Total Bile Acid Levels Research Articles

Berberine regulates glucose metabolism in largemouth bass by modulating intestinal microbiota.

This study examined the role of intestinal microbiota in berberine (BBR)-mediated glucose (GLU) metabolism regulation in largemouth bass. Four groups of largemouth bass (133.7 ± 1.43g) were fed with control diet, BBR (1g/kg feed) supplemented diet, antibiotic (ATB, 0.9g/kg feed) supplemented diet and BBR + ATB (1g/kg feed +0.9g/kg feed) supplemented diet for 50days. BBR improved growth, decreased the hepatosomatic and visceral weight indices, significantly downregulated the serum total cholesterol and GLU levels, and significantly upregulated the serum total bile acid (TBA) levels. The hepatic hexokinase, pyruvate kinase, GLU-6-phosphatase and glutamic oxalacetic transaminase activities in the largemouth bass were significantly upregulated when compared with those in the control group. The ATB group exhibited significantly decreased final bodyweight, weight gain, specific growth rates and serum TBA levels, and significantly increased hepatosomatic and viscera weight indices, hepatic phosphoenolpyruvate carboxykinase, phosphofructokinase, and pyruvate carboxylase activities, and serum GLU levels. Meanwhile, the BBR + ATB group exhibited significantly decreased final weight, weight gain and specific growth rates, and TBA levels and significantly increased hepatosomatic and viscera weight indices and GLU levels. High-throughput sequencing revealed that compared with those in the control group, the Chao one index and Bacteroidota contents were significantly upregulated and the Firmicutes contents were downregulated in the BBR group. Additionally, the Shannon and Simpson indices and Bacteroidota levels were significantly downregulated, whereas the Firmicutes levels were significantly upregulated in ATB and BBR + ATB groups. The results of in-vitro culture of intestinal microbiota revealed that BBR significantly increased the number of culturable bacteria. The characteristic bacterium in the BBR group was Enterobacter cloacae. Biochemical identification analysis revealed that E. cloacae metabolizes carbohydrates. The size and degree of vacuolation of the hepatocytes in the control, ATB, and ATB + BBR groups were higher than those in the BBR group. Additionally, BBR decreased the number of nuclei at the edges and the distribution of lipids in the liver tissue. Collectively, BBR reduced the blood GLU level and improved GLU metabolism in largemouth bass. Comparative analysis of experiments with ATB and BBR supplementation revealed that BBR regulated GLU metabolism in largemouth bass by modulating intestinal microbiota.

Unique microRNA expression profiles in plasmic exosomes from intrahepatic cholestasis of pregnancy

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is strongly associated with an increased risk of adverse perinatal outcomes. Total bile acid (TBA) levels in the late second or third trimester are a major factor in the diagnosis. Here, we sought to establish the miRNA expression profile of plasm exosomes of ICP and identify possible biomarkers for the diagnosis of ICP.MethodsThis case–control study involved 14 ICP patients as the experimental group and 14 healthy pregnant women as the control group. Electron microscopy was used to observe the presence of exosomes in plasma. Nanosight and Western blotting of CD63 was used to assess exosome quality. Among them, three ICP patients and three controls were used for isolation plasmic exosome and preliminary miRNA array analysis. The Agilent miRNA array was utilized to dynamically monitor the miRNA expression in plasmic exosomes of included patients in the first trimester(T1), second trimester (T2), third trimester (T3), and delivery (T4). Then, Quantitative real-time Polymerase chain reaction was used to identify and validate differentially expressed miRNAs in plasma-derived exosomes.ResultsThe expression levels of hsa-miR-940, hsa-miR-636, and hsa-miR-767-3p in plasma-derived exosomes of ICP patients were significantly higher than those of healthy pregnant women. Besides, these three miRNAs were also significantly up-regulated at the plasma, placental, and cellular levels (P < 0.05). The diagnostic accuracy of hsa-miR-940, hsa-miR-636, and hsa-miR-767-3p was further evaluated by the ROC curve, the area under the curve (AUC) values for each were 0.7591, 0.7727, and 0.8955, respectively.ConclusionsWe identified three differentially expressed miRNAs in the plasma exosomes of ICP patients. Hence, hsa-miR-940, hsa-miR-636, and hsa-miR-767-3p may be potential biomarkers for enhancing the diagnosis and prognosis of ICP.

A Three-Step Screening Procedure for Early Identification of Children at High Risk of Hemophagocytic Lymphohistiocytosis.

The first step in diagnosing hemophagocytic lymphohistiocytosis (HLH) is to suspect its presence and then order the appropriate diagnostic tests. The development of screening procedures for HLH could facilitate early diagnosis. In this study, we evaluated the utility of fever, splenomegaly, and cytopenias as screening criteria for identifying pediatric HLH at an early stage, built a screening model using commonly measured laboratory parameters, and developed a step-wise screening procedure for pediatric HLH. The medical records of 83,965 pediatric inpatients, including 160 patients with HLH, were collected retrospectively. The utility of fever, splenomegaly, hemoglobin level, and platelet and neutrophil counts at hospital admission as screening criteria for HLH was evaluated. For HLH patients who might be missed by screening based on the presence of fever, splenomegaly, and cytopenias, a screening model using common laboratory parameters was developed. Following that, a three-step screening procedure was then developed. The criteria of cytopenias affecting two or more lineages plus fever or splenomegaly had a sensitivity of 51.9% and a specificity of 98.4% for identifying HLH in pediatric inpatients. Our screening score model comprises six parameters: splenomegaly, platelet count, neutrophil count, albumin level, total bile acid level, and lactate dehydrogenase level. The use of the validation set had a sensitivity of 87.0% and a specificity of 90.6%. A three-step screening procedure has been developed: Step 1: Is fever or splenomegaly present? (Yes: risk for HLH should be considered, go to Step 2; No: less likely HLH); Step 2: Are cytopenias affecting at least two lineages? (Yes: consider HLH; No: go to Step 3); Step 3: Calculate the screening score. Is the sum of the score greater than 37? (Yes: consider HLH; No: less likely HLH). The overall sensitivity and specificity of the three-step screening procedure were 91.9% and 94.4%, respectively. A significant proportion of pediatric HLH patients present at the hospital without having all three symptoms: fever, splenomegaly, and cytopenias. Our three-step screening procedure, utilizing commonly available clinical and laboratory parameters, can effectively identify pediatric patients who may be at high risk for HLH.

Fetuin B may be a potential marker for predicting maternal and neonatal outcomes in intrahepatic cholestasis: Prospective case-control study.

To investigate the levels of serum fetuin B in healthy pregnant women and women with intrahepatic cholestasis of pregnancy (IHCP) and their association with pregnancy outcomes. This was a prospective case-control study, we included sixty singleton pregnant women with IHCP and sixty healthy-matched pregnant women in their third trimester. The serum fetuin B levels of these patients were analyzed. All the patients were followed up prospectively until delivery and data related to maternal, perinatal, and neonatal outcomes were obtained. Total bile acid levels and liver function tests were significantly higher in the IHCP group than in the control group (p<0.0001 and <0.0001, respectively). The serum fetuin B concentrations were higher in the IHCP group than in the control group, without any significant group difference (p=0.105). Preterm delivery, iatrogenic preterm delivery, and birth weight ≤2.500 gm are only significantly associated with serum fetuin B levels respectively (p<0.05). The diagnostic performance of serum bile acids [area under the curve (AUC)=0.998] was significantly better than that of fetuin B (AUC=0.586) (DeLong's test p≤0.001). We neither noted a significant difference between the IHCP and control groups concerning the serum fetuin B levels nor could we correlate its levels with adverse maternal and perinatal outcomes except with birth weight, thereby serum fetuin B was not an effective marker for use in shedding light on the pathophysiology of IHCP.

Cholestasis impairs gut microbiota development and bile salt hydrolase activity in preterm neonates

ABSTRACT Cholestasis refers to impaired bile flow from the liver to the intestine. In neonates, cholestasis causes poor growth and may progress to liver failure and death. Normal bile flow requires an intact liver-gut-microbiome axis, whereby liver-derived primary bile acids are transformed into secondary bile acids. Microbial bile salt hydrolase (BSH) enzymes are responsible for the first step, deconjugating glycine- and taurine-conjugated primary bile acids. Cholestatic neonates often are treated with the potent choleretic bile acid ursodeoxycholic acid (UDCA), although interactions between UDCA, gut microbes, and other bile acids are poorly understood. To gain insight into how the liver-gut-microbiome axis develops in extreme prematurity and how cholestasis alters this maturation, we conducted a nested case-control study collecting 124 stool samples longitudinally from 24 preterm infants born at mean 27.2 ± 1.8 weeks gestation and 946 ± 249.6 g, half of whom developed physiologic cholestasis. Samples were analyzed by whole metagenomic sequencing, in vitro BSH enzyme activity assays optimized for low biomass fecal samples, and quantitative mass spectrometry to measure the bile acid metabolome. In extremely preterm neonates, acquisition of the secondary bile acid biosynthesis pathway and BSH genes carried by Clostridium perfringens are the most prominent features of early microbiome development. Cholestasis interrupts this developmental pattern. BSH gene abundance and enzyme activity are profoundly reduced in cholestatic neonates, resulting in decreased quantities of unconjugated bile acids. UDCA restores total fecal bile acid levels in cholestatic neonates, but this is due to a 522-fold increase in fecal UDCA. A majority of bile acids in early development are atypical positional and stereo-isomers of bile acids. We report novel associations linking isomeric bile acids and BSH activity to neonatal growth trajectories. These data highlight deconjugation of bile acids as a key microbial function that is acquired in early neonatal development and impaired by cholestasis.

Factors influencing plasma concentration of voriconazole and voriconazole- N-oxide in younger adult and elderly patients.

Background: Voriconazole (VCZ) metabolism is influenced by many factors. Identifying independent influencing factors helps optimize VCZ dosing regimens and maintain its trough concentration (C0) in the therapeutic window. Methods: We conducted a prospective study investigating independent factors influencing VCZ C0 and the VCZ C0 to VCZ N-oxide concentration ratio (C0/CN) in younger adults and elderly patients. A stepwise multivariate linear regression model, including the IL-6 inflammatory marker, was used. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive effect of the indicator. Results: A total of 463 VCZ C0 were analyzed from 304 patients. In younger adult patients, the independent factors that influenced VCZ C0 were the levels of total bile acid (TBA) and glutamic-pyruvic transaminase (ALT) and the use of proton-pump inhibitors. The independent factors influencing VCZ C0/CN were IL-6, age, direct bilirubin, and TBA. The TBA level was positively associated with VCZ C0 (ρ = 0.176, p = 0.019). VCZ C0 increased significantly when the TBA levels were higher than 10μmol/L (p = 0.027). ROC curve analysis indicated that when the TBA level ≥4.05μmol/L, the incidence of a VCZ C0 greater than 5μg/ml (95% CI = 0.54-0.74) (p = 0.007) increased. In elderly patients, the influencing factors of VCZ C0 were DBIL, albumin, and estimated glomerular filtration rate (eGFR). The independent factors that affected VCZ C0/CN were eGFR, ALT, γ-glutamyl transferase, TBA, and platelet count. TBA levels showed a positive association with VCZ C0 (ρ = 0.204, p = 0.006) and C0/CN (ρ = 0.342, p < 0.001). VCZ C0/CN increased significantly when TBA levels were greater than 10μmol/L (p = 0.025). ROC curve analysis indicated that when the TBA level ≥14.55μmol/L, the incidence of a VCZ C0 greater than 5μg/ml (95% CI = 0.52-0.71) (p = 0.048) increased. Conclusion: TBA level may serve as a novel marker for VCZ metabolism. eGFR and platelet count should also be considered when using VCZ, especially in elderly patients.

Successful pregnancy of a patient with primary sclerosing cholangitis awaiting liver transplantation

In women, primary sclerotising cholangitis (PSC) associated with ulcerative colitis and intrahepatic cholestasis is a rare disease. To date, there are no data from Hungary on the fertility and pregnancy outcome of women with this chronic liver disease. Our aim is to present the favorable pregnancy outcome of a woman with PSC associated with ulcerative colitis, intrahepatic cholestasis and postpartum colectomy, and review of the literature. A young nulligravida was first diagnosed with ulcerative colitis. Five years later, PSC developed with progressive fibrosis and cholestasis necessitating liver transplantation. While on waiting list, spontaneous conception occurred. Except for pregnancy-induced hypertension, pregnancy uneventfully progressed until the third trimester when 8 g oral cholestyramine/day was administered to lower high maternal (over 100 μmol/L) total bile acid (TBA) level. In the 36th week of gestation acute exacerbation of ulcerative colitis resulted in maternal fever and chorioamnionitis leading to fetal distress. Elective delivery of the eutrophic neonate followed by emergency cesarean section. In the early puerperium, colitis progressed to septic pancolitis resistant to medical treatment. 12 days after laparoscopic subtotal colectomy, the patient was discharged in good health condition. 3 months later, ileostomy was closed and she got back on the transplantation waiting list. Our data correspond with previous reports and suggest that women with PSC with underlying ulcerative colitis and cholestasis have a good chance for favorable pregnancy outcome. However, both PSC and underlying colitis might progress during pregnancy and puerperium. Oral cholestyramin is an effective and safe treatment for high maternal TBA levels. Orv Hetil. 2023; 164(6): 234-240.

New IMB16-4 Hot-Melt Extrusion Preparation Improved Oral Bioavailability and Enhanced Anti-Cholestatic Effect on Rats.

Cholestasis is challenging to treat due to lacked effective drugs. N-(3,4,5-trichlorophenyl)-2 (3-nitrobenzenesulfonamido) benzamide, abbreviated as IMB16-4, which may be effective for the treatment of cholestasis. However, its poor solubility and bioavailability seriously obstruct the research programs. A hot-melt extrusion (HME) preparation was first applied to increase the bioavailability of IMB16-4, the oral bioavailability, anti-cholestatic effect and vitro cytotoxicity of IMB16-4 and IMB16-4-HME were evaluated. Meanwhile, the molecular docking and qRT-PCR were used to validate the mechanism behind. The oral bioavailability of IMB16-4-HME improved 65-fold compared with that of pure IMB16-4. Pharmacodynamics results demonstrated that IMB16-4-HME prominently decreased the serum levels of total bile acid (TBA) and alkaline phosphatase (ALP), but elevated the level of total bilirubin (TBIL) and direct bilirubin (DBIL). Histopathology revealed that IMB16-4-HME at lower dose exhibited stronger anti-cholestatic effect compared with pure IMB16-4. In addition, molecular docking demonstrated that IMB16-4 has great affinity with PPARα, and qRT-PCR results revealed that IMB16-4-HME significantly elevated the mRNA expression level of PPARα, but decreased the mRNA level of CYP7A1. Cytotoxicity assays demonstrated that the hepatotoxicity of IMB16-4-HME was absolutely attributed to IMB16-4, and the excipients of IMB16-4-HME may increase the drug load within HepG2 cells. The HME preparation significantly increased the oral bioavailability and anti-cholestatic effect of pure IMB16-4, but caused liver injury at high dose, which require a dose balance between the curative effect and safety in the future research.

Gestation and lactation triphenyl phosphate exposure disturbs offspring gut microbiota in a sex-dependent pathway.

Triphenyl phosphate (TPhP) is an Organophosphate flame retardant (OPFR) that has been widely used in many commercial products. Following its widely usage, its health risk has been concerned. In this study, mice were exposed to TPhP (1mg/kg) during pregnancy and lactation (E0-PND21), the effect of TPhP on gut microbiota and its role in TPhP mediated lipid metabolism disturbance of offspring was investigated. Our results showed that TPhP disturbed the gut microbiota in dam or offspring at different extent, with male offspring experiencing major effects. Both the composition, abundance or network of gut microbiome was affected in male offspring. In male offspring, expression of genes along gut-liver axis including FXR, CYP7A1, SREBP-1c and ChREBP was significantly up-regulated, and expression of SHP, FGF15 and ASBT was significantly down-regulated. Consistent with this, lipid accumulation in the liver, and increased level of triglyceride, total cholestrol and total bile acid in the serum was observed. The changed abundance of Ruminococcaceae, Clostridiaceae, and Bacteroidaceae shows strong correlation with disturbed lipid metabolism in male offspring. Our research showed that indirect TPhP exposure during early life stage could affect the gut microbiota and gene expression along gut-liver axis in offspring at sex-dependent pathways, with males experiencing more effects.

Obstetric outcome of elevated total serum bile acid levels in women with intrahepatic cholestasis of pregnancy

Obstetric outcome of elevated total serum bile acid levels in women with intrahepatic cholestasis of pregnancy

Efficacy and safety of ursodeoxycholic acid in children with cholestasis: A systematic review and meta-analysis.

Ursodeoxycholic acid (UDCA) is the main therapeutic drug for cholestasis, but its use in children is controversial. We conducted this study to evaluate the efficacy and safety of ursodeoxycholic acid in children with cholestasis. We searched Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, WanFang Data and VIP from the establishment of databases to July 2022. Eligible studies included Chinese or English randomized controlled trials (RCTs) comparing the efficacy and safety of no UDCA (placebo or blank control) and UDCA in children with cholestasis. This study had been registered with PROSPERO (CRD42022354052). A total of 32 RCTs proved eligible, which included 2153 patients. The results of meta-analysis showed that UDCA could improve symptoms of children with cholestasis (risk ratio 1.24, 95% CI 1.18 to 1.29; moderate quality of evidence), and serum levels of alanine aminotransferase, total bilirubin, direct bilirubin and total bile acid (low quality of evidence). For some children with specific cholestasis, UDCA could also effectively drop serum levels of aspartate aminotransferase (parenteral nutrition-associated cholestasis) and γ-glutamyl transferase (infantile hepatitis syndrome, parenteral nutrition-associated cholestasis). The most common adverse drug reactions (ADRs) of UDCA in children were gastrointestinal adverse reactions, with an incidence of 10.63% (67/630). There was no significant difference in the incidence of ADRs between UDCA and placebo/blank control groups (risk difference 0.03, 95%CI -0.01 to 0.06; moderate quality of evidence), and among children taking different UDCA doses (P = 0.27). The available short-term evidence showed that UDCA was effective and safe for children with cholestasis. Clinicians should use UDCA with caution (start with a low dose) until the long-term effect is further explored in future larger RCTs.

Swainsonine Induces Liver Inflammation in Mice via Disturbance of Gut Microbiota and Bile Acid Metabolism.

Swainsonine induced liver inflammation in livestock; however, the underlying mechanisms, especially the role of bile acids (BAs), in the pathogenesis remained elusive. Here, our results showed that swainsonine induced hepatic inflammation via changing BA metabolism and gut microbiota in mice. Swainsonine significantly upregulated the levels of deoxycholic acid (DCA) and taurine-β-muricholic acid (T-β-MCA) in the serum and liver of mice due to the markedly increased genus Clostridium and the decreased genus Lactobacillus in the gut. As antagonists of the farnesoid X receptor (FXR), elevated DCA and T-β-MCA inhibited hepatic Fxr gene expression and thus suppressed FXR-SHP signaling and activated hepatic Cyp7a1 gene expression, which induced a significant upregulation of the total BA level in serum, contributing to liver inflammation. These findings offer new insights into the underlying mechanisms in which swainsonine induced liver inflammation in mice via the gut-liver axis and suggest that gut microbiota and its metabolite BAs may be underlying triggering factors.

Severe Intrahepatic Cholestasis of Pregnancy-Potential Mechanism by Which Fetuses Are Protected from the Hazardous Effect of Bile Acids.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated total bile acids (TBA). Although elevated maternal TBA is a major risk factors for fetal morbidity and mortality, it is unclear why some fetuses are more prone to the hazardous effect of bile acids (BA) over the others. It is unclear whether fetuses are protected by placental BA uptake, or it is the fetal BA metabolism that reduces fetal BA as compared to maternal levels. Therefore, we aimed to compared TBA levels in the umbilical vein and artery to maternal TBA in women with ICP. The study included 18 women who had TBA > 40 μmol/L and their 23 fetuses. We found that the TBA level in umbilical vein was significantly lower compared to maternal TBA level. The TBA levels in umbilical vein and umbilical artery were similar. No fetus had a serious neonatal complication. Importantly, since TBA level remains low even though maternal TBA level is high the fetuses are protected from the hazardous effects of maternal BA. Our findings suggest that there is no effective metabolism of BA in the fetus and the main decrease in TBA in the fetus is related to placental BA uptake.

Modified myocardial performance index for evaluation of fetal heart function and perinatal outcomes in intrahepatic pregnancy cholestasis.

This study aims to evaluate cardiac function in cases of intrahepatic cholestasis of pregnancy (ICP) and compare results with those from healthy controls using the fetal left ventricular modified myocardial performance index (LMPI) and E-wave/A-wave peak velocities (E/A ratio). Moreover, the association between LMPI values, total bile acid (TBA) levels, fetal Doppler measurements, and adverse neonatal outcomes was evaluated. A prospective cross-sectional study of 120 pregnant women was conducted, with 60 having ICP and the other 60 serving as controls. Doppler ultrasound and two-dimensional gray-scale fetal echocardiography were used to calculate the LMPI values and E/A ratios, respectively. The association between LMPI values and TBA levels, fetal Doppler measurements, and adverse neonatal outcomes was evaluated. Fetal LMPI values were significantly higher in the ICP group than in the control group (0.54 ± 0.54 vs. 0.44 ± 0.03; p < 0.001), but the E/A ratio was similar in both groups (0.69 ± 0.10 vs. 0.66 ± 0.14; p = 0.203). TBA levels were positively and significantly correlated with LMPI values (r = 0.546, p < 0.01); however, no significant correlation was found between umbilical arterial pulsatility index values and LMPI values (r = 0.071, p > 0.01). LMPI values were not associated with adverse neonatal outcomes in ICP cases. Fetal cardiac function (LMPI) is associated with increased bile acid levels in ICP. However, because it was not associated with adverse neonatal outcomes in ICP cases, the clinical significance of this finding is unclear. Further studies are required to evaluate the implications of increased LMPI.

Triaging donor lungs based on a microaspiration signature that predicts adverse recipient outcome

Aspiration is a relative contraindication to accepting donor lungs for transplant and is currently assessed by visual inspection of the airways via bronchoscopy. However, this method is limited as it does not assess for microaspiration. Bile acids measured in large airway bronchial wash (LABW) samples have been shown to be a marker of aspiration in lung transplant recipients. Herein, we investigate the utility of measuring total bile acids (TBA) in donor LABW to predict performance of donor lungs and recipient outcomes. TBA was measured in 605 consecutive lung donors at the Toronto Lung Transplant Program. TBA levels were compared in donor lungs deemed unsuitable for transplant, requiring further assessment on ex vivo lung perfusion (EVLP), and those suitable for direct transplantation using Mann-Whitney-U tests. Relationships between LABW TBA concentrations and recipient outcomes were evaluated using multivariable Cox-PH models and log-rank analysis. Donor TBA was highest in lungs deemed unsuitable for transplant and correlated with clinical assessment of aspiration. LABW TBA concentration correlated with calcium, decreased pH, and increased pro-inflammatory mediators in EVLP perfusate. TBA cut-off of 1245 nM was able to differentiate donor lungs directly declined from those suitable for direct transplantation with a 91% specificity (AUROC: 73%). High donor TBA status was associated with the increased rate of primary graft dysfunction, longer time to extubation, and shorter time to chronic lung allograft dysfunction. In a large retrospective cohort, we observed that donor LABW TBA was associated with suitability of donor lungs for transplant, performance of the organ on EVLP, and adverse recipient outcomes.

Placental exosomal level of alanine aminotransferase is more accurate predictive biomarker of intrahepatic cholestasis of pregnancy than total bile acid

Aims: As a serious liver abnormality, intrahepatic cholestasis of pregnancy (ICP) uniquely occurs in pregnant women. In the present study, we examined whether placental exosomes and their protein contents could serve as novel indicators to help early diagnosis of ICP.&#x0D; Methods: The current retrospective stratified study design included a 100 healthy pregnant females and a 100 patients with ICP. Plancental exosomes were isolated to determine the exosomal levels of alanine aminotransferase (ALT) and total bile acid (TBA). The predictive values of placental exosomal TBA and ALT were determined using receiver operating characteristic (ROC) curve analysis.&#x0D; Results: The placental exosomal TBA level did not exhibit any obvious differences between healthy and ICP pregnancies. Moreover, placental exosomal ALT level was significantly higher in ICP-affected pregnancy than healthy control. Analysis of the ROC curve further demonstrated that placental exosomal level of ALT yields better sensitivity and specificity to distinguish ICP patients from healthy individuals, than that of TBA.&#x0D; Conclusions: Placental exosomal ALT is a more accurate predictive biomarker of ICP than TBA and, therefore, can be employed with reliability as a characteristic abnormality in diagnosis of ICP.

Effect of nicotine on cholesterol gallstone formation in C57BL/6J mice fed on a lithogenic diet.

Gallstones are diseases of the biliary system caused by cholesterol supersaturation and/or deficiency in bile salts in bile. Early studies have shown that symptomatic gallstones are primarily a disease of non-smokers, raising the possibility that nicotine can prevent gallstone formation. The present study investigated the effect of nicotine on the formation of cholesterol gallstone in C57BL/6J mice. C57BL/6J mice (eight-weeks-old) were fed a normal or lithogenic diet (basic feed 82.45%, fat 15.8%, cholesterol 1.25% and sodium cholate 0.5%) and divided into five groups: normal diet (ND); ND + high dose nicotine (H); lithogenic diet (LD); LD + low dose nicotine (L) and LD + nicotine (H). They were treated with or without nicotine injection for 10 weeks. Nicotine treatment did not change the rate of cholesterol gallstone formation. There was no difference in TNFα, IL-1β and IL-6 among the five groups. The LD group showed the highest cholesterol levels and there was significant suppression of the total cholesterol, low-density lipoprotein-cholesterol and total bile acid levels in the serum of the nicotine-treated mice. Quantitative PCR showed nicotine altered few bile acid metabolism-related genes expression in liver tissue and significantly altered cholesterol-metabolism genes in gallbladder tissue. Hematoxylin and eosin staining and western blotting showed that protein levels of farnesoid X receptor (FXR) and megalin in the gallbladder increased in the lithogenic-diet mice, which was significantly suppressed in the nicotine-treated mice. In vitro studies using gallbladder epithelial cells showed that chenodeoxycholic acids increased megalin expression, which could be attenuated by nicotine. Nicotine could regulate bile acid metabolism via the FXR-megalin/cubilin pathways, which potentially contribute to cholesterol nucleation and subsequent gallstone formation.

The triacylglycerol structure and composition of a human milk fat substitute affect the absorption of fatty acids and calcium, lipid metabolism and bile acid metabolism in newly-weaned Sprague-Dawley rats.

In this study, the effect of sn-2 palmitic triacylglycerols (sn-2 palmitic TAGs) and the ratio between the two major sn-2 palmitic TAGs (OPL to OPO ratio) in a human milk fat substitute (HMFS) on growth, fatty acid and calcium absorptions, and lipid and bile acid metabolic alterations was investigated in Sprague-Dawley rats. After 4 weeks of high-fat feeding, rats fed with the HMFS containing a sn-2 palmitic acid content of 57.87% and an OPL to OPO ratio of 1.4 showed the lowest TAG accumulation in their livers and hypertrophy of perirenal adipocytes, compared to the groups fed with fats containing a lower sn-2 palmitic acid content or a lower OPL to OPO ratio. Meanwhile, synergistically improved absorption of fatty acids and calcium and increased levels of total bile acids (BAs), especially for the tauro-conjugated BAs (TCDCA, TUDCA, TαMCA, TβMCA, TDCA and TωMCA), were observed in rats by both increasing the sn-2 palmitic acid content and the OPL to OPO ratio in HMFS. In addition, the levels of total BAs and tauro-conjugated BAs were negatively correlated with serum TAG, TC, and LDL-c levels and positively correlated with HDL-c levels according to Spearman's correlation analysis (P < 0.05). Collectively, these findings present new nutritional evidence for the potential effects of the TAG structure and composition of a human milk fat substitute on the growth and lipid and bile acid metabolism of the host in infancy.

Hepatic Aquaporin 10 Expression Is Downregulated by Activated NFκB Signaling in Human Obstructive Cholestasis.

Recent studies reported that the hepatic expression of AQP8 and AQP9 was downregulated in bile duct-ligated (BDL) rats and that overexpression of human AQP1 in the rat liver attenuated cholestasis. However, the hepatic expression of AQP10 and its regulatory mechanism in human cholestasis remain unclear. Serum and liver samples were collected from 34 patients with obstructive cholestasis and from 12 control patients. Eight-week-old male C57BL/6J mice were intravenously injected with an adeno-associated virus 8 (AAV8) encoding human AQP10 driven by a hepatocyte-specific Alb promotor (AAV8-Alb promotor-hAQP10) for functional studies. Constructs of the AQP10 promoter and PLC/PRF/5-ASBT cell lines were used for regulatory mechanism studies. AQP10 was significantly downregulated in patients with obstructive cholestasis and negatively associated with the serum levels of total bile acid (TBA). The hepatocyte-specific overexpression ofhAQP10significantly attenuated the cholestatic liver injury and intrahepatic bile acids (BA) accumulation in BDL mice. Conjugated BAs, such as TCA and inflammatory factor TNFα, significantly repressed AQP10 expression. Furthermore, NFκB p65/p50 directly bound to the AQP10 promotor and decreased its activity in PLC/RPF/5-ASBTcells and in the livers of patients with obstructive cholestasis. However, these changes were diminished by BAY 11-7082 (a specific inhibitor of NFκB signaling). We are the first to report that AQP10 was significantly decreased in patients with obstructive cholestasis. AQP10 overexpression significantly attenuated cholestatic liver injury in BDL mice. Therefore, overexpression of hAQP10 in the liver may be a valuable strategy for cholestasis intervention.

The regulatory effects of fucoidan and laminarin on functional dyspepsia mice induced by loperamide.

Gastrointestinal dysmotility is a common cause of functional dyspepsia. As two kinds of polysaccharides derived from brown algae, fucoidan and laminarin possess many physiological properties; however, their relative abilities in regulating gastrointestinal motility have not been illustrated yet. In this study, we aimed to investigate the regulatory effect of fucoidan and laminarin on functional dyspepsia mice induced by loperamide. Mice with gastrointestinal dysmotility were treated with fucoidan (100 and 200 mg per kg bw) and laminarin (50 and 100 mg per kg bw). As a result, fucoidan and laminarin reversed the dysfunction mainly through regulating gastrointestinal hormones (motilin and ghrelin), the cholinergic pathway, the total bile acid level, c-kit protein expression, and gastric smooth muscle contraction-related gene expression (ANO1 and RYR3). Moreover, fucoidan and laminarin intervention modulated the gut microbiota profile including the altered richness of Muribaculaceae, Lachnospiraceae, and Streptococcus. The results indicated that fucoidan and laminarin may restore the rhythm of the migrating motor complex and regulate gut microecology. In conclusion, we provided evidence to support that fucoidan and laminarin might have potential abilities to regulate gastrointestinal motility.