Labarrere Carlos A, Kassab Ghassan S
California Medical Innovations Institute, San Diego, CA, United States.
Front Nutr. 2022 Nov 1;9:1007816. doi: 10.3389/fnut.2022.1007816. eCollection 2022.
Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 19 (COVID-19), involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in the cell (1-10 mM) is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage. GSH activity is facilitated by activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory and immune system responses. GSH exists in the thiol-reduced (>98% of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and SARS-CoV-2 infection and COVID-19 disease. In this review, we emphasize on (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in SARS-CoV-2 infection and COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.
许多局部和全身性疾病，尤其是那些在全球范围内导致死亡的主要原因的疾病，如慢性阻塞性肺疾病、伴有缺血性心脏病和中风的动脉粥样硬化、癌症以及由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的冠状病毒病19（COVID-19），都涉及以下两个方面：（1）氧化应激，即活性氧（ROS）过度产生，导致谷胱甘肽（GSH）水平降低；（2）炎症。GSH三肽（γ-L-谷氨酰-L-半胱氨酰-甘氨酸）是细胞中最丰富的水溶性非蛋白质硫醇（1-10 mM），对生命至关重要，原因如下：（a）维持细胞内适当的氧化还原信号，这对于维持控制生命过程所需的氧化应激生理水平至关重要；（b）限制导致细胞和组织损伤的过度氧化应激。GSH的活性通过激活类 Kelch 样 ECH 相关蛋白 1（Keap1）-核因子红细胞 2 相关因子 2（Nrf2）-抗氧化反应元件（ARE）氧化还原调节途径来促进，释放出 Nrf2，Nrf2 可调节控制抗氧化、炎症和免疫系统反应的基因表达。GSH 以硫醇还原形式（占总 GSH 的>98%）和二硫键氧化形式（GSSG）存在，GSH 和 GSSG 的浓度及其摩尔比是细胞功能的指标。GSH 耗竭可能在炎症性疾病和 COVID-19 的病理生理学、宿主免疫反应以及疾病严重程度和死亡率中起核心作用。增强 GSH 的疗法可能成为降低炎症性疾病和 COVID-19 严重程度和致命后果的基石，提高 GSH 水平可能预防和控制这些疾病。GSH 的生命价值使其成为生物学和医学中一个至关重要的研究领域，可能是对抗全身炎症以及 SARS-CoV-2 感染和 COVID-19 疾病的关键。在本综述中，我们重点强调：（1）GSH 耗竭是慢性阻塞性肺疾病和动脉粥样硬化（缺血性心脏病和中风）等疾病的基本危险因素；（2）氧化应激和抗氧化剂在 SARS-CoV-2 感染和 COVID-19 疾病中的重要性；（3）GSH 对抗持续性破坏性炎症、炎症衰老和早期（过早）炎症衰老的意义，这些炎症衰老与年轻个体中过度氧化应激和缺乏足够抗氧化防御导致的细胞和组织损伤有关；（4）包括恢复抗氧化防御的新疗法。
