Mangione Renata, Giallongo Cesarina, Duminuco Andrea, La Spina Enrico, Longhitano Lucia, Giallongo Sebastiano, Tibullo Daniele, Lazzarino Giuseppe, Saab Miriam Wissam, Sbriglione Arianna, Palumbo Giuseppe A, Graziani Andrea, Alanazi Amer M, Di Pietro Valentina, Tavazzi Barbara, Amorini Angela Maria, Lazzarino Giacomo
Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Catholic University of the Sacred Heart of Rome, Largo F. Vito 1, 00168 Rome, Italy.
Departmental Faculty of Medicine, UniCamillus-Saint Camillus International University of Health and Medical Sciences, Via di Sant'Alessandro 8, 00131 Rome, Italy.
Antioxidants (Basel). 2024 Apr 19;13(4):490. doi: 10.3390/antiox13040490.
To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and pyrimidines) in patients with primary myelofibrosis (PMF), a rare form of myeloproliferative tumor causing a dramatic decrease in erythropoiesis and angiogenesis. In this study, using a targeted metabolomic approach, serum samples of 22 PMF patients and of 22 control healthy donors were analyzed to quantify the circulating concentrations of hypoxanthine, xanthine, uric acid (as representative purines), uracil, β-pseudouridine, uridine (as representative pyrimidines), reduced glutathione (GSH), ascorbic acid (as two of the main water-soluble antioxidants), malondialdehyde, nitrite, nitrate (as oxidative/nitrosative stress biomarkers) and creatinine, using well-established HPLC method for their determination. Results showed that PMF patients have dramatic depletions of both ascorbic acid and GSH (37.3- and 3.81-times lower circulating concentrations, respectively, than those recorded in healthy controls, < 0.0001), accompanied by significant increases in malondialdehyde (MDA) and nitrite + nitrate (4.73- and 1.66-times higher circulating concentrations, respectively, than those recorded in healthy controls, < 0.0001). Additionally, PMF patients have remarkable alterations of circulating purines, pyrimidines, and creatinine, suggesting potential mitochondrial dysfunctions causing energy metabolism imbalance and consequent increases in these cell energy-related compounds. Overall, these results, besides evidencing previously unknown serum metabolic alterations in PMF patients, suggest that the determination of serum levels of the aforementioned compounds may be useful to evaluate PMF patients on hospital admission for adjunctive therapies aimed at recovering their correct antioxidant status, as well as to monitor patients' status and potential pharmacological treatments.
迄今为止，对于原发性骨髓纤维化（PMF）患者体内与生化相关的代谢物（抗氧化剂、氧化/亚硝化应激生物标志物、嘌呤和嘧啶）的循环水平知之甚少。原发性骨髓纤维化是一种罕见的骨髓增殖性肿瘤，会导致红细胞生成和血管生成显著减少。在本研究中，采用靶向代谢组学方法，对22例PMF患者和22例健康对照者的血清样本进行分析，以使用成熟的HPLC方法测定次黄嘌呤、黄嘌呤、尿酸（作为代表性嘌呤）、尿嘧啶、β-假尿苷、尿苷（作为代表性嘧啶）、还原型谷胱甘肽（GSH）、抗坏血酸（作为两种主要的水溶性抗氧化剂）、丙二醛、亚硝酸盐、硝酸盐（作为氧化/亚硝化应激生物标志物）和肌酐的循环浓度。结果显示，PMF患者的抗坏血酸和GSH均显著减少（循环浓度分别比健康对照者低37.3倍和3.81倍，<0.0001），同时丙二醛（MDA）和亚硝酸盐+硝酸盐显著增加（循环浓度分别比健康对照者高4.73倍和1.66倍，<0.0001）。此外，PMF患者的循环嘌呤、嘧啶和肌酐有显著改变，提示可能存在线粒体功能障碍，导致能量代谢失衡，进而使这些与细胞能量相关的化合物增加。总体而言，这些结果除了证明PMF患者血清中存在此前未知的代谢改变外，还表明测定上述化合物的血清水平可能有助于在PMF患者入院时评估其辅助治疗情况，旨在恢复其正确的抗氧化状态，以及监测患者状态和潜在的药物治疗。
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