ursodesoxycholic acid in Barret esophagitis 2025-10-15 13:01:40

ursodesoxycholic acid in Barret esophagitis

Урсодезоксихолевая кислота при Барреттовом эзофагите: Научный обзор

Введение

Барреттов пищевод (БП) — это премалигнизированное состояние, при котором нормальный многослойный плоский эпителий дистального отдела пищевода замещается метапластическим цилиндрическим эпителием из-за хронического гастроэзофагеального рефлюкса. Самым тяжелым осложнением БП является развитие аденокарциномы пищевода, заболеваемость которой продолжает расти несмотря на успехи в терапии кислотозависимых состояний (Spechler, 2013).

На сегодняшний день стандартом терапии служит применение ингибиторов протонной помпы (ИПП) для контроля кислотного рефлюкса и эндоскопический мониторинг для раннего выявления дисплазии. Однако эти меры не останавливают полностью прогрессирование к раку, что вызывает интерес к новым методам химопрофилактики, в том числе — к применению урсодезоксихолевой кислоты (УДХК).

Роль желчных кислот в патогенезе Барреттового пищевода

В пищеводе пациентов с БП регистрация желчи по данным спектрофотометрии отмечается значительно чаще, чем у здоровых людей — медиана наличия желчи в пищеводе у пациентов с осложнённым БП составляет около 46% времени в сутки (от 20,8% до 77,5%), тогда как у здоровых — менее 2% (Vaezi & Richter, 1996). Концентрация токсичных гидрофобных желчных кислот (например, декоксихолевая кислота, DCA) может достигать 282 мкМ (Nehra et al., 1999).

Гидрофобные желчные кислоты вызывают повреждение ДНК, способствуют продукции реактивных форм кислорода (ROS) и активации NF-κB, что снижает апоптоз и способствует канцерогенезу (Huo et al., 2011).

Механизм действия и обоснование применения урсодезоксихолевой кислоты

УДХК — гидрофильная желчная кислота, традиционно используемая при заболеваниях печени (например, ПБЦ, холестаз). Она может замещать в пуле желчных кислот более токсичные гидрофобные фракции, действовать как антиоксидант и стабилизировать клеточные мембраны (Kowdley, 2000).

Данные предклинических исследований

В работе Peng и соавт. барреттовские эпителиальные клетки (линии BAR-T, BAR-10T) подвергались воздействию DCA в концентрациях, сопоставимых с наблюдаемыми in vivo, что приводило к значимому увеличению маркеров двойных разрывов ДНК (phospho-H2AX), ROS и активации NF-κB (Peng et al., 2014).

Предварительная обработка клеток УДХК (300 мкМ, 24 ч) предотвращала эти эффекты за счет увеличения внутриклеточных уровней антиоксидантных ферментов (глутатионпероксидаза 1 — GPX1, каталаза). Этот эффект сильно зависел от экспрессии GPX1 и каталаз — при применении siRNA для этих ферментов защитный эффект УДХК исчезал, что свидетельствует о ключевой роли антиоксидантного ответа (Peng et al., 2014).

УДХК активирует сигнальный путь Nrf2 — ключевого регулятора антиоксидантов. Было показано, что обработка клеток УДХК увеличивает фосфорилирование и ядерную транслокацию Nrf2, а knockdown Nrf2 отменяет индукцию GPX1 и каталазы (Peng et al., 2014).

Клинические наблюдения и интервенционные исследования

1. Piloting исследования:

2. В нерандомизированном исследовании 21 пациенту с БП назначали перорально УДХК 10 мг/кг/сут в течение 8 недель. После терапии наблюдалось значимое повышение экспрессии GPX1 и каталаз в биоптатах метаплазированных тканей, а также предотвращение возникновения повреждения ДНК и активации NF-κB при последующем экспериментальном перфузировании пищевода DCA (Peng et al., 2014).

3. Многоцентровое пилотное исследование (США):

4. 29 пациентов с подтверждённым БП (сегмент ≥2 см; большинство без дисплазии или с низкой степенью), шесть месяцев получали УДХК в дозе 13–15 мг/кг/сут.
5. Результаты: доля УДХК и её конъюгатов в составе желудочного содержимого возросла с медианы 18,2% до 93,4% (p<0,0001), а доля DCA снизилась с 38,9% до 4,18% (p<0,01).
6. Несмотря на выраженное смещение баланса желчных кислот в пользу УДХК, не было отмечено достоверных изменений в уровнях тканевых маркеров оксидативного повреждения ДНК (8-ОН-дезоксигуанозин), пролиферации (Ki-67), апоптоза (cleaved caspase-3), а также в морфологии и гистологии БП.

7. Статистические показатели: p>0,15 для всех биомаркеров; сколь-либо значимых корреляций между изменениями биомаркеров и фракционного состава желчи выявлено не было (Banerjee et al., 2016).

8. Комбинация УДХК + ИПП:

9. В исследовании Bozikas и соавт. (9 пациентов с БП, 6 месяцев высокодозового ИПП, затем 6 месяцев добавления УДХК) не выявлено значимых изменений в степени метаплазии, дисплазии, воспаления, пролиферации и выраженности экспрессии дифференцировочных белков или противовоспалительных маркеров (Bozikas et al., 2008).

Безопасность

В вышеуказанных исследованиях УДХК переносилась хорошо. Среди побочных эффектов отмечались только единичные случаи легкой или умеренно выраженной диареи, исчезающие после отмены препарата (Banerjee et al., 2016).

Ограничения текущих клинических данных

• Большинство доступных исследований — пилотные, маломощные, с коротким периодом наблюдения и зачастую отсутствием контрольной группы.
• Используемые тканевые биомаркеры (Ki-67, 8-ОН-дГ, CC3) — промежуточные показатели, их истинная прогностическая ценность для рака пищевода не подтверждена большими когортными исследованиями.
• Все пациенты параллельно принимали ИПП, что само по себе уменьшает повреждающее действие желчных кислот за счет нейтрализации среды, и могло нивелировать дополнительные эффекты УДХК.
• Нет данных о влиянии УДХК на "жесткие" исходы: частоту прогрессии дисплазии и развитие аденокарциномы пищевода.

Итоги и заключения

• В доклинических моделях УДХК эффективно предотвращает развитие оксидативного стресса, повреждений ДНК и активацию протоонкогенных сигнальных путей в клетках БП при воздействии токсичных желчных кислот. Механизм реализуется в первую очередь за счет активации Nrf2 и индукции антиоксидантных ферментов GPX1 и каталазы.
• В клинических исследованиях УДХК достоверно смещает состав желчных кислот в проксимальных отделах ЖКТ в сторону гидрофильных фракций, но не приводит к выраженным морфологическим или молекулярным улучшениям, по крайней мере на промежутке до 6 месяцев терапии.
• Безопасность Урсодезоксихолевая кислота хорошо переносится пациентами, серьезных нежелательных явлений не выявлено.

Перспективы

Данные исследований являются обнадеживающими с точки зрения молекулярных механизмов, однако клиническая эффективность УДХК для профилактики прогрессии БП и/или развития рака пищевода пока не доказана. Для однозначных выводов необходимы более масштабные, многоцентровые, рандомизированные, длительные исследования с клинически значимыми конечными точками (дисплазия высокой степени, аденокарцинома). Не исключено, что эффект может быть более выражен у определенных субгрупп пациентов или при более длительном наблюдении.

Основные использованные источники

• (Peng et al., 2014) — Ключевое исследование механизма и клинической эффективности УДХК в БП.
• (Banerjee et al., 2016) — Многоцентровое пилотное исследование эффективности УДХК.
• (Bozikas et al., 2008) — Оценка эффекта комбинации УДХК и ИПП.
• (Spechler, 2013) — Обзор прогрессии БП и стратегии ведения.
• (Nehra et al., 1999); (Vaezi & Richter, 1996) — Оценка патогенетической роли желчных кислот в развитии БП.

Вывод: На сегодняшний день УДХК — потенциально интересное средство для химической профилактики повреждения эпителия пищевода при БП, что подтверждено на молекулярном уровне, однако её клиническая эффективность в предотвращении прогрессии или малигнизации БП остается недоказанной и требует дальнейших исследований высокого уровня доказательности.

REFERENCES

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC - last accessed: 2025-10-15

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus - PubMed - last accessed: 2025-10-15

Ursodiol in Treating Patients With Barrett Esophagus and Low-Grade Dysplasia - last accessed: 2025-10-15

ClinicalTrials.gov - last accessed: 2025-10-15

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients - PubMed - last accessed: 2025-10-15

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC - last accessed: 2025-10-15

Sources used

Web Sources

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

ophageal carcinogenesis. Cancer Res
70: 6787–6796, 2010 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 27. Singh S, Khanna S, Pardi DS, Loftus EV, Jr, Talwalkar JA.
Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis
19: 1631–1638, 2013 [ DOI ] [ PubMed ] [ Google Scholar ] 28. Soyalan B, Minn J, Schmitz HJ, Schrenk D, Will F, Dietrich H, Baum M, Eisenbrand G, Janzowski C.
Apple juice intervention modulates expression of ARE-dependent genes in rat colon and liver. Eur J Nutr
50: 135–143, 2011 [ DOI ] [ PubMed ] [ Google Scholar ] 29. Spechler SJ.
Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA
310: 627–636, 2013 [ DOI ] [ PubMed ] [ Google Scholar ] 30. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ.
American Gastroenterological Association technical review on the management of Barrett's esophagus. Gastroenterology
140: e18–e52, 2011 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 31. Theisen J, Nehra D, Citron D, Johansson J, Hagen JA, Crookes PF, DeMeester SR, Bremner CG, DeMeester TR, Peters JH.
Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg
4: 50–54, 2000 [ DOI ] [ PubMed ] [ Google Scholar ] 32. Vaezi MF, Richter JE.
Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology
111: 1192–1199, 1996 [ DOI ] [ PubMed ] [ Google Scholar

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

notes Copyright and License information 1 Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, 2 Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas; 3 Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas; 4 Department of Research and Development, VA North Texas Heath Care System, Dallas, Texas; 5 Department of Pediatrics, Children's Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas; 6 Division of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China * S. Peng and X. Huo contributed equally to this work. ✉ Address for reprint requests and other correspondence: R. F. Souza, Dept. of Gastroenterology (111B1), Dallas VA Medical Center, 4500 S. Lancaster Rd., Dallas, TX 75216 (e-mail: rhonda.souza@utsouthwestern.edu ). ✉ Corresponding author. Series information Physiology and GI Cancer Received 2014 Mar 6; Accepted 2014 May 8; Issue date 2014 Jul 15. Copyright © 2014 the American Physiological Society PMC Copyright notice PMCID: PMC4101678  PMID: 24852569 Abstract Hydrophobic bile acids like deoxycholic acid (DCA), which cause oxidative DNA damage and activate NF-κB in Barrett's metaplasia, might contribute to carcinogenesis in Barrett's esophagus. We have explored mechanisms whereby ursodeoxycholic acid (UDCA, a hydrophilic bile acid) protects against DCA-induced injury in vivo in patients and in vitro using nonneoplastic, telomerase-immortalized Barrett's cell lines. We took biopsies of Barrett's esophagus from 21 patients before and after esophageal perfusion with DCA (250 μM) at baseline and after 8 wk of oral UDCA treatment. DNA damage was assessed by phospho-H2AX expression, neutral CometAssay, and phospho-H2AX nuclear foci formation. Quantitative PCR was performed for antioxidants including catalase and GPX1. Nrf2, catalase, and GPX1 were

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

. 1 ). All patients were treated with PPIs for at least 4 wk before the first endoscopy and all were maintained on omeprazole 20 mg bid for the duration of the study. Aspirin and nonsteroidal anti-inflammatory medications were withheld for at least 8 days before each endoscopy. During endoscopy, six biopsies of Barrett's metaplasia were taken by use of jumbo biopsy forceps (Olympus FB-50K-1) before and after perfusion of the distal esophagus with either 10 ml of 250 μM DCA or 10 ml of 250 μM UDCA over 5 min as described previously ( 11 ). A sealed-envelope strategy was used to randomly assign patients to receive either DCA or UDCA perfusion during the first endoscopy. One year later, patients underwent a second endoscopy, during which the esophagus was perfused with the bile acid not used in the first endoscopy; biopsies were obtained as described above. After the second endoscopy, patients were treated with oral UDCA (10 mg/kg) for 8 wk, after which they returned for a final endoscopy, during which the esophagus was perfused with 250 μM DCA and biopsy specimens were taken as described above. Fig. 1. Open in a new tab Flow diagram of the clinical trial. DCA, deoxycholic acid; UDCA, ursodeoxycholic acid. Cell lines. We used two nonneoplastic, telomerase-immortalized Barrett's epithelial cell lines (BAR-T, BAR-10T) created from endoscopic biopsy specimens of nondysplastic Barrett's esophagus ( 14 , 35 ). The Barrett's cells were cocultured with a fibroblast feeder layer and maintained in growth medium as previously described ( 14 , 35 ). For individual experiments, the Barrett's cells were seeded into collagen IV-coated wells (BD Biosciences, San Jose, CA) and maintained in growth medium. All cells were maintained at 37°C in a 5% CO 2 incubator. We selected to use the BAR-T line for all experiments (unless otherwise indicated) because this cell line has been extensively characterized by our laboratory ( 11 , 14 , 34 , 35 ). Bile salt exposure. For individual experiments, Barrett's cells

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

currently recommended for Barrett's esophagus involves endoscopic surveillance for dysplasia and treatment of the underlying GERD with proton pump inhibitors (PPIs) ( 30 ). The benefit of surveillance for these patients has never been established, and one recent, high-quality study found that endoscopic surveillance was not associated with a significant reduction in the risk of death from esophageal adenocarcinoma ( 5 ). PPIs are highly effective at decreasing gastric acid production and healing GERD. Despite the widespread use of PPIs, however, the incidence of esophageal adenocarcinoma continues to climb ( 25 ), suggesting that factors other than refluxed hydrochloric acid contribute to the development of this cancer. There are reasons to suspect that bile acids might have an important role in carcinogenesis in Barrett's esophagus ( 22 ). The gastroesophageal reflux of bile acids occurs frequently in patients with Barrett's esophagus ( 8 , 13 , 24 , 32 ). Esophageal monitoring studies using a spectrophotometric system to detect bile reflux have demonstrated bile in the esophagus of normal subjects for <2% of the day, whereas patients with complicated Barrett's have bile in the esophagus for a median 46% of the day (range 20.8–77.5%) ( 32 ). Studies in which material aspirated from the esophagus is analyzed by high-performance liquid chromatography confirm that bile acid reflux is common in Barrett's patients ( 8 , 13 , 24 ). For example, Nehra et al. ( 24 ) found refluxed bile acids in concentrations >200 μM in 50% of Barrett's patients, some of whom had refluxed deoxycholic acid (DCA, a toxic, hydrophobic bile acid) in concentrations as high as 282 μM. In an earlier report, we showed that DCA exposure caused Barrett's cells to produce reactive oxygen species (ROS) that induced DNA damage detectable by phospho-H2AX expression ( 11 ). In those same cells, DCA also activated nuclear factor (NF)-κB, which prevented the apoptosis often triggered by severe DNA damage. Furthermore, we documented DNA damage and NF-κB activation in biopsies of Barrett's metaplasia from five patients whose esophagus was perfused with DCA (250 μM) for only

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

ocarcinoma, future studies may consider determining the effects of UDCA on genomic alterations, as well as the effect of combining with PPI use, to determine its roles in prevention of neoplastic progression. Acknowledgments Financial support: This work was supported by a contract (N01CN35158 to HHS Chow) from the National Cancer Institute, the Arizona Cancer Center Support Grant (CA023074), and a Susan G. Komen Career Catalyst Award (CCR14299136). The authors thank Bonita Weible, Melissa Spacek, Valerie Butler, Kathy McDaniel, Lakshana Sreenivasan, Wade Chew, and Catherine Cordova for their excellent assistance in the performance of the clinical study and endpoint assays and Drs. Richard Sampliner, Ronnie Fass, Katerina Dvorak, and Michael Habib for their valuable contributions to the conduct of the study. Footnotes Conflict of Interest: The authors have no Conflict of Interest to disclose. Clinical Trial Registration: clinicaltrials.gov identifier: NCT01097304 References 1. DeMeester SR. Management of Barrett’s esophagus free of dysplasia. Semin Thorac Cardiovasc Surg. 1997;9:279–284. [ PubMed ] [ Google Scholar ] 2. Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barrett’s esophagus: a prospective study of 170 patients followed 4. 8 years. Am J Gastroenterol. 1997;92:212–215. [ PubMed ] [ Google Scholar ] 3. Nehra D, Howell P, Williams CP, Pye JK, Beynon J. Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity. Gut. 1999;44:598–602. doi: 10.1136/gut.44.5.598. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 4. Iftikhar SY, Ledingham S, Steele RJ, Evans DF, Lendrum K, Atkinson M, et al. Bile reflux in columnar-lined Barrett’s oesophagus. Ann R Coll Surg Engl. 1993;75:411–416. [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. V

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

Molecular aspects of membrane stabilization by ursodeoxycholate [see comment]. Gastroenterology
104: 1736–1744, 1993 [ DOI ] [ PubMed ] [ Google Scholar ] 10. Hu R, Saw CL, Yu R, Kong AN.
Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid Redox Signal
13: 1679–1698, 2010 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 11. Huo X, Juergens S, Zhang X, Rezaei D, Yu C, Strauch ED, Wang JY, Cheng E, Meyer F, Wang DH, Zhang Q, Spechler SJ, Souza RF.
Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells. Am J Physiol Gastrointest Liver Physiol
301: G278–G286, 2011 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 12. Huo X, Zhang X, Yu C, Zhang Q, Cheng E, Wang DH, Pham TH, Spechler SJ, Souza RF.
In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-kappaB and activator protein-1. Gut. 2013.
September
18. 10.1136/gutjnl-2013-305533
[Epub ahead of print]. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 13. Iftikhar SY, Ledingham S, Steele RJ, Evans DF, Lendrum K, Atkinson M, Hardcastle JD.
Bile reflux in columnar-lined Barrett's oesophagus. Ann R Coll Surg Engl
75: 411–416, 1993 [ PMC free article ] [ PubMed ] [ Google Scholar ] 14. Jaiswal KR, Morales CP, Feagins LA, Gandia KG, Zhang X, Zhang HY, Hormi-Carver K, Shen Y, Elder F, Ramirez RD, Sarosi GA, Jr, Spechler SJ, Souza RF.
Characterization of telomerase-immortalized

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

-dose proton pump inhibitors on the histology of Barrett's esophagus. Dis Esophagus
21: 346–354, 2008 [ DOI ] [ PubMed ] [ Google Scholar ] 4. Cheng E, Zhang X, Huo X, Yu C, Zhang Q, Wang DH, Spechler SJ, Souza RF.
Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut
62: 824–832, 2013 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Corley DA, Mehtani K, Quesenberry C, Zhao W, de Boer J, Weiss NS.
Impact of endoscopic surveillance on mortality from Barrett's esophagus-associated esophageal adenocarcinomas. Gastroenterology
145: 312–319, 2013 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 6. Frazzoni M, Conigliaro R, Melotti G.
Weakly acidic refluxes have a major role in the pathogenesis of proton pump inhibitor-resistant reflux oesophagitis. Aliment Pharmacol Ther
33: 601–606, 2011 [ DOI ] [ PubMed ] [ Google Scholar ] 7. Goldman A, Condon A, Adler E, Minnella M, Bernstein C, Bernstein H, Dvorak K.
Protective effects of glycoursodeoxycholic acid in Barrett's esophagus cells. Dis Esophagus
23: 83–93, 2010 [ DOI ] [ PubMed ] [ Google Scholar ] 8. Gotley DC, Morgan AP, Ball D, Owen RW, Cooper MJ.
Composition of gastro-oesophageal refluxate. Gut
32: 1093–1099, 1991 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 9. Guldutuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U.
Molecular aspects of membrane stabilization by ursodeoxycholate [see comment]. Gastroenterology
104: 1736–1744, 1993 [ DOI ] [ PubMed ] [ Google Scholar ] 10. Hu R, Saw CL,

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

, Zhang X, Zhang HY, Hormi-Carver K, Shen Y, Elder F, Ramirez RD, Sarosi GA, Jr, Spechler SJ, Souza RF.
Characterization of telomerase-immortalized, nonneoplastic, human Barrett's cell line (BAR-T). Dis Esophagus
20: 256–264, 2007 [ DOI ] [ PubMed ] [ Google Scholar ] 15. Kastelein F, Spaander MC, Steyerberg EW, Biermann K, Valkhoff VE, Kuipers EJ, Bruno MJ.
Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett's esophagus. Clin Gastroenterol Hepatol
11: 382–388, 2013 [ DOI ] [ PubMed ] [ Google Scholar ] 16. Kobayashi M, Yamamoto M.
Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal
7: 385–394, 2005 [ DOI ] [ PubMed ] [ Google Scholar ] 17. Kosoff RE, Gardiner KL, Merlo LM, Pavlov K, Rustgi AK, Maley CC.
Development and characterization of an organotypic model of Barrett's esophagus. J Cell Physiol
227: 2654–2659, 2012 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 18. Kowdley KV.
Ursodeoxycholic acid therapy in hepatobiliary disease. Am J Med
108: 481–486, 2000 [ DOI ] [ PubMed ] [ Google Scholar ] 19. Lapenna D, Ciofani G, Festi D, Neri M, Pierdomenico SD, Giamberardino MA, Cuccurullo F.
Antioxidant properties of ursodeoxycholic acid. Biochem Pharmacol
64: 1661–1667, 2002 [ DOI ] [ PubMed ] [ Google Scholar ] 20. Ljubuncic P, Abu-Salach O, Bomzon A.
Ursodeoxycholic acid and superoxide anion. World J Gastroenterol
11: 4875–4878, 2005 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 21. Masamune K, Kunitomo K

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients - PubMed

10.1158/1940-6207.CAPR-16-0059. Epub 2016 May 2. Cancer Prev Res (Phila). 2016. PMID: 27138791 Free PMC article. References DeMeester SR. Management of Barrett’s esophagus free of dysplasia. Semin Thorac Cardiovasc Surg. 1997;9:279–284.

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology
111: 1192–1199, 1996 [ DOI ] [ PubMed ] [ Google Scholar ] 33. Wali RK, Frawley BP, Jr, Hartmann S, Roy HK, Khare S, Scaglione-Sewell BA, Earnest DL, Sitrin MD, Brasitus TA, Bissonnette M.
Mechanism of action of chemoprotective ursodeoxycholate in the azoxymethane model of rat colonic carcinogenesis: potential roles of protein kinase C-alpha, -beta II, and -zeta. Cancer Res
55: 5257–5264, 1995 [ PubMed ] [ Google Scholar ] 34. Zhang HY, Hormi-Carver K, Zhang X, Spechler SJ, Souza RF.
In benign Barrett's epithelial cells, acid exposure generates reactive oxygen species that cause DNA double-strand breaks. Cancer Res
69: 9083–9089, 2009 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 35. Zhang X, Yu C, Wilson K, Zhang H, Melton SD, Huo X, Wang DH, Genta RM, Spechler SJ, Souza RF.
Malignant transformation of nonneoplastic Barrett's epithelial cells through well-defined genetic manipulations. PLoS One
5: e13093, 2010 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Articles from American Journal of Physiology - Gastrointestinal and Liver Physiology are provided here courtesy of American Physiological Society ACTIONS View on publisher site Cite Collections Permalink PERMALINK Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Add to Collections Create a new collection Add to an existing collection Name your collection * Choose a collection Unable to load your collection due to an error Please try again Add Cancel Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

ophagus. Using Barrett's epithelial cells in vitro, we have shown that UDCA activates Nrf2 to upregulate expression of GPX1 and catalase antioxidants, which prevent DCA-induced ROS generation, DNA damage, and NF-κB activation. Finally, we have verified this in vitro finding by demonstrating upregulation of GPX1 and catalase in biopsy specimens of Barrett's metaplasia taken from patients after oral UDCA treatment. These data elucidate a molecular pathway whereby treatment with UDCA protects against bile-acid induced oxidative injury in Barrett's esophagus and provide the rationale for clinical trials of UDCA for chemoprevention in patients with this common disorder. GRANTS This work was supported by the Office of Medical Research, Departments of Veterans Affairs (R. F. Souza, S. J. Spechler, D. H. Wang), the National Institutes of Health (R01-DK63621 and R01-CA134571 to R. F. Souza and S. J. Spechler, R01-DK097340 to D. H. Wang, K12 HD-068369-01 to E. Cheng), the American Gastroenterological Association Institute (Fellow to Faculty Transition Award to E. Cheng), and NASPGHAN Foundation/AstraZeneca Award (E. Cheng). DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS S.P., X.H., Q.Z., X.Z., C.Y., K.A., E.C., T.H.P., D.H.W., M.C., R.F.S., and S.J.S. conception and design of research; S.P., X.H., D.R., R.F.S., and S.J.S. performed experiments; S.P., X.H., R.F.S., and S.J.S. analyzed data; S.P., X.H., R.F.S., and S.J.S. interpreted results of experiments; S.P., X.H., R.F.S., and S.J.S. prepared figures; S.P., X.H., R.F.S., and S.J.S.

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus - PubMed

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
sharing sensitive information, make sure you’re on a federal
government site. The site is secure. The https:// ensures that you are connecting to the
official website and that any information you provide is encrypted
and transmitted securely. Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Email address has not been verified. Go to My NCBI account settings to confirm your email and then refresh this page. To: Subject: Body: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

exposure to acid that, like bile acids, can produce DNA DSBs ( 34 ). In earlier studies, we showed that PPIs block esophageal epithelial cells from secreting IL-8, a proinflammatory and proproliferative cytokine, through effects on NF-κB and activating protein-1 that are independent of effects on gastric acid secretion ( 12 ). Finally, observational studies suggest that PPIs protect against neoplasia in Barrett's esophagus ( 15 ). Despite their numerous beneficial effects, PPIs do nothing to correct the underlying reflux diathesis in Barrett's esophagus, and gastroesophageal reflux of acidic and nonacidic gastric material occurs frequently in Barrett's patients taking PPIs ( 6 , 32 ). In Barrett's patients, furthermore, PPI treatment increases gastric luminal concentrations of toxic, unconjugated bile acids like DCA, which can be especially damaging at the neutral pH levels common in gastric juice of patients on PPIs ( 31 ). Ongoing reflux of toxic bile acids during PPI therapy might contribute to carcinogenesis despite the otherwise beneficial actions of these agents. Thus a combination of PPIs and UDCA might be more effective for chemoprevention than either agent alone. To our knowledge, only one clinical study has explored the role of UDCA combined with PPIs for chemoprevention in Barrett's esophagus ( 3 ). That study found no effects of this combination therapy on inflammation, dysplasia, proliferation, differentiation, and p53 and p16 abnormalities. However, the study included only nine patients who took UDCA for only 6 mo and was not adequately powered to detect changes in some of the markers studied. Furthermore, these markers are of questionable validity as indexes for protection from oxidative DNA damage, the protective mechanism that we have demonstrated for UDCA. Our study provides strong rationale for future studies on UDCA combined with PPIs for chemoprevention in Barrett's esophagus. In conclusion, we have shown that oral treatment with UDCA prevents a toxic bile acid from causing DNA damage and NF-κB activation in the metaplastic mucosa of patients with Barrett's esophagus. Using Barrett's epithelial cells in vitro, we have shown that UDCA activates Nrf2 to upregulate expression of GPX1 and catalase antioxidants, which prevent DCA-induced ROS generation, DNA damage, and

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

2AX expression, neutral CometAssay, and phospho-H2AX nuclear foci formation. Quantitative PCR was performed for antioxidants including catalase and GPX1. Nrf2, catalase, and GPX1 were knocked down with siRNAs. Reporter assays were performed using a plasmid construct containing antioxidant responsive element. In patients, baseline esophageal perfusion with DCA significantly increased phospho-H2AX and phospho-p65 in Barrett's metaplasia. Oral UDCA increased GPX1 and catalase levels in Barrett's metaplasia and prevented DCA perfusion from inducing DNA damage and NF-κB activation. In cells, DCA-induced DNA damage and NF-κB activation was prevented by 24-h pretreatment with UDCA, but not by mixing UDCA with DCA. UDCA activated Nrf2 signaling to increase GPX1 and catalase expression, and protective effects of UDCA pretreatment were blocked by siRNA knockdown of these antioxidants. UDCA increases expression of antioxidants that prevent toxic bile acids from causing DNA damage and NF-κB activation in Barrett's metaplasia. Elucidation of this molecular pathway for UDCA protection provides rationale for clinical trials on UDCA for chemoprevention in Barrett's esophagus. Keywords: bile acids, chemoprevention, esophageal adenocarcinoma, catalase, GPX1 the frequency of adenocarcinoma of the esophagus has increased more than sevenfold over the past several decades in the United States ( 25 ). Major risk factors for this deadly cancer are gastroesophageal reflux disease (GERD) and its complication, Barrett's esophagus, the condition in which metaplastic columnar epithelium predisposed to malignancy replaces squamous epithelium of the distal esophagus ( 29 ). It has been estimated that 2–7% of adults in Western countries have Barrett's esophagus. Clearly, a safe and effective chemopreventive agent for these patients would be highly desirable. The cancer-prevention strategy currently recommended for Barrett's esophagus involves endoscopic surveillance for dysplasia and treatment of the underlying GERD with proton pump inhibitors (PPIs) ( 30 ). The benefit of surveillance for these patients has never been established, and one recent

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

Bile reflux in columnar-lined Barrett’s oesophagus. Ann R Coll Surg Engl. 1993;75:411–416. [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology. 1996;111:1192–1199. doi: 10.1053/gast.1996.v111.pm8898632. [ DOI ] [ PubMed ] [ Google Scholar ] 6. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res. 2005;589:47–65. doi: 10.1016/j.mrrev.2004.08.001. [ DOI ] [ PubMed ] [ Google Scholar ] 7. Dvorak K, Fass R, Dekel R, Payne CM, Chavarria M, Dvorakova B, et al. Esophageal acid exposure at pH < or = 2 is more common in Barrett’s esophagus patients and is associated with oxidative stress. Dis Esophagus. 2006;19:366–372. doi: 10.1111/j.1442-2050.2006.00596.x. [ DOI ] [ PubMed ] [ Google Scholar ] 8. Dvorak K, Payne CM, Chavarria M, Ramsey L, Dvorakova B, Bernstein H, et al. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett’s oesophagus. Gut. 2007;56:763–771. doi: 10.1136/gut.2006.103697. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 9. Huo X, Juergens S, Zhang X, Rezaei D, Yu C, Strauch ED, et al. Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-kappaB activation in benign Barrett’s epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;301:G278–286. doi: 10

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

acid causes DNA damage while inducing apoptotic resistance through NF-kappaB activation in benign Barrett’s epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;301:G278–286. doi: 10.1152/ajpgi.00092.2011. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 10. Goldman A, Condon A, Adler E, Minnella M, Bernstein C, Bernstein H, et al. Protective effects of glycoursodeoxycholic acid in Barrett’s esophagus cells. Dis Esophagus. 2010;23:83–93. doi: 10.1111/j.1442-2050.2009.00993.x. [ DOI ] [ PubMed ] [ Google Scholar ] 11. Rizvi S, Demars CJ, Comba A, Gainullin VG, Rizvi Z, Almada LL, et al. Combinatorial chemoprevention reveals a novel smoothened-independent role of GLI1 in esophageal carcinogenesis. Cancer Res. 2010;70:6787–6796. doi: 10.1158/0008-5472.CAN-10-0197. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 12. Peng S, Huo X, Rezaei D, Zhang Q, Zhang X, Yu C, et al. In Barrett’s esophagus patients and Barrett’s cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids. Am J Physiol Gastrointest Liver Physiol. 2014;307:G129–139. doi: 10.1152/ajpgi.00085.2014. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 13. Alberts DS, Martinez ME, Hess LM, Einspahr JG, Green SB, Bhattacharyya AK, et al. Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst. 2005;97:846–853. doi: 10.1093/jnci/dji144. [ DOI ] [ PubMed ] [ Google Scholar ] 14. Pardi

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus - PubMed

reviewed for the extent of metaplasia, dysplasia, and acute and chronic inflammation. In addition, proliferation (Ki67), differentiation (villin, cytokeratins 7 and 20) and inflammation (COX-2) were investigated by immunohistochemistry (IHC). Nine patients (mean age 60 years, median BE length 7 cm) were included, of whom six had no dysplasia and three had low-grade dysplasia. pH measurements revealed a normal acid exposure in most patients at t = 0 and t = 6 months. In addition, bile composition analysis demonstrated the efficacy of UDCA. Combining the results of both phases of the study, no significant changes were seen in any of the histological or IHC parameters. Differentiation and proliferation parameters showed no significant changes. In this study, in BE patients who were clinically asymptomatic on PPI, increasing the PPI dose to the maximum for 6 months followed by the addition of UDCA for 6 months did not result in significant histological or IHC changes in their BE. PubMed Disclaimer Publication types Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search MeSH terms Administration, Oral Actions Search in PubMed Search in MeSH Add to Search Barrett Esophagus / drug therapy Actions Search in PubMed Search in MeSH Add to Search Barrett Esophagus / pathology Actions Search in PubMed Search in MeSH Add to Search Cholagogues and Choleretics / administration & dosage Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Prospective Studies Actions Search in PubMed Search in MeSH Add to Search Proton Pump Inhibitors / administration & dosage Actions Search in PubMed Search in MeSH Add to Search Ursodeoxycholic Acid / administration & dosage* Actions Search in PubMed Search in MeSH Add to Search Substances Cholagogues and Choleretics Actions Search in PubMed Search in MeSH Add to Search Proton Pump Inhibitors Actions Search in PubMed Search in MeSH Add to Search Ursodeoxycholic Acid Actions Search in PubMed Search in MeSH Add to Search LinkOut - more resources Full Text Sources Silverchair

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

The study endpoints were changes in oxidative DNA damage (measured by 8-hydroxydeoxyguanosine levels), cell proliferation (measured by Ki-67 expression), and apoptosis (measured by cleaved caspase 3) in the BE epithelium and changes in gastric bile acid composition. Study Drug Ursodiol (300 mg) capsules were supplied by the National Cancer Institute, Division of Cancer Prevention. The initial supply was manufactured by CorePharma LLC for Rising Phamaceuticals. Following expiration of the initial supply in August 2010, the replacement supply for the remainder of the trial was manufactured by Watson Pharma Private Limited and distributed by Watson Pharma, Inc.. The study capsules were stored at room temperature and protected from environmental extremes. Study population We recruited healthy women and men ≥ 18 years of age with a diagnosis of BE with histologically-confirmed intestinal metaplasia anywhere in the tubular esophagus either with ≥ 2 cm of involvement or with a minimum of circumferential BE length of 1 cm. Participants were required to have normal liver and renal function. Study exclusion criteria included BE with high grade dysplasia or carcinoma, medical conditions which would make completing endoscopies or completing the trial difficult, use of other investigational agents within 1 month, use of NSAIDs for more than 5 days a month within 1 month (except low dose aspirin (81 mg QD)), history of allergic reactions attributed to UDCA, uncontrolled acute and chronic diseases, pregnant and breast feeding women, major upper GI surgery within 6 months, erosive esophagitis at baseline endoscopy, chemotherapy, radiotherapy, or cancer-related hormonal or immunotherapy within the last 18 months, current or planned use of anticoagulant drugs, or use of cyclosporine. Written informed consent was obtained from all participants. Study procedure During the initial visit, consented study subjects underwent medical and surgical history evaluation and had a blood sample collected for complete blood count (CBC) and comprehensive metabolic panel (CMP). Following the initial eligibility evaluation, subjects underwent upper endoscopy with biopsies. Prior to any mucosal irrigation, gastric fluid was aspirated through the endoscope and collected. The circumferential and maximum extents of metaplasia were determined using the Prague C&M criteria [ 15 ]. Systematic biopsies – one in each of four quadrants every 2 cm in the appropriate areas of the BE –

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients - PubMed

75:411–416.

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

for 8 weeks increased the levels of two antioxidant enzymes (glutathione peroxidase 1 and catalase) in esophageal biopsies collected from patients with BE. The treatment also prevented DNA damage and NF-κB activation induced by esophageal DCA perfusion in patients with BE. However, it is unknown whether UDCA treatment will decrease the extent of DNA damage under physiological condition (i.e., without esophageal DCA perfusion). UDCA is an attractive candidate for chemoprevention because of its long-term safety record. It has been used safely at the dose of 8–10 mg/kg/day in patients with gallstone disease in the U.S. since 1987 and later in patients with primary biliary cirrhosis (PBC) at the dose of 13–15 mg/kg/day. In the clinical trial setting, it has demonstrated potential for risk reduction for colorectal cancer with a good safety profile. UDCA treatment at a dose of 8–10 mg/kg/day for a mean of 32 months was associated with a statistically significant 39% reduction in recurrence of colorectal adenomas with high-grade dysplasia [ 13 ]. A study of 52 patients with ulcerative colitis and primary sclerosing cholangitis showed that treatment with UDCA (at a dose of 13–15 mg/kg/day for a median duration of 42 months) significantly reduced the risk of colorectal dysplasia or cancer compared with placebo [ 14 ]. We conducted a pilot clinical study to assess the clinical activity of UDCA in patients with BE. The central hypothesis to be tested in the clinical study is that supplementation with UDCA would alter bile acid composition in the refluxate and subsequently decrease oxidative DNA damage, and cell proliferation and increase apoptosis in the BE epithelium. Materials and Methods Study Design The study was an open label, single-arm intervention trial conducted at the University of Arizona (UA), University of North Carolina (UNC), and Southern Arizona VA Health Care System (SAVAHCS). The study was approved by the Institutional Review Board at each institution. The study endpoints were changes in oxidative DNA damage (measured by 8-hydroxydeoxyguanosine levels), cell proliferation (measured by Ki-67 expression), and apoptosis (measured by cleaved caspase 3)

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

p65 expression in Barrett's metaplasia. In those same patients, 8 wk of oral treatment with UDCA prevented DNA damage and NF-κB activation induced by DCA perfusion. Using Barrett's cell lines to explore molecular mechanisms underlying these effects, we found that UDCA activated Nrf2 signaling to increase intracellular levels of GPX1 and catalase antioxidants, and that pretreating cells with UDCA prevented DCA from inducing DNA damage and NF-κB activation. This protective effect of UDCA pretreatment could be blocked in vitro by siRNA knockdown of GPX1 and catalase and, in patients, we demonstrated that oral UDCA treatment increased protein levels of these antioxidants in Barrett's metaplasia. Thus we have shown that UDCA increases expression of antioxidants that prevent DNA damage and NF-κB activation in Barrett's metaplasia exposed to a toxic bile acid found in refluxed gastric juice. These findings suggest a potential chemopreventive role for UDCA in Barrett's esophagus. In Barrett's epithelial cells, we found that DCA caused DNA damage with DSBs. DSBs are dangerous mutations because they can cause genomic instability contributing to carcinogenesis, and agents that cause DSBs are considered carcinogens ( 2 , 23 ). Since DCA can be considered a carcinogen in Barrett's esophagus, an agent that can counter DCA's DNA-damaging effects might have a role in chemoprevention. Our findings suggest that UDCA might be such an agent. As in our earlier studies ( 11 ), we found that a 5-min esophageal perfusion with UDCA caused no DNA damage and no NF-κB activation in Barrett's metaplasia for any study patient. We treated our patients with oral UDCA in a dose of 10 mg/kg because this dosage has been used safely to treat patients with liver diseases and, on this dosage, UDCA replaces hydrophobic bile acids to comprise 40–50% of the bile salt pool ( 18 ). Thus we anticipated that oral UDCA treatment would decrease concentrations of toxic bile acids like DCA in refluxed gastric juice and increase its concentration of the cytoprotective bile acid UDCA. We found that oral UDCA treatment prevented DCA from inducing DNA damage and NF-κB activation in Barrett's metaplasia, and we performed experiments to deline

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

. We selected to use the BAR-T line for all experiments (unless otherwise indicated) because this cell line has been extensively characterized by our laboratory ( 11 , 14 , 34 , 35 ). Bile salt exposure. For individual experiments, Barrett's cells were treated with experimental medium (pH 7.2) containing DCA alone (125 or 250 μM, Sigma, St. Louis, MO), experimental medium (pH 7.2) containing DCA mixed with UDCA (125 or 250 μM, Calbiochem, San Diego, CA), or control medium (pH 7.2) without bile acids. We selected to use DCA, which has been measured in the refluxed gastric juice of Barrett's patients in concentrations as high as 282 μM, to explore mechanisms whereby UDCA protects against the genotoxic effects of a physiologically relevant, toxic, hydrophobic bile acid ( 24 ). Media were added for 5 min to equally seeded wells of subconfluent cells, then removed and replaced with growth medium. Cells were pretreated with UDCA (300 μM) for 24 h prior to exposure to 250 μM DCA for 5 min. Cells were also treated with UDCA (300 μM) for times ranging from 0.5–24 h. Detection of intracellular ROS. ROS were detected by using the OxiSelect Intracellular ROS assay kit (Cell Biolabs, San Diego, CA) per manufacturer's instructions. Equally seeded wells of cells were pretreated with or without 300 μM UDCA for 24 h and then washed twice with wash buffer and incubated with 100 μl of 1× DCFH-DA for 45 min at 37°C while protected from light. Cells were then exposed to medium containing 250 μM DCA for 5 min, after which the assay was terminated by adding 100 μl of 2× cell lysis buffer. The lysates were analyzed by a fluorometric plate reader, and fluorescence intensity was immediately measured at 480/530 nm by using the POLARstar Omega software (BMG Labtech, Cary, NC). A higher florescence reading indicates greater production of intracellular ROS. Protein extraction and immunoblotting. For Barrett's epithelial cell lines, total protein was extracted using 200 μl of 1× cell lysis buffer supplemented with 0.5 mM phenylmethylsulfonyl fluoride (PMSF) according to manufacturer

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

changes in gastric bile acid composition of changes in tissue biomarker expression. Bile Acid 8OHdG (N=25) Ki67 (N=28) CC3 (N=26) Total UDCA 0.04; p=0.85 0.01; p=0.94 0.29; p=0.15 Total CDCA −0.16; p=0.43 −0.20; p=0.31 0.24; p=0.24 Total DCA −0.14; p=0.49 −0.19; p=0.34 −0.09; p=0.65 Total CA 0.24; p=0.26 −0.04 p=0.28 −0.23; p=0.26 Total LCA −0.07; p=0.74 0.01; p=0.96 0.06; p=0.78 Open in a new tab Abbreviations: UDCA: ursodeoxycholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; CA: cholic acid; LCA: lithocholic acid; 8OHdG: 8-hydroxydeoxyguanosine; CC3: cleaved caspase 3 Discussion Our single-arm pilot clinical study was designed to evaluate the clinical activity of UDCA in patients with BE. We evaluated the clinical activity of UDCA by assessing changes in gastric bile acid composition and markers of oxidative DNA damage, cell proliferation, and apoptosis in the BE epithelium because prior research suggested that these markers could be modulated with UDCA intervention [ 10 , 12 ]. The study showed that supplementation with UDCA at a daily dose of 13–15 mg/kg/day for six months in patients with BE increased proportions of cytoprotective bile acids and decreased proportions of cytotoxic bile acids in the gastric fluid. Despite the favorable change in the bile acid composition, we did not observe any significant changes in markers of oxidative DNA damage, cell proliferation, and apoptosis in the BE epithelium. In our study, all but one participant were treated with PPI for symptom control with most treated for more than 6 months prior to initiation of the UDCA intervention. The PPI treatment may have contributed to the lack of UDCA effects on tissue markers of

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

our study, all but one participant were treated with PPI for symptom control with most treated for more than 6 months prior to initiation of the UDCA intervention. The PPI treatment may have contributed to the lack of UDCA effects on tissue markers of oxidative DNA damage, cell proliferation, and apoptosis. In a multicenter prospective cohort study of 540 patients with BE, PPI use was associated with a reduced risk of neoplastic progression [ 16 ]. High-dose PPI treatment in patients with BE that results in effective esophageal acid suppression has been shown to decrease the markers of cell proliferation and inflammation and increase apoptosis [ 17 ]. PPI treatment reduces the acidity and the volume of the refluxate, which may diminish the exposure of esophagus to cytotoxic bile acids [ 18 ]. Therefore, modulation of bile acid composition with the UDCA intervention may not result in any further improvement in histology and the selected tissue biomarkers. Furthermore, bile acids that are cytotoxic to the mucosa in an acidic environment may lose their damaging activity at neutral pH from PPI treatment. Bozikas et al. [ 19 ] evaluated the effect of six months of UDCA (600 mg BID) intervention in nine Barrett’s patients treated with high dose PPI. Similarly, UDCA intervention did not lead to significant changes in histology and markers of proliferation, differentiation, and inflammation in this study with limited sample size. An alternative explanation for the lack of change in the selected tissue biomarkers is that cytotoxic bile acid reflux may not a causative factor in the pathogenesis of progression in BE. It was recently demonstrated in an animal model that cytotoxic bile acids and not gastric acid were pathogenic in the development of Barrett’s-like metaplasia [ 20 ], however the progression to dysplasia may be caused by other, unknown factors. The development of BE results in a more durable epithelium that may be more resistant to insult by refluxate. Thus, UDCA treatment may be more effective to prevent the development of BE than to prevent the pathogenesis of BE. It is important to note that the null findings in the tissue biomarkers from this single-arm pilot study will need to be interpreted with caution as the study is limited by the lack of a control arm and the small sample size. The study selected an intervention duration of 6 months to coincide with the recommended interval for

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus - PubMed

Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Silverchair Information Systems Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Permalink Permalink Copy Display options Display options Format Abstract PubMed PMID Page navigation Title & authors Abstract Publication types MeSH terms Substances LinkOut - more resources Title & authors Abstract Publication types MeSH terms Substances LinkOut - more resources Dis Esophagus Actions Search in PubMed Search in NLM Catalog Add to Search . 2008;21(4):346-54. doi: 10.1111/j.1442-2050.2007.00782.x. The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus A Bozikas 1 , W A Marsman , W D Rosmolen , J W P M van Baal , W Kulik , F J W ten Kate , K K Krishnadath , J J G H M Bergman Affiliations Expand Affiliation 1 Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. PMID: 18477258 DOI: 10.1111/j.1442-2050.2007.00782.x Item in Clipboard The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus A Bozikas et al. Dis Esophagus . 2008 . Show details Display options Display options Format Abstract PubMed PMID Dis Esophagus Actions Search in PubMed Search in NLM Catalog Add to Search . 2008;21(4):346-54. doi: 10.1111/j.1442-

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients - PubMed

first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Silverchair Information Systems Free PMC article Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Permalink Permalink Copy Display options Display options Format Abstract PubMed PMID Page navigation Title & authors Abstract Conflict of interest statement Comment in References Publication types MeSH terms Substances Grants and funding LinkOut - more resources Title & authors Abstract Conflict of interest statement Comment in References Publication types MeSH terms Substances Grants and funding LinkOut - more resources Clinical Trial Cancer Prev Res (Phila) Actions Search in PubMed Search in NLM Catalog Add to Search . 2016 Jul;9(7):528-33. doi: 10.1158/1940-6207.CAPR-15-0276. Epub 2016 Feb 23. Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients Bhaskar Banerjee 1 , Nicholas J Shaheen 2 , Jessica A Martinez 3 , Chiu-Hsieh Hsu 4 , Eugene Trowers 1 , Blake A Gibson 1 , Gary Della'Zanna 5 , Ellen Richmond 5 , H-H Sherry Chow 6 Affiliations Expand Affiliations 1 College of Medicine, University of Arizona, Tucson, Arizona. 2 Division of Gastroenterology & Hepatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina. 3 University of Arizona Cancer Center, Tucson, Arizona. Department of Nutritional Sciences, University of Arizona, Tucson, Arizona. 4 University of Arizona Cancer Center, Tucson, Arizona. 5 Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland. 6 University of Arizona Cancer Center, Tucson, Arizona. schow@azcc.arizona.edu. PMID: 26908564 PMCID:

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

interpreted results of experiments; S.P., X.H., R.F.S., and S.J.S. prepared figures; S.P., X.H., R.F.S., and S.J.S. drafted manuscript; S.P., X.H., D.R., Q.Z., X.Z., C.Y., K.A., E.C., T.H.P., D.H.W., R.F.S., and S.J.S. edited and revised manuscript; S.P., X.H., D.R., Q.Z., X.Z., C.Y., K.A., E.C., T.H.P., D.H.W., M.C., R.F.S., and S.J.S. approved final version of manuscript. ACKNOWLEDGMENTS We are grateful to Dr. Daisha J. Cipher, Associate Professor, University of Texas at Arlington School of Nursing, for her contribution to the power calculations for our patient studies. REFERENCES 1. Araki Y, Andoh A, Bamba H, Yoshikawa K, Doi H, Komai Y, Higuchi A, Fujiyama Y.
The cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids in intestinal cell lines IEC-6 and Caco-2. Oncol Rep
10: 1931–1936, 2003 [ PubMed ] [ Google Scholar ] 2. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, Pommier Y.
GammaH2AX and cancer. Nat Rev Cancer
8: 957–967, 2008 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 3. Bozikas A, Marsman WA, Rosmolen WD, van Baal JW, Kulik W, Ten Kate FJ, Krishnadath KK, Bergman JJ.
The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett's esophagus. Dis Esophagus
21: 346–354, 2008 [ DOI ] [ PubMed ] [ Google Scholar ] 4. Cheng E, Zhang X, Huo X

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

[ PubMed ] [ Google Scholar ] 18. Dunbar KB, Souza RF, Spechler SJ. The Effect of Proton Pump Inhibitors on Barrett’s Esophagus. Gastroenterol Clin North Am. 2015;44:415–424. doi: 10.1016/j.gtc.2015.02.010. [ DOI ] [ PubMed ] [ Google Scholar ] 19. Bozikas A, Marsman WA, Rosmolen WD, van Baal JW, Kulik W, ten Kate FJ, et al. The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett’s esophagus. Dis Esophagus. 2008;21:346–354. doi: 10.1111/j.1442-2050.2007.00782.x. [ DOI ] [ PubMed ] [ Google Scholar ] 20. Sun D, Wang X, Gai Z, Song X, Jia X, Tian H. Bile acids but not acidic acids induce Barrett’s esophagus. International journal of clinical and experimental pathology. 2015;8:1384–1392. [ PMC free article ] [ PubMed ] [ Google Scholar ] 21. Binato M, Gurski RR, Fagundes RB, Meurer L, Edelweiss MI. P53 and Ki-67 overexpression in gastroesophageal reflux disease--Barrett’s esophagus and adenocarcinoma sequence. Dis Esophagus. 2009;22:588–595. doi: 10.1111/j.1442-2050.2009.00953.x. [ DOI ] [ PubMed ] [ Google Scholar ] 22. Coban S, Ormeci N, Savas B, Ekiz F, Ensari A, Kuzu I, et al. Evaluation of Barrett’s esophagus with CK7, CK20, p53, Ki67, and COX2 expressions using chromoendoscopical examination. Dis Esophagus. 2013;26:189–196. doi: 10.1111/j.1442-2050.2012.01352.x. [ DOI ] [ PubMed ] [ Google Scholar ] 23. Sikkema M, Kerkhof M, Steyerberg EW

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

biomarkers from this single-arm pilot study will need to be interpreted with caution as the study is limited by the lack of a control arm and the small sample size. The study selected an intervention duration of 6 months to coincide with the recommended interval for surveillance endoscopy for BE patients with low grade dysplasia at the time of the study protocol development. Based on prior research [ 10 , 12 ], it was anticipated that 6 months of UDCA intervention would be sufficient to modulate the selected tissue biomarkers. It is not known whether the selected tissue biomarkers would be modulated with a longer intervention duration. The tissue biomarkers employed in this study have been correlated with the histological grade of Barrett’s esophagus [ 21 – 24 ] and used as intermediate biomarkers to assess preventive interventions in BE patients [ 17 , 19 , 25 , 26 ]. However, these markers have not been proven in large, well-designed study to predict the risk of development of high grade dysplasia or adenocarcinoma. Multiple studies have shown that esophageal adenocarcinomas have extensive chromosomal instability, high levels of chromosome copy-number alterations, and frequent catastrophic chromosomal events [ 27 – 30 ]. Li and colleagues showed that esophageal adenocarcinoma risk predicted by somatic chromosome alterations outperformed risk predicted by TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia [ 31 ]. This line of research may offer unique opportunities to identify exposures that lead to the mutation signatures in esophageal adenocarcinoma to better develop preventive strategies to target mutagens leading to the genomic alterations. We conclude that high dose supplementation with UDCA for six months in patients with Barrett’s esophagus increased proportions of cytoprotective bile acids and decreased proportions of cytotoxic bile acids in the gastric fluid. Despite of the favorable change in the bile acid composition in the gastric fluid, we did not observe any significant changes in markers of oxidative DNA damage, cell proliferation, and apoptosis in the BE epithelium. Given recent research describing genomic alterations that develop in esophageal adenocarcinoma, future studies may consider determining the effects of UDCA on genomic alterations, as well as the effect of combining with PPI use, to determine its roles in prevention of neoplastic progression. Acknowledgments Financial support: This

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

acid and superoxide anion. World J Gastroenterol
11: 4875–4878, 2005 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 21. Masamune K, Kunitomo K, Sasaki K, Yagi K, Komi N, Tashiro S.
Bile-induced DNA strand breaks and biochemical analysis of bile acids in an experimental model of anomalous arrangement of the pancreaticobiliary ducts. J Med Invest
44: 47–51, 1997 [ PubMed ] [ Google Scholar ] 22. McQuaid KR, Laine L, Fennerty MB, Souza R, Spechler SJ.
Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment Pharmacol Ther
34: 146–165, 2011 [ DOI ] [ PubMed ] [ Google Scholar ] 23. Mills KD, Ferguson DO, Alt FW.
The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev
194: 77–95, 2003 [ DOI ] [ PubMed ] [ Google Scholar ] 24. Nehra D, Howell P, Williams CP, Pye JK, Beynon J.
Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity. Gut
44: 598–602, 1999 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 25. Pohl H, Sirovich B, Welch HG.
Esophageal adenocarcinoma incidence: are we reaching the peak?
Cancer Epidemiol Biomarkers Prev
19: 1468–1470, 2010 [ DOI ] [ PubMed ] [ Google Scholar ] 26. Rizvi S, DeMars CJ, Comba A, Gainullin VG, Rizvi Z, Almada LL, Wang K, Lomberk G, Fernandez-Zapico ME, Buttar NS.
Combinatorial chemoprevention reveals a novel smoothened-independent role of GLI1 in esophageal carcinogenesis. Cancer Res
70: 6787–6796, 2010 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 27. Singh S, Khanna S, Pardi DS, Loftus EV

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

entially prior to incubating with the mouse monoclonal antibody for 8OHdG (QED Bioscience, #12501 (clone 15A3), diluted 1:1000)). Slides were then incubated with secondary biotinylated rabbit anti-mouse IgG antibody, Vectastain Elite ABC reagent, and DAB prior to counterstaining with hematoxylin. Human esophageal carcinoma and tonsil carcinoma were used as the positive controls. On the IHC slides, longitudinally sectioned crypts opening to the lumen were selected for scoring. The percent of nuclei stained positive for Ki67, CC3, and 8OHdG in the selected regions was quantified by Aperio Spectrum software and confirmed by a trained pathologist. Slides with fewer than 500 total nuclei in the selected regions were excluded for the statistical analysis. The marker expression from different segments was averaged for participants with tissue sections from multiple esophageal segments. Statistical Analysis Descriptive statistics were calculated to summarize the demographic characteristics and disease characteristics at baseline and post-intervention. The primary endpoint was the effect of UDCA intervention on 8OHdG levels in BE epithelium. Signed rank test was performed to assess pre to post-intervention change in percentage of nuclei stained strongly and moderately for 8OHdG. The secondary endpoints were measurements of changes in gastric bile acid composition and Ki67 and CC3 expression. Signed rank test was performed to assess the change for each of the secondary endpoints. Spearman correlation coefficients were calculated to assess the relationship between changes in gastric bile acid composition and changes in 8OHdG, Ki67, and CC3, respectively. Results The study opened to accrual in April 2010 and closed to accrual in November 2013. Eighty potentially eligible participants were consented, 39 from UA, 26 from UNC, and 15 from SAVAHCS. Forty-four consented individuals did not meet all the eligibility criteria. Thirty-six met all eligibility criteria to initiate agent intervention; of these 29 completed agent intervention, 1 was taken off agent intervention due to grade 2 diarrhea, an AE probably related to the study agent, that did not resolve within the protocol specified timeframe, 3 were taken off agent intervention due to AEs deemed unlikely to be related or not related to the study agent, and 3 withdrew consent. UDCA treatment was well

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

site in promoter regions of antioxidant target genes ( 16 , 28 ). Using an ARE reporter assay, we found that UDCA increased activity of the ARE reporter, confirming that UDCA upregulates transcription of antioxidant genes in Barrett's cells. The induction of antioxidants by chemopreventive agents often involves Nrf2, an ARE-binding transcription factor and member of the basic leucine zipper (bZIP) protein family ( 10 ). Nrf2 normally is sequestered in cytoplasm by binding to Keap1. With phosphorylation, Nrf2 dissociates from Keap1, heterodimerizes with other bZIP proteins, translocates to the nucleus, and binds to ARE that regulate transcription of antioxidants ( 10 ). In Barrett's cells, we have shown that UDCA increases phospho-Nrf2 and causes its nuclear translocation. In addition, we have shown that knockdown of Nrf2 by siRNA prevents upregulation of GPX1 and catalase by UDCA. These findings show that UDCA treatment activates Nrf2 signaling to increase intracellular levels of antioxidants. To confirm the physiological importance of antioxidant upregulation in UDCA protection from oxidative stress, we studied the effects of UDCA pretreatment on DCA-induced DNA damage in cells transfected with siRNA against GPX1 or catalase. We found that transfection with either siRNA abolished the protective effect of UDCA. In patients with Barrett's esophagus, furthermore, we found that 8 wk of oral treatment with UDCA increased protein levels of GPX1 and catalase in Barrett's metaplasia. These data indicate that UDCA protects against oxidative stress induced by toxic bile acids in Barrett's esophagus by upregulating expression of GPX1 and catalase antioxidants. All patients in our study were given omeprazole before and during UDCA treatment, and there is plausible rationale for using PPIs in chemoprevention for Barrett's esophagus. PPIs heal reflux esophagitis and thus might protect against cancer-promoting effects of chronic esophageal inflammation. PPIs reduce esophageal exposure to acid that, like bile acids, can produce DNA DSBs ( 34 ). In earlier studies, we showed that PPIs block esophageal epithelial cells from secreting IL-8, a proinflammatory and propro

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

agus increases phospho-H2AX and phospho/total p65 expression. B : UDCA perfusion does not alter phospho-H2AX and phospho/total p65 expression. C : 8 wk of oral UDCA treatment prevents the increase in phospho-H2AX and phospho-p65/total p65 levels following DCA perfusion. Horizontal dotted line beside each column represents the mean for 21 patients. D : representative Western blots from Barrett's mucosa of 2 patients demonstrating phospho-H2AX, phospho-p65, and total p65 before (pre) and after (post) esophageal perfusion with DCA, UDCA, or DCA after 8 wk of oral UDCA. In contrast to the experiments performed before UDCA treatment, esophageal perfusion with DCA did not increase phospho-H2AX or phospho-p65/total p65 expression in biopsy specimens of Barrett's metaplasia taken after patients were treated with UDCA for 8 wk ( Fig. 2 , C and D ). This demonstrates that oral treatment with UDCA protects against bile acid-induced DNA damage and NF-κB activation in the metaplastic mucosa of Barrett's patients. Mixing DCA and UDCA together does not prevent DNA damage or activation of p65 in Barrett's cells. We treated BAR-T and BAR-10T cells with DCA alone (at concentrations of 250 or 125 μM), or with a mixture of DCA and UDCA (both at concentrations of 250 or 125 μM, resulting in total bile acid concentrations of 250 and 500 μM), and determined effects on phospho-H2AX and phospho-p65 expression. In both cell lines, there were no apparent differences in phospho-H2AX and phospho-p65 expression between DCA treatment alone and DCA mixed with UDCA at either dose ( Fig. 3 A ). These findings suggest that UDCA does not interfere directly with the ability of DCA to cause DNA damage and activate NF-κB in Barrett's cells. Fig. 3. Open in a new tab Pretreatment with UDCA prevents DCA-induced phosphorylation of H2AX and p65. Representative Western blots for phospho-H2AX, phospho-p65, and total p65 in ( A ) BAR-T

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

collected from at least two independent experiments. Quantitative data are expressed as means ± SE. Statistical analyses were performed using a paired or unpaired Student's t -test with the Instat for Windows or Prism statistical software package (GraphPad Software, San Diego, CA). For multiple comparisons, an ANOVA and the Student-Newman-Keuls multiple-comparisons test was performed with the Instat for Windows statistical software package (GraphPad). P values ≤0.05 were considered significant for all analyses. RESULTS Clinical characteristics of study subjects. Thirty patients were enrolled and had the first endoscopy. During the course of the study, two experienced medical problems precluding further participation, one developed diarrhea on UDCA, four declined further participation, and two developed exclusionary criteria ( Fig. 1 ). Thus 21 patients (19 male; mean age 58 ± 2.3 yr, range 38–82 yr; 20 Caucasian, 1 African-American) completed all phases of the study, and all 21 patients were included in the molecular analyses described below. In patients with Barrett's esophagus, oral UDCA prevents DCA-induced DNA damage and activation of NF-κB subunit p65. Esophageal perfusion with DCA for 5 min caused a significant increase in phospho-H2AX and phospho-p65 (relative to total p65) in Barrett's metaplasia ( Fig. 2 , A and D ). In contrast, esophageal perfusion with UDCA had no significant effect on phospho-H2AX and phospho-p65 levels in those same patients ( Fig. 2 , B and D ). The DCA-induced increase in phospho-p65/total p65 was due to a significant increase in phospho-p65 levels; total p65 levels did not change significantly (data not shown). UDCA perfusion did not significantly alter either phospho-p65 or total p65 levels (data not shown). Fig. 2. Open in a new tab Oral UDCA treatment prevents DCA-induced phosphorylation of H2AX and p65 in Barrett's esophagus. A : DCA perfusion of the esophagus increases phospho-H2AX and phospho/total p65 expression. B : UDCA perfusion does not alter phospho-H2AX and phospho/total p65 expression. C : 8 wk of oral UDCA

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

after DCA exposure in BAR-T cells. A : representative Western blot demonstrating GPX1 and catalase knockdown by siRNA. BAR-T cells were exposed to DCA with and without 24-h pretreatment with UDCA. Representative Western blots demonstrating that GPX1 siRNA ( B ) and catalase siRNA ( C ) prevented the UDCA-induced decease in phospho-H2AX expression after DCA exposure. In patients with Barrett's esophagus, 8 wk of oral UDCA treatment significantly increases expression of GPX1 and catalase protein in Barrett's metaplasia. After demonstrating in our Barrett's cells that UDCA increases expression of GPX1 and catalase, and that these antioxidants contribute to the protective effect of UDCA in reducing DNA damage after DCA exposure, we sought to confirm that these same effects occur in patients with Barrett's esophagus who are treated with oral UDCA for 8 wk. In agreement with our in vitro data, we found significantly increased protein levels of GPX1 and catalase in biopsy specimens of Barrett's metaplasia from our 21 patients ( Fig. 8 , A and B ). Fig. 8. Open in a new tab Oral UDCA treatment for 8 wk increases expression of GPX1 and catalase protein in Barrett's metaplasia. A : left , representative Western blots of Barrett's mucosa from 2 patients demonstrating GPX1 expression before (pre) and after (post) 8 wk of oral UDCA. Right , oral UDCA increases GPX1 in the esophagus of patients with Barrett's mucosa. B : left , representative Western blots from Barrett's mucosa from 2 patients demonstrating catalase expression before (pre) and after (post) 8 wk of oral UDCA. Right , oral UDCA increases catalase in Barrett's esophagus. Horizontal line in each column represents the mean for all 21 patients. DISCUSSION In patients with Barrett's esophagus, we found that esophageal perfusion with DCA for only 5 min significantly increased phospho-H2AX and phospho-p65 expression in Barrett's metaplasia. In those same patients, 8 wk of oral treatment with UDCA prevented DNA damage and NF-κB activation induced by DCA perfusion. Using Barrett's cell lines to explore molecular mechanisms underlying

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

collected. The circumferential and maximum extents of metaplasia were determined using the Prague C&M criteria [ 15 ]. Systematic biopsies – one in each of four quadrants every 2 cm in the appropriate areas of the BE – were taken. These biopsies were processed for histopathology based on the institutional standards. One additional BE biopsy was collected close to the distal end of the BE segment and flash frozen. Eligible subjects then initiated the six months of UDCA treatment at 13–15 mg/kg per day. Subjects returned to the clinic after three months of agent intervention to return unused pills for a pill count, receive a new supply of agents, have a blood sample collected for CBC/diff and CMP, and review the side effects with study staff. At the end of the six-month intervention, subjects returned to the clinic to return unused pills, have a blood samples collected for CBC/diff and CMP, review the side effects with study staff, and undergo the post-intervention endoscopy to obtain gastric fluid and biopsies of the BE as described for the baseline endoscopy. Safety of UDCA intervention was assessed by reported adverse events and clinical labs. Adverse events were graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Analysis of Bile Acid Concentrations in Gastric Fluid Bile acid concentrations in the gastric fluid were analyzed by HPLC tandem mass spectrometry. Briefly, an aliquot of gastric fluid was mixed with the internal standards (deoxycholic acid-d4 and glycoursodeoxycholic acid-d4) and then alkalized with 1N NaOH. The mixture was extracted with hexane. The aqueous phase was collected and acidified with 5N HCl and extracted with ethyl acetate. The organic layer was dried and reconstituted with 10 mM ammonium acetate/methanol (50/50) and injected onto the LC-MS system. The chromatographic separation was achieved using a gradient system of methanol and 10 mM ammonium acetate on an Ultrasphere XL column. Mass spectrometry was run in negative ion mode using eletrospray ionization. Detection of five bile acids (UDCA, deoxycholic acid (DCA), cholic acid (CA), chenodeoxy

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

juice and increase its concentration of the cytoprotective bile acid UDCA. We found that oral UDCA treatment prevented DCA from inducing DNA damage and NF-κB activation in Barrett's metaplasia, and we performed experiments to delineate mechanisms underlying these effects. In cell-free systems, UDCA has antioxidant properties, scavenging ROS such as superoxide and hydroxyl radicals ( 19 , 20 ). Other studies have suggested that UDCA protects cells by binding to and stabilizing their plasma membranes ( 9 ). Cell protection due to antioxidant and cell membrane stabilizing effects would be expected to be manifest immediately upon exposure to UDCA, but we observed no differences in phospho-H2AX and phospho-p65 expression between cells treated with DCA alone and cells treated with an equimolar mixture of DCA and UDCA. In contrast, Goldman et al. ( 7 ) found that CPA Barrett's cells exposed to acidic bile salts developed less DNA damage when UDCA was added to the medium. It is not clear why our findings differ from Goldman's, but a number of differences in design of these studies might account for discrepant results. For example, we exposed cells to a single hydrophobic bile acid (DCA) at neutral pH, whereas Goldman used a bile acid “cocktail” of conjugated bile acids and DCA in a medium acidified to pH 4. In addition, we used a telomerase-immortalized Barrett's cell line that has no neoplastic features, whereas the CPA cell line used by Goldman exhibits invasive features in 3D organotypic culture ( 7 , 17 ). After finding that mixing UDCA with DCA did not prevent DNA damage, our next experiments involved pretreating Barrett's cells with UDCA for 24 h prior to DCA exposure. UDCA pretreatment prevented DCA-induced ROS production, DNA damage, and NF-κB activation. Protection from oxidative stress might be explained by increases in intracellular antioxidant levels, and we found that UDCA pretreatment indeed upregulated mRNA and protein expression of GPX1 and catalase. The expression of antioxidant proteins is regulated by the ARE binding site in promoter regions of antioxidant target genes ( 16 , 28 ). Using an ARE reporter assay, we found that UDCA increased activity of the ARE reporter, confirming that UDCA upregulates transcription of antioxidant genes in Barrett's cells. The induction of

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

/increased 7/18/4 Pathology grade, ND/LGD/HGD Baseline 20/9/0 Post-intervention 24/4/1 Change in pathology grade, improved/no change/worsened 5/22/2 Open in a new tab Abbreviations: ND: no dysplasia; LGD: low grade dysplasia; HGD: high grade dysplasia For disease characteristics of participants that completed the intervention, the median length of circumferential involvement was 4.0 cm at baseline, 13 participants with length < 3 cm and 16 participants with length ≥ 3 cm. The median circumferential involvement was 3.8 cm post intervention, 16 participants with length < 3 cm, 13 participants with length ≥ 3 cm. The circumferential length decreased in 24% of participants, was unchanged in 62% of participants, and increased in 14% of participants. Biopsies from 69% of participants were not dysplastic at baseline whereas 31% of participants had at least one biopsy with low grade dysplasia. Post intervention, biopsies from 83% participants were not dysplastic and at least one biopsy from 14% and 3% of participants had low grade and high grade dysplasia, respectively. The pathology grade improved in 17% of participants but worsened in 7% of participants. There were 28 participants with gastric fluid collected at both the baseline and end of study endoscopies for bile acid analysis. Due to the large variation in gastric bile acid concentrations, the individual bile acids were expressed as the percent of total bile acid concentrations in the gastric fluid. The sum of each individual bile acid and its respective glycine and taurine conjugates is summarized in Table 2 . At baseline, UDCA, CDCA, DCA, CA, LCA and their respective glycine and taurine conjugates accounted for 18.2, 10.99, 38.87, 16.94, and 0.66% of total gastric bile acids. Post intervention, UDCA and its glycine and taurine conjugates increased significantly to account for 93.39% of total gastric bile acids whereas the composition of the other bile acids decreased significantly. Glycine conjugates constituted the majority of each of the five bile acid groups in the gastric fluid. We performed exploratory stratified analysis

Ursodiol in Treating Patients With Barrett Esophagus and Low-Grade Dysplasia

to compounds of similar chemical or biologic composition to UDCA - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant and breastfeeding women are excluded from this study; breastfeeding should be discontinued during treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately - Have had major upper gastrointestinal (GI) surgeries within 6 months of enrollment including, but not limited to, fundoplication, bariatric surgery, cholecystectomy - Erosive esophagitis detected at the baseline endoscopy - Participants who need concurrent chemotherapy, radiotherapy, or cancer-related hormonal or immunotherapy during the time of study - Participants who have had chemotherapy, radiotherapy, or cancer-related hormonal or immunotherapy within 18 months of the baseline visit - Current or planned use of anticoagulant drugs including, but not limited to, warfarin, heparin, low molecular weight heparin, Plavix, or Aggrenox - Use of cyclosporine during the time of study Type of Study: Interventional Study Design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention Outcome Measure: Reversal of oxidative DNA damage as assessed by changes in 8OHdG immunostaining Outcome Description: A paired t-test at a one-sided 0.05 significance level will be used to assess change during intervention. The observed results will be reported along with the corresponding confidence intervals. Outcome Time Frame: 6 months Safety Issue: No Principal Investigator Bhaskar Banerjee Investigator Role: Principal Investigator Investigator Affiliation: University of Arizona Health Sciences Center Authority: United States: Food and Drug Administration Study ID: NCI-2012-00450 NCT ID: NCT01097304 Start Date: March 2012 Completion Date: Related Keywords: Barrett Esophagus Esophageal Cancer Barrett Esophagus Esophageal Diseases Esophageal Neoplasms Name Location University of North Carolina Chapel Hill, North Carolina  27599 University of Arizona Health Sciences Center Tucson, Arizona  85724 Southern Arizona Veterans

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

–196. doi: 10.1111/j.1442-2050.2012.01352.x. [ DOI ] [ PubMed ] [ Google Scholar ] 23. Sikkema M, Kerkhof M, Steyerberg EW, Kusters JG, van Strien PM, Looman CW, et al. Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett’s esophagus: a case-control study. Am J Gastroenterol. 2009;104:2673–2680. doi: 10.1038/ajg.2009.437. [ DOI ] [ PubMed ] [ Google Scholar ] 24. Dvorakova K, Payne CM, Ramsey L, Bernstein H, Holubec H, Chavarria M, et al. Apoptosis resistance in Barrett’s esophagus: ex vivo bioassay of live stressed tissues. Am J Gastroenterol. 2005;100:424–431. doi: 10.1111/j.1572-0241.2005.40932.x. [ DOI ] [ PubMed ] [ Google Scholar ] 25. Chak A, Buttar NS, Foster NR, Seisler DK, Marcon NE, Schoen R, et al. Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol. 2015;13:665–672. e661–664. doi: 10.1016/j.cgh.2014.08.040. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 26. Lao-Sirieix P, Roy A, Worrall C, Vowler SL, Gardiner S, Fitzgerald RC. Effect of acid suppression on molecular predictors for esophageal cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:288–293. doi: 10.1158/1055-9965.EPI-05-0528. [ DOI ] [ PubMed ] [ Google Scholar ] 27. Dulak AM, Schumacher SE, van Lieshout J, Imamura Y, Fox C, Shim B, et al. Gastrointestinal adenocarcinomas of the esophagus,

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

of total gastric bile acids whereas the composition of the other bile acids decreased significantly. Glycine conjugates constituted the majority of each of the five bile acid groups in the gastric fluid. We performed exploratory stratified analysis on the gastric bile acid composition by PPI use (< 6 months vs. ≥ 6 months), ASA use (yes vs. no), smoking status (never smokers vs. current or former smokers), alcohol intake (no current intake vs. any current intake), baseline BE length (<3 cm vs. ≥ 3cm), change in BE length (shortened vs. no change or increased), baseline pathology grade (ND vs. LGD), and change in pathology grade (improved vs. no change or worsened). There was no difference in the baseline gastric bile acid composition in most of the stratified analysis (data not shown) except that baseline DCA and its glycine and taurine conjugates accounted for a higher fraction of total gastric bile acid in ASA users than that in non-users [median (interquartile range): 44.99 (29.51)% (n=12) vs. 15.71 (37.41)% (n=16), respectively, p = 0.04]. Post intervention, the DCA and its glycine and taurine conjugates composition was similar between the ASA users and non- users [median (interquartile range): 2.87 (2.75)% vs. 5.88 (15.35)%, respectively, p = 0.12]. The stratified analysis showed that the pre to post-intervention change in bile acid composition was different between the ASA users and non-users [median change (interquartile range) of UDCA/conjugates: +75.65 (17.93) vs. +54.5 (57.13), p = 0.04; DCA/conjugates: −43.61 (44.61) vs. −8.43 (25.63), p < 0.05; and CA/conjugates: −15.69 (9.68) vs. −4.22 (12.12), p = 0.02]. LCA and its glycine and taurine conjugates accounted for a small fraction of the bile acid composition. Stratified analysis showed that those who did

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

column. Mass spectrometry was run in negative ion mode using eletrospray ionization. Detection of five bile acids (UDCA, deoxycholic acid (DCA), cholic acid (CA), chenodeoxycholic acid (CDCA), and lithodeoxycholic acid (LCA)) and their respective glycine and taurine conjugates was achieved by multiple reaction monitoring. Immunohistochemistry (IHC) for Tissue Biomarkers IHC assays were used to assess markers of cell proliferation (Ki67), apoptosis (cleaved caspase 3, CC3), and oxidative DNA damage (8-hydroxydeoxyguanosine, 8OHdG) in BE epithelium tissue sections. The Ki67 and CC3 IHC was performed on a Discovery XT Automated Immunostainer (VMSI - Ventana Medical Systems, Tucson, Arizona) using VMSI validated reagents, including deparaffinization, antigen retrieval with a borate-EDTA buffer, primary antibody staining, detection and amplification and hematoxylin counterstaining. A biotin-free DAB (diaminobenzidine) detection system was used for CC3 and a biotinylated-streptavidin-HRP and DAB system was used for Ki67. For Ki67, mouse monoclonal antibody (clone: MIB-1, Dako) was diluted 1:100. Human tonsil carcinoma was used as a positive control. For CC3, anti-CC3 rabbit polyclonal antibody (Cell Signaling Technology #9661L) was diluted 1:8,000. Human tonsil carcinoma was used as a positive control. The 8OHdG IHC was performed as described previously [ 8 ] with minor modifications. Briefly, the slides were baked at 65°C for 1 hr, followed by deparaffinization with xylene, isopropanol, and water. Slides were then treated with 10% H 2 O 2 , 4N HCl, 0.1M borax, and 5% horse serum sequentially prior to incubating with the mouse monoclonal antibody for 8OHdG (QED Bioscience, #12501 (clone 15A3), diluted 1:1000)). Slides were then incubated with secondary biotinyl

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

enterology & Hepatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina Find articles by Nicholas J Shaheen 2 , Jessica A Martinez Jessica A Martinez 3 University of Arizona Cancer Center, Tucson, Arizona 4 Department of Nutritional Sciences, University of Arizona, Tucson, Arizona Find articles by Jessica A Martinez 3, 4 , Chiu-Hsieh Hsu Chiu-Hsieh Hsu 3 University of Arizona Cancer Center, Tucson, Arizona Find articles by Chiu-Hsieh Hsu 3 , Eugene Trowers Eugene Trowers 1 College of Medicine, University of Arizona, Tucson, Arizona Find articles by Eugene Trowers 1 , Blake A Gibson Blake A Gibson 1 College of Medicine, University of Arizona, Tucson, Arizona Find articles by Blake A Gibson 1 , Gary Della’Zanna Gary Della’Zanna 5 Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland Find articles by Gary Della’Zanna 5 , Ellen Richmond Ellen Richmond 5 Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland Find articles by Ellen Richmond 5 , H-H Sherry Chow H-H Sherry Chow 3 University of Arizona Cancer Center, Tucson, Arizona Find articles by H-H Sherry Chow 3 Author information Article notes Copyright and License information 1 College of Medicine, University of Arizona, Tucson, Arizona 2 Division of Gastroenterology & Hepatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 3 University of Arizona Cancer Center, Tucson, Arizona 4 Department of Nutritional Sciences, University of Arizona, Tucson, Arizona 5 Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland ✉ Correspondence: H-H. Sherry Chow, Ph.D., 1515 N Campbell Ave., University of Arizona Cancer Center, Tucson, AZ 85724, Voice: (520) 626-3358, Fax: (520) 626-5348, schow@azcc.arizona.edu Issue date 2016 Jul. PMC Copyright notice PMCID: PMC4930711  NIHMSID: NIHMS751477  PMID: 26908564 The publisher's version of this article is available at Cancer Prev Res (Phila) Abstract Prior research strongly implicates gastric acid and bile acids, two major components of the gastroesophageal refluxate,

Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients - PubMed

olic Acid / therapeutic use* Actions Search in PubMed Search in MeSH Add to Search Substances Bile Acids and Salts Actions Search in PubMed Search in MeSH Add to Search Cholagogues and Choleretics Actions Search in PubMed Search in MeSH Add to Search Ursodeoxycholic Acid Actions Search in PubMed Search in MeSH Add to Search Grants and funding K24 DK100548/DK/NIDDK NIH HHS/United States N01 CN035158/CA/NCI NIH HHS/United States N01 CN035158/CN/NCI NIH HHS/United States P30 CA023074/CA/NCI NIH HHS/United States LinkOut - more resources Full Text Sources Europe PubMed Central PubMed Central Silverchair Information Systems Other Literature Sources scite Smart Citations Research Materials NCI CPTC Antibody Characterization Program Full text links [x] Silverchair Information Systems Free PMC article [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited. Follow NCBI Twitter Facebook LinkedIn GitHub Connect with NLM Twitter SM-Facebook SM-Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids - PMC

0.05 compared with control; ** P ≤ 0.01 compared with control; *** P ≤ 0.001 compared with corresponding control; ++ P ≤ 0.01 compared with DCA treatment alone; +++ P ≤ 0.001 compared with DCA treatment alone. UDCA treatment increases mRNA and protein expression of antioxidants GPX1 and catalase in Barrett's cells. Since UDCA pretreatment suppressed ROS production induced by DCA, we next determined whether UDCA pretreatment increased expression of antioxidants including GPX1, catalase, superoxide dismutase (SOD)1 and SOD2. Treatment of both Barrett's cell lines with UDCA for 24 h increased expression of GPX1 and catalase, but not SOD1 or SOD2 ( Fig. 5 A ). We then determined whether the increase in antioxidant protein levels was associated with increased mRNA expression. By 6 h of UDCA treatment, we found that both cell lines exhibited significant elevations in expression of GPX1 and catalase mRNAs by qPCR ( Fig. 5 B ). Fig. 5. Open in a new tab UDCA treatment increases protein and mRNA expression of the antioxidants GPX1 and catalase in Barrett's cells. A : representative experiments of Western blotting for GPX1, catalase, SOD1, and SOD2 protein. Numbers represent the relative quantity of protein with respect to the loading control. B : representative experiments of qPCR for GPX1 and catalase mRNA. * P ≤ 0.05 compared with control; ** P ≤ 0.01 compared with control. UDCA treatment increases activity of ARE reporter, increases expression of phospho-Nrf2, and causes nuclear translocation of phospho-Nrf2 in Barrett's cells. Antioxidant proteins are expressed through a coordinated response regulated by ARE in the promoters of target genes including GPX1 and catalase ( 16 , 28 ). We determined whether UDCA activates the ARE reporter in Barrett's cells. After transient transfection with ARE reporter, we treated cells with UDCA for 6 h, which significantly increased ARE reporter activity ( Fig. 6 A ). Fig. 6. Open in a new tab A : UDCA treatment increases luciferase production from the antioxidant-responsive element (ARE) reporter in BAR-T and BAR-10T cells. Data are means + SE of 2 separate experiments. ** P ≤ 0

Clinical Study of Ursodeoxycholic Acid in Barrett’s Esophagus Patients - PMC

vs. −4.22 (12.12), p = 0.02]. LCA and its glycine and taurine conjugates accounted for a small fraction of the bile acid composition. Stratified analysis showed that those who did not currently consume alcohol had a larger fraction of LCA/conjugates than those who consumed alcohol [median (interquartile range): 0.52 (1.01)% (n = 7) vs. 0.12 (0.25)% (n = 20), respectively, p = 0.03]. Nevertheless, the stratified analysis will need to be interpreted with caution due to the small sample size and multiple comparisons. Table 2. Gastric bile acid composition at baseline and post-intervention (n = 28). Baseline (% of total bile acid) Post-Intervention (% of total bile acid) P value b UDCA and glycine/taurine conjugates 18.2 (26.1) a 93.4 (31.7) <0.0001 CDCA and glycine/taurine conjugates 11.0 (10.2) 1.01 (3.90) <0.0001 DCA and glycine/taurine conjugates 38.9 (44.0) 4.18 (7.82) <0.01 CA and glycine/taurine conjugates 16.9 (18.9) 1.72 (7.21) <0.0001 LCA and glycine/taurine conjugates 0.66 (1.30) 0.17 (0.37) <0.001 Open in a new tab a median (interquartile range) b derived from signed rank test Abbreviations: UDCA: ursodeoxycholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; CA: cholic acid; LCA: lithocholic acid The tissue biomarker data are summarized in Table 3 . Adequate baseline and post-intervention data on 8OHdG, Ki67, and CC3 expression were obtained from 25, 29, and 27 participants, respectively. Due to the concern of non-specific 8OHdG staining, only the percent of strongly and moderately stained nuclei was used for the statistical analysis. The median (interquartile range) baseline