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1.
Fitoterapia ; 139: 104400, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669962

RESUMO

Two novel epimer pairs of acetaminophen derivatives penicilquei A-D (1-4) were isolated from Penicillium herquei JX4. Their structures were elucidated using comprehensive spectroscopic methods. The absolute configurations of penicilquei A-D (1-4) were determined by modifified Mosher's method, and comparing their experimental and calculated electronic circular dichroism (ECD) spectra. Penicilquei A-D (1-4) are the first example of acetaminophen derivatives featuring an unprecedented carbon skeleton. The inhibitory activities of all compounds against nine phytopathogenic fungi and α-glucosidase were evaluated. Penicilquei A-D (1-4) showed strong inhibitory activities against at least eight phytopathogenic fungus.


Assuntos
Acetaminofen/farmacologia , Fungicidas Industriais/farmacologia , Penicillium/química , Acetaminofen/química , China , Fungicidas Industriais/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Estrutura Molecular , Rhizophoraceae/microbiologia
2.
Chem Commun (Camb) ; 55(95): 14307-14310, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31713549

RESUMO

A novel hepatocyte-targeting near-infrared fluorescent probe named Gal-NIR is developed. Gal-NIR shows ratiometric response to ONOO- with high sensitivity and selectivity. Moreover, the probe can accurately target the hepatocyte, and thus is used for assessing drug-induced hepatotoxicity and its remediation by using hepatoprotective medicines in living cells and mice.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Corantes Fluorescentes/análise , Hepatócitos/efeitos dos fármacos , Imagem Óptica , Ácido Peroxinitroso/análise , Acetaminofen/administração & dosagem , Acetaminofen/farmacologia , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/química , Humanos , Raios Infravermelhos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular
3.
Chemosphere ; 236: 124391, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31545194

RESUMO

Acetaminophen (ACT) is commonly used as a counter painkiller and nowadays, it is increasingly present in the natural water environment. Although its concentrations are usually at the ppt to ppm levels, ACT can transform into various intermediates depending on the environmental conditions. Due to the complexity of the ACT degradation products and the intermediates, it poses a major challenge for monitoring, detection and to propose adequate treatment technologies. The main objectives of this review study were to assess (i) the occurrences and toxicities, (2) the removal technologies and (3) the transformation pathways and intermediates of ACT in four environmental compartments namely wastewater, surface water, ground water, and soil/sediments. Based on the review, it was observed that the ACT concentrations in wastewater can reach up to several hundreds of ppb. Amongst the different countries, China and the USA showed the highest ACT concentration in wastewater (≤300 µg/L), with a very high detection frequency (81-100%). Concerning surface water, the ACT concentrations were found to be at the ppt level. Some regions in France, Spain, Germany, Korea, USA, and UK comply with the recommended ACT concentration for drinking water (71 ng/L). Notably, ACT can transform and degrade into various metabolites such as aromatic derivatives or organic acids. Some of them (e.g., hydroquinone and benzoquinone) are toxic to human and other life forms. Thus, in water and wastewater treatment plants, tertiary treatment systems such as advanced oxidation, membrane separation, and hybrid processes should be used to remove the toxic metabolites of ACT.


Assuntos
Acetaminofen/efeitos adversos , Poluição Ambiental/análise , Poluentes Químicos da Água/química , Acetaminofen/farmacologia , Humanos
4.
BMC Bioinformatics ; 20(1): 417, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409281

RESUMO

BACKGROUND: The development of high throughput sequencing techniques provides us with the possibilities to obtain large data sets, which capture the effect of dynamic perturbations on cellular processes. However, because of the dynamic nature of these processes, the analysis of the results is challenging. Therefore, there is a great need for bioinformatics tools that address this problem. RESULTS: Here we present DynOVis, a network visualization tool that can capture dynamic dose-over-time effects in biological networks. DynOVis is an integrated work frame of R packages and JavaScript libraries and offers a force-directed graph network style, involving multiple network analysis methods such as degree threshold, but more importantly, it allows for node expression animations as well as a frame-by-frame view of the dynamic exposure. Valuable biological information can be highlighted on the nodes in the network, by the integration of various databases within DynOVis. This information includes pathway-to-gene associations from ConsensusPathDB, disease-to-gene associations from the Comparative Toxicogenomics databases, as well as Entrez gene ID, gene symbol, gene synonyms and gene type from the NCBI database. CONCLUSIONS: DynOVis could be a useful tool to analyse biological networks which have a dynamic nature. It can visualize the dynamic perturbations in biological networks and allows the user to investigate the changes over time. The integrated data from various online databases makes it easy to identify the biological relevance of nodes in the network. With DynOVis we offer a service that is easy to use and does not require any bioinformatics skills to visualize a network.


Assuntos
Redes Reguladoras de Genes , Interface Usuário-Computador , Acetaminofen/farmacologia , Biologia Computacional/métodos , Bases de Dados Factuais , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
5.
Paediatr Drugs ; 21(3): 177-183, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155693

RESUMO

AIM: Studies in adults have reported frequent episodes of blood pressure drops following intravenous paracetamol administration. We aimed to investigate the hemodynamic effects of intravenous paracetamol in critically ill children. METHODS: The charts of 100 pediatric intensive care patients (age range 0.1-18 years) who were treated with intravenous paracetamol between March and September 2017 were retrospectively reviewed. A hemodynamic event was defined as a drop of > 15% in systolic or mean arterial blood pressure within 120 min after drug administration. Hypotension was defined as either a drop in systolic blood pressure (SBP) below the 5th percentile for age or a hemodynamic event associated with tachycardia, increased lactate level, or treatment with a fluid bolus or vasopressors. RESULTS: A hemodynamic event was observed in 39 patients (39%). In these patients, SBP was in the pre-hypertension or hypertension values in 36/39 patients before paracetamol administration, median (IQR) SBP decreased from the 99th (95-99) percentile for age before to the 50th (50-95) percentile after paracetamol (p < 0.001) and mean heart rate was 137 bpm before treatment and 115 bpm after (p = 0.002). SBP values did not drop below the 5th percentile in any patient. In 15 patients diagnosed with shock on admission, paracetamol treatment did not cause an increase in vasopressor treatment after drug administration. CONCLUSIONS: In the present study of critically ill pediatric patients, intravenous paracetamol administration was associated with a drop in SBP from high to normal values for age, possibly due to pain relief, with no evidence for a negative hemodynamic event.


Assuntos
Acetaminofen/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Acetaminofen/farmacologia , Administração Intravenosa , Adolescente , Analgésicos não Entorpecentes/farmacologia , Criança , Pré-Escolar , Feminino , Hemodinâmica , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
6.
J Mol Model ; 25(7): 181, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175465

RESUMO

In order to reveal the essence of the pharmaceutical incompatibility, the cooperativity effects of the drug-drug intermolecular π∙∙∙π and H∙∙∙O H-bonding interactions involving hydration were evaluated in the phenobarbital∙∙∙paracetamol∙∙∙H2O complex at the M06-2X/6-311++G** and MP2/6-311++G** levels. The thermodynamic cooperativity effects were also investigated by the statistical thermodynamic method. The results show that the π∙∙∙π stacking ternary complexes with the moderate anti-cooperativity effects are dominant in controling the aggregation process of phenobarbital, paracetamol, and H2O, as is confirmed by the atoms-in-molecules (AIM) and reduced density gradient (RDG) analyses. Therefore, it can be inferred that the anti-cooperativity effect plays an important role in forming the pharmaceutical incompatibility, and thus a deduction on the formation process of the pharmaceutical incompatibility between phenobarbital and paracetamol, with the hydration effect, is given. Several valuable models that relate the features of molecular surface electrostatic potentials or their statistical parameters, such as the surface areas, average values ([Formula: see text]), variances ([Formula: see text], [Formula: see text] and [Formula: see text]), and product of [Formula: see text] and electrostatic balance parameter (ν) ([Formula: see text]ν), to the values of the cooperativity effects were predicted. The formation of the pharmaceutical incompatibility is a thermodynamic cooperativity process driven by the enthalpy change. Graphical abstract Anti-cooperativity effect plays an important role in forming the pharmaceutical incompatibility.


Assuntos
Acetaminofen/química , Incompatibilidade de Medicamentos , Interações de Medicamentos , Modelos Teóricos , Fenobarbital/química , Água/química , Acetaminofen/farmacologia , Algoritmos , Humanos , Ligações de Hidrogênio , Modelos Moleculares , Conformação Molecular , Fenobarbital/farmacologia , Eletricidade Estática , Relação Estrutura-Atividade
7.
Biomed Pharmacother ; 117: 109097, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31212128

RESUMO

An overdose of the most popular analgesic, acetaminophen (APAP), is one of the leading causes of acute liver failure. It is well established that glutathione is exhausted by APAP-reactive intermediate N­acetyl­p­benzoquinone-imine (NAPQI). This leads to elevated phosphorylated-c-Jun N-terminal kinase (p-JNK), which further activates reactive oxygen species (ROS), initiates an inflammatory response, and finally leads to severe hepatic injury. The present study was conducted to investigate the protective role of mangiferin (MAN), a naturally occurring xanthone and anti-oxidant, on APAP-induced hepatotoxicity. C57BL/6 mice were pretreated with or without MAN at 1 h prior to APAP challenge. MAN was administered at a dose of 12.5-50 mg/kg along with APAP at a dose of 400 mg/kg. According to the ALT/AST ratio, 25 mg/kg MAN was the most potent dose for further experiments. Serum ALT and AST depletion were observed in APAP + MAN (25 mg/kg)-treated mice at 6, 12, and 24 h. Early (1 h after APAP treatment) GSH depletion by APAP overdose was restored by MAN treatment, which reduced APAP-Cys adduct formation and promoted protection. p-JNK downregulation and AMPK activation were observed in MAN-treated mice, which could mechanistically reduce oxidative stress and inflammation. MAN up-regulated liver GSH and SOD and reduced lipid peroxidation. HO-1 protein and p47 phox mRNA expression indicated that MAN regulated oxidative stress along with JNK deactivation. The expression of inflammatory response genes TNF-α, IL-6, MCP-1, CXCL-1, and CXCL-2 reached the basal levels after MAN treatment. mRNA, protein, and serum levels of IL-1ß were reduced, and NF-κB expression was similar to that of the MAN-treated APAP mice. MAN post-treatment (1 h after APAP treatment) also protected the mice from hepatotoxicity. In conclusion, MAN had a protective and therapeutic role in APAP-induced hepatotoxicity by improving the metabolism of acetaminophen and APAP-Cys adduct formation followed by JNK-mediated oxidative stress and inflammation.


Assuntos
Acetaminofen/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Xantonas/farmacologia , Animais , Antioxidantes/farmacologia , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Oxid Med Cell Longev ; 2019: 2745352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049130

RESUMO

N-Acetyl-p-aminophenol (APAP) or acetaminophen is the most common drug ingredient worldwide. It is found in more than 600 different over-the-counter and prescription medicines. Its long-term and overdose use is highly toxic and may result in liver injury. Thus, this study was designed to assess the preventive effects and to suggest the mechanisms of action of the navel orange peel hydroethanolic extract, naringin, and naringenin in APAP-induced hepatotoxicity in male Wistar rats. APAP was administered to male Wistar rats at a dose level of 0.5 g/kg body weight (b.w.) by oral gavage every other day for 4 weeks. APAP-administered rats were treated with the navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.), and naringenin (20 mg/kg b.w.) by oral gavage every other day during the same period of APAP administration. The treatments of APAP-administered rats with the peel extract, naringin, and naringenin produced a significant decrease in the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-α levels while they induced a significant increase in the lowered serum albumin and IL-4 levels. The treatments also resulted in a significant decrease in the elevated liver lipid peroxidation and enhanced the liver GSH content and SOD, GST, and GPx activities as compared with APAP-administered control; the peel extract was the most potent in improving the liver LPO, GSH content, and GPx activity. In addition, the three treatments significantly downregulated the elevated hepatic proapoptotic mediators p53, Bax, and caspase-3 and significantly upregulated the suppressed antiapoptotic protein, Bcl-2, in APAP-administered rats. In association, the treatments markedly amended the APAP-induced liver histopathological deteriorations that include hepatocyte steatosis, cytoplasmic vacuolization, hydropic degeneration, and necrosis together with mononuclear leucocytic and fibroblastic inflammatory cells' infiltration. In conclusion, the navel orange peel hydroethanolic extract, naringin, and naringenin may exert their hepatopreventive effects in APAP-administered rats via enhancement of the antioxidant defense system and suppression of inflammation and apoptosis.


Assuntos
Acetaminofen/efeitos adversos , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Citrus sinensis/química , Flavanonas/efeitos adversos , Frutas/química , Extratos Vegetais/farmacologia , Acetaminofen/farmacologia , Animais , Antioxidantes/química , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Flavanonas/farmacologia , Hepatócitos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Extratos Vegetais/química , Ratos , Ratos Wistar
9.
Phytochemistry ; 163: 126-131, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059964

RESUMO

Four undescribed cembrane-type diterpenoids, boscartins L-O, as well as five known compounds (1S, 3R, 11S, 12R, 7E)-1,12-epoxy-4-methylenecembr-7- ene- 3,11-diol, isoincensole oxide, incensole oxide, incensole acetate and incensole oxide acetate were isolated from the gum resin of Boswellia sacra Flueck. (Burseraceae). The structures of these compounds were elucidated by extensive 1D and 2D NMR spectroscopic and mass spectrometric analysis, as well as comparisons with known compounds. The absolute configurations of the known compound (1S, 3R, 7E, 11S, 12R)-1,12-epoxy-4-methylenecembr-7-ene-3,11-diol was unequivocally confirmed by single-crystal X-ray diffraction analysis with Cu Kα radiation. Incensole acetate exhibited significant hepatoprotective activity at 10 µM against paracetamol-induced HepG2 cell damage.


Assuntos
Boswellia/química , Diterpenos/farmacologia , Acetaminofen/antagonistas & inibidores , Acetaminofen/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Pak J Pharm Sci ; 32(2): 581-592, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31081770

RESUMO

Pyrexia occurs due to infection, malignancy and other diseases. Majority of the antipyretic drugs are synthetic in nature which exerts side effects such as gastric ulcer, hepatic necrosis and renal damage. The antipyretic potential of the hydro-alcoholic extracts of Achillea millefolium, Taraxacum officinale, Salix alba and Trigonella foenum were investigated on the yeast-induced pyrexia in albino rats. Paracetamol was used as a positive control. Rectal temperature of albino rats was verified immediately before the administration of the extracts or vehicle or paracetamol and yet again at 1-hour gap for 6 hours using a digital thermometer. The animals having pyrexia were divided into four groups Group1: Paracetamol was given to positive control. Group 2: Distilled water was given to negative control. Group 3: (250mg/kg) extract of the plant was given to rats (treatment group 1). Group 4: (500mg/kg) extracts of the plant was given to albino rats (Treatment group 2). The extracts were also phytochemically screened for alkaloids, tannins, saponins, flavonoids, cardiac glycosides and phenols. The hydro-alcoholic extracts of plants with the dose of 500mg/kg showed significant (p<0.0001) decrease in yeast-induced pyrexia, as compared with that of set drug paracetamol (150mg/kg) where the extract dose 250mg/kg was less effective than that of standard drug (p<0.05). Phytochemical screening showed the presence of alkaloids, tannins, flavonoids, saponins and phenols. This study showed that hydro-alcoholic extracts of all plants under study at a dose of 500mg/kg have significant antipyretic potential in yeast-induced elevated temperature.


Assuntos
Antipiréticos/química , Antipiréticos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Acetaminofen/farmacologia , Achillea/química , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Febre/tratamento farmacológico , Febre/etiologia , Masculino , Paquistão , Compostos Fitoquímicos/análise , Ratos , Salix/química , Taraxacum/química , Trigonella/química
11.
Immunopharmacol Immunotoxicol ; 41(3): 413-419, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31142171

RESUMO

Objectives: Accumulating evidence indicates that combination of therapeutic agents may increase their pharmacological properties with fewer undesired side effects. Acetaminophen (APAP) has been widely used to treat pain and fever in many countries. However, APAP only possesses a weak anti-inflammatory property at therapeutic dose, and exhibits hepatotoxicity at high dose. On other hand, sulforaphane (SFN) has been well-known as a potential anti-inflammatory and antioxidant agent. In this study, we investigated the anti-inflammatory and antioxidant effects of combination between APAP and SFN in LPS-stimulated RAW 264.7 macrophage cells. Methods: Nitric oxide (NO) assay was determined using the Griess assay. Reactive oxygen species (ROS) formation was measured using an ROS-sensitive fluorescence indicator, DCFH-DA. The protein expression was determined by western blot analysis. Results: Our results showed that the combination of SFN and APAP exhibited an inhibitory effect on inflammatory markers such as NO, iNOS, COX-2, and IL-1ß, and this effect was more pronounced than the compound was used alone. In addition, the combination of SFN and APAP at low doses decreased intracellular ROS formation and increased the protein levels of CAT, GPx, Nrf2, NQO1, and HO-1, which were much better than APAP alone and were equivalent to SFN at full dose. Conclusions: Our findings suggest that the combination of APAP and SFN enhanced anti-inflammatory and anti-oxidant activities in stimulated macrophages, which provide an important rationale to utilize drug and food in combination for prevention and/or treatment inflammation-related diseases.


Assuntos
Acetaminofen/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/farmacologia , Lipopolissacarídeos/toxicidade , Animais , Regulação da Expressão Gênica/imunologia , Camundongos , Células RAW 264.7
12.
Int Immunopharmacol ; 73: 270-279, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125926

RESUMO

BACKGROUND: Dengue fever is a re-emerging viral disease and affects millions of population worldwide. Monocytes are involved in dengue viral disease, however, their exact role is still not clear. In the present study, we investigated, the effect of NS1 antigen of dengue virus and paracetamol on THP-1 monocytes associated to expressions of matrix metalloproteinases (MMPs) and cytokine release. METHODS: Assessment of cell morphology by bright field microscopy, cell viability by MTT assay, protein estimation by Bradford reagent were done in cells exposed to NS1 antigen in the presence and absence of paracetamol. Cytokines estimations were done by ELISA. Expression profile of matrix metalloproteinase genes was done using real-time PCR and reverse-transcriptase PCR. RESULTS: NS1 exposure of THP-1 monocytes cells, changed their cell morphology and activated them for release of proteins in 24 h. Expressions of MMP-2, MMP-8, MMP-9 and MMP-14 genes were upregulated by NS1 exposure. Further, exposure of NS1 to THP-1 monocytes cells increased expression profile of MMP-10 and MMP-13 genes to a lesser extent. Treatment with paracetamol (1 mg/ml and 2 mg/ml), significantly down-regulated the expression profile of MMP-2, MMP-8, MMP-9 and 14 in dose dependent manner. NS1 exposure also increased the release of cytokines IL-4, IL-6, and IL-10 but decreased the release of TNF-α and IL-15. Interestingly, paracetamol reversed NS1 induced changes in the release of these cytokine in dose dependent manner. CONCLUSION: Monocytes mediated expression of MMPs participates in the development of dengue pathogenesis in the severe cases of disease and paracetamol may have a protective effect in dengue viral disease.


Assuntos
Acetaminofen/farmacologia , Metaloproteinases da Matriz/genética , Monócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteínas não Estruturais Virais/farmacologia , Citocinas/metabolismo , Dengue , Humanos , Monócitos/metabolismo , RNA Mensageiro/metabolismo , Células THP-1
13.
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
14.
Biochem Cell Biol ; 97(2): 176-186, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30933551

RESUMO

This study was designed to evaluate the possible mechanisms through which Echinops spinosus (ES) extract demonstrates nephroprotective effect on the paracetamol acetominophen (N-acetyl-p-aminophenol (APAP)) induced nephrotoxicity in rats. Twenty-four Swiss albino rats were divided into four groups (six rats each). The placebo group was orally administered sterile saline, the APAP group received APAP (200 mg·kg-1·day-1 i.p.) daily, the ES group was given ES extract orally (250 mg/kg), and the APAP + ES group received APAP as for the APAP group and administrated the ES extract as for the ES group. Pretreatment of methyl alcohol extract of ES reduced the protein expression of inflammatory parameters including cyclooxygenase-2 and nuclear factor κB in the kidney. It also reduced the mRNA gene expression of tumor necrosis factor-α and interleukin-1ß. The ES extract compensated for deficits in the total antioxidant activity, suppressed lipid peroxidation, and amended the APAP-induced histopathological kidney alterations. Moreover, ES treatment restored the elevated levels of urea nitrogen in the blood and creatinine in the serum by APAP. The ES extract attenuated the APAP-induced elevations in renal nitric oxide levels. We clarified that the ES extract has the potential to defend the kidney from APAP-induced inflammation, and the protection mechanism might be through decreasing oxidative stress and regulating the inflammatory signaling pathway through modulating key signaling inflammatory biomarkers.


Assuntos
Acetaminofen/efeitos adversos , Echinops (Planta)/química , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Rim/metabolismo , Extratos Vegetais/farmacologia , Acetaminofen/farmacologia , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Extratos Vegetais/química , Ratos
15.
J Biochem Mol Toxicol ; 33(7): e22321, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30925002

RESUMO

miR-122 and miR-192 were investigated as indicators of toxic liver injury caused by acetaminophen, but their role in idiosyncratic toxic liver injury remains controversial. So, this work aimed to assess and compare the expressions of miR-122 and miR-192 in two different types of toxic liver injury (intrinsic [acetaminophen] and idiosyncratic [diclofenac]). Forty male adult Wistar albino rats were divided into equal five groups, in which serum liver enzymes; microRNAs (miRNAs) expressions (miR-122 and miR-192) and histopathological findings were studied. The present study showed that (1) miR-122 and miR-192 are good serum biomarkers of toxic liver injury whatever its etiology, as their serum levels exhibited a significantly earlier increase and earlier return to normal baseline levels as compared to serum aminotransferase levels; (2) miR-122 is more specific than miR-192; and (3) both serum levels of miR-122 and miR-192 showed non-significant differences in relation to the type of toxic liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , MicroRNAs/sangue , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Animais , Biomarcadores/sangue , Masculino , Ratos , Ratos Wistar
16.
Nurs Womens Health ; 23(2): 105-113, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826322

RESUMO

OBJECTIVE: To decrease hospital expenses by administering oral acetaminophen rather than intravenous (IV) acetaminophen to women who undergo laparoscopic hysterectomy. DESIGN: A quality improvement project using a between-groups, pre-/postimplementation design for women undergoing total laparoscopic hysterectomy. Retrospective chart review was used to compare data of women who received intraoperative IV acetaminophen before implementation versus women who received oral acetaminophen after implementation. Pain scores and opioid consumption in morphine equivalents were recorded at four time points. SETTING/LOCAL PROBLEM: A 369-bed hospital in the southeastern United States, where, in 2016, nearly $260,000 was spent on perioperative IV acetaminophen for all operating room cases. PARTICIPANTS: Women between the ages of 18 and 55 years scheduled to have total laparoscopic hysterectomy were included. Excluded were women with a history of chronic pain, opioid use, or liver pathology; women with a contraindication to nonsteroidal anti-inflammatory drugs; and women whose procedures were converted from laparoscopic to open. INTERVENTION/MEASUREMENTS: Women were instructed to take oral acetaminophen the day before surgery in divided doses, with 1 g every 6 hours, for a total dose of 3 g. On the day of surgery, women received the final 1-g dose of oral acetaminophen. RESULTS: There were no significant differences between groups for pain scores or total opioids received before implementation (mean = 3.28, standard deviation = 2.05) compared with after implementation (mean = 3.65, standard deviation = 1.63; t [18] = -.043, p = .674). The preimplementation cost per individual was $30.03 for 1 g of IV acetaminophen, and the postimplementation cost was $0.36 for 2 500-mg oral acetaminophen tablets, a 98.8% relative cost decrease per woman. CONCLUSION: Replacing IV acetaminophen with preemptive oral acetaminophen has the potential to save money without compromising care.


Assuntos
Acetaminofen/uso terapêutico , Histerectomia/métodos , Laparoscopia/métodos , Manejo da Dor/normas , Acetaminofen/farmacologia , Administração Oral , Adolescente , Adulto , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Pessoa de Meia-Idade , Manejo da Dor/métodos , Medição da Dor/métodos , Medição da Dor/normas , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/prevenção & controle , Melhoria de Qualidade , Estudos Retrospectivos , Sudeste dos Estados Unidos
17.
Gene ; 702: 46-55, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898700

RESUMO

Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44high/CD24low phenotype, we screened the impacts of APAP (1 mM, 72 h) on the Epithelial to mesenchymal transition (EMT)-related expression of miRs. APAP significantly overexpressed hsa-miR-130a-3p, 192-5p, 214-3p, 101-3p, 30d-5p, 10a-5p, 99a-5p, 200c-3p, 143-3p, 30b-5p and let-7f-5p showed significant overexpression, but suppressed the expression of hsa-miR-7-5p, 149-3p, 215, 150-5p, 205-5p, 206, 10b-5p, 20b-5p, 145-5p, 26b-5p, 223-3p, 17-5p, 186-5p, 146a-5p and let-7c. It also altered on the expression of selected EMT-related genes, significantly upregulated the expression of KRT19, AKT2, CD24, and TIMP1; but downregulated the expression of MMP2, ALDH1, MMP9, TWIST, NOTCH1, and AKT1. Such shifts in expression profiles increased the population of the cells with CD44high/CD24high, and CD44low/CD24high phenotypes, significantly reduced the Twist protein and shifted the balance of E-cadherin and Vimentin proteins in favor of differentiation. Treated cells showed a significant reduction of in vitro migration and were significantly chemosensitized to Camptothecin. In conclusion, APAP, at a safe clinical dose, induced a set of targeted alterations in the EMT-related miRs which implicate, even in part, significant mitigation in chemoresistance and in vitro migration. Further studies should also be piloted to elucidate the most crucial miRs and to evaluate its clinical effectiveness.


Assuntos
Acetaminofen/farmacologia , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/genética , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Acetaminofen/toxicidade , Antineoplásicos/toxicidade , Antígeno CD24/metabolismo , Camptotecina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/fisiopatologia
18.
Bioanalysis ; 11(5): 349-364, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30873855

RESUMO

AIM: Two rapid and sensitive chromatographic methods have been developed and validated for simultaneous analysis of sofosbuvir (SOF) in rat plasma with two co-administered drugs, paracetamol (PAR) and DL-methionine (MET). MATERIALS & METHODS: The first method relied on using TLC-densitometry with a developing system consisted of chloroform: methanol: glacial acetic acid: formic acid in the ratio of 9.5: 1: 1.5: 0.5, by volume. The studied analytes and the internal standard naphazoline hydrochloride were scanned at 210 nm. The second method was HPLC method, whereas the analytes and the internal standard cinnarizine were separated on XTerra® HPLC RP C18 column using gradient elution mode and a mobile phase consisted of methanol: 0.1% aqueous TEA at pH 3 adjusted with orthophosphoric acid at 210 nm. RESULTS: The TLC-densitometry method showed linearity over concentration ranges of 160-3000 ng/band for SOF and PAR, 300-3000 ng/band for MET, but HPLC method was linear and validated over concentration ranges of 150-5000 ng/ml for SOF, 300-5000 ng/ml for both PAR and MET. CONCLUSION: All validation parameters met the acceptance criteria according to US FDA guidelines. Pharmacokinetic study was successfully applied and proved the possibility of co-administration of SOF with PAR and MET.


Assuntos
Acetaminofen/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Antivirais/sangue , Cromatografia Líquida/métodos , Quimioterapia Combinada/métodos , Metionina/uso terapêutico , Sofosbuvir/sangue , Espectrometria de Massas em Tandem/métodos , Acetaminofen/farmacologia , Analgésicos não Entorpecentes/farmacologia , Animais , Feminino , Metionina/farmacologia , Ratos
19.
Cell Mol Neurobiol ; 39(5): 605-617, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30850915

RESUMO

Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.


Assuntos
Neoplasias Mamárias Animais/patologia , Nociceptividade , Acetaminofen/farmacologia , Acetaminofen/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Neoplasias Ósseas/sangue , Neoplasias Ósseas/secundário , Cálcio/sangue , Canabinoides/agonistas , Linhagem Celular Tumoral , Codeína/farmacologia , Codeína/uso terapêutico , Modelos Animais de Doenças , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Locomoção , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/fisiopatologia , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Morfina/uso terapêutico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Medição da Dor
20.
Biotech Histochem ; 94(5): 313-319, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30777790

RESUMO

Exposure to high doses of acetaminophen is the most common cause of drug induced liver injury. We investigated the protective effects of Hedera helix extract against acetaminophen induced oxidative stress and hepatotoxicity using a mouse model. We used two control groups: group A was given 0.9% NaCl, group B was an acetaminophen control that was given a single injection of 600 mg/kg acetaminophen. T1-T4 groups were pretreated orally with different doses of H. helix extract. The mice were sacrificed and blood samples were collected to estimate the levels of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) and total bilirubin. Liver samples also were used for histopathological studies. We found that acetaminophen significantly increased the levels of serum ALP, ALT, AST and MDA, and also significantly reduced the antioxidant factors, CAT, GPX and SOD. H. helix extract treatment produced a significant reduction in the levels of ALP, ALT, AST and MDA in serum and restored the levels of CAT, GPX and SOD to control levels. The histopathological findings were consistent with the biochemical findings. H. helix extract exhibited antioxidant and hepatoprotective effects against acetaminophen induced liver damage.


Assuntos
Acetaminofen/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hedera , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Acetaminofen/envenenamento , Alanina Transaminase/metabolismo , Animais , Antioxidantes/uso terapêutico , Aspartato Aminotransferases/metabolismo , Antagonismo de Drogas , Glutationa Peroxidase/metabolismo , Interações Ervas-Drogas , Fígado/enzimologia , Fígado/fisiopatologia , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Superóxido Dismutase/metabolismo
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