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1.
J Chin Med Assoc ; 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39017659

RESUMO

BACKGROUND: Surgical resection (SR) is the main treatment for small bowel adenocarcinoma (SBA), but it increases metabolic demand, systemic inflammation, and digestive dysfunction, resulting in major impacts on the postoperative outcomes of patients. This study, we aimed to investigate the role of the postoperative prognostic nutritional index (PNI), a surrogate marker of inflammation and nutrition, in patients with SBA after resection. METHODS: From June 2014 to March 2022, 44 consecutive patients who underwent SR for SBA in Taipei Veterans General Hospital were retrospectively reviewed. Factors associated with survival including PNI were analyzed. RESULTS: PNI decreased in patients after SR for SBA (median change: -1.82), particularly in those who underwent Whipple operation or developed postoperative pancreatic fistula. Postoperative PNI < 45.2 best predicted overall survival (OS) (AUROC: 0.826, p = 0.001). Patients with lower postoperative PNI had significantly worse OS compared to those higher postoperative values (median OS: 19.3 months vs. not reached, p < 0.001). Low postoperative PNI (hazard ratio [HR]: 11.404, p = 0.002), tumoral lymphovascular invasion (HR: 8.023, p = 0.012), and adjuvant chemotherapy (HR: 0.055, p = 0.002) were independent risk factors for OS. Postoperative PNI also significantly predicted recurrence-free survival independent of lymphovascular invasion and adjuvant chemotherapy (HR: 6.705, p = 0.001). CONCLUSION: PNI commonly decreases in patients with SBA who undergo Whipple surgery or develop postoperative pancreatic fistula. Postoperative PNI independently predicts survival and may serve as a clinical marker to optimize patient outcomes.

2.
Eur J Clin Invest ; : e14287, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39017981

RESUMO

BACKGROUND: Portal hypertension leads to lethal complications in liver cirrhosis. Oxidative stress induced hepatic vascular dysfunction, which exaggerated vasoconstriction and increases hepatic vascular resistance (HVR). Gut dysbiosis further exacerbates portal hypertension. Fructooligosaccharides are prebiotics with potent antioxidant effect. This study aimed to evaluate the roles of fructooligosaccharides in portal hypertension-related vascular dysregulation and gut microbiome. METHODS: Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The rats then randomly received fructooligosaccharides or vehicle for 4 weeks. Experiments were performed on the 29th day after operations. RESULTS: Fructooligosaccharides did not affect portal pressure. Interestingly, fructooligosaccharides significantly attenuated HVR (p = .03). Malondialdehyde, an oxidative stress marker, reduced significantly in the liver in fructooligosaccharides-treated group. In addition, superoxide dismutase and trolox equivalent antioxidant capacity increased in the treatment group. On the other hand, vasodilatation-related protein expressions, GTPCH and phospho-eNOS, enhanced significantly. Fructooligosaccharides had no adverse vasodilatation effects on splanchnic vascular system or porto-systemic collateral systems. Locomotor function was not affected by fructooligosaccharides. Faecal microbiota analysis showed that Negativicutes, Selenomonadales and Lactobacillus salivarius reduced in the fructooligosaccharides-treated group. CONCLUSION: In conclusion, fructooligosaccharides attenuate hepatic vascular dysfunction in cirrhotic rats via at least partly, ameliorate of dysbiosis and oxidative stress.

3.
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.

4.
Sensors (Basel) ; 24(12)2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38931555

RESUMO

Well-being can reflect people's psychological conditions and be used alongside physiological parameters to evaluate patients' physical and mental health. The modern medical environment increasingly incorporates digital carriers, human-computer interaction devices, sensible spaces, and the execution of suitable algorithms. Slow design in healthy human-computer interaction is often used to reflect people's dependence on or support from behaviors or objects, promoting the stability of behaviors as well as meaningful and positive changes. Therefore, in this study, we propose a slow sensing model, develop a Slow Well-Being Gardening system, and use it to evaluate behavioral data from radiation therapy patients during treatment sessions and horticultural therapy. This study is based on SENS and slow design, setting the hospital lounge as a sensible space and establishing a sensor system. After a 10-day inspection, the process was evaluated and verified. Ultimately, data from facial detection (smile) and HRV showed that the patients in the experimental group experienced a significant improvement in their well-being, feeling better than those in the control group who maintained the most common state in normal treatment. Therefore, it can be inferred that the Slow Well-Being Gardening model is indeed valid and can be further developed.


Assuntos
Jardinagem , Horticultura Terapêutica , Humanos , Jardinagem/métodos , Feminino , Masculino , Algoritmos , Pessoa de Meia-Idade , Sorriso , Frequência Cardíaca/fisiologia , Radioterapia
5.
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
6.
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
7.
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
9.
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
10.
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
11.
Int J Mol Sci ; 23(13)2022 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-35806383

RESUMO

Hyperlipidemia and oxidative stress with elevated oxidized low-density lipoprotein (ox-LDL) exacerbate hepatic inflammation and fibrosis. The plasma level of low-density lipoprotein (LDL) is controlled by proprotein convertase subtilisin/kexin 9 (PCSK9). Alirocumab is a monoclonal antibody that decreases LDL via inhibiting PCSK9 function. Apart from lipid-lowering effects, alirocumab exerts anti-inflammation, anti-angiogenesis and anti-oxidant effects. This study aims to investigate the impact of alirocumab treatment on common bile duct ligation (BDL)-induced biliary cirrhotic rats. After a 4-week treatment of alirocumab, the hemodynamic data, blood biochemistry, ox-LDL level, oxidative stress markers, severity of hepatic encephalopathy and abnormal angiogenesis of BDL rats were measured and compared to the control group. BDL rats presented cirrhotic pictures and elevated ammonia, total cholesterol, LDL and ox-LDL levels compared to the control group. Alirocumab decreased plasma levels of total cholesterol, LDL, and oxidative stress markers; however, it did not affect the hemodynamics, liver and renal biochemistry, and the plasma levels of ammonia and ox-LDL. The motor activities, portal-systemic collaterals and mesenteric vascular density were not significantly different between alirocumab-treated and control groups. In addition, it did not affect hepatic inflammation, intrahepatic angiogenesis, liver fibrosis and free cholesterol accumulation in the liver of BDL rats. In conclusion, PCSK9 inhibition by alirocumab treatment ameliorates hyperlipidemia and systemic oxidative stress in biliary cirrhotic rats. However, it does not affect the plasma level of ox-LDL, intrahepatic inflammation and fibrosis. In addition, PCSK9 inhibition has a neutral effect on abnormal angiogenesis and hepatic encephalopathy in biliary cirrhotic rats.


Assuntos
Encefalopatia Hepática , Hiperlipidemias , Amônia , Animais , Anticorpos Monoclonais Humanizados , LDL-Colesterol , Fibrose , Cirrose Hepática , Pró-Proteína Convertase 9 , Ratos
12.
J Chin Med Assoc ; 85(4): 414-420, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35120355

RESUMO

BACKGROUND: Liver cirrhosis is characterized by liver fibrosis and pathological angiogenesis, which results in hyperdynamic circulation, portal-systemic collateral vascular formation, and abnormal angiogenesis. Lycopene is a nutrient mostly found in tomatoes. The beneficial effects of lycopene include anti-inflammation, anti-oxidation, anti-fibrosis, and anti-angiogenesis; however, the association between liver cirrhosis and pathological angiogenesis has yet to be studied. This study aimed to investigate the effects of lycopene on biliary cirrhotic rats. METHODS: The efficacy of lycopene treatment in common bile duct ligation (BDL)-induced biliary cirrhotic rats was evaluated. Sham-operated rats served as surgical controls. Lycopene (20 mg/kg/day, oral gavage) or vehicle was administered to BDL or sham-operated rats for 4 weeks, after which the hemodynamics, liver biochemistry, portal-systemic shunting, liver and mesenteric angiogenesis, and hepatic angiogenesis-related protein expressions were examined. RESULTS: Lycopene alleviated hyperdynamic circulation as evidenced by decreased cardiac index and increased peripheral vascular resistance (p < 0.05), but it did not affect portal pressure or liver biochemistry in the BDL rats (p > 0.05). Lycopene significantly diminished the shunting degree of portal-systemic collaterals (p = 0.04) and mesenteric vascular density (p = 0.01), and also ameliorated intrahepatic angiogenesis and liver fibrosis. In addition, lycopene upregulated endothelial nitric oxide synthase, protein kinase B (Akt) and phosphatidylinositol 3-kinases (PI3K), and downregulated vascular endothelial growth factor receptor 2 (VEGFR-2) protein expressions (p < 0.05) in the livers of the BDL rats. CONCLUSION: Lycopene ameliorated liver fibrosis, hyperdynamic circulation, and pathological angiogenesis in biliary cirrhotic rats, possibly through the modulation of intrahepatic Akt/PI3K/eNOS and VEGFR-2 pathways.


Assuntos
Cirrose Hepática , Licopeno , Animais , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Licopeno/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Ratos , Ratos Sprague-Dawley
13.
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
14.
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
15.
J Chin Med Assoc ; 84(12): 1092-1099, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34670224

RESUMO

BACKGROUND: Portal hypertension is a pathophysiological abnormality with distinct vascular derangements associated with liver cirrhosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents which exert pleiotropic vascular effects, but their relevant impact on portal hypertension and liver cirrhosis remains unclear. This study aims to clarify this issue. METHODS: Rats receiving partial portal vein ligation (PVL) and common bile duct ligation (BDL) served as experimental models for portal hypertension and cirrhosis, respectively. After linagliptin (a DPP-4 inhibitor) treatment, the survival rate, hemodynamics, biochemistry parameters and liver histopathology were evaluated. In addition, the collateral vascular responsiveness and severity of portal-systemic shunting were examined. mRNA and protein expression in the vasculature and liver were also examined. RESULTS: Linagliptin significantly reduced portal pressure (control vs linagliptin: 12.9 ± 1.2 vs 9.1 ± 2.0 mmHg, p = 0.001) and upregulated nitric oxide synthase expression in the collateral vessel, superior mesentery artery, and liver of PVL rats. However, the portal hypotensive effect was insignificant in BDL rats. Glucose plasma levels, liver and renal biochemistry parameters were not significantly altered by linagliptin. The degree of portal-systemic shunting and collateral vascular responsiveness were also not significantly altered by linagliptin treatment. Linagliptin did not improve liver fibrosis and hepatic inflammation in BDL rats. CONCLUSION: DPP-4 inhibition by linagliptin reduced portal pressure in portal hypertensive rats but not in cirrhotic rats. It may act by decreasing intrahepatic resistance via upregulation of hepatic nitric oxide synthase in portal hypertensive rats.


Assuntos
Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/complicações , Cirrose Hepática/etiologia , Animais , Cirrose Hepática/fisiopatologia , RNA Mensageiro/genética , Ratos
16.
J Chin Med Assoc ; 84(8): 778-782, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34225335

RESUMO

BACKGROUND: Medical students in Taiwan start their clerkship in their fifth year. A lack of early clinical exposure can mean they have a lack of medical professionalism and collaborative practice. This study investigates whether early engagement in hospital-based clinical practice could improve their understanding of these requirements. METHODS: From 2017 to 2019, a total of 59 medical students at the end of their third year joined a 2-week summer camp at the hospital. Every participant was assigned to work with one patient and they accompanied this patient throughout their hospital course. The students were also asked to interview other medical professionals within the hospital and to write up interview reports. In addition, they had to complete pre- and postcamp questionnaires which included 10 questions to evaluate their recognition of professionalism, doctor-patient relationships, and interprofessional collaboration. Answers to the questions were all rated using a 5-score Likert scale. RESULTS: The total postcamp Likert scores were significantly increased after the 2-week training camp compared with the precourse scores (pre- vs postcourse: 44.08 ± 0.45 vs 46.66 ± 0.33, p < 0.001). In addition, the students' recognition of medical professionalism, the importance of communication with patients, and their respect for other medical professionals were significantly improved after the 2-week training. CONCLUSION: Our data showed that early clinical exposure through a preclerkship summer camp can help medical students improve their recognition of medical professionalism and interprofessional collaboration.


Assuntos
Estágio Clínico , Relações Interprofissionais , Profissionalismo , Estudantes de Medicina , Humanos , Relações Médico-Paciente , Inquéritos e Questionários , Taiwan
17.
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
18.
J Chin Med Assoc ; 84(2): 183-190, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32925298

RESUMO

BACKGROUND: This study aimed to evaluate whether the role-play (RP) of real patients by medical students as part of interactive clinical reasoning training can improve medical students' clinical performance. METHODS: A total of 26 medical students volunteered to portray real patients within this program and were treated as the RP group while the other 72 students as the non-RP group. In the interactive morning meeting, the medical students practiced how to approach the RP student as if they were encountering a real patient. All students were evaluated by mini-clinical evaluation exercises (mini-CEX) before and after this training program. RESULTS: We found that all students had an increased total mini-CEX score after 4-week training, especially for interviewing skills. Notably, after training, the RP students had significantly elevated total mini-CEX scores (51.23 ± 1.06 vs 53.12 ± 1.11, p = 0.028), and for counselling (7.15 ± 0.14 vs 7.54 ± 0.18, p = 0.015) and overall clinical competence (7.27 ± 0.15 vs 7.65 ± 0.16, p = 0.030). In contrast, the non-RP students had lower scores compared with the RP group, as revealed by both the pre- and post-training tests. Moreover, their mini-CEX scores were not improved after training. CONCLUSION: Medical students who were motivated to RP real patients had better performance scores than those who did not. In addition, RP can enhance their counselling skills and clinical competences.


Assuntos
Competência Clínica/normas , Simulação de Paciente , Desempenho de Papéis , Estudantes de Medicina , Feminino , Humanos , Masculino , Avaliação de Programas e Projetos de Saúde , Melhoria de Qualidade
19.
BMC Med Educ ; 20(1): 155, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414406

RESUMO

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) core competencies (CC) in general medicine-based primary care are essential for junior medical trainees. In this country, a regular faculty development (FD) program aimed at training faculty in instructing (teaching and assessing) these CC had operated. However, leadership was not emphasized. In a new intervention module, the roles and associated responsibilities of clinical instructors to conduct, design, and lead CC-based education were emphasis. AIMS: This follow-up explanatory case study compares the effectiveness of intervention module with that of the previous regular module. METHODS: The regular group (n = 28) comprised clinical instructors who participated in the FD module during the 2013-2014 year while the intervention group (n = 28) was composed of 2015-2016 participants. Prior to the formal (hands-on) training, participants in the intervention group were asked to study the online materials of the regular module. These participants then received a 30-h hands-on training in conducting, designing, and leading skills. Finally, they prepared a 10-h reflective end-of-module presentation of their real-world practices. RESULTS: Following the training, a higher degree improvement in participants self-reported familiarity with CC education, self-confidence in their ability to deliver CC education and sustained involve CC education were noted among the intervention FD group, compared with the regular FD group. In the intervention group, senior academicians (associate and full professor) are more substantially involved in designing and leading CC-based courses than junior academicians (lecturers and assistant professors). Among non-teaching award winners of in the intervention FD group, the follow-up degree of sustained involvement in delivering, designing and leading CC-based courses was significantly higher than that of the regular group. CONCLUSIONS: Our study demonstrated that leadership training in the intervention FD modules substantially motivated clinical instructors to become leaders in CC education.


Assuntos
Competência Clínica , Educação Médica , Docentes de Medicina/educação , Liderança , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taiwan
20.
Pharmaceutics ; 12(5)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32354071

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is linked with metabolic syndrome. Previous studies showed that obesity may disrupt adrenal function and adversely affect its counter-regulations against shock. This study hence evaluated adrenal function abnormalities in NAFLD with shock. METHODS: Sprague-Dawley rats were fed with regular chow-diet (control) or high fat diet (HFD, 60% energy derived from fat). Blood tests were performed at the end of the 4th, 6th and 8th week, respectively. Experiments were performed at the end of the 8th week. RESULTS: HFD rats developed NAFLD. HFD rats had 27% and 51% increase in plasma corticosterone at the 6th and 8th week in usual status. However, HFD rats had 5 times more reduction of mean arterial pressure in response to lipopolysaccharide-induced sepsis as compared to control rats. The corticosterone increment ratio was also lower in HFD rats, even after ACTH administration. 11ß-HSD system tended to generate more corticosterone in HFD rats under hemodynamic stable status without shock and the trend was lost in HFD rats with septic shock. CONCLUSION: Rats with NAFLD had profound septic shock due to inadequate corticosterone response. This is, at least partly, due to 11ß-HSDs dysregulation in sepsis.

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