Historically, advanced head and neck cancer was treated primarily with radical surgery. However, radiotherapy and concurrent chemoradiotherapy, particularly cisplatin-based regimens, have become the preferred approach due to their efficacy in tumor control while preserving normal tissue function. Despite these advantages, radiotherapy induces significant adverse effects, including oral mucositis, xerostomia, salivary gland dysfunction, neuropathies, dysphagia, and dysphonia, which impair quality of life(1). Preclinical and clinical studies have demonstrated the ability of antioxidants to mitigate radiation-induced damage to normal tissues. However, their potential to attenuate the tumoricidal effects of radiotherapy remains controversial. Clinical evidence suggests that systemic antioxidant administration may negatively impact oncological outcomes, reducing tumor control and survival rates(2). Consequently, non-selective antioxidant therapy is generally discouraged in this setting. Recent advances in oxidative stress quantification, such as measuring derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP), have improved our ability to assess oxidative balance in cancer patients(3). These developments may offer personalized strategies for antioxidant use.Future research should focus on developing tissue-selective antioxidants that protect normal structures without interfering with ROS-mediated tumor suppression. Large-scale randomized controlled trials (RCTs) will be necessary to validate tailored approaches that optimize therapeutic efficacy while minimizing normal tissue toxicity.

Mitochondria maintain continuous, dynamic communication with the nucleus and other organelles through a diverse array of signaling molecules, including tricarboxylic acid cycle intermediates, energy metabolites (ATP, ADP, AMP), reactive oxygen species, and other metabolic messengers. This process, termed mitocellular communication, orchestrates cellular adaptation to fluctuating energy demands and metabolic stress, serving as a central mechanism to preserve cellular function and survival.

We have shown that mild, targeted inhibition of mitochondrial complex I using small molecules activates this signaling axis, engaging multiple beneficial mechanisms. Treatment with these compounds promoted both healthspan and lifespan in wild-type mice. Benefits were observed in natural aging and in a high-fat diet model of accelerated aging. Treatment enhanced systemic energy homeostasis, reduced oxidative stress, and improved performance across multiple behavioral and cognitive assays. Integrated biochemical and systems biology approaches identified key regulatory pathways underpinning these outcomes, highlighting mechanisms essential to the therapeutic response.

Crucially, this strategy demonstrated strong efficacy in preclinical models of neurodegeneration. In multiple Alzheimer’s disease mouse models, treatment arrested neurodegeneration and preserved cognitive function. Similarly, in Huntington’s disease models, these compounds protected against neuronal loss and maintained motor performance. These results underscore the potential of mitocellular communication as a therapeutic axis, enabling simultaneous activation of multiple neuroprotective pathways, an approach that mimics polypharmacy and is well-suited to address the multifactorial nature of neurodegenerative diseases.

We have developed novel mitochondria-targeted molecules with excellent drug-like properties and demonstrated safety profiles, making them promising candidates for human clinical translation. Ongoing efforts are focused on advancing this strategy into clinical development, with broad potential applications beyond neurodegeneration, including mitochondrial and age-related metabolic and inflammatory diseases

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.

Nowadays, our surroundings are filled with electrical devices that emit electromagnetic waves. The electromagnetic waves emitted by devices such as mobile phones, wireless earphones, high-voltage power lines, electric cookers and electric blankets have the same properties as radiation; they differ only in wavelength. Exposure to these waves causes water molecules in the body to ionize, producing hydrogen peroxide and increasing oxidative stress. Oxidative stress contributes to numerous diseases and adverse effects of electromagnetic waves have been reported, including infertility, leukaemia and cancer. As it is impractical to avoid electromagnetic wave-emitting devices entirely, it is necessary to take measures to counteract the oxidative stress they cause.
Twendee X (TwX) is an antioxidant supplement containing vitamins, amino acids and CoQ10. It has passed pharmaceutical-level safety tests and can be used safely by both children and adults. Previous studies have proven that TwX suppresses the increase in oxidative stress caused by radiation exposure. Here, we discuss the potential effectiveness of an antioxidant in countering electromagnetic wave-induced oxidative stress in everyday environments. It incorporates measurement results of electromagnetic waves from common electronic devices, such as mobile phones and wireless earbuds.

Reactive oxygen species (ROS) are closely associated with brain dysfunction, particularly cognitive decline, which often accompanies aging. Antioxidant supplementation is a promising strategy to mitigate these effects [1,2]. In this study, we investigated the effects of Twendee X, a combination antioxidant supplement containing eight active ingredients, on cognitive and motor functions in middle-aged mice. Male C57BL/6 mice (49 weeks old) were administered Twendee X orally for one month. Behavioral assessments using the Morris water maze test revealed significant improvements in spatial memory, while the Rota-rod test indicated enhanced motor coordination. To explore the potential mechanisms underlying these effects, we performed western blot analyses of neurotrophic factors in the brain; however, no significant changes were detected among the experimental groups. These results suggest that combination antioxidant supplementation may enhance brain function in aging individuals, although the precise molecular mechanisms remain to be elucidated. Regular antioxidant intake may contribute to the prevention of age-related cognitive and motor decline.

The COVID-19 pandemic has led to an increase in the number of people suffering from various diseases, with patients becoming younger. In addition, rising medical costs and drug shortages are exacerbating the situation, such as becoming impossible to adequately treat diseases that should normally be treatable, raising concerns about future health risks. As the current state of medical care is likely to persist, disease prevention will become increasingly important in the future. Inflammation is at the root of all diseases, including aging, common lifestyle-related diseases, designated intractable diseases, and even unknown diseases. Oxidative stress is closely associated with inflammation. Prolonged exposure to inflammation and oxidative stress can accelerate the onset of diseases, making it crucial to suppress oxidative stress. We have been investigating the effects of Twendee X and Twendee Mtcontrol, antioxidant combinations, on various diseases. While it is well known that oxidative stress increases with age, lifestyle factors are also closely related. These factors can be broadly categorized into preferences, diet, exercise, and sleep. We summarized the results of previous studies on how these factors increase oxidative stress and how they affect the body's homeostasis. Based on these findings, we discuss the importance of improving lifestyle through antioxidant supplements.

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.

Reactive oxygen species (ROS) contribute to oxidative stress, which plays a critical role in aging and neurodegenerative diseases such as Alzheimer’s disease and dementia. Among ROS, hydrogen peroxide is known to particularly target lipids and impair neuronal function. Although the body possesses antioxidant defense mechanisms, their efficiency declines with age.

In this study, we investigated the effects of low concentrations of hydrogen peroxide on cultured neuronal cells. Treatment induced neurite degeneration characterized by bead-like swellings [1]. This degeneration was associated with disrupted calcium homeostasis and a marked increase in mitochondrial superoxide production [2]. Electron microscopy revealed abnormal accumulation of mitochondria at the beaded regions of neurites [3].

These findings suggest that ROS-induced neurite degeneration occurs prior to neuronal cell death and involves mitochondrial dysfunction driven by calcium dysregulation. Such early pathological changes may increase our understanding of neurodegenerative disorders. Antioxidant supplementation could represent a potential strategy to mitigate oxidative neuronal damage during aging.

Assessing the levels of oxidative stress markers and antioxidant enzymes in the brain is crucial in evaluating its antioxidant capacity and understanding the influence of various dietary patterns on brain well-being. This study aimed to investigate the antioxidant status and oxidative damage in the brain of bat species with different feeding habits to gain insights into their protective mechanisms against oxidative stress and their interspecific variation. The levels of oxidative damage markers and the activities of antioxidants were measured in the brain of four bat species with different feeding habits, namely insectivorous, frugivorous, nectarivorous, and hematophagous. Insectivorous bats showed higher levels of SOD and fumarase compared to the other groups, while hematophagous bats showed lower levels of these enzymes. On the other hand, the activities of glutathione peroxidase and glutathione S-transferase were higher in hematophagous bats and lower in insectivorous bats. The carbonyl groups and malondialdehyde levels were lower in frugivores, while they were similar in the other feeding guilds. Nitrite and nitrate levels were higher in the hematophagous group and relatively lower in all other groups. The GSSG/GSH ratio was higher in the hematophagous group and lower in frugivores. Overall, our results indicate that the levels of oxidative stress markers and the activities of antioxidant enzymes in the brain vary significantly among bat species with different feeding habitats. The findings suggest that the antioxidant status of the brain is influenced by diet and feeding habits.

Oxidative stress plays a central role in the pathogenesis of cardiovascular and metabolic diseases, contributing to endothelial dysfunction, inflammation, and progression of tissue damage [1,2]. Advances in nanomedicine have opened new possibilities for targeted drug delivery, offering potential to enhance therapeutic efficacy while minimizing systemic side effects [3,4].

This study aimed to investigate the cardiovascular and metabolic effects of aliskiren and simvastatin delivered via biodegradable polymeric nanoparticles in experimental models of hypertension and metabolic syndrome, with a focus on modulation of oxidative stress and nitric oxide (NO) signaling.

Spontaneously hypertensive rats (SHR) and obese Zucker rats with metabolic syndrome were used as experimental models. Aliskiren-loaded poly(lactic acid) (PLA) nanoparticles (25 mg/kg/day) were administered to SHR for 3 weeks, and simvastatin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (15 mg/kg/day) were given to obese rats for 6 weeks. Blood pressure was measured weekly. Nanoparticle distribution was assessed using confocal microscopy. Plasma lipid profiles and tissue levels of conjugated dienes were analyzed. In cardiac tissue, gene expression of (pro)renin receptor (Atp6ap2), angiotensin II receptor (Agtr1), and angiotensin-converting enzyme (ACE) was quantified. Nitric oxide synthase (NOS) activity and the protein expression of Akt, endothelial NOS (eNOS), phosphorylated eNOS (p-eNOS), neuronal NOS (nNOS), NADPH oxidase, and NF-κB were evaluated in the heart and aorta.

Aliskiren-loaded nanoparticles significantly reduced blood pressure in SHR, downregulated Atp6ap2 and ACE gene expression, and increased cardiac NOS activity. These changes were associated with decreased expression of NADPH oxidase and reduced lipid peroxidation markers, indicating a reduction in oxidative stress. Simvastatin-loaded nanoparticles decreased plasma LDL-cholesterol levels and, when co-administered with coenzyme Q10, further increased NOS activity and the expression of Akt, eNOS, and p-eNOS in both heart and aorta. Both nanoparticle formulations downregulated NF-κB and NADPH oxidase, confirming their anti-inflammatory and antioxidant potential. In conclusion, these results suggest that targeted delivery of cardiovascular drugs via nanoparticles may effectively modulate ROS/NO balance and improve cardiometabolic outcomes.

DNA methylation at cytosine bases (5-methylcytosine, 5mC) is a heritable epigenetic mark regulating gene expression. While enzymes that metabolize 5mC are well-characterized, endogenous signaling molecules that regulate DNA methylation machinery have not been described. We report that physiological nitric oxide (NO) concentrations reversibly inhibit the DNA demethylases TET and ALKBH2 by binding to the mononuclear non-heme iron atom forming a dinitrosyliron complex (DNIC) and preventing cosubstrates from binding. In cancer cells treated with exogenous NO, or endogenously synthesizing NO, 5mC and 5-hydroxymethylcytosine (5hmC) increase, with no changes in DNA methyltransferase activity. 5mC is also significantly increased in NO-producing patient-derived xenograft tumors from mice. Genome-wide methylome analysis of cells chronically treated with NO (10 days) shows enrichment of 5mC and 5hmC at gene-regulatory loci, correlating with altered expression of NO-regulated tumor-associated genes. This is the first study to demonstrate that NO is an endogenous regulator of TET activity and DNA methylation which is distinctly different from canonical NO signaling and represents a unique epigenetic role for NO. Our previous work demonstrated that NO is an endogenous regulator of histone post-translational modifications, and mRNA methylation, and here we show an unprecedented functional role for NO in regulating steady-state DNA methylation (and hydroxymethylation). Therefore, in addition to its canonical roles in cell signaling and gene expression, NO should now be recognized as a dominant regulator of the epigenetic landscape. 

Head and neck cancers occur in the oral cavity, pharynx, and larynx, which compromise several fundamental functions such as swallowing, voicing, respiration, and articulation. Advanced cancers are usually treated by radiotherapy or radical surgery, however, post-treatment QOL is often severely deteriorated. Photoimmunotherapy (PIT) is a innovative treatment that can kill cancers cells in pinpoint manner, preserving surrounding healthy tissues. PIT consists of systemic administration of antibody-photoabsorbance conjugate (APC) followed by irradiation of near infrared light. The tumor can be immediately diminished, and since the membrane of the cell is destroyed, neoantigen is emitted, which can lead to strengthening of cancer immune system. PIT is approved only in Japan now, but clinical trials are under way in manay countries. PIT also produces reactive oxygen speices (ROS) which may be effective for cancer treatment, but on the other hand, it is suggested that ROS may cause post-treatment laryngeal edema which occasionally requires tracheostomy. The edema can ocuur even without lightening to the larynx. It is important to correctly use PIT to have the best effects in mean time to avoid edema. Recent researches suggest that anti-oxidant can prevent the laryngeal edema without decreasing the therapeutic effects for cancer. The current status of PIT for head and neck caners is reported.

Human hair has various functions, including physical protection, insulation, and waste disposal function for the head. It also plays a significant role in social and aesthetic aspects. In many cultures, hair loss and greying are seen as undesirable signs of aging because they contradict the desire to appear younger.
In healthy individuals, around 90 hairs are shed daily and replaced by new hair within 4–6 months; however, factors such as lifestyle habits, stress and hormonal changes can disrupt this cycle, resulting in increased hair loss or delayed growth. Grey hair, on the other hand, occurs when melanocytes — cells that produce melanin, the pigment that gives hair its color — are damaged and can no longer produce melanin. Both conditions are known to be significantly influenced by oxidative stress.
Twendee X and Twendee M are mixed antioxidant supplements composed of vitamins and amino acids, for which safety tests have been conducted. Previous studies have shown that these supplements reduce oxidative stress in the body through their mitochondrial protective effects. In this presentation, we will discuss the potential of antioxidant treatment for grey hair and hair loss based on antioxidant data from the Twendee series, as well as questionnaire results and case reports from human participants.
 

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.

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.

Orthostatic dysregulation (OD) is most common during adolescence, with approximately 5-10% of junior high and high school students in Japan believed to be affected. According to Japanese clinical guidelines, this condition is classified into four subtypes: “instantaneous orthostatic hypotension (INOH)”, “postural tachycardia syndrome (POTS)”, “vasovagal syncope (VVS)” and “delayed orthostatic hypotension (delayed OH)”. Additionally, it is noted that various factors, including idiopathic causes, nutritional deficiencies, developmental disorders, and mental health issues, may contribute to its onset.

On the other hand, cases of OD symptoms have been reported among adult patients with chronic fatigue syndrome (ME/CFS), and it has been clarified that increased oxidative stress is involved in some of these cases. Additionally, there are cases where symptom improvement has been observed through antioxidant therapy.

Based on a summary of previous studies and initial data obtained, this report examines the trends in the association between each subtype of pediatric OD and oxidative stress markers, and discusses the potential involvement of oxidative stress in pediatric OD and implications for future treatment strategies. 

In recent years, alongside the trend towards postponed marriage and childbirth, factors such as diets high in additives, increased pesticide use, and changes in lifestyle and living environments have contributed to an increasing trend in infertility compared to previous years. While infertility has traditionally been considered to attribute to female factors, it is now proven that approximately half of cases are attributable to male factors. The involvement of oxidative stress (OS) has been indicated as a factor behind this. We investigated the effects of evidence-based antioxidants on male infertility. 

Orthophenyl phenol (OPP) is a fungicide used on citrus fruits. Exposure to OPP through contact with the fruit or the fungicide itself has been reported to increase OS in the body. In this study, long-term exposure to OPP showed an upward trend in OS in the sperm, the testes and the cauda epididymis, with a significant increase in sperm. Furthermore, Claudin1, a tight junction-associated protein found in the testes and the cauda epididymis, demonstrated a downward trend, indicating that elevated OS may result in testicular dysfunction or spermatogenesis disorders. In contrast, the group administered the antioxidant supplement Twendee X (TwX) suppressed the effects of OS. Furthermore, when TwX and Twendee Mtcontrol (TwM), which contains TwX plus seven additional ingredients, were administered to men and women with infertility for six months to one year, both TwX and TwM improved human male function. Notably, the pregnancy rate in the TwM group exceeded 30% after one year. The antioxidant supplements TwX and TwM was suggested to possess the potential to enhance male fertility, thereby improving infertility.

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that primarily affects infants and young children. In Japan, it represents the leading cause of acquired heart disease in children. The most serious complication is the development of coronary artery lesions (CAL), which are directly associated with long-term cardiovascular risk. Although immune dysregulation, genetic predisposition, and infectious triggers have been implicated in the pathogenesis of KD, increasing attention has been directed toward the involvement of oxidative stress (OS). 

During the acute phase of KD, OS caused by excessive production of reactive oxygen species (ROS) and impaired antioxidant defense mechanisms contributes to vascular inflammation through endothelial cell injury, enhanced cytokine production, and platelet dysfunction. High OS levels in the early phase have been associated with an increased risk of CAL, and OS biomarkers may serve as potential predictors of disease severity. Moreover, OS may persist into the subacute and chronic phases, even after the resolution of overt inflammation. This ongoing oxidative imbalance may impair vascular recovery and contribute to long-term vascular dysfunction, possibly accelerating the development of atherosclerosis. In recent years, the clinical application of OS-related biomarkers has emerged, offering new opportunities for mechanistic disease assessment and the development of personalized treatment strategies.

This presentation summarized current evidence regarding the role of OS in the pathophysiology of KD, and explores how OS-based evaluation and therapeutic approaches may enhance clinical care and prognosis in pediatric patients.