Chronic rhinosinusitis with eosinophilia (ECRS) is a refractory sinusitis characterized by eosinophilia in the nasal mucosa and peripheral blood. In ECRS, multiple nasal polyps are present in the ethmoid sinuses, and the disease is often accompanied by olfactory dysfunction and asthma. It is a disease that significantly impairs the quality of life of patients by causing persistent nasal congestion and thick nasal discharge, leading to decreased concentration and insomnia. From previous studies, we found that (1) defects in Cu,Zn-SOD in ECRS epithelium contribute to increased IL-17A, macrophage infiltration in the subepithelial tissue, and excessive production of mucin gene (MUC5AC) in the epithelium, thereby potentially exacerbating inflammation and excessive mucus secretion, and (2) reduced HO-1 expression in the epithelium and macrophage infiltration are associated with epithelial damage in CRS accompanied by eosinophil infiltration. These findings suggest that antioxidants may play a crucial role in elucidating the pathophysiology of refractory diseases such as ECRS and may provide new therapeutic strategies. In this paper, three new comprehensive molecular signaling pathway networks of (1) oxidative stress, (2) inflammation inhibition mechanisms and (3) inflammation in ECRS were developed for the first time, based on a critical analysis of scientific literature. In addition, three immunology flowsheets related to oxidative stress, inflammation and carbon monoxide-based inflammation inhibition mechanisms of ECRS were developed for the first time and examined from both clinical and biochemical perspectives. Based on these pathways, this study identified the treatment targets which can be used in future ECRS treatments.

Treatments for advanced head and neck cancer previously relied on radical surgery. However, radiation therapy and concurrent chemoradiotherapy, particularly using cisplatin, have gained preference due to their effectiveness and the preservation of normal tissues and their functions. A significant drawback of radiotherapy is its adverse effects, including oral mucositis, xerostomia, salivary gland dysfunction, neurological disorders, dysphagia, and dysphonia. Research in vitro, in vivo, and clinical trials has demonstrated that antioxidants effectively protect normal tissues from radiation-induced damage. However, the potential for antioxidants to compromise the tumoricidal efficacy of radiotherapy remains a subject of controversy. Clinical studies on head and neck cancer suggest that antioxidant use may negatively impact cancer control and survival outcomes. Consequently, non-selective systemic antioxidant therapy is not generally recommended. Recent advancements in the quantification of oxidative stress and biological antioxidant potential provide new opportunities to customize antioxidant therapies for individual patients. To optimize outcomes, further research is needed to elucidate the complex interactions between antioxidants, reactive oxygen species (ROS), and tumors. The development of novel antioxidant agents that can selectively protect normal tissue is also required. Subsequently, large-scale randomized controlled trials will be necessary to evaluate the efficacy of antioxidant therapies tailored to tumor characteristics and the specific conditions of individual patients. Below is the first part series of a work in progress regarding combinative antioxidant-proapoptotic therapies for head and neck cancer patients during radiotherapy.

Respiratory-swallowing coordination is essential for safe swallowing and the prevention of aspiration. The pontine respiratory group, particularly the Kölliker-Fuse nucleus (KF), plays a crucial role in maintaining respiratory rhythm and proper laryngeal movement. Additionally, the KF regulates the initiation and motor activity of pharyngeal swallowing and is interconnected with the nucleus tractus solitarius, receiving both visceral and somatic sensory information from the larynx and nose. Therefore, lesions in the pontine brainstem, including damage to the KF, can lead to a deterioration in respiratory rhythm and coordination between respiration and swallowing. Furthermore, the deterioration of the oxidative and antioxidative balance caused by brain ischemia may contribute to the dysfunction of neuronal systems. However, little is known about the relationship between respiratory rhythm generation and oxidative stress, as well as the effects of lesions in the respiratory center on oxidative and antioxidative systems. We investigate the impact of inhibiting the KF on respiratory and swallowing activities, as well as changes in oxidative and antioxidative stress, both before and after the pontine lesion. To monitor respiration and swallowing, we recorded the activity of the vagus, hypoglossal, phrenic, and abdominal nerves in a perfused brainstem preparation of rats. Additionally, a multi-electrode array was used to record respiratory and swallowing-related neurons in the dorsal medulla, and the KF was inhibited through the microinjection of a GABA agonist. Changes in respiratory rhythm and motor activities were analyzed, and we measured derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) to evaluate levels of oxidative and antioxidative stress before and after the lesion.
The post-inspiratory activity of the vagus nerve was inhibited, and activity patterns of swallowing were changed following the KF inhibition. The BAP levels were increased after KF inhibition.
Our findings suggest that the KF contributes to mediating glottal adduction and controlling post-inspiratory activity. The KF may significantly impact the oxidative and antioxidative balance.

Dysphagia has become a significant and increasingly widespread issue, especially given the rapidly aging global population. Various factors, such as cerebrovascular lesions and neurodegenerative diseases, can lead to swallowing impairments. Specifically, brainstem ischemia in the dorsolateral medulla and other brainstem regions, such as the dorsolateral pons, can result in severe swallowing disorders, ultimately leading to aspiration pneumonia. Moreover, reoxygenation during reperfusion after ischemic brain damage triggers oxidative reactions of reactive oxygen species (ROS) in the ischemic and surrounding areas, which can exacerbate neuronal damage in and around the ischemic lesion. However, our understanding of how ischemia and reperfusion in the brainstem affect swallowing function and oxidative stress is limited.

To clarify the impact of brainstem ischemia and subsequent reperfusion on swallowing function and oxidative stress, we studied changes in motor activities of respiration and swallowing, as well as oxidative stress, before, during, and after brainstem ischemia induced by transient clamping of the carotid or vertebral arteries. 

We monitored respiration and swallowing by recording the activity of the vagus, hypoglossal, phrenic, and abdominal nerves in a perfused brainstem preparation of rats. Swallowing was induced through electrical stimulation of the superior laryngeal nerve and by administering water orally. We analyzed changes in respiratory rhythm and motor activities and measured derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) to evaluate the levels of oxidative and antioxidative stress before, during, and after the clamping of the bilateral carotid artery (group 1) and the ipsilateral vertebral artery (group 2).

The respiratory-related and swallowing-related activities of the vagus and hypoglossal nerves were modestly altered following the clamping of the arteries. The BAP levels tended to be increased after reperfusion.

Our findings suggest that brainstem ischemia and subsequent reperfusion mediate changes in respiratory and swallowing function concurrent with alterations in the oxidative and antioxidative balance.

Airway defensive reflexes, such as pharyngeal swallowing, coughing, and sneezing, play a pivotal role in maintaining airway homeostasis. These reflexes are controlled by complex mechanisms primarily governed by specific neuronal circuitry in the brainstem, referred to as central pattern generators. These behaviors also require optimal conditions for the peripheral organs within the airway and alimentary tracts, including the nose, pharynx, larynx, and trachea, which are vital for ensuring appropriate responsiveness and motor outputs. Oxidative stress is linked to the development and progress of impaired functions of those behaviors. Dysphagia caused by central or peripheral impairments, such as neurodegeneration of related neuronal networks and laryngeal desensitization, is likely associated with an increased level of oxidative stress. Chronic inflammation and allergic airway sensitization in the lower airways, including asthma, elevate oxidative stress levels and diminish the activity of antioxidant defense enzymes, which exacerbate the severity of respiratory conditions. Antioxidant supplements offer promising therapeutic benefits by facilitating the recovery of distorted airway defensive reflexes, although limited information has been provided concerning therapeutic strategies. Further studies are necessary to enhance our understanding of the pathophysiology of dysphagia and airway diseases related to oxidative stress, as well as to develop new treatment strategies for these disorders.

The respiratory system is essential for efficient gas exchange in the lungs and for maintaining airway clearance. Various factors, including allergies and inflammation, can adversely impact both respiratory function and the non-respiratory behaviors that protect the airways. Conditions such as asthma and other chronic respiratory diseases increase significant health risks, with an increasing number of cases reported. Moreover, allergic responses and chronic inflammation in the upper and lower airways can trigger excessive reflexes, such as sneezing and coughing, which may exacerbate respiratory conditions.

Research on oxidative stress in chronic airway diseases has demonstrated a correlation between chronic airway inflammation and elevated oxidative stress levels. Increased oxidative stress may affect not only inflammation in peripheral tissues but also the central mechanisms that regulate coughing and sneezing. However, theoretical evidence on this topic remains limited. In this overview, we will outline the clinical features of allergic and inflammatory respiratory diseases, including allergic rhinitis and asthma. We will also highlight the basic peripheral and central mechanisms controlling airway reflexes, including sneezing and coughing.

In addition, we will explore the relationships between respiratory disorders and oxidative stress and propose potential benefits of antioxidants, such as Twendee X®, in alleviating pathogenic respiratory distress and reducing hypersensitivity of airway protective reflexes.

Airway reflexes are essential physiological responses that involve the coordinated activities of respiratory-related muscles in both the upper airway and the alimentary tract. Dysphagia is critical not only for ensuring adequate nutrition but also for managing respiratory conditions, thereby supporting overall homeostasis. Additionally, airway protective reflexes, such as coughing, are necessary for clearing the airways, which is vital for effective breathing and maintaining the swallowing reflex.

Oxidative stress can lead to DNA damage and changes in other biomolecules within peripheral tissues and the central nervous system. This stress may be linked to the pathological conditions of dysphagia, particularly in chronic respiratory diseases and cerebrovascular and neurodegenerative disorders. Aging also affects swallowing function due to the diminished activity of swallowing-related muscles and reduced sensitivity of the larynx in inducing the swallowing reflex, which is likely related to decreased antioxidant levels.

The central nervous system, particularly the brainstem, plays a critical role in regulating the mechanisms of swallowing and coughing to ensure the effective transfer of food to the stomach and to protect the airway. Therefore, understanding the neuronal mechanisms involved in these functions is essential for assessing swallowing functions and managing effective treatment strategies for patients with dysphagia.

Moreover, exploring the relationship between the pathophysiology of dysphagia and oxidative stress could provide significant insights into improving swallowing function after cerebrovascular events, neurodegenerative diseases, and damage to peripheral tissues in the alimentary tract. This review aims to highlight the fundamental mechanisms of airway protective reflexes and their relations to oxidative stress while also addressing the clinical management of dysphagia. Additionally, we will examine the potential therapeutic effects of antioxidants, such as Twendee X®, on dysphagia and the deterioration of other airway protective reflexes.

Respiration-swallowing coordination is essential for preventing aspiration, which is regulated by brainstem neuronal networks referred to as the central pattern generators (CPGs) for respiration (respiratory-CPG) and swallowing (swallowing-CPG). Damage to the swallowing CPG, such as that caused by a medullary stroke, can lead to delayed initiation of swallowing and impair the motor sequences involved in the swallowing process. Reoxygenation following ischemic brainstem damage can exacerbate neuronal injury due to oxidative reactions involving reactive oxygen species (ROS) in both the ischemic area and surrounding tissues. The effects of antioxidants on swallowing and respiratory CPG dysfunction following ischemia/reperfusion remain largely unexplored.

To investigate the potential role of antioxidant therapy in brainstem ischemia/reperfusion, we examined changes in the motor activities of respiration and swallowing before, during, and after a transient vertebral artery clamping-induced brainstem ischemia. We assessed the impact of the antioxidant Twendee X on these activities. Using a perfused brainstem preparation of rats, we recorded respiration and swallowing activities via the vagus, hypoglossal, and phrenic nerves. Swallowing was induced through electrical stimulation of the superior laryngeal nerve or by administering oral water. We analyzed changes in respiratory rhythm and motor activity. We also measured reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) in the perfusate to evaluate oxidative and antioxidative stress levels before and after clamping. Additionally, we assessed whether Twendee X administration influenced the changes resulting from ipsilateral brainstem ischemia/reperfusion.

Following the artery clamping, respiration and swallowing-related activities in the vagus and hypoglossal nerves were modestly altered. BAP levels tended to increase after reperfusion, whereas d-ROM levels attributable to brainstem ischemia/reperfusion appeared to be affected by Twendee X administration. These findings may suggest a potential therapeutic role for Twendee X in mitigating neuronal damage in the brainstem caused by ischemia/reperfusion.