RESUMO
1. In order to compare the difference between different derivatisations for amino acids determination of foie gras via, reversed phase high performance liquid chromatography (HPLC), O-phthalaldehyde and 9-fluorenyl-methyl chloroformate (OPA-FMOC group), phenylisothiocyanate (PITC group) and 6-Aminoquinolyl-N-hydrox-ysuccinimidyl Carbamate (AQC group) were applied to derivatisation reagent in this current experiment. The determination results of automatic amino acid analyser were applied, and 17 amino acids were detected by these three derivatisation methods.2. The running times of OPA-FMOC group, PITC group and AQC group were 18, 45 and 35 min, respectively. There was a large difference between the results of OPA-FMOC group and results from the automatic amino acid analyser, although the difference between the results from PITC and the automatic amino acid analyser was minimal.3. In conclusion, the running time of OPA-FMOC group was shorter than that of PITC group and AQC group; the accuracy of the former was better than the OPA-FMOC group and AQC group for the determination of amino acid of foie gras.
RESUMO
Langerhans cell histiocytosis (LCH) is a disease whose physiopathology remains unclear, involving both inflammatory processes and clonal proliferation. It is observable at any given age, although about ten times more frequent in children than adults. Hepatic involvement is not rare, mostly part of a systemic disease, and linked to a poor prognosis. We report here a case of LCH with solitary hepatic involvement in a 74 year-old patient. This case demonstrated molecular anomaly of the MAPK pathway, BRAF N486_P490del. Through this observation, we precise the epidemiological and histological aspects and diagnostic criteria of this rare disease.
Assuntos
Histiocitose de Células de Langerhans , Idoso , Humanos , Histiocitose de Células de Langerhans/diagnóstico , Fígado/patologia , Doenças RarasRESUMO
Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin RING E3 ligases (CRLs) regulate the turnover of â¼20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation, and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1-UBC12 interaction inhibitor HZX-960 was discovered with an IC50 value of 9.37 nmol/L, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate transforming growth factor ß-induced liver fibrotic responses by reducing the deposition of collagen I and α-smooth muscle actin, and upregulating cellular NF-E2-related factor 2, hemeoxygenase 1, and NADPH quinone oxidoreductase-1 levels in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl4-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability and that DCN1 may be a potential therapeutic target for liver fibrosis treatment.
Assuntos
Inibidores Enzimáticos , Cirrose Hepática , Enzimas de Conjugação de Ubiquitina , Ubiquitina-Proteína Ligases , Animais , Proteínas Culina/metabolismo , Inibidores Enzimáticos/farmacologia , Cirrose Hepática/tratamento farmacológico , Camundongos , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , UbiquitinaçãoRESUMO
Metformin, a traditional first-line pharmacological treatment for type 2 diabetes, has recently been shown to have anti-cancer effects on hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the anti-tumor activity of metformin remains unclear. The Sonic hedgehog (Shh) signaling pathway is closely associated with the initiation and progression of HCC. Therefore, the aim of the current study was to investigate the effects of metformin on the biological behavior of HCC and the underlying functional mechanism of metformin in the Shh pathway. HCC was induced in HepG2 cells using recombinant human Shh (rhShh). The effects of metformin on proliferation and metastasis were evaluated using in vitro proliferation, wound healing, and invasion assays. The mRNA and protein expression levels of proteins related to the Shh pathway were measured using western blotting, quantitative PCR, and immunofluorescence staining. Metformin inhibited rhShh-induced proliferation and metastasis. Furthermore, metformin decreased the mRNA and protein expression of Shh pathway components, including Shh, Ptch, Smo, and Gli-1. Silencing of AMPK in the presence of metformin revealed that metformin exerted its inhibitory effects via AMPK. Our findings demonstrate that metformin suppresses the migration and invasion of HepG2 cells via AMPK-mediated inhibition of the Shh pathway.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Metformina/farmacologia , Transdução de Sinais , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/farmacologiaRESUMO
OBJECTIVES: To develop and validate a new semiquantitative fluorescence optical imaging (FOI) scoring system-the FOI Enhancement-Generated RA Score (FOIE-GRAS) for synovitis assessment in the hand. METHODS: The development of FOIE-GRAS was based on consensus of four experts in musculoskeletal imaging. Forty-six RA patients, eligible for treatment intensification and with ≥1 clinically swollen joints in the hands, and 11 healthy controls were included. FOI, ultrasound and clinical assessment of both hands were obtained at baseline and for RA patients after 3 and 6 months' follow-up. Twenty RA patients had an FOI rescan after 4 h. Synovitis was scored using FOIE-GRAS and the OMERACT ultrasound synovitis scoring system. All FOI images were scored by two readers. Inter-scan, inter- and intra-reader reliability were determined. Furthermore, FOIE-GRAS agreement with ultrasound and responsiveness was assessed. RESULTS: FOIE-GRAS synovitis was defined as early enhancement, and scores were based on the degree of coverage of the specific joint region after 3 s (0-3). Inter-scan, intra- and inter-reader intraclass correlations coefficients (ICC) were good to excellent for all baseline scores (0.76-0.98) and moderate to good for change (0.65-76).The FOIE-GRAS had moderate agreement with ultrasound (ICC 0.30-0.54) for total score, a good standardized response mean (>0.80), and moderate correlation with clinical joint assessment and DAS28-CRP. The median (interquartile range) reading time per FOI examination was 133 (109, 161) s. Scores were significantly lower in controls [1 (0, 4)] than RA patients [11 (6, 19)]. CONCLUSION: The FOIE-GRAS offers a feasible and reliable assessment of synovitis in RA, with a moderate correlation with ultrasound and DAS28-CRP, and good responsiveness.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Imagem Óptica/métodos , Sinovite/diagnóstico por imagem , Adulto , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Feminino , Articulação da Mão/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Gravidade do Paciente , Reprodutibilidade dos Testes , Sinovite/patologia , UltrassonografiaRESUMO
Ischemia-reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules, has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Forty rats were divided randomly into four groups: sham group, colchicine-treated group, IRI group, and colchicine-treated + IRI group. Treatment with colchicine significantly reduced hepatic toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) transcription factor, myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-alpha (TNF-α) contents; downregulated BCL2 associated X apoptosis regulator (BAX) gene expression, transforming growth factor-ß (TGF-ß) content, and upregulated hepatic B cell lymphoma 2 (Bcl-2) gene expression as compared with the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.
Assuntos
Colchicina/farmacologia , Colchicina/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Animais , Anti-Inflamatórios , Antifibróticos , Apoptose/efeitos dos fármacos , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologiaRESUMO
Chinese indigenous pig and Western commercial pig breeds show different patterns of lipid metabolism, fat deposition, and fatty acid composition; for these reasons, they have become vitally important models of energy metabolism and obesity in humans. To compare the mechanisms underlying lipid metabolism between Yorkshire pigs (lean type) and Anqing six-end-white pigs (obese type), the liver transcriptomes of six castrated boars with a body weight of approximately 100 kg (three Yorkshire and three Anqing) were analyzed by RNA-seq. The total number of reads produced for each liver sample ranged from 47.05 to 62.6 million. Among 362 differentially expressed genes, 142 were up-regulated and 220 were down-regulated in Anqing six-end-white pigs. Based on these data, 79 GO terms were significantly enriched. The top 10 (the 10 with lowest corrected P-value) significantly enriched GO terms were identified, including lipid metabolic process and carboxylic acid metabolic process. Pathway analysis revealed three significantly enriched KEGG pathways including PPAR signaling pathway, steroid hormone biosynthesis, and retinol metabolism. Based on protein-protein interaction networks, multiple genes responsible for lipid metabolism were identified, such as PCK1, PPARA, and CYP7A1, and these were considered promising candidate genes that could affect porcine liver lipid metabolism and fat deposition. Our results provide abundant transcriptomic information that will be useful for animal breeding and biomedical research.
Assuntos
Metabolismo dos Lipídeos , Suínos/genética , Transcriptoma , Animais , Peso Corporal , Ácidos Graxos , Perfilação da Expressão Gênica , Fígado/metabolismo , Masculino , Obesidade , Análise de Sequência de RNA , Suínos/metabolismoRESUMO
Ischemia-reperfusion injury (IRI) induces an inflammatory response and production of reactive oxygen species, which affects the organs remote to the sites of renal IR. However, remote effects of renal IRI on the liver need further investigations. Renal injury associated with liver disease is a common clinical problem. Colchicine is an established drug for microtubule stabilization that may reduce tissue injury and has antioxidant and antiinflammatory effects. The aim of the present study was (i) to assess the hepatic changes after induction of renal IRI, (ii) to explore the possible protective effect of colchicine on liver injury following renal IRI, and (iii) to investigate the possible mechanisms underlying the potential effect. Forty rats were randomly divided into four groups: sham operation group, colchicine-treated group, IR group, and colchicine-treated IR group. Colchicine treatment improved liver function (ALT/AST) after renal IRI, decreased hepatic oxidative stress and cell apoptosis by reducing hepatic MDA, upregulating hepatic total antioxidant capacity, Nrf2, and HO-1. Furthermore, colchicine inhibited inflammatory responses by downregulating hepatic NLRP3 inflammasome, IL-1ß, and caspase-1. Colchicine attenuates renal IRI-induced liver injury in rats. This effect may be due to reducing inflammation and oxidative stress markers.
Assuntos
Colchicina/farmacologia , Inflamassomos/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Apoptose/efeitos dos fármacos , Caspase 1/metabolismo , Citoproteção/efeitos dos fármacos , Rim/lesões , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
Leukocyte cell-derived chemotaxin 2-associated amyloidosis (ALECT2) is a recently described of amyloidosis described in the United States in 2007. It is a systemic disease that is predominantly associated with some ethnics groups. ALECT2 is usually diagnosed on a kidney biopsy performed in the context of slowly progressive chronic renal disease but can also be found incidentally on a liver sample. We report the case of a Syrian patient who benefited from a partial hepatectomy for the treatment of multiple metastasis of a colorectal adenocarcinoma. Microscopic analysis of the surgical specimen revealed numerous amyloid deposits that did not match any of the usual forms of liver amyloidosis after immunohistochemistry typing. Some morphologic features of the deposits were highly suggestive of ALECT2. Complementary immunohistochemical study and mass spectrometry confirmed the diagnosis.
Assuntos
Amiloidose , Fatores Quimiotáticos , Amiloidose/complicações , Amiloidose/diagnóstico , Humanos , Achados Incidentais , Leucócitos , Fígado/patologia , SíriaRESUMO
Expensive and unsustainable fishmeal is increasingly being replaced with cheaper lipids and carbohydrates as sources of energy in aquaculture. Although it is known that the excess of lipids and carbohydrates has negative effects on nutrient utilization, growth, metabolic homeostasis, and health of fish, our current understanding of mechanisms behind these effects is limited. To improve the understanding of diet-induced metabolic disorders (both in fish and other vertebrates), we conducted an eight-week high-fat-high-carbohydrate diet feeding trial on blunt snout bream (Megalobrama amblycephala), and studied gene expression changes (transcriptome and qPCR) in the liver. Disproportionately large numbers of differentially expressed genes were associated with mitochondrial metabolism, neurodegenerative diseases (Alzheimer's, Huntington's, and Parkinson's), and functional categories indicative of liver dysfunction. A high-fat-high-carbohydrate diet may have caused mitochondrial dysfunction, and possibly downregulated the mitochondrial biogenesis in the liver. While the relationship between diet and neurodegenerative disorders is well-established in mammals, this is the first report of this connection in fish. We propose that fishes should be further explored as a potentially promising model to study the mechanisms of diet-associated neurodegenerative disorders in humans.
Assuntos
Cyprinidae/genética , Dieta Hiperlipídica/efeitos adversos , Doenças dos Peixes/etiologia , Mitocôndrias Hepáticas/metabolismo , Transcriptoma , Ração Animal/efeitos adversos , Animais , Cyprinidae/metabolismo , Mitocôndrias Hepáticas/genética , Mitocôndrias Hepáticas/patologiaRESUMO
In high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD), there is an increase in the endocannabinoid system activity, which significantly contributes to steatosis development. The aim of our study was to investigate the effects of cannabinoid receptor type 1 blockade on adipokine and proinflammatory cytokine content in adipose and hepatic tissue in mice with NAFLD. Male mice C57BL/6 were divided into a control group fed with a control diet for 20 weeks (C, n = 6) a group fed with a HFD for 20 weeks (HF, n = 6), a group fed with a control diet and treated with rimonabant after 18 weeks (R, n = 9), and a group fed with HFD and treated with rimonabant after 18 weeks (HFR, n = 10). Rimonabant significantly decreased leptin, resistin, apelin, visfatin, interleukin 6 (IL-6), and interferon-γ (IFN-γ) concentration in subcutaneous and visceral adipose tissue in the HFR group compared to the HF group (p < 0.01). Rimonabant reduced hepatic IL-6 and IFN-γ concentration as well as plasma glucose and insulin concentration and the homeostatic model assessment index in the HFR group compared to the HF group (p < 0.01). It can be concluded that the potential usefulness of CB1 blockade in the treatment of HFD-induced NAFLD is due to modulation of the adipokine profile and proinflammatory cytokines in both adipose tissues and liver as well as glucose metabolism.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Citocinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Rimonabanto/uso terapêuticoRESUMO
The objective of this study was to evaluate the value of real-time contrast-enhanced ultrasound in differential diagnosis of malignant liver tumors. Sixty patients pathologically diagnosed with liver cancer from May 2016 to May 2017 were selected as the subjects. All patients received ultrasonic diagnosis followed by the observation on dynamic contrast enhancement of the image and the analysis on perfusion characteristics and difference in contrast-enhanced ultrasound results in patients with different types of liver cancer. The signal during the arterial phase of 21 patients with well-differentiated hepatocellular carcinoma increased, including 12 cases of slow withdrawal of portal venous phase. The relative height of artery of 30 patients with middle-low differentiation of hepatocellular carcinoma increased along with the speed at which the contrast media was washed out at the end of the portal phase. In 9 patients with intrahepatic bile duct cancer, the enhancement of the arteries was slightly increased in the periphery of the tumor and low enhancement was found in the portal venous phase. There were some differences in the timing and the intensity of the enhancement of the ultrasound signals with 3 different types of diseases (P < 0.05). There are obvious differences in real-time contrast-enhanced ultrasound features of patients with different types of malignant liver tumor, which may provide references for clinical diagnosis.
Assuntos
Meios de Contraste , Neoplasias Hepáticas/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , UltrassonografiaRESUMO
Vitamin E and caloric restriction have antioxidant effects in mammals. The aim of this study was to evaluate effects of vitamin E supplementation and caloric restriction upon insulin secretion and glucose homeostasis in rats. Male Wistar rats were distributed among the following groups: C, control group fed ad libitum; R, food quantity reduction of 40%; CV, control group supplemented with vitamin E [30 mg·kg-1·day-1]; and RV, food-restricted group supplemented with vitamin E. The experiments ran for 21 days. Glucose tolerance and insulin sensitivity was higher in the CV, R, and RV groups. Insulin secretion stimulated with different glucose concentrations was lower in the R and RV groups, compared with C and CV. In the presence of glucose and secretagogues, insulin secretion was higher in the CV group and was lower in the R and RV groups. An increase in insulin receptor occurred in the fat pad and muscle tissue of groups CV, R, and RV. Levels of hepatic insulin receptor and phospho-Akt protein were higher in groups R and RV, compared with C and CV, while muscle phospho-Akt was increased in the CV group. There was a reduction in hepatic RNA levels of the hepatocyte growth factor gene and insulin degrading enzyme in the R group, and increased levels of insulin degrading enzyme in the CV and RV groups. Thus, vitamin E supplementation and caloric restriction modulate insulin secretion by different mechanisms to maintain glucose homeostasis.
Assuntos
Glicemia/metabolismo , Homeostase/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Vitamina E/farmacologia , Animais , Antioxidantes/metabolismo , Homeostase/fisiologia , Resistência à Insulina/fisiologia , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos WistarRESUMO
Portal vein occlusion increases the resectability of initially unresectable liver cancer by inducing hypertrophy in non-occluded liver lobes. However, the mechanisms of how portal vein occlusion induces hepatic hypertrophy remain unclear. A cDNA microarray was used to identify the gene expression signatures of ligated (LLLs) and nonligated liver lobes (NLLLs) at different time points after portal vein ligation (PVL). The results of a bioinformatics analysis revealed that LLLs and NLLLs displayed different gene expression profiles. Moreover, the expression levels of both coding and noncoding RNA were different between LLLs and NLLLs at different time points after PVL. A series test of cluster analysis revealed that the No. 22 and No. 5 expression patterns, which showed altered expression at 24 h and maintained this altered expression over the following 14 days, had the lowest P values and the highest number of differentially expressed genes in both the LLLs and NLLLs. The results of a GO analysis showed the activation of hypoxia pathways in LLLs and the activation of cell proliferation and cell-cycle pathways in NLLLs, suggesting the involvement of these pathways in PVL-induced hepatic hypertrophy and regeneration. These results provide insight into the molecular mechanisms underlying hepatic hypertrophy and regeneration induced by portal vein occlusion, and they identify potential targeting pathways that can promote the clinical application of PVL in liver cancer therapy.
Assuntos
Neoplasias Hepáticas/genética , Fígado/metabolismo , Veia Porta/cirurgia , Animais , Biologia Computacional , Perfilação da Expressão Gênica , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
This study examined the effects of vanadyl sulfate (VOSO4) on the livers of nondiabetic and streptozotocin-induced diabetic rats. Rats were divided into 6 groups. Groups 1, 2, and 3 consisted of nondiabetic rats that were, respectively, control animals or those receiving an intraperitoneal (i.p.) injection of either 5 or 10 mg·kg-1 (i.p.) VOSO4 for 30 days. Groups 4, 5, and 6 consisted of diabetic animals that were, respectively, control animals or those treated with 5 or 10 mg·kg-1 (i.p.) VOSO4 for 30 days. Results showed that VOSO4 reduced body mass in nondiabetic rats, whereas it increased body mass in diabetic groups. Plasma transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, and alkaline phosphatase activities and malondialdehyde levels were increased, while liver catalase and superoxide dismutase activities were profoundly decreased in diabetic animals in comparison with enzyme activities in the nondiabetic group. Rats in the diabetic group also showed notable oxidative damage to the liver. Treatment of diabetic rats with VOSO4 decreased the hepatotoxic markers, significantly restored the activities of antioxidant enzymes, and attenuated histopathological changes in liver tissue. In nondiabetic rats, VOSO4 treatment increased most of the hepatotoxic markers, reduced antioxidant enzyme activities, and induced pronounced oxidative damage in liver tissue. These data suggest that treatment with VOSO4 exerts toxic effects in healthy animals and significantly prevents liver oxidative damage in streptozotocin-induced diabetic rats, but without total safety. Further studies are needed to clarify its mechanism of action.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Fígado/efeitos dos fármacos , Compostos de Vanádio/efeitos adversos , Animais , Glicemia , Peso Corporal/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Humanos , Fígado/patologia , Testes de Função Hepática , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Resultado do TratamentoRESUMO
Atorvastatin (ATO) was commonly used to lower blood cholesterol, but it caused harmful effects to organs, including the liver. Thymoquinone (TQ), a prominent constituent of Nigella sativa, has antioxidant, antiinflammatory, antiapoptotic, antimicrobial, and anticancer activity. The current study investigated the mechanism of ATO-induced hepatotoxicity, whether posttreatment TQ could reverse ATO-induced hepatic injury, and the mechanism of action of TQ as a hepatoprotective agent. Forty adult male Sprague Dawley rats were divided into four equal groups: control, TQ-treated, ATO-treated, and combined ATO/TQ-treated. Rats were treated for 8 weeks and 10 days and euthanized by cervical dislocation 3 days after the last treatment. Blood samples and livers were tested for liver enzymes, oxidative stress, and apoptosis markers and used for histopathological and ultrastructural examination. The ATO-treated group showed an increase in liver enzymes, decreases in reduced glutathione and catalase, and increases in the malondialdehyde lipid peroxidation marker, protein carbonylation, and caspase 3 activity. Posttreatment TQ in the ATO/TQ-treated group seemed to reverse these changes. Histopathological and ultrastructural examination supported these data. Results from the current study suggested that posttreatment TQ may reverse oxidative stress injury in rat liver produced by ATO, suggesting a potential clinical application of using TQ to prevent ATO-induced hepatic injury.
Assuntos
Atorvastatina/efeitos adversos , Benzoquinonas/farmacologia , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Masculino , Avaliação de Resultados em Cuidados de Saúde , Ratos Sprague-DawleyRESUMO
Liver ischemia-reperfusion (IR) injury is inevitable in surgical procedures such as hepatic resection and liver transplantation. It represents a leading cause of liver graft dysfunction and primary nonfunction after transplantation. Phosphodiesterase (PDE) inhibitors are emerging as effective drugs able to reduce IR damage. The aim of this study was to investigate the effect of selective PDE-3 inhibitor olprinone (Olp) against liver IR injury. Male Wistar rats were subjected to 1 h of partial warm ischemia (70%) followed by 6 h of reperfusion. Before ischemia, rats were treated with saline (IR group), Olp (Olp group), or Olp with Akt inhibitor LY294002 (Olp plus LY group). After reperfusion, hepatic injury (transaminase activities), mitochondrial damage (glutamate dehydrogenase activity), oxidative stress (malondialdehyde and glutathione concentrations and catalase and superoxide dismutase activities), and protein kinase Akt activation were evaluated. Rat treatment with Olp reduced liver injury, prevented mitochondrial damage, decreased lipid peroxidation, and enhanced antioxidant enzymes. Also, Olp induced a significant activation in protein kinase Akt. Inhibition of Akt with LY294002 abolished all of the protective effects of Olp. In conclusion, Olp treatment may be an effective strategy in reducing liver IR injury through oxidative stress prevention and Akt activation.
Assuntos
Citoproteção/efeitos dos fármacos , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridonas/farmacologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Catalase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/irrigação sanguínea , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologiaRESUMO
Rat bile duct ligation (BDL) represents a useful method that mimics obstructive extrahepatic cholestasis, which is known to be a frequent disorder in humans. Polyamines (putrescine, spermidine, and spermine) are one of the key molecules regulating cell proliferation and differentiation. This work aimed to evaluate the potential beneficial properties of putrescine in rat BDL model by studying several biochemical parameters reflecting liver function and polyamine metabolism. Rats that were subjected to BDL were injected with putrescine (150 mg/kg) for 9 days, while in parallel another group with BDL remained untreated. Two control groups were included as well, sham-opened and putrescine-treated group. The following plasma parameters: ALT, AST, γ-GT, ALP, bilirubin, bile acids, as well as liver malondialdehyde and polyamine concentration and the activity of enzymes involved in polyamine metabolism were studied. After BDL, significant alterations in plasma biochemical parameters occurred, where a 9-day putrescine treatment significantly alleviated liver function deterioration. Putrescine also increased liver polyamines' concentrations and polyamine and diamine oxidase activities in rats submitted to BDL. Our results demonstrated, for the first time, that putrescine plays an important role in preserving liver tissue function in rats with experimentally induced cholestasis.
Assuntos
Arginina/metabolismo , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Poliaminas/metabolismo , Putrescina/farmacologia , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colestase/tratamento farmacológico , Colestase/metabolismo , Testes de Função Hepática/métodos , Masculino , Malondialdeído/metabolismo , Plasma/metabolismo , Ratos , Ratos WistarRESUMO
Elevated circulating uric acid has been postulated to play an important pathophysiological role in estrogen-progestin combined oral contraceptive (COC)-induced hypertension and endothelial dysfunction. We hypothesized that disruption of glucoregulation and liver triglyceride (TG) accumulation induced by COC use would be abated by valproic acid (VPA) treatment through suppression of adenosine deaminase (ADA) and xanthine oxidase (XO) activities. Female Wistar rats aged 9-10 weeks were treated with a combination of estrogen-progestin COC steroids (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; p.o.) with or without VPA (100.0 mg/kg; p.o.) daily for 6 weeks. The result shows that the disrupted glucoregulation and associated elevated hepatic ADA activity, plasma and hepatic XO activity, uric acid (UA), TG/HDL-cholesterol, total cholesterol, and malondialdehyde induced by COC treatment were attenuated by VPA treatment. However, VPA did not have any effect on plasma aldosterone, corticosterone, ADA, circulating and hepatic free fatty acid. Our results demonstrate that suppression of plasma and hepatic XO activities, along with hepatic ADA activity and UA by VPA treatment, protects against disrupted glucoregulation and increased liver TG by COC independent of elevated corticosteroids. The findings imply that VPA would provide protection against the development of cardiometabolic disorder via inhibition of the ADA/XO/UA-mediated pathway.
Assuntos
Inibidores de Adenosina Desaminase/farmacologia , Anticoncepcionais Orais Combinados/efeitos adversos , Hipertensão/tratamento farmacológico , Ácido Valproico/farmacologia , Xantina Oxidase/antagonistas & inibidores , Adenosina Desaminase/sangue , Adenosina Desaminase/metabolismo , Inibidores de Adenosina Desaminase/uso terapêutico , Aldosterona/sangue , Animais , Anticoncepcionais Orais Combinados/administração & dosagem , Corticosterona/sangue , Modelos Animais de Doenças , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Feminino , Glucose/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Progestinas/administração & dosagem , Progestinas/efeitos adversos , Ratos , Ratos Wistar , Triglicerídeos/metabolismo , Ácido Úrico/sangue , Ácido Valproico/uso terapêutico , Xantina Oxidase/metabolismoRESUMO
Oxidative stress is involved in the development of various cancers. In the present study, the effect of long-term administration of peroral antidiabetic metformin and pineal hormone melatonin on liver antioxidant and aerobic status in female Sprague-Dawley rats carrying mammary tumors induced by N-methyl-N-nitrosourea was evaluated. Both substances were administered in a preventive and curative manner (12 days before and 16 weeks after the carcinogen application). Carcinogen administration induced oxidative stress: the level of thiobarbituric acid reactive substances (TBARS) considered as a marker of reactive oxygen species (ROS) generation in liver increased as well as the level of oxidatively modified protein content (OMP; aldehyde and ketone derivates). Metformin administration restored succinate dehydrogenase and lactate dehydrogenase activity and associated ROS production and OMP content to the level of intact rats, with predominant activation of superoxide dismutase (SOD) and glutathione reductase (GR). Melatonin alone and in combination with metformin also decreased TBARS content. OMP content decreased in all groups receiving chemoprevention. The rise in total antioxidant capacity after melatonin and particularly metformin and melatonin combination might result from the initiation of anaerobic metabolism and increasing SOD, GR, and glutathione peroxidase activity. Long-term administration of metformin and melatonin exerts antioxidant properties in liver, especially in combination.