluating the toxicity of mixtures of pharmaceuticals, since they might have distinct toxic effects when compared to the single compounds, and also because, probably, it is the closest scenario to the reality that can be found in the environment.


Assuntos
Germinação/efeitos dos fármacos , Alface/efeitos dos fármacos , Poluentes do Solo/toxicidade , Acetaminofen/toxicidade , Amoxicilina/toxicidade , Ibuprofeno/toxicidade , Sementes/efeitos dos fármacos
18.
Gastroenterology ; 157(2): 552-568, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31029706

RESUMO

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/patologia , Fosfoproteínas/metabolismo , Adulto , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Overdose de Drogas/complicações , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/transplante , Humanos , Lipogênese/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfoproteínas/genética , Esteroides/metabolismo , Quimeras de Transplante , Regulação para Cima , Ácido Valproico/administração & dosagem
19.
Aquat Toxicol ; 211: 73-80, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954018

RESUMO

Paracetamol (APAP) is one of the most widely used anti-inflammatory and analgesic drugs in human being health care and has been universally detected in various aquatic environments. However, its potential adverse effects and toxic mechanisms on freshwater invertebrates still remain unclear. In the present study, the effects of APAP on the expressions of Nrf1 and the antioxidant related genes including GCLC, GST, GPX, CAT, TRX, TrxR and Prx1 in Daphnia magna (D. magna) were evaluated after 24, 48 and 96 h, and the changes of GPX, GST and CAT enzyme activities, as well as the GSH and MDA content under APAP exposure for 48 h were also determined. Results showed that paracetamol affected the expressions of Nrf1 and antioxidant related genes in D. magna, which were related to the exposure time and concentration of APAP. Nrf1 was inhibited at 48 h, but induced at 96 h under the APAP exposure, being about two fold of the control in 5.0 µg/L. CAT were significantly induced in all treatments. But Prx decreased in an concentration-dependent manner in all treatments. In comparison with the mRNA expression, antioxidant enzymes activity displayed less changes in D. magna. Overall, APAP exposure altered the expression of Nrf1 and genes related to antioxidant system and disturbed the redox homeostasis of D. magna.


Assuntos
Acetaminofen/toxicidade , Antioxidantes/metabolismo , Daphnia/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Daphnia/genética , Daphnia/metabolismo , Relação Dose-Resposta a Droga , Água Doce/química , Oxirredução , Estresse Oxidativo/genética
20.
Nat Commun ; 10(1): 1076, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842418

RESUMO

Phagocytes, including neutrophils and macrophages, have been suggested to function in a cooperative way in the initial phase of inflammatory responses, but their interaction and integration in the resolution of inflammation and tissue repair remain unclear. Here we show that neutrophils have crucial functions in liver repair by promoting the phenotypic conversion of pro-inflammatory Ly6ChiCX3CR1lo monocytes/macrophages to pro-resolving Ly6CloCX3CR1hi macrophages. Intriguingly, reactive oxygen species (ROS), expressed predominantly by neutrophils, are important mediators that trigger this phenotypic conversion to promote liver repair. Moreover, this conversion is prevented by the depletion of neutrophils via anti-Ly6G antibody, genetic deficiency of granulocyte colony-stimulating factor, or genetic deficiency of NADPH oxidase 2 (Nox2). By contrast, adoptive transfer of WT rather than Nox2-/- neutrophils rescues the impaired phenotypic conversion of macrophages in neutrophil-depleted mice. Our findings thus identify an intricate cooperation between neutrophils and macrophages that orchestrate resolution of inflammation and tissue repair.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Regeneração Hepática/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Acetaminofen/toxicidade , Transferência Adotiva/métodos , Animais , Transplante de Medula Óssea , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Humanos , Fígado/imunologia , Fígado/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , NADPH Oxidase 2/genética , NADPH Oxidase 2/imunologia , Neutrófilos/metabolismo , Neutrófilos/transplante , Cultura Primária de Células , Quimeras de Transplante
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