• YAKHAK HOEJI
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• v.40 no.3
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• pp.311-319
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• 1996

DWP305, a preparation containing combination of ursodeoxycholic acid(UDCA), silymarin and vitamins ($B_1\;and\;B_2$), is a drug currently being developed for hep atic disorders. In order to evaluate the changes in hepatic function by multiple oral administration(2 and 4 weeks) of DWP305 in rats, several biochemical parameters in blood, bile acid composition, and the accumulation of UDCA and lithocholic acid(LCA),a toxic metabolite formed by enterobacteria, were examined using HPLC. In blood biochemical findings, DWP305 did not affect the normal level and there was no difference in total bile acid composition for UDCA, cholic acid(CA), deoxycholic acid(DCA), chenodeoxycholic acid(CDCA) and LCA compared to the UDCA administered group, although total ratio of UDCA and CA was different from normal group. In case of ratio of taurine and glycine conjugated forms, DWP305(186mg/kg as a UDCA) administered group was also similar to normal group and UDCA administered group, while high dosing of DWP305 was not different in the ratio of UDCA administered group(930mg/kg) but normal group. And the ratio of LCA was in order of UDCA(930mg/kg), DWP305(930mg/kg as a UDCA), UDCA(186mg/kg) and DWP305(186mg/kg as a UDCA) administered group, which was less than 4%. The free form of UDCA as well as most of bile acids was not detected at all in rat liver, indicating that there's no accumulation. These results suggest that multiple dosing of DWP305 in rats may not affect hepatic biotransformation and metabolism of bile acids.

• Journal of the Korean Institute of Electrical and Electronic Material Engineers
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• v.28 no.11
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• pp.731-736
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• 2015

Rhodamine B (RhB) was utilized as a dye sensitizer for dye-sensitized solar cells (DSSCs) and its photovoltaic property was examined under the illumination of AM 1.5 G, $100mWcm^{-2}$. DSSCs based on RhB exhibited typical photovoltaic properties with an open-circuit voltage ($V_{OC}$) of 0.34 V, a short-circuit current ($J_{SC}$) of $1.55mA{\cdot}cm^{-2}$, a fill factor (FF) of 50%, and a conversion efficiency (PCE) of 0.26%. In order to further improve the photovoltaic properties of RhB-based DSSCs, the effect of (i) incorporating a strong electron-donating NCS unit into the RhB molecular backbone, (ii) combining a bis-negatively charged zinc complex anion ($Zn-dmit_2$, dmit=di-mercapto-dithiol-thione) with the amine cation of RhB, (iii) co-adsorbing RhB dyes with chenodeoxycholic acid (CDCA) molecules onto porous $TiO_2$ electrodes, was investigated and discussed.

• Biomolecules & Therapeutics
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• v.18 no.1
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• pp.83-91
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• 2010

Bear bile has been used as a therapeutic for cerebral and coronary thrombosis, convulsion, hepatitis, jaundice, and abscess in traditional oriental medicine. In recent decades, the effects of bile acids on cancer, cholestasis, and liver injury have been investigated in many studies. In this study, we investigated the anti-inflammatory effects of whole bear bile (WBB) and its two major components, chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), on rectal inflammation in rats. Bile acids in WBB were quantitatively analyzed by HPLC. Rectal inflammation was induced in male Sprague-Dawley rats by insertion of croton oil-saturated cotton tips. WBB, UDCA or CDCA solution was orally administered to rats one hour after induction of rectal inflammation. Rats were sacrificed 4 or 24 hours after induction of rectal inflammation. The evaluation included measurement of weight and thickness of rectum and histopathologic examination of rectal tissue. Furthermore, we examined the inhibitory effect of WBB, UDCA or CDCA against NO production in LPS-stimulated RAW 264.7 cells. The contents of UDCA and CDCA in WBB were $39.26{\mu}g/mg$ and $47.11{\mu}g/mg$, respectively. WBB treatment significantly reduced the weight and thickness of rectum compared with UDCA or CDCA treatment. The inhibition of NO production by WBB, UDCA and CDCA in LPS-stimulated RAW 264.7 cells was much higher than that by the control. And, WBB treatment suppressed the induction of NO synthase in rectum homogenates. These results suggest that the anti-inflammatory effect of WBB is related to the suppression of NO synthase induction and the inhibition of NO production by UDCA, CDCA and other bile acids of WBB.

• Journal of Genetic Medicine
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• v.19 no.1
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• pp.22-26
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• 2022

Cerebrotendinous xanthomatosis (CTX) is a rare genetic disease caused by a deficiency of enzymes for the synthesis of bile acid, resulting in the accumulation of cholestanol with reduced chenodeoxycholic acid (CDCA) production and causing various symptoms such as chronic diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas in adolescence and young adulthood, and progressive neurologic dysfunction in adulthood. Because oral CDCA replacement therapy can effectively prevent disease progression, early diagnosis and treatment are critical in CTX. This study reports the case of CTX in a 10-year-old male who presented with Achilles tendon xanthoma and mild intellectual disability. Biochemical testing showed normal cholesterol and sitosterol levels but elevated cholestanol levels. Genetic testing showed compound heterozygous variants of CYP27A1, c.379C>T (p.Arg127Trp), and c.1214G>A (p.Arg405Gln), which confirmed the diagnosis of CTX. The patient had neither cataracts nor other focal neurologic deficits and showed no abnormalities on brain imaging. The patient received oral CDCA replacement therapy without any adverse effects; thereafter, the cholestanol level decreased and no disease progression was noted. The diagnostic possibility of CTX should be considered in patients with tendon xanthoma and normolipidemic conditions to prevent neurological deterioration.

• Journal of Gastric Cancer
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• v.1 no.3
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• pp.144-149
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• 2001

Purpose: Gastric stump cancer is defined as a cancer that develops in the stomach after a resection in cases of non-malignant or malignant gastric disease. The interval between the gastrectomy and the detection of gastric stump cancer must be over 5 years. Since duodenogastric reflux gastritis is a precancerous condition and one of the most important factors inducing gastric stump cancer, we compared the bile-acid content of gastric juice between gastric stump cancer patients and controls. Materials and Methods: To evaluate retrospectively the surgical treatment of patients with gastric stump cancer, we reviewed the cases histories of 1016 stomach cancer patients who had been operated on at the Department of General Surgery, Kosin University Gospel Hospital, between 1995 and 1998. The gastric juice was collected during the operations on the gastric stump cancer patients by using a needle puncture of the fundus of the stomach and during the endoscopic examinations of the control subjects. The samples were analyzed for various bile acids (gas chromatography/mass spectrometry). Results: The 6 gastric stump cancer cases accounted for $0.6\%$ of all gastric cancer patients; 5 patients were first operated on for a peptic ulcer and the remaining one for an adenocarcinoma of the stomach. All of the cases were men. The reconstruction method after the initial gastrectomy was a Billroth II in all cases. The sites of the gastric stump cancer were the anastomotic sitein 2 patients, the upper body in 2, the fundus in 1 and the cardia in 1. The operative methods were 3 total gastrectomies, 2 subtotal gastrectomies with Roux en Y anastomosis, and 1 partial gastrectomy with lymph node dissection and had a curative intention in all patients. All of the patients were still surviving at the time of this report. The gastric juices of 4 gastric stump patients showed significantly higher contents of cholic acid ($36.42{\mu}g/ml$) compared to the gastric juices of 35 control subjects ($36.42{\mu}g/ml$)(p$\leq0.0001$). Chenodeoxycholic acid and lithocholic acid were not significantly different. Conclusion: The gastric juice of gastric stump cancer patients contained a significantly higher cholic acid content. At the time of the initial gastrectomy, an operative method that prevents duodenogastric reflux may prevent or minimize the development of gastric stump cancer, and more aggressive surgical treatment may improve survival.

• Radiation Oncology Journal
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• v.22 no.2
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• pp.145-154
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• 2004

Purpose : To examine whether a synthetic bile acid derivatives (HS-1200) sensitizes the radiation-induced apoptosis in human breast cancer cells (MCF-7) and to investigate the underlying mechanism. Materials and Methods : Human breast cancer cells (MCF-7) in exponential growth phase were treated with HS-1200 for 24 hours at 37$^{\circ}C$ with 5$\%$ CO$_{2}$ in air atmosphere. After removal of HS-1200, cells were irradiated with 2$\~$8 Gy X-ray, and then cultured Ii drug-free media for 24-96 hours. The effect of radiation on the clonogenicity of MCF-7 cells was determined with clonogenic cell survival assay with 16$\mu$M of HS-1200. The induction of apoptosis was determined using agarose gel electrophoresis and Hoechst staining. The expression level of apoptosis-related molecules, such as PARP, Bax, Bcl-2, Bak and AIF, were assayed by Western blotting analysis with 40$\mu$M of HS-1200 combined with 8 Gy irradiation. To examine the cellular location of cytochrome c, bax and AIF immunofluorescent stainings were undertaken. Results : Treatment of MCF-7 cells with 40$\mu$M of HS-1200 combined with 8 Gy irradiation showed several changes associated with enhanced apoptosis by agarose gel electrophoresis and Hoechst staining. HS-1200 combined with 8 Gy irradiation treatment also enhanced production of PARP cleavage products and increased Bax/Bcl-2 ratio by Western blotting. Loss of mitochondrial membrane potential ($\Delta$$\psi$$_{m}$) and increased cytochrome c staining indicated that cytochrome c had been released from the mitochondria in HS-1200 treated cells. Conclusion : We demonstrated that combination treatment with a synthetic chenodeoxycholic acid derivative HS-1200 and irradiation enhanced radiation-induced apoptosis of human breast cancer cells (MCF-7). We suggest that the increased Bax/Bcl-2 ratio In HS-1200 co-treatment group underlies the increased radio sensitivity of MCF-7 cells. Further futures studies are remained elusive.

• International Journal of Oral Biology
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• v.37 no.3
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• pp.91-102
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• 2012

Bcl-2 protects tumor cells from the apoptotic effects of various anti-neoplastic agents. Increased expression of Bcl-2 has been associated with a poor response to chemotherapy in various malignancies, including leukemia. Hence, bypassing the resistance conferred by anti-apoptotic factors such as Bcl-2 represents an attractive therapeutic strategy against cancer cells, including leukemic cells. This study was undertaken to examine whether the anticancer drug, cisplatin and the synthetic chenodeoxycholic acid (CDCA) derivative, HS-1200 show anti-tumor activity in U937 and U937/Bcl-2 cells. Viability assays revealed that HS-1200 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Various apoptosis assessment assays further demonstrated that HS-1200 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells by inducing apoptosis. In addition HS-1200, but not cisplatin, overcomes the anti-apoptotic effects of Bcl-2 in Bcl-2 over-expressing human leukemic cells (U937/Bcl-2 cells). Notably, we observed that the HS-1200-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with a suppression of the anti-apoptotic effects of Bcl-2 in human leukemic cells over-expressing this protein (U937/Bcl-2 cells). Furthermore, HS-1200 was found to induce the association between PML and SUMO-1, Daxx, Sp100, p53 or CBP in the aggregated PML-NBs of U937/Bcl-2 cells. Thus, PML protein and the formation of mature PML-NBs could be considered as therapeutic targets that may help to bypass the resistance to apoptosis conferred by Bcl-2. Elucidating the exact mechanism by which PML regulates Bcl-2 will require further work.

• Molecules and Cells
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• v.43 no.5
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• pp.459-468
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• 2020

Nuclear receptor subfamily group H member 4 (NR1H4), also known as farnesoid X receptor, has been implicated in several cellular processes in the liver and intestine. Preclinical and clinical studies have suggested a role of NR1H4 in colon cancer development; however, how NR1H4 regulates colon cancer cell growth and survival remains unclear. We generated NR1H4 knockout (KO) colon cancer cells using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (CAS9) technology and explored the effects of NR1H4 KO in colon cancer cell proliferation, survival, and apoptosis. Interestingly, NR1H4 KO cells showed impaired cell proliferation, reduced colony formation, and increased apoptotic cell death compared to control colon cancer cells. We identified MYC as an important mediator of the signaling pathway alterations induced by NR1H4 KO. NR1H4 silencing in colon cancer cells resulted in reduced MYC protein levels, while NR1H4 activation using an NR1H4 ligand, chenodeoxycholic acid, resulted in time- and dose-dependent MYC induction. Moreover, NR1H4 KO enhanced the anti-cancer effects of doxorubicin and cisplatin, supporting the role of MYC in the enhanced apoptosis observed in NR1H4 KO cells. Taken together, our findings suggest that modulating NR1H4 activity in colon cancer cells might be a promising alternative approach to treat cancer using MYC-targeting agents.

• Molecules and Cells
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• v.26 no.4
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• pp.409-414
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• 2008

The cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism, has been shown to promote the transfer of triglycerides from very low density lipoprotein (VLDL) and low density lipoprotein (LDL) to high density lipoprotein (HDL) in exchange for cholesterol ester. Here we demonstrate that farnesoid X receptor ${\alpha}$ ($FXR{\alpha}$; NR1H4) down-regulates CETP expression in HepG2 cells. A $FXR{\alpha}$ ligand, chenodeoxycholic acid (CDCA), suppressed basal mRNA levels of the CETP gene in HepG2 cells in a dose-dependent manner. Using gel shift and chromatin immunoprecipitation (ChIP) assays, we found that $FXR{\alpha}$ could bind to the liver X receptor ${\alpha}$ ( $LXR{\alpha}$; NR1H3) binding site (LXRE; DR4RE) located within the CETP 5' promoter region. $FXR{\alpha}$ suppressed $LXR{\alpha}$-induced DR4RE-luciferase activity and this effect was mediated by a binding competition between $FXR{\alpha}$ and $LXR{\alpha}$ for DR4RE. Furthermore, the addition of CDCA together with a $LXR{\alpha}$ ligand, GW3965, to HepG2 cells was shown to substantially decrease mRNA levels of hepatic CETP gene, which is typically induced by GW3965. Together, our data demonstrate that $FXR{\alpha}$ down-regulates CETP gene expression via binding to the DR4RE sequence within the CETP 5' promoter and this $FXR{\alpha}$ binding is essential for $FXR{\alpha}$ inhibition of $LXR{\alpha}$-induced CETP expression.

• The Korean Journal of Pharmacology
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• v.18 no.1
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• pp.43-54
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• 1982

Bile formation is a complex process comprised of three separate physiologic mechanism operating at two anatomical sites. At present time, it was known that at least two processes are responsible for total canalicular secretion at the bile canaliculus. One of the processes is bile salt-dependent secretion (BSDS) hypothesis that the active transport of bile salts from plasma to bile provided a primary stimulus for bile formation: the osmotic effect of actively transported bile acid was responsible for the movement of water and ions into bile. The other process is bile salt-independent secretion (ESIS), which is unrelated to bile salt secretion at the canaliculus and which may involve the active transport of sodium. The third process for bile formation involves the biliary ductal epithelium. Secretin-stimulated bile characteristically contained bicarbonate in high concentration. Therefor, it was suggested that secretin stimulated water and bicarbonate secretion from the biliary ductules. One the other hand, it was found that a large amounts of cAMP was present in canine bile but no apparent relationship between bile salt secretion and cAMP content in dog bile. However, bile flow studies in human have demonstrated that secretin and glucagon increase bile cAMP secretion as does secretin in baboons. Secretin increases baboon bile duct mucosal cAMP levels in addition to bile CAMP levels suggesting that in that species secretin-stimulated bile flow may be cAMP mediated. It has been postulated that glucagon and theophylline which increase the bile salt-independent secretion in dogs might act through an increased in liver cAMP content. In a few studies, the possible role of cAMP on bile formation has teen tested by administration of an exogenous derivative of cAMP, dibutyryl cAMP. In the rat, DB cAMP did not modify bile flow, but injection of DB cAMP in the dog promoted an increase in the bile salt-independent secretion. Because of these contradictory results, this study was carried out to examine the relationship between cyclic nucleotides and bile flow due to various bile salts as well as secretin or theophylline. Experiments were performed in rabbits with anesthesia produced by the injection of seconal(30 mg/kg). Rabbits had the cystic duct ligated and the proximal end of the divided common duct cannulated with an appropriately sized polyethylene catheter. A similar catheter was placed into the inferior vena cava for administration of drugs. Bile was collected for determination of cyclic nucleotides and total cholate in 15 min. intervals for a few hours. The results are summerized as followings. 1) Administrations of taurocholic acid or chenodeoxycholic acid increased significantly the concentrations of cAMP and cGMP in bile of rabbits. 2) Concentration of cAMP in bile during the continuous infusion of ursodeoxycholic acid, was remarkedly increased in accordance with the increase of bile flow, while on the contrary concentration of cGMP in bile was decreased significantly. 3) Dehydrocholic acid and deoxycholic acid significantly increased bile flow, total cholate output and cyclic nucleotides in bile. 4) Only cAMP concentration in bile was significantly increased from control value by secretin, while theophylline increased cAMP as well as cGMP in rabbit bile. 5) In addition, the administration of secretin to taurocholic acid-stimulated bile flow increased cAMP while theophylline produced the increases of cAMP and cGMP in bile. 6) The administration of insulin to taurocholic acid-stimulated bile flow decreased cAMP concentration, while on the contrary cGMP was remarkedly increased in rabbit bile.