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1.
Chemosphere ; 239: 124747, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514003

RESUMO

BACKGROUNDS: Polychlorinated biphenyls are persistent environmental pollutants associated with the onset of non-alcoholic fatty liver disease in humans, but there is limited information on the underlying mechanism. In the present study, we investigated the alterations in gene expression profiles in normal human liver cells L-02 following exposure to 2, 3, 3', 4, 4', 5 - hexachlorobiphenyl (PCB 156), a potent compound that may induce non-alcoholic fatty liver disease. METHODS: The L-02 cells were exposed to PCB 156 for 72 h and the contents of intracellular triacylglyceride and total cholesterol were subsequently measured. Microarray analysis of mRNAs and long non-coding RNAs (lncRNAs) in the cells was also performed after 3.4 µM PCB 156 treatment. RESULTS: Exposure to PCB 156 (3.4 µM, 72 h) resulted in significant increases of triacylglyceride and total cholesterol concentrations in L-02 cells. Microarray analysis identified 222 differentially expressed mRNAs and 628 differentially expressed lncRNAs. Gene Ontology and pathway analyses associated the differentially expressed mRNAs with metabolic and inflammatory processes. Moreover, lncRNA-mRNA co-expression network revealed 36 network pairs comprising 10 differentially expressed mRNAs and 34 dysregulated lncRNAs. The results of bioinformatics analysis further indicated that dysregulated lncRNA NONHSAT174696, lncRNA NONHSAT179219, and lncRNA NONHSAT161887, as the regulators of EDAR, CYP1B1, and ALDH3A1 respectively, played an important role in the PCB 156-induced lipid metabolism disorder. CONCLUSION: Our findings provide an overview of differentially expressed mRNAs and lncRNAs in L-02 cells exposed to PCB 156, and contribute to the field of polychlorinated biphenyl-induced non-alcoholic fatty liver disease.


Assuntos
Fígado/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Transcriptoma/efeitos dos fármacos , Aldeído Desidrogenase/genética , Linhagem Celular , Colesterol/metabolismo , Citocromo P-450 CYP1B1/genética , Receptor Edar/genética , Perfilação da Expressão Gênica , Humanos , Fígado/citologia , Fígado/fisiologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante , RNA Mensageiro/metabolismo , Testes de Toxicidade , Triglicerídeos/metabolismo
2.
Gene ; 725: 144167, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639434

RESUMO

Osteoporosis in advanced cholestatic and end-stage liver disease is related to low bone formation. Previous studies have demonstrated the deleterious consequences of lithocholic acid (LCA) and bilirubin on osteoblastic cells. These effects are partially or completely neutralized by ursodeoxycholic acid (UDCA). We have assessed the differential gene expression of osteoblastic cells under different culture conditions. The experiments were performed in human osteosarcoma cells (Saos-2) cultured with LCA (10 µM), bilirubin (50 µM) or UDCA (10 and 100 µM) at 2 and 24 h. Expression of 87 genes related to bone metabolism and other signalling pathways were assessed by TaqMan micro fluidic cards. Several genes were up-regulated by LCA, most of them pro-apoptotic (BAX, BCL10, BCL2L13, BCL2L14), but also MGP (matrix Gla protein), BGLAP (osteocalcin), SPP1 (osteopontin) and CYP24A1, and down-regulated bone morphogenic protein genes (BMP3 and BMP4) and DKK1 (Dickkopf-related protein 1). Parallel effects were observed with bilirubin, which up-regulated apoptotic genes and CSF2 (colony-stimulating factor 2) and down-regulated antiapoptotic genes (BCL2 and BCL2L1), BMP3, BMP4 and RUNX2. UDCA 100 µM had specific consequences since differential expression was observed, up-regulating BMP2, BMP4, BMP7, CALCR (calcitonin receptor), SPOCK3 (osteonectin), BGLAP (osteocalcin) and SPP1 (osteopontin), and down-regulating pro-apoptotic genes. Furthermore, most of the differential expression changes induced by both LCA and bilirubin were partially or completely neutralized by UDCA. Conclusion: Our observations reveal novel target genes, whose regulation by retained substances of cholestasis may provide additional insights into the pathogenesis of osteoporosis in cholestatic and end-stage liver diseases.


Assuntos
Bilirrubina/metabolismo , Osteoblastos/metabolismo , Osteoporose/genética , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Linhagem Celular Tumoral , Colestase/genética , Regulação para Baixo/efeitos dos fármacos , Perfil Genético , Humanos , Ácido Litocólico/farmacologia , Fígado/metabolismo , Fígado/fisiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Osteoporose/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia
3.
Georgian Med News ; (295): 132-137, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31804215

RESUMO

Patients with refractory cardiac arrest, who have undergone Extracorporeal Life Support (ECLS) for resuscitation, but have not achieved cardiac recovery, can be considered as potential donors (Cardiac Death Donors). In such cases, it takes time to notify and obtain the principle consent of the relatives and finalize the clinical and legal documents. During this time, prior to obtaining consent for the removal of organs, ECLS can be extended. In this case, the extracorporeal circulation implies organ preservation "in situ" until the ethical, religious and organizational problems should be decided. Correspondingly, the identification of safe time terms during which the donor organs do not suffer by the changes not compatible with transplantation is extremely important. We aimed to study the morphological changes in the liver after 8 hours of extracorporeal circulation in experiments. The investigation was performed on 6 sheep with simulated cardiac arrest and undergone 8-hours extracorporeal circulation with own blood by using of new portable perfusion apparatus, made on the basis of a universal volumetric blood pump of our own design. The device was connected to the body through the femoral artery and vein with special cannulas. The biopsy of the liver was performed before the starting of perfusion, and on 4 and 8 hours of the experiment. The histological slices were stained by H&E and were assessed by standard criteria: level of steatosis (large-droplet macrovesicular steatosis [ld-MaS] and/or small-droplet macrovesicular steatosis [sd-MaS]); mononuclear portal inflammatory cell infiltrates; bile ductular proliferation; cholestasis; venous congestion; hepatocellular necrosis. Before the perfusion, no venous congestion, hepatocellular necrosis or ld-MaS were observed; Less than 3% of cells were suffered by sd-MaS; mononuclear portal inflammatory cell infiltrates were found only in several areas. Mild mixed ld-MaS and sd-MaS was found in less than 5 % and 10% of the cells accordingly on the 4 and 8 hours after in vivo Machine perfusion. Similarly the mild venous congestion was present in 1 out of 6 livers after 4-hours perfusion and in 2 out of 6 livers after 8-hours Perfusion. The number of necrotic hepatocytes and portal triads infiltrated with mononuclear cells did not exceed 10% and 15% accordingly. However, there were no differences in the degree of biliary damage - cholestasis or ductular proliferation - correlating with the terms of the experiment. Taking into the consideration all internationally accepted criteria of donor liver histological assessment, 8-hour in vivo perfusion of the liver in Cardiac Death Donors by using of the machine of own design providing the pulsatile blood flow guarantees the satisfactory preservation of liver making it useful for successful transplantation.


Assuntos
Transplante de Fígado , Fígado , Preservação de Órgãos , Perfusão , Animais , Morte , Modelos Animais de Doenças , Humanos , Fígado/fisiologia , Doadores Vivos , Ovinos
4.
Rozhl Chir ; 98(10): 388-393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31842567

RESUMO

Repopulation of decellularized tissue with cells is a very promising approach in tissue engineering, with liver tissue engineering not being an exception. Decellularized liver scaffolds can serve as an excellent 3D environment for recellularization as it maintain tissue-specific microarchitecture of ECM proteins with important spatial cues for cell adhesion, migration, growth and differentiation. Moreover, by using autologous cells the newly constructed graft should lack immunogenicity in the host organism and thus eliminate the need for immunosuppressive therapy in the post-transplant period. This review provides an overview of liver decellularization and repopulation experiments done so far while highlighting the advances as well as pin-pointing the challenges that remain to be solved.


Assuntos
Fígado/fisiologia , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Fenômenos Fisiológicos Celulares , Matriz Extracelular/fisiologia , Humanos , Fígado/citologia , Suínos
5.
Acta Cir Bras ; 34(7): e201900707, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31531528

RESUMO

PURPOSE: To evaluate the effects of splenic ischemic preconditioning (sIPC) on oxidative stress induced by hepatic ischemia-reperfusion in rats. METHODS: Fifteen male Wistar rats were equally divided into 3 groups: SHAM, IRI and sIPC. Animals from IRI group were subjected to 45 minutes of partial liver ischemia (70%). In the sIPC group, splenic artery was clamped in 2 cycles of 5 min of ischemia and 5 min of reperfusion (20 min total) prior to hepatic ischemia. SHAM group underwent the same surgical procedures as in the remaining groups, but no liver ischemia or sIPC were induced. After 1h, hepatic and splenic tissue samples were harvested for TBARS, CAT, GPx and GSH-Rd measurement. RESULTS: sIPC treatment significantly decreased both hepatic and splenic levels of TBARS when compared to IRI group (p<0.01). Furthermore, the hepatic and splenic activities of CAT, GPx and GSH- Rd were significantly higher in sIPC group than in IRI group. CONCLUSION: sIPC was able to attenuate hepatic and splenic IRI-induced oxidative stress.


Assuntos
Precondicionamento Isquêmico/métodos , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Fígado/fisiologia , Hepatopatias/fisiopatologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
6.
Nat Biotechnol ; 37(10): 1131-1136, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501557

RESUMO

The inability to preserve vascular organs beyond several hours contributes to the scarcity of organs for transplantation1,2. Standard hypothermic preservation at +4 °C (refs. 1,3) limits liver preservation to less than 12 h. Our group previously showed that supercooled ice-free storage at -6 °C can extend viable preservation of rat livers4,5 However, scaling supercooling preservation to human organs is intrinsically limited because of volume-dependent stochastic ice formation. Here, we describe an improved supercooling protocol that averts freezing of human livers by minimizing favorable sites of ice nucleation and homogeneous preconditioning with protective agents during machine perfusion. We show that human livers can be stored at -4 °C with supercooling followed by subnormothermic machine perfusion, effectively extending the ex vivo life of the organ by 27 h. We show that viability of livers before and after supercooling is unchanged, and that after supercooling livers can withstand the stress of simulated transplantation by ex vivo normothermic reperfusion with blood.


Assuntos
Temperatura Baixa , Fígado/fisiologia , Preservação de Órgãos/métodos , Humanos , Soluções para Preservação de Órgãos , Perfusão , Sobrevivência de Tecidos
7.
Int J Nanomedicine ; 14: 5753-5783, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413573

RESUMO

Tissue engineering embraces the potential of recreating and replacing defective body parts by advancements in the medical field. Being a biocompatible nanomaterial with outstanding physical, chemical, optical, and biological properties, graphene-based materials were successfully employed in creating the perfect scaffold for a range of organs, starting from the skin through to the brain. Investigations on 2D and 3D tissue culture scaffolds incorporated with graphene or its derivatives have revealed the capability of this carbon material in mimicking in vivo environment. The porous morphology, great surface area, selective permeability of gases, excellent mechanical strength, good thermal and electrical conductivity, good optical properties, and biodegradability enable graphene materials to be the best component for scaffold engineering. Along with the apt microenvironment, this material was found to be efficient in differentiating stem cells into specific cell types. Furthermore, the scope of graphene nanomaterials in liver tissue engineering as a promising biomaterial is also discussed. This review critically looks into the unlimited potential of graphene-based nanomaterials in future tissue engineering and regenerative therapy.


Assuntos
Grafite/química , Fígado/fisiologia , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Microambiente Celular , Humanos , Nanocompostos/química
8.
Diabetes Metab Syndr ; 13(4): 2705-2713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405697

RESUMO

BACKGROUND: Yoga is an ancient system of wellness with Asana and Pranayama as its most popular and propagated modules for management of lifestyle disorders. OBJECTIVES: The aim of the study was to characterise the liver abnormalities, biochemical changes, and stress levels after Yoga intervention in prediabetic females. MATERIALS AND METHODS: 37 females were randomly divided into Yoga practising and non-practising control groups. The Yoga practising group performed Diabetic Yoga Protocol (DYP) for 3 months. Parameters including size of liver, fatty infiltration, and grade of severity were measured using ultrasonography along with biochemical parameters and stress levels at baseline and after Yoga practice. RESULTS: The glycosylated hemoglobin (HbA1c) and glucose levels were found significantly reduced in prediabetic (p = 0.015) women after practising DYP, although cholesterol levels increased in menopausal women. No escalation of fatty liver was noted among women practising DYP. CONCLUSION: DYP reduced the HbA1c and stress levels and therefore, could be a cost-effective tool for preventing prediabetes to diabetes progression.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/prevenção & controle , Fígado/fisiologia , Estado Pré-Diabético/terapia , Estresse Fisiológico , Ioga , Glicemia/análise , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Estilo de Vida , Fígado/diagnóstico por imagem , Pessoa de Meia-Idade , Estado Pré-Diabético/diagnóstico por imagem , Prognóstico , Ultrassonografia/métodos
9.
Cancer Genomics Proteomics ; 16(5): 333-344, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467227

RESUMO

BACKGROUND: Vitamin C has been used in combination with several target genes in the treatment of leukemia. Tet methylcytosine dioxygenase (Tet2), B-cell lymphoma 2 (Bcl2), and solute carrier family 23 member 2 (Slc23a2) are the major target genes in the treatment of leukemia and are relevant to vitamin C. MATERIALS AND METHODS: Using whole-genome expression profiles from mouse livers, the expression quantitative trait locus (eQTL), correlation matrix, and gene network graph were constructed with probes from each of these three genes and with their relative genes. The function of key genes was examined by their pathways and reported information. The results indicated that although direct correlations among their expression levels were not strong, alternative connecting pathways were discovered. By comparing the expression levels of one probe with known sequences from each of the three genes, we identified several key genes, induced myeloid leukemia cell differentiation protein (Mcl1), far upstream element-binding protein 1 (Fubp1), and tumor protein D52-like 2 (Tpd52l2), which play important roles in acute lymphocytic leukemia and acute myelocytic leukemia. In conclusion, Alternative pathways and key genes that connect Tet2, Bcl2, and Slc23a2 for their therapeutic applications with vitamin C were identified.


Assuntos
Ácido Ascórbico/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas/genética , Transportadores de Sódio Acoplados à Vitamina C/genética , Animais , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Fígado/fisiologia , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Locos de Características Quantitativas , Proteínas de Ligação a RNA/genética
10.
Environ Pollut ; 254(Pt B): 113061, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454574

RESUMO

Perfluoroalkyl acids (PFAAs) are persistent in the environment, highly bio-accumulative in the body, and likely hepatotoxic in humans. There is evidence of sex-specific physiological responses to PFAA exposure. However, epidemiological studies seldom stratify the analyses by sex. Given the high prevalence of liver disease in general population adolescents, this study was designed to determine whether or not there is association between exposure to PFAAs and biomarkers of liver function in adolescent participants of the 2013-2016 National Health and Nutrition Examination Survey, and whether or not such association is sex-specific. Multivariate linear regressions were performed to examine the association between single PFAAs [perfluorooctane sulfonic acid (PFOS); linear form of perfluorooctanoic acid (PFOA); perfluorohexane sulfonic acid (PFHxS); perfluorononanoic acid (PFNA)], and biomarkers of liver function - gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin. Multivariate logistic regressions were performed to estimate adjusted odd ratios (aOR) of elevated ALT, AST and GGT. The study results show that, in females, there was a positive association of the highest PFOA quartile with increased ALT, AST and GGT, and the highest PFNA quartile with increased ALT and AST. Conversely, in male adolescents there was an association of the highest linear PFOA quartile with decreased ALT, and the highest PFNA quartile with ALT and AST. Females had higher odds of clinically-defined elevated ALT with increased PFOA (aOR = 1.79; 95% CI: 1.05, 3.04) or PFNA (aOR = 2.28; 95% CI: 1.08, 2.28), whereas males had decreased odds of clinically-defined elevated ALT with increased n-PFOA (aOR = 0.43; 95% CI: 0.20, 0.93) or PFNA (aOR = 0.5; 95% CI: 0.28, 0.89). In conclusion, there were sex differences in the association between serum PFAA levels and biomarkers of liver function. These results may provide support for analyzing sex-based adverse effects of PFAAs.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Fluorcarbonetos/metabolismo , Fígado/fisiologia , Inquéritos Nutricionais , Adolescente , Ácidos Alcanossulfônicos/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Caprilatos/metabolismo , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Razão de Chances , Prevalência , Fatores Sexuais , Ácidos Sulfônicos/sangue
11.
Biol Pharm Bull ; 42(8): 1253-1267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366863

RESUMO

Systemic platelet behaviors in experimental animals are often assessed by infusion of isotope-labeled platelets and measuring them under anesthesia. However, such procedures alter, therefore may not reveal, real-life platelet behaviors. 5-Hydroxytryptamine (5HT or serotonin) is present within limited cell-types, including platelets. In our studies, by measuring 5HT as a platelet-marker in non-anesthetized mice, we identified stimulation- and time-dependent accumulations in liver, lung, and/or spleen as important systemic platelet behaviors. For example, intravenous, intraperitoneal, or intragingival injection of lipopolysaccharide (LPS, a cell-wall component of Gram-negative bacteria), interleukin (IL)-1, or tumor necrosis factor (TNF)-α induced hepatic platelet accumulation (HPA) and platelet translocation into the sinusoidal and perisinusoidal spaces or hepatocytes themselves. These events occurred "within a few hours" of the injection, caused hypoglycemia, and exhibited protective or causal effects on hepatitis. Intravenous injection of larger doses of LPS into normal mice, or intravenous antigen-challenge to sensitized mice, induced pulmonary platelet accumulation (PPA), as well as HPA. These reactions occurred "within a few min" of the LPS injection or antigen challenge and resulted in shock. Intravenous injection of 5HT or a catecholamine induced a rapid PPA "within 6 s." Intravenous LPS injection, within a minute, increased the pulmonary catecholamines that mediate the LPS-induced PPA. Macrophage-depletion from liver and spleen induced "day-scale" splenic platelet accumulation, suggesting the spleen is involved in clearing senescent platelets. These findings indicate the usefulness of 5HT as a marker of platelet behaviors, and provide a basis for a discussion of the roles of platelets as both "defenders" and "guardians."


Assuntos
Plaquetas/fisiologia , Fígado/fisiologia , Pulmão/fisiologia , Serotonina/fisiologia , Baço/fisiologia , Animais , Humanos , Camundongos
12.
Nat Commun ; 10(1): 3518, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388006

RESUMO

Diurnal light-dark cycle resets the master clock, while timed food intake is another potent synchronizer of peripheral clocks in mammals. As the largest metabolic organ, the liver sensitively responds to the food signals and secretes hepatokines, leading to the robust regulation of metabolic and clock processes. However, it remains unknown which hepatokine mediates the food-driven resetting of the liver clock independent of the master clock. Here, we identify Angptl8 as a hepatokine that resets diurnal rhythms of hepatic clock and metabolic genes in mice. Mechanistically, the resetting function of Angptl8 is dependent on the signal relay of the membrane receptor PirB, phosphorylation of kinases and transcriptional factors, and consequently transient activation of the central clock gene Per1. Importantly, inhibition of Angptl8 signaling partially blocks food-entrained resetting of liver clock in mice. We have thus identified Angptl8 as a key regulator of the liver clock in response to food.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Comportamento Alimentar/fisiologia , Fígado/fisiologia , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Proteínas Semelhantes a Angiopoietina/genética , Animais , Relógios Circadianos/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Fígado/metabolismo , Masculino , Camundongos , Modelos Animais , Proteínas Circadianas Period/metabolismo , Fosforilação , Fotoperíodo , Receptores Imunológicos/metabolismo
14.
Pak J Pharm Sci ; 32(3): 1033-1042, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278717

RESUMO

Ketoconazole is a first orally available anti-fungal drug which has been reported as a potent inhibitor of human cytochrome P-450. The present study was designed to examine the heptoprotective effect of ketoconazole in both in vitro and in vivo liver injury models. Hepatocyte injury was induced by 8mM CCl4 while hepatic fibrosis model was established by injecting 1 ml/kg CCl4 followed by treatment with ketoconazole. Effect of ketoconazole treatment on injured hepatocytes was determined by lactate dehydrogenase release and trypan blue assay. Analysis of ketoconazole treatment and prevention on liver fibrosis was assessed by sirius red staining, masson trichome staining, PCR and liver function tests for bilirubin and alanine transaminase (ALAT).A significant reduction (P<0.05) in LDH release and reduced number of dead cells was observed in hepatocytes treated with ketoconazole. Sirus red and masson trichome stainings showed reduced levels of collagen in both treated and preventive groups and down regulation of alpha smooth muscle actin was observed with up-regulations of MMP-2, CK-8 and CK-18. Hepatic functional assessment demonstrated reduced serum levels of bilirubin and ALAT. Treatment of fibrotic liver with ketoconazole improves hepatic microenvironment and enhanced reduction of liver injury after fibrosis. Cytochrome P-450 inhibitors seems a favored therapeutic option in attenuation of liver fibrosis.


Assuntos
Hepatócitos/efeitos dos fármacos , Cetoconazol/farmacologia , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Actinas/genética , Animais , Tetracloreto de Carbono/toxicidade , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , L-Lactato Desidrogenase/metabolismo , Fígado/fisiologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Metaloproteinase 2 da Matriz/genética , Camundongos Endogâmicos C57BL
15.
Sci Total Environ ; 689: 149-159, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271984

RESUMO

Numerous studies suggest that amphibians are highly sensitive to endocrine disruptors (ED) but their precise role in population decline remains unknown. This study shows that frogs exposed to a mixture of ED throughout their life cycle, at environmentally relevant concentrations, developed an unexpected metabolic syndrome. Female Silurana (Xenopus) tropicalis exposed to a mixture of benzo[a]pyrene and triclosan (50 ng·L-1 each) from the tadpole stage developed liver steatosis and transcriptomic signature associated with glucose intolerance syndrome, and pancreatic insulin hyper secretion typical of pre-diabetes. These metabolic disorders were associated with delayed metamorphosis and developmental mortality in their progeny, both of which have been linked to reduced adult recruitment and reproductive success. Indeed, F1 females were smaller and lighter and presented reduced reproductive capacities, demonstrating a reduced fitness of ED-exposed Xenopus. Our results confirm that amphibians are highly sensitive to ED even at concentrations considered to be safe for other animals. This study demonstrates that ED might be considered as direct contributing factors to amphibian population decline, due to their disruption of energetic metabolism.


Assuntos
Benzo(a)pireno/toxicidade , Disruptores Endócrinos/toxicidade , Doenças Metabólicas/veterinária , Metamorfose Biológica/efeitos dos fármacos , Triclosan/toxicidade , Xenopus/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Fígado/efeitos dos fármacos , Fígado/fisiologia , Fígado/fisiopatologia , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/metabolismo , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/metabolismo , Síndrome Metabólica/veterinária , Reprodução/efeitos dos fármacos , Transcriptoma
16.
Ann Transplant ; 24: 401-406, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31273186

RESUMO

BACKGROUND We assessed the alterations in portal hemodynamics associated with donor right hepatectomy and its effects on functional regeneration of the remnant liver. MATERIAL AND METHODS This prospective study included 30 adult living donors who underwent right hepatectomy in the Liver Transplantation Unit, Faculty of Medicine, Cairo University from June 2015 to October 2016. During donor surgery, portal venous pressure (PVP) was measured using an antithrombotic catheter inserted into the main portal vein, and was measured before and after clamping of the right portal vein. Postoperatively, liver function tests were done daily until normalization. The outcome measures were the time to normalization of liver function tests and effect of residual volume and steatosis on PVP. RESULTS All donors had normal PVP before clamping and changed significantly after clamping (p<0.001). After clamping, 25 donors (83%) had a PVP above 12 mmHg; i.e. had high portal pressure. The median percentage of change was 55%. There were obvious increases in liver enzymes and bilirubin after surgery, but albumin and international normalized ratio showed progressive decreases postoperatively. The percent change in PVP was positively correlated with the levels of liver enzymes, time to normalization of liver enzymes, albumin, and bilirubin, and with the degree of steatosis, bit it was negatively correlated with residual liver volume. CONCLUSIONS During living donor liver transplantation, PVP increases by over 50% after clamping of the right portal vein of the donor's liver. This increase is associated with temporary delay of normalization of liver function of the donors.


Assuntos
Transplante de Fígado/métodos , Fígado/fisiologia , Doadores Vivos , Pressão na Veia Porta/fisiologia , Veia Porta/fisiologia , Adulto , Feminino , Hepatectomia , Humanos , Fígado/irrigação sanguínea , Testes de Função Hepática , Masculino , Estudos Prospectivos , Adulto Jovem
17.
Mol Med Rep ; 20(2): 1663-1671, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257470

RESUMO

A limited number of studies have revealed that adding kidneys to liver perfusion may maintain an improved physiological balance; however, the underlying mechanism remains to be elucidated. The preset study confirmed the protective role of this new model and investigated the underlying mechanisms. Methods: A total of 12 rats were randomly assigned into two groups (n=6 for each group): The kidney­liver perfusion (KL) group and liver perfusion (LP) group. Perfusate samples were collected during the perfusion process for the analysis of pH, K+ and liver function. Liver tissues were obtained for the evaluation of adenosine triphosphate (ATP), terminal deoxynucleotidyl­transferase­mediated dUTP nick end labelling and immunohistochemistry of Ki67. Cell cycle inhibitors, apoptosis­associated genes and signal transducer and activator of transcription 3 (Stat3) were analyzed using quantitative polymerase chain reaction and western blot analysis. Results: Overall pH and K+ values of the KL group were significantly different from the LP group and more stable; aspartate aminotransferase, alanine transaminase and lactate dehydrogenase levels increased progressively over time in the LP group and were significantly different at different time points compared with pre­perfusion levels and the KL group, which suggested the KL group was superior to the LP group. In addition, KL reduced portal vein resistance and was associated with lower ATP consumption compared with the LP group. Furthermore, liver proliferation was upregulated with the upregulation of the interleukin 6 (IL­6)/Stat3 signaling pathway in KL compared with LP. The present study revealed for the first time that KL and hypothermic machine perfusion demonstrated a more proactive repair capability by maintaining liver regeneration via the upregulation of the IL­6/Stat3 signaling pathway.


Assuntos
Interleucina-6/metabolismo , Rim/fisiologia , Fígado/fisiologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Temperatura Baixa , Transplante de Fígado , Masculino , Preservação de Órgãos/métodos , Perfusão/métodos , Ratos , Ratos Sprague-Dawley
19.
Fish Shellfish Immunol ; 92: 341-347, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202964

RESUMO

The yellow drum (Nibea albiflora) is an economically important maricultured fish in China, but the aquaculture of this species has recently been limited by an increase in overwinter mortalities associated with cold and starvation stress due to global climate changes. To better understand the interaction between starvation and cold-stress-driven overwinter mortality, we investigated the effects of these stresses on the growth performance, liver lesions, and immune response of yellow drum fish. The fish were subjected to different cold treatments and under starvation stress. The experiment lasted 30 days and involved four experimental groups: a fed group and a fasted group maintained at 16 °C (control), and a fed group and a fasted group subjected to cold stress at 8 °C. We found that the growth of yellow drum was severely affected by cold temperatures and starvation. Throughout the experimental period, the body weights were significantly lower in the groups subjected to starvation and cold stress than in the control group. The liver cells showed irregular shapes and disorderly arrangements in the stress groups; indicating liver lesions. The gene expressions of antioxidant enzymes (copper, zinc superoxide dismutase, manganese superoxide dismutase, iron superoxide dismutase, and catalase) in the liver were lower in the groups subjected to starvation and cold stress than in the control groups. These results were basically consistent with the enzyme activities of superoxide dismutase and catalase tested in the livers. In addition, activities of immunomodulatory enzymes (alkaline phosphatase and acid phosphatase) were also inhibited in groups subjected to stress throughout the experiment period. These findings suggested that starvation and cold stress inhibited growth, depressed liver function, and suppressed the immune system of yellow drum, which likely would lead to physiological failure and increased susceptibility to infection. The present study offers insights into the physiological and immune response of yellow drum under cold and starvation stress. These insights not only provide baseline information from which effective strategies can be established and appropriate management decisions formulated, but can also be used to improve the overwinter survival of this important fish species in China.


Assuntos
Privação de Alimentos , Imunidade Inata , Longevidade , Perciformes/imunologia , Animais , Temperatura Baixa/efeitos adversos , Fígado/anatomia & histologia , Fígado/fisiologia , Perciformes/crescimento & desenvolvimento
20.
Endocrinology ; 160(9): 2061-2073, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199473

RESUMO

Inhibition of 5α-reductases impairs androgen and glucocorticoid metabolism and induces insulin resistance in humans and rodents. The contribution of hepatic glucocorticoids to these adverse metabolic changes was assessed using a liver-selective glucocorticoid receptor (GR) antagonist, A-348441. Mice lacking 5α-reductase 1 (5αR1-KO) and their littermate controls were studied during consumption of a high-fat diet, with or without A-348441(120 mg/kg/d). Male C57BL/6 mice (age, 12 weeks) receiving dutasteride (1.8 mg/kg/d)) or vehicle with consumption of a high-fat diet, with or without A-348441, were also studied. In the 5αR1-KO mice, hepatic GR antagonism improved diet-induced insulin resistance but not more than that of the controls. Liver steatosis was not affected by hepatic GR antagonism in either 5αR1KO mice or littermate controls. In a second model of 5α-reductase inhibition using dutasteride and hepatic GR antagonism with A-348441 attenuated the excess weight gain resulting from dutasteride (mean ± SEM, 7.03 ± 0.5 vs 2.13 ± 0.4 g; dutasteride vs dutasteride plus A-348441; P < 0.05) and normalized the associated hyperinsulinemia after glucose challenge (area under the curve, 235.9 ± 17 vs 329.3 ± 16 vs 198.4 ± 25 ng/mL/min; high fat vs high fat plus dutasteride vs high fat plus dutasteride plus A-348441, respectively; P < 0.05). However, A-348441 again did not reverse dutasteride-induced liver steatosis. Thus, overall hepatic GR antagonism improved the insulin resistance but not the steatosis induced by a high-fat diet. Moreover, it attenuated the excessive insulin resistance caused by pharmacological inhibition of 5α-reductases but not genetic disruption of 5αR1. The use of dutasteride might increase the risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids might be beneficial.


Assuntos
Colestenona 5 alfa-Redutase/deficiência , Fígado/fisiologia , Receptores de Glucocorticoides/fisiologia , Animais , Colestenona 5 alfa-Redutase/fisiologia , Ácidos Cólicos/farmacologia , Dieta Hiperlipídica , Dutasterida/farmacologia , Estrona/análogos & derivados , Estrona/farmacologia , Gluconeogênese , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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