Effect of rectal indomethacin on the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography for choledocholithiasis: a prospective randomized clinical trial.

BACKGROUND AND AIM: the aim of this study was to evaluate the efficacy and safety of rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients with common bile duct (CBD) stones. METHODS: a total of 167 patients undergoing ERCP between November 2019 and November 2022 for CBD stones in the First Affiliated Hospital of Dalian Medical University were prospectively analyzed. The patients were divided into an indomethacin group (n = 58) and a control group (n = 109). The primary endpoint was the percent of patients who experienced PEP. RESULTS: PEP was observed in a total of 26 patients (15.57 %); four patients (6.90 %) in the indomethacin group and 22 (20.18 %) in the control group (p = 0.042). Mild, moderate and severe PEP was observed in three (5.17 %), one (1.72 %) and zero patients, respectively, in the indomethacin group, and in eleven (10.09 %), nine (8.26 %) and two (1.83 %) patients, respectively, in the control group. There was one case (0.92 %) of death due to PEP in the control group. No cases of moderate or severe bleeding were observed in either group. CONCLUSIONS: rectal indomethacin is an effective and safe method to prevent PEP for patients with CBD stones undergoing ERCP.

Effect of rectal indomethacin on the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography for choledocholithiasis: a prospective randomized clinical trial

Background and aim: the aim of this study was to evaluate the efficacy and safety of rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients with common bile duct (CBD) stones. Methods: a total of 167 patients undergoing ERCP between November 2019 and November 2022 for CBD stones in the First Affiliated Hospital of Dalian Medical University were prospectively analyzed. The patients were divided into an indomethacin group (n = 58) and a control group (n = 109). The primary endpoint was the percent of patients who experienced PEP. Results: PEP was observed in a total of 26 patients (15.57 %); four patients (6.90 %) in the indomethacin group and 22 (20.18 %) in the control group (p = 0.042). Mild, moderate and severe PEP was observed in three (5.17 %), one (1.72 %) and zero patients, respectively, in the indomethacin group, and in eleven (10.09 %), nine (8.26 %) and two (1.83 %) patients, respectively, in the control group. There was one case (0.92 %) of death due to PEP in the control group. No cases of moderate or severe bleeding were observed in either group. Conclusions: rectal indomethacin is an effective and safe method to prevent PEP for patients with CBD stones undergoing ERCP. (AU)

Clinical Value of Clip-and-Snare Assisted Endoscopic Submucosal Resection in Treatment of Rectal Neuroendocrine Tumors.

Introduction: The aim of the study was to introduce a new endoscopic technology, clip-and-snare assisted endoscopic submucosal resection (CS-ESMR), for treatment of rectal neuroendocrine tumors (NETs) and then to investigate the therapeutic value of CS-ESMR. Methods: In this retrospective study, 67 patients who underwent endoscopic treatment of rectal NETs from March 2017 to December 2021 were analyzed. According to the endoscopic resection methods (endoscopic mucosal resection [EMR], CS-ESMR, and endoscopic submucosal dissection [ESD]), the cases were divided into CS-ESMR group (27 cases), ESD group (31 cases), and EMR group (9 cases). The pathological R0 resection rate and the incidence of adverse events (bleeding and perforation) were compared among the three groups. Results: There was a significant difference about the pathological R0 resection between the CS-ESMR group and the EMR group and between the CS-ESMR group and the ESD group (both p < 0.05). Compared with ESD group, the procedure time, intraoperative bleeding, and the cost of CS-ESMR group are significantly decreased (p < 0.001, p < 0.05, p < 0.001, respectively). Conclusion: CS-ESMR may be a safe and effective treatment for rectal NETs with a diameter of less than 10 mm, without muscularis propria invasion and metastasis.

Clinical value of sigmoid colon water exchange colonoscopy: a prospective randomized clinical trial.

This prospective randomized controlled trial investigated the clinical value of sigmoid colon water exchange (SWE) colonoscopy by comparing it with air insufflation (AI) colonoscopy in terms of the patient's pain score, insertion time, and screening quality. Consecutive patients who underwent colonoscopy without sedation were randomized into an AI group (n = 267) or an SWE group (n = 255). Patient characteristics, history of abdominal or pelvic surgery, maximum pain score, insertion time, cecal intubation rate, polyp detection rate, and the need for maneuvers were recorded. There was no significant between-group difference in insertion time, cecal intubation rate, assisted maneuvers (abdominal pressure, changing patients' position), or polyp detection rate (P > 0.05). The mean maximum pain score was significantly lower in the SWE group than in the AI group. (3.57 ± 2.01 vs. 4.69 ± 1.83, P < 0.001). For patients with a history of abdominal or pelvic surgery and those who were overweight (body mass index > 24), the maximum pain scores were lower in the SWE group than in the AI group (3.67 ± 1.95 vs. 4.88 ± 1.80, P < 0.001; 3.40 ± 1.96 vs. 4.79 ± 1.97, P < 0.001, respectively). SWE colonoscopy can significantly reduce abdominal pain with non-inferior screening quality and does not increase insertion time.Trial registration number: ChiCTR2200059057 (date April 23, 2022).

Correction to "Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation".

[This corrects the article on p. 2921 in vol. 19, PMID: 23704825.].

TMEM16A overexpression indicates poor prognosis in colorectal cancer patients

Aim: to investigate the relationship between TMEM16A and the clinicopathological features and prognosis of patients with colorectal cancer (CRC).Methods: ninety-six patients with CRC confirmed by pathology after undergoing surgery at the First Affiliated Hospital of Dalian Medical University between June 2009 and December 2011 were enrolled and followed up. The expression of the TMEM16A protein in CRC was detected by immunohistochemistry in 96 cases. The relationship between the expression of the TMEM16A protein in CRC and the clinical features and clinical prognosis were analyzed.Results: there was no correlation between the TMEM16A protein expression and gender, age, tumor location, size and degree of differentiation (p > 0.05). However, the expression of the TMEM16A protein was significantly associated with the depth of invasion, lymph node metastasis and Dukes stage (p < 0.05). Kaplan-Meier survival curves showed that CRC patients with high expression of the TMEM16A protein had a poorer overall survival compared with those with low expression levels (68.2 % vs 92.3 %, X2 = 9.892, p = 0.002). Multivariate Cox regression analysis showed that upregulation of the TMEM16A protein expression is an independent predictive factor for poor prognosis in patients with CRC (p < 0.05, RR = 6.467, 95 % CI: 1.777-23.538).Conclusions: the expression of the TMEM16A protein in CRC was associated with tumor invasion, lymph node metastasis and Dukes stage. High expression of the TMEM16A protein in CRC can be used as an independent predictive factor for a poor prognosis of patients with CRC. (AU)

Altered expression of TMEM16A in colorectal carcinoma and its clinical significance.

TMEM16A has been reported to be over-expressed in some malignant tumors recently. The aim of this study was to investigate the role of TMEM16A in the progression of colorectal carcinoma (CRC) by detecting the expression of TMEM16A in CRC tissues, adjacent normal tissues, and adenoma tissues. Then, to investigate the relationship between TMEM16A expression and the clinicopathological features of patients with CRC.

TMEM16A overexpression indicates poor prognosis in colorectal cancer patients.

AIM: to investigate the relationship between TMEM16A and the clinicopathological features and prognosis of patients with colorectal cancer (CRC). METHODS: ninety-six patients with CRC confirmed by pathology after undergoing surgery at the First Affiliated Hospital of Dalian Medical University between June 2009 and December 2011 were enrolled and followed up. The expression of the TMEM16A protein in CRC was detected by immunohistochemistry in 96 cases. The relationship between the expression of the TMEM16A protein in CRC and the clinical features and clinical prognosis were analyzed. RESULTS: there was no correlation between the TMEM16A protein expression and gender, age, tumor location, size and degree of differentiation (p > 0.05). However, the expression of the TMEM16A protein was significantly associated with the depth of invasion, lymph node metastasis and Dukes stage (p < 0.05). Kaplan-Meier survival curves showed that CRC patients with high expression of the TMEM16A protein had a poorer overall survival compared with those with low expression levels (68.2 % vs 92.3 %, X2 = 9.892, p = 0.002). Multivariate Cox regression analysis showed that upregulation of the TMEM16A protein expression is an independent predictive factor for poor prognosis in patients with CRC (p < 0.05, RR = 6.467, 95 % CI: 1.777-23.538). CONCLUSIONS: the expression of the TMEM16A protein in CRC was associated with tumor invasion, lymph node metastasis and Dukes stage. High expression of the TMEM16A protein in CRC can be used as an independent predictive factor for a poor prognosis of patients with CRC.

MicroRNA-936/ERBB4/Akt axis exhibits anticancer properties of gastric cancer through inhibition of cell proliferation, migration, and invasion.

Gastric cancer is one of the most common cancers globally and has a poor prognosis. MiR-936 has been reported to regulate cell activity and tumor progression in non-small cell lung cancer, glioma, and epithelial ovarian cancer. However, the specific role and mechanism of miR-936 in gastric cancer have not been explored. In present study, gastric cancer cells were transfected with miR-936 mimic, and cell proliferation, cell cycle distribution, cell apoptosis, migration and invasion were assessed via cell-counting kit-8, flow cytometry, wound healing, and transwell assay, respectively. Dual luciferase reporter assay was used to check miR-936 binding to its downstream target. It was shown that miR-936 was downregulated in gastric cancer tissues and cells. Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) was confirmed as a direct target of miR-936 and negatively regulated its expression by miR-936. Overexpression of miR-936 suppressed cell proliferation, cell cycle progression, cell migration and invasion, and enhanced cell apoptosis in gastric cancer cells, which could be reversed by further ERBB4 overexpression. Western blot results showed that miR-936/ERBB4 axis regulated Akt-related pathways to control gastric cancer cell activities. Therefore, our data suggest that miR-936 overexpression inhibits cell proliferation and invasion and promotes cell apoptosis through Akt-related pathways by targeting ERBB4, which provides novel insight to target miR-936 or miR-936/ERBB4 axis for the treatment of gastric cancer.

The influence of periampullary diverticula on ERCP for treatment of common bile duct stones.

In order to evaluate the effectiveness of various methods we applied to decrease the influence of periampullary diverticula (PAD) on the success rate and complications of endoscopic retrograde cholangiopancreatography (ERCP) in the treatment of common bile duct (CBD) stones, we enrolled patients with CBD stones who had been treated by ERCP in our hospital between January 2015 and December 2018. According to the presence of PAD, the patients were divided into a PAD group and a non-PAD group. The rate of complete stone removal in the first session, the rate of overall stone removal, the frequency of application of mechanical lithotripsy, and procedure-related complications, including bleeding, hyperamylasemia, pancreatitis, perforation, and infection of biliary tract were recorded. A total of 183 cases, including 72 cases in the PAD group and 111 cases in the non-PAD group were enrolled. There was no statistical difference between the two groups regarding gender (P = 0.354). However, regarding age, there was a statistical difference (P = 0.002), and the incidence of PAD increased with age. There were 5 (6.9%) cases in the PAD group and 14 (12.6%) cases in the non-PAD group where mechanical lithotripsy was applied. There were 59 (81.9%) cases in the PAD group and 102 (91.9%) cases in the non-PAD group where there was complete removal of CBD stones in the first session, and there were 68 (94.4%) cases in the PAD group and 107 (96.4%) cases in the non-PAD group where there was complete removal of all stones. In the PAD group, there were 0 cases (0%) with gastrointestinal bleeding, 0 cases (0%) with gastrointestinal perforation, 13 cases (18.1%) with post-ERCP hyperamylasemia, 3 cases (4.2%) with post-ERCP pancreatitis, and 4 cases (5.6%) with biliary tract infection. In the non-PAD group, 1 case (0.9%) had gastrointestinal bleeding, 0 cases had gastrointestinal perforation, 18 cases (16.2%) had post-ERCP hyperamylasemia, 5 cases (4.5%) had post-ERCP pancreatitis, and 11 cases (9.9%) had biliary tract infection. This retrospective study showed that there was a statistical difference between the two groups regarding complete removal of CBD stones in the first session and application of mechanical lithotripsy (both P < 0.05), but no statistical difference according to the rates of overall stone removal and the complications (P > 0.05), which means that we can reduce the influence of PAD on ERCP for treatment of common bile duct stones.

Three-hour post-ERCP amylase level: a useful indicator for early prediction of post-ERCP pancreatitis.

BACKGROUND: To evaluate the value of the 3-h post-ERCP serum amylase level for early prediction of post-ERCP pancreatitis (PEP). METHOD: A study of 206 patients performed ERCP (Encoscopic Retrograde Cholangio-Pancreatography) at a single centre was done from Jan. 2011 to Nov. 2016. The serum amylase or lipase level was measured at 3 h after ERCP. The patients with PEP were recorded. ROC curves were used to statistically analyze the data: The enrolled patients were divided into two groups according to gender, then we analyzed the data respectively. We comprehensively evaluated the predictive value of PEP by 3-h post-ERCP serum amylase level based on the results above. RESULTS: Two hundred six patients (92 males, 114 females) were enrolled. PEP occurred in 21 patients (10.19%) among them. The median time to discharge was 7 days (min = 1d, max = 13d) after the procedure. In the 206 patients, the 3-h post-ERCP pancreatic amylase level was used as the test variable, and the PEP occurrence as the state variable to plot the ROC curve. The area under the curve (AUC) was 0.816, and was statistically significant (P < 0.001). The standard error (SE) was 0.0507, the 95% confidence interval (CI) was 0.756-0.866, and the optimal cut-off value was 351 U/L (sensitivity 76.19%, specificity 83.24%, positive likelihood ratio 4.55, negative likelihood ratio 0.29, Youden index 59.43%). Of the 206 patients, there were 83 patients with both 3-h post-ERCP amylase level and lipase level detected, and the ROC curves were plotted for both serum amylase and lipase respectively. The ROC curve matched-pair testing was carried out: The areas under the ROC curves were statistically significant. (P < 0.001) The area under the ROC curve for the 3-h post-ERCP lipase was 0.778, the 95% confidence interval was 0.673-0.862, and optimal cut-off value was 1834 U/L. The area under the ROC curve for the 3-h post-ERCP serum amylase was 0.780, and the 95% confidence interval was 0.676-0.864. The optimal cut-off is 380 U/L, and there was no statistically significant difference between the two for diagnostic accuracy. According to gender, 206 patients were divided into 2 groups, and the ROC curves were drawn respectively. Based on statistical analysis, there was no statistically significant difference in the diagnostic accuracy of the two groups. In the male group, 436 U/L serum amylase provided the greatest diagnostic accuracy with sensitivity (SE) of 70.5%, specificity (SP) of 89.2%, positive predictive value (PPV) 87.5%, and negative predictive value (NPV) 78.1%. Whereas, in the female group, 357 U/L serum amylase provided the greatest diagnostic accuracy with sensitivity of 76.9%, specificity of 81.2%, positive predictive value of 80.4%, negative predictive value of 77.9%. CONCLUSIONS: 1. The 3-h post-ERCP serum amylase level is a useful measurement for predicting post-ERCP pancreatitis. 2. There was no significant difference between serum amylase and lipase 3-h post-ERCP for predicting PEP. 3. There was no statistically significant difference between male and female using the 3-h post-ERCP serum amylase level to predict PEP. For female, the optimal cut-off value was 357 U/L, whereas male 436 U/L .

Endogenous carbon monoxide downregulates hepatic cystathionine-γ-lyase in rats with liver cirrhosis.

The aim of the present study was to investigate the effect of endogenous carbon monoxide (CO) on the hydrogen sulfide/cystathionine-γ-lyase (H2S/CSE) pathway in cirrhotic rat livers. The rats were allocated at random into four groups: Sham, cirrhosis, cobalt protoporphyrin (CoPP) and zinc protoporphyrin IX (ZnPP). The expression of hepatic CSE mRNA was evaluated using a quantitative polymerase chain reaction, while CSE protein expression was determined using immunohistochemical analysis. Hematoxylin and eosin staining was performed for the histological evaluation of liver fibrosis. The levels of H2S, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in the arterial blood were determined, in addition to the portal vein pressure. The mRNA and protein expression levels of hepatic CSE and the serum levels of H2S were significantly decreased in the cirrhosis group compared with those in the sham group (P<0.05). Compared with the cirrhosis group, rats in the ZnPP group had significantly lower levels of serum ALT, AST and TBIL, arterial COHb and hepatic fibrosis, while hepatic CSE expression and the production of H2S were significantly increased (P<0.05). The CoPP group exhibited decreased hepatic CSE expression and H2S production, but aggravated hepatic function and fibrosis (P<0.05). In conclusion, the H2S/CSE pathway is involved in the formation of liver cirrhosis and serves a crucial function in protecting liver cells against the progression of liver fibrosis. Endogenous CO downregulates hepatic CSE mRNA and protein expression and the production of H2S in rats with liver cirrhosis.

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression.

The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase-1 (HO-1) expression, together with the influence of altered hepatic HO-1 expression levels on hepatic function and fibrosis in bile duct-ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO-1 mRNA were measured by reverse-transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson's staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO-1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide-treated group exhibited significantly reduced hepatic HO-1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO-1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO-1 overexpression in cirrhotic rats, reduced hepatic HO-1 expression levels to relieve liver injury and attenuated liver fibrosis.

Small sphincterotomy combined with endoscopic papillary large balloon dilation vs sphincterotomy alone for removal of common bile duct stones.

AIM: To evaluate the efficacy and safety of endoscopic papillary large diameter balloon dilation (EPLBD) following limited endoscopic sphincterotomy (EST) and EST alone for removal of large common bile duct (CBD) stones. METHODS: We retrospectively compared EST + EPLBD (group A, n = 64) with EST alone (group B, n = 89) for the treatment of large or multiple bile duct stones. The success rate of stone clearance, procedure-related complications and incidents, frequency of mechanical lithotripsy use, and recurrent stones were recorded. RESULTS: There was no statistically significant difference between the two groups regarding periampullary diverticula (35.9% vs 34.8%, P > 0.05), pre-cut sphincterotomy (6.3% vs 6.7%, P > 0.05), size (12.1 ± 2.0 mm vs 12.9 ± 2.6 mm, P > 0.05) and number (2.2 ± 1.9 vs 2.4 ± 2.1, P > 0.05) of stones or the diameters of CBD (15.1 ± 3.3 mm vs 15.4 ± 3.6 mm, P > 0.05). The rates of overall stone removal and stone removal in the first session were not significantly different between the two groups [62/64 (96.9%) vs 84/89 (94.4%), P > 0.05; and 58/64 (90.6%) vs 79/89 (88.8%), P > 0.05, respectively]. The rates of post-endoscopic retrograde cholangiopancreatography pancreatitis and hyperamylasemia were not significantly different between the two groups [3/64 (4.7%) vs 4/89 (4.5%), P > 0.05; 7/64 (10.9%) vs 9/89 (10.1%), P > 0.05, respectively]. There were no cases of perforation, acute cholangitis, or cholecystitis in the two groups. The rate of bleeding and the recurrence of CBD stones were significantly lower in group A than in group B [1/64 (1.6%) vs 5/89 (5.6%), P < 0.05; 1/64 (1.6%) vs 6/89 (6.7%), P < 0.05, respectively]. CONCLUSION: EST + EPLBD is an effective and safe endoscopic approach for removing large or multiple CBD stones.

Decompression of acute left-sided malignant colorectal obstruction: comparing transanal drainage tube with metallic stent.

BACKGROUND AND AIM: Acute left-sided colorectal malignant obstruction is a life-threatening condition and need emergent treatment. Many nonsurgical treatments to palliate obstruction have been developed in clinics. The aim of this study was to evaluate the clinical effects of transanal drainage tube (TDT) and metallic stent for the decompression of acute left-sided malignant colorectal obstruction. MATERIALS AND METHODS: Twenty-nine patients with acute left-sided malignant colorectal obstruction were enrolled in this study from January 2005 to December 2010, they were randomly divided into TDT group (13 patients) and metallic stent group (16 patients). RESULTS: There were 13 cases in TDT group (male:female=8:5, age from 65 to 80 y, mean age was 72.6±4.7 y). The sites of lesions were located in the rectum of 3 patients, sigmoid colon of 7 patients, and descending colon of 3 patients. TDT was successfully inserted in 11 cases (84.6%). Among the 11 patients, 1-stage operation with sufficient lymph node dissection was performed in 8 cases after adequate lavage without complications. One case underwent emergent Hartmann operation because of colonic tumor perforation 3 days after ileus tube decompression. Two cases were discharged without surgery after relief of symptom. There were 16 cases in the metallic stent group (male:female=10:6 age from 48 to 86 y, mean age was 73.3±8.5 y). The sites of the lesions were located in the rectum of 4 patients, sigmoid colon of 6 patients, and descending colon of 6 patients. Successful stent placement was achieved in 13 cases (81.3%) with no severe complications. Among the 13 patients, 1-stage operation with sufficient lymph node dissection was performed in 7 cases and 6 cases refused to underwent surgery with stent as the definitive palliative treatment. The price of a TDT is only one third of an expandable metallic stent. CONCLUSIONS: Both TDT and metallic stent can achieve preoperative colonic lavage for 1-stage operation for patients with acute left-sided malignant colorectal obstruction with no increase in complications.

Age at menarche and risk of colorectal cancer: a meta-analysis.

BACKGROUND: Various observational studies have focused on the relationship between menarcheal age and the risk of colorectal cancer (CRC). However, the association is still controversial because of inconsistent results. Therefore, we performed a meta-analysis to assess this issue from epidemiological studies. METHODS: After a literature search in MEDLINE, EMBASE, and Web of Science for studies of menarcheal age and CRC risk published through the end of January 2013, we pooled the relative risks (RRs) from included studies using a fixed- or random-effects model and performed heterogeneity and publication bias analyses. All statistical tests were two-sided. RESULTS: Eleven case-control and 11 cohort studies were eligible for inclusion in our analysis. The random-effects pooled RR for oldest versus youngest menarcheal age was 0.95 [95% confidence intervals (CIs) = 0.85-1.06], with significant heterogeneity (Q = 61.03, P<0.001, I (2) = 65.6%). When separately analyzed, case-control (RR = 0.95, 95% CI = 0.75-1.21) and cohort studies (RR = 0.97, 95% CI = 0.90-1.04) yielded similar results. Moreover, similar results were also observed among the subgroup analyses by study quality, population, exposure assessment, anatomic cancer site, subsite of colon cancer, and several potential important confounders and risk factors. There was no evidence of publication bias and significant heterogeneity between subgroups detected by meta-regression analyses. CONCLUSIONS: Findings from this meta-analysis demonstrated that menarcheal age was not associated with the risk of CRC in humans. Further studies are warranted to stratify results by the subsite of colon cancer and menopause status in the future.

Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation.

AIM: To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL). METHODS: Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson's stain, hydroxyproline, transforming growth factor-ß1 (TGF-ß1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS: Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-ß1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis. CONCLUSION: Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.

Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a severe complication of liver cirrhosis and its pathogenesis has yet to be fully elucidated. Previous studies have demonstrated that heme oxygenase-1 (HO-1) is important in the induction of liver cirrhosis. The present study aimed to investigate the role of HO-1 in the pathogenesis of HE. Rats were divided into 5 treatment groups; sham, bile duct ligation (BDL), HE, zinc protoporphyrin (ZnPP) and cobalt protoporphyrin (CoPP). The levels of HO-1 were examined by western blotting and quantitative real-time PCR (qRT-PCR). Serum levels of carboxyhemoglobin (COHb), ammonia levels in the plasma and brain, brain water content and portal vein pressure (PVP) were also quantified. Aquaporin-4 expression levels were measured by immunohistochemistry and qRT-PCR. The results demonstrated that the levels of HO-1 in the brain and the serum levels of COHb were significantly increased in the HE group compared with the BDL group. Brain water content, PVP and ammonia levels in the plasma and brain were increased in the HE and CoPP groups; however, these were reduced following the treatment with ZnPP. The levels of AQP-4 expression and oxidative stress in the brain were reduced following treatment with ZnPP and increased following treatment with CoPP. In conclusion, following the inhibition of HO-1 expression, treatment with ZnPP improved HE due to reducing the expression levels of AQP-4 and oxidative stress. Therefore, ZnPP treatment may represent a novel therapeutic approach for HE.