Pioglitazone attenuates the severity of sodium taurocholate-induced severe acute pancreatitis

AIM： To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ, （PPARγ） ligand, on development of severe acute pancreatitis （SAP） and expression of nuclear factor-kappa B （NF-κB） and intercellular adhesion molecule-1 （ICAM-1） in the pancreas. METHODS： Male Sprague-Dawley （SD） rats （160-200 g） were randomly allocated into three groups （n = 18 in each group）： severe acute pancreatitis group, pioglitazone group, sham group. SAP was induced by retrograde infusion of 1 mL/kg body weight 5% sodium taurocholate （STC） into the biliopancreatic duct of male SD rats. Pioglitazone was injected intraperitoneally two hours piror to STC infusion. Blood and ascites were obtained for detecting amylase and ascitic capacity. Pancreatic wet/dry weight ratio, expression of NF-κB and ICAM-1 in pancreatic tissues were detected by immunohistochemical staining. Pancreatic tissue samples were stained with hematoxylin and eosin （HE） for routine optic microscopy. RESULTS： Sham group displayed normal pancreatic structure. SAP group showed diffuse hemorrhage, necrosis and severe edema in focal areas of pancreas. There was obvious adipo-saponification in abdominal cavity. Characteristics such as pancreatic hemorrhage, necrosis, severe edema and adipo-saponification were found in pioglitazone group, but the levels of those injuries were lower in pioglitazone group than those in SAP group. The wet/dry pancreatic weight ratio, ascetic capacity, serum and ascitic activities of anylase in the SAP group were significantly higher than those in the sham group and pioglitazone group respectively （6969.50 ± 1368.99 vs 2104.67 ± 377.16, 3.99 ± 1.22 vs 2.48 ± 0.74, P 〈 0.01 or P 〈 0.05）. According to Kusske criteria, the pancreatic histologic score showed that interstitial edema, inflammatory infiltration, parenchyma necrosis and parenchyma hommorrhage in SAP group significantly differed from those in the sham group and pioglitazone group （7.17 ± 1.83 vs 0.50 ± 0.55, 7.67 ± 0.82 vs 6.83 ± 0.75, P 〈 0.01, P 〈 0.05. The expression of NF-κB and ICAM-1 in sham group was lower than that in SAP group and pioglitazone group （0.50 ± 0.55 vs 33 ± 1.21, P 〈 0.01）. There was a significant difference in the expression of NF-κB and ICAM-1 between SAP group and pioglitazone group （7.50 ±1.05 vs 11.33 ± 1.75, 0.80 ± 0.53 vs 1.36 ± 0.54, P 〈 0.01 or P 〈 0.05） at 12 h after the induction of pancreatitis. CONCLUSION： Pioglitazone attenuates the severity of SAP. The beneficial effect of pioglitazone is multifactorial due to its anti-inflammatory activities, most likely through the inhibition of ICAM-1 expression and NF-κB activation. Specific ligands of PPARy may represent the novel and effective means of clinical therapy for SAP.

Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats

AIM: To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats.METHODS: In this study, we have investigated the therapeutic effects of DA-9601 on chronic erosive and atrophic gastritis induced by 6 mo of TCA administration (5 mmol/L in drinking water) in SD rats. RESULTS: Four weeks of DA-9601 administration (0.065%, 0.216% in rat chow), following the withdrawal of TCA treatment, resulted in a significant decrease in total length of erosions in rats in a dose-dependent manner. Furthermore, the indicators of atrophic gastritis, such as reduced mucosal thickness and reduction in the number of parietal cells, were improved by the administration of DA-9601 in a dose-related manner. DA-9601 also attenuated inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa. The improvement in the reduction of the gastric mucus was observed in the rats receiving a high dose of DA-9601 (0.216%). The therapeutic effect of DA-9601 on experimental chronic erosive gastritis was superior to that of rebamipide (1.08% in rat chow). Biochemical analyses showed increased mucosal prostaglandin E2 and reduced glutathione levels by DA-9601 treatment. CONCLUSION: We suggest that DA-9601 is apromising agent for the treatment of chronic erosive and atrophic gastritis with an etiological factor of bile reflux. Increasedmucosal prostaglandin E2 and reduced glutathione by DA-9601 treatment may be therapeutic mechanisms for chronic erosive and atrophic gastritis.

De novo mutation loci and clinical analysis in a child with sodium taurocholate cotransport polypeptide deficiency: A case report

BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transport protein NTCP in hepatocytes.A variety of clinical manifestations and genetic mutation loci have been reported for this disease.However,specific therapeutic measures are lacking,and the long-term effects are unknown.CASE SUMMARY An infant with elevated bile acids and behavioral neurodevelopmental delay failed to respond to bile acid-lowering therapy.Genetic testing for metabolic liver disease revealed that the child had NTCP deficiency due to the SLC10A1 mutation:c.422dupA(p.Y141X),which is a novel mutation site.The current followup revealed a gradual decrease in bile acid levels after 1 year of age,but the child still had behavioral neurodevelopmental delays.CONCLUSION The clinical manifestations,genetic characteristics,treatment and long-term prognosis due to NTCP deficiency remain poorly defined and need to be further confirmed by more studies and reports.

Establishment of an Infected Necrotizing Pancreatitis Model by Retrograde Pancreatic Duct Injection of Sodium Taurocholate and E. coli in Rats

A stable and reliable infected necrotizing pancreatitis （INP） model in rats was established in order to study the pathophysiological mechanism and pathological development role of INP and explore the new therapeutic methods for the diseases. Forty-six SD rats were randomly divided into 5 groups. The animals in group A received the injection of 5% sodium taurocholate into the pancreatic duct and those in group B underwent that of E. coli into the pancreatic duct. The rats in groups C, D and E were subjected to the injection of 5% sodium taurocholate in combination with different concentrations of E. coli （10^3, 10^4, 10^5/mE, respectively） into the pancreatic duct. The dose of injection was 0.1 mL/100 g and the velocity of injection was 0.2 mL/min in all the 5 groups. Eight h after the injection, the survival rate of animals was recorded and the surviving rats were killed to determine the serum content of amylase and perform pathological examination and germ cultivation of the pancreatic tissue. The results showed that acute necrotizing pancreatitis model was induced by injection of 5% sodium taurocholate into the pancreatic duct. The positive rate of germ cultivation in group A was 12.5%. The acute necrotizing pancreatitis model was not induced by injection of E. coli into the pancreatic duct and the positive rate of germ cultivation in group B was 0. The INP model was established in groups C to E. The positive rate of germ cultivation was 60%, 100% and 100% and 8-h survival-rate 100%, 100% and 70% in groups C, D and E, respectively. It was concluded that a stable and reliable model of INP was established by injection of 5% sodium taurocholate in combination with 10^4/mL E. coli into the pancreatic duct with a dose of 0.1 mL/100 g and a velocity of 0.2 mL/min. The pathogenesis of INP might be that the hemorrhage and necrosis of pancreatic tissue induced by sodium taurocholate results in weakness of pancreatic tissue in fighting against the germs. Meanwhile, the necrotic pancreatic tissue provides a good proliferative environment for the germs.

Discovery of a novel sodium taurocholate cotransporting polypeptide(NTCP) inhibitor: Design, synthesis, and anti-proliferative activities

Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.

The S267F variant of sodium taurocholate co-transporting polypeptide is strongly associated with resistance to chronic hepatitis B and high level of serum total bile acids

Background and aims:The sodium taurocholate co-transporting polypeptide(NTCP)is a functional receptor for the hepatitis B virus(HBV),and it is critical for bile acid homeostasis.Previous studies of the association between the S267F variant and chronic hepatitis B(CHB)have generated conflicting results.This study analyzed the correlation between the NTCP S267F variant and CHB susceptibility by using a large sample of participants classified by gender and age,and this study also analyzed the relationship between this variant and the level of serum total bile acids.Methods:In total,543 patients with CHB and 429 control subjects underwent S267F variant genotyping using SNaPshot technology.Logistic regression was utilized to evaluate any association of the NTCP S267F variant with CHB susceptibility.Results:The S267F variant was inversely correlated with the risk of chronic HBV infection in both the dominant model(GG genotype vs.AG genotype:odds ratio(OR)=0.46,95%confidence interval(CI)0.30 -0.71,P<0.001)and the allele model(G allele vs.A allele:OR=0.50,95%CI 0.33-0.76,P=0.001),and this correlation was not affected by gender and age stratification.The carriers of the heterozygous NTCP variant exhibited higher total bile acids levels than the carriers of wild-type NTCP,regardless of whether they were control subjects or patients with CHB.Heterozygous carriers exhibited reduced hepatitis B e antigen(HBeAg)-positivity rates and had lower ALT,AST,and lg DNA concentrations compared with wild-type carriers in patients with CHB.Conclusions:The S267F variant of NTCP is a protective factor that reduces the risk of chronic HBV infection and exhibits a higher total bile acids level.Patients with CHB who carry this variant may have a better prognosis than those carrying wild-type NTCP.