Enhancing Bioavailability of Resveratrol

提高白藜芦醇的生物利用度

• 批准号: 8035875
• 负责人: Nihal Ahmad
• 金额: $ 18.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035875
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenocarcinoma; Alkaloids; American; Animals; Antioxidants; Apoptosis; Berry; Binding Proteins; Biological; Biological Availability; Black Pepper; Cancer Etiology; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Research; Clinical Trials; Complementary and alternative medicine; DNA Fragmentation; Data; Development; Diet; Disease; Doppler Ultrasound; Dose; Drug Kinetics; Effectiveness; Goals; Grapes; Growth Factor; Human; Human Volunteers; Image; Individual; Insulin; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammals; Marketing; Metabolism; Modeling; Mus; Neoplasm Metastasis; Oral; Oral Administration; Organ; Pathway interactions; Peanuts - dietary; Phase; Piper; Prevention; Preventive; Prostate; Prostate Adenocarcinoma; Protein Family; Rattus; Resveratrol; Secondary to; Serum; Testing; Therapeutic; Time; Toxic effect; Transgenic Organisms; Tumor Weights; Validation; Western Blotting; base; cancer cell; in vivo; male; mouse model; novel; novel strategies; phytoalexin; phytoalexins; piperine; preclinical study; public health relevance; red wine; research study; response; safety study; sulfation; trans-resveratrol; treatment effect; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Studies have shown that resveratrol (trans-3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found in grapes, red wines, berries and peanuts, imparts protection against several diseases. A plethora of pre-clinical studies have shown that resveratrol imparts chemopreventive as well as therapeutic response against several cancers. Further, resveratrol is being widely used as a supplement as well as a complementary and alternative medicine (CAM) approach for the management of several diseases/conditions. However, an important issue with resveratrol, especially in prevention settings (through diet or supplements), is believed to be its low bioavailability due to its rapid metabolism in mammals. It is known that during metabolism, the majority of resveratrol undergoes glucuronidation and sulfation. Studies have also shown that piperine, an alkaloid derived from black pepper (Piper spp.), inhibits glucuronidation in vivo. We believe that piperine will inhibit glucuronidation of resveratrol thereby enhancing its bioavailability leading to a superior chemopreventive response. This assumption is supported by our recent exciting preliminary data showing that piperine (20 mg/kg; oral gavage) enhances the bioavailability of resveratrol (500 mg/kg; oral gavage) in serum by ~175%. In this application, we propose to test the hypothesis that piperine will enhance the bioavailability of resveratrol leading to a superior chemopreventive and therapeutic response. In this application, we propose to conduct a clinical study (in human volunteers) as well as a preclinical trial (in a mouse model of prostate cancer. For our preclinical trial, we will conduct proof of principle study in a mouse model of prostate cancer (PCa). Our choice of PCa is based on the following point. PCa, next only to lung cancer, is the second leading cause of cancer related deaths in American males and because of its slow progression and long latency, is believed to be an ideal candidate disease for chemoprevention. Further, we have demonstrated that resveratrol imparts antiproliferative effects against human PCa cells, possibly via modulation of phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and Bcl-2 family of proteins. Furthermore, recent studies have demonstrated that resveratrol suppresses PCa progression in TRAMP (transgenic adenocarcinoma of mouse prostate) and TRAP (Transgenic Rat for Adenocarcinoma of Prostate) models suggesting the potential of this agent for the prevention and treatment of PCa. The following two specific aims are proposed: 1) To determine the influence of piperine on the bioavailability of resveratrol in human volunteers; and 2) To determine if piperine coadministration enhances the bioavailability and chemopreventive effects of resveratrol on PCa development in TRAMP mice. We believe that a successful completion of this proposal may pave the way for the development of novel strategies to enhance the bioavailability of resveratrol. PUBLIC HEALTH RELEVANCE: Studies have shown that resveratrol, an antioxidant found in grapes, red wines, berries and peanuts, imparts protection against many diseases including certain cancers. Further, resveratrol is being widely used as a supplement as well as a complementary and alternative medicine (CAM) approach for the management of several diseases/conditions. However, an important issue with resveratrol, especially in prevention settings (through diet or supplements), is believed to be its low bioavailability due to its rapid metabolism in mammals. In this application, we will conduct a clinical study and a preclinical study to test the hypothesis that piperine (a chemical in black pepper) will enhance the bioavailability of resveratrol (via inhibiting its metabolism) leading to a superior chemopreventive and therapeutic response. We believe that a successful completion of this proposal may pave the way for the development of novel strategies to enhance the bioavailability and therefore preventive and/or therapeutic response of resveratrol.

描述（由申请人提供）：研究表明，白藜芦醇（反式-3，5，4 '-三羟基芪）是一种植物抗氧化剂，存在于葡萄、红葡萄酒、浆果和花生中，可预防多种疾病。大量的临床前研究表明，白藜芦醇赋予化学预防以及对几种癌症的治疗反应。此外，白藜芦醇被广泛用作补充剂以及补充和替代医学（CAM）方法，用于管理多种疾病/病症。然而，一个重要的问题 与白藜芦醇，特别是在预防设置（通过饮食或补充剂），被认为是其低 由于其在哺乳动物中的快速代谢而具有生物利用度。已知在代谢过程中，大部分白藜芦醇经历葡萄糖醛酸化和硫酸化。研究还表明，胡椒碱，一种来自黑胡椒（胡椒属）的生物碱，抑制体内葡萄糖醛酸化。我们相信胡椒碱将抑制白藜芦醇的葡萄糖醛酸化，从而提高其生物利用度，导致上级化学预防反应。这一假设得到了我们最近令人兴奋的初步数据的支持，这些数据显示胡椒碱（20 mg/kg;口服灌胃）使血清中白藜芦醇（500 mg/kg;口服灌胃）的生物利用度提高了约175%。在本申请中，我们提出测试胡椒碱将提高白藜芦醇的生物利用度，从而导致上级化学预防和治疗反应的假设。在本申请中，我们建议进行临床研究（在人类志愿者中）以及临床前试验（在前列腺癌小鼠模型中）。对于我们的临床前试验，我们将在前列腺癌（PCa）的小鼠模型中进行原理验证研究。我们选择PCa是基于以下几点。PCa仅次于肺癌，是美国男性癌症相关死亡的第二大原因，并且由于其进展缓慢和潜伏期长，被认为是化学预防的理想候选疾病。此外，我们已经证明，白藜芦醇赋予抗增殖， 可能通过调节磷脂酰肌醇3 '-激酶对人前列腺癌细胞的作用 （PI 3 K）/Akt通路和Bcl-2蛋白家族。此外，最近的研究表明， 白藜芦醇在TRAMP（小鼠前列腺的转基因腺癌）和TRAP（前列腺癌的转基因大鼠）模型中抑制PCa进展，表明该药剂用于预防和治疗PCa的潜力。提出了以下两个具体目标：1）确定胡椒碱对人类志愿者中白藜芦醇生物利用度的影响;和2）确定胡椒碱联合施用是否增强TRAMP小鼠中白藜芦醇对PCa发展的生物利用度和化学预防作用。我们相信，这一建议的成功完成可能为开发新的策略，以提高白藜芦醇的生物利用度铺平道路。 公共卫生相关性：研究表明，白藜芦醇是一种存在于葡萄、红葡萄酒、浆果和花生中的抗氧化剂，可以预防许多疾病，包括某些癌症。此外，白藜芦醇被广泛用作补充剂以及补充和替代医学（CAM）方法，用于管理多种疾病/病症。然而，白藜芦醇的一个重要问题，特别是在预防环境中（通过饮食或补充剂），被认为是由于其在哺乳动物中的快速代谢而导致的低生物利用度。在本申请中，我们将进行临床研究和临床前研究，以检验胡椒碱（黑胡椒中的一种化学物质）将提高白藜芦醇的生物利用度（通过抑制其代谢），从而产生上级化学预防和治疗反应的假设。我们认为，成功完成这项工作， 该提案可能为开发新的策略铺平道路，以提高白藜芦醇的生物利用度，从而提高白藜芦醇的预防和/或治疗反应。

项目成果

Methaneseleninic acid and γ-Tocopherol combination inhibits prostate tumor growth in Vivo in a xenograft mouse model.

• DOI: 10.18632/oncotarget.1979
• 发表时间: 2014-06-15
• 期刊: Oncotarget
• 作者: Singh CK;Ndiaye MA;Siddiqui IA;Nihal M;Havighurst T;Kim K;Zhong W;Mukhtar H;Ahmad N
• 通讯作者: Ahmad N

Resveratrol and cancer: Challenges for clinical translation.

• DOI: 10.1016/j.bbadis.2014.11.004
• 发表时间: 2015-06
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Singh, Chandra K.;Ndiaye, Mary A.;Ahmad, Nihal
• 通讯作者: Ahmad, Nihal