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1.
Gene ; 725: 144167, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639434

RESUMO

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


Assuntos
Bilirrubina/metabolismo , Osteoblastos/metabolismo , Osteoporose/genética , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Linhagem Celular Tumoral , Colestase/genética , Regulação para Baixo/efeitos dos fármacos , Perfil Genético , Humanos , Ácido Litocólico/farmacologia , Fígado/metabolismo , Fígado/fisiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Osteoporose/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia
2.
J Agric Food Chem ; 67(47): 13082-13092, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31671940

RESUMO

Elevated circulating level of the intestinal microbiota-derived l-carnitine metabolite trimethylamine-N-oxide (TMAO) has recently been linked to many chronic diseases. The purpose of our study was to investigate the effects of omega-7-enriched Decaisnea insignis seed oil (DISO) on reducing TMAO formation to prevent the l-carnitine-induced hepatic damage in mice. Feeding of mice with 3% l-carnitine in drinking water clearly increased the serum and urinary levels of TMAO (p < 0.05 vs Normal), whereas the serum and urinary TMAO formation was sharply reduced by DISO administration (p < 0.05). Meanwhile, DISO resulted in strong inhibition against the elevation of hepatic injury marker (AST, ALT, and ALP) activities and dyslipidemia (TC, TG, LDL-C, and HDL-C), as well as liver inflammatory cytokine (IL-1, IL-6, TNF-α, and TNF-ß) release in l-carnitine-fed mice (p < 0.05). As revealed by 16S rDNA gene sequencing, DISO significantly inhibited the l-carnitine-induced elevations in the abundance of Firmicutes, Proteobacteria, and Erysipelotrichaceae and the increases in the proportion of Lactobacillus and Akkermansia, revealing that DISO attenuated the l-carnitine-caused gut dysbiosis. These findings suggested that DISO could alleviate liver dysfunction in l-carnitine-fed mice, which might be due to the protection against TMAO formation by modulating the gut microbiota.


Assuntos
Carnitina/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias/tratamento farmacológico , Magnoliopsida/química , Óleos Vegetais/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Masculino , Metilaminas/efeitos adversos , Camundongos , Sementes/química
3.
J Agric Food Chem ; 67(50): 13948-13959, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31698901

RESUMO

The aim of this study was to investigate the protective effect of punicalagin (PU), which is a main component of pomegranate polyphenols, against liver injury induced by Type 2 diabetes mellitus (T2DM) and to explore the molecular mechanism based on autophagy in vivo and in vitro. In T2DM mice, we found that PU significantly improved liver histology, reversed serum biochemical abnormalities, and increased the autophagosome number in the liver. In HepG2 cells cultured in a high-glucose environment, PU upregulated the glucose uptake level. Both in vivo and in vitro, PU upregulated the expression of autophagy-related proteins, such as LC3b and p62, and reduced the phosphorylated Akt/total Akt and phosphorylated FoxO3a/total FoxO3a protein ratios, and these effects were enhanced by LY294002 (a PI3K/Akt inhibitor). In summary, our current findings suggest that PU protects against liver injury induced by T2DM by restoring autophagy through the Akt/FoxO3a signaling pathway.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Proteína Forkhead Box O3/metabolismo , Taninos Hidrolisáveis/administração & dosagem , Hepatopatias/prevenção & controle , Fígado/lesões , Substâncias Protetoras/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Proteína Forkhead Box O3/genética , Humanos , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
4.
Vasc Health Risk Manag ; 15: 309-316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692533

RESUMO

Experimentally induced injury triggers up-regulation and mobilization of stem cells in Apoe -/- mice that causes accelerated atherosclerosis. Abca1 -/- Abcg1-/- mice have chronic activation of stem cell up-regulation/mobilization and accelerated atherosclerosis. In addition, the Abca1 -/- Abcg1-/- mice have elevation of serum cytokines G-CSF, IL-17 and IL-23, each necessary for stem cell mobilization. IL-17 and IL-23 are elevated in two human illnesses that have cardiovascular (CV) risk independent of traditional risk factors-SLE and psoriasis. Serum G-CSF, which can be elevated in liver disease, predicts major adverse cardiovascular events in humans. These serum cytokine elevations suggest activation of the stem cell mobilization mechanism in humans that results, as in mice, in accelerated atherosclerosis. Efforts to reduce CV disease in these patient populations should include mitigation of the diseases that trigger stem cell mobilization. Since activation of the stem cell up-regulation/mobilization mechanism appears to accelerate human atherosclerosis, use of stem cells as therapy for arterial occlusive disease should distinguish between direct administration of stem cells and activation of the stem cell up-regulation/mobilization mechanism.


Assuntos
Doenças Cardiovasculares/patologia , Movimento Celular , Hepatopatias/patologia , Psoríase/patologia , Células-Tronco/patologia , Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mediadores da Inflamação/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/terapia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos Knockout para ApoE , Fenótipo , Prognóstico , Psoríase/genética , Psoríase/metabolismo , Psoríase/terapia , Fatores de Risco , Células-Tronco/metabolismo
5.
J Agric Food Chem ; 67(41): 11474-11480, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31537057

RESUMO

Patulin (PAT) is the most common food-borne mycotoxin found in fruits and fruit-derived products, while chlorpyrifos (CPF) is a widely used pesticide on fruit and other crops. On the basis of the residue data, certain types of fruits can be contaminated simultaneously by patulin and chlorpyrifos. However, there are no available data about the combined toxicity. Since liver is a possible toxic target of both patulin and chlorpyrifos, we tested whether the combination exposure can cause enhanced hepatotoxicity using both cell culture and animal models. Results showed that the combination resulted in synergistic cytotoxicity in vitro and significantly enhanced liver toxicity in vivo. Mechanistically, PAT inhibited catalase activity via PIG3 induction, while CPF decreased catalase expression. These two mechanisms were converged in response to the combination, leading to enhanced inactivating catalase and boosted reactive oxygen species generation. The finding implicated that it is necessary to consider the combined toxicity in safety assessment of these food-borne contaminants.


Assuntos
Inibidores de Caspase/toxicidade , Clorpirifos/toxicidade , Hepatopatias/etiologia , Patulina/toxicidade , Praguicidas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Caspases/metabolismo , Catalase/antagonistas & inibidores , Catalase/metabolismo , Sinergismo Farmacológico , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
6.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491992

RESUMO

Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.


Assuntos
Fosfatases de Especificidade Dupla/genética , Estresse do Retículo Endoplasmático , Hepatócitos/metabolismo , Transdução de Sinais , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismo , Animais , Apoptose/genética , Morte Celular/genética , Expressão Gênica , Hepatócitos/patologia , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Camundongos
7.
Transplant Proc ; 51(8): 2828-2832, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31493917

RESUMO

OBJECTIVE: Hepatic ischemia and reperfusion (I/R) is a destructive event associated with high rates of liver failure after liver transplantation. Hesperidin significantly contributes to the antioxidant defense system and has been reported to act as a powerful agent against superoxide and hydroxyl radicals. Our objective was to investigate the protective effect of hesperidin against hepatic IR injury in a rat model. METHODS: We fed Sprague-Dawley rats either hesperidin (100 mg/kg/d) or saline. One week later, ischemia was induced by clamping the rats' common hepatic artery and portal vein for 30 minutes. The rats were divided into 3 groups: 1. the sham operated group; 2. the I/R group; and 3. the I/R-hesperidin group. RESULTS: Compared to the sham group, the I/R group had higher expression of serum aspartate aminotransferase and serum alanine aminotransferase and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, nitric oxide, and albumin. Compared to the I/R group, the I/R-hesperidin group had higher expression of catalase, superoxide dismutase, antioxidant and nitric oxide and lower expression of serum aspartate aminotransferase and serum alanine aminotransferase. CONCLUSIONS: Our findings suggest that hesperidin is a potential therapeutic agent for hepatic I/R injury.


Assuntos
Antioxidantes/uso terapêutico , Hesperidina/uso terapêutico , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Hesperidina/farmacologia , Hepatopatias/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
8.
Transplant Proc ; 51(8): 2823-2827, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31493918

RESUMO

OBJECTIVE: Hepatic ischemia reperfusion (I/R) injury is regarded as a serious concern in clinical practice. Citric acid reduces oxidative stress and inflammation during hypoxia and reoxygenation. Our objective was to investigate the protective effect of citric acid against hepatic I/R injury in rats. METHODS: We fed Sprague-Dawley rats either citric acid (100 mg/kg/d) or saline. One week later, ischemia was induced by clamping the rats' common hepatic artery and portal vein for 30 minutes. The rats were randomly divided into 3 major groups that were treated as follows: 1. the sham operated group; 2. the I/R group; and 3. the I/R-citric acid group. RESULTS: Compared to the sham group, the I/R group had higher expression of aspartate aminotransferase and alanine aminotransferase and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, nitric oxide, and albumin. Compared to the I/R group, the I/R-citric acid group had higher expression of catalase, superoxide dismutase, antioxidants, and nitric oxide, and lower expression of aspartate aminotransferase and alanine aminotransferase. CONCLUSIONS: These results suggest that citric acid therapy has significant therapeutic potential in ischemic liver injury.


Assuntos
Antioxidantes/uso terapêutico , Ácido Cítrico/uso terapêutico , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/metabolismo , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/metabolismo , Catalase/metabolismo , Ácido Cítrico/farmacologia , Glutationa Peroxidase/metabolismo , Hepatopatias/metabolismo , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
9.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404995

RESUMO

The enzyme vascular non-inflammatory molecule-1 (vanin 1) is highly expressed at gene and protein level in many organs, such as the liver, intestine, and kidney. Its major function is related to its pantetheinase activity; vanin 1 breaks down pantetheine in cysteamine and pantothenic acid, a precursor of coenzyme A. Indeed, its physiological role seems strictly related to coenzyme A metabolism, lipid metabolism, and energy production. In recent years, many studies have elucidated the role of vanin 1 under physiological conditions in relation to oxidative stress and inflammation. Vanin's enzymatic activity was found to be of key importance in certain diseases, either for its protective effect or as a sensitizer, depending on the diseased organ. In this review, we discuss the role of vanin 1 in the liver, kidney, intestine, and lung under physiological as well as pathophysiological conditions. Thus, we provide a more complete understanding and overview of its complex function and contribution to some specific pathologies.


Assuntos
Amidoidrolases/metabolismo , Estresse Oxidativo , Amidoidrolases/análise , Animais , Proteínas Ligadas por GPI/análise , Proteínas Ligadas por GPI/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Enteropatias/metabolismo , Enteropatias/fisiopatologia , Intestinos/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia
10.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31443090

RESUMO

Omentin and vaspin are adipokines potentially considered in the development of liver pathology. Irisin is new myokin potentially participating in energy processes in the organisms. The aim of this study was to evaluate the plasma concentration of these cytokines and the relationships of them with selected parameters of laboratory tests and of histopathological changes in selected chronic liver diseases: non-alcoholic fatty liver diseases (NAFLD), primary biliary cholangitis (PBC) and alcoholic cirrhosis (AC). The plasma concentration of omentin was the highest in AC group and the lowest in control group (CG). Irisin plasma concentration was the highest in CG and the lowest in AC. Mean vaspin concentrations did not differ significantly between groups. Among many laboratory parameters, only in the AC group positive relationships were found between omentin concentration and bilirubin, as well as glucose, and negative between omentin level and the number of platelets and erythrocytes; there was a positive relationship between the concentration of vaspin and bilirubin, as well as negative between vaspin level and the number of erythrocytes or hematocrit value in this group. INR value had positive correlation with vaspin concentration and negative with irisin level in NAFLD group. No significant dependences between the concentrations of explored cytokines and laboratory tests were found in PBC group. It was found the positive correlation between the plasma concentration of irisin and fibrosis as well as inflammation in PBC group. The negative correlation between irisin level and inflammation in NAFLD was also showed. Omentin can be considered as an indicator for predicting inflammation, steatosis and balloon degeneration in NAFLD and PBC. Summarizing, it is unclear but possible that explored cytokines have some relationships with certain features of liver damage and development of chronic diseases of this organ.


Assuntos
Citocinas/metabolismo , Fibronectinas/metabolismo , Lectinas/metabolismo , Hepatopatias/metabolismo , Serpinas/metabolismo , Adulto , Idoso , Doença Crônica , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
BMC Vet Res ; 15(1): 263, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31352899

RESUMO

BACKGROUND: Across China and Southeast Asia, an estimated 17,000 bears are currently farmed for bile, primarily for traditional medicines. Depending on country, bile is extracted daily via transabdominal gallbladder fistulas, indwelling catheters, or needle aspiration. Despite claims that bears do not develop adverse effects from bile extraction, health issues identified in bears removed from bile farms include bile-extraction site infections, abdominal hernias, peritonitis, cholecystitis, hepatic neoplasia, cardiac disease, skeletal abnormalities, and abnormal behaviors. We present a comprehensive assessment of the effects of bile farming by comparing serum biochemical and hematological values of bears from farms that were bile-extracted (BE) and bears from farms not bile-extracted (FNE) with bears from non-farm captive (ZOO) and free-range (FR) environments. We hypothesized BE bears would have significant laboratory abnormalities compared to all non-extracted bear groups. We also hypothesized BE bears would have reduced long-term survival compared to FNE bears despite removal from farms. RESULTS: BE bears exhibited the highest values and greatest variation (on a population level) in laboratory parameters compared to all non-extracted bear groups particularly for alanine transaminase, gamma glutamyltransferase (GGT), total bilirubin (TBIL), alkaline phosphatase (ALKP), blood urea nitrogen, creatinine (CREA), and total white blood cell count. Significant differences were detected between bear groups when accounting for season, sex, and/or age. BE bears exhibited greater mean serum GGT compared to all non-extracted bear groups, and the odds of having elevated TBIL were 7.3 times greater for BE bears, consistent with hepatobiliary disease. Biochemical parameter elevations in BE bears persisted up to 14 years post-rescue, consistent with long-term effects of bile-extraction. BE bears that arrived with elevated CREA and ALKP had median survival times of 1 and 4 years respectively, and regardless of laboratory abnormalities, BE bears had significantly shorter survival times compared to FNE bears. CONCLUSIONS: Our results provide strong evidence that bile extraction practices not only represent a temporary constraint for bears' welfare, but confer distinct long-term adverse health consequences. Routine laboratory panels may be insensitive to detect the extent of underlying illness in BE bears as these bears have significantly reduced survival regardless of biochemical assessment compared to FNE bears.


Assuntos
Criação de Animais Domésticos/métodos , Bile , Ursidae/metabolismo , Fosfatase Alcalina/sangue , Bem-Estar do Animal , Animais , Doenças Biliares/metabolismo , Doenças Biliares/veterinária , Bilirrubina/sangue , Creatinina/sangue , Feminino , Hepatopatias/metabolismo , Hepatopatias/veterinária , Masculino , Análise de Sobrevida , gama-Glutamiltransferase/sangue
12.
Int J Immunopathol Pharmacol ; 33: 2058738419862736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31298048

RESUMO

Hepatic ischemia/reperfusion injury (IRI) is a clinical condition that may lead to cellular injury and organ dysfunction that can be observed in different conditions, such as trauma, shock, liver resection, and transplantation. Moderate levels of nitric oxide (NO) produced by the endothelial isoform of the NO synthase protect against liver IRI. GIT-27NO is a NO-derivative of the toll-like receptor 4 antagonist VGX-1027 that has been shown to possess both antineoplastic and immunomodulatory properties in vitro and in vivo. In this study, we have investigated the effects of this compound in vitro, in a model of oxidative stress induced in HepG2 cells by hydrogen peroxide (H2O2), and in vivo, in a rat model of IRI of the liver. GIT-27NO significantly counteracted the toxic effects induced by the H2O2 on the HepG2 cells and in vivo, GIT-27NO reduced the transaminase levels and the histological liver injury by reducing necrotic areas with preservation of viable tissue. These effects were almost similar to that of the positive control drug dimethyl fumarate. These data suggest that the beneficial effect of GIT-27NO in the hepatic IRI can be secondary to anti-oxidative effects and hepatocyte necrosis reduction probably mediated by NO release.


Assuntos
Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Óxido Nítrico/metabolismo , Oxidiazóis/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo
13.
Int J Mol Sci ; 20(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323789

RESUMO

The ginseng berry contains a variety of biologically active compounds and has a higher ginsenoside content than its roots. This study focused on the hepatoprotective activity of ginseng berry extract prepared by enzyme treatment (EGB) compared to the non-enzyme-treated ginseng berry extract (GB) and quality control of EGB. The feeding effect of EGB on alcohol-induced liver damage (AILD) was investigated by measuring the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) compared with those of EtOH-fed mice. Furthermore, cytokine levels in the culture supernatants of EGB- or GB-treated RAW 264.7 cells were determined by enzyme-linked immunosorbent assay. The developed method was applied to the simultaneous quantification of four major ginsenosides in EGB using UPLC-QTOF/MS. Treatment with EGB at a dose of 0.5 or 1 mg/mouse significantly suppressed the AST and ALT levels in mice with AILD. Enzyme-treated ginseng berry was also found to suppress the production of inflammatory mediators like nitric oxide (NO), tumor-necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, showing higher activity than that of GB. The amount of ginsenoside Re, F5, F3, and Rd in the EGB obtained using UPLC-QTOF/MS was 45.9, 3.3, 4.0, and 6.2 mg/g, respectively. These results suggest that EGB has a potential effect on AILD, and its hepatoprotective effect provides beneficial insights into developing new candidates for the prevention and cure of AILD. Also, this study demonstrated the utility of UPLC-QTOF/MS-based major compounds for quality control (QC) of EGB.


Assuntos
Anti-Inflamatórios/uso terapêutico , Frutas/química , Fígado/efeitos dos fármacos , Panax/química , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/sangue , Ginsenosídeos/química , Ginsenosídeos/uso terapêutico , Interleucina-6/sangue , Lipopolissacarídeos/toxicidade , Fígado/lesões , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Células RAW 264.7 , Fator de Necrose Tumoral alfa
14.
Am J Med Sci ; 358(2): 127-133, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31331450

RESUMO

BACKGROUND: Many guidelines addressing the approach to abnormal liver chemistries, including bilirubin, transaminases and alkaline phosphatase, recommend repeating the tests. However, when clinicians repeat testing is unknown. MATERIAL AND METHODS: This retrospective study followed adult patients with abnormal liver chemistries in a patient-centered medical home (PCMH) from 2007 to 2016. All PCMH patients possessing at least 1 abnormal liver test (total bilirubin, aminotransferases and alkaline phosphatase) were included. Patients were followed from the index abnormal liver chemistry until the next liver test result, or the end of the study period. The primary predictor variable of interest was the number of abnormal chemistries (out of 4) on index testing. Demographic and clinical variables served as other potential predictors of outcome. A Cox proportional hazards model was applied to investigate associations between the predictor variables and the time to repeat liver chemistry testing. RESULTS: Of 9,545 patients with at least 2 PCMH visits and 1 liver test abnormality, 6,489 (68%) obtained repeat testing within 1 year, and 80% of patients had follow-up tests within 2 years. Patients with multiple abnormal liver tests and those with higher degrees of abnormality were associated with shorter time to repeat testing. CONCLUSIONS: A large proportion of patients with abnormal liver tests still lack repeat testing at 1 year. The number of liver abnormal liver tests and degree of elevation were inversely associated with the time to repeat testing.


Assuntos
Hepatopatias/diagnóstico , Fígado , Médicos de Atenção Primária/normas , Atenção Primária à Saúde/métodos , Registros Eletrônicos de Saúde , Feminino , Seguimentos , Humanos , Fígado/metabolismo , Hepatopatias/epidemiologia , Hepatopatias/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Atenção Primária à Saúde/estatística & dados numéricos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , South Carolina , Fatores de Tempo
15.
J Therm Biol ; 83: 8-21, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31331528

RESUMO

Heat stress (HS) is a major international problem which has attracted a considerable attention due to its oxidative tissue effects and high morbidity and mortality rates, especially among elderly people. Discovering an effective antioxidant is pivotal for overcoming HS-induced injury. Therefore, the aim of this study was to estimate the hepatic protective effects of orally supplemented resveratrol (RES) against HS-mediated liver injury in young and old male Wistar albino rats. Compared to control rats, RES administered orally at a dose of 20 mg/kg BW for 21 successive days efficiently ameliorated HS-induced oxidative damage by significantly increasing (P ≤ 0.05) the level of reduced glutathione and glutathione peroxidase, and decreasing the levels of malondialdehyde and TNF-α in hepatic tissue of both young and aged rats. However, level of NF-κB was downregulated significantly in aged rats rather than young rats. Moreover, RES significantly decreased (P ≤ 0.05) the serum levels of aspartate transaminase and alkaline phosphatase in both ages of rats compared to their corresponding HS-stressed rats. Furthermore, RES upregulated the immunohistochemical expression of caspase 3 and heat shock protein 70 in young and aged rats, however it was more pronounced in young one. In addition, RES administration moderately normalized (P ≤ 0.0001) the harmful effects of HS on the hepatic architecture of both young and aged rats. In conclusion, this study reveals for the first time that RES exerts promising hepato-ameliorative effects against HS-induced oxidative stress in the young and aged rats via its antioxidant, anti-inflammatory, and anti-apoptotic effect, as well as via its inhibitory effect against the NF-κB signalling in a cellular system.


Assuntos
Antioxidantes/uso terapêutico , Proteínas de Choque Térmico HSP70/metabolismo , Transtornos de Estresse por Calor/complicações , Hepatopatias/tratamento farmacológico , NF-kappa B/metabolismo , Resveratrol/uso terapêutico , Fosfatase Alcalina/sangue , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose , Aspartato Aminotransferases/sangue , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
16.
Curr Drug Metab ; 20(5): 377-389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258056

RESUMO

BACKGROUND: Sodium Taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) play significant roles as membrane transporters because of their presence in the enterohepatic circulation of bile salts. They have emerged as promising drug targets in related liver disease. METHODS: We reviewed the literature published over the last 20 years with a focus on NTCP and BSEP. RESULTS: This review summarizes the current perception about structure, function, genetic variation, and regulation of NTCP and BSEP, highlights the effects of their defects in some hepatic disorders, and discusses the application prospect of new transcriptional activators in liver diseases. CONCLUSION: NTCP and BSEP are important proteins for transportation and homeostasis maintenance of bile acids. Further research is needed to develop new models for determining the structure-function relationship of bile acid transporters and screening for substrates and inhibitors, as well as to gain more information about the regulatory genetic mechanisms involved in the processes of liver injury.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Hepatopatias/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Animais , Humanos
17.
Monoclon Antib Immunodiagn Immunother ; 38(4): 137-144, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31361582

RESUMO

Among multiple parameters, applied in the immunologic monitoring of transplantation, the levels of serum soluble CD30 (sCD30) and peripheral regulatory T cells (Tregs) are very promising. These are relatively new biomarkers, considered to reflect immune activation and tolerance in solid organ transplantation. Results are shown here from a preliminary study on the relevance of sCD30 and Tregs in the monitoring of the early post-transplantation period. Sixteen patients with chronic liver or kidney disease were examined. Nine of them were further selected for transplantation. Follow-up of sCD30 and Tregs was carried out during the first month after transplantation. Until day 30 (D30) after transplantation, a progressive decrease in sCD30 levels was observed in all patients. Conversely, the dynamic of Tregs was dependent on the transplanted organ: in liver recipients, an increase of Tregs was detected at day 7 (D7) followed by a gradual decrease until D30, whereas in kidney recipients, a sustained downward trend starting on D7 was observed. In liver recipients, the increase in Tregs preceded albumin normalization, whereas in kidney recipients, sCD30 was found to have predictive significance for the creatinine levels. Our results demonstrated that peripheral blood sCD30 and Tregs are valuable parameters in the immunologic monitoring of transplanted patients.


Assuntos
Sobrevivência de Enxerto/imunologia , Antígeno Ki-1/metabolismo , Nefropatias/imunologia , Transplante de Rim/métodos , Hepatopatias/imunologia , Transplante de Fígado/métodos , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Biomarcadores/análise , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Nefropatias/metabolismo , Nefropatias/cirurgia , Hepatopatias/metabolismo , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Complicações Pós-Operatórias , Prognóstico , Adulto Jovem
18.
Molecules ; 24(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151312

RESUMO

Curcuma zedoaria (dry stenophora of Curcuma phaeocaulis Val., Curcuma kwangsiensis S. G. Lee et C. F. Liang, or Curcuma wenyujin Y. H. Chen et C.Ling) is a representative herb with clinical effects on liver diseases after being vinegar-processed. The crude Curcuma zedoaria and the processed Curcuma zedoaria (vinegar-boil) have been widely used as mixtures, but their equivalence has not been fully investigated. In this manuscript, quality markers of processed (vinegar-boil) Curcuma zedoaria were investigated by comparison of the compounds and hepatoprotective activities with the crude (three spices) ones. First, GC-MS-based untargeted metabolomics were applied to reveal the discriminatory components and discover potential markers. As a result, a total of six components were identified as potential markers. Then, the hepatoprotective activities were evaluated by dual cell damage models induced by a certain concentration of H2O2 or tertbutyl hydfroperoxide (t-BHP) (55 µM H2O2 or 40 µM t-BHP), which highlighted the potential of the processed Curcuma zedoaria on oxidative stress. Finally, epicurzerenone was identified as its quality marker on oxidative liver injury based on the above results and the cell-based biological assay. Overall, vinegar-processed Curcuma zedoaria was more suitable for the treatment of oxidative liver diseases, and epicurzerenone could be considered as its quality marker.


Assuntos
Ácido Acético , Curcuma/química , Hepatopatias/etiologia , Hepatopatias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores , Hepatopatias/tratamento farmacológico , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Solventes
19.
PLoS One ; 14(5): e0217797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150490

RESUMO

Chronic hepatic disease can present a diagnostic challenge with different etiologies being associated with similar clinical and laboratory findings. The histopathological assessment of a liver biopsy specimen is usually required in order to make a definitive diagnosis and the availability of non-invasive prognostic biomarkers is limited. The emerging science of metabolomics is used to detect changes in endogenous low molecular weight metabolites in biological samples and offers the possibility of identifying noninvasive markers of disease. The objective of this study was to investigate differences in the urine metabolome between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Stored urine samples from 10 healthy dogs, 10 dogs with chronic hepatitis, 6 dogs with hepatocellular carcinoma, and 5 dogs with a congenital portosystemic shunt were analyzed. The urine metabolome was analyzed by gas chromatography-quadrupole time of flight mass spectrometry and 220 known metabolites were identified. Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering between groups. Random forest analysis showed differences in the abundance of various metabolites including putrescine, gluconic acid, sorbitol, and valine. Based on univariate statistics, 37 metabolites were significantly different between groups. In, conclusion, the urine metabolome varies between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Further targeted assessment of these metabolites is needed to assess their diagnostic utility.


Assuntos
Biomarcadores/urina , Hepatopatias/urina , Fígado/metabolismo , Metaboloma/genética , Animais , Doença Crônica/veterinária , Doenças do Cão/metabolismo , Doenças do Cão/urina , Cães , Humanos , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Hepatopatias/veterinária , Metabolômica
20.
Bioanalysis ; 11(11): 1067-1083, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31251104

RESUMO

Aim: Mass spectrometry (MS)-based proteomics, particularly with the development of nano-ESI, have been invaluable to our understanding of altered proteins related to human disease. Niemann-Pick, type C1 (NPC1) disease is a fatal, autosomal recessive, neurodegenerative disorder. The resulting defects include unesterified cholesterol and sphingolipids accumulation in the late endosomal/lysosomal system resulting in organ dysfunction including liver disease. Materials & methods: First, we performed MS analysis of a complex mammalian proteome using both nano- and standard-flow ESI with the intent of developing a differential proteomics platform using standard-flow ESI. Next, we measured the differential liver proteome in the NPC1 mouse model via label-free quantitative MS using standard-flow ESI. Results: Using the standard-flow ESI approach, we found altered protein levels including, increased Limp2 and Rab7a in liver tissue of Npc1-/- compared to control mice. Conclusion: Standard-flow ESI can be a tool for quantitative proteomic studies when sample amount is not limited. Using this method, we have identified new protein markers of NPC1.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/análise , Hepatopatias/diagnóstico , Fígado/química , Doença de Niemann-Pick Tipo C/diagnóstico , Temperatura Ambiente , Animais , Cromatografia Líquida , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Camundongos , Camundongos Knockout , Doença de Niemann-Pick Tipo C/metabolismo , Proteômica , Espectrometria de Massas por Ionização por Electrospray
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