Depression, insulin resistance and xanthurenic acid in hepatitis C virus patients

丙型肝炎病毒患者的抑郁、胰岛素抵抗和黄嘌呤酸

• 批准号: 8772121
• 负责人: Gregory F Oxenkrug
• 金额: $ 8.76万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772121
• 关键词: Adverse effects; Aging; Antidepressive Agents; Apoptosis; Biological; Blood; Blood specimen; Chronic; Clinical Research; Data; Excretory function; Genes; Genetic Polymorphism; Goals; Hepatitis C; Hepatitis C virus; Homeostasis; Incidence; Infection; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferon Type II; Interferon-alpha; Interferons; Kynurenic Acid; Kynurenine; Literature; Liver Cirrhosis; Major Depressive Disorder; Mediating; Mental Depression; Metabolic syndrome; Metabolism; Modeling; Molecular; Neopterin; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Odds Ratio; Participant; Patients; Pilot Projects; Predictive Value; Prevention; Primary carcinoma of the liver cells; Production; Pyridoxal Phosphate; Recording of previous events; Recovery; Reporting; Risk; Risk Factors; Sampling; Serotonin; Serum; Staging; Structure of beta Cell of islet; Suggestion; Treatment outcome; Tryptophan; Tryptophan Metabolism Pathway; Urine; Work; Xanthurenic Acid; caspase-3; diabetic; improved; public health relevance; research study; tool

DESCRIPTION (provided by applicant): Hepatitis C virus, the most common blood-borne infection and a major cause of liver cirrhosis and carcinoma, is characterized by a 30 - 50% rate of depression as a side-effect of interferon (IFN)-alpha therapy, and by similarly high incidence of insulin resistance (IR), diabetes type 2 risk factor. Chronic inflammation was suggested as a common denominator for both depression and IR. Molecular mechanisms mediating impact of chronic, Th-1 type, inflammation on depression and IR are not clear. This proposal aims to explore the possibility that up-regulated formation of xanthurenic acid (XA) is associated with both IFN-alpha induced depression and IR. Pro-inflammatory factors (e.g., IFN) down-regulate tryptophan (TRP) conversion into serotonin, a major target of antidepressant action, and up-regulate TRP metabolism into kynurenine (KYN), a substrate for production of 3-hydroxyKYN (HK), a precursor of XA. Increased urine excretion of XA, and elevated serum HK were observed in major depressive disorder while normalization of XA predicted the recovery. Further metabolism of HK towards NAD+ formation, depends on pyridoxal'-5-phosphate (P5P). Inflammation reduces availability of P5P, and, thus, diverts excessively produced HK from formation of NAD+ towards production of XA. Possible mechanisms of diabetogenic effects of XA might include , an induction of pathological apoptosis of pancreatic beta cells through caspase 3-dependent mechanism. Our working hypothesis suggests that up-regulated formation of XA is a marker associated with both IFN-alpha induced depression and IR. This suggestion is partly supported by our observation of correlation (r=0.32, p=0.01) between IR and serum KYN in 60 HCV patients. However, we did not assess HK, XA and P5P, and had not enough samples to assess the correlation of XA and IR with depression. As a proof-of-concept pilot study we propose to evaluate IR, XA (and TRP, KYN and KYNA), and P5P in already collected blood samples of 300 HCV participants of our completed R21 study of IFNG(+874)T/A gene polymorphisms in IFN-alpha induced depression. Obtained results will be merged with our already collected data on incidence of IFN-alpha induced depression and serum levels of neopterin, a marker of IFN-related inflammation, that, as we reported previously,, correlates with IR and, inversely, with P5P. We will analyze associations of these markers with each other, and also with incidence of IFN-alpha induced depression. We predict positive correlations between XA and IR, and also between XA and the likelihood of having IFN-alpha associated depression. We also expect inverse correlations between XA and IR and P5P. Results of this pilot study will help to develop new tools for prevention/treatment of depression and type 2 diabetes in HCV and other conditions associated with chronic inflammation and (e.g., major depressive disorder, metabolic syndrome, obesity and aging).

描述（由申请人提供）：丙型肝炎病毒是最常见的血液传播感染，也是肝硬化和肝癌的主要原因，其特征在于干扰素（IFN）-α治疗的副作用是30 - 50%的抑郁率，以及胰岛素抵抗（IR）、2型糖尿病风险因素的相似高发病率。慢性炎症被认为是抑郁症和IR的共同点。慢性Th-1型炎症对抑郁症和IR影响的分子机制尚不清楚。该提议旨在探索黄尿酸（XA）的上调形成与IFN-α诱导的抑郁和IR两者相关的可能性。IFN）下调色氨酸（TRP）转化为血清素（抗抑郁作用的主要靶标），并上调TRP代谢为犬尿氨酸（KYN）（产生XA前体3-羟基KYN（HK）的底物）。在重度抑郁症患者中观察到尿XA排泄增加和血清HK升高，而XA正常化预测恢复。HK朝向NAD+形成的进一步代谢取决于吡哆醛-5-磷酸（P5 P）。炎症降低了P5 P的可用性，并且因此将过度产生的HK从NAD+的形成转向XA的产生。XA致糖尿病作用的可能机制可能包括通过caspase 3依赖性机制诱导胰腺β细胞病理性凋亡。我们的工作假设表明，上调形成XA是一个标志物与IFN-α诱导的抑郁症和IR。这一建议部分支持我们的观察IR和血清KYN之间的相关性（r=0.32，p=0.01）在60例HCV患者。然而，我们没有评估HK，XA和P5 P，也没有足够的样本来评估XA和IR与抑郁症的相关性。作为一项概念验证的初步研究，我们建议评估IR，XA（和TRP，KYN和KYNA）和P5 P在我们完成的R21研究IFNG（+874）T/A基因多态性在IFN-α诱导的抑郁症中的300名HCV参与者的血液样本中。所获得的结果将与我们已经收集的关于IFN-α诱导的抑郁症的发生率和新蝶呤血清水平的数据合并，新蝶呤是IFN相关炎症的标志物，正如我们先前报道的，与IR相关，与P5 P相反。我们将分析这些标记物之间的关联，以及与IFN-α诱导的抑郁症的发生率之间的关联。我们预测XA和IR之间以及XA和IFN-α相关抑郁症的可能性之间存在正相关关系。我们还预期XA与IR和P5 P之间存在负相关。这项试点研究的结果将有助于开发新的工具，用于预防/治疗HCV和其他与慢性炎症相关的疾病中的抑郁症和2型糖尿病，严重抑郁症、代谢综合征、肥胖症和衰老）。