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1.
Ecotoxicol Environ Saf ; 203: 111041, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888612

RESUMO

Although the production and use of PCB153 have been banned globally, PCB153 pollution remains because of its persistence and long half-life in the environment. There is ongoing evidence that exposure to PCB153 may influence gut microbiota health and increase the risk of host health. It is needed to illuminate whether there are associations between gut microbiota dysregulation and PCB153-induced host diseases. Importantly, it is urgently needed to find specific strains as biomarkers to monitor PCB153 pollution and associated disorders. The work aims to investigate the change of gut microbiota composition, structure and diversity and various host physiological indexes, to ravel the chain causality of PCB153, gut microbiota health and host health, and to find potential gut microbiota markers for PCB153 pollution. Here, adult female mice were administrated with PCB153. Obtained results indicated that PCB153 led to gut microbiota health deterioration. PCB153 exposure also induced obesity, hepatic lipid accumulation, abdominal adipose tissue depots and dyslipidemia in mice. Furthermore, specific gut microbiota significantly correlated with the host health indexes. This work provides support for the relationship between gut microbiota aberrance derived from PCB153 and risk of host health, and offers some indications of possible indicative functions of gut microbiota on PCB153 pollution.


Assuntos
Dislipidemias/induzido quimicamente , Monitoramento Ambiental/métodos , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Bifenilos Policlorados/toxicidade , Animais , Biomarcadores/análise , Colo/microbiologia , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Feminino , Conteúdo Gastrointestinal/microbiologia , Microbioma Gastrointestinal/genética , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia , RNA Ribossômico 16S
2.
Aquat Toxicol ; 227: 105590, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32891021

RESUMO

The aim of the present study was to investigate effects of defined mixtures of polycyclic aromatic hydrocarbons (PAHs) and perfluoroalkyl substances (PFASs), at low, environmentally relevant (1× = L), or high (20× = H) doses, on biological responses in Atlantic cod (Gadus morhua). To this end, farmed juvenile cod were exposed at day 0 and day 7 via intraperitoneal (i.p.) injections, in a two-week in vivo experiment. In total, there were 10 groups of fish (n = 21-22): two control groups, four separate exposure groups of PAH and PFAS mixtures (L, H), and four groups combining PAH and PFAS mixtures (L/L, H/L, L/H, H/H). Body burden analyses confirmed a dose-dependent accumulation of PFASs in cod liver and PAH metabolites in bile. The hepatosomatic index (HSI) was significantly reduced for three of the combined PAH/PFAS exposure groups (L-PAH/H-PFAS, H-PAH/L-PFAS, H-PAH/H-PFAS). Analysis of the hepatic proteome identified that pathways related to lipid degradation were significantly affected by PFAS exposure, including upregulation of enzymes in fatty acid degradation pathways, such as fatty acid ß-oxidation. The increased abundances of enzymes in lipid catabolic pathways paralleled with decreasing levels of triacylglycerols (TGs) in the H-PFAS exposure group, suggest that PFAS increase lipid catabolism in Atlantic cod. Markers of oxidative stress, including catalase and glutathione S-transferase activities were also induced by PFAS exposure. Only minor and non-significant differences between exposure groups and control were found for cyp1a and acox1 gene expressions, vitellogenin concentrations in plasma, Cyp1a protein synthesis and DNA fragmentation. In summary, our combined proteomics and lipidomics analyses indicate that PFAS may disrupt lipid homeostasis in Atlantic cod.


Assuntos
Fluorcarbonetos/toxicidade , Gadus morhua/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bile/metabolismo , Biomarcadores/metabolismo , Fluorcarbonetos/análise , Lipidômica , Fígado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/análise , Proteoma/metabolismo , Proteômica , Vitelogeninas/metabolismo , Poluentes Químicos da Água/análise
3.
Environ Health Prev Med ; 25(1): 53, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917140

RESUMO

BACKGROUND: Pilea umbrosa (Urticaceae) is used by local communities (district Abbotabad) for liver disorders, as anticancer, in rheumatism and in skin disorders. METHODS: Methanol extract of P. umbrosa (PUM) was investigated for the presence of polyphenolic constituents by HPLC-DAD analysis. PUM (150 mg/kg and 300 mg/kg) was administered on alternate days for eight weeks in rats exposed with carbon tetrachloride (CCl4). Serum analysis was performed for liver function tests while in liver tissues level of antioxidant enzymes and biochemical markers were also studied. In addition, semi quantitative estimation of antioxidant genes, endoplasmic reticulum (ER) induced stress markers, pro-inflammatory cytokines and fibrosis related genes were carried out on liver tissues by RT-PCR analysis. Liver tissues were also studied for histopathological injuries. RESULTS: Level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione (GSH) decreased (p < 0.05) whereas level of thiobarbituric acid reactive substance (TBARS), H2O2 and nitrite increased in liver tissues of CCl4 treated rat. Likewise increase in the level of serum markers; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin was observed. Moreover, CCl4 caused many fold increase in expression of ER stress markers; glucose regulated protein (GRP-78), x-box binding protein1-total (XBP-1 t), x-box binding protein1-unspliced (XBP-1 u) and x-box binding protein1-spliced (XBP-1 s). The level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) was aggregated whereas suppressed the level of antioxidant enzymes; γ-glutamylcysteine ligase (GCLC), protein disulfide isomerase (PDI) and nuclear erythroid 2 p45-related factor 2 (Nrf-2). Additionally, level of fibrosis markers; transforming growth factor-ß (TGF-ß), Smad-3 and collagen type 1 (Col1-α) increased with CCl4 induced liver toxicity. Histopathological scrutiny depicted damaged liver cells, neutrophils infiltration and dilated sinusoids in CCl4 intoxicated rats. PUM was enriched with rutin, catechin, caffeic acid and apigenin as evidenced by HPLC analysis. Simultaneous administration of PUM and CCl4 in rats retrieved the normal expression of these markers and prevented hepatic injuries. CONCLUSION: Collectively these results suggest that PUM constituted of strong antioxidant chemicals and could be a potential therapeutic agent for stress related liver disorders.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Urticaceae/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose/genética , Inflamação/genética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
4.
Chem Biol Interact ; 330: 109245, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866465

RESUMO

The calcineurin inhibitor, cyclosporin A (CsA) is one of the most common immunosuppressive agents used in organ transplantation. However, its clinical use is often limited by several unwanted effects including nephrotoxicity and hepatotoxicity. By using immunohistochemical and ELISA techniques, it was found that CsA administration causes a rapid activation of a disintegrin and metalloproteases-17 (ADAM-17), epidermal growth factor receptor (EGFR) and subsequent ERK1/2 phosphorylation in the liver and kidney of albino mice. Furthermore, this study presents mechanistic relevance of this signaling cascade involving reactive oxygen species (ROS)-mediated ADAM-17/EGFR/ERK1/2 activation as indicated by a clear reduction in ADAM-17 and EGFR activities as well as ERK1/2 phosphorylation when the animals pretreated with Polyethylene glycol-superoxide dismutase (PEG-SOD) before CsA administration. Collectively, our findings demonstrate that CsA has the ability to activate ADAM-17-mediated EGFR/ERK1/2 phosphorylation in the liver and kidney of albino mice in ROS-dependent manner. Finally, these data may support the concept of using antioxidant therapy as a valuable approach for the prevention of CsA-induced nephrotoxicity and hepatotoxicity.


Assuntos
Ciclosporina/toxicidade , Rim/metabolismo , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Superóxido Dismutase/farmacologia , Proteína ADAM17/metabolismo , Animais , Ciclosporina/farmacologia , Interações Medicamentosas , Receptores ErbB/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
5.
Bull Environ Contam Toxicol ; 105(4): 565-571, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32918564

RESUMO

Fish consumption from contaminated water-bodies is a serious health issue. This study conducted to reveal the presence of heavy metals and bisphenols in Vembanad lake, an exploiting tourist spot in Kerala, receiving untreated agricultural, domestic, municipal, and industrial effluents. We evaluated aquatic contaminant impact on hepatic stress markers in Etroplus suratensis from fragile Vembanad lake. The significant difference in water physiochemical parameters, the concentration of heavy metals, and bisphenols (BPA and BPS) were studied. Hepatic tissue of E. suratensis inhabited in lake featured with high iron (11.29 ± 0.39 ppm) and BPA (0.02412 ± 0.0031 µg/mL) content along with an increased hepatic stress marker and distorted hepatic structure. The study highlights the presence of high iron and BPA in edible fish. The study recommends monitoring of physiochemical characters of freshwater lakes is essential for better survival of freshwater flora and fauna.


Assuntos
Compostos Benzidrílicos/toxicidade , Ciclídeos , Exposição Ambiental/efeitos adversos , Fígado/efeitos dos fármacos , Metais Pesados/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores , Feminino , Índia , Lagos , Fígado/anatomia & histologia , Fígado/metabolismo , Masculino
6.
Bull Environ Contam Toxicol ; 105(4): 582-587, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32948914

RESUMO

Oreochromis niloticus was exposed to 10.0 ppb of organophosphate insecticide chlorpyrifos (CPF) and avermectin insecticides abamectin (ABM) and emamectin benzoate (EB) for 48 and 96 h. RBC and Hb decreased in CPF- and ABM-exposed fish after 96-h. Plasma ALT, AST, cortisol, and glucose increased in 96-h CPF-, ABM- and EB-exposed fish, while plasma ions declined in 96-h CPF-exposed ones. Insecticides caused alterations in liver oxidative stress parameters. In fish exposed to CPF, CAT increased after 48-h whereas it decreased after 96-h. Also, CAT declined in 48- and 96-h ABM-exposed fish, whereas it elevated in 48-h EB-exposed ones. Insecticides caused decreases in SOD at 48- and 96-h and in GR after 96-h. GSH elevated in CPF-exposed fish after 48-h, while it decreased in all the tested insecticide exposures after 96-h. Malondialdehyde of fish exposed to insecticides for 96-h increased. Consequently, toxic effects of insecticides on O. niloticus were generally as CPF > ABM > EB.


Assuntos
Clorpirifos/toxicidade , Ciclídeos , Inseticidas/toxicidade , Ivermectina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Animais , Análise Química do Sangue/veterinária , Testes Hematológicos/veterinária , Ivermectina/toxicidade , Fígado/efeitos dos fármacos , Fígado/enzimologia , Oxirredução , Distribuição Aleatória , Testes de Toxicidade Aguda/veterinária
7.
Life Sci ; 259: 118382, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898532

RESUMO

AIM: Vancomycin (VCM) is a glycopeptide antibiotic widely used to treat serious infections caused by methicillin-resistant Staphylococcus aureus and has been associated with some severe side effects such as hepatotoxicity and nephrotoxicity. However, the underlying mechanism of VCM-induced hepatotoxicity is not yet fully understood. Therefore, the current study was designed to evaluate the protective effects of zingerone (Zin) against VCM-induced hepatotoxicity in rats. MATERIALS AND METHODS: VCM was intraperitoneally administered at a dose of 200 mg/kg body weight (b.w.) for 7 days alone and in combination with the orally administered Zin (25 and 50 mg/kg b.w). KEY FINDINGS: Zin treatment significantly improved VCM-induced hepatic lipid peroxidation, glutathione depletion, reduced antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities and liver function markers (aspartate aminotransferase, alkaline phosphatase and alanine aminotransferase). Histopathological integrity and immunohistochemical expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the VCM-induced liver tissue were ameliorated after Zin administration. In addition, Zin reversed the changes in levels and/or activities of inflammatory and apoptotic parameters such as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), p53, cysteine aspartate specific protease-3 (caspase-3), cysteine aspartate specific protease-8 (caspase-8), cytochrome c, Bcl-2 associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) in the VCM-induced hepatotoxicity. SIGNIFICANCE: Collectively, these results reveal probable ameliorative role of Zin against VCM-induced hepatotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Guaiacol/análogos & derivados , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Vancomicina/toxicidade , Animais , Western Blotting , Ciclo-Oxigenase 2/metabolismo , Guaiacol/uso terapêutico , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
8.
Ann Agric Environ Med ; 27(3): 368-373, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955216

RESUMO

INTRODUCTION: Chlorpyrifos (CPF) is a organophosphate insecticide widely used in agriculture with attendant adverse health outcomes. Chronic exposure to CPF induces oxidative stress and elicits harmful effects, including hepatic dysfunction. Molecular hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. OBJECTIVE: The aim of this study was to determine whether the intake of hydrogen-rich water (HRW) could protect rats from hepatotoxicity caused by sub-chronic exposure to CPF. MATERIAL AND METHODS: Rats were treated with hydrogen-rich water by oral intake for 8 weeks. Biochemical indicators of liver function, SOD and CAT activity, GSH and MDA levels were determined by the spectrophotometric method. Liver cell damage induced by CPF was evaluated by histopathological and electron microscopy analysis. PCR array analysis was performed to investigated the effects of molecular hydrogen on the regulation of oxidative stress related genes. RESULTS: Both the hepatic function tests and histopathological analysis showed that the liver damage induced by CPF could be ameliorated by HRW intake. HRW intake also attenuated CPF induced oxidative stress, as evidenced by restored SOD activities and MDA levels. The results of PCR Array identified 12 oxidative stress-related genes differentially expressed after CPF exposure, 8 of chich, including the mitochondrial Sod2 gene, were significantly attenuated by HRW intake. The electron microscopy results indicated that the mitochondrial damage caused by CPF was alleviated after HRW treatment. CONCLUSIONS: The results obtained suggest that HRW intake can protect rats from CPF induced hepatotoxicity, and the oxidative stress signaling and the mitochondrial pathway may be involved in the protection of molecular hydrogen.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Clorpirifos/toxicidade , Hidrogênio/farmacologia , Inseticidas/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Masculino , Estresse Oxidativo/genética , Ratos , Ratos Wistar
9.
Ecotoxicol Environ Saf ; 202: 110944, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800225

RESUMO

Bisphenol A (BPA), a weak estrogenic endocrine disruptor and a well-known plasticizer, has the potential to perturb diverse physiological functions; however, its impact on immune and metabolic function in aquatic vertebrates is relatively less understood. The present study aims to investigate the impact of BPA on hepatotoxicity, metabolic and immune parameters vis-à-vis estrogen receptor expression modulation in a freshwater teleost, Labeo bata (Cyprinidae, Cypriniformes). The 96-h median lethal concentration of BPA in L. bata has been determined as 4.79 mg/L. Our data demonstrate that congruent with induction of plasma vitellogenin (VTG), chronic exposure to sub-lethal BPA (2 and 4 µM/L) attenuates erythrocyte count, hemoglobin concentration, packed cell volume, mean corpuscular hemoglobin, but not leukocyte number. Further, a significant increase in MDA, concomitant with diminished catalase and heightened GST activity corroborates well with hepatic dystrophic changes, appearance of fatty liver (macrovesicular steatosis) and elevated serum lipids (triglyceride, cholesterol, LDL, VLDL) in BPA-treated groups. Interestingly, a differential regulation of estrogen receptor (ER) subtypes at transcript and protein level signifies negative influence of BPA on hepatic ERα/ERß homeostasis in this species. While at a lower dose it promotes Akt phosphorylation (activation), BPA at the higher dose attenuates ERK1/2 phosphorylation (activation), suggesting potential alteration in insulin sensitivity. Importantly, dose-dependent decrease in hepatic TNF-α, IL-1ß, iNOS (NOS2) expression and nitric oxide (NO) level corresponds well with progressive decline in p-NF-κB, p-p38 MAPK, albeit with differential sensitivity, in BPA-exposed groups. Collectively, BPA exposure has wide-spread negative influence on hematological, biochemical and hepatic events in this species.


Assuntos
Compostos Benzidrílicos/toxicidade , Cyprinidae/metabolismo , Disruptores Endócrinos/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Receptores Estrogênicos/genética , Animais , Cyprinidae/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Água Doce/química , Expressão Gênica/efeitos dos fármacos , Homeostase , Inflamação , Fígado/imunologia , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Vitelogeninas/metabolismo
10.
Ecotoxicol Environ Saf ; 202: 110962, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800233

RESUMO

Chronic exposure to fluoride (F) beyond the permissible limit (1.5 ppm) is known to cause detrimental health effects by induction of oxidative stress-mediated DNA damage overpowering the DNA repair machinery. In the present study, we assessed F induced oxidative stress through monitoring biochemical parameters and looked into the effect of chronic F exposure on two crucial DNA repair genes Ogg1 and Rad51 having important role against ROS induced DNA damages. To address this issue, we exposed Swiss albino mice to an environmentally relevant concentration of fluoride (15 ppm NaF) for 8 months. Results revealed histoarchitectural damages in liver, brain, kidney and spleen. Depletion of GSH, increase in lipid peroxidation and catalase activity in liver and brain confirmed the generation of oxidative stress. qRT-PCR result showed that expressions of Ogg1 and Rad51 were altered after F exposure in the affected organs. Promoter hypermethylation was associated with the downregulation of Rad51. F-induced DNA damage and the compromised DNA repair machinery triggered intrinsic pathway of apoptosis in liver and brain. The present study indicates the possible association of epigenetic regulation with F induced neurotoxicity.


Assuntos
Dano ao DNA , DNA Glicosilases/genética , Reparo do DNA , Epigênese Genética/efeitos dos fármacos , Fluoretos/toxicidade , Rad51 Recombinase/genética , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
11.
Int J Nanomedicine ; 15: 4859-4876, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764923

RESUMO

Introduction: CoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance. Methods: We tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity. Results: Nano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-κB expression and Interleukin 1ß and 6 production during anticancer treatments. Discussion: Anthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.


Assuntos
Antraciclinas/efeitos adversos , Fígado/citologia , Miócitos Cardíacos/efeitos dos fármacos , Nanoestruturas/química , Trastuzumab/efeitos adversos , Ubiquinona/análogos & derivados , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cápsulas , Cardiotônicos/química , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Feminino , Hepatócitos/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ubiquinona/química , Ubiquinona/farmacologia
12.
Medicine (Baltimore) ; 99(34): e21952, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846865

RESUMO

BACKGROUND: Sodium cantharidinate/vitamin B6 (SC/VB6) injection, a famous insect-derived traditional Chinese medicine preparation, has been widely applied as a promising adjunctive drug for hepatocellular carcinoma (HCC). However, its exact clinical efficacy and safety is still not well investigated. In this study, we aimed to summarize the efficacy of SC/VB6 injection on survival, liver function, immune function, and quality of life (QoL) in patients with HCC through the meta-analysis. METHODS: All available randomized controlled trials (RCTs) and high-quality prospective cohort studies that investigated the efficacy and safety of SC/VB6 for patients with HCC were searched from ten electronic databases including PubMed, Google Scholar, Cochrane Library, Excerpt Medica Database (Embase), Medline, Web of Science (WOS), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), China Scientific Journal Database (CSJ), and Wanfang Database. Papers in Chinese or English published from January 2000 to July 2020 will be included without any restrictions.Study selection and data extraction will be performed independently by 2 researchers. The clinical outcomes including overall survival (OS), QoL, liver function, immune function, and adverse events, were systematically evaluated. Review Manager 5.3 and Stata 14.0 were used for data analysis, and the quality of the clinical trials was also evaluated. RESULTS: The results of this study will be published in a peer-reviewed journal, and provide a helpful evidence for clinicians to formulate the best postoperative adjuvant treatment strategy for HCC patients. CONCLUSION: Our study will draw an objective conclusion of the efficacy of SC/VB6 on survival, liver function, immune function, and QoL in patients with HCC. INPLASY REGISTRATION NUMBER: INPLASY202070121.


Assuntos
Cantaridina/análogos & derivados , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/patologia , Vitamina B 6/farmacologia , Complexo Vitamínico B/farmacologia , Cantaridina/administração & dosagem , Cantaridina/farmacologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/psicologia , China/epidemiologia , Quimioterapia Combinada/métodos , Humanos , Sistema Imunitário/efeitos dos fármacos , Injeções/métodos , Fígado/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Sobrevida , Resultado do Tratamento , Vitamina B 6/administração & dosagem , Complexo Vitamínico B/administração & dosagem
13.
Ecotoxicol Environ Saf ; 204: 111036, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32784013

RESUMO

Human exposure to methylmercury (MeHg) due to contaminated fish intake as part of a high-fat (HFD), high-carbohydrate diets is a reality today for many populations. HFD is associated with hypertension and hyperlipidemia, primary cardiovascular disease (CVD) risk factors. Some studies suggest that MeHg induces those risk factors. We evaluated the effect of MeHg exposure in mice fed with HFD or control diet for eight weeks. In the last experimental 15 days, the half group received a MeHg solution (20 mg/L) replacing water. Blood pressure (BP), heart rate, lipoprotein concentrations, and paraoxonase activity were evaluated. Liver cholesterol, triacylglycerol, and IBA-1+ cells, as well as transcriptional levels of genes related to lipid metabolism and inflammatory response, were also assessed. HFD and both MeHg groups presented increased BP and total cholesterol (TC). In the liver, HFD but not MeHg was related to an increase in TC. Also, MeHg intoxication reduced paraoxonase activity regardless of diet. MeHg intoxication and HFD increased steatosis and the number of IBA-1+ cells and modified some gene transcripts associated with lipid metabolism. In conclusion, we demonstrated that MeHg effects on CVD risk factors resemble those caused by HFD.


Assuntos
Pressão Arterial/efeitos dos fármacos , Aterosclerose/epidemiologia , Dieta Hiperlipídica/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Compostos de Metilmercúrio/efeitos adversos , Estado Nutricional , Animais , Aterosclerose/induzido quimicamente , Fígado Gorduroso/metabolismo , Feminino , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Lipoproteínas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco
14.
Aquat Toxicol ; 227: 105583, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32835849

RESUMO

The presence of diclofenac in the aquatic environment and the risks for aquatic wildlife, especially fish, have been raised in several studies. One way to manage risks without enforcing improved wastewater treatment would be to substitute diclofenac (when suitable from a clinical perspective) with another non-steroidal anti-inflammatory drug (NSAID) associated with less environmental risk. While there are many ecotoxicity-studies of different NSAIDs, they vary extensively in set-up, species studied, endpoints and reporting format, making direct comparisons difficult. We previously published a comprehensive study on the effects of diclofenac in the three-spined stickleback (Gasterosteus aculeatus). Our present aim was to generate relevant effect data for another NSAID (naproxen) using a very similar setup, which also allowed direct comparisons with diclofenac regarding hazards and risks. Sticklebacks were therefore exposed to naproxen in flow-through systems for 27 days. Triplicate aquaria with 20 fish per aquarium were used for each concentration (0, 18, 70, 299 or 1232 µg/L). We investigated bioconcentration, hepatic gene expression, jaw lesions, kidney and liver histology. On day 21, mortalities in the highest exposure concentration group unexpectedly reached ≥ 25 % in all three replicate aquaria, leading us to terminate and sample that group the same day. On the last day (day 27), the mortality was also significantly increased in the second highest exposure concentration group. Increased renal hematopoietic hyperplasia was observed in fish exposed to 299 and 1232 µg/L. This represents considerably higher concentrations than those expected in surface waters as a result of naproxen use. Such effects were observed already at 4.6 µg/L in the experiment with diclofenac (lowest tested concentration). Similar to the responses to diclofenac, a concentration-dependent increase in both relative hepatic gene expression of c7 (complement component 7) and jaw lesions were observed, again at concentrations considerably higher than expected in surface waters. Naproxen bioconcentrated less than diclofenac, in line with the observed effect data. An analysis of recent sales data and reported concentrations in treated sewage effluent in Sweden suggest that despite higher dosages used for naproxen, a complete substitution would only be expected to double naproxen emissions. In summary, naproxen and diclofenac produce highly similar effects in fish but the environmental hazards and risks are clearly lower for naproxen. Hence, if there are concerns for environmental risks to fish with diclofenac, a substitution would be advisable when naproxen presents an adequate alternative from a clinical point-of-view.


Assuntos
Bioacumulação , Diclofenaco/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Naproxeno/toxicidade , Smegmamorpha/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Diclofenaco/metabolismo , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Modelos Teóricos , Naproxeno/metabolismo , Smegmamorpha/genética , Suécia , Poluentes Químicos da Água/metabolismo
15.
PLoS One ; 15(8): e0236104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776939

RESUMO

There is an increasing emphasis on effects-based monitoring to document responses associated with exposure to complex mixtures of chemicals, climate change, pathogens, parasites and other environmental stressors in fish populations. For decades aquatic monitoring programs have included the collection of tissues preserved for microscopic pathology. Consequently, formalin-fixed, paraffin-embedded (FFPE) tissue can be an important reservoir of nucleic acids as technologies emerge that utilize molecular endpoints. Despite the cross-linking effects of formalin, its impact on nucleic acid quality and concentration, amplification, and sequencing are not well described. While fresh-frozen tissue is optimal for working with nucleic acids, FFPE samples have been shown to be conducive for molecular studies. Laser capture microdissection (LCM) is one technology which allows for collection of specific regions or cell populations from fresh or preserved specimens with pathological alterations, pathogens, or parasites. In this study, smallmouth bass (Micropterus dolomieu) liver was preserved in three different fixatives, including 10% neutral buffered formalin (NBF), Z-Fix® (ZF), and PAXgene® (PG) for four time periods (24 hr, 48 hr, seven days, and 14 days). Controls consisted of pieces of liver preserved in RNALater® or 95% ethanol. Smallmouth bass were chosen as they are an economically important sportfish and have been utilized as indicators of exposure to endocrine disruptors and other environmental stressors. Small liver sections were cut out with laser microdissection and DNA and RNA were purified and analyzed for nucleic acid concentration and quality. Sanger sequencing and the NanoString nCounter® technology were used to assess the suitability of these samples in downstream molecular techniques. The results revealed that of the formalin fixatives, NBF samples fixed for 24 and 48 hr were superior to ZF samples for both Sanger sequencing and the Nanostring nCounter®. The non-formalin PAXgene® samples were equally successful and they showed greater stability in nucleic acid quality and concentration over longer fixation times. This study demonstrated that small quantities of preserved tissue from smallmouth bass can be utilized in downstream molecular techniques; however, future studies will need to optimize the methods presented here for different tissue types, fish species, and pathological conditions.


Assuntos
Bass/genética , DNA/efeitos dos fármacos , Monitoramento Ambiental/métodos , Fixadores/efeitos adversos , RNA/efeitos dos fármacos , Animais , Clivagem do DNA/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Formaldeído/efeitos adversos , Perfilação da Expressão Gênica/métodos , Fígado/efeitos dos fármacos , Fígado/patologia , Microdissecção , Desnaturação de Ácido Nucleico/efeitos dos fármacos , RNA/isolamento & purificação , Estabilidade de RNA/efeitos dos fármacos , Análise de Sequência de DNA , Fatores de Tempo , Fixação de Tecidos/métodos , West Virginia
16.
Ecotoxicol Environ Saf ; 203: 111032, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745774

RESUMO

Titanium dioxide nanoparticles (Np-TiO2) have become the common component of sunscreen cosmetic products. Np-TiO2 can affect especially aquatic ecosystems health, including aquatic organisms such as fish. It is therefore necessary to acquire a better understanding of the effect of Np-TiO2 on aquatic organisms. This study evaluated the biological effects of Np-TiO2 on Danio rerio, such as survival rate and weight change and, in particular, the Ti content or retention in the intestine and liver, as well as the activities of catalase and superoxide dismutase enzymes. In addition, the structure of the intestine, kidney, and liver was investigated through histological analysis. Ninety zebrafish were used, randomly divided into three treatment-groups: a control group (fed with food without adding Np-TiO2) and two groups of fish fed with food containing Np-TiO2 exposed for 7 and 14 days. The amount of Ti in the liver and intestine was measured using atomic absorption spectrophotometry coupled to a graphite furnace (GFAAS). Morphological analysis and enzyme catalase and superoxide dismutase assays were likewise performed. Ti was detected in all fish even in control group; probably Ti must have been introduced during production by the fish food industry. Structural changes were detected in fish fed with Np-TiO2 as vacuolization and disruption of the apical cytoplasm of epithelial cells that covered the intestinal villi. Although kidney morphology appeared intact, the lumen of the proximal tubule was enlarged, and the cells of the distal tubule were vacuolated. No morphological changes in the liver were detected; however, superoxide dismutase activity decreased, suggesting that liver changes occurred at the molecular level. Thus, Np-TiO2 causes morphological changes in the intestine, kidney, and liver of zebrafish and biochemical changes in the liver exposed for 7 and 14 days. Although not highly lethal, Np-TiO2 in the food chain can interfere with the morphophysiology of aquatic organisms. Neither mortalities nor body weight losses were recorded among fish in all groups over the duration of the experiment.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas/toxicidade , Titânio/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Bioacumulação , Catalase , Relação Dose-Resposta a Droga , Ecossistema , Cadeia Alimentar , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Nanopartículas/metabolismo , Distribuição Aleatória , Protetores Solares/química , Titânio/metabolismo , Poluentes Químicos da Água/metabolismo
17.
Chem Biol Interact ; 329: 109220, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32763245

RESUMO

The sepsis is considered as serious clinic-pathological condition related with high rate of morbidity and mortality in critical care settings. In the proposed study, the hydrazides derivatives N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) were investigated against the LPS-induced sepsis in rodents. The NCHDH and NTHDH markedly improved the physiological sign and symptoms associated with the sepsis such as mortality, temperature, and clinical scoring compared to negative control group, which received only LPS (i.p.). The NCHDH and NTHDH also inhibited the production of the NO and MPO compared to the negative control. Furthermore, the treatment control improved the histological changes markedly of all the vital organs. Additionally, the Masson's trichrome and PAS (Periodic Acid Schiff) staining also showed improvement in the NCHDH and NTHDH treated group in contrast to LPS-induced group. The antioxidants were enhanced by the intervention of the NCHDH and NTHDH and the level of the MDA and POD were attenuated marginally compared to the LPS-induced group. The hematology study showed marked improvement and the reversal of the LPS-induced changes in blood composition compared to the negative control. The synthetic function of the liver and kidney were preserved in the NCHDH and NTHDH treated group compared to the LPS-induced group. The NCHDH and NTHDH markedly enhanced the Nrf2, HO-1 (Heme oxygenase-1), while attenuated the Keap1 and TRPV1 expression level as compared to LPS treated group. Furthermore, the NCHDH and NTHDH treatment showed marked increased in the mRNA expression level of the HSP70/90 proteins compared to the negative control.


Assuntos
Hidrazinas/farmacologia , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Hidrazinas/química , Hidrazinas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/mortalidade , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
18.
Chem Biol Interact ; 330: 109199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32805210

RESUMO

Obesity is characterized by the deposition of excessive body fat, and is caused by energy imbalance, especially when consuming fat-rich diets. High fat diet (HFD)-associated obesity is greatly common in patients with non-alcoholic fatty liver disease (NAFLD) that is emerging as one of the most universal causes of liver disease worldwide, especially in Western countries. In spite of its high prevalence, only a small proportion of affected individuals will become inflamed, followed by fibrosis and chronic liver diseases, and most patients only show simple steatosis. In this case, the full comprehension of the mechanisms underlying the progression of NAFLD is of extreme significance; in spite of progress in this field, awareness on the development of NAFLD is still incomplete. Traditionally, liver steatosis is commonly connected with HFD, obesity, and insulin resistance (IR). Recently, various possible mechanisms have been put forward for liver damage, including endoplasmic reticulum stress, perturbation of autophagy, mitochondrial dysfunction, hepatocellular apoptosis, gut microbiota imbalance, dysregulation of microRNAs, and genetic/epigenetic risk factors, as well as an increase in inflammatory responses, among many others. Collectively, these proposed mechanisms allow for a variety of hits acting together on subjects to mediated NAFLD and will offer a more accurate explanation for progression of NAFLD. Therefore, this review summarizes the present information concerning NAFLD after HFD exposure, as well as discusses possible mechanisms through which it may arise.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações
19.
PLoS One ; 15(8): e0237236, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764799

RESUMO

We previously reported that the non-immunosuppressive cyclophilin inhibitors (CypIs)-cyclosporin A analog CRV431 and sanglifehrin analog NV556-efficiently inhibit HCV replication in vitro. In this study, we asked whether they can also reduce HCV replication in vivo. We found that a single oral administration of CRV431 and NV556 to HCV-infected humanized-liver mice drastically reduced HCV blood levels. The antiviral effect was observed when CRV431 or NV556 were each individually administered with HCV, 3, 6 weeks or even 3 months post-infection when viral replication is robust. These results were confirmed in chimeric mice implanted with human hepatocytes isolated from three distinct donors. Remarkably, no viral rebound was observed 5 months after a single dose administration of 50 mg/kg of CRV431 or NV556 four weeks post-HCV infection, indicating the possibility of suppression of an established viral infection. Since we recently demonstrated that both CRV431 and NV556 also inhibit the development of liver fibrosis and hepatocellular carcinoma in nonviral-induced non-alcoholic steatohepatitis mouse models, our present data suggest that the two entirely structurally different CypIs-CRV431 and NV556-derived from unrelated natural products, represent attractive partners to current direct-acting agent (DAA) regimens for the treatment of hepatitis C and liver diseases.


Assuntos
Antivirais/uso terapêutico , Ciclosporinas/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Animais , Antivirais/farmacologia , Ciclosporinas/farmacologia , Hepacivirus/fisiologia , Hepatite C/virologia , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Camundongos , Camundongos SCID , Camundongos Transgênicos , Replicação Viral/efeitos dos fármacos
20.
Chem Biol Interact ; 330: 109234, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860823

RESUMO

Cisplatin is an antineoplastic drug well recognized for its success in the battle against several types of cancer in adult, juvenile, and child populations. Meanwhile, this drug is also famous due to its serious side effects, such as hepatotoxicity. This study evaluated the hepatoprotective effectiveness of Diphenyl Diselenide (PhSe)2 and Ebselen in a model of cisplatin-induced toxicity in juvenile rats. Juvenile Wistar rats received a single intraperitoneal (i.p) injection of cisplatin (6 mg/kg) or saline solution, at postnatal day (PND) 21. Ebselen (11 mg/kg) or (PhSe)2 (12 mg/kg) was intragastrically (i.g) administered in rats from PND 21 to PND 25. At PND 26, the blood and liver were collected for the biochemistry assays. A single administration of cisplatin was enough to alter the makers of hepatic function (an increase of AST activity) and the blood lipid profile (an increase of cholesterol and triglycerides, TG). The cisplatin-induced metabolic disruption was demonstrated by the increase of hepatic glycogen and TG contents and hexokinase, glucose-6-phosphatase, and tyrosine aminotransferase activities; a decrease of citrate synthase activity and the levels of GLUT-2. Cisplatin-induced hepatic oxidative stress was characterized by an increase in reactive oxygen species, TBARS, protein carbonyl, and Nox levels as well as the decrease in NPSH levels. Ebselen and (PhSe)2 were effective against all alterations caused by this chemotherapy medication. The present findings highlight the (PhSe)2 and Ebselen similar hepatoprotective effectiveness against cisplatin-induced disruption of metabolic homeostasis and redox balance in juvenile rats.


Assuntos
Azóis/farmacologia , Derivados de Benzeno/farmacologia , Cisplatino/toxicidade , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Lipídeos/sangue , Fígado/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos
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