The effects of cholic acid and eight related cholanic acid analogs on bile flow and biliary excretion of bile salts and cholesterol were studied in rabbits. Bile acids were infused intravenously in anesthetized rabbits. In all except hyodeoxycholic or lithocholic acid treated animals increases in bile flow were recorded within 10 minutes during infusion of bile acid-The increase in bile f1ow associated with an increase in bile salt level in bile after cholic acid infusion was observed, however, there were little changes in biliary, cholesterol levels. Bile salt level in bile was not associated with bile flow after chenodeoxycholic acid infusion but the cholesterol level in bile was significantly increased. Ursodeoxycholic acid similarly increased cholesterol but to a lesser extent. Keto-forms of chenodeoxycholic acid were without action. These results indicate that both cholic and chenodeoxycholic acids have the capacity to alter specific biliary excretion of bile components, the former on bile salts and the latter on cholesterol-a precursor of bile acids in bile.
Animal ; Bile/analysis ; Bile/secretion* ; Bile Acids and Salts/administration & dosage ; Bile Acids and Salts/metabolism ; Bile Acids and Salts/pharmacology* ; Bilirubin/analysis ; Cholesterol/analysis ; Cholesterol/metabolism* ; Cholic Acids/analogs & derivatives ; Cholic Acids/analysis ; Female ; Liver/metabolism ; Male ; Rabbits

OBJECTIVETo discuss the rationality of the clinical replacement of traditional Chinese medicine (TCM) bear bile with bile acid constituents, and analyze the difference between these constituents and bear bile in drug properties.

METHODSummarizing the drug properties of bear bile by reference to medical literatures for drug properties of TCM bear bile and Science of Traditional Chinese Medicine (China Press of Traditional Chinese Medicine, 2007). Analyzing and summarizing the pharmacological effects of main bile acid constituents according to relevant literatures for studies on pharmacological effects of main bile acid constituents in CNKI database. Predicating the drug properties of these bile acid constituents by using the drug property predication model established by the study group according the pharmacological effects of main bile acid constituents in the paper, and compare the prediction results with the drug properties of bear bile.

RESULTBile acid constituents in bear bile were mostly cold in property, bitter in taste, and the combination of their drug properties could reflect the combined drug properties of bear bile.

CONCLUSIONAll of these bile acid constituents in bear bile could show part of effects of bear bile. Attention shall be given to regulate the medication scheme in clinical application according to actual conditions.

Animals ; Bile ; chemistry ; Bile Acids and Salts ; chemistry ; pharmacology ; Humans ; Medicine, Chinese Traditional ; Taste ; Ursidae

In this paper, a detailed analysis was made on relevant literatures about bear bile powder in terms of chemical component, pharmacological effect and clinical efficacy, indicating bear bile powder's significant pharmacological effects and clinical application in treating various diseases. Due to the complex composition, bear bile powder is relatively toxic. Therefore, efforts shall be made to study bear bile powder's pharmacological effects, clinical application, chemical composition and toxic side-effects, with the aim to provide a scientific basis for widespread reasonable clinical application of bear bile powder.
Animals ; Bile ; chemistry ; metabolism ; Bile Acids and Salts ; chemistry ; pharmacology ; Humans ; Medicine, Chinese Traditional ; Powders ; chemistry ; metabolism ; pharmacology ; Ursidae ; metabolism

OBJECTIVETo research the effects of bile acids on the expression of interleukin-6 (IL-6) and the cell viability in QBC939 cell line.

METHODSHuman cholangiocarcinoma cells were stimulated with 800 µmol/L bile acid (CA), 100 µmol/L deoxycholate (DCA), 100 µmol/L chenodeoxycholic acid (CDCA), 1200 µmol/L gly acid (GCA), 200 µmol/L glycodeoxycholic acid (GDCA) and 300 µmol/L gly chenodeoxycholic acid (GCDCA).MTT assay and ELISA were used to detect the cell viability and the expression of IL-6 at 24 h, 48 h and 72 h.

RESULTSTreated by DCA, CDCA and GCDCA for 48 hours, the cell viability ratios changed to 0.61, 0.58 and 1.26, which were significant differences between control group and treated groups. And after 72 hours, the viability ratios of group CA, group DCA, group CDCA, group GCA, group GDCA and group GCDCA turned into 0.48, 0.50, 0.42, 1.29, 1.30 and 1.41. The differences of cell viability between bile acid-treated groups and control group were significant (P < 0.05). The expression of IL-6 in control group at 48 h and 72 h was (198 ± 32) ng/L and (323 ± 34) ng/L, while treated by CA, DCA, CDCA, GCA, GDCA and GCDCA respectively for 48 hours, the expression of IL-6 altered to (106 ± 33) ng/L, (88 ± 29) ng/L, (116 ± 54) ng/L, (413 ± 21) ng/L, (587 ± 32) ng/L and (366 ± 30) ng/L. After 72 hours, the expression of IL-6 of each bile acid-treated groups as above was (123 ± 66) ng/L, (45 ± 21) ng/L, (74 ± 45) ng/L, (792 ± 13) ng/L, (1310 ± 22) ng/L and (845 ± 18) ng/L, respectively. The differences between each bile acid-treated group and control group were significant (P < 0.05).

CONCLUSIONSFree bile acids (CA, DCA and CDCA) can inhibit the expression of IL-6 and the cell viability, while glycine conjugates (GCA, GDCA and GCDCA) can promote the expression of IL-6 and the cell viability. Bile acids can change tumor cell viability via IL-6 pathway.

Bile Acids and Salts ; pharmacology ; Bile Duct Neoplasms ; metabolism ; pathology ; Cell Line, Tumor ; Cell Survival ; drug effects ; Humans ; Interleukin-6 ; metabolism

Daily administration of glucocorticoids for 10 days to dogs resulted in a significant increase in the hepatic bile secretion in response to secretory stimulants. The response of hepatic bile in testosterone-treated animals was not changed and the response was increased in DOCA--treated animals. A significant increase of liver weight was induced by the animals receiving glucocorticoids. Other organ weight was not changed; however, a slight reduction of kidney weight was seen in prednisolone, dexamethasone, and DOCA treated animals and also in animals supplemented with cortisone following adrenalectomy. The presence of large areas of ballooning and vesicular changes of liver cells was seen in glucocorticoid treated animals, particularly in cases of dexamethasone and prednisolone. Both vesicular changes of liver cell and its glycogen content were increased by the repeated administration of prednisolone and reduced by the cessation of treatment. Special stain and liver glycogen determination demonstrated the material distending the liver cell was glycogen. These findings indicate that long term administration of glucocorticoids results in an increase of liver weight and hepatic glycogen content as well as increased bile secretion.
Animal ; Bile/secretion* ; Bile Acids and Salts/metabolism ; Bilirubin/secretion ; Cholagogues and Choleretics/pharmacology ; Dogs ; Glucocorticoids/pharmacology* ; Liver/drug effects* ; Liver/pathology ; Liver Glycogen/metabolism ; Organ Weight ; Substances: ; Bile Acids and Salts ; Cholagogues and Choleretics ; Glucocorticoids ; Liver Glycogen ; Bilirubin

OBJECTIVETo explore the effects of the simultaneous activation of liver X receptor (LXR) and peroxisome proliferator-activated receptor alpha (PPARalpha) on bile acid biosynthesis in rats.

METHODSTotally 36 male SD rats were divided into three groups with 12 rats in each group: control group, high cholesterol (HC) group, and high cholesterol + fenofibrate (HC + FENO) group. Total bile acids (serum bile acids plus fecal bile acids) level was assayed. The levels of mRNA for peroxisomal palmitoyl-CoA oxidase (Acox1), LXR, cholesterol 7alpha-hydroxylase (CYP7A1), D-bifunctional protein (DBP), trihydroxycoprostanoyl-CoA oxidase (Acox2), sterol 12alpha-hydroxylase (CYP8B1), and sterol 27-hydroxylase (CYP27A1) in liver were detected by RT-PCR.

RESULTSTotal bile acid level was significantly higher in HC + FENO group than in HC group (P < 0.01), and both were significantly higher than that in control group (P < 0.01). Compared with HC group, the mRNA expression of Acox1 and DBP was significantly higher in HC + FENO group (P < 0.01), but no statistical differences was found between HC group and control group. The mRNA levels of LXR and CYP7A1 in HC + FENO group and HC group were not significantly different but were both significantly higher than that in control group (P < 0.01, P < 0.05). No changes were observed in Acox2, CYPSB1, and CYP27A1 mRNA levels among these three groups.

CONCLUSIONSimultaneous activation of LXR and PPARalpha can increase of CYP7A1 and DBP mRNA exDression and thus accelerates the biosynthesis of bile acid.

Animals ; Bile Acids and Salts ; biosynthesis ; Cholesterol ; pharmacology ; Fenofibrate ; pharmacology ; Hypolipidemic Agents ; pharmacology ; Liver ; drug effects ; enzymology ; Liver X Receptors ; Male ; Orphan Nuclear Receptors ; agonists ; PPAR alpha ; agonists ; Rats

OBJECTIVETo investigate the effects and mechanism of farnesoid X receptor (FXR) and its ligands on the metabolism of bile acids in rats with estrogen-induced intrahepatic cholestasis of pregnancy (ICP).

METHODSAn ICP rat model was established with estradiol benzoate (EB) injections. Then FXR ligand chenodeoxycholic acid (CDCA) was administrated (100 mg/kg daily) to ICP rats for 5 days. The serum TBA and expression of FXR and bile salt export pump (BSEP) in the rat livers were examined by immunohistochemistry and reverse transcription PCR.

RESULTSThe levels of TBA in the CDCA group rats were significantly lower than the untreated rats [(17.2+/-4.1)micromol/L vs (29.3+/-6.4)micromol/L], and the expressions of mRNA and protein of FXR were significantly higher [(0.76+/-0.09 vs 0.53+/-0.06, P<0.05 and 2.35+/-0.06 vs 1.83+/-0.05, P<0.017, respectively)], and the expressions of BSEP were also higher [(0.99+/-0.21 vs 0.76+/-0.07, P<0.017 and 1.88+/-0.03 vs 1.46+/-0.06, P<0.017, respectively)].

CONCLUSIONSFXR plays an important role in modulating the metabolism of bile acids. CDCA can lower the levels of serum TBA by upregulating the expression of FXR and BSEP and then increasing the transport of the bile acids. These facts might present a new idea and target for the treatment of ICP.

Animals ; Bile Acids and Salts ; metabolism ; Chenodeoxycholic Acid ; pharmacology ; Cholestasis, Intrahepatic ; chemically induced ; genetics ; metabolism ; Estrogens ; pharmacology ; Female ; Pregnancy ; Pregnancy Complications ; chemically induced ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Cytoplasmic and Nuclear ; agonists

OBJECTIVE: To determine whether SC-435, a new ileal apical sodium-codependent bile acid transporter (IBAT) inhibitor, can alter the gastrointestinal motility in guinea pigs. METHODS: Sixty guinea pigs received regular diet or IBAT inhibitor (SC-435) diet for 2, 4, and 8 weeks, respectively. At the end of the feeding period, the gallbladder motility was assessed and then four bipolar silver electrodes were implanted on the antrum, duodenum, jejunum, and ileum. Seven days later, migrating motor complex (MMC) was recorded and the total bile acid pool size was measured according to the isotope dilution principle in the meantime. RESULTS: After feeding SC435, the gallbladder motility was declined in the 4-week group and the 8-week group. The bile acid pool size decreased by 17.11% (P <0.05) in the 4-week group and 48.35% (P < 0.05) in the 8-week group. The places of origin of MMC were changed where antral origins (37%) and duodenal origins (46%) decreased whereas jejunal origins (17%) increased. The MMC cycle period was prolonged in the duodenum (1.16 times in the 4-week group, P < 0.05; 1.38 times in the 8-week group, P < 0.05) whereas MMC amplitude fell in the duodenum (10.58% in the 4-week group, P <0.05; 49.17% in the 8-week group, P <0.05). There were not significant differences in all parameters of MMC between the control group and the 2-week group in guinea pigs. CONCLUSION The IBAT inhibitor (SC-435) reduces the bile acid pool size and inhibits the MMC cycle activity. MMC is related to the enterohepatic circulation of bile acids, which is consistent with the changes of the bile acid pool size in guinea pigs.
Animals ; Bile Acids and Salts ; Cyclic N-Oxides ; pharmacology ; Female ; Gallbladder ; physiology ; Gastrointestinal Motility ; drug effects ; physiology ; Guinea Pigs ; Myoelectric Complex, Migrating ; drug effects ; Organic Anion Transporters, Sodium-Dependent ; antagonists & inhibitors ; Random Allocation ; Symporters ; antagonists & inhibitors ; Tropanes ; pharmacology

OBJECTIVE: To Investigate the effects of lithocholic acid (LCA) on the balance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). METHODS: Twelve 10-week-old SPF C57BL/6J female mice were randomly divided into an experimental group (undergoing bilateral ovariectomy) and a control group (only removing the same volume of adipose tissue around the ovaries), with 6 mice in each group. The body mass was measured every week after operation. After 4 weeks post-surgery, the weight of mouse uterus was measured, femur specimens of the mice were taken for micro-CT scanning and three-dimensional reconstruction to analyze changes in bone mass. Tibia specimens were taken for HE staining to calculate the number and area of bone marrow adipocytes in the marrow cavity area. ELISA was used to detect the expression of bone turnover markers in the serum. Liver samples were subjected to real-time fluorescence quantitative PCR (RT-qPCR) to detect the expression of key genes related to bile acid metabolism, including cyp7a1, cyp7b1, cyp8b1, and cyp27a1. BMSCs were isolated by centrifugation from 2 C57BL/6J female mice (10-week-old). The third-generation cells were exposed to 0, 1, 10, and 100 μmol/L LCA, following which cell viability was evaluated using the cell counting kit 8 assay. Subsequently, alkaline phosphatase (ALP) staining and oil red O staining were conducted after 7 days of osteogenic and adipogenic induction. RT-qPCR was employed to analyze the expressions of osteogenic-related genes, namely ALP, Runt-related transcription factor 2 (Runx2), and osteocalcin (OCN), as well as adipogenic-related genes including Adiponectin (Adipoq), fatty acid binding protein 4 (FABP4), and peroxisome proliferator-activated receptor γ (PPARγ). RESULTS: Compared with the control group, the body mass of the mice in the experimental group increased, the uterus atrophied, the bone mass decreased, the bone marrow fat expanded, and the bone metabolism showed a high bone turnover state. RT-qPCR showed that the expressions of cyp7a1, cyp8b1, and cyp27a1, which were related to the key enzymes of bile acid metabolism in the liver, decreased significantly ( P<0.05), while the expression of cyp7b1 had no significant difference ( P>0.05). Intervention with LCA at concentrations of 1, 10, and 100 μmol/L did not demonstrate any apparent toxic effects on BMSCs. Furthermore, LCA inhibited the expressions of osteogenic-related genes (ALP, Runx2, and OCN) in a dose-dependent manner, resulting in a reduction in ALP staining positive area. Concurrently, LCA promoted the expressions of adipogenic-related genes (Adipoq, FABP4, and PPARγ), and an increase in oil red O staining positive area. CONCLUSION After menopause, the metabolism of bile acids is altered, and secondary bile acid LCA interferes with the balance of osteogenic and adipogenic differentiation of BMSCs, thereby affecting bone remodelling.
Female ; Mice ; Animals ; Core Binding Factor Alpha 1 Subunit/pharmacology* ; PPAR gamma/metabolism* ; Steroid 12-alpha-Hydroxylase/metabolism* ; Mice, Inbred C57BL ; Cell Differentiation ; Osteogenesis ; Mesenchymal Stem Cells ; Bile Acids and Salts/pharmacology* ; Bone Marrow Cells ; Cells, Cultured ; Azo Compounds

To study the mechanism and action of Cinnamomi Ramulus in ameliorating intrahepatic cholestasis induced by α-isothiocyanate( ANIT) in rats by regulating FXR pathway. Forty SD rats were randomly divided into normal group,model group,positive control( ursodeoxycholic acid) group( 60 mg·kg~(-1)),Cinnamomi Ramulus treatment( 60 mg·kg~(-1)·d~(-1)) group,and Cinnamomi Ramulus treatment( 20 mg·kg~(-1)·d~(-1)) group,with 8 rats in each group. Except for the normal control group,the other groups were intragastrically administered with the corresponding concentrations of continuous aqueous solution( 0. 005 m L·g~(-1)),once a day,for 7 days.Except for the normal group,the other groups were treated with ANIT( 100 mg·kg~(-1)),once a day,for 3 days. Blood was taken from the abdominal aorta 24 hours after the last administration,and serum alanine aminotransferase( ALT),aspartate aminotransferase( AST),total bilirubin( TBi L),and total bile acid( TBA) were measured. 1. 5-2 cm of rat liver tissue was taken. After fixation with10% formaldehyde,paraffin-embedded sections were taken,HE staining was performed,and immunohistochemistry( IHC) was used to analyze the expression of FXR. RNA and protein were extracted from rat liver tissue to detect FXR mRNA expression,as well as bile acid synthesis and detoxification,transport related SHP,UGT2 B4,BSEP protein expressions at downstream of FXR. Compared with the normal group,serum ALT,AST,TBi L,and TBA levels were elevated in the model group( P<0. 01),liver damage was severe,FXR protein's optical density decreased,FXR mRNA expression decreased,and SHP,UGT2 B4,BSEP protein expressions were decreased( P<0. 05,P<0. 01). Compared with the model group,the drug group could reduce serum ALT,AST,TB,TBA levels to different degrees( P<0. 05,P<0. 01),alleviate liver tissue damage,increase the optical density of FXR protein,and promote the expressions of FXR mRNA and FXR,SHP,BSEP and UGT2 B4 proteins( P<0. 05,P<0. 01). Cinnamomi Ramulus can alleviate ANIT-induced intrahepatic cholestasis,and reduce hepatocyte injury and serum ALT,AST,TBi L and TBA levels. The mechanism may be through FXR-SHP,FXR-UGT2 B4,FXR-BSEP signaling pathways. Therefore,in the pathogenesis of intrahepatic cholestasis,we can try to further explore in alleviating intrahepatic cholestasis with Cinnamomi Ramulus,so as to provide effective drugs for clinical treatment of intrahepatic cholestasis.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Bile Acids and Salts ; blood ; Bilirubin ; blood ; Cholestasis, Intrahepatic ; chemically induced ; drug therapy ; Cinnamomum ; chemistry ; Isothiocyanates ; Liver ; Plant Extracts ; pharmacology ; RNA-Binding Proteins ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley