Estrogen/Progesterone Receptor Expression and Cancer Antigen 125 Level as Preoperative Predictors to Estimate Lymph Node Metastasis in Endometrioid Endometrial Cancer.

Loss of estrogen receptor/progesterone receptor (ER/PR) in endometrial cancer (EC) is associated with tumor progression and poor outcomes. Elevated pretreatment cancer antigen 125 (CA 125) level is a risk factor for lymph node metastasis (LNM). We evaluated whether the combination of ER/PR expression and CA 125 level could be used as a biomarker to predict LNM. We retrospectively investigated patients with endometrioid EC who underwent complete staging surgery during January 2015 to December 2020. We analyzed ER/PR status using immunohistochemical staining, and quantified its expression using the sum of both ER/PR H-scores. Receiver operating characteristic curves were used to identify optimal cutoff values of H-score and CA 125 levels for predicting LNM. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. In 396 patients, the optimal cutoff values of the ER/PR H-score and CA 125 were 407 (area under the receiver operating characteristic curve: 0.645, P=0.001) and 40 U/mL (area under the receiver operating characteristic curve: 0.762, P<0.001), respectively. Multivariate analysis showed that CA 125 ≥40 UmL (odds ratio: 10.02; 95% CI: 4.74-21.18) and ER/PR H-score <407 (odds ratio: 4.20; 95% CI: 1.55-11.32) were independent predictors. An LNM predictive nomogram was constructed using these 2 variables and our model yielded a negative predictive value and negative likelihood ratio of 98.3% and 0.14, respectively. ER/PR expression with pretreatment CA 125 levels can help estimate LNM risk and aid in decision-making regarding the need for lymphadenectomy in patients with endometrioid EC.

Pretreatment carcinoembryonic antigen combined with cancer antigen-125 for predicting lymph node metastasis in endometrial carcinoma: a retrospective cohort study.

PURPOSE: To investigate whether the cost-effective, pretreatment tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) can be used to predict lymph node metastasis (LNM) in endometrioid-type endometrial cancer (EC) and to develop a predictive model. METHODS: This was a single-center retrospective study of patients with endometrioid-type EC who underwent complete staging surgery between January 2015 and June 2022. We identified the optimal cut-off values of CEA and CA-125 for predicting LNM using receiver operating characteristic (ROC) curves. Stepwise multivariate logistic regression analysis was used to identify independent predictors. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. RESULTS: The optimal cut-off values of CEA and CA-125 were 1.4 ng/mL (area under the ROC curve (AUC) 0.62) and 40 U/mL (AUC 0.75), respectively. Multivariate analysis showed that CEA (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.01-3.74) and CA-125 (OR 8.75; 95% CI 4.42-17.31) were independent predictors of LNM. Our nomogram showed adequate discrimination with a concordance index of 0.78. Calibration curves for the probability of LNM showed optimal agreement between the predicted and actual probabilities. The risk of LNM for markers below the cut-offs was 3.6%. The negative predictive value and negative likelihood ratio were 96.6% and 0.26, respectively, with moderate ability to rule out the possibility of LNM. CONCLUSION: We report a cost-effective method of using pretreatment CEA and CA-125 levels to identify patients with endometrioid-type EC who are at a low risk for LNM, which may guide decision-making regarding aborting lymphadenectomy.

Characteristics of Cancer-Related Fatigue and an Efficient Model to Identify Patients with Gynecological Cancer Seeking Fatigue-Related Management.

Cancer-related fatigue (CRF) is the most common somatic discomfort in patients with gynecological cancers. CRF is often overlooked; however, it can impair the patients' quality of life considerably. This cross-sectional study aimed to identify the clinical characteristics of CRF in gynecological cancer patients. Questionnaires and the International Classification of Diseases 10th Revision (ICD-10) criteria were used to identify CRF. The enrolled patients were further categorized according to the amount of fatigue-related management received. Of the enrolled 190 patients, 40.0% had endometrial cancer, 28.9% had cervical cancer, and 31.1% had ovarian cancer. On the basis of the ICD-10 diagnostic criteria, 42.6% had non-cancer-related fatigue, 10% had CRF, and 51% had BFI-T questionnaire-based fatigue. Moreover, 77.9% of the study cohort had ever received fatigue-related management. Further analysis showed that patients with endometrial/cervical cancer, International Federation of Gynecology and Obstetrics stage >1, Eastern Cooperative Oncology Group performance status score ≥1, inadequate cancer treatment response, and receiving cancer treatment in the past week had a higher probability of receiving more fatigue-related management. The five-item predictive model developed from these factors may help physicians recognize patients seeking more fatigue-related management more efficiently. This is important as they may suffer from a more profound CRF.

Human BMP8A suppresses luteinization of rat granulosa cells via the SMAD1/5/8 pathway.

Bone morphogenetic proteins (BMPs) are known to play an indispensable role in preventing the precocious luteinization of granulosa cells within growing ovarian follicles. In this study, we found that the transcripts of BMP8 genes are enriched in the ovaries of humans and rodents. When analyzing transcriptomic datasets obtained from human mature granulosa cells, we further found that the BMP8 transcripts not only show the highest abundance among the searchable BMP-related ligands but also decrease significantly in women of advanced age or women with polycystic ovarian syndrome. The correlation between the BMP8 levels in granulosa cells and the decline in ovarian function in these subjects suggests that BMP8 protein may be involved in the regulation of granulosa cell function(s). Using a rat model, we demonstrated that human BMP8A protein activates the SMAD1/5/8 and the SMAD2/3 pathways simultaneously in both immature and mature granulosa cells. Furthermore, the expression of potential type I and type II receptors used by BMP8 in rat granulosa cells was characterized. We found that BMP8A treatment can significantly inhibit gonadotropin-induced progesterone production and steroidogenesis-related gene expression in granulosa cells. Pathway dissection using receptor inhibitors further revealed that such inhibitory effects occur specifically through the BMP8-activated SMAD1/5/8, but not SMAD2/3, pathway. Taken together, considering its abundance and possible functions in granulosa cells, we suggest that BMP8 may act as a novel luteinization inhibitor in growing follicles.

Hemoglobin A1C Levels are Independently Associated with the Risk of Coronary Atherosclerotic Plaques in Patients without Diabetes: A Cross-Sectional Study.

AIM: Coronary atherosclerotic plaques can be detected in asymptomatic subjects and are related to low-density lipoprotein cholesterol (LDL) levels in patients with coronary artery disease. However, researchers have not yet determined the associations between various plaque characteristics and other lipid parameters, such as HDL-C and TG levels, in low-risk populations. METHODS: One thousand sixty-four non-diabetic subjects (age, 57.86±9.73 years; 752 males) who underwent coronary computed tomography angiography (CCTA) were enrolled and the severity and patterns of atherosclerotic plaques were analyzed. RESULTS: Statin use was reported by 25% of the study population, and subjects with greater coronary plaque involvement (segment involvement score, SIS) were older and had a higher body mass index (BMI), blood pressure, unfavorable lipid profiles and comorbidities. After adjusting for comorbidities, only age (ß=0.085, p＜0.001), the male gender (ß=1.384, p＜0.001), BMI (ß=0.055, p=0.019) and HbA1C levels (ß=0.894, p＜0.001) were independent factors predicting the greater coronary plaque involvement in non-diabetic subjects. In the analysis of significantly different (＞50%) stenosis plaque patterns, age (OR: 1.082, 95% CI: 10.47-1.118) and a former smoking status (OR: 2.061, 95% CI: 1.013-4.193) were independently associated with calcified plaques. For partial calcified (mixed type) plaques, only age (OR: 1.085, 95% CI: 1.052-1.119), the male gender (OR: 7.082, 95% CI: 2.638-19.018), HbA1C levels (OR: 2.074, 95% CI: 1.036-4.151), and current smoking status (OR: 1.848, 95% CI: 1.089-3.138) were independently associated with the risk of the presence of significant stenosis in mixed plaques. CONCLUSIONS: A higher HbA1c levels is independently associated with the presence and severity of coronary artery atherosclerosis in non-diabetic subjects, even when LDL-C levels are tightly controlled.

InVestiGation of the Association of Physical Activity and Sedentary Behavior with tHe Occurrence of Future Cardiovascular Disease and Long Term Outcome in General Population Using the HEALTHCARE Database (VGH-HEALTHCARE).

BACKGROUND: Current evidence supports the beneficial effect of physical activity in reducing adverse events, however studies on Asian populations are limited and have reported inconsistent findings. The aim of this study was to investigate the association between physical activity and the development of cardiovascular disease, diabetes, hypertension and malignancy in a large Asian cohort. We also investigated interactions between the intensity of physical activity, environmental exposure and biochemical markers. METHODS: Subjects who received annual checkups at Taipei Veterans General Hospital were invited to join this study. Information on physical activity was evaluated using the International Physical Activity Questionnaire Short Form (IPAQ-SF). Associations between the occurrence of clinical events including cardiovascular events, diabetes and malignancies and the intensity of physical activity, biochemical markers, imaging findings, personality trait evaluations and nutrition were evaluated. RESULTS: In the initial stage of this study, a total of 1010 patients enrolled, 626 (62%) were male, 74 (7.4%) had diabetes, 183 (18.3%) had hypertension, and 220 (21.8%) were smokers. The total cholesterol was 202.1 ± 36.2 mg/dL and low-density lipoprotein-cholesterol was 125.7 ± 32.9 mg/dL, including 49.3 ± 13.1 mg/dL for serum high-density lipoprotein-cholesterol and 120.7 ± 70.7 mg/dL for triglycerides. The fasting glucose level was 93.8 ± 21.9 mg/dL, and HbA1c was 5.7 ± 0.7%. All information collected will be incorporated with future events to analyze the relationship between biochemical parameters, physical activity and future adverse events. CONCLUSIONS: These findings will contribute to the understanding of the value of physical activity in determining future cardiovascular and non-cardiovascular events in Asian populations.

In vivo selection reveals autophagy promotes adaptation of metastatic ovarian cancer cells to abdominal microenvironment.

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV-3. Microarray and gene profiling analyses indicated that autophagy-related genes were enriched in selected malignant sublines. Detection of LC3-II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high-density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy-related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti-autophagy cancer drugs.

Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.

AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. METHODS: Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. RESULTS: Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. CONCLUSION: The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.

Hypertension is an important predictor of recurrent colorectal adenoma after screening colonoscopy with adenoma polypectomy.

BACKGROUND: The predictors of recurrent colorectal adenoma have not been fully examined. This study aimed to evaluate the predictors of recurrent colorectal adenoma after initial screening colonoscopy with adenoma polypectomy. METHODS: A retrospective cohort study was conducted at the Taipei Veterans General Hospital from 2003 to 2011. After screening, 356 patients who had undergone two consecutive colonoscopies with colorectal adenoma polypectomy at the initial colonoscopy were enrolled. The recurrence group was patients with recurrent colorectal adenoma at the second colonoscopy, whereas the nonrecurrence group was patients without recurrence. Anthropometric data, biochemical tests, metabolic comorbidities, and adenoma characteristics at initial colonoscopy were compared between the two groups. Cox proportional hazard regression analysis was conducted to identify the predictors of recurrent colorectal adenoma. RESULTS: During a mean follow-up interval of 3.07 ± 1.42 years, 94 patients (26.4%) were in the recurrence group, 262 patients (73.6%) were in the nonrecurrence group. The recurrence group was older, had a wider waist circumference, higher levels of serum alanine aminotransferase (ALT) and triglyceride, a higher prevalence of smoking, nonalcoholic fatty liver disease, metabolic syndrome, and hypertension, and a higher occurrence of initial multiply-located adenomas when compared with the nonrecurrence group (p < 0.05). Cox regression analysis showed that hypertension, smoking, higher ALT level (>40 IU/mL), and multiply-located adenomas were independent predictors for recurrent colorectal adenoma. The risk of recurrent adenoma increased when hypertension was combined with smoking, high ALT level, or multiply-located adenomas. CONCLUSION: Hypertension is an important predictor for recurrent colorectal adenoma after screening colonoscopy with polypectomy.

Long-term cannabinoid type 2 receptor agonist therapy decreases bacterial translocation in rats with cirrhosis and ascites.

BACKGROUND & AIMS: Intestinal hyperpermeability, impaired peritoneal macrophages (PMs) phagocytosis, and bacterial translocation (BT), resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP) together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of the cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokine release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats. METHODS: Vehicle, archidonyl-2-chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA) and common bile duct ligation (BDL) cirrhotic rats with ascites for two weeks and various measurement were performed. RESULTS: Compared to sham rats, CB2Rs were downregulated in cirrhotic rat intestines and PMs. The two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFα and inflammatory mediators, infection, intestinal mucosal damage and hyperpermeability; the JWH133 treatment also decreased bacterial overgrowth/adhesion, BT and SBP, upregulated intestinal tight junctions and downregulated the PM TNFα receptor/NFκBp65 protein expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFα-induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment. CONCLUSIONS: Our study suggests that CB2R agonists have the potential to treat BT and various relevant abnormalities through inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα release in cirrhosis. Overall, the chronic CB2R agonist treatment affects multiple approach mechanisms, and its direct effect on the hyperdynamic circulation is only minor.

Benzodiazepine-associated hepatic encephalopathy significantly increased healthcare utilization and medical costs of Chinese cirrhotic patients: 7-year experience.

BACKGROUND AND OBJECTIVES: In cirrhosis, hypersensitivity to benzodiazepines (BZD) and precipitating hepatic encephalopathy (HE) have been reported. The aim of this study was to evaluate the safety, economic impact and modifiable factors that are associated with the excess risk of BZD-associated HE in cirrhotic patients. METHODS: Between July 2005 and March 2012, 1,612 Chinese cirrhotic patients with and without using long-t 1/2-BZD or short-t 1/2-BZD were enrolled and followed up for 6 months. RESULTS: Among BZD users, the per-person HE-related healthcare utilization and medical costs were found to have progressively increased from 2005 to 2012. Cirrhotic BZD users had a higher percentage of smoking, alcohol drinking, simultaneous consumption of non-BZD drugs, and had a higher incidence of non-cirrhotic chronic illness than non-BZD users. Multivariate analysis indicated that hypoalbuminemia (<3 g/dL), long-acting (t 1/2 > 12-h), high-dosage (>1.5 defined daily dose equivalents) and long-duration (>2-months) BZD use, carrier of variant genotypes (AG + GG) of GABRA 1 (rs2290732) and having the wild genotype (TT) of GABRG 2 (rs211037) were significant predictors of the development of BZD-associated HE in cirrhotic patients. Additionally, synergistic effects of the above significant predictors on BZD-associated HE risk could be identified. CONCLUSIONS: Our study confirms the clinical and economic impact of BZD-associated HE in cirrhotic BZD-users. Accordingly, extra caution is needed when treating cirrhotic BZD users with the above risk factors in order to avoid the BZD-associated HE in cirrhotic patients.

The diminished expression of proangiogenic growth factors and their receptors in gastric ulcers of cirrhotic patients.

OBJECTIVES: The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms. METHODS: Eligible cirrhotic patients (n = 55) and non-cirrhotic patients (n = 55) who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF]) and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2) were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other. RESULTS: The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (p<0.05). The cirrhotic patients had diminished mRNA expressions of PDGFB, VEGFR2, FGFR1, and FGFR2 in gastric ulcer margin when compared with those of the non-cirrhotic patients (p<0.05). Diminished expressions of PDGFB and VEGFR2, FGFR1, and FGFR2 were well correlated with the degree of thrombocytopenia in these cirrhotic patients (ρ>0.5, p<0.001). CONCLUSIONS: Our findings implied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.

Multiple effects of Honokiol on the life cycle of hepatitis C virus.

BACKGROUND: Honokiol, a small active molecular compound extracted from magnolia, has recently been shown to inhibit hepatitis C virus (HCV) infection in vitro. AIMS: This study further characterized aspects of the HCV lifecycle affected by the antiviral functions of honokiol. METHODS: The influence of honokiol on HCV infection, entry, translation and replication was assessed in Huh-7.5.1 cells using cell culture-derived HCV (HCVcc), HCV pseudo-type (HCVpp) and sub-genomic replicons. RESULTS: Honokiol had strong antiviral effect against HCVcc infection at non-toxic concentrations. Combined with interferon-α, its inhibitory effect on HCVcc was more profound than that of ribavirin. Honokiol inhibited the cell entry of lentiviral particles pseudo-typed with glycoproteins from HCV genotypes 1a, 1b, and 2a, but not of the vesicular stomatitis virus. It had inefficient activity on HCV internal ribosome entry site (IRES)-translation at concentrations with significant anti-HCVcc effects. The expression levels of components of replication complex, NS3, NS5A and NS5B, were down-regulated by honokiol in a dose-dependent manner. It also inhibited HCV replication dose dependently in both genotypes 1b and 2a sub-genomic replicons. CONCLUSIONS: Honokiol inhibits HCV infection by targeting cell entry and replication and, only at a concentration >30 µM, IRES-mediated translation of HCV life cycle. Based on its high therapeutic index (LD(50) /EC(90)  = 5.4), honokiol may be a promising drug for the treatment of HCV infection.

Gastropericardial fistula and Candida albicans pericarditis: a rare complication of gastric adenocarcinoma treated with radiation and chemotherapy.

Gastropericardial fistula is generally associated with benign gastric diseases and is an uncommon complication of gastric adenocarcinoma. Pericarditis and cardiac tamponade are the ultimate outcome, with extremely high mortality rates. We report a 47-year-old man with gastric adenocarcinoma who had completed radiotherapy and was on scheduled chemotherapy, who presented with fever and chest pain. Gastric adenocarcinoma complicated with gastropericardial fistula and Candida albicans pericarditis were diagnosed and treated successfully with conservative management. Initial chest radiography and computed tomography (CT) revealed no evident pericardial air or fluid. However, follow-up panendoscopy 2 weeks later revealed a malignant ulcer with a fistula opening over the lesser curvature of the high body of the stomach. Subsequent chest radiography and CT revealed pneumopericardium with fluid accumulation. Emergent CT-guided pericardial drainage was performed. The fluid was positive for Candida albicans. Total parenteral nutrition and antifungal therapy were administered. The patient refused surgical intervention and survived with medical management alone. This case demonstrates that first, panendoscopy may be safely performed in patients with gastropericardial fistula without significant risk of cardiac tamponade; second, although early diagnosis of gastropericardial fistula is generally important, delayed recognition may not lead to devastating outcomes even in the absence of surgical intervention.

Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis.

BACKGROUND/AIMS: Increased intrahepatic resistance (IHR) in cirrhosis is due to fibrosis and hepatic endothelial dysfunction (HED). Besides producing fibrosis, increased reactive oxygen species (ROS) promotes ROS-related nitration of anti-oxidative enzymes in cirrhotic livers. Tyrosine nitration (nitrotyrosilation)-related inactivation of anti-oxidative enzymes is increased in cirrhotic livers. This study investigates effects of N-acetylcysteine (NAC) administrations in bile-duct-ligation (BDL) rats. METHODS: This study measured portal venous pressure (PVP), IHR, hepatic endothelial function, hepatic levels of anti-oxidants and oxidants, type III procollagen (PIIIP), proteins expression of thromboxane synthase (TXS), nitrotyrosine, manganese superoxide dismutase (MnSOD), and hepatic NOx and thromboxane A(2) (TXA(2)) production in perfusates. RESULTS: The improvement of HED was associated with decreased PVP and IHR, hepatic protein and mRNA levels of PIIIP, protein expression of TXS and nitrotyrosine, oxidants and production of TXA(2) in NAC-treated BDL rat livers. Conversely, hepatic NOx production, anti-oxidants, and protein expression of MnSOD were increased in NAC-treated BDL rat livers. CONCLUSIONS: In NAC-treated cirrhotic rats, the decrease in IHR was mainly caused by its anti-oxidative effect-related prevention of hepatic fibrogenesis associated with the decrease of oxidants-related nitrotyrosilation and improvement of HED.

Role of Ca2+-dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis.

BACKGROUND/AIM: Anandamide can activate potassium (K(+)) channels to induce an endothelium-dependent vasorelaxation in normal rat mesenteric arteries. Cannabinoids contribute partly to the splanchnic vasodilation in cirrhosis. This study investigated the roles of vascular K(+) channels in anandamide-induced mesenteric vasorelaxation in isolated rat cirrhotic vessels. METHODS: The effects of the pretreatment of AM251, a specific CB(1) receptor antagonist, were assessed on the vascular reactivity to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh) and sodium nitroprusside (SNP). Additionally, cannabinoid (CB(1) and CB(2)) receptors' protein expression and the effects of different K(+) channel blockers on vascular reactivity to anandamide were also studied. RESULTS: Cirrhotic mesenteric arteries showed an overexpression of CB(1) receptor associated with hyporeactivity to PE and KCl, and hyper-response to ACh, SNP and anandamide. Pretreatment with AM251 significantly improved the hyporeactivity to KCl and ameliorated the hyper-response to ACh in cirrhotic vessels. Increased relaxation response to anandamide was suppressed by combinations of vascular Ca(2+)-dependent K(+) channel blockers (including apamin+charybdotoxin+iberiotoxin or apamin+TRAM-34+iberiotoxin) (TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole). CONCLUSIONS: In cirrhotic mesenteric arteries, vascular CB(1) receptor and anandamide contribute to the in vitro hyporeactivity to KCl. In addition, hyper-response to ACh may probably act through the modulation of vascular Ca(2+)-dependent K(+) channels.

Effect of chronic CB1 cannabinoid receptor antagonism on livers of rats with biliary cirrhosis.

Recent studies have shown that the activated endocannabinoid system participates in the increase in IHR (intrahepatic resistance) in cirrhosis. The increased hepatic production of vasoconstrictive eicosanoids is involved in the effect of endocannabinoids on the hepatic microcirculation in cirrhosis; however, the mechanisms of these effects are still unknown. The aim of the present study was to investigate the effects of chronic CB(1) (cannabinoid 1) receptor blockade in the hepatic microcirculation of CBL (common bile-duct-ligated) cirrhotic rats. After 1 week of treatment with AM251, a specific CB(1) receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB(2) (thromboxane B(2)), 6-keto PGF(1alpha) (prostaglandin F(1alpha)) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB(1) receptor, TGF-beta(1) (transforming growth factor beta(1)), cPLA(2) [cytosolic PLA(2) (phospholipase A(2))], sPLA(2) (secreted PLA(2)) and collagen deposition were also measured. In AM251-treated cirrhotic rats, a decrease in portal venous pressure was associated with the decrease in IHR and SMA blood flow. Additionally, the protein levels of hepatic CB(1) receptor, TGF-beta(1), cPLA(2) and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB(2) and Cys-LTs in perfusates, were significantly decreased after 1 week of AM251 treatment in cirrhotic rats. Furthermore, acute infusion of AM251 resulted in a decrease in SMA blood flow and an increase in SMA resistance in CBL rats. In conclusion, the chronic effects of AM251 treatment on the intrahepatic microcirculation were, at least partly, mediated by the inhibition of hepatic TGF-beta(1) activity, which was associated with decreased hepatic collagen deposition and the activated PLA(2)/eicosanoid cascade in cirrhotic livers.

Hemodynamic effects of one week of carvedilol administration on cirrhotic rats.

BACKGROUND: Carvedilol is a nonselective beta-blocker with alpha(1)-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. The current study was undertaken to evaluate the possible mechanism of carvedilol on hemodynamics in cirrhotic rats with portal hypertension produced by common bile duct ligation. METHODS: Male Sprague-Dawley rats received either a sham operation or common bile duct ligation. Three weeks after surgery, both sham-operated and cirrhotic rats were randomly assigned to receive vehicle or carvedilol 5 mg.kg(-1).12 h(-1) by gastric gavage for 1 week. Hemodynamic measurements, serum biochemistry, serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, and aortic mRNA expression of eNOS and COX-1 were performed on the eighth day after drug administration. RESULTS: Carvedilol treatment did not affect serum biochemistry in either sham-operated or cirrhotic rats. In sham-operated rats, administration of carvedilol significantly decreased the heart rate without affecting other hemodynamic values. In contrast, in cirrhotic rats, administration of carvedilol significantly decreased the cardiac index, portal pressure, heart rate, and portal territory blood flow, and it significantly increased systemic and portal territory vascular resistances. The hepatocollateral resistance was significantly decreased, but the hepatic arterial blood showed no significant changes. In sham-operated rats treated with carvedilol, serum nitrate/nitrite and 6-keto-PGF(1alpha) levels were not affected. In contrast, cirrhotic rats receiving carvedilol showed a significant decrease in serum nitrate/nitrite and 6-keto-PGF(1alpha) levels, associated with a decrease in aortic mRNA expression of eNOS and COX-1 compared with those receiving vehicle. CONCLUSIONS: Carvedilol decreased portal pressure through a reduction of splanchnic blood flow associated with a decrease in hepatocollateral resistance. Additionally, administration of carvedilol decreased endothelial-related vasodilatory activities.

Roles of anandamide in the hepatic microcirculation in cirrhotic rats.

Cannabinoids have been reported to participate in the pathogenesis of peripheral vasodilatation in cirrhosis. However, their roles in increased intrahepatic resistance (IHR) in cirrhotic livers are unknown. We aimed to investigate the effects of cannabinoids in the hepatic microcirculation of cirrhotic rats produced by bile duct ligation. In isolated liver perfusion, portal perfusion pressure (PPP) and the production of eicosanoids in the perfusate were measured. In addition, various hepatic protein levels [cyclooxygenase (COX) isoform and 5-lipoxygenase (5-LOX)] were also determined. Finally, concentration-response curves for PPP and the corresponding production of eicosanoids in response to anandamide (1.44 x 10(-10)-1.44 x 10(-3) M) after indomethacin (COX inhibitor), piriprost (5-LOX inhibitor), or furegrelate (thromboxane A(2) synthase inhibitor) preincubation were obtained. The study showed that cirrhotic livers had significantly higher levels of PPP, COX-2 and 5-LOX protein expression, and production of thromboxane B(2) (TXB(2)) and cysteinyl leukotrienes (Cys-LTs) than normal livers. Anandamide induced a dose-dependent increase in PPP in both normal and cirrhotic livers. The anandamide-induced increase in PPP was found concomitantly with a significant increase in TXB(2) and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB(2) and Cys-LTs than normal livers. Indomethacin and furegrelate, but not piriprost, significantly ameliorated the anandamide-induced increase in IHR in cirrhotic livers. In conclusion, anandamide plays, in part, an important role in increased IHR of cirrhotic livers. The anandamide-induced increase in IHR in cirrhotic livers may be mediated by increased COX-derived eicosanoid (mainly thromboxane A(2)) production.