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1.
Molecules ; 26(7)2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33917585

RESUMEN

Cadmium (Cd) is a heavy metal that occurs in all areas of the environment, including the food chain. In the body, it causes oxidative stress by producing free radicals that are harmful to the cells. Grape seed extract (GSE) contains a wide range of biologically active components that help to neutralize the adverse effects of free radicals. In this study, the effects of GSE prepared form semi-resistant grapevine cultivar Cerason, which is rich in phenolics, on biochemical markers of brown rats exposed to the effects of cadmium were monitored. GSE increased the plasma antioxidant activity and, in the kidneys and the liver, Cd content was significantly lowered by GSE co-administration. Accordingly, the increase in creatinine content and alanine aminotransferase activity and the decrease of catalase and superoxide dismutase activities caused by cadmium were slowed down by GSE co-administration. The results of this work reveal that grape seed extract offers a protective effect against the intake of heavy metals into the organism.


Asunto(s)
Biomarcadores/metabolismo , Extracto de Semillas de Uva/farmacología , Salud , Riñón/metabolismo , Hígado/metabolismo , Alanina Transaminasa/sangre , Animales , Antioxidantes/análisis , Aspartato Aminotransferasas/sangre , Cadmio/sangre , Catalasa/metabolismo , Creatinina/sangre , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Metalotioneína/metabolismo , Fitoquímicos/análisis , Ratas Wistar , Semillas/química , Superóxido Dismutasa/metabolismo , Urea/sangre
2.
Nat Commun ; 12(1): 2073, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824313

RESUMEN

Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.


Asunto(s)
Amiloide/metabolismo , Hígado/enzimología , Mutación/genética , Estrés Oxidativo , Fenilalanina Hidroxilasa/genética , Agregado de Proteínas , Animales , Autofagia , Biomarcadores/metabolismo , Peso Corporal , Cruzamiento , Femenino , Regulación de la Expresión Génica , Genotipo , Metabolismo de los Lípidos , Hígado/patología , Masculino , Metaboloma , Ratones , Proteínas Mutantes/metabolismo , Neurotransmisores/metabolismo , Estrés Oxidativo/genética , Fenilalanina/metabolismo , Fenilalanina Hidroxilasa/metabolismo , Fenilcetonurias/enzimología , Pterinas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Respiración , Ubiquitina/metabolismo , Ubiquitinación
3.
Artículo en Inglés | MEDLINE | ID: mdl-33664052

RESUMEN

BACKGROUND AND AIMS: Patients infected with the SARS-CoV-2 usually report fever and respiratory symptoms. However, multiple gastrointestinal (GI) manifestations such as diarrhoea and abdominal pain have been described. The aim of this study was to evaluate the prevalence of GI symptoms, elevated liver enzymes and mortality of patients with COVID-19. METHODS: A systematic review and meta-analysis of published studies that included a cohort of patients infected with SARS-CoV-2 were performed from 1 December 2019 to 15 December 2020. Data were collected by conducting a literature search using PubMed, Embase, Scopus, and Cochrane according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We analysed pooled data on the prevalence of individual GI symptoms and elevated liver enzymes and performed subanalyses to investigate the relationship between GI symptoms/elevated liver enzymes, geographical location, mortality, and intensive care unit (ICU) admission. RESULTS: The available data of 78 798 patients positive for SARS-CoV-2 from 158 studies were included in our analysis. The most frequent manifestations were diarrhoea (16.5%, 95% CI 14.2% to 18.4%), nausea (9.7%, 95% CI 9.0% to 13.2%) and elevated liver enzymes (5.6%, 95% CI 4.2% to 9.1%). The overall mortality and GI mortality were 23.5% (95% CI 21.2% to 26.1%) and 3.5% (95% CI 3.1% to 6.2%), respectively. Subgroup analysis showed non-statistically significant associations between GI symptoms/elevated liver enzymes and ICU admissions (OR=1.01, 95% CI 0.55 to 1.83). The GI mortality was 0.9% (95% CI 0.5% to 2.2%) in China and 10.8% (95% CI 7.8% to 11.3%) in the USA. CONCLUSION: GI symptoms/elevated liver enzymes are common in patients with COVID-19. Our subanalyses showed that the presence of GI symptoms/elevated liver enzymes does not appear to affect mortality or ICU admission rate. Furthermore, the proportion of GI mortality among patients infected with SARS-CoV-2 varied based on geographical location.


Asunto(s)
/complicaciones , Enfermedades Gastrointestinales/epidemiología , Enfermedades Gastrointestinales/virología , Hepatopatías/epidemiología , Hepatopatías/virología , /mortalidad , Cuidados Críticos/estadística & datos numéricos , Enfermedades Gastrointestinales/mortalidad , Hospitalización/estadística & datos numéricos , Humanos , Hígado/enzimología , Hepatopatías/mortalidad , Pandemias , Prevalencia , Índice de Severidad de la Enfermedad
4.
Medicine (Baltimore) ; 100(11): e24545, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725937

RESUMEN

ABSTRACT: The objective of the present study was to assess the allelic variations of Cytochrome P450 (CYP) enzymes Cytochrome P450 2C19 (CYP2C19), Cytochrome P450 2C9 (CYP2C9), and Cytochrome P450 2D6 (CYP2D6) as they play a major role in drug metabolism. The interindividual genetic variabilities of these enzymes can account for different responsiveness as well as concentration fluctuations for a particular drug.During the period of 2017 to 2018 a total of 54 patients have received pharmacogenetic testing at the Department of Genetics and Molecular Medicine at Kaunas Clinics. According to the genotype-metabolic phenotypes of CYP2C19, CYP2D6, CYP2C9 enzymes patients were classified according to the guidelines by Clinical Pharmacogenetics Implementation Consortium (CPIC): normal metabolizers (NMs), intermediate metabolizers (IMs), rapid metabolizers (RMs), ultrarapid metabolizers (UMs), and poor metabolizers (PMs).CYP2C19 enzyme allelic distribution: 18 patients (33.33%) with ∗1/∗1 genotype were NMs; 14 patients (25.93%) with ∗1/∗2; ∗2/∗17 genotypes were classified as IMs; 15 patients (27.78%) possessed ∗1/∗17 genotype and were RMs; 4 patients (7.4%) had ∗17/∗17 genotype with increased enzyme activity compared with RMs, were classified as UMs; 3 patients (5.56%) had ∗2/∗2 genotype and were marked as PMs. CYP2D6 enzyme allelic distribution: 26 patients (48.148%) contained ∗1/∗1,∗2/∗2,∗1/∗2,∗1/∗41,∗2/∗41 genotypes with normal enzymatic function so were accounted as NMs; 21 patients (38.89%) with ∗1/∗5, ∗2/∗4, ∗10/∗41, ∗1/∗4, ∗1/∗3, ∗2/∗5, ∗2/∗4, ∗2/∗6 genotypes were accounted as IMs; 2 patients (3.7%) possessed ∗2XN genotype and were accounted as UMs and 5 patients (9.26%) possessed ∗4/∗5,∗4/∗10,∗4/∗9,∗4/∗41 genotypes and had non-functional enzymatic activity so were accounted as PMs; CYP2C9 enzyme allelic distribution: 44 patients (81.48%) with∗1/∗1 genotype were NMs; 10 patients (18.52%) with ∗1/∗2;∗1/∗3 genotypes were IMs.The results of our study indicate that deviations from the normal enzymatic activity is common amongst Lithuanian people and combinatory genotyping of CYP2D6, CYP2C9, and CYP2C19 has to be promoted as an advanced method because of most commonly prescribed medicines like analgesics, antihypertensive, antidepressants are metabolized by multiple pathways involving enzymes in the CYP450 family.


Asunto(s)
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Preparaciones Farmacéuticas/metabolismo , Variantes Farmacogenómicas/efectos de los fármacos , Alelos , Grupo de Ascendencia Continental Europea/genética , Genotipo , Humanos , Lituania , Hígado/enzimología , Pruebas de Farmacogenómica , Estudios Retrospectivos
5.
Arch Biochem Biophys ; 701: 108825, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33675814

RESUMEN

Enzymes typically have high specificity for their substrates, but the structures of substrates and products differ, and multiple modes of binding are observed. In this study, high resolution X-ray crystallography of complexes with NADH and alcohols show alternative modes of binding in the active site. Enzyme crystallized with the good substrates NAD+ and 4-methylbenzyl alcohol was found to be an abortive complex of NADH with 4-methylbenzyl alcohol rotated to a "non-productive" mode as compared to the structures that resemble reactive Michaelis complexes with NAD+ and 2,2,2-trifluoroethanol or 2,3,4,5,6-pentafluorobenzyl alcohol. The NADH is formed by reduction of the NAD+ with the alcohol during the crystallization. The same structure was also formed by directly crystallizing the enzyme with NADH and 4-methylbenzyl alcohol. Crystals prepared with NAD+ and 4-bromobenzyl alcohol also form the abortive complex with NADH. Surprisingly, crystals prepared with NAD+ and the strong inhibitor 1H,1H-heptafluorobutanol also had NADH, and the alcohol was bound in two different conformations that illustrate binding flexibility. Oxidation of 2-methyl-2,4-pentanediol during the crystallization apparently led to reduction of the NAD+. Kinetic studies show that high concentrations of alcohols can bind to the enzyme-NADH complex and activate or inhibit the enzyme. Together with previous studies on complexes with NADH and formamide analogues of the carbonyl substrates, models for the Michaelis complexes with NAD+-alcohol and NADH-aldehyde are proposed.


Asunto(s)
Alcohol Deshidrogenasa/química , Alcoholes/química , Caballos , Hígado/enzimología , Modelos Químicos , NAD/química , Animales , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X
6.
Toxicol Appl Pharmacol ; 418: 115494, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33722668

RESUMEN

Tumor progression locus 2 (Tpl2, gene name MAP3K8), a mitogen-activated protein kinase, is widely expressed in immune and non-immune cells to integrate tumor necrosis factor (TNF), toll-like receptors (TLRs), and interleukin-1 (IL1) receptor signaling to regulate inflammatory response. Given its central role in inflammatory response, Tpl2 is an attractive small molecule drug target. However, the role of Tpl2 as an oncogene or tumor suppressor gene remains controversial, and its function outside immune cells is not understood. We therefore utilized a Tpl2 kinase dead (Tpl2-KD) mouse model in an 18-month aging study to further elucidate Tpl2 effects on lifespan and chronic disease. Histopathological studies revealed the incidence and severity of spontaneous tumors and non-neoplastic lesions were comparable between wild type and Tpl2-KD mice. The only finding was that male Tpl2-KD mice had higher bodyweight and an increased incidence of liver steatosis, suggesting a sex-specific role for Tpl2 in hepatic lipid metabolism. In conclusion, loss of Tpl2 kinase activity did not lead to increased tumorigenesis over aging in mice but affected likely alterations in lipid metabolism in male animals.


Asunto(s)
Hígado Graso/enzimología , Inflamación/enzimología , Hígado/enzimología , Quinasas Quinasa Quinasa PAM/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Factores de Edad , Animales , Hígado Graso/genética , Hígado Graso/patología , Femenino , Genotipo , Inflamación/genética , Metabolismo de los Lípidos , Hígado/patología , Quinasas Quinasa Quinasa PAM/deficiencia , Quinasas Quinasa Quinasa PAM/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/genética , Neoplasias/patología , Fenotipo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Factores Sexuales
7.
J Gastroenterol ; 56(5): 409-420, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33759041

RESUMEN

Although primarily a respiratory illness, several studies have shown that COVID-19 causes elevation of liver enzymes and various gastrointestinal (GI) symptoms. The aim of this study was to undertake a systematic review and meta-analysis to determine whether the presence of gastrointestinal (GI) symptoms contributed toward COVID-19 severity, and identify the GI symptoms characteristic of severe COVID-19. We conducted a literature search of PubMed from December 1, 2019, to June 30, 2020, and identified all reports with GI symptoms reported. A meta-analysis comparing the severity of COVID-19 with the presence of liver enzyme elevation and GI symptoms was performed using RevMan version 5.4. Pooled data from 15,305 unique reverse transcriptase-polymerase chain reaction positive COVID-19 patients from 44 studies were analyzed. We found that the severe COVID-19 patients significantly had abdominal pain compared to the non-severe COVID-19 patients (OR = 2.70, 95% CI 1.17-6.27, Z = 2.32, p = 0.02, I2 = 0%) by analyzed 609 patients of 4 studies who reported both abdominal pain and COVID-19 severity. However, there was no significant difference in the incidence of diarrhea, nausea, or vomiting between the two groups. Thus, this systematic review and meta-analysis demonstrated that abdominal pain could be characteristic of severe COVID-19 infections. Compared with other viral infections that primarily infect the respiratory system, patients with COVID-19 have a slightly lower frequency of diarrheal symptoms with abdominal pain. However, to confirm this, further studies with COVID-19 patients across various countries and ethnicities are required.


Asunto(s)
/complicaciones , Enfermedades Gastrointestinales/epidemiología , Hígado/enzimología , Dolor Abdominal/etiología , Diarrea/epidemiología , Diarrea/virología , Enfermedades Gastrointestinales/virología , Humanos , Hígado/virología , Náusea/epidemiología , Náusea/virología , Índice de Severidad de la Enfermedad , Vómitos/epidemiología , Vómitos/virología
8.
Sci Rep ; 11(1): 5494, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750841

RESUMEN

It is important to pay attention to the indirect effects of the social distancing implemented to prevent the spread of coronavirus disease 2019 (COVID-19) pandemic on children and adolescent health. The aim of the present study was to explore impacts of a reduction in physical activity caused by COVID-19 outbreak in pediatric patients diagnosed with obesity. This study conducted between pre-school closing and school closing period and 90 patients aged between 6- and 18-year-old were included. Comparing the variables between pre-school closing period and school closing period in patients suffering from obesity revealed significant differences in variables related to metabolism such as body weight z-score, body mass index z-score, liver enzymes and lipid profile. We further evaluated the metabolic factors related to obesity. When comparing patients with or without nonalcoholic fatty liver disease (NAFLD), only hemoglobin A1c (HbA1c) was the only difference between the two time points (p < 0.05). We found that reduced physical activity due to school closing during COVID-19 pandemic exacerbated obesity among children and adolescents and negatively affects the HbA1C increase in NAFLD patients compared to non-NAFLD patients.


Asunto(s)
/patología , Intolerancia a la Glucosa/diagnóstico , Obesidad Pediátrica/diagnóstico , Adolescente , Alanina Transaminasa/análisis , Aspartato Aminotransferasas/análisis , Índice de Masa Corporal , Peso Corporal , Niño , Ejercicio Físico , Femenino , Intolerancia a la Glucosa/complicaciones , Hemoglobina A Glucada/análisis , Humanos , Lípidos/análisis , Hígado/enzimología , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Obesidad Pediátrica/complicaciones , Cuarentena , /aislamiento & purificación
9.
Aquat Toxicol ; 233: 105771, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33578303

RESUMEN

Present study aims to investigate interaction of molecular chaperons (heat shock protein 70, heat shock protein 90) with transcriptional factors (nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1) to evaluate their role during metal induced stress in fish hepatocytes. Adult Puntius ticto were exposed to lead nitrate at 0 mg/l (control), 1/50th (0.04 mg/l) and 1/20th (0.12 mg/l) of LC50 for 30 days and sacrificed to collect liver tissues. Activity of selected liver enzymes, antioxidants and metallothionein were analyzed. Levels of heat shock protein 70, heat shock protein 90, nuclear factor kappa B, nuclear factor E2-related factor 2 and Kelch-like ECH-associated protein 1 were also measured. Liver enzymes showed a significant increase (p < 0.05) in both Pb exposed groups indicating that the liver might be at risk of damage. Increased level of lipid peroxidation due to metal stress was marked by significant increase (p < 0.05) in malondialdehyde level in fish exposed to the higher Pb concentration compared to control (+ 13.7 %). Significant increase (p < 0.05) in gluthathione reductase (+ 35 %, + 39.2 %), glutathione s-transferase (+ 22.4 %, + 50.4 %) activities and decrease in reduced glutathione level (- 6.75 %, - 12.25 %) in fish exposed to both lower and higher Pb concentration compared to control also indicated metal induced oxidative damage in fish liver. Super oxide dismutase and catalase activities increased significantly (p < 0.05) during exposure to lower Pb concentration, while decreased significantly (p < 0.05) during exposure to higher Pb concentration compared to those in control. Significant (P < 0.05) increase (+ 52.63 %, + 89.47 %) in metallothionein in Pb exposed groups confirmed its role in detoxification process of the metal. Heat shock protein 70 and heat shock protein 90 expression levels increased significantly (p < 0.05) during metal exposure indicating their role as modulator of stress-induced antioxidant protein remodelling. A positive correlation between nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1 with gluthathione regulatory enzymes (gluthathione reductase and glutathione s-transferase) was noted. Current study effectively illuminates the critical role of different factors (heat shock proteins/nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1) to influence the expression and synthesis of antioxidants and other functional enzymes in lead-exposed fish liver.


Asunto(s)
Antioxidantes/metabolismo , Cyprinidae/metabolismo , Proteínas de Choque Térmico/metabolismo , Plomo/toxicidad , Hígado/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Contaminantes Químicos del Agua/toxicidad , Animales , Peroxidación de Lípido/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Nitratos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal
10.
Eur J Endocrinol ; 184(4): 513-520, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524005

RESUMEN

Context: Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, anti-androgens, and oral contraceptives, which is potentially fatal. Objective: The incidence of liver injury in a transgender population using gender-affirming hormone therapy. Design: Multicentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020. Methods: The following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2× upper limit of normal (ULN) of ALP, 3× ULN of ALT, or 3× ULN of AST. Results: 889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after the start of hormone therapy, without attribution to alcohol abuse, medical history, or comedication was 0.1 and 0.0%. in transgender women according to female and male reference intervals respectively, and 0.6 and 0.4% in transgender men (female and male reference intervals). Conclusion: The incidence of liver injury is found to be very low. We, therefore, conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary for a transgender population.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Disforia de Género/tratamiento farmacológico , Hormonas Esteroides Gonadales/efectos adversos , Hormonas Esteroides Gonadales/uso terapéutico , Hígado/enzimología , Personas Transgénero , Adulto , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Bélgica/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Estudios de Cohortes , Estradiol/efectos adversos , Estradiol/uso terapéutico , Femenino , Humanos , Italia/epidemiología , Masculino , Países Bajos/epidemiología , Noruega/epidemiología , Estudios Prospectivos , Testosterona/efectos adversos , Testosterona/uso terapéutico
11.
Nat Commun ; 12(1): 816, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547301

RESUMEN

Serum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations.


Asunto(s)
Alanina Transaminasa/genética , Fosfatasa Alcalina/genética , Aspartato Aminotransferasas/genética , Genoma Humano , Hepatopatías/genética , Hígado/enzimología , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Aspartato Aminotransferasas/sangre , Bancos de Muestras Biológicas , Células Endoteliales/enzimología , Células Endoteliales/patología , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Hepatocitos/enzimología , Hepatocitos/patología , Humanos , Japón , Células Asesinas Naturales/enzimología , Células Asesinas Naturales/patología , Macrófagos del Hígado/enzimología , Macrófagos del Hígado/patología , Hígado/patología , Hepatopatías/sangre , Hepatopatías/clasificación , Hepatopatías/patología , Sitios de Carácter Cuantitativo , Carácter Cuantitativo Heredable , Análisis de la Célula Individual , Reino Unido
13.
Toxicol Lett ; 341: 1-10, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33429014

RESUMEN

Piscine cytochrome P450 (CYP) enzymes play an important role in the metabolism of xenobiotics. Xenobiotics often act as inducers of CYP1A1 and CYP3A expression and activity in fish. We compared constitutive mRNA expression of CYP1A1, CYP3A27, and CYP3A45 and catalytic activity of CYP1A (7-ethoxyresorufin-O-deethylation, EROD) and CYP3A-like (benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylation, BFCOD) enzymes in the following six rainbow trout tissues: liver, gill, heart, brain, intestine, and gonad. mRNA expression and activity were present in all investigated tissues. The CYP1A1 mRNA expression was higher in the liver, gill, heart, and brain compared to gonad and intestine. The intestine was the main site of CYP3A27 and CYP3A45 expression. The highest EROD and BFCOD activity was observed in liver tissue followed in descending order by heart, brain, gill, intestine, and gonad. Such differences might be related to the role of CYP physiological functions in the specific tissue. Rainbow trout exposure to 50 mg/kg of ß-naphthoflavone for 48 h resulted in a 7.5- and 5.9-fold increase in liver EROD and BFCOD activity, respectively. In vitro EROD activity inhibition with ellipticine showed tissue-specific inhibition, while ketoconazole decreased BFCOD activity by 50-98 % in all tissues. Further studies are needed to identify all CYP isoforms that are responsible for these activities and modes of regulation.


Asunto(s)
Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Oncorhynchus mykiss/metabolismo , Animales , Encéfalo/enzimología , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP3A/genética , Femenino , Branquias/enzimología , Intestinos/enzimología , Hígado/enzimología , Masculino , Miocardio/enzimología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Caracteres Sexuales
14.
Int J Biol Macromol ; 171: 288-307, 2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33418046

RESUMEN

A novel nanocarrier system of phospholipids complex loaded chitosan nanoparticles (FAPLC CNPs) was developed to improve the oral bioavailability and antioxidant potential of FA. FAPLC CNPs were optimized using a Box-Behnken Design (BBD). FAPLC CNPs were characterized using differential scanning calorimetry, Fourier transforms infrared spectroscopy, powder x-ray diffractometry, proton nuclear magnetic resonance, solubility, in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCl4)-induced albino rat model. The characterization studies indicated a formation of the complex as well as FAPLC CNPs. The FAPLC CNPs exhibited a lower particle size ~123.27 nm, PDI value ~0.31, and positive zeta potential ~32 mV respectively. Functional characterization studies revealed a significant improvement in the aqueous solubility, dissolution, and permeation rate of FAPLC and FAPLC CNPs compared to FA and FA CNPs. The FAPLC CNPs showed significant enhancement of in vivo antioxidant activity of FA by restoring the elevated marker enzymes in the CCl4-intoxicated rat model compared to FA CNPs. Moreover, the pharmacokinetic analysis demonstrated a significant enhancement of oral bioavailability of FA from FAPLC CNPs compared to FA CNPs. These findings show that FAPLC CNPs could be used as an effective nanocarrier for improving the oral delivery of FA.


Asunto(s)
Antioxidantes/química , Quitosano/química , Ácidos Cumáricos/administración & dosificación , Portadores de Fármacos/química , Nanopartículas/química , Fosfolípidos/química , Administración Oral , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacocinética , Disponibilidad Biológica , Intoxicación por Tetracloruro de Carbono/tratamiento farmacológico , Técnicas de Química Analítica , Quitosano/administración & dosificación , Quitosano/farmacocinética , Ácidos Cumáricos/farmacocinética , Preparaciones de Acción Retardada , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Femenino , Absorción Intestinal , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Microscopía Electrónica de Rastreo , Modelos Químicos , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Fosfolípidos/administración & dosificación , Fosfolípidos/farmacocinética , Ratas , Ratas Wistar , Solubilidad , Electricidad Estática
15.
Int J Biol Macromol ; 171: 502-513, 2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33422513

RESUMEN

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.


Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Crotonatos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Durapatita/química , Ácido Hialurónico/química , Metotrexato/administración & dosificación , Nanopartículas/administración & dosificación , Toluidinas/administración & dosificación , Animales , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapéutico , Antirreumáticos/toxicidad , Artritis Experimental/patología , Crotonatos/farmacocinética , Crotonatos/uso terapéutico , Crotonatos/toxicidad , Citocinas/sangre , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidad , Evaluación Preclínica de Medicamentos , Liberación de Fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Metotrexato/farmacocinética , Metotrexato/uso terapéutico , Metotrexato/toxicidad , Ratones , Nanopartículas/toxicidad , Células RAW 264.7 , Ratas , Ratas Wistar , Espectroscopía Infrarroja por Transformada de Fourier , Distribución Tisular , Toluidinas/farmacocinética , Toluidinas/uso terapéutico , Toluidinas/toxicidad
16.
Trop Anim Health Prod ; 53(1): 82, 2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33411066

RESUMEN

The aim of the present study was to assess the effects of plantain herb (Plantago lanceolata L.) supplementation on growth, plasma metabolites, liver enzymatic activity, hormonal status, gastrointestinal parasites, and carcass characteristics of lambs. A total of 24 lambs, aged 6 months weighing 8.0 ± 0.5 kg were randomly allocated to one of two dietary treatments: (1) CL diet-roadside grass and concentrate mixture; (2) PL diet-CL diet + 5% fresh plantain supplementation on a DM basis. The PL diet group exhibited 23% higher (P = 0.01) average daily gain and 15% improved (P = 0.03) feed conversion efficiency. Circulating cholesterol concentrations were suppressed by 9% (P = 0.03), and liver enzyme activity was improved by 5-25% (P < 0.05) in the lamb fed PL diet, compared with CL diet only. The inclusion of plantain in the diet was highly effective at suppressing the parasites, Paramphistomum spp. (P = 0.003) and coccidial parasites (P = 0.04), but not stomach worms. Moreover, plantain supplementation increased growth hormone and insulin concentrations in plasma level, whereas decreased carcass fat by 32.7%. Therefore, supplementation of the lambs' diet with plantain showed some beneficial effects on productivity and parasitic infection, while it led to a leaner carcass.


Asunto(s)
Dieta/veterinaria , Enfermedades Gastrointestinales/veterinaria , Carne/análisis , Plantago/química , Enfermedades de las Ovejas/prevención & control , Oveja Doméstica/fisiología , Alimentación Animal/análisis , Animales , Suplementos Dietéticos/análisis , Enfermedades Gastrointestinales/parasitología , Enfermedades Gastrointestinales/prevención & control , Hormonas/sangre , Hígado/enzimología , Plasma/química , Distribución Aleatoria , Ovinos , Enfermedades de las Ovejas/parasitología , Oveja Doméstica/sangre , Oveja Doméstica/crecimiento & desarrollo
17.
Toxicol Appl Pharmacol ; 412: 115389, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33385404

RESUMEN

Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.


Asunto(s)
Variación Biológica Poblacional , Sistema Enzimático del Citocromo P-450/genética , Hígado/enzimología , MicroARNs/genética , Factores de Transcripción/genética , Factores de Edad , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica , Heterogeneidad Genética , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Humanos , Isoenzimas , Masculino , MicroARNs/metabolismo , Fenotipo , Fumar/genética , Fumar/metabolismo , Factores de Transcripción/metabolismo
18.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G531-G542, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33470903

RESUMEN

Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study, we aimed to explore the role of GCSF in nonalcoholic fatty liver disease (NAFLD). Male GCSF-/- mice were used to investigate the function of GCSF in vivo after high-fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF-/- mice exhibited alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD.NEW & NOTEWORTHY We found GCSF was involved in lipid metabolism and NAFLD development. GCSF administration increased serum triglyceride levels in patients. GCSF deficiency alleviated HFD-induced insulin resistance and hepatic steatosis in mice. GCSF could directly act on hepatocytes through GCSFR-SOCS3-JAK-STAT3 pathway, and regulate the infiltration of immune cells into the liver to indirectly modulate NAFLD. Our finding indicates that GCSF may provide new strategies for the treatment of NAFLD.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/deficiencia , Hepatocitos/enzimología , Quinasas Janus/metabolismo , Hígado/enzimología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Receptores del Factor Estimulante de Colonias/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/genética , Hepatocitos/inmunología , Hepatocitos/patología , Humanos , Resistencia a la Insulina , Metabolismo de los Lípidos , Hígado/inmunología , Hígado/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/inmunología , Neutrófilos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/enzimología , Obesidad/inmunología , Obesidad/prevención & control , Transducción de Señal
19.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G450-G463, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33439102

RESUMEN

Nonalcoholic steatohepatitis (NASH) could progress to hepatic fibrosis in the absence of effective control. The purpose of our experiment was to investigate the protective effect of drinking water with a high concentration of hydrogen, namely, hydrogen-rich water (HRW), on mice with nonalcoholic fatty liver disease to elucidate the mechanism underlying the therapeutic action of molecular hydrogen. The choline-supplemented, l-amino acid-defined (CSAA) or the choline-deficient, l-amino acid-defined (CDAA) diet for 20 wk was used to induce NASH and fibrosis in the mice model and simultaneously treated with the high-concentration 7-ppm HRW for different periods (4 wk, 8 wk, and 20 wk). Primary hepatocytes were stimulated by palmitate to mimic liver lipid metabolism during fatty liver formation. Primary hepatocytes were cultured in a closed vessel filled with 21% O2 + 5% CO2 + 3.8% H2 and N2 as the base gas to verify the response of primary hepatocytes in a high concentration of hydrogen gas in vitro. Mice in the CSAA + HRW group had lower serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and milder histological damage. The inflammatory cytokines were expressed at lower levels in the HRW group than in the CSAA group. Importantly, HRW reversed hepatocyte fatty acid oxidation and lipogenesis as well as hepatic inflammation and fibrosis in preexisting hepatic fibrosis specimens. Molecular hydrogen inhibits the lipopolysaccharide-induced production of inflammation cytokines through increasing heme oxygenase-1 (HO-1) expression. Furthermore, HRW improved hepatic steatosis in the CSAA + HRW group. Sirtuin 1 (Sirt1) induction by molecular hydrogen via the HO-1/adenosine monophosphate activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway suppresses palmitate-mediated abnormal fat metabolism. Orally administered HRW suppressed steatosis induced by CSAA and attenuated fibrosis induced by CDAA, possibly by reducing oxidative stress and the inflammation response.NEW & NOTEWORTHY The mRNA expression of inflammatory cytokines in the HRW group was lower than in the CSAA group. HRW reversed hepatocyte apoptosis as well as hepatic inflammation and fibrosis in NASH specimens. Molecular hydrogen inhibits LPS-induced inflammation via an HO-1/interleukin 10 (IL-10)-independent pathway. HRW improved hepatic steatosis in the CSAA + HRW group. Sirt1 induction by molecular hydrogen via the HO-1/AMPK/PPARα/PPARγ pathway suppresses palmitate-mediated abnormal fat metabolism.


Asunto(s)
Hemo-Oxigenasa 1/metabolismo , Hepatocitos/efectos de los fármacos , Hidrógeno/farmacología , Interleucina-10/metabolismo , Cirrosis Hepática Experimental/prevención & control , Hígado/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Sirtuina 1/metabolismo , Agua/farmacología , Animales , Hepatocitos/enzimología , Hepatocitos/patología , Hidrógeno/química , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Lipólisis/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Cirrosis Hepática Experimental/enzimología , Cirrosis Hepática Experimental/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/patología , Células RAW 264.7 , Transducción de Señal
20.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G464-G473, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33439105

RESUMEN

Polycystic liver disease (PLD) is a hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with the activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. PCK rats were randomly divided into a control (Con) group and a metformin-treated (Met) group. The Met group was treated orally with metformin in drinking water. After 12 wk, liver function, histology, and signaling cascades of PLD were examined in the groups. Metformin did not affect the body weight or liver weight, but it reduced liver cyst formation, cholangiocyte proliferation, and fibrosis around the cyst. Metformin increased the phosphorylation of AMPK and tuberous sclerosis complex 2 and decreased the phosphorylation of mammalian target of rapamycin, S6, and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-ß, and type 1 collagen without changes in apoptosis or collagen degradation factors in the liver. Metformin slows the development of cyst formation and fibrosis with the activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats.NEW & NOTEWORTHY This study indicates that metformin, an indirect AMPK activator slows liver cyst formation and fibrosis in PLD rat model. Metformin attenuates excessive cell proliferation in the liver with the inactivation of mTOR and ERK pathways. Metformin also reduces the expression of proteins responsible for cystic fluid secretion and liver fibrosis. Metformin and AMPK activators may be potent drugs for polycystic liver disease.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proliferación Celular/efectos de los fármacos , Quistes/tratamiento farmacológico , Activadores de Enzimas/farmacología , Cirrosis Hepática Experimental/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Hígado/efectos de los fármacos , Metformina/farmacología , Animales , Quistes/enzimología , Quistes/patología , Progresión de la Enfermedad , Activación Enzimática , Hígado/enzimología , Hígado/patología , Cirrosis Hepática Experimental/enzimología , Cirrosis Hepática Experimental/patología , Hepatopatías/enzimología , Hepatopatías/patología , Masculino , Fosforilación , Ratas , Transducción de Señal , Factores de Tiempo
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