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1.
Biosci Rep ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38967060

RESUMO

BACKGROUND: Portal hypertension affects hepatic, splanchnic and portosystemic collateral systems. Although alcohol is a well-known risk factor for liver cirrhosis, it also affects vascular contractility. However, the relevant effects on portal hypertension have not been evaluated in non-alcoholic cirrhosis. This study aimed to investigate the impacts of low-dose alcohol on portal hypertension-related derangements in non-alcoholic cirrhotic rats.  Methods: Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The chronic or acute effects of low-dose alcohol (2.4 g/kg/day, oral gavage, approximately 1.3 drinks/day in humans) were evaluated.

 Results: The chronic administration of low-dose alcohol did not precipitate liver fibrosis in the sham or cirrhotic rats, however it significantly increased splanchnic blood inflow (P=0.034) and portosystemic collaterals (P=0.001). Mesenteric angiogenesis and pro-angiogenic proteins were upregulated in the alcohol-treated cirrhotic rats, and poorer collateral vasoresponsiveness to vasoconstrictors (P<0.001) was noted. Consistently, acute alcohol administration reduced splenorenal shunt resistance. Collateral vasoresponsiveness to vasoconstrictors also significantly decreased (P=0.003).

 Conclusions: In non-alcoholic cirrhosis rats, a single dose of alcohol adversely affected portosystemic collateral vessels due to vasodilatation. Long-term alcohol use precipitated splanchnic hyperdynamic circulation, in which mesenteric angiogenesis played a role. Further studies are warranted to evaluate the benefits of avoiding low-dose alcohol consumption in patients with non-alcoholic cirrhosis.

2.
J Chin Med Assoc ; 87(5): 463-470, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38380910

RESUMO

BACKGROUND: In liver cirrhosis, chronic inflammation is associated with an increase in oxidative stress, and subsequently an increase in the concentration of oxidized low-density lipoprotein (ox-LDL). Ezetimibe is a lipid-lowering agent with anti-inflammation and anti-oxidative stress activities. This study aimed to investigate the effect of ezetimibe treatment on ox-LDL in cirrhotic rats. METHODS: Biliary cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL). Sham-operated rats served as surgical controls. Ezetimibe (10 mg/kg/d) or vehicle was administered in the sham-operated or BDL rats for 4 weeks, after which hemodynamic parameters, biochemistry data, and oxidative stress were evaluated. Plasma and intrahepatic ox-LDL levels were also examined, and hepatic proteins were analyzed to explore the mechanism of ezetimibe treatment. RESULTS: The BDL rats had typical features of cirrhosis including jaundice, impaired liver function, hyperlipidemia, and elevated ox-LDL levels compared to the sham-operated rats. Ezetimibe treatment did not affect hemodynamics, liver biochemistry, or plasma lipid levels. However, it significantly reduced oxidative stress, plasma levels of ox-LDL, and tumor necrosis factor α. In addition, ezetimibe upregulated the hepatic protein expression of an ox-LDL scavenger (lectin-like ox-LDL rececptor-1), which resulted in reductions in intrahepatic ox-LDL and fat accumulation in the BDL rats. Nevertheless, ezetimibe treatment did not ameliorate hepatic inflammation or liver fibrosis. CONCLUSION: Ezetimibe reduced plasma and intrahepatic ox-LDL levels in the cirrhotic rats. Furthermore, it ameliorated intrahepatic fat accumulation and oxidative stress. However, ezetimibe did not alleviate hepatic fibrosis or inflammation in the biliary cirrhotic rats.


Assuntos
Ezetimiba , Lipoproteínas LDL , Cirrose Hepática Biliar , Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Ezetimiba/farmacologia , Ezetimiba/uso terapêutico , Ratos , Lipoproteínas LDL/sangue , Cirrose Hepática Biliar/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Masculino , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico
3.
J Chin Med Assoc ; 87(3): 245-251, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38109364

RESUMO

Hepatic encephalopathy (HE) is one of the major complications of liver disease and significantly affects the quality of life (QOL) of patients. HE is common and frequently relapses in cirrhotic patients. The management of HE is supportive, and precipitating conditions should be eliminated. Most drugs used to treat HE are conventional and include nonabsorbable disaccharides such as lactulose, and antibiotics such as rifaximin. However, their therapeutic efficacy is still suboptimal, and novel therapeutic agents are urgently needed. In addition, the optimal management and diagnosis of minimal HE/covert HE are under debate. In this review, we focus on novel pathogenetic mechanisms such as central nervous system clearance, and emerging therapeutic targets of HE, such as fecal material transplantation. We also discuss different classifications and etiologies of HE.


Assuntos
Encefalopatia Hepática , Humanos , Encefalopatia Hepática/terapia , Encefalopatia Hepática/tratamento farmacológico , Qualidade de Vida , Fármacos Gastrointestinais , Lactulose/uso terapêutico , Rifaximina/uso terapêutico
4.
J Chin Med Assoc ; 86(9): 786-794, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37462441

RESUMO

BACKGROUND: Portal hypertension develops along with the progression of liver cirrhosis. Natriuretic peptides have been shown to reduce portal pressure but concomitantly activate the renin-angiotensin-aldosterone system (RAAS). Angiotensin receptor-neprilysin inhibitors (ARNIs) upregulate natriuretic peptides and avoid the adverse effects of RAAS activation. ARNIs have been shown to reduce portal pressure in rats with pre-hepatic portal hypertension, which involves relatively little liver injury. This study aimed to evaluate the relevant effects of an ARNI in rats with both liver cirrhosis and portal hypertension. METHODS: Male Sprague-Dawley rats received common bile duct ligation to induce liver cirrhosis and portal hypertension. Sham-operated rats served as surgical controls. All rats were randomly allocated into three groups to receive distilled water (vehicle), LCZ696 (an ARNI), or valsartan for 4 weeks. Portal hypertension and relevant derangements were assessed after treatment. RESULTS: Portal hypertension and hyperdynamic circulation developed in the cirrhotic rats. In the rats with cirrhosis and portal hypertension, both LCZ696 and valsartan reduced portal hypertension, mean arterial pressure, and systemic vascular resistance. The decrease in portal pressure was highly associated with the reduction in arterial pressure and systemic vascular resistance. Blood flow in hepatic, splanchnic, and portosystemic collateral systems was not altered. LCZ696 did not significantly influence liver injury or plasma cytokine levels. Liver fibrosis and splanchnic angiogenesis were not affected. CONCLUSION: ARNI treatment exerted portal pressure lowering effects via peripheral vasodilatation and decreasing systemic arterial pressure in the rats with liver cirrhosis and portal hypertension. Caution should be taken when using ARNIs in liver cirrhosis.


Assuntos
Pressão Arterial , Hipertensão Portal , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Neprilisina/farmacologia , Vasodilatação , Receptores de Angiotensina/uso terapêutico , Pressão na Veia Porta , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/complicações , Hipertensão Portal/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Antivirais/uso terapêutico , Valsartana/uso terapêutico
5.
Clin Sci (Lond) ; 136(20): 1449-1466, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36205102

RESUMO

Exposure to low temperatures has been associated with increased gastroesophageal variceal bleeding in patients with cirrhosis and portal hypertension; however, the mechanism remains unclear. Therefore, the aim of the present study was to evaluate the impact of environmental temperature reduction on portal hypertension and the role of adrenergic signaling pathways in this phenomenon. Male Sprague-Dawley rats underwent common bile duct ligation or partial portal vein ligation to induce liver cirrhosis and/or portal hypertension. The impacts of acute or chronic changes in environmental temperature were surveyed. The results showed that acute cooling from 25 to 15°C and 5°C increased the portal pressure by 10.6% and 15.5% in cirrhotic rats, and by 22.2% and 36.1% in portal hypertensive rats, respectively. The transient portal pressure surge started shortly after cooling, reached a peak within 5 min and returned to baseline after 10 min. Systemic vascular resistance, mean arterial pressure and splanchnic blood flow increased significantly at the same time. Plasma epinephrine and norepinephrine concentrations, phospholipase C, protein kinase C activity and myosin phosphorylation of peripheral arteries increased significantly in response to cooling. Phentolamine (an α-blocker) but not propranolol (a non-selective ß-blocker) dose-dependently inhibited the transient portal pressure surge and aforementioned molecular changes. In conclusion, environmental temperature reduction induced peripheral vasoconstriction via α-adrenergic pathways, and redistribution of blood flow to the splanchnic system led to a surge in transient portal pressure. Treatment with α-adrenergic receptor antagonists may exert additional benefits in controlling portal hypertension, especially on exposure to low temperatures.


Assuntos
Varizes Esofágicas e Gástricas , Hipertensão Portal , Ratos , Masculino , Animais , Pressão na Veia Porta , Temperatura , Fentolamina/farmacologia , Circulação Esplâncnica , Ratos Sprague-Dawley , Hemorragia Gastrointestinal , Antagonistas Adrenérgicos beta/farmacologia , Cirrose Hepática , Hemodinâmica , Norepinefrina/farmacologia , Epinefrina/farmacologia , Fosfolipases Tipo C , Proteína Quinase C
6.
J Pharmacol Exp Ther ; 383(1): 25-31, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35926870

RESUMO

In liver cirrhosis, hepatic inflammation and abundant portal-systemic collaterals are indicated for the development of hepatic encephalopathy. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a type of anti-diabetic agent which exert pleiotropic and anti-inflammatory effects. Diabetes and chronic liver disease often coexist, but the influence of SGLT-2 inhibition on liver cirrhosis and hepatic encephalopathy remains unknown. This study investigated the effect of SGLT-2 inhibition on cirrhotic rats. Biliary cirrhosis was induced in Sprague-Dawley rats via common bile duct ligation. A total of two weeks of treatment with the SGLT-2 inhibitor, empagliflozin 30 mg/kg/d, was applied. The motor activities, hemodynamics, biochemistry parameters, plasma levels of vascular endothelial growth factor (VEGF), and the severity of portal-systemic collateral shunts were measured. The hepatic histopathology and protein expressions were examined. We found that empagliflozin treatment did not affect hemodynamics, liver biochemistry, or blood glucose levels in cirrhotic rats. Empagliflozin did not affect hepatic inflammation and fibrosis. The protein expression of factors related to liver injury were not influenced by empagliflozin. However, empagliflozin decreased motor activities in cirrhotic rats and increased portal-systemic collateral shunts and VEGF plasma levels. In summary, SGLT-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic inflammation in cirrhotic rats. In contrast, it exacerbated hepatic encephalopathy, which was evidenced by a decrease in motor activity. A possible mechanism could be an increase of portal-systemic shunts related to VEGF upregulation. Therefore, empagliflozin use should be cautious in cirrhotic patients regarding the development of hepatic encephalopathy. SIGNIFICANCE STATEMENT: Sodium-glucose cotransporter-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic inflammation in cirrhotic rats. In contrast, it exacerbated hepatic encephalopathy through increased portal-systemic shunts related to VEGF up-regulation.


Assuntos
Encefalopatia Hepática , Hipertensão Portal , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Ratos , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/complicações , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/metabolismo , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
7.
Clin Sci (Lond) ; 135(24): 2709-2728, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34870313

RESUMO

Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis-related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation (BDL) in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P=0.010, 0.044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated endothelial nitric-oxide synthase (eNOS) was down-regulated. Portosystemic shunts determined by splenorenal shunt (SRS) flow decreased in both transplantation groups (P=0.037, 0.032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared with sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.


Assuntos
Transplante de Microbiota Fecal , Hipertensão Portal/microbiologia , Cirrose Hepática/fisiopatologia , Circulação Esplâncnica , Animais , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Fezes/microbiologia , Microbioma Gastrointestinal , Hipertensão Portal/patologia , Ligadura , Masculino , Pressão na Veia Porta , Derivação Portossistêmica Cirúrgica , Ratos Sprague-Dawley
8.
J Cell Mol Med ; 25(21): 10073-10087, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34647412

RESUMO

Liver cirrhosis and portal hypertension are accompanied by hyperdynamic circulation, angiogenesis and portosystemic collaterals. Matrix metalloproteinases (MMPs) participate in fibrogenesis and angiogenesis, however, whether they can be targeted in cirrhosis treatment is unclear. Therefore, we performed three series of experiments to investigate this issue. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. Sham-operated rats served as controls. Rats were randomly allocated to receive vehicle, minocycline (a nonselective MMP inhibitor) or SB-3CT (MMP-2 and -9 inhibitor) for 28 days in the first and second series, respectively. MMP-9 knockout mice were used in the third series. The results showed that minocycline ameliorated portal hypertension, hemodynamic abnormalities, reduced collateral shunting, mesenteric vascular density, plasma VEGF level and alleviated liver fibrosis. SB-3CT attenuated portal hypertension, hemodynamic derangements, reduced shunting, mesenteric vascular density, mesenteric VEGF protein expression, and liver fibrosis. Knockout BDL mice had significantly alleviated portal hypertension, liver fibrosis, liver α-SMA and mesenteric eNOS protein expressions compared to wild-type BDL mice. Liver SMAD2 phosphorylation was down-regulated in all series with MMP inhibition or knock-out. In conclusion, MMP-9 inhibition or deletion ameliorated the severity of cirrhosis, portal hypertension, and associated derangements. MMP-9 may be targeted in the treatment of liver cirrhosis.


Assuntos
Deleção de Genes , Hipertensão Portal/etiologia , Hipertensão Portal/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imunofluorescência , Predisposição Genética para Doença , Hemodinâmica , Hipertensão Portal/diagnóstico , Imuno-Histoquímica , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Minociclina/farmacologia , Neovascularização Patológica , Ratos , Roedores , Circulação Esplâncnica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299285

RESUMO

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.


Assuntos
Circulação Colateral/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática Experimental/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Hipertensão Portal/etiologia , Masculino , Neovascularização Patológica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Circulação Esplâncnica/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Phys Rev E ; 101(2-1): 022103, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32168561

RESUMO

We show that the Olami-Feder-Christensen model exhibits an effective ergodicity breaking transition as the noise is varied. Above the critical noise, the system is effectively ergodic because the time-averaged stress on each site converges to the global spatial average. In contrast, below the critical noise, the stress on individual sites becomes trapped in different limit cycles, and the system is not ergodic. To characterize this transition, we use ideas from the study of dynamical systems and compute recurrence plots and the recurrence rate. The order parameter is identified as the recurrence rate averaged over all sites and exhibits a jump at the critical noise. We also use ideas from percolation theory and analyze the clusters of failed sites to find numerical evidence that the transition, when approached from above, can be characterized by exponents that are consistent with hyperscaling.

11.
Phys Rev E ; 101(2-1): 022102, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32168593

RESUMO

Prediction in complex systems at criticality is believed to be very difficult, if not impossible. Of particular interest is whether earthquakes, whose distribution follows a power-law (Gutenberg-Richter) distribution, are in principle unpredictable. We study the predictability of event sizes in the Olmai-Feder-Christensen model at different proximities to criticality using a convolutional neural network. The distribution of event sizes satisfies a power law with a cutoff for large events. We find that predictability decreases as criticality is approached and that prediction is possible only for large, nonscaling events. Our results suggest that earthquake faults that satisfy Gutenberg-Richter scaling are difficult to forecast.

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