Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells.

Radiotherapy is an essential and effective treatment modality for cancer. Excessive levels of reactive oxygen species (ROS) induced by ionizing radiation disrupt the redox homeostasis and lead to oxidative stress that may result in cell death. However, the tumor cell microenvironment is dynamic and responds to radiotherapy by activating numerous cellular signaling pathways. By scavenging excess ROS, the activity levels of the endogenous antioxidant enzymes result in radioresistance and worsen the clinical outcomes. To assess the full potential of radiotherapy, it is essential to explore the underlying mechanisms of oxidative stress in radiotherapy for potential target identification. The present review article summarized recent data demonstrating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) as a powerful transcription factor and one of the major cellular defense mechanisms that protect against oxidative stress in response to radiotherapy; the glutathione (GSH) and thioredoxin (Trx) systems complement each other and are effective antioxidant mechanisms associated with the protection of cancer cells from radiation damage. In addition, it is suggested that dual targeting to inhibit GSH and Trx enzymes may be a potential strategy for the development of radiosensitive and radioprotective drugs.

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Molecular pathways associated with oxidative stress and their potential applications in radiotherapy (Review)

Pulmonary hypertension (PH) refers to a clinical and pathophysiological syndrome in which pulmonary vascular resistance and pulmonary arterial pressure are increased due to structural or functional changes in pulmonary vasculature caused by a variety of etiologies and different pathogenic mechanisms. It is followed by the development of right heart failure and even death. In recent years, most studies have found that PH and cancer shared a complex common pathological metabolic disturbance, such as the shift from oxidative phosphorylation to glycolysis. During the shifting process, there is an upregulation of glutamine decomposition driven by glutaminase. However, the relationship between PH and glutamine hydrolysis, especially by glutaminase is yet unclear. This review aims to explore the special linking among glutamine hydrolysis, glutaminase and PH, so as to provide theoretical basis for clinical precision treatment in PH.

The Role of Glutamine and Glutaminase in Pulmonary Hypertension

Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.

https://www.mdpi.com/2227-9059/10/1/98/pdf?version=1641288892

Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

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.

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Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation

Reactive oxygen species (ROS), either derived from exogenous sources or overproduced endogenously, can disrupt the body's antioxidant defenses leading to compromised redox homeostasis. The lungs are highly susceptible to ROS-mediated damage. Oxidative stress (OS) caused by this redox imbalance leads to the pathogenesis of multiple pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). OS causes damage to important cellular components in terms of lipid peroxidation, protein oxidation, and DNA histone modification. Inflammation further enhances ROS production inducing changes in transcriptional factors which mediate cellular stress response pathways. This deviation from normal cell function contributes to the detrimental pathological characteristics often seen in pulmonary diseases. Although antioxidant therapies are feasible approaches in alleviating OS-related lung impairment, a comprehensive understanding of the updated role of ROS in pulmonary inflammation is vital for the development of optimal treatments. In this chapter, we review the major pulmonary diseases-including COPD, asthma, ARDS, COVID-19, and lung cancer-as well as their association with ROS.

Denethi Wijegunawardana

Papers

Redox Role of ROS and Inflammation in Pulmonary Diseases.