• 한국식품과학회지
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• 제38권3호
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• pp.452-455
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• 2006

퇴행성뇌질환인 치매의 정확한 원인은 아직 불분명하나 빠른 뇌세포사멸이 주요한 원인으로 알려져 있다. 특히, 알츠하이머형 치매는 다량 생성되는 활성산소에 의한 뇌세포사멸이 주요원인인 것으로 입증되고 있다. 따라서 본 연구에서는 웅담활성성분인 UDCA의 세포보호 및 항산화효과로부터 알츠하이머형 치매와 같은 퇴행성 뇌질환억제 또는 치료물질로서의 가능성을 입증하고자 하였고 뇌의 대식세포인 소교세포(microglia)를 cell model로 하였다. MTT 실험결과 UDCA에 의한 세포보호효과는 $7.5\;{\mu}g/mL$ 주변 농도에서 관찰되었고 NO에 의한 세포손상 유도억제효과를 확인하였다(Fig. 2). 이와 같은 결과는 형광현미경하에서 보다 명확히 관찰되어(Fig. 3) 결국 UDCA에 의한 항세포사효과가 있음을 알 수 있었다. UDCA의 항산효과는 활성산소인 $H_2O_2$의 단백질 분해 저해능을 관찰하는 금속이온촉매 산화효과를 통해 확인하였다(Fig. 4). 즉, UDCA는 농도의존적으로$(1{\sim}100\;{\mu}g/mL)$ 단백질 분해억제능을 보였으며 $100\;{\mu}g/mL$ 이상의 농도에서 양성대조군인 ascorbic acid와 유사한 억제효과를 나타냈다. 이와 같은 UDCA의 항산화효과는 $10\;{\mu}g/mL$ 전후에서 관찰되어 세포보호효과를 나타내는 농도$(7.5\;{\mu}g/mL)$와 큰 차이가 없는 것으로 사료되었고 따라서 UDCA의 농도범주는 일괄적 적용이 가능할 것으로 판단된다. 결론적으로 웅담활성성분인 UDCA는 일반적으로 사용하여온 간질환 및 소화계질환의 보조요법제의 개념을 벗어나 항염 및 항산화효과에 잠재능을 가지며 나아가 뇌신경세포를 보호하고 세포사를 차단하여 알츠하이머와 같은 퇴행성뇌질환 조절 후보물질로 적용이 가능할 것으로 판단되나 보다 심도 있는 in vivo 및 임상적 차원의 연구가 요구된다.

• Food Science and Biotechnology
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• 제17권3호
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• pp.598-602
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• 2008

Concentrated catfish Silurus asotus bile (SAB) containing high amounts of ursodeoxycholic acid (UDCA) and taurocholic acid may have immunosuppressive properties. To investigate the putative immunosuppressive properties of SAB, the anti-proliferation and suppression of early T cell activation markers, and the inhibition of cytokines induced by T cells in response to anti-CD3 mAb activation in mouse splenocytes were examined. The suppression of these activation repertoires are the main properties of calcineurin inhibitors. It was found that SAB effectively suppressed the activation of T cells, and cytokines from T cell activation, at levels similar to cyclosporine A, a calcineurin inhibitor. Although the mechanism in which suppression occurs is not clear, we speculate that SAB from Silurus asotus, which has been known to switch their intake habits to zoophagy during an early adult stage, may explain the suppressive effect of SAB as a result of high amounts of functional UDCA in bile. Our results suggest that the treatment or intake of SAB, either in therapy or as a food supplement, may act as an adjuvant therapy for the prevention of transplant rejection, although further investigation is required before this treatment can be applied clinically.

• 약학회지
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• 제42권1호
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• pp.82-88
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• 1998

The effect of hepatoprotective agents and bile acids on tumor necrosis factor-alpha, (TNF-${\alpha}$) production in murine and human macrophage cell line (RAW264.7 and U937) was inve stigated. The hepatoprotective agents including silymarin and its major component, silybin, significantly inhibited TNF-alpha production in a concentration dependent manner ($IC_50$ of silybin=67.7${\mu}g$/ml (140.3${\mu}g$M)). In differentiated U937 cells, especially, silybin showed more effective inbitory activity ($IC_50$=35.1${\mu}g$g/ml (72.7${\mu}g$M)). These results suggest that silymarin and silybin may inhibit TNF-alpha production in the process of hepatic diseases in human. However, biphenyldimethyl dicarboxylate (DDB) was not effective. In the case of bile acids, chenodeoxycholic acid (CDCA) showed a concentration dependent inhibitory effect on TNF-alpha production ($IC_50$ of CDCA= 71.5${\mu}g$g/ml (182.1${\mu}g$M)). In contrast, glycine or taurine conjugated form (G-CDCA or T-CDCA) restored to the control level or significantly increased TNF-${\alpha}$ production. And also ursodeoxycholic acid (UDCA) and its conjugated forms (G-UDCA and T-UDCA) showed a variety of patterns on TNF-${\alpha}$ production by changes of functional groups and concentration. These results also indicate that bile acids may regulate TNF-${\alpha}$ production in normal hepatic function or disease conditions.

• Archives of Pharmacal Research
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• 제27권9호
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• pp.954-960
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• 2004

Expression of the NF-$textsc{k}$B-dependent genes responsible for inflammation, such as TNF-$\alpha$, IL-1$\beta$, and nitric oxide synthase (NOS), contributes to chronic inflammation which is a major cause of neurodegenerative diseases (i.e. Alzheimer＇s disease). Although NF-$textsc{k}$B plays a biphasic role in different cells like neurons and microglia, controlling the activation of NF-$textsc{k}$B is important for its negative feedback in either activation or inactivation. In this study, we found that ursodeoxycholic acid (UDCA) inhibited I$textsc{k}$B$\alpha$ degradation to block expression of the NF-$textsc{k}$B-dependent genes in microglia when activated by $\beta$-amyloid peptide (A$\beta$). We also showed that when microglia is activated by $A\beta$42, the expression of A20 is suppressed. These findings place A20 in the category of ' protective ' genes, protecting cells from pro-inflammatory reper-toires induced in response to inflammatory stimuli in activated microglia via NF-$textsc{k}$B activation. In light of the gene and proteins for NF-$textsc{k}$B-dependent gene and inactivator for NF-$textsc{k}$B (I$textsc{k}$B$\alpha$), the observations now reported suggest that UDCA plays a role in supporting the attenuation of the production of pro-inflammatory cytokines and NO via inactivation of NF-$textsc{k}$B. Moreover, an NF-$textsc{k}$B inhibitor such as A20 can collaborate and at least enhance the anti-inflammatory effect in microglia, thus giving a potent benefit for the treatment of neurodegenerative diseases such as AD.uch as AD.

• Biomolecules & Therapeutics
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• 제18권1호
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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.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.246.1-246.1
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• 2002

We studied the effects of ursodeoxycholic acid (UDCA) and its synthetic derivatives. HS-l030 and HS-1183. and chenodeoxycholic acid (CDCA) and its synthetic derivatives, HS-1199 and HS-1200. on the human colon adenocarcinoma cell line. HT -29 (p53 mutant type). The effects on cell viability and growth were assessed by MTT assay and cell growth study. While UDCA and CDCA exhibited no significant effect, their novel derivatives inhibited the proliferation of HT-29 cell line in a concentration- and time-dependent manners. (omitted)

• Archives of Pharmacal Research
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• 제28권4호
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• pp.451-457
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• 2005

Experimental studies have demonstrated that the triple combination of amantadine (A)/ ursodeoxycholic acid (UDCA, U)/ biphenyl dimethyl dicarboxylate (DDB, D) might have a preferential antiviral effect compared with that observed in interferon-induced antiviral signal pathways, such as those of $STAT1\alpha$ and the 6-16 genes. To confirm the results, this study examined whether th signal transduction for the antiviral activity in HepG2 2.2.15 was induced dependently or independently of interferon. To accomplish this, the correlation between the $STAT1\alpha$ and 6-16 genes, and nitric oxide, for the mediation of the antiviral activity was assessed. The increase in nitric oxide in the UDCA groups suggests that the inhibition of viral gene replication was enhanced by the amantadine combinations (AU and AUD), and might be more effective if incubated for longer periods. It was found that $STAT1\alpha$ was activated by the amantadine combination, although to a lesser extent than that of $interferon-\alpha$, and the primary endpoints examined for the inhibition of gene expression (HBsAg and HBcAg) were remarkably well regulated. This suggests that the amantadine triple, or at least the double, combination had better clinical benefits than those of $IFN-\alpha$ and the nucleoside analogue single treatment. This demonstrates that the amantadine combination might be a substitute for the existing HBV therapy if the results of in vivo and in vitro studies concur.

• The Korean Journal of Physiology and Pharmacology
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• 제1권1호
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• pp.107-115
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• 1997

We studied the effects of bile acids on the induction ofapoptosis in HepG2 human hepatocellular carcinoma cells. Treatment with either ursodeoxycholic acid (UDCA) or lithocholic acid (LCA) resulted in a dose- and time-dependent decrease in cell viability assessed by MTT assay. Both UDCA and LCA also induced genomic DNA fragmentation, a hallmark of apoptosis, indicating that the mechanism by which these bile acids induce cell death was through apoptosis. Cycloheximide, a protein synthesis inhibitor, blocked the apoptosis induced by these bile acids, implying that new protein synthesis may be required for the apoptosis. Intracellular $Ca^{2+}$ release blockers (dantrolene and 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester) inhibited decreased cell viability and DNA fragmentation induced by these bile acids. Treatment of HepG2 cells with calcium ionophore A23l87 induced DNA fragmentation. These results suggest that UDCA and LCA induce apoptosis in the HepG2 cells and that the activation of intracellular $Ca^{2+}$ signals may play an important role in the apoptosis induced by these bile acids.

• Journal of Periodontal and Implant Science
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• 제29권1호
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• pp.1-14
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• 1999

Ursodeoxycholic acid(UDCA) is a hydrophilic gall bladder acid and has been used as a effective drug for liver disease related to in1munity. This drug inhibits secretions of IL-2, IL-4, and $IFN-{\gamma}$ from T-cells and production of immunoglobulin from B-cells. Also it has been reported that UDCA inhibits production of IL-1 related to the progression of periodontal disease and activation of collagenases. The purpose of the present study was to elucidate the effects of UDCA on inhibition of periodontal disease progression using clinical, microbiological and histometrical parameters. Twelve pure bred, 16 month-old-beagle dogs were used in the study. After ligature-induced periodontal diseases were formed, experimental drugs were applied twice a day and then the results of clinical, microbiological, and histometrical parameters were measured at baselie(initiation of experiment) , 4weeks and 8weeks. The gel with UDCA(concentration 0.5%, 5% 3 dogs in each) was applied to experimental group, chlorhexidine to positive control group(3dogs) and the gel without UDCA(base) to negative control group. After induction of general anesthesia, the maxillary 2nd, 3rd premolars and 1st molar and the mandibular 2nd, 3rd, 4th premolars and 1st molar were ligated in one side selected randomly and were not ligated in the opposite side. The plaque index(PI), gingival index(GI), pocket depth(PD) and gingival crevicular fluid(GCF) volum were measured clinically. The PI and GI were measured at 3 buccal points of all experimental teeth and the GCF was measured only at the 3rd premolar in the maxilla and the 4th premolar in the mandible. In the microbiological study, the samples extracted from the 3rd premolar of the maxilla and the 4th premolar of the mandible at the center of buccal surface were analyzed aerobics, anaerobics and Streptococcus colony forming units, After clinical and microbiological examination at 8weeks, the dogs were sacrificed by carotid artery perfusion. The samples were fixed and sectioned including interproximal area, and the distance from cementoenamel junction(CEJ) to alveolar crest was measured. The results were that PI, GI and PD increased until 4 weeks and decreased at 8 weeks in three groups but the differences between all the groups were not significant. The 0.5% UDCA in non-ligated group showed remarkable decrease of GCF. The experimental group applied 5% UDCA decreased the number of aerobics and anaerobics. The distance from CEJ to alveolar crest was greater in the negative control group on both ligated and non-ligated sides, but the differences were not significant stastically.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.245.2-246
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• 2002

We studied on the antiproliferative effects of bile acids and their derivatives on HepG2 human hepatocellular carcinoma cells. Ursodeoxycholic acid (UDCA) and its synthetic derivative HS-1030. and chenodeoxycholic acid (CDCA) and its synthetic derivatives. HS-1199 and HS\ulcorner200, were used. We focused on the regulation of cell cycle and induction of apoptosis by these bile acid derivatives. (omitted)