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1.
PLoS Pathog ; 16(8): e1008131, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866196

RESUMO

Invasion of hepatocytes by Plasmodium sporozoites initiates the pre-erythrocytic step of a malaria infection. Subsequent development of the parasite within hepatocytes and exit from them is essential for starting the disease-causing erythrocytic cycle. Identification of signaling pathways that operate in pre-erythrocytic stages provides insight into a critical step of infection and potential targets for chemoprotection from malaria. We demonstrate that P. berghei homologs of Calcium Dependent Protein Kinase 1 (CDPK1), CDPK4 and CDPK5 play overlapping but distinct roles in sporozoite invasion and parasite egress from hepatocytes. All three kinases are expressed in sporozoites. All three are required for optimal motility of sporozoites and consequently their invasion of hepatocytes. Increased cGMP can compensate for the functional loss of CDPK1 and CDPK5 during sporozoite invasion but cannot overcome loss of CDPK4. CDPK1 and CDPK5 expression is downregulated after sporozoite invasion. CDPK5 reappears in a subset of late stage liver stages and is present in all merosomes. Chemical inhibition of CDPK4 and depletion of CDPK5 in liver stages implicate these kinases in the formation and/or release of merosomes from mature liver stages. Furthermore, depletion of CDPK5 in merosomes significantly delays initiation of the erythrocytic cycle without affecting infectivity of hepatic merozoites. These data suggest that CDPK5 may be required for the rupture of merosomes. Our work provides evidence that sporozoite invasion requires CDPK1 and CDPK5, and suggests that CDPK5 participates in the release of hepatic merozoites.


Assuntos
Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Malária/epidemiologia , Merozoítos/enzimologia , Plasmodium berghei/enzimologia , Proteínas Quinases/biossíntese , Proteínas de Protozoários/biossíntese , Esporozoítos/enzimologia , Animais , Eritrócitos/enzimologia , Eritrócitos/parasitologia , Feminino , Células Hep G2 , Humanos , Fígado/enzimologia , Fígado/parasitologia , Malária/patologia , Camundongos
2.
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
3.
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
4.
Life Sci ; 259: 118200, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758621

RESUMO

AIMS: Diet is one of the factors affecting the pathogenicity of Helicobacter pylori (H. pylori) infection. Choline is a dietary component that is crucial for normal cellular function. However, choline intake imbalance can lead to liver injury, inflammation, and changes of the gut microbiota composition. The study aimed to explore the effects of choline supplementation on liver biology, gut microbiota, and inflammation in H. pylori-infected mice. MAIN METHODS: Liver function was detected by biochemical and histopathological analysis. Serum inflammatory markers were measured using ELISA. Fecal microbial profiles were determined via 16S rRNA sequencing. KEY FINDINGS: The results showed that choline supplementation decreased serum LDL level, while increased the activities of serum AST and ALT in normal BALB/c mice. Besides, choline also reduced hepatic SOD and GSH-Px activities, and elevated hepatic MDA level of H. pylori-infected mice. Moreover, choline markedly enhanced the concentrations of inflammatory factors including LPS, CRP, IL-6, TNF-α, and CXCL1 in H. pylori-infected mice. Meanwhile, choline and H. pylori cotreatment altered the richness and diversity of the mice gut microbiota, and increased the relative abundance of Escherichia_Shigella, which had a significant positive correlation with the levels of LPS, CRP, IL-6, TNF-α and CXCL1. SIGNIFICANCE: Our data suggest, for the first time, that choline can aggravate H. pylori-induced inflammation, which may be associated with the alterations of gut microbiota. This study may provide novel insights into the possible effects of food-derived choline on H. pylori infection-related diseases.


Assuntos
Colina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Infecções por Helicobacter/microbiologia , Helicobacter pylori , Fígado/efeitos dos fármacos , Animais , LDL-Colesterol/sangue , Dieta , Fezes/microbiologia , Feminino , Infecções por Helicobacter/patologia , Inflamação/sangue , Fígado/enzimologia , Fígado/patologia , Testes de Função Hepática , Camundongos , Camundongos Endogâmicos BALB C , RNA Ribossômico 16S/genética
5.
Life Sci ; 258: 118204, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763296

RESUMO

AIMS: Liver kinase B1 (LKB1) is a serine/threonine kinase. Although many biological functions of LKB1 have been identified, the role of hypothalamic LKB1 in the regulation of central energy metabolism and susceptibility to obesity is unknown. Therefore, we constructed POMC neuron-specific LKB1 knockout mice (PomcLkb1 KO) and studied it at the physiological, morphological, and molecular biology levels. MAIN METHODS: Eight-week-old male PomcLkb1 KO mice and their littermates were fed a standard chow fat diet (CFD) or a high-fat diet (HFD) for 3 months. Body weight and food intake were monitored. Dual-energy X-ray absorptiometry was used to measure the fat mass and lean mass. Glucose and insulin tolerance tests and serum biochemical markers were evaluated in the experimental mice. In addition, the levels of peripheral lipogenesis genes and central energy metabolism were measured. KEY FINDINGS: PomcLkb1 KO mice did not exhibit impairments under normal physiological conditions. After HFD intervention, the metabolic phenotype of the PomcLkb1 KO mice changed, manifesting as increased food intake and an enhanced obesity phenotype. More seriously, PomcLkb1 KO mice showed increased leptin resistance, worsened hypothalamic inflammation and reduced POMC neuronal expression. SIGNIFICANCE: We provide evidence that LKB1 in POMC neurons plays a significant role in regulating energy homeostasis. LKB1 in POMC neurons emerges as a target for therapeutic intervention against HFD-induced obesity and metabolic diseases.


Assuntos
Deleção de Genes , Neurônios/enzimologia , Obesidade/enzimologia , Pró-Opiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica , Epididimo/patologia , Comportamento Alimentar , Regulação da Expressão Gênica , Glucose/metabolismo , Hipotálamo/patologia , Inflamação/patologia , Leptina/metabolismo , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Obesidade/sangue , Obesidade/patologia , Pró-Opiomelanocortina/genética , Ganho de Peso
6.
Artigo em Inglês | MEDLINE | ID: mdl-32602765

RESUMO

The purpose of this study was to identify the long-term effect of chemical exposure on the liver. Laboratory tests included alanine aminotransferase (ALT) dosage and oxidative stress tests, such as thiobarbituric acid reactive substances in plasma and superoxide dismutase (SOD) and glutathione S-transferase analysis in erythrocytes. The cross-sectional study comprised 70 workers, 30 of them exposed to organic solvents and 40 not exposed. All those exposed presented at least 5 years of exposure to solvents. Hepatitis B and C, known hepatic disease, comorbidities, use of alcohol, illicit drugs or hepatotoxic medications, smoking, body mass index >30, female sex and age (<18 or >65) were excluded from the sample. Results indicated that elevated ALT was more frequent in the exposed group compared to controls: 33% vs. 10.5%, with a statistical significance (p < 0.05). Thiobarbituric acid reactive substances were significantly elevated (p < 0.01) in the exposed group in comparison to controls. Antioxidant enzymes were more elevated in the exposed group compared to controls: SOD 7.29 (4.30-8.91) USOD/mg of protein vs. 3.48 (2.98-5.28) USOD/mg of protein and GST 2.57 µmol/min/mg of protein (1.80-4.78) vs. 1.81 µmol/min/mg of protein (1.45- 2.30) µM/min/mg of protein. The results suggest an association between exposure to organic solvents and hepatotoxicity.


Assuntos
Antioxidantes/metabolismo , Hidrocarbonetos Aromáticos/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Solventes/toxicidade , Alanina Transaminase/sangue , Animais , Brasil , Estudos Transversais , Feminino , Glutationa Transferase/sangue , Humanos , Hidrocarbonetos Aromáticos/análise , Indústrias , Fígado/enzimologia , Fígado/metabolismo , Masculino , Exposição Ocupacional/análise , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Solventes/análise , Superóxido Dismutase/sangue
7.
Liver Int ; 40(9): 2110-2116, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32654359

RESUMO

SARS2-CoV-2 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection, very few information are available about liver involvement, possibly evocating a systemic disease. Post-mortem wedge liver biopsies from 48 patients died from severe pulmonary COVID-19 disease with respiratory failure were collected from two main hospitals in northern Italy. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase in number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. SARS-CoV-2 was found in 15 of 22 samples tested by in situ hybridization method. Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. It still remains unclear if the mentioned changes are directly related to virus infection or if SARS-CoV-2 triggers a series of reactions leading to striking vascular alterations.


Assuntos
Infecções por Coronavirus/patologia , Fígado/patologia , Pneumonia Viral/patologia , Veia Porta/patologia , Insuficiência Respiratória/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Infecções por Coronavirus/complicações , Feminino , Humanos , Fígado/irrigação sanguínea , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Insuficiência Respiratória/virologia
8.
Science ; 369(6500): 167-173, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32646997

RESUMO

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.


Assuntos
Envelhecimento/sangue , Encéfalo/fisiologia , Cognição/fisiologia , Fígado/enzimologia , Neurogênese , Fosfolipase D/sangue , Condicionamento Físico Animal , Animais , Circulação Sanguínea , Encéfalo/irrigação sanguínea , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Glicosilfosfatidilinositóis/metabolismo , Camundongos , Fosfolipase D/metabolismo , Regeneração , Transdução de Sinais
9.
Exp Parasitol ; 216: 107935, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32569599

RESUMO

Toxoplasma gondii is an important pathogen that causes serious public health problems. Currently, therapeutic drugs for toxoplasmosis cause serious side effects, and more effective and novel substances with relatively low toxicity are urgently needed. Ursolic acid (UA) has many properties that can be beneficial to healthcare. In this study, we synthesized eight series of UA derivatives bearing a tetrazole moiety and evaluated their anti-T. gondii activity in vitro using spiramycin as a positive control. Most of the synthesized derivatives exhibited better anti-T. gondii activity in vitro than UA, among which compound 12a exhibited the most potent anti-T. gondii activity. Furthermore, the results of biochemical parameter determination indicated that 12a effectively restored the normal body weight of mice infected with T. gondii, reduced hepatotoxicity, and exerted significant anti-oxidative effects compared with the findings for spiramycin. Additionally, our molecular docking study indicated that the synthesized compounds could act as potential inhibitors of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), with 12a possessing strong affinity for TgCDPK1 via binding to the key amino acids GLU129 and TYR131.


Assuntos
Anti-Infecciosos/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasmose Animal/tratamento farmacológico , Toxoplasmose/tratamento farmacológico , Triterpenos/farmacologia , Alanina Transaminase/sangue , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Aspartato Aminotransferases/sangue , Coccidiostáticos/química , Coccidiostáticos/farmacologia , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Malondialdeído/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Tamanho do Órgão/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases , Distribuição Aleatória , Espiramicina/farmacologia , Baço/efeitos dos fármacos , Baço/patologia , Triterpenos/química , Triterpenos/uso terapêutico
10.
J Trauma Acute Care Surg ; 89(1): 230-237, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32569106

RESUMO

BACKGROUND: Outcome data on the very elderly patients undergoing emergency general surgery (EGS) are sparse. We sought to examine short- and long-term mortality in the 80 plus years population following EGS. METHODS: Using our institutional 2008-2018 EGS Database, all the 80 plus years patients undergoing EGS were identified. The data were linked to the Social Security Death Index to determine cumulative mortality rates up to 3 years after discharge. Univariate and multivariable logistic regression analyses were used to determine predictors of in-hospital and 1-year cumulative mortality. RESULTS: A total of 385 patients were included with a mean age of 84 years; 54% were female. The two most common comorbidities were hypertension (76.1%) and cardiovascular disease (40.5%). The most common procedures performed were colectomy (20.0%), small bowel resection (18.2%), and exploratory laparotomy for other procedures (15.3%; e.g., internal hernia, perforated peptic ulcer). The overall in-hospital mortality was 18.7%. Cumulative mortality rates at 1, 2, and 3 years after discharge were 34.3%, 40.5%, and 43.4%, respectively. The EGS procedure associated with the highest 1-year mortality was colectomy (49.4%). Although hypertension, renal failure, hypoalbuminemia, hyperbilirubinemia, and elevated liver enzymes predicted in-hospital mortality, the only independent predictors of cumulative 1-year mortality were hypoalbuminemia (odds ratio, 2.17; 95% confidence interval, 1.10-4.27; p = 0.025) and elevated serum glutamic pyruvic transaminase (SGOT) level (odds ratio, 2.56; 95% confidence interval, 1.09-4.70; p = 0.029) at initial presentation. Patients with both factors had a cumulative 1-year mortality rate of 75.0%. CONCLUSION: More than half of the very elderly patients undergoing major EGS were still alive at 3 years postdischarge. The combination of hypoalbuminemia and elevated liver enzymes predicted the highest 1-year mortality. Such information can prove useful for patient and family counseling preoperatively. LEVEL OF EVIDENCE: Prognostic, Level III.


Assuntos
Mortalidade/tendências , Procedimentos Cirúrgicos Operatórios , Fatores Etários , Idoso de 80 Anos ou mais , Comorbidade , Emergências , Feminino , Humanos , Hipoalbuminemia/complicações , Fígado/enzimologia , Masculino , Alta do Paciente , Complicações Pós-Operatórias/mortalidade , Fatores de Risco
11.
Toxicol Lett ; 332: 1-6, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32579995

RESUMO

Non-alcoholic fatty liver disease (NAFLD) can be typically classified into two subgroups: non-alcoholic fatty liver and non-alcoholic steatohepatitis. Mouse models of NAFLD are useful tools for understanding the pathogenesis and progression of NAFLD and for developing drugs for its treatment. Here, we investigated the time-dependent changes in serum lipids and biochemical markers of hepatic function, hepatic inflammation, and fibrosis in mice fed a normal diet (ND) or a NAFLD diet (choline deficient, L-amino acid-defined, high-fat diet; CDAHFD) for 12 weeks. CDAHFD-fed mice showed significantly reduced serum levels of total cholesterol, triglyceride, and high-density lipoprotein cholesterol throughout the treatment period compared with ND-fed mice. The changes in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and total bilirubin showed an inverse U-shaped curve in the CDAHFD-fed mice. The serum alkaline phosphatase levels decreased in both ND- and CDAHFD-fed mice in a time-dependent manner. Furthermore, CDAHFD-fed mice showed a significant increase in the number of inflammatory foci and hepatic fibrosis at 6-12 weeks, although inflammatory foci and hepatic fibrogenesis were observable at relatively early stages as well (1-4 weeks). In conclusion, the long-term profile of serological biomarkers, hepatic inflammation, and fibrosis in CDAHFD-fed mice identified in this study may provide a better understanding of NAFLD pathogenesis.


Assuntos
Hepatite/patologia , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Biomarcadores/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , HDL-Colesterol/sangue , Dieta , Hepatite/sangue , Hepatite/enzimologia , Metabolismo dos Lipídeos , Fígado/enzimologia , Fígado/metabolismo , Cirrose Hepática/sangue , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Triglicerídeos/sangue
12.
PLoS Comput Biol ; 16(6): e1007622, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32484845

RESUMO

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.


Assuntos
Alanina Transaminase/sangue , Biomarcadores/sangue , Hepatócitos/efeitos dos fármacos , Necrose , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas , Biologia Computacional , Simulação por Computador , Hepatócitos/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Método de Monte Carlo , Software
13.
Medicine (Baltimore) ; 99(24): e20624, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541499

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis, which is considered as the hepatic manifestation of metabolic syndrome, has a great prevalence all over the world. New drugs are urgently needed for the treatment of NAFLD. This review will be to assess the efficacy and safety of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on liver-related outcomes (liver histology and liver enzymes) in patients with NAFLD. METHODS: We will search 5 databases for relative studies: Medline, the Cochrane Library, EMBASE, Web of Science, and ClinicalTrials.gov and identified all reports of randomized controlled trials published prior to July 2020. Two authors will independently scan the articles searched, extract the data from articles included, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Fixed-effects model or random-effects model will be used to calculate pooled estimates of weighted mean difference with 95% confidence intervals. RESULTS: This systematic review aims to examine the effect of n-3 PUFAs on liver histology and liver enzymes in patients with NAFLD. CONCLUSIONS: These findings will provide guidance to clinicians and patients on the use of n-3 PUFAs for NAFLD. ETHICS AND DISSEMINATION: This study is a protocol for a systematic review of n-3 PUFAs as a treatment of NAFLD patients. This review will be published in a journal and disseminated in print by peer-review. SYSTEMATIC REVIEW REGISTRATION: INPLASY202050008.


Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Metanálise como Assunto , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Ácidos Graxos Ômega-3/efeitos adversos , Humanos , Fígado/enzimologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
14.
Toxicol Lett ; 331: 143-151, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32525014

RESUMO

Although organotin compounds are known to disturb thyroid signaling and antioxidant defense system, the sex-differences underlying these effects of triphenyltin chloride (TPT) in fish remain unclear. To understand these differences, adult zebrafish (Danio rerio) were exposed to different concentrations of TPT (0, 10, 100, or 1000 ng/L) for 28 days. Female zebrafish exposed to TPT showed significantly increased thyroxine (T4) content and decrease triiodothyronine (T3) content, possibly due to downregulation of deiodinase (dio2) and uridine diphosphate glucuronosyl transferase (ugt1ab). However, decreased T4 and T3 contents in male zebrafish accompanied with upregulation of dio1, dio2 and ugt1ab. TPT exposure can lead to sex-specific thyroid disruption in adult zebrafish via alterations the Hypothalamus-pituitary-thyroid-liver axis. In addition, the gene expression levels of metabolizing enzymes, such as cyp1b, cyp1c, gpx1a, or sult1st1 were also to vary in a sex-dependent manner in adult zebrafish liver. Downregulation of cyp19a and cyp19b and decreased 17ß-estradiol (E2) contents were detected in both female and male zebrafish. Therefore, a sex-specific of thyroid disruption response after TPT exposure was observed in adult zebrafish, possibly due to inherent in female or males detoxifying enzyme capacities.


Assuntos
Disruptores Endócrinos/toxicidade , Compostos Orgânicos de Estanho/toxicidade , Caracteres Sexuais , Glândula Tireoide/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra , Peixe-Zebra/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Glândula Tireoide/metabolismo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
15.
Int J Nanomedicine ; 15: 3497-3509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547009

RESUMO

Purpose: The existing treatment modalities for rheumatoid arthritis are less effective and safe, therefore it is essential to develop new treatments that particularly target the inflamed joints with decreased off-target side-effects. The current study proposes a nanoparticle-based therapeutic approach to target the anti-oxidant defense system of arthritic Balb/c mice. Methods: Biogenic selenium nanoparticles (SeNPs) were synthesized by using Trachyspermum ammi seed extract and were evaluated for their toxicological, as well as their therapeutic potential in collagen-induced arthritic mice. Results: The tested doses of SeNPs had no significant toxic effects on liver, kidney, spleen, and serum biochemical parameters in comparison to healthy mice. The SeNPs treatment reduced the disease severity, as demonstrated by decreased paw edema along with reduced lymphocytic cellular infiltration in the histopathological findings. SeNPs also revealed dose-independent improvement in the redox state of inflamed synovium by significantly improving the activity of antioxidant enzymes in comparison to the arthritic controls. Conclusion: It is therefore concluded that nano-selenium in combination with TAE extract showed enhanced therapeutic efficacy as compared to their individual effects.


Assuntos
Antirreumáticos/uso terapêutico , Apiaceae/química , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/química , Selênio/toxicidade , Selênio/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antirreumáticos/farmacologia , Artrite Reumatoide/patologia , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Bovinos , Edema/patologia , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Oxirredução , Extratos Vegetais/química , Selênio/administração & dosagem , Selênio/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Baço/efeitos dos fármacos , Baço/patologia
16.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 23-26, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476369

RESUMO

OBJECTIVE: To investigate the effects of aerobic exercise on Cdc2-like kinase (CLK2) protein expression and the fat content in liver of mice fed with high fat diet. METHODS: C57BL/6 mice were distributed in normal diet, high fat diet (fed with highfat diet during 16 weeks) and trained high fat diet group (fed with high-fat diet during 16 weeks and exercised during 8 weeks),10 mice in each group. The expression of CLK2 protein in liver of each group was detected by Western blot. The fat content of liver in each group was detected by oil red O staining, and the relative genes of fat metabolism in each group were evaluated by real-time quantitative PCR. RESULTS: The mice fed with high fat diet showed insulin resistance, the hepatic CLK2 content and fat content were increased compared to the normal diet group. Otherwise, the chronic physical exercise improved insulin resistance state, prevented the increasing of CLK2 in the liver and attenuated hepatic fat accumulation. CONCLUSION: Aerobic exercise could reduce the expression of CLK2 protein in the liver of mice fed with high fat diet.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina , Fígado/enzimologia , Condicionamento Físico Animal , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL
17.
Lancet Oncol ; 21(5): e265-e279, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32359502

RESUMO

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.


Assuntos
Antineoplásicos/efeitos adversos , Interações Alimento-Droga , Interações Ervas-Drogas , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Biotransformação , Absorção Gástrica , Humanos , Absorção Intestinal , Fígado/enzimologia , Terapia de Alvo Molecular , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Fatores de Risco
18.
PLoS One ; 15(5): e0234073, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470062

RESUMO

Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro CT. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p<0.02) and the incidence of malocclusion from 82.4% to 34.7% (p<0.03), with no effect on cranial bone in C57BL/6 FGFR2C342Y/+ mice. In contrast, treatment with TNAP increased cranial bone volume (p< 0.01), density (p< 0.01) and mineral content (p< 0.01) as compared to vehicle treated controls, but had no effect on craniosynostosis or malocclusion in BALB/c FGFR2C342Y/+ mice. These results indicate that postnatal recombinant TNAP enzyme therapy diminishes craniosynostosis severity in the C57BL/6 FGFR2C342Y/+ neonatal onset mouse model of Crouzon syndrome, and that effects of exogenous TNAP are genetic background dependent.


Assuntos
Fosfatase Alcalina/genética , Disostose Craniofacial/terapia , Craniossinostoses/terapia , Técnicas de Transferência de Genes , Fosfatase Alcalina/sangue , Animais , Animais Recém-Nascidos , Peso Corporal , Densidade Óssea , Suturas Cranianas/patologia , Disostose Craniofacial/diagnóstico por imagem , Craniossinostoses/diagnóstico por imagem , Modelos Animais de Doenças , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Microtomografia por Raio-X
19.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R43-R49, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432915

RESUMO

γ-Butyrobetaine hydroxylase (γ-BBH) is the last limiting enzyme of the l-carnitine biosynthesis pathway and plays an important role in catalyzing the hydroxylation of γ-butyrobetaine (γ-BB) to l-carnitine. To study the developmental effect of substrate concentration on the enzyme's specific activity, kinetics of γ-BBH were measured in liver and kidney from newborn and 1-, 7-, 21-, 35-, 56-, and 210-day-old domestic pigs. Fresh tissue homogenates were assayed under nine concentrations of γ-BB from 0 to 1.5 mM. Substrate inhibition associated with age was observed at ≥0.6 mM of γ-BB. Hepatic activity was low at birth but increased after 1 day. By 21 days, the activity rose by 6.6-fold (P < 0.05) and remained constant after 56 days. Renal activity was higher than in liver at birth but remained constant through 35 days. By 56 days, the velocity increased by 44% over the activity at birth (P < 0.05). The apparent Km for γ-BB at birth on average was 2.8-fold higher than at 1 day. The Km value was 60% higher in kidney than liver during development but showed no difference in adult pigs. The total organ enzyme activity increased by 130-fold for liver and 18-fold for kidney as organ weight increased from birth to 56 days. In conclusion, age and substrate affect γ-BBH specific activity and Km for γ-BB in liver and kidney. Whereas the predominant organ for carnitine synthesis is likely the kidney at birth, the liver appears to predominate after the pig exceeds 7 days of age.


Assuntos
Carnitina/biossíntese , gama-Butirobetaína Dioxigenase/metabolismo , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal , Inibidores Enzimáticos/farmacologia , Rim/enzimologia , Rim/crescimento & desenvolvimento , Rim/metabolismo , Cinética , Fígado/enzimologia , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Tamanho do Órgão , Sus scrofa , Suínos , gama-Butirobetaína Dioxigenase/antagonistas & inibidores
20.
J Food Sci ; 85(6): 1907-1914, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32421231

RESUMO

Different chain lengths diacylglycerols (DAG) (long- and medium-chain) were synthesized from peanut and coconut oils. The effects of DAG with different chain lengths on body fat, blood lipids, and lipid metabolism-related enzymes in the liver and adipose tissue of C57BL/6J mice were investigated. Compared to peanut and coconut oils containing triacylglycerol (TAG), DAG-rich oils can significantly reduce the body weight, kidney weight, serum triglyceride (TG) content, hepatic fatty acid synthase (FAS), and Acetyl-CoA carboxylase (ACC) enzyme levels (p < 0.05) in C57BL/6J mice. Therefore, the effect of coconut oil DAG on improving body fat metabolism was probably due to the impact of DAG. Meanwhile, the body weight and serum TG content in coconut oil DAG group were lower than those in peanut oil DAG group. In addition, the spleen weight, hepatic ACC, and lipoprotein lipase (LPL) enzymes in coconut oil DAG group (0.07 ± 0.01 g, 2.08 ± 0.42 ng/mg pro, and 18.44 ± 5.23 ng/mg pro, respectively) were significantly lower than those in peanut oil DAG group. Although coconut oil DAG and peanut oil DAG have different fatty acid compositions, their effects on lipid metabolism showed no significant changes. Coconut oil DAG (peanut oil DAG) showed the improved lipid metabolism than that of coconut oil (peanut oil), which was probably due to the effect of DAG. PRACTICAL APPLICATION: Peanut and coconut oils are common edible oils. The oil containing DAG synthesized decreased the body weight and lipid accumulation in mice. Coconut oil is rich in medium-chain fatty acids, while peanut oil mainly consists of long-chain fatty acids. Due to the different contents of fatty acids, the synthesized structural lipids have different effects on lipid metabolism. Medium-chain triglycerides were considered as agents to alleviate obesity.


Assuntos
Óleo de Coco/metabolismo , Diglicerídeos/metabolismo , Obesidade/dietoterapia , Óleo de Amendoim/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/metabolismo , Animais , Óleo de Coco/química , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/fisiopatologia , Óleo de Amendoim/química
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