• 약학회지
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• 제39권5호
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• pp.548-553
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• 1995

Effects of restraint stress and its modulations by ursodeoxycholic acid(UDCA) were evaluated on some biochemical and biophysical parameters in rats. Restraint stress induced elevations in blood alkaline phosphatase (ALP). cholesterol (CHOL), aspartate transaminase (GOT), alanine transaminase (GPT), lactate dehydrogenase (LDH) levels. It was also caused adrenal hypertrophy, decrease in weight of spleen and contents of ascorbic acid in stressed rats. As a results, stress indicators such as spleen, ascorbic acid, GOT, GPT, LDH were fastly changed after imposing stress, but those such as ALP, CHOL, adrenal were induced relatively later. UDCA was tested if it has an inhibitory effect against 18-hr restraint induced stress. UDCA lowered ALP, CHOL, LDH level and also effectively elevated the ascorbic acid contents in 25 mg/kg dosage of UDCA. In organ weights. the restraint stress induced increases in spleen and adrenal were attenuated by UDCA in 50 mg/kg dosage. However. stress-induced GOT and GPT levels were unaffected by UDCA.

• 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.

• Molecules and Cells
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• 제38권10호
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• pp.851-858
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• 2015

Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis.

• IMMUNE NETWORK
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• 제14권1호
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• pp.45-53
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• 2014

Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage. And, increased oxidative stress plays a relevant role in the pathogenesis of OA. Ursodeoxycholic acid (UDCA) is a used drug for liver diseases known for its free radical-scavenging property. The objectives of this study were to investigate the in vivo effects of UDCA on pain severity and cartilage degeneration using an experimental OA model and to explore its mode of actions. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration UDCA was initiated on the day of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-$1{\beta}$ (IL-$1{\beta}$), IL-6, nitrotyrosine and inducible nitric oxide synthase (iNOS) in knee joints. UDCA showed an antinociceptive property and attenuated cartilage degeneration. OA rats given oral UDCA significantly exhibited a decreased number of osteoclasts in subchondral bone legion compared with the vehicle-treated OA group. UDCA reduced the expression of IL-$1{\beta}$, IL-6, nitrotyrosine and iNOS in articular cartilage. UDCA treatment significantly attenuated the mRNA expression of matrix metalloproteinase-3 (MMP-3), -13, and ADAMTS5 in IL-$1{\beta}$-stimulated human OA chondrocytes. These results show the inhibitory effects of UDCA on pain production and cartilage degeneration in experimentally induced OA. The chondroprotective properties of UDCA were achieved by suppressing oxidative damage and inhibiting catabolic factors that are implicated in the pathogenesis of cartilage damage in OA.

• 약학회지
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• 제54권4호
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• pp.270-281
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• 2010

Total parenteral nutrition (TPN) is necessary to neonates in neonatal intensive care unit (NICU) for survival and growth because of impossible of enteral feeding. Long-term TPN can be associated with a broad spectrum of hepatobiliary disorder, ranging from mild hepatic dysfunction to severe end-stage liver disease. Cholestasis developed most commonly in neonate, ursodeoxycholic acid (UDCA) is widely used in adult with cholestatic and non-cholestatic liver diseases but there have been limited data on the effects in neonate with PNAC. This study was performed retrospectively to review all medical histories of the total 30 neonates with was administrated UDCA for treatment to parenteral nutrition associated cholestasis (PNAC) at Chungbuk National University Hospital NICU from April 2002 to December 2008. UDCA was administrated at bilirubin is over 2 mg/dl. The criterias for drug evaluation were included hepatic biochemical marker such as direct bilirubin, total bilirubin, AST, ALT, ALP and GGT, TPN therapy period, cholestasis development period, UDCA treatment period, UDCA dosage and adverse effect. In the results, Post-UDCA treatment significant was decreased direct bilirubin, total bilirubin, AST and ALP (p<0.05), and was decreased GGT (p>0.05) and slightly was increased ALT (p>0.05). Reffective timect biDCA was appear at mean $10.5{\pm}1.3$ days, iDCA administration period was mean $64.4{\pm}5.9$ days, cholestasis period was mean $71.9{\pm}6.4$ days and UDCA dosage was mean $22.9{\pm}0.9$ mg/kg/day. Common adverse effects is diarrhea, 5 patients arised mild diarrhea but it possible also related with increased enteral feeding. In conclusion, iDCA can decrease direct bilirubin that major parameter t bcholestasis and oher hepatic biochemical makers. UDCA is effective on PNAC without any serious side effect and cost-effective. Although no greatly shortening cholestasis period, but can protect to develop into severe liver disease and other complication or death. Based on these result, UDCA is recommended for treatment of cholestasis at direct bilirubin is over 2 mg/dl.

• Journal of Periodontal and Implant Science
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• 제26권4호
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• pp.1013-1021
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• 1996

There are many important factors in periodontal inflammation. $IL-1{\beta}$, $PGE_2$ and collagenase are predorminantly key factors. These inflammatory mediators induce gingival tissue and alveolar bone destruction. For the prevention and treatment of periodontal disease, it is necessary to inhibit $IL-1{\beta}$, $PGE_2$ production and collagenase activity. Ursodeoxycholic acid(UDCA) has immunomodulatory properties, and there is evidence that some natural extracts show antiinflammatory activity to some degree. The purpose of this study was to assess the inhibitory effect of UDCA and its mixture with natural extracts on $IL-1{\beta}$, $PGE_2$ production and collagenase activity. Accordingly we assessed the effect of UDCA and its mixture combined with some natural extracts on inhibition of $IL-1{\beta}$, $PGE_2$ production and collagenase activity. For the $IL-l{\beta}$ inhibition study, cultured cells were exposed to $25{\mu}g/ml$ LPS. $IL-1{\beta}$ activity was measured by $IL-1{\beta}$ enzyme immunoassay system. Human gingival fibroblasts were prepared and cells (l05/well) were seeded into culture plates. $rhIL-1{\beta}$ was added to induce $PGE_2$. The amount of $PGE_2$ in sample media was measured using enzyme immunoassay system. Crude collagenase was prepared from Porphyromonas gingivalis and collagenolytic activity was determined using a Collageno kit CLN-100. The test inhibitor was added to the assay mixture consisting of 0.1ml of 50mM Tris buffer(pH 7.5) and 0.2ml of substrate solution. UDCA and UDCA combined with natural extracts generally inhibited $IL-1{\beta}$ production. groups above 0.01% UDCA strongly inhibited $IL-l{\beta}$ synthesis. Both groups inhibited $IL-1{\beta}-induced$ synthesis of $PGE_2$. In low concentration, the degree of inhibition was as same as prednisolone. In high concentration, each group was superior to prednisolone. UDCA group and UDCA mixture group exerted a moderate inhibition of collagenolytic enzyme. The present study suggested that UDCA and its mixture with natural extracts could be further investigated as antiinflammatory drug for periodontal disease.

• BMB Reports
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• 제49권2호
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• pp.105-110
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• 2016

Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-γ, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli.

• 한국임상약학회지
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• 제15권1호
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• pp.9-20
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• 2005

Cholestatic liver disease is a frequent complication of prolonged parenteral nutrition, especially in premature infants. Numerous factors have been cited as contributing to TPN associated cholestasis. However the exact etiology remains obscure. Ursodeoxycholic acid (UDCA) has been reported to be beneficial far children and adults with various chronic cholestatic liver disease. The aim of this prospective, randomized, double-blind, placebo-controlled study was to determine the preventive effects of UDCA administration during TPN. Seventeen pediatric patients (8 boys and 9 girls) undergoing TPN were assigned randomly to two groups, UDCA and placebo group. UDCA group (n=9) received 15 mg/kg/day UDCA and placebo group (n=8) received 15 mg/kg/day placebo enterally during the TPN period. Liver function tests (total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) were per-formed before TPN and weekly or three times a week. The patients' weights, complete blood count, composition of TPN, and the infusion rate of TPN and lipid were monitored everyday. Calcium and phosphate were monitored twice a week. Between the UDCA and placebo groups, there were no differences in weight at the onset of TPN, birth weight, duration of TPN, respiratory distress syndrome associated with prematurity, age at the onset of TPN, gestational age, the number of days the patients received antibiotics, the number of patients received enteral nutritions and the composition of TPN. In contrast, there was a significant difference between the UDCA and placebo groups in alanine aminotransferase levels during TPN. It doesn't seem that UDCA administration during TPN correlates directly with improvement of liver function. But the preventive administration of UDCA may be effective in reducing liver enzyme, alanine aminotransferase and has no adverse effects.

• Archives of Pharmacal Research
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• 제22권5호
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• pp.479-484
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• 1999

In this study, the effects of ursodeoxycholic acid (UDCA) on ischemia/reperfusion injury were investigated on isolated heart perfusion model. Hearts were perfused with oxygenated Krebs-Henseleit solution (pH 7.4, $37^{\circ}C$) on a Langendroff apparatus. After equilibration, isolated hearts were treated with UDCA 20 to 160 $\mu$M or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. After global ischemia (30 min), ischemic hearts were reperfused and allowed to recover for 30 min. The physiological (i.e. heart rate, left ventricular developed pressure, coronary flow, double product and time to contracture formation) and biochemical (lactate dehydrogenase; LDH) parameters were evaluated. In vehicle-treated group, time to contracture formation was 21.4 min during ischemia, LVDP was 18.5 mmHg at the endpoint or reperfusion and LDH activity in total reperfusion effluent was 54.0 U/L. Cardioprotective effects of UDCA against ischemia/reperfusion consisted of a reduced TTC $(EC_{25}=97.3{\mu}M)$, reduced LDH release and enhanced recovery of cardiac contractile function during reperfusion. Especially, the treatments of UDCA 80 and $160 {\mu}M $ significantly increased LVDP and reduced LDH release. Our findings suggest that UDCA ameliorates ischemia/reperfusion-induced myocardial damage.

• 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.