Role of apical sodium-dependent bile acid transporter in hepatobiliary diseases / 临床肝胆病杂志

Apical sodium-dependent bile acid transporter （ASBT） is a key transporter responsible for intestinal reabsorption of bile acid and plays an important role in maintaining bile acid and cholesterol homeostasis， and its expression is regulated by various factors including transcription factors， nuclear receptors， and intestinal microflora. The abnormal expression and function of ASBT can lead to disorders in the metabolism of bile acid and cholesterol， causing a variety of hepatobiliary diseases. At present， ASBT has attracted wide attention as a therapeutic target. This article elaborates on the biological characteristics and expression regulation mechanism of ASBT and reviews the role of ASBT in hepatobiliary diseases， in order to provide a new direction for the treatment of related diseases.

A Retrospective Analysis of Fetal and Maternal Outcome in Patients with Intrahepatic Cholestasis of Pregnancy

Background: Introduction: Intrahepatic cholestasis of pregnancy (ICP), is the most common liver disease specific to pregnancy. Previous studies of fetal effects have suggested that ICP is associated with a higher rate of adverse neonatal outcomes including preterm birth, neonatal respiratory distress syndrome (RDS), meconium-stained amniotic fluid, neonatal intensive care unit admission, and stillbirth. Material & Methods: This was a 4 year retrospective observational study including 43,344 female who delivered in our hospital out of which 1126 cases of ICP were identified, who were compared with 1136 age and parity matched controls. Results: : Previous history and family history of ICP was significant in the ICP group. Gestational diabetes and preterm labour were more frequent in the ICP group. Mean birth weight was lower in the ICP group, rate of small for gestational age foetuses was not significantly different. Cesearean section and post-partum haemorrhage was more frequent in the ICP group. Adverse neonatal outcomes i.e. respiratory distress syndrome (RDS) and need for NICU admission were more in the ICP group. Conclusion: ICP is associated with increased rate of preterm delivery, post-partum hemorrhage and increased neonatal morbidity. Management of patients with ICP should be individualized based on the severity of symptoms and associated medical complications.

Effect of Modified Gegen Qinliantang on TGR5/cAMP/GLP-1 Signaling Pathway in Pancreatic Tissue of Type 2 Diabetes Mellitus db/db Mice / 中国实验方剂学杂志

ObjectiveTo discuss the effect of modified Gegen Qinliantang （MGQT） on blood glucose and lipids and Takeda G protein-coupled receptor 5 （TGR5）-related pathways in pancreatic tissue of obese type 2 diabetes mellitus （T2DM） mice. MethodA total of 10 male specific pathogen free （SPF） m/m mice （7 weeks old） and 50 male SPF （7 weeks old） were adaptively fed for one week in SPF laboratory. The m/m mice were included in the blank group. T2DM was induce d in the 50 db/db mice. The model mice were randomized into the model group， metformin group （0.2 g·kg-1）， high-dose， medium-dose， and low-dose （31.9， 19.1， 6.4 g·kg-1） MGQT groups， with 10 in each group， and the drug dose was10 mL·kg-1. The model group and the blank group received distilled water of the same volume. The administration lasted 12 weeks （once/day）. Fasting blood glucose （FBG） was detected regularly. After 12 weeks of administration， serum levels of glycated serum protein （GSP）， serum glucose （GLU）， total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） were detected. Pathological changes in the pancreatic tissue were based on hematoxylin-eosin （HE） staining. Western blot was used to determine the protein expression of TGR5， protein kinase A （PKA）， phosphorylated （p）-PKA， cyclic-AMP response element binding protein （CREB）， p-CREB， proprotein convertase 1/3 （PC1/3）， and glucagon-like peptide-1 （GLP-1） in pancreatic tissues. The level of cyclic adenosine monophosphate （cAMP） in pancreatic tissue was determined by enzyme-linked immunosorbent assay （ELISA）. ResultCompared with the blank group， the model group had pathological changes in pancreatic tissue， high levels of FBG， GSP， GLU， TC， TG， and LDL-C （P<0.01）， low level of HDL-C （P<0.05）， low protein expression of TGR5， p-PKA （Thr197）/PKA， p-CREB （Ser133）/CREB， PC1/3， and GLP-1 in pancreatic tissue （P<0.01）， and low content of cAMP in the pancreas （P<0.01）. Pancreatic tissue lesion in the treatment groups were milder than that in the model group. Both the high-dose MGQT and metformin can reduce the levels of FBG， GSP， GLU， TC， TG， and LDL-C in db/db mice （P<0.05， P<0.01） and increase the level of HDL-C （P<0.01）. Except the GLP-1 protein in the medium-dose MGQT group， the protein expression of TGR5， p-PKA （Thr197）/PKA， p-CREB （Ser133）/CREB， PC1/3， and GLP-1 in the high-dose and medium-dose MGQT groups and the metformin group increased compared with that in the model group （P<0.05， P<0.01）. The content of cAMP in the pancreatic tissue of the high-dose and medium-dose MGQT groups and the metformin group was raised compared with that in model group （P<0.05， P<0.01）. ConclusionMGQT can improve the glucose homeostasis in db/db mice with T2DM by regulating TGR5/cAMP/GLP-1 signaling pathway-related protein expression.

Biological Connotation of Pathogenesis of Ulcerative Colitis with Liver Depression and Spleen Deficiency Based on Bile Acid-intestinal Flora Axis / 中国实验方剂学杂志

Ulcerative colitis （UC） is one of the chronic refractory inflammatory bowel diseases characterized by abdominal pain， diarrhea， and mucus， pus and blood in the stool. In recent years， with changes in human life style and improvements of the diagnosis， the incidence and prevalence of UC have been increasing. The pathogenesis of UC is closely related to intestinal mucosal immune dysfunction， intestinal flora disturbance， and abnormal bile acid secretion. Patients with UC have abnormal bile acid secretion and intestinal flora imbalance. A large number of studies have found that abnormal bile acid secretion inhibits immune function， affects signal transduction， and destroys the intestinal mucosal barrier. Intestinal flora disturbance has an important impact on the occurrence and development of inflammation， immune homeostasis， and stress. Bile acids indirectly or directly affect the structure and function of intestinal flora， and at the same time， they produce secondary bile acids under the modification of intestinal flora， entering the liver through enterohepatic circulation. Therefore， the complex dialogue mechanism of bile acid-intestinal flora axis is closely related to the occurrence and development of UC. Based on the basic theory of traditional Chinese medicine（TCM） and clinical research， it is found that emotion is an important factor that induces this disease， spleen and stomach weakness is the root of the disease， and liver depression and spleen deficiency are the key pathogenesis of UC. Combined with modern medicine and molecular biology research， it is believed that abnormal secretion of bile acids is a microscopic manifestation of liver depression in TCM， and intestinal flora disturbance is the biological basis of spleen deficiency. In the pathogenesis of UC， the imbalanced bile acid-intestinal flora axis is consistent with the pathogenesis of liver depression and spleen in TCM. The exploration of the biological connotation of the pathogenesis of UC with liver depression and spleen deficiency from the perspective of bile acid-intestinal flora axis can better explain the scientific nature of its pathogenesis， which provides new clinical solutions and reliable references for studying the pathogenesis of UC with liver depression and spleen deficiency and finding representative prescriptions to prevent and treat this disease.

Advances in analytical methods for endogenous bile acids based on UPLC-MS/MS technology / 药学学报

Bile acids (BAs) are a group of endogenous steroid molecules that regulate lipid, glucose and energy metabolism. They play an important role in maintaining body homeostasis and physiological functions as key signaling molecules for host and gut microbial metabolism. The accurate characterization and quantification of BAs in vivo is of great importance in basic and clinical research. Over the past decades, enzymatic assay, enzyme-linked immunoassay, nuclear magnetic resonance (NMR), chromatography, and other related techniques have been developed and applied to the detection of BAs. The diverse structures of BAs, the existence of isomers and the complex matrix of biological samples pose great challenges for the detection of endogenous BAs. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is a robust analytical technique that combines the rapid separation capacities of UPLC with the powerful structural identification capabilities of MS/MS, facilitating the more rapid separation, characterization and accurate quantitative of target analytes in biological samples. UPLC-MS/MS has been widely used in the quantitative analysis of BAs in recent years for its high selectivity, high sensitivity, and high accuracy. This paper summarized the biosynthetic pathways of BAs, sample pretreatment methods, common analytical detection techniques, and highlights the current status of the application of UPLC-MS/MS technology in the analysis of endogenous BAs over the past five years, to provide a reference for the accurate detection of endogenous BAs and further research development and application.

Value of the combined use of aminotransferase-to-platelet ratio index and total bile acid for predicting parenteral nutrition-associated cholestasis in preterm infants with gestational age <34 weeks / 中国当代儿科杂志

OBJECTIVES@#To explore the value of the combined use of aspartate aminotransferase-to-platelet ratio index (APRI) and total bile acid (TBA) for predicting parenteral nutrition-associated cholestasis (PNAC) in preterm infants with gestational age <34 weeks.@*METHODS@#A retrospective analysis was performed on medical data of 270 preterm infants born at <34 weeks of gestation who received parenteral nutrition (PN) during hospitalization in the First Affiliated Hospital of Wannan Medical College from January 2019 to September 2022, including 128 infants with PNAC and 142 infants without PNAC. The medical data between the two groups were compared, and predictive factors for the development of PNAC were explored through multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve was used to evaluate the value of APRI alone, TBA alone, and the combination of both for predicting PNAC.@*RESULTS@#TBA levels in the PNAC group after 1, 2, and 3 weeks of PN were higher than those in the non-PNAC group (P<0.05). APRI in the PNAC group after 2 and 3 weeks of PN was higher than that in the non-PNAC group (P<0.05). Multivariate logistic regression analysis showed that elevated APRI and TBA after 2 weeks of PN were predictive factors for PNAC in preterm infants (P<0.05). ROC curve analysis showed that the sensitivity, specificity, and area under the curve (AUC) for predicting PNAC by combining APRI and TBA after 2 weeks of PN were 0.703, 0.803, and 0.806, respectively. The AUC for predicting PNAC by combining APRI and TBA was higher than that of APRI or TBA alone (P<0.05).@*CONCLUSIONS@#After 2 weeks of PN, the value of combining APRI and TBA for predicting PNAC is high in preterm infants with gestational age <34 weeks.

Protective mechanism of Yinchenzhufu decoction against cholestatic liver injury induced by lithic acid based on network pharmacology / 药学学报

Yinchenzhufu decoction (YCZFD) is a classic formula for treating Yin Huang syndrome, which can improve liver injury caused by cholestasis. However, the mechanism of action of YCZFD still remains unclear. This article used network pharmacology, molecular docking, animal experiments, and molecular biology methods to explore the mechanism of YCZFD in treating liver injury caused by cholestasis. A mouse model of acute cholestasis induced by lithocholic acid was used to investigate the effects of YCZFD on liver injury. The experimental procedures described in this paper were reviewed and approved by the Ethical Committee at the Shanghai University of Traditional Chinese Medicine (approval NO. PZSHUTCM190823002). The results showed that YCZFD could reduce the levels of blood biochemical indicators and improve hepatocyte damage of cholestatic mice. Then, multiple databases were used to predict the corresponding targets of YCZFD active components on cholestatic liver injury. An intersection target protein-protein interaction (PPI) networks based on String database and Cytoscape software was used to demonstrate the possible core targets of YCZFD against cholestatic liver injury. The results indicated that core targets of YCZFD include tumor necrosis factor, interleukin-1β, non-receptor tyrosine kinase Src, interleukin-6, etc. GO (gene ontology) and KEGG (kyoto encyclopedia of genes and genomes) enrichment analysis indicated that YCZFD may regulate the tumor necrosis factor signaling pathway, nuclear factor-κB signaling pathway, bile secretion, and other related factors to ameliorate the cholestatic liver injury. AutoDockTools software was used to perform molecular docking verification on the core targets and components of YCZFD. To verify the results of network pharmacology, UPLC-MS/MS method was used to determine the effect of YCZFD on levels of bile acid profiles in mouse liver tissues. It was found that treatment with YCZFD significantly reduced the content of free bile acids, taurine bound bile acids, and total bile acids in the liver tissues of cholestatic mice. Then, results from real time PCR and Western blot also found that YCZFD can upregulate the expression of hepatic nuclear receptor farnesoid X receptor, metabolizing enzyme (UDP glucuronidase transferase 1a1), and efflux transporters (bile salt export pump, multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, etc) in cholestasis mice, promote bile acid metabolism and excretion, and improve bile acid homeostasis. Moreover, YCZFD can also inhibit pyroptosis and inflammation by regulating NOD-like receptors 3 pathway, thereby inhibiting cholestatic liver injury.

Fexaramine improves non-alcoholic fatty liver disease in mice by stimulating intestinal FXR / 药学学报

Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of metabolic syndrome and has become one of the chronic diseases that endanger health around the world. There is still a lack of effective therapeutic drugs in clinical practice. Farnesoid X receptor (FXR) has been a popular target for NAFLD research in recent years. Fexaramine (Fex) is a potent and selective agonist of FXR, and its mechanism of action to improve NAFLD is unclear. Therefore, in this study, a mouse model of NAFLD was constructed using a high-fat, high-cholesterol diet and treated with Fex orally for 6 weeks. We evaluated the ameliorative effect of Fex on disorders of glucolipid metabolism in NAFLD mice, and preliminarily explored its potential mechanism of action. The animal experiments were approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (approval number: PZSHUTCM210913011). In this study, it was found that 100 mg·kg-1 Fex significantly inhibited body weight gain, alleviated insulin resistance, improved liver injury and lipid accumulation in NAFLD mice. The effect of Fex on the expression of hepatic intestinal FXR and its target genes in NAFLD mice was further examined. Analysis of serum and hepatic bile acid profiles and expression related to hepatic lipid metabolism. It was found that Fex could stimulate intestinal FXR, promote fibroblast growth factor 15 (FGF15) secretion, inhibit the expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, regulate bile acid synthesis by negative feedback, and improve the disorder of bile acid metabolism. At the same time, Fex reduces liver lipid synthesis and absorption, increases fatty acid oxidation, thus improving liver lipid metabolism. This study shows that Fex can improve NAFLD by activating intestinal FXR-FGF15 signal pathway and regulating liver lipid metabolism.

Therapeutic effect of retention enema with compound rhubarb decoction on a rat model of minimal hepatic encephalopathy based on bile acid metabolomics / 临床肝胆病杂志

ObjectiveTo investigate the therapeutic effect of rhubarb decoction （RD） retention enema on a rat model of minimal hepatic encephalopathy （MHE） and its mechanism of action based on bile acid （BA） metabolomics. MethodsA total of 55 male Sprague－Dawley rats were randomly divided into blank group （NC group with 10 rats）， hepatic encephalopathy group （HE group with 15 rats）， MHE group with 15 rats， and MHE+rhubarb decoction treatment group （MHEY group with 15 rats）. Intraperitoneal injection of carbon tetrachloride （CCl4） and thioacetamide （TAA） was performed to establish a rat model of MHE or HE， and the rats were sacrificed after 2 weeks of administration. The serum levels of aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， alkaline phosphatase （ALP）， total bilirubin （TBil）， and total bile acid （TBA） and the concentration of blood ammonia were measured； the colonic contents were collected to measure pH value； liver and brain tissue samples were collected， and HE staining was used to observe the histopathological changes of the liver； the bile was collected， and liquid chromatography－mass spectrometry was used to perform BA－targeted metabolomics analysis. Continuous data were expressed as mean±standard deviation； a one－way analysis of variance was used for comparison between multiple groups， and the least significant difference t－test was used for further comparison between two groups. ResultsCompared with the NC group， the HE group and the MHE group had a significant increase in searching platform latency （after modelling and after administration） and a significant reduction in the number of platform crossings （all P<0.05）； compared with the MHE group， the MHEY group had a significant reduction in searching platform latency （after administration） and a significant increase in the number of platform crossings， and the HE group had a significant increase in searching platform latency and a significant reduction in the number of platform crossings （all P<0.05）. Compared with the NC group， the HE group and the MHE group had significant increases in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）； compared with the MHE group， the MHEY group had significant reductions in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）， and the HE group had significant increases in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）. The MHE group had significantly lower TBA， primary BA， and secondary BA than the NC group （all P<0.05）； compared with the MHE group， the HE group had significantly lower TBA and primary BA （all P<0.05）， and the MHEY group had significantly higher TBA and primary BA （all P<0.05）. Compared with the NC group， the MHE group had significant reductions in GCDCA， GUDCA， GHDCA， TCDCA， TUDCA， GLCA， and TLCA （all P<0.05） and significant increases in γ－MCA， THCA， 7－KDCA， AlloLCA， and α－MCA （all P<0.05）， and compared with the MHE group， the MHEY group had significant increases in THDCA， TMCA， TCDCA， TUDCA， and TLCA （all P<0.05）. ConclusionRD retention enema can improve liver injury and cognitive function in a rat model of MHE induced by CCl4 and TAA by regulating the enterohepatic circulation of BA， possibly by increasing the synthesis of taurine－binding BA.

Correlation between serum bile acid and glucose and lipid metabolism in type 2 diabetes patients with metabolic fatty liver disease / 中国综合临床

Objective:To analyze the correlation between serum bile acid and glycolipid metabolism in patients with type 2 diabetic mellitus (T2DM) and metabolically associated fatty liver disease (MAFLD).Methods:A total of 387 T2DM patients hospitalized in Jinan Central Hospital in Shandong Province from July 2020 to November 2021 were selected, including 140 T2DM patients (T2DM group) and 247 T2DM patients with MAFLD (T2DM with MAFLD group). Clinical data were collected of all patients for retrospective analysis and compare the differences in clinical datas in the T2DM group and the T2DM with MAFLD group. Analyze the influencing factors of T2DM with MAFLD. The serum total bile acid (S-TBA) of the T2DM with MAFLD group was divided into T1, T2 and T3 groups by the method of trisection. Triglyceride glucose index (TyG) and hemoglobin glycation index (HGI) were divided into low TyG group, high TyG group and low HGI group, high HGI group by their median values. The incidence of hyperlipidemia, degree of insulin resistance and glycosylated hemoglobin variation was compared among the three groups. To analyze the influencing factors of TyG and HGI. The measurement data conforming to the normal distribution were compared between two groups by independent sample t-test, the comparison between multiple groups by ANOVA, the comparison between two groups of measurement data not conforming to the normal distribution by Mann Whitney U test, and the comparison between multiple groups by Kruskal Wallis H test, χ 2 test was used for comparison of count data between groups. The influencing factors of T2DM with MAFLD and high HGI were analyzed by multivariate binary Logistic regression. The influencing factors of TyG were analyzed using multiple stepwise linear regression. Results:There was no significant difference between the S-TBA of T2DM group and T2DM with MAFLD group ( P>0.05). TyG ( OR=1.788, 95% CI: 1.223-2.614), superoxide dismutase (SOD) ( OR=1.019, 95% CI: 1.009-1.030) and VFA (visceral fat area) ( OR=1.021, 95% CI: 1.013-1.028) were risk factors for the occurrence of T2DM with MAFLD ( P values are 0.003, 0.001 and 0.001, respectively). The incidence of high TyG in T3 group (61.0% (50/82)) as higher than that in T1 group (40.0% (32/80)), the incidence of high HGI in T3 group (61.0% (50/82)) was higher than that in T2 group (41.2% (35/85)), the morbidity of hypercholesterolemia in T3 group (15.9% (13/82)) was higher than that in T2 group (4.7% (4/85)), the differences were statistically significant (χ 2 values were 7.13, 6.55, 5.67; the P values were 0.008, 0.011, 0.017). S-TBA, hepatic steatosis index (HSI) and VFA were independent influencing factors of TyG (the P values were 0.003, <0.001, <0.001). S-TBA ( OR=0.940, 95% CI:0.887-0.997) and fasting C peptide ( OR=0.454, 95% CI:0.219-0.940) were protective factors for the occurrence of high HGI (the P values were 0.039, 0.034). Conclusion:S-TBA was positively correlated with the degree of insulin resistance and incidence of hypercholesterolemia in patients with T2DM and MAFLD, negatively correlated with the degree of glycated hemoglobin variation.

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor / 中西医结合学报

OBJECTIVE@#This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR).@*METHODS@#Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway.@*RESULTS@#Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon.@*CONCLUSION@#Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Lesión de la mucosa intestinal asociada a cristales: serie de casos y revisión de la literatura / Intestinal mucosal lesion associated with crystals: Case series and literature review

Resumen La lesión de la mucosa asociada a cristales es un cuadro clínico importante en un subconjunto de pacientes urémicos a los que se les administran resinas de intercambio catiónico como el sulfonato de poliestireno sódico (Kayexalate) y sevelamer para el tratamiento de la hiperpotasemia y la hiperfosfatemia, respectivamente. La necrosis colónica en estos pacientes es rara, pero puede estar asociada a una lesión gastrointestinal mortal, con una tasa de mortalidad del 33%. Los secuestrantes de ácidos biliares son otro tipo de resina que teóricamente son biológicamente inertes. Se presentan dos casos de colitis asociada a cristales. El primer paciente tenía antecedentes de múltiples intervenciones quirúrgicas y patologías del tracto gastrointestinal, y estaba en manejo con colestiramina. Se realizó una sigmoidectomía en la que se encontraron varios focos de cristales. El segundo paciente tenía antecedente de enfermedad renal crónica que requirió el uso de Kayexalate y se presentó al servicio de urgencias con una hemorragia grave del tracto gastrointestinal inferior. Se realizó una colectomía parcial en la que se detectaron cambios morfológicos relacionados con el depósito de cristales. Las resinas pueden producir un amplio espectro de lesiones mortales de la mucosa, por lo que el diagnóstico precoz es fundamental para disminuir la mortalidad y mejorar el pronóstico. Sin embargo, es incierto si el consumo de colestiramina y Kayexalate, así como el depósito de sus cristales en el tracto gastrointestinal son el factor causal de la lesión de las mucosas. Por tanto, la presencia de resinas debería ayudar a establecer el diagnóstico correcto y el tratamiento médico oportuno para evitar resultados nocivos.

Abstract Crystal-associated mucosal injury is a crucial clinical picture in a subset of uremic patients who are given cation exchange resins such as sodium polystyrene sulfonate (Kayexalate) and sevelamer to treat hyperkalemia and hyperphosphatemia, respectively. Colonic necrosis in these patients is rare but may be associated with fatal gastrointestinal injury, with a mortality rate of 33%. Bile acid sequestrants are another type of resin that is theoretically biologically inert. Two cases of colitis associated with crystals are presented. The first patient had a history of multiple surgeries and pathologies of the gastrointestinal tract and was treated with cholestyramine. A sigmoidectomy was performed in which several crystal foci were found. The second patient had a history of chronic kidney disease requiring Kayexalate and attended the emergency department with severe lower GI bleeding. A partial colectomy was performed in which morphological changes related to the deposit of crystals were detected. Resins can cause a broad spectrum of malignant mucosal lesions, so early diagnosis is essential to reduce mortality and improve prognosis. However, it is uncertain whether the consumption of cholestyramine and kayexalate, as well as the deposition of their crystals in the GI tract, are the causative factor of mucosal damage. Therefore, resins should help establish the correct diagnosis and prompt medical treatment to avoid harmful results.

Asociación de los niveles de ácidos biliares y hormonas tiroideas en la colestasis intrahepática del embarazo

La colestasis intrahepática del embarazo (CIE) conduce a resultados perinatales adversos y estos resultados se ven afectados por los niveles elevados de ácido biliar total (ABT). Los estudios han demostrado que las hormonas tiroideas regulan el metabolismo de los ácidos biliares. Sin embargo, pocos estudios han evaluado el papel de las hormonas tiroideas en la CIE. Objetivo: Evaluar la función tiroidea junto con los niveles de ABT en la CIE. Métodos. En este estudio retrospectivo, se evaluaron 252 mujeres embarazadas, incluyendo 126 CIE y 126 controles. Se determinaron los niveles de ABT, hormona estimulante de la tiroides (TSH) y tiroxina libre (fT4) del tercer trimestre de todas las embarazadas. Se examinó la correlación entre los niveles de ABT, fT4 y TSH. Además, se estudiaron los resultados perinatales de ambos grupos. Resultados. Los niveles de fT4 fueron significativamente mayores en la CIE. También hubo una correlación positiva entre los niveles de fT4 y ABT. Los niveles de TSH fueron similares en ambos grupos y no hubo una correlación significativa con los niveles de ABT. No hubo diferencias significativas entre los dos grupos en cuanto a enfermedades tiroideas en el tercer trimestre. Conclusiones. Un mayor nivel de fT4 se asoció a un mayor nivel de ABT y el nivel de fT4 se asoció a un mayor riesgo de CIE y a la gravedad de la CIE, pero el nivel de TSH no se asoció a un mayor riesgo de ABT y de CIE.

Intrahepatic cholestasis of pregnancy (ICP) leads to adverse perinatal outcomes and these outcomes are affected by high total bile acid (TBA) levels. Studies have shown that thyroid hormones regulate bile acid metabolism. However, few studies have evaluated the role of thyroid hormones in ICP. Objective: To evaluate thyroid function along with TBA levels in ICP. Methods: In this retrospective study, 252 pregnant women, including 126 ICP and 126 controls, were evaluated. Third trimester TBA, thyroid-stimulating hormone (TSH), and free thyroxine (fT4) levels of all pregnant women were assessed. Correlation between TBA and fT4, TSH levels were examined. In addition, the perinatal outcomes of both groups were determined. Results: fT4 levels were significantly higher in ICP. There was also a positive correlation between fT4 and TBA levels. TSH levels were similar in both groups and there was no significant correlation with TBA levels. There was no significant difference between the two groups in thyroid diseases in the third trimester. Conclusions: Higher fT4 level was associated with higher TBA level and fT4 level was associated with higher ICP risk and ICP severity, but TSH level was not associated with higher TBA and higher ICP risk.

Neonatal cholestasis – A case report on congenital bile acid synthetic defect type 4 and severe anemia

Congenital defects of bile acid synthesis are rare disorders that cause progressive liver dysfunction. We present a case of alpha methyl acyl-CoA racemase (AMACR) deficiency with non-spherocytic hemolytic anemia who presented with rapidly progressive severe cholestasis and liver failure with normal gamma-glutamyl transferase levels. After extensive investigation, he was found to have AMACR deficiency with HBB gene mutation associated with non-spherocytic hemolytic anemia possibly explaining the severity of the disease. To the best of our knowledge, a similar association has not been reported so far.

Recent advances in drug development targeting bile acids transporters and related disease / 药学学报

Bile acids (BAs) are a major component of bile salt, which plays a vital role in the metabolism of lipids in humans. Ninety-five percent of bile acids are recycled by the enterohepatic circulation (EHC), and therefore EHC is essential for bile acid homeostasis. There are four transporters that mediate the transmembrane transport of bile acids, each of which plays an important role in the enterohepatic circulation. Gene defects in bile acid transporters can lead to disorders of the enterohepatic circulation, ultimately leading to clinical phenotypes such as metabolic diseases and even death. Bile transporter expression is altered in patients with various metabolic disease states, suggesting that disruption of bile acid transporters may be a pivotal pathological mechanism for the development of metabolism diseases. Thus, many drugs targeting bile acid transporters are being developed. We provide a concise overview of the progress of bile acid transporters research, discuss the relationship between different bile acid transporters and disease development, and summarize the current progress in drug development targeting bile acid transporters.

Effect of noise on morphological structure and functions of rat liver / 环境与职业医学

Background Noise can cause not only auditory system injury, but also liver damage. However, the biomarkers and pathological mechanism of noise-induced liver injury are not clear yet. Objective To observe the effect of noise on the morphological structure and functions of rat liver. Methods A total of 30 Wistar rats were randomly divided into a normal control group, a low noise exposure group [(95 dB sound pressure level (SPL)], and a high noise exposure group (105 dB SPL). After 30 days of noise exposure, blood was collected, and livers were harvested and fixed. The pathological changes of livers were observed. The levels of biochemical indicators of liver function, blood glucose, and blood lipid were measured. Serum metabolites were detected by ultra-high-pressure liquid chromatography-tandem quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). Differential metabolite markers and metabolic pathways were identified. Results Compared with the control group, the body weight gain decreased in the low noise group and the high noise group after noise exposure (P<0.001, P<0.05). The pathological results showed that noise caused the rat livers’ morphological and structural damage at various degrees, and damage of the high noise exposure group was more serious. Compared with the control group, the serum levels of aspartate aminotransferase, albumin, and glycosylated serum protein in the low noise exposure group were increased (P<0.05), but the total bile acid level was decreased (P<0.05). The serum levels of alanine aminotransferase, aspartate aminotransferase, albumin, triglyceride, low density lipoprotein, and glycosylated serum protein in the high noise group exposure were increased (P<0.05), but the glucose level was decreased (P<0.05). In the serum metabolomics analysis, 11 differential metabolites were screened out in the low noise exposure group, which were mainly enriched in 3 pathways (thiamine metabolism, primary bile acid biosynthesis, and bile secretion) related to liver metabolism. Four differential metabolites were screened out in the high exposure noise group, which were mainly enriched in four significantly different metabolic pathways (insulin signaling pathway, non-alcoholic fatty liver disease, bile secretion, and insulin secretion). All the metabolic pathways involved in bile acid secretion and metabolism. Conclusion Nosie exposure can not only damage the liver structure of rats, but also affects the metabolism functions of liver. The mechanism may be related to bile acid secretion metabolic pathway.

Metabolomics Analysis of Plasma at Different Stages Based on UPLC-Q-TOF/MS： Modeling of Spleen Deficiency with Dampness Retention-ulcerative Colitis Rats and Administration of Shenling Baizhusan / 中国实验方剂学杂志

ObjectiveBased on ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF/MS）， the changes of endogenous markers in rat plasma at the different stage， namely modeling and administration of Shenling Baizhusan （SLBZS）， and the mechanism of SLBZS in the treatment of ulcerative colitis （UC） were studied. MethodIn the modeling stage， rats were randomly divided into normal group， spleen deficiency with dampness retention-UC （SDDR-UC） and pure-UC （P-UC） model group. In the administration stage， SLBZS was given to the above two different model groups. After modeling and administration， rat plasma was collected and determined by UPLC-Q-TOF/MS. The mobile phase was 0.1% formic acid aqueous solution （A）-acetonitrile （B） for gradient elution （in positive ion mode：0-2 min， 99%A； 2-9 min， 99%-73%A； 9-10 min， 73%-44%A； 10-13 min， 44%-38%A； 13-19 min， 38%-28%A； 19-21 min， 28%-2%A； 21-23 min， 2%A； 23-25 min， 2%-10%A； 25-27 min， 10%-99%A； in negative ion mode：0-2 min， 85%A； 2-3 min， 85%-65%A； 3-5.5 min， 65%-44%A； 5.5-8 min， 44%-25%A； 8-10 min， 25%-2%A； 10-16 min， 2%-85%A）. The electrospray ionization （ESI） temperature was 120 ℃ under the positive and negative ion modes， and the acquisition range was 50-1 000. Partial least squares-discriminant analysis （PLS-DA） was used to analyze the changes of endogenous metabolites in the above two different model rats from the different stage. MetaboAnalyst 5.0 was used to analyze the metabolic pathways of these identified metabolites. ResultSixteen potential biomarkers were screened and identified in the modeling stage， among which 11 potential biomarkers were common in the two model rats， which mainly affected the primary bile acid biosynthesis pathway. Twenty-three potential biomarkers were screened and identified during the administration stage， among which 3 potential biomarkers were shared by the two model rats， and SDDR-UC and P-UC model rats had 11 and 9 potential biomarkers， respectively. It mainly affected 6 pathways such as purine metabolism， pentose phosphate pathway， pyrimidine metabolism， retinol metabolism， primary bile acid biosynthesis and steroid hormone synthesis. ConclusionThe primary bile acid biosynthesis pathway appears in the different stage of modeling and administration of UC， showing a dynamic change process. The therapeutic effect of SLBZS on SDDR-UC rats may be related to inhibiting the expression of nuclear transcription factor -κB （NF-κB） signaling pathway， activating farnesoid X receptor （FXR） and enhancing the expression of cytochrome P450.

Isolation and Identification of Arisaema Cum Bile Fermentation Strain and Preliminary Investigation on Its Compound Strain Fermentation / 中国实验方剂学杂志

ObjectiveIn order to solve the problem that the quality and stability of Arisaema Cum Bile in the fermentation process with hybrid bacteria were not easy to control， the microorganism in the fermentation process of Arisaema Cum Bile was isolated and identified， the dominant strains were screened and the fermentation process of Arisaema Cum Bile with compound bacteria was investigated. MethodThe submerged culture during the fermentation process of Arisaema Cum Bile was taken out for strain separation and purification. Bacteria and fungi multiphase identification and detection methods and automatic microbial analysis system were used to analyze and compare DNA sequences and identify microorganisms. The isolated and identified strains were respectively inoculated and fermented. After screening the dominant strains， a preliminary exploration of compound strain fermentation were carried out. The contents of index components in Arisaema Cum Bile fermented by compound strain and traditional Arisaema Cum Bile were compared by ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry （UPLC-QqQ-MS/MS）. Mmobile phase was 0.1% formic acid acetonitrile solution （A）-0.1% formic acid aqueous solution （B） for gradient elution （0-2 min， 35%-45%A； 2-10 min， 45%-48%A； 10-12 min， 48%-100%A； 12-12.01 min， 100%-35%A； 12.01-15 min， 35%-65%A）， the flow rate was set at 0.35 mL·min-1. The mass spectrographic analysis employed electrospray ionization （ESI）， negative ion acquisition mode and multiple reaction monitoring （MRM） scanning mode were adopted to collect information， the collection range was m/z 50-1 000. ResultEight microorganisms were isolated and identified from the submerged culture of Arisaema Cum Bile. Among them， Enterococcus sp. （anaerobic） and E. casseliflavus were selected as the dominant strains in the fermentation process. Compared with the traditional fermentation method， the contents of chenodeoxycholic acid， hyodeoxycholic acid and hyocholic acid in free cholic acid increased by 1.76， 0.06， 0.19 mg·g-1， respectively. In bound cholic acid， glycochenodeoxycholic acid， taurochenodeoxycholic acid， glycohyodeoxycholic acid， taurohyodeoxycholic acid， glycohyocholic acid， taurine porcine cholic acid decreased by 0.63， 0.23， 0.26， 0.16， 0.03， 0.04 mg·g-1， respectively. ConclusionArisaema Cum Bile with compound strain fermentation （Enterococcus sp. and E. casseliflavus） can be fermented more completely， the fermentation cycle can be shortened， and the quality and stability of products can be improved.

Effect of Modified Da Chaihutang on FXR/FGF15/FGFR4 Signaling Pathway in Mice with Cholesterol Gallstone Differentiated into Damp-Heat Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the effect of modified Da Chaihutang on cholesterol gallstone （CS） in mice due to damp-heat based on the farnesoid X receptor （FXR）/fibroblast growth factor 15 （FGF15）/fibroblast growth factor receptor 4 （FGFR4） pathway and explore the molecular biological mechanisms of CS differentiated into damp-heat syndrome from the perspective of correspondence between prescription and syndrome. MethodForty-eight six-week-old mice were randomly divided into the blank group， model group， modified Da Chaihutang （23.4 g·kg-1） group， and ursodeoxycholic acid （0.12 g·kg-1） group， with 12 mice in each group. The ones in the latter three groups were exposed to "internal dampness + external dampness + high-cholesterol diet" for 12 weeks for inducing CS due to damp-heat. Mice in the modified Da Chaihutang group and ursodeoxycholic acid group were gavaged with the corresponding drugs， while those in the model and blank groups with the same amount of normal saline for a total of four weeks. Before and after modeling， mice in each group were subjected to open field tests for determining their activities and mental states. Such general conditions as body mass， food intake， fur， and urine and stool of mice in each group were observed and recorded weekly for judging the damp-heat syndrome. After the intervention， the sampled liver and gallbladder tissues of mice in each group were stained with hematoxylin-eosin （HE） staining， and the serum γ-glutamyltransferase （GGT）， alkaline phosphatase （ALP）， and total bilirubin （TBIL） were determined. The total cholesterol （TC） and total bile acid （TBA） contents in bile were measured by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of FXR， FGF15， FGFR4， and cholesterol 7α-hydroxylase gene （CYP7A1） were assayed by real-time fluorescence quantitative polynucleotide chain reaction （Real-time PCR） and Western blot. ResultCompared with the blank group， the model group exhibited enlarged gallbladder， brown turbid bile with flocculent precipitation visible to the naked eye， obvious damp-heat syndrome， lipoid degeneration in the liver tissue， rough and thickened gallbladder wall， elevated ALP， GGT， and TBIL in serum （P<0.01） and TC in bile （P<0.01）， reduced TBA （P<0.01）， up-regulated FXR， FGF15， and FGFR4 mRNA and protein expression in ileum （P<0.05， P<0.01）， and down-regulated CYP7A1 mRNA and protein expression （P<0.01）. Compared with the model group， the two medication groups displayed improved bile turbidity， and the bile in the modified Da Chaihutang group became clearer. After intervention， the damp-heat syndrome of mice in the modified Da Chaihutang group was significantly alleviated. The liver and gallbladder lesions of mice in the two medication groups were significantly relieved， manifested as reduced serum ALP， GGT， and TBIL （P<0.01）. The reduction in ALP and TBIL of the modified Da Chaihutang group was more significant （P<0.01）. The TC contents in the bile of mice from the two medication groups were significantly lowered， whereas the TBA contents were elevated （P<0.01）， with more significant changes present in the modified Da Chaihutang group （P<0.01）. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the modified Da Chaihutang group were down-regulated （P<0.05， P<0.01）， while the mRNA and protein expression levels of CYP7A1 rose （P<0.05）， except that the elevation in FGF15 and FGFR4 protein expression and reduction in CYP7A1 protein expression were not significant. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the ursodeoxycholic acid group all decreased， among which the reduction in FXR was remarkable （P<0.05）， and the mRNA and protein expression levels of CYP7A1 were significantly up-regulated （P<0.05）. ConclusionModified Da Chaihutang significantly improves the stone， liver function， bile composition， abnormal cholesterol-bile acid metabolism， and damp-heat syndrome in the model mice of CS differentiated into damp-heat syndrome， which may be related to its regulation of key factors FXR， FGF15， FGFR4， and CYP7A1 mRNA and protein expression in the cholesterol-bile acid metabolism pathway.