Cellular selenium and PGJ2 metabolism

细胞硒和 PGJ2 代谢

• 批准号: 10411868
• 负责人: KUMBLE SANDEEP PRABHU
• 金额: $ 38.6万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411868
• 关键词: Address; Adoptive Transfer; Amino Acids; Anti-Inflammatory Agents; Apoptotic; Arachidonic Acids; Bacteria; Carbohydrates; Cell Cycle Regulation; Cells; Chemical Injury; Citric Acid Cycle; Citrobacter rodentium; Clinical Data; Complex; Data; Diet; Dietary Selenium; Dinoprostone; Disease remission; Eicosanoids; Epithelial; Event; Funding; Gastrointestinal Injury; Genetic Transcription; Glycolysis; Health Benefit; Hematopoietic; Histopathology; Immunoglobulin Class Switching; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intervention; Knockout Mice; Lamina Propria; Mediating; Metabolic; Metabolism; Micronutrients; Modeling; Mucous Membrane; Mus; Neutrophil Infiltration; Nippostrongylus; Nuclear; PPAR gamma; Parasites; Pathway interactions; Patients; Pentosephosphate Pathway; Pharmacology; Phase; Phenotype; Phosphotransferases; Process; Prostaglandin D2; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Proteomics; Pyruvate Kinase; Regulation; Resolution; Role; SelW protein; Selenium; Selenocysteine; Shapes; Sodium Dextran Sulfate; Succinate Dehydrogenase; Testing; Tissues; Trace Elements; Ulcerative Colitis; Warburg Effect; cyclopentenone; differential expression; enteric infection; first responder; gastrointestinal; gut health; healing; indexing; inflammatory disease of the intestine; intestinal homeostasis; lipidomics; macrophage; metabolomics; mouse model; neutrophil; response; response to injury; selenoprotein; shunt pathway; small molecule; transcription factor

Understanding the anti-inflammatory and pro-resolving functions of micronutrient selenium (Se) incorporated as the 21st amino acid, selenocysteine (Sec), into selenoproteins may hold the key to controlling gastrointestinal (GI) homeostasis in patients with inflammatory bowel disease (IBD). Despite advances, complete mucosal healing remains a difficult treatment target for many patients with IBD. Localized response to injury involves first responders, polymorphonuclear cells (neutrophils; PMNs), and macrophages that not only display an inflammatory phenotype, but also aid in resolving inflammation via efferocytosis of apoptotic PMNs, to initiate a cascade of pro-resolution events involving metabolic reprogramming. We have demonstrated an essential role for selenoproteins in effectively shunting pathways of arachidonic acid (ARA) metabolism in macrophages to effect resolution by skewing macrophage polarization towards an anti-inflammatory/pro-resolutory (M2) phenotype. Selenoprotein-dependent differential modulation of transcription factors, nuclear factor (NF)-κB and peroxisome proliferator activated receptor (PPAR)-γ, led to eicosanoid class switching resulting in decreased cyclooxygenase (COX)-derived pro-inflammatory prostaglandin E2 (PGE2) and high PGD2 and its anti-inflammatory and pro-resolutory cyclopentenone prostaglandins (CyPGs) metabolites, ∆12-prostaglandin J2 and 15-deoxy-∆12,14-PGJ2, in three models of GI injury involving chemical injury with dextran sodium sulfate, enteric infection with bacterium Citrobacter rodentium and helminthic parasite, Nippostrongylus brasiliensis. In these models, macrophage selenoprotein expression was key to mitigating inflammation and increasing the polarization of classically activated (M1) to pro-resolving alternatively activated (M2)-like cells that was dependent on CyPG production suggesting resolution. Our studies led us to a selenoprotein, SelenoW, a highly expressed selenoprotein in macrophages in response to dietary Se supply. Apart from its function in cell cycle regulation, the role of SelenoW in GI inflammation and resolution is not well understood. Clinical data indicated that SelenoW levels in inflamed colonic tissue of ulcerative colitis patients were decreased along with PGD2 levels compared to healthy controls and those in active remission, respectively. Guided by exciting feasibility data, we hypothesize that regulation of SelenoW expression by dietary Se and/or other transcriptional mechanisms, mediated by CyPGs, may hold a key to increasing pro-resolution mechanisms to ultimately effect mucosal healing from GI injury. We will test the hypothesis in murine models lacking SelenoW to: 1) Examine the role of SelenoW in resolution of GI inflammation; 2) Examine the role of SelenoW in the interaction of macrophages and PMNs during resolution of inflammation; and 3) Examine the role of SelenoW in metabolic adaptation during resolution of inflammation. Successful completion of these studies will provide new information highlighting the interplay between specific selenoproteins and pathways of resolution of inflammation, essential to increase our understanding of the role of dietary Se in optimal gut health.

了解微量营养素硒 (Se) 作为第 21 个氨基酸硒代半胱氨酸 (Sec) 融入硒蛋白中的抗炎和促消化功能，可能是控制炎症性肠病患者胃肠道 (GI) 稳态的关键。 IBD）尽管取得了进展，但对于许多 IBD 患者来说，完全粘膜愈合仍然是一个困难的治疗目标。对损伤的局部反应涉及第一反应者、多形核细胞。 （中性粒细胞；PMN）和巨噬细胞不仅表现出炎症表型，而且还通过凋亡 PMN 的胞吞作用帮助解决炎症，从而启动涉及代谢重编程的一系列促消退事件。有效地分流巨噬细胞中花生四烯酸 (ARA) 的代谢途径，通过使巨噬细胞极化偏斜来实现分辨率转录因子、核因子 (NF)-κB 和过氧化物酶体增殖物激活受体 (PPAR)-γ 的硒蛋白依赖性差异调节，导致类二十烷酸类别转换，导致环加氧酶 (COX) 减少。 ) 衍生的促炎性前列腺素 E2 (PGE2) 和高 PGD2 及其抗炎性和促溶解性环戊烯酮前列腺素(CyPGs) 代谢物 Δ12-前列腺素 J2 和 15-脱氧-Δ12,14-PGJ2，在三种胃肠道损伤模型中，涉及葡聚糖硫酸钠化学损伤、啮齿类柠檬酸杆菌和蠕虫寄生虫巴西圆线虫肠道感染。模型中，巨噬细胞硒蛋白表达是关键减轻炎症并增加经典活化 (M1) 向促分解选择性活化 (M2) 样细胞的极化，这些细胞依赖于 CyPG 的产生，这表明了解决问题的方法。除了其在细胞周期调节中的作用外，SelenoW 在胃肠道炎症和消退中的作用尚不清楚。临床数据表明 SelenoW 在发炎结肠组织中的水平。与健康对照组和主动缓解期患者相比，溃疡性结肠炎患者的 PGD2 水平分别降低，在令人兴奋的可行性数据的指导下，我们发现膳食 Se 和/或 CyPG 介导的其他转录机制对 SelenoW 表达的调节可能。掌握增强促消退机制以最终影响胃肠道损伤粘膜愈合的关键我们将在缺乏 SelenoW 的小鼠模型中测试这一假设：1）检查 SelenoW 在消退胃肠道炎症中的作用； 2) 检查 SelenoW 在炎症消退过程中巨噬细胞和 PMN 相互作用中的作用；3) 检查 SelenoW 在炎症消退过程中代谢适应中的作用。这些研究的成功完成将提供强调特定硒蛋白之间相互作用的新信息。以及炎症消退的途径，对于加深我们对膳食补充剂在最佳肠道健康中的作用的理解至关重要。

项目成果

Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-κB activation in murine macrophages via changes in intracellular calcium.

Crth2 受体信号传导通过细胞内钙的变化下调脂多糖诱导的小鼠巨噬细胞中的 NF-κB 激活。

• 发表时间: 2019
• 作者: Diwakar, Bastihalli T;Yoast, Ryan;Nettleford, Shaneice;Qian, Fenghua;Lee, Tai;Berry, Svanjita;Huffnagle, Ian;Rossi, Randall M;Trebak, Mohamed;Paulson, Robert F;Prabhu, K Sandeep
• 通讯作者: Prabhu, K Sandeep

Selenium supplementation through Se-rich dietary matrices can upregulate the anti-inflammatory responses in lipopolysaccharide-stimulated murine macrophages.

通过富硒膳食基质补充硒可以上调脂多糖刺激的小鼠巨噬细胞的抗炎反应。

• 发表时间: 2017
• 影响因子: 3
• 作者: Dhanjal, Noorpreet Inder Kaur;Sharma, Siddharth;Prabhu, K Sandeep;Prakash, N Tejo
• 通讯作者: Prakash, N Tejo

Selenoprotein W Ameliorates Experimental Colitis and Promotes Intestinal Epithelial Repair.

硒蛋白 W 改善实验性结肠炎并促进肠上皮修复。

• 发表时间: 2023-04-01
• 作者: Nettleford, Shaneice K;Liao, Chang;Short, Sarah P;Rossi, Randall M;Singh, Vishal;Prabhu, K Sandeep
• 通讯作者: Prabhu, K Sandeep

Selenium levels affect the IL-4-induced expression of alternative activation markers in murine macrophages.

硒水平影响小鼠巨噬细胞中 IL-4 诱导的替代激活标记物的表达。

• DOI: 10.3945/jn.111.141176
• 发表时间: 2011-09-01
• 期刊: The Journal of nutrition
• 作者: S. Nelson;Xingen Lei;K. S. Prabhu
• 通讯作者: K. S. Prabhu

The role of selenoproteins in neutrophils during inflammation.

炎症过程中中性粒细胞中硒蛋白的作用。

• DOI: 10.1016/j.abb.2022.109452
• 发表时间: 2022-11-01
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Tai;Shaneice K. Nettleford;Allison McGlynn;B. Carlson;G. Kirimanjeswara;K. S. Prabhu
• 通讯作者: K. S. Prabhu