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1.
Food Funct ; 13(18): 9383-9390, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-35959802

RESUMO

A placebo-controlled, randomised, double-blind, parallel-group comparative study was conducted to investigate the effect of continuous intake of salmon milt (SM) DNA for 12 weeks on the improvement of liver function in 50 healthy Japanese participants aged 30 to 70 years with alanine aminotransferase (ALT) levels of 25-87 U L-1 in men, 22-66 U L-1 in women, of BMI 22.1-29.4 kg m-2. Comparative analysis of hepatic functions and several other parameters, including anthropometric parameters in placebo and SM DNA administered groups, revealed no significant differences in serum ALT level. SM DNA significantly improved the liver-to-spleen (L/S) ratio, body weight, and BMI in the main group. In addition to these parameters, in the BMI < 25 kg m-2 subgroup, the leptin level was significantly reduced. No adverse reactions or abnormal changes, symptoms, or findings in the clinical examination after intake of the test food containing SM DNA were observed. Furthermore, no significant difference in uric acid levels between SM DNA and placebo groups indicated the safety of using SM DNA as a food supplement. These results demonstrated the potential fatty liver improvement and anti-obesity action of continuous intake of SM DNA for 12 weeks without any significant adverse effects.


Assuntos
DNA , Suplementos Nutricionais , Fígado , Alanina Transaminase , Animais , DNA/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Japão , Leptina , Fígado/fisiologia , Masculino , Oncorhynchus keta , Ácido Úrico
2.
Biochem Biophys Res Commun ; 599: 106-112, 2022 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-35180469

RESUMO

OBJECTIVE: To explore whether hyperbaric oxygen therapy(HBO) can promote weight loss and recovery of hyperlipidemia in rats, and to explore the possible mechanism. METHODS: 180 SD rats were divided into 6 groups with 30 rats in each group. The first 3 groups were intraperitoneally injected with fat emulsion to make hyperlipidemia models, and the last three groups were injected with normal saline. The first three groups received 3 h/d, 6 h/d, 0 h/d HBO therapy respectively, and the last three groups received the same treatment. Body weight, blood lipid and transaminase were measured in all SD rats, and pathological sections of heart, liver and kidney were observed. RESULTS: Hyperlipidemia group treated with 3 h/d hyperbaric oxygen has the effect of reducing hyperlipidemia compared with other groups and has the effect of heart and kidney protection. Although 6 h/d HBO therapy has a more noticeable effect on lowering hyperlipidemia, it has more apparent liver damage effects. The normal group treated with HBO for 3 h/d or 6 h/d both have the effect of weight loss, and the impact of liver injury is not apparent. However, the 6 h/d HBO therapy group had a more prominent weight loss effect. CONCLUSION: HBO therapy can promote weight loss and reduce hyperlipidemia. Our experiments have shown that 6 h/d and 3 h/d HBO therapy reduces blood lipids in hyperlipidemia SD rats. However, the former has noticeable liver damage effects on SD rats, and the latter is adequate for protecting the liver in normal or hyperlipidemia SD rats. At the same time, it has been proved that HBO therapy has cardio and kidney protection in hyperlipidemia SD rats.


Assuntos
Oxigenoterapia Hiperbárica/métodos , Hiperlipidemias/terapia , Redução de Peso/fisiologia , Animais , Oxigenoterapia Hiperbárica/instrumentação , Rim/fisiologia , Lipídeos/sangue , Fígado/fisiologia , Masculino , Ratos Sprague-Dawley
3.
Fish Shellfish Immunol ; 120: 706-715, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34954371

RESUMO

The present study was conducted to investigate the effects of yeast culture on the growth, health and microflora of the juvenile largemouth bass fed high-starch diet. The experiment set three isonitrogenous and isolipidic diets, control (high-starch diet), HSY1 (high-starch diet with 1% yeast culture) and HSY3 (high-starch diet with 3% yeast culture). A feeding trial was conducted in largemouth bass juveniles for 8 weeks. The results indicated fish fed with 3% yeast culture not only could improve specific growth rate (SGR), but also significantly decreased hepatic lipid content, hepatic glycogen content, and hepatopancreas somatic index (HSI) compared with the control group (p<0.05). The total superoxide dismutase (T-SOD) and catalase (CAT) activities of HSY3 group significantly increased while malondialdehyde (MDA) content significantly reduced in liver compared with the control group (p<0.05). Meanwhile, the mRNA expression levels of hepatic Sod and Cat were up-regulated (p<0.05), and liver metabolism showed 111 metabolites were significantly changed in HSY3 group, liver lipid metabolism pathway remarkably changed. Besides, the intestinal anti-inflammatory cytokines were significantly up-regulated, and the pro-inflammatory cytokines were significantly down-regulated as the inclusion of yeast culture (p<0.05). Notably, HSY3 group diet up-regulated the expression of Zo-1, Claudin and Occludin in intestine compared with the other groups (p<0.05). Serum d-lactate (D-lac), diamine oxidase (DAO) and lipopolysaccharide (LPS) decreased significantly with the inclusion of yeast culture (p<0.05). Furthermore, the abundance of probiotics (such as Lactobacillus, Bacillus and Bifidobacterium) increased significantly, and the abundance of intestinal potential pathogenic bacteria (Plesiomonas) decreased in HSY3 group (p<0.05). The phenotypic analysis showed that gram-negative bacteria significantly decreased while gram-positive bacteria increased in HSY3 group (p<0.05). All in all, this study revealed that supplementation of 3% yeast culture can improve the growth performance and the health of juvenile largemouth bass, and has the potential to be used as an effective synbiotics for M. salmoides.


Assuntos
Bass , Dieta , Microbiota , Saccharomyces cerevisiae , Amido/administração & dosagem , Ração Animal/análise , Animais , Antioxidantes , Bass/imunologia , Bass/microbiologia , Catalase , Citocinas , Dieta/veterinária , Intestinos/fisiologia , Fígado/fisiologia , Superóxido Dismutase
4.
Cell Mol Biol (Noisy-le-grand) ; 67(1): 142-146, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-34817355

RESUMO

Present research project was an attempt to explore the functional/nutraceutical worth of guava leaves from two locally grown varieties (Ruby & Safeda). For the purpose, guava leaves extract was fed to experimental male Sprague Dawley rats to explore the nutraceutical potential of guava leaves against hepatotoxicity. Two studies were performed on two types of rats i.e. study I (normal rats), study II (hepatotoxic rats). In both studies, 250 mg/kg each of pink guava leaves extracts (T1) and white guava leaves extracts (T2) was added in the feed. Feed intake and body weights of the rats were recorded. At the end of the first and eighth week of study, the blood samples of the rats were analyzed to check the effect of guava leaves extracts on renal functioning (Alkaline Phosphatase, Alanine Transaminase and Aspartate Transaminase) as well as liver functioning parameters including urea and creatinine. In both studies, comparatively higher feed consumption was observed in the control group than the rest of the treatments. At the end of study I, the highest weight (207±9.21 g) was observed in T0 whereas, during study II, the maximum value (202±5.58 g) was found in T2 (rats consuming white guava leaves extract) that indicates its effectiveness against hepatotoxicity. Regarding renal functioning tests, pink guava leaves were more effective in decreasing urea and creatinine levels in rats as compared to the white guava leaves in both study plans. Likewise, in each of study trial, pink guava leaves were more effective in reducing AST, ALT and ALP than white guava leaves and control. From the present investigation, it is deduced that guava leaves were effective against hepatotoxicity.


Assuntos
Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Psidium/química , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Rim/metabolismo , Rim/fisiologia , Fígado/metabolismo , Fígado/fisiologia , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Psidium/classificação , Ratos Sprague-Dawley , Especificidade da Espécie
5.
Food Funct ; 12(19): 9300-9314, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606525

RESUMO

In this study, Ougan juice (OJ) and lactic acid bacteria fermented Ougan juice (FOJ) were investigated individually for their capability of preventing obesity in high-fat diet (HFD)-fed C57BL/6J mice. After being administered with OJ or FOJ for 10 weeks, the body weight gain, hyperlipidemia, and gut microbiota dysbiosis of HFD-fed mice were examined. The results showed that OJ or FOJ supplementation inhibited weight gain, lowered fat accumulation, reduced liver steatosis, improved glucose homeostasis and insulin sensitivity, increased brown adipose tissue (BAT) activity, and promoted white adipose tissue (WAT) browning. Both OJ and FOJ additions increased the diversity of gut microbiota. OJ reduced the relative abundance of phylum Erysipelatoclostridiaceae and genus Erysipelatoclostridium and remarkably increased SCFA-producing bacteria Blautia, while FOJ reduced the ratio of Firmicutes to Bacteroidetes and enhanced the relative abundance of family Lactobacillaceae. Spearman's correlation analysis revealed that Akkermansia, Dubosiella, and Muribaculaceae were significantly negatively correlated with obesity-related indexes. In general, FOJ exhibited a better inhibitory effect on obesity than OJ, and the possible inhibitory mechanism lies in promoting WAT browning and increasing intestinal probiotics. This study provides the guidance for developing fermented Ougan juice as an obesity-inhibiting functional food.


Assuntos
Citrus , Suplementos Nutricionais , Bebidas Fermentadas , Sucos de Frutas e Vegetais , Microbioma Gastrointestinal , Obesidade/prevenção & controle , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Animais , Glicemia/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Bebidas Fermentadas/análise , Flavonoides/análise , Resistência à Insulina , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Tamanho do Órgão , Termogênese , Aumento de Peso
6.
Am J Physiol Gastrointest Liver Physiol ; 321(4): G400-G412, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34346773

RESUMO

Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Ritmo Circadiano , Encefalopatia Hepática/tratamento farmacológico , Fígado/metabolismo , Animais , Fármacos Gastrointestinais/uso terapêutico , Encefalopatia Hepática/metabolismo , Humanos , Fígado/fisiologia , Fígado/fisiopatologia
7.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201697

RESUMO

The p-methoxycinnamic acid (p-MCA) is one of the most studied phenylpropanoids with high importance not only in the wide spectrum of therapeutic activities but also its potential application for the food industry. This natural compound derived from plants exhibits a wide range of biologically useful properties; therefore, during the last two decades it has been extensively tested for therapeutic and nutraceutical applications. This article presents the natural sources of p-MCA, its metabolism, pharmacokinetic properties, and safety of its application. The possibilities of using this dietary bioactive compound as a nutraceutical agent that may be used as functional food ingredient playing a vital role in the prevention and treatment of many chronic diseases is also discussed. We present the antidiabetic, anticancer, antimicrobial, hepato-, and neuroprotective activities of p-MCA and methods of its lipophilization that have been developed so far to increase its industrial application and bioavailability in the biological systems.


Assuntos
Cinamatos/química , Cinamatos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cinamatos/metabolismo , Cinamatos/uso terapêutico , Suplementos Nutricionais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Polifenóis/análise , Polifenóis/farmacologia , Propanóis/análise , Propanóis/farmacologia
8.
J Diabetes Res ; 2021: 6659415, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816636

RESUMO

Methanol and methanol/water extracts of olive stones and seeds from Olea europaea var. meski were analyzed by reversed-phase high-performance liquid chromatography (HPLC) with diode array detection and mass spectrometry (LC-MS/MS). A total of 28 metabolites were identified; among them are hydroxycinnamic acid derivatives, phenolic alcohols, flavonoids and flavonoid glucosides, secoiridoids, and terpenes. All the extracts were screened for the inhibitory effect of key enzymes related to diabetes and obesity, such as α-amylase and lipase. An in vitro study revealed that Olea meski stone ethanol (MSE) and methanol (MSM) extracts and Olea meski seed ethanol (MSE1) and methanol (MSM1) extracts exert an inhibitory action against lipase and α-amylase. The most potent activity was observed in the StM extract with IC50 equal to 0.19 mg/ml against DPPH oxidation, 1.04 mg/ml against α-amylase, and 2.13 mg/ml against lipase. In HFFD rats, the findings indicated that the increase of body weight, LDL, TC, and glucose levels and then the decrease in HDL-C were significantly suppressed in the MSM-treated group than those in HFFD rats. Moreover, the MSM extract exhibited a prominent selective inhibitory effect against intestinal lipase and α-amylase activities. The MSM extract was also able to protect the liver-kidney functions efficiently, which was evidenced by biochemicals and histological studies.


Assuntos
Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Olea/química , Extratos Vegetais/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Fígado/fisiologia , Masculino , Compostos Fitoquímicos/análise , Ratos , Ratos Wistar , Sementes , Espectrometria de Massas por Ionização por Electrospray , alfa-Amilases/metabolismo
9.
Mol Genet Genomics ; 296(4): 863-876, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33899140

RESUMO

Picrorhiza kurroa is a medicinal herb with diverse pharmacological applications due to the presence of iridoid glycosides, picroside-I (P-I), and picroside-II (P-II), among others. Any genetic improvement in this medicinal herb can only be undertaken if the biosynthetic pathway genes are correctly identified. Our previous studies have deciphered biosynthetic pathways for P-I and P-II, however, the occurrence of multiple copies of genes has been a stumbling block in their usage. Therefore, a methodological strategy was designed to identify and prioritize paralogues of pathway genes associated with contents of P-I and P-II. We used differential transcriptomes varying for P-I and P-II contents in different tissues of P. kurroa. All transcripts for a particular pathway gene were identified, clustered based on multiple sequence alignment to notify as a representative of the same gene (≥ 99% sequence identity) or a paralogue of the same gene. Further, individual paralogues were tested for their expression level via qRT-PCR in tissue-specific manner. In total 44 paralogues in 14 key genes have been identified out of which 19 gene paralogues showed the highest expression pattern via qRT-PCR. Overall analysis shortlisted 6 gene paralogues, PKHMGR3, PKPAL2, PKDXPS1, PK4CL2, PKG10H2 and PKIS2 that might be playing role in the biosynthesis of P-I and P-II, however, their functional analysis need to be further validated either through gene silencing or over-expression. The usefulness of this approach can be expanded to other non-model plant species for which transcriptome resources have been generated.


Assuntos
Glicosídeos Iridoides/metabolismo , Picrorhiza , Plantas Medicinais , Vias Biossintéticas/genética , Cinamatos/metabolismo , Cinamatos/farmacologia , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes/fisiologia , Genes de Plantas , Ensaios de Triagem em Larga Escala , Glucosídeos Iridoides/metabolismo , Glucosídeos Iridoides/farmacologia , Glicosídeos Iridoides/farmacologia , Fígado/efeitos dos fármacos , Fígado/fisiologia , Picrorhiza/química , Picrorhiza/genética , Picrorhiza/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Brotos de Planta/genética , Brotos de Planta/metabolismo , Plantas Medicinais/química , Plantas Medicinais/genética , Plantas Medicinais/metabolismo , Homologia de Sequência , Transcriptoma/fisiologia
10.
Vet Med Sci ; 7(3): 800-811, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33570254

RESUMO

A major mean to minimize feeding costs and faecal nitrogen excretion on poultry farms is to decrease the supplied dietary protein content. This, however, is associated with the declines in productive performance and systemic health indices. Sanguinarine may improve protein efficiency via decreasing the intestinal amino acid decarboxylation and stimulating the tryptophan-serotonin pathway. The present study was carried out to investigate the effects of dietary supplementation of sanguinarine on the performance, egg yolk biochemical parameters, serum enzyme activities, nutrient digestibility, ovarian follicles, and hepatic health indices in laying hens fed decremental levels of crude protein (CP). For this purpose, 180 laying hens were allocated into nine dietary treatments with four replicates of five birds each. The experimental treatments consisted of three levels of CP (85.0%, 92.5%, and 100% of Hy-Line W-36 manual recommendation) and three levels of sanguinarine (0.00, 3.75, and 7.50 mg/kg) in a 3 × 3 factorial arrangement administered during a 70-day feeding trial. Results showed that the decremental levels of CP led to significant increases in serum aspartate aminotransferase (p < .05), alanine aminotransferase, and alkaline phosphatase (p < .01) activities, egg yolk cholesterol concentration (p = .064), and hepatic fat and malondialdehyde (MDA) contents (p < .05). It also caused the significant declines in ileal dry matter (DM) digestibility (p < .05) and eggshell strength (p < .05), and also tended to decrease CP digestibility (p = .071), Haugh unit (p = .057) and egg production percentage (p = .062). The interaction effects of the experimental factors indicated that dietary supplementation of sanguinarine, especially at 7.50 mg/kg, led to significant improvements in serum aspartate aminotransferase and alanine aminotransferase activities (p < .01), egg yolk cholesterol (p < .001) and triglyceride (p < .05) concentrations, eggshell strength (p < .001), Haugh unit (p < .05), hepatic fat (p < .001) and MDA (p = .059) contents, ileal DM and CP digestibility (p < .01) as well as egg production, egg mass and feed conversion ratio (FCR; p < .05) in birds receiving decremental levels of CP. Taken together, the results indicate that dietary administration of sanguinarine could enhance productive performance via improving nutrient digestibility, hepatic health indices and fortifying systemic antioxidant capacity in laying hens fed low-CP diets.


Assuntos
Benzofenantridinas/metabolismo , Galinhas/fisiologia , Digestão/efeitos dos fármacos , Isoquinolinas/metabolismo , Fígado/efeitos dos fármacos , Nutrientes/fisiologia , Reprodução/efeitos dos fármacos , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Benzofenantridinas/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Feminino , Isoquinolinas/administração & dosagem , Fígado/fisiologia , Distribuição Aleatória , Reprodução/fisiologia
11.
Molecules ; 26(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440603

RESUMO

Okara is a white-yellow fibrous residue consisting of the insoluble fraction of the soybean seeds remaining after extraction of the aqueous fraction during the production of tofu and soymilk, and is generally considered a waste product. It is packed with a significant number of proteins, isoflavones, soluble and insoluble fibers, soyasaponins, and other mineral elements, which are all attributed with health merits. With the increasing production of soy beverages, huge quantities of this by-product are produced annually, which poses significant disposal problems and financial issues for producers. Extensive studies have been done on the biological activities, nutritional values, and chemical composition of okara as well as its potential utilization. Owing to its peculiar rich fiber composition and low cost of production, okara might be potentially useful in the food industry as a functional ingredient or good raw material and could be used as a dietary supplement to prevent varied ailments such as prevention of diabetes, hyperlipidemia, obesity, as well as to stimulate the growth of intestinal microbes and production of microbe-derived metabolites (xenometabolites), since gut dysbiosis (imbalanced microbiota) has been implicated in the progression of several complex diseases. This review seeks to compile scientific research on the bioactive compounds in soybean residue (okara) and discuss the possible prebiotic impact of this fiber-rich residue as a functional diet on eubiosis/dysbiosis condition of the gut, as well as the consequential influence on liver and kidney functions, to facilitate a detailed knowledge base for further exploration, implementation, and development.


Assuntos
Disbiose/terapia , Manipulação de Alimentos/métodos , Alimento Funcional , Glycine max/química , Prebióticos , Animais , Disbiose/microbiologia , Alimento Funcional/análise , Microbioma Gastrointestinal , Humanos , Rim/fisiologia , Fígado/fisiologia , Prebióticos/análise
12.
Arch Physiol Biochem ; 127(2): 170-181, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31210545

RESUMO

We investigated the effects of Medicago sativa supplementation on the lipid profiles and antioxidant capacities of ovariectomized mice.The study was performed on white Swiss female mice that were divided into five groups: control, treated with Medicago sativa (0.75 g/kg/day), ovariectomized, ovariectomized treated with ß-estradiol (1 µg/day) or with Medicago sativa. The mice were sacrificed after 3 and 8 weeks of treatment.Ovariectomy induced a decrease in overall growth, uterine atrophy, and hyperlipidemia demonstrated by increased cholesterol, triglycerides, and decreased HDL. We have shown the involvement of oxidative stress in this hepatic lesion proven by increased levels of TBARS, GPX, and GSH, and decreased levels of SOD and catalase.Treatment with Medicago sativa restores lipid balance, the activity of antioxidant enzymes and improves lipid peroxidation. This is probably due to the richness of this plant in polyphenols and flavonoids considered as an antioxidant and phytoestrogenic elements.


Assuntos
Antioxidantes/farmacologia , Estrogênios/deficiência , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/fisiologia , Medicago sativa/química , Extratos Vegetais/farmacologia , Útero/crescimento & desenvolvimento , Animais , Feminino , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Malondialdeído/metabolismo , Camundongos , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Útero/efeitos dos fármacos
13.
Hepatology ; 74(1): 397-410, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33314176

RESUMO

BACKGROUND AND AIMS: Following mild liver injury, pre-existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC-driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end-stage liver diseases. Despite this attention, the molecular basis of BEC-driven liver regeneration remains poorly understood. APPROACH AND RESULTS: By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC-driven liver regeneration. Here we show that FXR activation blocks the process through the FXR-PTEN (phosphatase and tensin homolog)-PI3K (phosphoinositide 3-kinase)-AKT-mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC-to-hepatocyte differentiation, but not BEC-to-LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena/b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC-driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K-AKT-mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC-driven liver regeneration, as did FXR activation. CONCLUSIONS: FXR activation impairs BEC-driven liver regeneration by enhancing PTEN activity; the PI3K-AKT-mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Células-Tronco/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Sistema Biliar/citologia , Proliferação de Células , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Fígado/efeitos dos fármacos , Fígado/fisiologia , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Células-Tronco/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
14.
Future Oncol ; 17(9): 1055-1068, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33222542

RESUMO

Background: The study assessed the cost-utility of selective internal radiation therapy (SIRT) with Y-90 resin microspheres versus sorafenib in UK patients with unresectable hepatocellular carcinoma ineligible for transarterial chemoembolization. Materials & methods: A lifetime partitioned survival model was developed for patients with low tumor burden (≤25%) and good liver function (albumin-bilirubin grade 1). Efficacy, safety and quality of life data were from a European Phase III randomized controlled trial and published studies. Resource use was from registries and clinical surveys. Results: Discounted quality-adjusted life-years were 1.982 and 1.381, and discounted total costs were £29,143 and 30,927, for SIRT and sorafenib, respectively. Conclusion: SIRT has the potential to be a dominant (more efficacious/less costly) or cost-effective alternative to sorafenib in patients with unresectable hepatocellular carcinoma.


Assuntos
Braquiterapia/economia , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Radioisótopos de Ítrio/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Análise Custo-Benefício , Custos de Cuidados de Saúde , Humanos , Fígado/fisiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Microesferas , Seleção de Pacientes , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Sorafenibe/economia , Sorafenibe/uso terapêutico , Análise de Sobrevida , Carga Tumoral , Reino Unido/epidemiologia , Radioisótopos de Ítrio/economia
15.
Elife ; 92020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289482

RESUMO

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17ß-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.


Assuntos
Estradiol/fisiologia , Receptor alfa de Estrogênio/fisiologia , Longevidade , Animais , Feminino , Regulação da Expressão Gênica/fisiologia , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/fisiologia , Longevidade/fisiologia , Masculino , Camundongos , Camundongos Knockout , Ratos
16.
Mol Metab ; 42: 101095, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045433

RESUMO

OBJECTIVE: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. METHODS: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. RESULTS: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. CONCLUSIONS: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.


Assuntos
Adipócitos/metabolismo , Receptores de Calcitriol/metabolismo , Deficiência de Vitamina D/metabolismo , Tecido Adiposo/metabolismo , Adulto , Animais , Dieta Hiperlipídica , Feminino , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/metabolismo , Sobrepeso/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/fisiopatologia
17.
Arch Anim Nutr ; 74(6): 476-495, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33059482

RESUMO

The current study aimed to examine the effects of dietary spirulina supplementation in high-energy (HE) diets on fatty acid metabolism in sheep, and preliminarily explored the potential mechanisms underlying the associated autophagy-mediated regulation of lipid metabolism. In a 2 × 3 factorial design, including six treatment combinations of two metabolisable energy diets (10 and 11 MJ/kg DM), three spirulina supplementation levels (0, 1%, and 3%) were used. Serum alanineaminotransferase (ALT) (p = 0.003) and aspartatetransaminase (AST) (p = 0.002) activities increased, whereas total PUFA content (p < 0.001) decreased in the liver of lambs fed a HE diet. With the addition of spirulina, serum ALT (p = 0.037) and AST (p = 0.014) activities decreased, whereas EPA (p = 0.004), GLA (p = 0.019), n-6 PUFA (p = 0.005), and total PUFA contents (p = 0.019) increased. Moreover, the crude protein content in the Longissimus thoracis et lumborum (LTL) increased (p = 0.013), the expression of PPARα and PPARγ was up-regulated, while ELOVL2 was down-regulated in liver and LTL (p < 0.05). Spirulina supplementation increased mRNA expression levels of autophagy-associated genes, including that of Beclin-1, AMPK, and ULK1 (p < 0.05). In conclusion, spirulina supplementation in a HE diet exerted a protective effect on the liver, increased PUFA content, and modulated expression levels of autophagy-related genes in growing lambs.


Assuntos
Autofagia/efeitos dos fármacos , Dieta/veterinária , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Carneiro Doméstico/fisiologia , Spirulina/química , Ração Animal/análise , Animais , Dieta/classificação , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Fígado/fisiologia , Masculino , Músculo Esquelético/fisiologia , Distribuição Aleatória
18.
PLoS One ; 15(9): e0238115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915812

RESUMO

This work provides an in-depth computational performance study of the parallel finite-difference time-domain (FDTD) method. The parallelization is done at various levels including: shared- (OpenMP) and distributed- (MPI) memory paradigms and vectorization on three different architectures: Intel's Knights Landing, Skylake and ARM's Cavium ThunderX2. This study contributes to prove, in a systematic manner, the well-established claim within the Computational Electromagnetic community, that the main factor limiting FDTD performance, in realistic problems, is the memory bandwidth. Consequently a memory bandwidth threshold can be assessed depending on the problem size in order to attain optimal performance. Finally, the results of this study have been used to optimize the workload balancing of simulation of a bioelectromagnetic problem consisting in the exposure of a human model to a reverberation chamber-like environment.


Assuntos
Algoritmos , Campos Eletromagnéticos , Osso e Ossos/fisiologia , Dispositivos de Armazenamento em Computador , Sistemas Computacionais , Humanos , Rim/fisiologia , Fígado/fisiologia , Modelos Teóricos , Software
19.
Mol Nutr Food Res ; 64(20): e2000354, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32918392

RESUMO

SCOPE: To investigate the effects of squalene, the main hydrocarbon present in extra virgin olive oil, on liver transcriptome in different animal models and to test the influence of sex on this action and its relationship with hepatic lipids. METHODS AND RESULTS: To this purpose, male C57BL/6J Apoe-deficient mice are fed a purified Western diet with or without squalene during 11 weeks and hepatic squalene content is assessed, so are hepatic lipids and lipid droplets. Hepatic transcriptomic changes are studied and confirmed by RT-qPCR. Dietary characteristics and influence of squalene doses are tested in Apoe-deficient on purified chow diets with or without squalene. These diets are also given to Apoa1 and wild-type mice on C57BL/6J background and to C57BL/6J xOla129 Apoe-deficient mice. Squalene supplementation increases its hepatic content without differences among sexes and hormonal status. The Cyp2b10 and Cyp2c55 gene expressions are significantly up-regulated by the squalene intake in all models, with independence of sex, sexual hormones, dietary fat content, genetic background and dose, and in Apoe-deficient mice consuming extra-virgin olive oil. CONCLUSION: Hepatic squalene increases the expression of these cytochromes and their changes in virgin olive oil diets may be due to their squalene content.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Família 2 do Citocromo P450/genética , Fígado/efeitos dos fármacos , Esqualeno/farmacologia , Esteroide Hidroxilases/genética , Animais , Apolipoproteína A-I/genética , Apolipoproteínas E/genética , Castração , Citocromo P-450 CYP2B6/genética , Dieta Ocidental , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Esqualeno/administração & dosagem
20.
Int J Med Mushrooms ; 22(6): 509-519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865893

RESUMO

Over the years, the gut microbiota has become a main focus in gastroenterology and hepatology research. It is made up of billions of bacteria that can have essential functions ranging from digestion to the control of the immune response through the production of substances resulting from microbial metabolic activities. However, the liver remains the primordial organ as the first filter of toxins, nutrients, as well as its bacterial metabolic products from the intestines and passing through the portal vein which is the main junction connecting them and constituting about 75% of liver blood supply. Hence, the importance of their interactions, which, associated with the immune system, play mediating roles both in normal physiology and in the predisposition to disease, especially liver disease. In addition, possible therapeutic manifestations due to the modification of the intestinal microflora through prebiotics can come from nutrition such as mushroom consumption. Although used for food and medical needs for centuries, mushrooms have not yet fully disclosed their positive effects on health, particularly on the regulation of intestinal microbiota and subsequent effect on liver diseases. This review will present the knowledge acquired on the contribution of the intestinal microbiota to the functioning of the liver; factors causing dysbiosis, the process by which it causes disorders of intestinal homeostasis and induces the genesis of liver diseases; and the therapeutic benefits of culinary-medicinal mushrooms on the body in general through the intestinal microbiota. Mushrooms have several bioactive compounds, for example, polysaccharides such as xylans, galactans, ß and α-glucans, and chitin, that justify their use as prebiotics to promote the growth of intestinal bacteria and to induce beneficial effects in the health of the host.


Assuntos
Agaricales , Microbioma Gastrointestinal/fisiologia , Hepatopatias/etiologia , Hepatopatias/prevenção & controle , Fígado/fisiologia , Prebióticos , Agaricales/química , Animais , Bactérias/crescimento & desenvolvimento , Dieta , Disbiose/etiologia , Microbioma Gastrointestinal/genética , Humanos
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