There is a newer version of the record available.

Published March 26, 2026 | Version v1.0.0.
Preprint Open

Low-Dose Singlet Oxygen as a Hormetic Agent: Mechanisms, Physiological Effects, and Physiological Potential

  • 1. Independent Chief Scientific Consultant

Description

This review characterizes the role of low-dose singlet oxygen (1O2) as a non-pharmacological, hormetic stimulus. It provides the comprehensive biological and chemical framework for the generation method detailed in U.S. Patent 11,007,129 B2, bridging the gap between engineered molecular physics and cellular signaling.

Key thematic areas include:

  • Molecular Mechanisms: Analysis of the Nrf2-Keap1-SIRT6 axis and MAPK-mediated kinase rheostats.

  • Cellular Adaptations: Induction of autophagic flux, including mitophagy and lipophagy.

  • Technical Innovation: Comparison of traditional irradiative methods vs. non-irradiative catalytic generation for stable, sub-toxic output.

  • Systemic Physiology: Integration of clinical observations regarding respiratory, sleep, and metabolic recalibration.

This work serves as a theoretical foundation for understanding how controlled oxidative stimuli can trigger organism-level adaptive resilience.

Files

Abraham_Y_Singlet_Oxygen_Hormesis_Review_2026.pdf

Files (1.6 MB)

Additional details

Related works

Dates

Submitted
2026-03-27
First version submitted

References

  • (a) Klotz, L. O., Kröncke, K. D., & Sies, H. (2003). Singlet oxygen-induced signaling effects in mammalian cells. Photochemical & photobiological sciences, 2(2), 88-94. (b) Jones, D. P., & Sies, H. (2015). The redox code. Antioxidants & redox signaling, 23(9), 734-746. Zheng, C., Chen, J. P., Wang, X. W., & Li, P. (2025). Reactive Oxygen Species in Plants: Metabolism, Signaling, and Oxidative Modifications. Antioxidants, 14(6), 617. Murotomi, K., Umeno, A., Shichiri, M., Tanito, M., & Yoshida, Y. (2023). Significance of singlet oxygen molecule in pathologies. International Journal of Molecular Sciences, 24(3), 2739. Calabrese, E. J., & Mattson, M. P. (2011). Hormesis provides a generalized quantitative estimate of biological plasticity. Journal of cell communication and signaling, 5(1), 25-38. Wilkinson, F., Helman, W. P., & Ross, A. B. (1995). Rate constants for the decay and reactions of the lowest electronically excited singlet state of molecular oxygen in solution. An expanded and revised compilation. Journal of Physical and Chemical Reference Data, 24(2), 663-677. (a) Hasegawa, K., Yamada, K., Sasase, R., Miyazaki, R., Kikuchi, A., & Yagi, M. (2008). Direct measurements of absolute concentration and lifetime of singlet oxygen in the gas phase by electron paramagnetic resonance. Chemical Physics Letters, 457(4-6), 312-314. (b) Wang, K. K., Song, S., Jung, S. J., Hwang, J. W., Kim, M. G., Kim, J. H., ... & Kim, Y. R. (2020). Lifetime and diffusion distance of singlet oxygen in air under everyday atmospheric conditions. Physical Chemistry Chemical Physics, 22(38), 21664-21671. Hurst, J. R., McDonald, J. D., & Schuster, G. B. (1982). Lifetime of singlet oxygen in solution directly determined by laser spectroscopy. Journal of the American Chemical Society, 104(7), 2065-2067. (a) Noronha-Dutra, A. A., Epperlein, M. M., & Woolf, N. (1993). Reaction of nitric oxide with hydrogen peroxide to produce potentially cytotoxic singlet oxygen as a model for nitric oxide-mediated killing. FEBS letters, 321(1), 59-62. (b) Kanofsky, J. R. (1984). Singlet oxygen production by chloroperoxidase-hydrogen peroxide-halide systems. Journal of Biological Chemistry, 259(9), 5596-5600. (c) Foote, C. S., Wexler, S., Ando, W., & Higgins, R. (1968). Chemistry of singlet oxygen. IV. Oxygenations with hypochlorite-hydrogen peroxide. Journal of the American Chemical Society, 90(4), 975-981. (d) Stephenson, L. M., & McClure, D. E. (1973). Mechanisms in phosphite ozonide decomposition to phosphate esters and singlet oxygen. Journal of the American Chemical Society, 95(9), 3074-3076. Barry Halliwell; John MC. (1982) Free Radical in Biology and Medicine. Second Edition. Clarwndon Press. OxFord. Makuch, S., Dróżdż, M., Makarec, A., Ziółkowski, P., & Woźniak, M. (2022). An Update on Photodynamic Therapy of Psoriasis—Current Strategies and Nanotechnology as a Future Perspective. International journal of molecular sciences, 23(17), 9845. Jiang, J., Lv, X., Cheng, H., Yang, D., Xu, W., Hu, Y., ... & Zeng, G. (2024). Type I photodynamic antimicrobial therapy: principles, progress, and future perspectives. Acta Biomaterialia, 177, 1-19. Singh, S., & Awasthi, R. (2023). Breakthroughs and bottlenecks of psoriasis therapy: Emerging trends and advances in lipid based nano-drug delivery platforms for dermal and transdermal drug delivery. Journal of Drug Delivery Science and Technology, 104548. DeRosa, M. C., & Crutchley, R. J. (2002). Photosensitized singlet oxygen and its applications. Coordination Chemistry Reviews, 233, 351-371. (a) Eisenberg, W. C., & DeSilva, M. (1990). Atmospheric gas phase generation of singlet oxygen by homogeneous photosensitization. Tetrahedron letters, 31(41), 5857-5860. (b) Eisenberg, W. C., & DeSilva, M. (1990). Atmospheric gas phase generation of singlet oxygen by homogeneous photosensitization. Tetrahedron letters, 31(41), 5857-5860. (c) Funken, K. H., Horneck, G., Milow, B., Schafer, M., Schmitz, C., Faust, D., ... & Sattlegger, M. (2000). U.S. Patent No. 6,107,480. Washington, DC: U.S. Patent and Trademark Office. (d) Sunday, M. O., & Sakugawa, H. (2020). A simple, inexpensive method for gas-phase singlet oxygen generation from sensitizer-impregnated filters: Potential application to bacteria/virus inactivation and pollutant degradation. Science of the Total Environment, 746, 141186. (1) Ihalagedara, H. B., Xu, Q., Greer, A., & Lyons, A. M. (2025). Singlet oxygen generation on a superhydrophobic surface: Effect of photosensitizer coating and incident wavelength on 1O2 yields. Photochemistry and Photobiology, 101(1), 167-179. (2) Arpa, E. M., & Corral, I. (2023). Unveiling Photodegradation and Photosensitization Mechanisms of Unconjugated Pterins. Chemistry–A European Journal, 29(29), e202300519. (a) Gorbanev, Y., & Bogaerts, A. (2018). Chemical detection of short-lived species induced in aqueous media by atmospheric pressure plasma. In Atmospheric Pressure Plasma-from Diagnostics to Applications. IntechOpen. (b) Cabrellon, G., Tampieri, F., Rossa, A., Barbon, A., Marotta, E., & Paradisi, C. (2020). Application of fluorescence-based probes for the determination of superoxide in water treated with air non-thermal plasma. ACS sensors, 5(9), 2866-2875. (c) Aggelopoulos, C. A., Tataraki, D., & Rassias, G. (2018). Degradation of atrazine in soil by dielectric barrier discharge plasma–potential singlet oxygen mediation. Chemical Engineering Journal, 347, 682-694. (d) Jablonowski, H., Santos Sousa, J., Weltmann, K. D., Wende, K., & Reuter, S. (2018). Quantification of the ozone and singlet delta oxygen produced in gas and liquid phases by a non-thermal atmospheric plasma with relevance for medical treatment. Scientific reports, 8(1), 12195. (e) Lim, J., Park, S., Ryu, S., Park, S., & Kim, M. S. (2025). Different inactivation mechanisms of Staphylococcus aureus and Escherichia coli in water by reactive oxygen and nitrogen species generated from an argon plasma jet. Environmental Science & Technology, 59(6), 3276-3285. (a) Kuk, S. K., Ji, S. M., Kang, S., Yang, D. S., Kwon, H. J., Koo, M. S., ... & Lee, H. C. (2023). Singlet-oxygen-driven photocatalytic degradation of gaseous formaldehyde and its mechanistic study. Applied Catalysis B: Environmental, 328, 122463. (b) Zollo, A., Livraghi, S., Giamello, E., Cioni, A., Dami, V., Lorenzi, G., ... & Zaleska-Medynska, A. (2023). How to guide photocatalytic applications of titanium dioxide co-doped with nitrogen and carbon by modulating the production of reactive oxygen species. Journal of Environmental Chemical Engineering, 11(6), 111523. (c) Li, Q., Zhao, J., Shang, H., Ma, Z., Cao, H., Zhou, Y., ... & Li, H. (2022). Singlet Oxygen and Mobile Hydroxyl Radicals Co-operating on Gas–solid Catalytic Reaction Interfaces for Deeply Oxidizing NO x. Environmental Science & Technology, 56(9), 5830-5839. (d) Ibhadon, A. O., & Fitzpatrick, P. (2013). Heterogeneous photocatalysis: recent advances and applications. Catalysts, 3(1), 189-218. (e) Shi, Y., Yang, Z., Shi, L., Li, H., Liu, X., Zhang, X., ... & Zhang, L. (2022). Surface boronizing can weaken the excitonic effects of BiOBr nanosheets for efficient O2 activation and selective NO oxidation under visible light irradiation. Environmental Science & Technology, 56(20), 14478-14486. (f) Yaghmaei Sabegh, M. (2024). Advancements in Photochemistry and Flow Systems for Synthesis and Analysis (Doctoral dissertation, Université d'Ottawa| University of Ottawa). Badash, Z. (2021). U.S. Patent No. 11,007,129. Washington, DC: U.S. Patent and Trademark Office. Carbogno, C., Groß, A., Meyer, J., & Reuter, K. (2013). O2 Adsorption Dynamics at Metal Surfaces: Non-Adiabatic Effects, Dissociation and Dissipation. In Dynamics of Gas-Surface Interactions (pp. 389-419). Springer Berlin Heidelberg. Devasagayam, T., & Kamat, J. P. (2002). Biological significance of singlet oxygen. Dmitrieva, V. A., Tyutereva, E. V., & Voitsekhovskaja, O. V. (2020). Singlet oxygen in plants: Generation, detection, and signaling roles. International journal of molecular sciences, 21(9), 3237. Kiryu, C., Makiuchi, M., Miyazaki, J., Fujinaga, T., & Kakinuma, K. (1999). Physiological production of singlet molecular oxygen in the myeloperoxidase-H2O2-chloride system. FEBS letters, 443(2), 154-158. Sun, Y., Lu, Y., Saredy, J., Wang, X., Drummer IV, C., Shao, Y., ... & Yang, X. (2020). ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes. Redox biology, 37, 101696. Sokolovski, S. G., Rafailov, E. U., Abramov, A. Y., & Angelova, P. R. (2021). Singlet oxygen stimulates mitochondrial bioenergetics in brain cells. Free Radical Biology and Medicine, 163, 306-313. Szechyńska-Hebda, M., Ghalami, R. Z., Kamran, M., Van Breusegem, F., & Karpiński, S. (2022). To Be or Not to Be? Are Reactive Oxygen Species, Antioxidants, and Stress Signalling Universal Determinants of Life or Death? Cells, 11(24), 4105. Davies, M. J. (2004). Reactive species formed on proteins exposed to singlet oxygen. Photochemical & Photobiological Sciences, 3, 17-25. (a) Di Mascio, P., Martinez, G. R., Miyamoto, S., Ronsein, G. E., Medeiros, M. H., & Cadet, J. (2019). Singlet molecular oxygen reactions with nucleic acids, lipids, and proteins. Chemical reviews, 119(3), 2043-2086. (b) Juan, C. A., Pérez de la Lastra, J. M., Plou, F. J., & Pérez-Lebeña, E. (2021). The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. International Journal of Molecular Sciences, 22(9), 4642. (a) Forman, H. J., & Zhang, H. (2021). Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nature Reviews Drug Discovery, 20(9), 689-709. (b) Brieger, K., Schiavone, S., Miller Jr, F. J., & Krause, K. H. (2012). Reactive oxygen species: from health to disease. Swiss medical weekly, 142, w13659. (c) Rahman, T., Hosen, I., Islam, M. T., & Shekhar, H. U. (2012). Oxidative stress and human health. Advances in Bioscience and Biotechnology, 3(07), 997. Dmitrieva, V. A., Tyutereva, E. V., & Voitsekhovskaja, O. V. (2020). Singlet Oxygen in Plants: Generation, Detection, and Signaling Roles. International journal of molecular sciences, 21(9), 3237. Saed-Moucheshi, A., Sohrabi, F., & Shirkhani, A. (2023). A review on reactive oxygen species (ROS): production, function, and their influence on plants. Crop Biotechnology, 13(44), 53-70. Ziegelhoffer, E. C., & Donohue, T. J. (2009). Bacterial responses to photo-oxidative stress. Nature Reviews Microbiology, 7(12), 856-863. Maharjan, P. S., & Bhattarai, H. K. (2022). Singlet oxygen, photodynamic therapy, and mechanisms of cancer cell death. Journal of oncology, 2022(1), 7211485. Poli, G., Leonarduzzi, G., Biasi, F., & Chiarpotto, E. (2004). Oxidative stress and cell signalling. Current medicinal chemistry, 11(9), 1163-1182. (a) Iuliano, L. (2011). Pathways of cholesterol oxidation via non-enzymatic mechanisms. Chemistry and physics of lipids, 164(6), 457-468. (b) Kulig, W., Olżyńska, A., Jurkiewicz, P., Kantola, A. M., Komulainen, S., Manna, M., ... & Jungwirth, P. (2015). Cholesterol under oxidative stress—How lipid membranes sense oxidation as cholesterol is being replaced by oxysterols. Free radical biology and medicine, 84, 30-41. (a) Lorenzen, I., Eble, J. A., & Hanschmann, E. M. (2021). Thiol switches in membrane proteins-Extracellular redox regulation in cell biology. Biological chemistry, 402(3), 253-269. (b) Bigelow, D. J., & Squier, T. C. (2011). Thioredoxin-dependent redox regulation of cellular signaling and stress response through reversible oxidation of methionines. Molecular Biosystems, 7(7), 2101-2109. Gems, D., & Partridge, L. (2008). Stress-response hormesis and aging:"that which does not kill us makes us stronger". Cell metabolism, 7(3), 200-203. Shaw, P., & Chattopadhyay, A. (2020). Nrf2–ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. Journal of Cellular Physiology, 235(4), 3119-3130. Baird, L., Llères, D., Swift, S., & Dinkova-Kostova, A. T. (2013). Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proceedings of the National Academy of Sciences, 110(38), 15259-15264. Liu, X., Ren, S., Li, Z., Hao, D., Zhao, X., Zhang, Z., & Liu, D. (2023). Sirt6 mediates antioxidative functions by increasing Nrf2 abundance. Experimental cell research, 422(1), 113409. Rezazadeh, S., Yang, D., Tombline, G., Simon, M., Regan, S. P., Seluanov, A., & Gorbunova, V. (2019). SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic acids research, 47(15), 7914-7928. Lu, S. C. (2013). Glutathione synthesis. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(5), 3143-3153. Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol., 47(1), 89-116. Conrad, M., & Pratt, D. A. (2019). The chemical basis of ferroptosis. Nature chemical biology, 15(12), 1137-1147. Flohé, L., Toppo, S., & Orian, L. (2022). The glutathione peroxidase family: Discoveries and mechanism. Free Radical Biology and Medicine, 187, 113-122. Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and toxicology, 53(1), 401-426. Grek, C. L., Zhang, J., Manevich, Y., Townsend, D. M., & Tew, K. D. (2013). Causes and consequences of cysteine S-glutathionylation. Journal of Biological Chemistry, 288(37), 26497-26504. Telorack, M., Meyer, M., Ingold, I., Conrad, M., Bloch, W., & Werner, S. (2016). A glutathione-Nrf2-thioredoxin cross-talk ensures keratinocyte survival and efficient wound repair. PLoS genetics, 12(1), e1005800. (a) Ross, D., & Siegel, D. (2021). The diverse functionality of NQO1 and its roles in redox control. Redox Biology, 41, 101950. (b) Lee, W. S., Ham, W., & Kim, J. (2021). Roles of NAD (P) H: quinone oxidoreductase 1 in diverse diseases. Life, 11(12), 1301. (a) Waza, A. A., Hamid, Z., Ali, S., Bhat, S. A., & Bhat, M. A. (2018). A review on heme oxygenase-1 induction: is it a necessary evil. Inflammation Research, 67, 579-588. (b) Loboda, A., Damulewicz, M., Pyza, E., Jozkowicz, A., & Dulak, J. (2016). Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cellular and molecular life sciences, 73, 3221-3247. (c) Son, Y., Lee, J. H., Chung, H. T., & Pae, H. O. (2013). Therapeutic roles of heme oxygenase‐1 in metabolic diseases: curcumin and resveratrol analogues as possible inducers of heme oxygenase‐1. Oxidative medicine and cellular longevity, 2013(1), 639541. Knoops, B., Argyropoulou, V., Becker, S., Ferté, L., & Kuznetsova, O. (2016). Multiple roles of peroxiredoxins in inflammation. Molecules and cells, 39(1), 60-64. Bafana, A., Dutt, S., Kumar, A., Kumar, S., & Ahuja, P. S. (2011). The basic and applied aspects of superoxide dismutase. Journal of Molecular Catalysis B: Enzymatic, 68(2), 129-138. Kirkman, H. N., & Gaetani, G. F. (2007). Mammalian catalase: a venerable enzyme with new mysteries. Trends in biochemical sciences, 32(1), 44-50. Lu, J., & Holmgren, A. (2014). The thioredoxin antioxidant system. Free radical biology and medicine, 66, 75-87. Greeshma, M. V., Baidya, A., Mabalirajan, U., Madhunapantula, S. V., Thimmulappa, R. K., & Mahesh, P. A. (2024). Deciphering the role of 12/15-lipoxygenase in asthma: insights into mitochondrial dysfunction and therapeutic implications. Exploration of Asthma & Allergy, 2(6), 529-550. Zhang, J., Zhang, M., Tatar, M., & Gong, R. (2025). Keap1-independent Nrf2 regulation: A novel therapeutic target for treating kidney disease. Redox Biology, 103593. Dong, H., Lyu, Y., Huang, C. Y., & Tsai, S. Y. (2025). Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle. Autophagy, 21(6), 1212-1227. Kiang, J. G., & Tsokos, G. C. (1998). Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacology & therapeutics, 80(2), 183-201. Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21. (a) Richter-Landsberg, C., Wyttenbach, A., & Arrigo, A. P. (2009). The role of heat shock proteins during neurodegeneration in Alzheimer's, Parkinson's and Huntington's disease. Heat shock proteins in neural cells, 81-99. (b) Zhang, N., Nao, J., Zhang, S., & Dong, X. (2024). Novel insights into the activating transcription factor 4 in Alzheimer's disease and associated aging-related diseases: Mechanisms and therapeutic implications. Frontiers in Neuroendocrinology, 101144. (a) Bjørklund, G., Zou, L., Peana, M., Chasapis, C. T., Hangan, T., Lu, J., & Maes, M. (2022). The role of the thioredoxin system in brain diseases. Antioxidants, 11(11), 2161. (b) Cimini, A., Gentile, R., Angelucci, F., Benedetti, E., Pitari, G., Giordano, A., & Ippoliti, R. (2013). Neuroprotective effects of PrxI over‐expression in an in vitro human Alzheimer's disease model. Journal of cellular biochemistry, 114(3), 708-715. (c) Zeng, X. S., Jia, J. J., Kwon, Y., Wang, S. D., & Bai, J. (2014). The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radical Biology and Medicine, 67, 10-18. (a) Ahsan, M. K., Lekli, I., Ray, D., Yodoi, J., & Das, D. K. (2009). Redox regulation of cell survival by the thioredoxin superfamily: an implication of redox gene therapy in the heart. Antioxidants & redox signaling, 11(11), 2741-2758. (b) Chong, C. R., Chan, W. P. A., Nguyen, T. H., Liu, S., Procter, N. E., Ngo, D. T., ... & Horowitz, J. D. (2014). Thioredoxin-interacting protein: pathophysiology and emerging pharmacotherapeutics in cardiovascular disease and diabetes. Cardiovascular drugs and therapy, 28, 347-360. Hao, X., Zhao, B., Towers, M., Liao, L., Monteiro, E. L., Xu, X., ... & Zhang, R. (2024). TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation. Nature Aging, 4(2), 185-197. Yang, Z. F., Drumea, K., Mott, S., Wang, J., & Rosmarin, A. G. (2014). GABP transcription factor (nuclear respiratory factor 2) is required for mitochondrial biogenesis. Molecular and cellular biology, 34(17), 3194-3201. (a) Gureev, A. P., Shaforostova, E. A., & Popov, V. N. (2019). Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Frontiers in genetics, 10, 435. (b) St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jäger, S., ... & Spiegelman, B. M. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2), 397-408. Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P. Y. (2006). DJ-1, a cancer-and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proceedings of the National Academy of Sciences, 103(41), 15091-15096. (a) Maiorino, M., Conrad, M., & Ursini, F. (2018). GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxidants & redox signaling, 29(1), 61-74. (b) Lu, L., Oveson, B. C., Jo, Y. J., Lauer, T. W., Usui, S., Komeima, K., ... & Campochiaro, P. A. (2009). Increased expression of glutathione peroxidase 4 strongly protects retina from oxidative damage. Antioxidants & redox signaling, 11(4), 715-724. Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nature communications, 12(1), 3208. Cheng, J., Keuthan, C. J., & Esumi, N. (2023). The many faces of SIRT6 in the retina and retinal pigment epithelium. Frontiers in Cell and Developmental Biology, 11, 1244765. Palmeira, C. M., Teodoro, J. S., Amorim, J. A., Steegborn, C., Sinclair, D. A., & Rolo, A. P. (2019). Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins. Free Radical Biology and Medicine, 141, 483-491. Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., ... & Yamamoto, M. (2016). Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nature communications, 7(1), 1-14. Guo, Z., Li, P., Ge, J., & Li, H. (2022). SIRT6 in aging, metabolism, inflammation and cardiovascular diseases. Aging and disease, 13(6), 1787. He, Y., Yang, G., Sun, L., Gao, H., Yao, F., Jin, Z., ... & Lin, R. (2021). SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular endothelial cells. International immunopharmacology, 99, 107926. Xu, W. D., Yang, C., & Huang, A. F. (2024). The role of Nrf2 in immune cells and inflammatory autoimmune diseases: a comprehensive review. Expert Opinion on Therapeutic Targets, 28(9), 789-806. (a) Dodson, M., Shakya, A., Anandhan, A., Chen, J., Garcia, J. G., & Zhang, D. D. (2022). NRF2 and diabetes: the good, the bad, and the complex. Diabetes, 71(12), 2463-2476. (b) Vasileva, L. V., Savova, M. S., Amirova, K. M., Dinkova-Kostova, A. T., & Georgiev, M. I. (2020). Obesity and NRF2-mediated cytoprotection: Where is the missing link?. Pharmacological research, 156, 104760. (c) Li, S., Eguchi, N., Lau, H., & Ichii, H. (2020). The role of the Nrf2 signaling in obesity and insulin resistance. International journal of molecular sciences, 21(18), 6973. (a) Zhang, Y., Wang, J., Wang, Y., & Lei, K. (2024). Nrf2/HO-1 signaling activation alleviates cigarette smoke-induced inflammation in chronic obstructive pulmonary disease by suppressing NLRP3-mediated pyroptosis. Journal of Cardiothoracic Surgery, 19(1), 58. (b) Audousset, C., McGovern, T., & Martin, J. G. (2021). Role of Nrf2 in disease: novel molecular mechanisms and therapeutic approaches–pulmonary disease/asthma. Frontiers in Physiology, 12, 727806. Saha, S., Buttari, B., Profumo, E., Tucci, P., & Saso, L. (2022). A perspective on Nrf2 signaling pathway for neuroinflammation: a potential therapeutic target in Alzheimer's and Parkinson's diseases. Frontiers in cellular neuroscience, 15, 787258. Shi, T., & Dansen, T. B. (2020). Reactive oxygen species induced p53 activation: DNA damage, redox signaling, or both?. Antioxidants & Redox Signaling, 33(12), 839-859. Klotz, L. O., Briviba, K., & Sies, H. (1997). Singlet oxygen mediates the activation of JNK by UVA radiation in human skin fibroblasts. FEBS letters, 408(3), 289-291. Makino, T., Jinnin, M., Muchemwa, F. C., Fukushima, S., Kogushi‐Nishi, H., Moriya, C., ... & Ihn, H. (2010). Basic fibroblast growth factor stimulates the proliferation of human dermal fibroblasts via the ERK1/2 and JNK pathways. British Journal of Dermatology, 162(4), 717-723. (a) Cuenda, A., & Rousseau, S. (2007). p38 MAP-kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1773(8), 1358-1375. Klionsky, D. J. (2005). The molecular machinery of autophagy: unanswered questions. Journal of cell science, 118(Pt 1), 7. (b) Martindale, J. L., & Holbrook, N. J. (2002). Cellular response to oxidative stress: signaling for suicide and survival. Journal of cellular physiology, 192(1), 1-15. (a) Wei, Y., Pattingre, S., Sinha, S., Bassik, M., & Levine, B. (2008). JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Molecular cell, 30(6), 678-688. (b) Yu, C., Minemoto, Y., Zhang, J., Liu, J., Tang, F., Bui, T. N., ... & Lin, A. (2004). JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Molecular cell, 13(3), 329-340. (a) Zhou, J., Li, X. Y., Liu, Y. J., Feng, J., Wu, Y., Shen, H. M., & Lu, G. D. (2022). Full-coverage regulations of autophagy by ROS: from induction to maturation. Autophagy, 18(6), 1240-1255. (b) Przygoda, M., Bartusik-Aebisher, D., Dynarowicz, K., Cieślar, G., Kawczyk-Krupka, A., & Aebisher, D. (2023). Cellular mechanisms of singlet oxygen in photodynamic therapy. International Journal of Molecular Sciences, 24(23), 16890. (c) Liang, P., Kolodieznyi, D., Creeger, Y., Ballou, B., & Bruchez, M. P. (2020). Subcellular singlet oxygen and cell death: location matters. Frontiers in chemistry, 8, 592941. (a) Davies, K. J. (2000). Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB life, 50(4‐5), 279-289. (b) Gao, Q. (2019). Oxidative stress and autophagy. Autophagy: biology and diseases: basic science, 179-198. (a) Kaminskyy, V. O., & Zhivotovsky, B. (2014). Free radicals in cross talk between autophagy and apoptosis. Antioxidants & redox signaling, 21(1), 86-102. (b) Yue, J., & López, J. M. (2020). Understanding MAPK signaling pathways in apoptosis. International journal of molecular sciences, 21(7), 2346. Kang, R., Zeh, H. J., Lotze, M. T., & Tang, D. J. C. D. (2011). The Beclin 1 network regulates autophagy and apoptosis. Cell Death & Differentiation, 18(4), 571-580. Asgari, R., Yarani, R., Mohammadi, P., & Emami Aleagha, M. S. (2022). HIF-1α in the crosstalk between reactive oxygen species and autophagy process: a review in multiple sclerosis. Cellular and molecular neurobiology, 42(7), 2121-2129. Romero, N. R., & Agostinis, P. (2014). Molecular mechanisms underlying the activation of autophagy pathways by reactive oxygen species and their relevance in cancer progression and therapy. In Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging (pp. 159-178). Academic Press. Horan, M. P., Pichaud, N., & Ballard, J. W. O. (2012). Quantifying mitochondrial dysfunction in complex diseases of aging. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 67(10), 1022-1035. Osellame, L. D., Rahim, A. A., Hargreaves, I. P., Gegg, M. E., Richard-Londt, A., Brandner, S., ... & Duchen, M. R. (2013). Mitochondria and quality control defects in a mouse model of Gaucher disease—links to Parkinson's disease. Cell metabolism, 17(6), 941-953. Morciano, G., Patergnani, S., Bonora, M., Pedriali, G., Tarocco, A., Bouhamida, E., ... & Pinton, P. (2020). Mitophagy in cardiovascular diseases. Journal of clinical medicine, 9(3), 892. Miao, M. Q., Han, Y. B., & Liu, L. (2023). Mitophagy in metabolic syndrome. The Journal of Clinical Hypertension, 25(5), 397-403. Park, J. H., Ko, J., Park, Y. S., Park, J., Hwang, J., & Koh, H. C. (2017). Clearance of damaged mitochondria through PINK1 stabilization by JNK and ERK MAPK signaling in chlorpyrifos-treated neuroblastoma cells. Molecular neurobiology, 54, 1844-1857. (a) Chen, M., Chen, Z., Wang, Y., Tan, Z., Zhu, C., Li, Y., ... & Chen, Q. (2016). Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy, 12(4), 689-702. (b) Park, S. Y., & Koh, H. C. (2020). FUNDC1 regulates receptor-mediated mitophagy independently of the PINK1/Parkin-dependent pathway in rotenone-treated SH-SY5Y cells. Food and Chemical Toxicology, 137, 111163. (c) He, H., Huang, W., Xiong, L., Ma, C., Wang, Y., Sun, P., ... & Wu, Y. (2024). FUNDC1-mediated mitophagy regulates photodamage independently of the PINK1/Parkin-dependent pathway. Free Radical Biology and Medicine, 225, 630-640. Majeski, A. E., & Dice, J. F. (2004). Mechanisms of chaperone-mediated autophagy. The international journal of biochemistry & cell biology, 36(12), 2435-2444. Xiong, Y., Contento, A. L., Nguyen, P. Q., & Bassham, D. C. (2007). Degradation of oxidized proteins by autophagy during oxidative stress in Arabidopsis. Plant physiology, 143(1), 291-299. Kiffin, R., Christian, C., Knecht, E., & Cuervo, A. M. (2004). Activation of chaperone-mediated autophagy during oxidative stress. Molecular biology of the cell, 15(11), 4829-4840. Cuervo, A. M., & Dice, J. F. (2000). Unique properties of lamp2a compared to other lamp2 isoforms. Journal of cell science, 113(24), 4441-4450. Zhang, Q., Kang, R., Zeh, III, H. J., Lotze, M. T., & Tang, D. (2013). DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death. Autophagy, 9(4), 451-458. (a) Deretic, V. (2021). Autophagy in inflammation, infection, and immunometabolism. Immunity, 54(3), 437-453. (b) Tsuji, Y., Kuramochi, M., Golbar, H. M., Izawa, T., Kuwamura, M., & Yamate, J. (2020). Acetaminophen-induced rat hepatotoxicity based on M1/M2-macrophage polarization, in possible relation to damage-associated molecular patterns and autophagy. International Journal of Molecular Sciences, 21(23), 8998. (c) Levy, J. M. M., Towers, C. G., & Thorburn, A. (2017). Targeting autophagy in cancer. Nature Reviews Cancer, 17(9), 528-542. Levine, B., Mizushima, N., & Virgin, H. W. (2011). Autophagy in immunity and inflammation. Nature, 469(7330), 323-335. Deretic, V., Saitoh, T., & Akira, S. (2013). Autophagy in infection, inflammation and immunity. Nature Reviews Immunology, 13(10), 722-737. Moore, M. N. (2020). Lysosomes, autophagy, and hormesis in cell physiology, pathology, and age-related disease. Dose-Response, 18(3), 1559325820934227. García-Prat, L., Martínez-Vicente, M., Perdiguero, E., Ortet, L., Rodríguez-Ubreva, J., Rebollo, E., ... & Muñoz-Cánoves, P. (2016). Autophagy maintains stemness by preventing senescence. Nature, 529(7584), 37-42. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., ... & Mizushima, N. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 441(7095), 885-889. Zapata-Muñoz, J., Villarejo-Zori, B., Largo-Barrientos, P., & Boya, P. (2021). Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health. Cell Stress, 5(7), 99. Nixon, R. A. (2013). The role of autophagy in neurodegenerative disease. Nature medicine, 19(8), 983-997. Tomoda, T., Yang, K., & Sawa, A. (2020). Neuronal autophagy in synaptic functions and psychiatric disorders. Biological psychiatry, 87(9), 787-796. Sil, P., Wong, S. W., & Martinez, J. (2018). More than skin deep: autophagy is vital for skin barrier function. Frontiers in immunology, 9, 1376. Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The role of autophagy in skin fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Journal of Investigative Dermatology, 140(9), 1691-1697. Richmond, J. M., & Harris, J. E. (2014). Immunology and skin in health and disease. Cold Spring Harbor perspectives in medicine, 4(12), a015339. Pivarcsi, A., Nagy, I., & Kemeny, L. (2005). Innate immunity in the skin: how keratinocytes fight against pathogens. Current immunology reviews, 1(1), 29-42. Davidson, S., Coles, M., Thomas, T., Kollias, G., Ludewig, B., Turley, S., ... & Buckley, C. D. (2021). Fibroblasts as immune regulators in infection, inflammation and cancer. Nature Reviews Immunology, 21(11), 704-717. Zhang, H., Xia, M., Li, H., Zeng, X., Jia, H., Zhang, W., & Zhou, J. (2025). Implication of Immunobiological Function of Melanocytes in Dermatology. Clinical Reviews in Allergy & Immunology, 68(1), 30. Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The role of autophagy in skin fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Journal of Investigative Dermatology, 140(9), 1691-1697. Ren, H., Zhao, F., Zhang, Q., Huang, X., & Wang, Z. (2022). Autophagy and skin wound healing. Burns & trauma, 10, tkac003. Li, X., Wu, J., Sun, X., Wu, Q., Li, Y., Li, K., ... & Chen, H. (2020). Autophagy reprograms alveolar progenitor cell metabolism in response to lung injury. Stem Cell Reports, 14(3), 420-432. de la Vega, M. R., Dodson, M., Gross, C., Mansour, H. M., Lantz, R. C., Chapman, E., ... & Zhang, D. D. (2016). Role of Nrf2 and autophagy in acute lung injury. Current pharmacology reports, 2, 91-101. Yin, X., Xin, H., Mao, S., Wu, G., & Guo, L. (2019). The role of autophagy in sepsis: protection and injury to organs. Frontiers in physiology, 10, 1071. Barnes, P. J., Baker, J., & Donnelly, L. E. (2022). Autophagy in asthma and chronic obstructive pulmonary disease. Clinical Science, 136(10), 733-746. Mizumura, K., Maruoka, S., Shimizu, T., & Gon, Y. (2018). Autophagy, selective autophagy, and necroptosis in COPD. International journal of chronic obstructive pulmonary disease, 3165-3172. Araya, J., Kojima, J., Takasaka, N., Ito, S., Fujii, S., Hara, H., ... & Kuwano, K. (2013). Insufficient autophagy in idiopathic pulmonary fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 304(1), L56-L69. Patel, A. S., Lin, L., Geyer, A., Haspel, J. A., An, C. H., Cao, J., ... & Morse, D. (2012). Autophagy in idiopathic pulmonary fibrosis. PloS one, 7(7), e41394. McAlinden, K. D., Deshpande, D. A., Ghavami, S., Xenaki, D., Sohal, S. S., Oliver, B. G., ... & Sharma, P. (2019). Autophagy activation in asthma airways remodeling. American journal of respiratory cell and molecular biology, 60(5), 541-553. Liu, C., Liu, Y., Chen, H., Yang, X., Lu, C., Wang, L., & Lu, J. (2023). Myocardial injury: where inflammation and autophagy meet. Burns & Trauma, 11, tkac062. Alcalai, R., Arad, M., Wakimoto, H., Yadin, D., Gorham, J., Wang, L., ... & Seidman, C. E. (2021). LAMP2 cardiomyopathy: consequences of impaired autophagy in the heart. Journal of the American Heart Association, 10(17), e018829. Liu, Y., Wang, Y., Bi, Y., Zhao, Z., Wang, S., Lin, S., ... & Mao, J. (2023). Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy. Cell Cycle, 22(8), 906-918. Shen, Y., Liu, X., Shi, J., & Wu, X. (2019). Involvement of Nrf2 in myocardial ischemia and reperfusion injury. International journal of biological macromolecules, 125, 496-502. Chen, X., Ji, Y., Liu, R., Zhu, X., Wang, K., Yang, X., ... & Sun, H. (2023). Mitochondrial dysfunction: roles in skeletal muscle atrophy. Journal of Translational Medicine, 21(1), 503. Li, P., Ma, Y., Yu, C., Wu, S., Wang, K., Yi, H., & Liang, W. (2021). Autophagy and aging: Roles in skeletal muscle, eye, brain and hepatic tissue. Frontiers in Cell and Developmental Biology, 9, 752962. Ferraro, E., Giammarioli, A. M., Chiandotto, S., Spoletini, I., & Rosano, G. (2014). Exercise-induced skeletal muscle remodeling and metabolic adaptation: redox signaling and role of autophagy. Antioxidants & redox signaling, 21(1), 154-176. Weckman, A., Di Ieva, A., Rotondo, F., Syro, L. V., Ortiz, L. D., Kovacs, K., & Cusimano, M. D. (2014). Autophagy in the endocrine glands. J Mol Endocrinol, 52(2), R151-R163. (a) Afzal, A., Zhang, Y., Afzal, H., Saddozai, U. A. K., Zhang, L., Ji, X. Y., & Khawar, M. B. (2024). Functional role of autophagy in testicular and ovarian steroidogenesis. Frontiers in Cell and Developmental Biology, 12, 1384047. (b) Xu, R., Wang, F., Zhang, Z., Zhang, Y., Tang, Y., Bi, J., ... & Tang, Z. (2023). Diabetes‐induced autophagy dysregulation engenders testicular impairment via oxidative stress. Oxidative medicine and cellular longevity, 2023(1), 4365895. (a) Kong, X., Wang, X., Xia, Q., Hu, Q., Yu, W., Huang, Q., ... & Yu, J. (2025). Unveiling the nexus between environmental exposures and testicular damages: revelations from autophagy and oxidative stress imbalance. Cell Death Discovery, 11(1), 258. (b) Jung, H. S., & Lee, M. S. (2010). Role of autophagy in diabetes and mitochondria. Annals of the New York Academy of Sciences, 1201(1), 79-83. Zhao, X., Jiang, Y., Jiang, T., Han, X., Wang, Y., Chen, L., & Feng, X. (2020). Physiological and pathological regulation of autophagy in pregnancy. Archives of Gynecology and Obstetrics, 302(2), 293-303. Chen, H., Chen, Y., & Zheng, Q. (2024). The regulated cell death at the maternal-fetal interface: beneficial or detrimental?. Cell Death Discovery, 10(1), 100. Zhou, P., Wang, J., Wang, J., & Liu, X. (2024). When autophagy meets placenta development and pregnancy complications. Frontiers in Cell and Developmental Biology, 12, 1327167. Wang, Y., Singh, R., Xiang, Y., & Czaja, M. J. (2010). Macroautophagy and chaperone‐mediated autophagy are required for hepatocyte resistance to oxidant stress. Hepatology, 52(1), 266-277. Xu, F., Hua, C., Tautenhahn, H. M., Dirsch, O., & Dahmen, U. (2020). The role of autophagy for the regeneration of the aging liver. International journal of molecular sciences, 21(10), 3606. (a) Cursio, R., Colosetti, P., Codogno, P., Cuervo, A. M., & Shen, H. M. (2015). The role of autophagy in liver diseases: mechanisms and potential therapeutic targets. BioMed Research International, 2015, 480508. (b) Ruart, M., Chavarria, L., Campreciós, G., Suárez-Herrera, N., Montironi, C., Guixé-Muntet, S., ... & Hernández-Gea, V. (2019). Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. Journal of hepatology, 70(3), 458-469. Jaganjac, M., Milkovic, L., Zarkovic, N., & Zarkovic, K. (2022). Oxidative stress and regeneration. Free Radical Biology and Medicine, 181, 154-165. Franzini, M., Valdenassi, L., Pandolfi, S., Tirelli, U., Ricevuti, G., & Chirumbolo, S. (2023). The role of ozone as an Nrf2-keap1-ARE activator in the anti-microbial activity and immunity modulation of infected wounds. Antioxidants, 12(11), 1985. Clavo, B., Rodríguez-Esparragón, F., Rodríguez-Abreu, D., Martínez-Sánchez, G., Llontop, P., Aguiar-Bujanda, D., ... & Santana-Rodríguez, N. (2019). Modulation of oxidative stress by ozone therapy in the prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants, 8(12), 588. (a) Ristow, M., & Zarse, K. (2010). How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Experimental gerontology, 45(6), 410-418. (b) Calabrese, E. J., Osakabe, N., Di Paola, R., Siracusa, R., Fusco, R., D'Amico, R., ... & Calabrese, V. (2023). Hormesis defines the limits of lifespan. Ageing research reviews, 102074. Hulten, L. M., Holmström, M., & Soussi, B. (1999). Harmful singlet oxygen can be helpful. Free Radical Biology and Medicine, 27(11), 1203-1207. (a) Bieber, K., Hundt, J. E., Yu, X., Ehlers, M., Petersen, F., Karsten, C. M., ... & Ludwig, R. J. (2023). Autoimmune pre-disease. Autoimmunity Reviews, 22(2), 103236. (b) Xiao, Z. X., Miller, J. S., & Zheng, S. G. (2021). An updated advance of autoantibodies in autoimmune diseases. Autoimmunity Reviews, 20(2), 102743. (a) Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. (2012). Into the eye of the cytokine storm. Microbiology and molecular biology reviews, 76(1), 16-32. (b) Karki, R., & Kanneganti, T. D. (2021). The 'cytokine storm': Molecular mechanisms and therapeutic prospects. Trends in immunology, 42(8), 681-705. Fridovich, I. (2013). Oxygen: how do we stand it?. Medical Principles and Practice, 22(2), 131-137. (a) Meyer, J. G., Garcia, T. Y., Schilling, B., Gibson, B. W., & Lamba, D. A. (2019). Proteome and secretome dynamics of human retinal pigment epithelium in response to reactive oxygen species. Scientific reports, 9(1), 15440. (b) Yi, Y., Wang, X. R., Chen, H. T., Huang, W. Y., Feng, L. X., Fang, S. B., & Xiong, G. X. (2023). Development of a serum-free culture method for endothelial cells of the stria vascularis and their pro-inflammatory secretome changes induced by oxidative stress. Clinical and Experimental Otorhinolaryngology, 16(1), 37-48. Eldh, M., Ekström, K., Valadi, H., Sjöstrand, M., Olsson, B., Jernås, M., & Lötvall, J. (2010). Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PloS one, 5(12), e15353. (a) Evren, E., Ringqvist, E., Tripathi, K. P., Sleiers, N., Rives, I. C., Alisjahbana, A., ... & Willinger, T. (2021). Distinct developmental pathways from blood monocytes generate human lung macrophage diversity. Immunity, 54(2), 259-275. (b) Tan, S. Y., & Krasnow, M. A. (2016). Developmental origin of lung macrophage diversity. Development, 143(8), 1318-1327. Chinnery, H. R., McMenamin, P. G., & Dando, S. J. (2017). Macrophage physiology in the eye. Pflügers Archiv-European Journal of Physiology, 469, 501-515. Puttur, F., Gregory, L. G., & Lloyd, C. M. (2019). Airway macrophages as the guardians of tissue repair in the lung. Immunology and cell biology, 97(3), 246-257. Rahman, I., & Adcock, I. M. (2006). Oxidative stress and redox regulation of lung inflammation in COPD. European respiratory journal, 28(1), 219-242. Arora, S., Dev, K., Agarwal, B., Das, P., & Syed, M. A. (2018). Macrophages: Their role, activation and polarization in pulmonary diseases. Immunobiology, 223(4-5), 383-396. Ogura, M., & Kitamura, M. (1998). Oxidant stress incites spreading of macrophages via extracellular signal-regulated kinases and p38 mitogen-activated protein kinase. The Journal of Immunology, 161(7), 3569-3574. Reichard, A., Wanner, N., Farha, S., & Asosingh, K. (2023). Hematopoietic stem cells and extramedullary hematopoiesis in the lungs. Cytometry Part A, 103(12), 967-977. (a) Lämmermann, T., & Sixt, M. (2008). The microanatomy of T‐cell responses. Immunological reviews, 221(1), 26-43. (b) Chinnery, H. R., McMenamin, P. G., & Dando, S. J. (2017). Macrophage physiology in the eye. Pflügers Archiv-European Journal of Physiology, 469, 501-515. (a) Andersson, D. A., Gentry, C., Moss, S., & Bevan, S. (2008). Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. Journal of Neuroscience, 28(10), 2485-2494. (b) Kozai, D., Ogawa, N., & Mori, Y. (2014). Redox regulation of transient receptor potential channels. Antioxidants & redox signaling, 21(6), 971-986. (a) Tracey, K. J. (2002). The inflammatory reflex. Nature, 420(6917), 853-859. (b) Pavlov, V. A., & Tracey, K. J. (2017). Neural regulation of immunity: molecular mechanisms and clinical translation. Nature neuroscience, 20(2), 156-166. (a) Antunes, G. L., Silveira, J. S., Kaiber, D. B., Luft, C., da Costa, M. S., Marques, E. P., ... & da Cunha, A. A. (2020). Cholinergic anti‐inflammatory pathway confers airway protection against oxidative damage and attenuates inflammation in an allergic asthma model. Journal of Cellular Physiology, 235(2), 1838-1849. (b) Kelly, M. J., Breathnach, C., Tracey, K. J., & Donnelly, S. C. (2022). Manipulation of the inflammatory reflex as a therapeutic strategy. Cell Reports Medicine, 3(7). Kozai, D., Ogawa, N., & Mori, Y. (2014). Redox regulation of transient receptor potential channels. Antioxidants & redox signaling, 21(6), 971-986. Gupta, A. K., Gupta, S., Mehan, S., Khan, Z., Das Gupta, G., & Narula, A. S. (2025). Exploring the connection between BDNF/TrkB and AC/cAMP/PKA/CREB signaling pathways: potential for neuroprotection and therapeutic targets for neurological disorders. Molecular Neurobiology, 62(11), 14627-14659. Bellavance, M. A., & Rivest, S. (2014). The HPA–immune axis and the immunomodulatory actions of glucocorticoids in the brain. Frontiers in immunology, 5, 136. Sockrider, M., & Fussner, L. (2020). What is asthma?. American journal of respiratory and critical care medicine, 202(9), P25-P26. Venkatesan, P. (2023). 2023 GINA report for asthma. The Lancet Respiratory Medicine, 11(7), 589. To be published Adeloye, D., Song, P., Zhu, Y., Campbell, H., Sheikh, A., & Rudan, I. (2022). Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. The Lancet Respiratory Medicine, 10(5), 447-458. Erpenbach, K. H., Brailey, M. A., & Stentiford, N. Bronchial Asthma and Chronic Obstructive Lung Diseases: Improvement of the 6. minute walking test and the lung function by inhaling activated air produced by the SOE. TIE therapeutic inhalation equipment. Duan, K. I., Birger, M., Au, D. H., Spece, L. J., Feemster, L. C., & Dieleman, J. L. (2023). Health Care Spending on Respiratory Diseases in the United States, 1996–2016. American Journal of Respiratory and Critical Care Medicine, 207(2), 183-192. Paulson, K. R., Kamath, A. M., Alam, T., Bienhoff, K., Abady, G. G., Abbas, J., ... & Chanie, W. F. (2021). Global, regional, and national progress towards Sustainable Development Goal 3.2 for neonatal and child health: all-cause and cause-specific mortality findings from the Global Burden of Disease Study 2019. The Lancet, 398(10303), 870-905. Gordon, B. R. (2008). Asthma history and presentation. Otolaryngologic Clinics of North America, 41(2), 375-385. Burgel, P. R. (2012). Chronic cough and sputum production: a clinical COPD phenotype?. European Respiratory Journal, 40(1), 4-6. Diehr, P., Wood, R. W., Bushyhead, J., Krueger, L., Wolcott, B., & Tompkins, R. K. (1984). Prediction of pneumonia in outpatients with acute cough—a statistical approach. Journal of chronic diseases, 37(3), 215-225. Tollerud, D. J., O'connor, G. T., Sparrow, D., & Weiss, S. T. (1991). Asthma, hay fever, and phlegm production associated with distinct patterns of allergy skin test reactivity, eosinophilia, and serum IgE levels. The Normative Aging Study. Am Rev Respir Dis, 144(4), 776-81. Heijdra, Y. F., Pinto-Plata, V. M., Kenney, L. A., Rassulo, J., & Celli, B. R. (2002). Cough and phlegm are important predictors of health status in smokers without COPD. Chest, 121(5), 1427-1433. (a) Pitts, T., Bolser, D., Rosenbek, J., Troche, M., & Sapienza, C. (2008). Voluntary cough production and swallow dysfunction in Parkinson's disease. Dysphagia, 23, 297-301. (b) Heijdra, Y. F., Pinto-Plata, V. M., Kenney, L. A., Rassulo, J., & Celli, B. R. (2002). Cough and phlegm are important predictors of health status in smokers without COPD. Chest, 121(5), 1427-1433. (c) Davies, D. (1974). Disability and coal workers' pneumoconiosis. British medical journal, 2(5920), 652. (d) Warren, C. P. (1979). Acute respiratory failure and tracheal obstruction in the elderly with benign goitres. Canadian Medical Association Journal, 121(2), 191. Whitsett, J. A., & Alenghat, T. (2015). Respiratory epithelial cells orchestrate pulmonary innate immunity. Nature immunology, 16(1), 27-35. Voynow, J. A., & Rubin, B. K. (2009). Mucins, mucus, and sputum. Chest, 135(2), 505-512. (a) Biswas, S. K., & Rahman, I. (2009). Environmental toxicity, redox signaling and lung inflammation: the role of glutathione. Molecular aspects of medicine, 30(1-2), 60-76. (b) Shao, M. X., & Nadel, J. A. (2005). Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proceedings of the National Academy of Sciences, 102(3), 767-772. Price, M. E., & Sisson, J. H. (2019). Redox regulation of motile cilia in airway disease. Redox Biology, 27, 101146. Rancourt, R. C., Lee, R. L., O'Neill, H., Accurso, F. J., & White, C. W. (2007). Reduced thioredoxin increases proinflammatory cytokines and neutrophil influx in rat airways: modulation by airway mucus. Free Radical Biology and Medicine, 42(9), 1441-1453. Zhang, M., Wang, J., Liu, R., Wang, Q., Qin, S., Chen, Y., & Li, W. (2024). The role of Keap1-Nrf2 signaling pathway in the treatment of respiratory diseases and the research progress on targeted drugs. Heliyon. (a) Barnes, P. J. (2008). The cytokine network in asthma and chronic obstructive pulmonary disease. The Journal of clinical investigation, 118(11), 3546-3556. (b) Xu, W., Zhao, T., & Xiao, H. (2020). The implication of oxidative stress and AMPK-Nrf2 antioxidative signaling in pneumonia pathogenesis. Frontiers in Endocrinology, 11, 400. Kume, H., Yamada, R., Sato, Y., & Togawa, R. (2023). Airway smooth muscle regulated by oxidative stress in COPD. Antioxidants, 12(1), 142. Michaeloudes, C., Abubakar-Waziri, H., Lakhdar, R., Raby, K., Dixey, P., Adcock, I. M., ... & Chung, K. F. (2022). Molecular mechanisms of oxidative stress in asthma. Molecular aspects of medicine, 85, 101026. (a) Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., ... & Cao, B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet, 395(10229), 1054-1062. (b) George, P. M., Barratt, S. L., Condliffe, R., Desai, S. R., Devaraj, A., Forrest, I., ... & Spencer, L. G. (2020). Respiratory follow-up of patients with COVID-19 pneumonia. Thorax, 75(11), 1009-1016. Wu, Z., & McGoogan, J. M. (2020). Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. jama, 323(13), 1239-1242. "Post COVID-19 condition (long COVID)." World Health Organization (WHO), 26 February 2025, https://www.who.int/news-room/fact-sheets/detail/post-covid-19-condition-(long-covid). Accessed 2 August 2025. (a) Nalbandian, A., Sehgal, K., Gupta, A., Madhavan, M. V., McGroder, C., Stevens, J. S., ... & Wan, E. Y. (2021). Post-acute COVID-19 syndrome. Nature medicine, 27(4), 601-615. (b) Yong, S. J. (2021). Persistent brainstem dysfunction in long-COVID: a hypothesis. ACS chemical neuroscience, 12(4), 573-580. Sakaguchi, R., & Mori, Y. (2020). Transient receptor potential (TRP) channels: Biosensors for redox environmental stimuli and cellular status. Free Radical Biology and Medicine, 146, 36-44. Zielinski, M. R., McKenna, J. T., & McCarley, R. W. (2016). Functions and mechanisms of sleep. AIMS neuroscience, 3(1), 67. Peliciari-Garcia, R. A., Darley-Usmar, V., & Young, M. E. (2018). An overview of the emerging interface between cardiac metabolism, redox biology and the circadian clock. Free radical biology and medicine, 119, 75-84. (a) Reimund, E. (1994). The free radical flux theory of sleep. Medical hypotheses, 43(4), 231-233. (b) Villafuerte, G., Miguel-Puga, A., Murillo Rodríguez, E., Machado, S., Manjarrez, E., & Arias-Carrión, O. (2015). Sleep deprivation and oxidative stress in animal models: a systematic review. Oxidative medicine and cellular longevity, 2015(1), 234952. (a) Bryndin, E., & Bryndina, I. (2020). Self healing of healthy condition at cellular level. Medical Case Reports and Reviews, 3, 1-4. (b) Adam, K., & Oswald, I. (1984). Sleep helps healing. British medical journal (Clinical research ed.), 289(6456), 1400. (a) Garbarino, S., Lanteri, P., Bragazzi, N. L., Magnavita, N., & Scoditti, E. (2021). Role of sleep deprivation in immune-related disease risk and outcomes. Communications biology, 4(1), 1304. (b) Tobaldini, E., Costantino, G., Solbiati, M., Cogliati, C., Kara, T., Nobili, L., & Montano, N. (2017). Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases. Neuroscience & Biobehavioral Reviews, 74, 321-329. Wilking, M., Ndiaye, M., Mukhtar, H., & Ahmad, N. (2013). Circadian rhythm connections to oxidative stress: implications for human health. Antioxidants & redox signaling, 19(2), 192-208. Atrooz, F., & Salim, S. (2020). Sleep deprivation, oxidative stress and inflammation. Advances in protein chemistry and structural biology, 119, 309-336. Patki, G., Solanki, N., Atrooz, F., Allam, F., & Salim, S. (2013). Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain research, 1539, 73-86. Mattson, M. P. (2008). Hormesis defined. Ageing research reviews, 7(1), 1-7. Besedovsky, L., Lange, T., & Haack, M. (2019). The sleep-immune crosstalk in health and disease. Physiological reviews. (a) Deary, V., Ellis, J. G., Wilson, J. A., Coulter, C., & Barclay, N. L. (2014). Simple snoring: not quite so simple after all?. Sleep medicine reviews, 18(6), 453-462. (b) Sarkis, L. M., Jones, A. C., Ng, A., Pantin, C., Appleton, S. L., & MacKay, S. G. (2023). Australasian Sleep Association position statement on consensus and evidence based treatment for primary snoring. Respirology, 28(2), 110-119. Gonzalez-Rothi, E. J., Lee, K. Z., Dale, E. A., Reier, P. J., Mitchell, G. S., & Fuller, D. D. (2015). Intermittent hypoxia and neurorehabilitation. Journal of applied physiology, 119(12), 1455-1465. Swart, M. L., Van Schagen, A. M., Lancee, J., & Van Den Bout, J. (2013). Prevalence of nightmare disorder in psychiatric outpatients. Psychotherapy and psychosomatics, 82(4), 267-268. (a) Levin, R., & Nielsen, T. A. (2007). Disturbed dreaming, posttraumatic stress disorder, and affect distress: a review and neurocognitive model. Psychological bulletin, 133(3), 482. (b) Gieselmann, A., Ait Aoudia, M., Carr, M., Germain, A., Gorzka, R., Holzinger, B., ... & Pietrowsky, R. (2019). Aetiology and treatment of nightmare disorder: State of the art and future perspectives. Journal of sleep research, 28(4), e12820. Krakow, B., & Zadra, A. (2006). Clinical management of chronic nightmares: imagery rehearsal therapy. Behavioral Sleep Medicine, 4(1), 45–70. Germain, A., Buysse, D. J., & Nofzinger, E. (2008). Sleep-specific mechanisms underlying posttraumatic stress disorder: integrative review and neurobiological hypotheses. Sleep medicine reviews, 12(3), 185-195. Hsieh, C. F., Huang, C. T., Chang, C. C., & Hung, T. P. (2025). Singlet Oxygen Energy for Enhancing Physiological Function and Athletic Performance. Bioengineering, 12(2), 118. Martinez-Canton, M., Galvan-Alvarez, V., Martin-Rincon, M., Calbet, J. A., & Gallego-Selles, A. (2024). Unlocking peak performance: The role of Nrf2 in enhancing exercise outcomes and training adaptation in humans. Free Radical Biology and Medicine, 224, 168-181. Taskin, S., Celik, T., Demiryurek, S., Turedi, S., & Taskin, A. (2022). Effects of different-intensity exercise and creatine supplementation on mitochondrial biogenesis and redox status in mice. Iranian Journal of Basic Medical Sciences, 25(8), 1009. Sun, Y., Jin, L., Qin, Y., Ouyang, Z., Zhong, J., & Zeng, Y. (2024). Harnessing mitochondrial stress for health and disease: Opportunities and challenges. Biology, 13(6), 394. Viollet, B. (2017). The energy sensor AMPK: adaptations to exercise, nutritional and hormonal signals. Hormones, metabolism and the benefits of exercise, 13. Meng, Q., & Su, C. H. (2024). The impact of physical exercise on oxidative and nitrosative stress: balancing the benefits and risks. Antioxidants, 13(5), 573. World Health Organization. (2023). Accelerating anaemia reduction: Acomprehensive framework for action. World Health Organization. Weiss, G., Ganz, T., & Goodnough, L. T. (2019). Anemia of inflammation. Blood, The Journal of the American Society of Hematology, 133(1), 40-50. Shaw, P., & Chattopadhyay, A. (2020). Nrf2–ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. Journal of Cellular Physiology, 235(4), 3119-3130. Dewhirst, M. W. (2009). Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiation research, 172(6), 653-665. Wang, J., & Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochemical Journal, 434(3), 365-381. ORINO, K., LEHMAN, L., TSUJI, Y., AYAKI, H., TORTI, S. V., & TORTI, F. M. (2001). Ferritin and the response to oxidative stress. Biochemical Journal, 357(1), 241-247. Wilson, B. E., Jacob, S., Yap, M. L., Ferlay, J., Bray, F., & Barton, M. B. (2019). Estimates of global chemotherapy demands and corresponding physician workforce requirements for 2018 and 2040: a population-based study. The Lancet Oncology, 20(6), 769-780. Sano, M., & Fukuda, K. (2008). Activation of mitochondrial biogenesis by hormesis. Circulation research, 103(11), 1191-1193. Clavo, B., Rodríguez-Esparragón, F., Rodríguez-Abreu, D., Martínez-Sánchez, G., Llontop, P., Aguiar-Bujanda, D., ... & Santana-Rodríguez, N. (2019). Modulation of oxidative stress by ozone therapy in the prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants, 8(12), 588. Li, N., & Karin, M. (1999). Is NF‐κB the sensor of oxidative stress?. The FASEB Journal, 13(10), 1137-1143. (a) Pradat, P. F., & Delanian, S. (2013). Late radiation injury to peripheral nerves. Handbook of clinical neurology, 115, 743-758. (b) Pariset, E., Malkani, S., Cekanaviciute, E., & Costes, S. V. (2021). Ionizing radiation-induced risks to the central nervous system and countermeasures in cellular and rodent models. International Journal of Radiation Biology, 97(sup1), S132-S150. (c) Azzam, P., Mroueh, M., Francis, M., Abou Daher, A., & Zeidan, Y. H. (2020). Radiation-induced neuropathies in head and neck cancer: prevention and treatment modalities. ecancermedicalscience, 14, 1133. Yoon, K. C., Jeong, I. Y., Park, Y. G., & Yang, S. Y. (2007). Interleukin-6 and tumor necrosis factor-α levels in tears of patients with dry eye syndrome. Cornea, 26(4), 431-437. Pflugfelder, S. C., & de Paiva, C. S. (2017). The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology, 124(11), S4-S13. Böhm, E. W., Buonfiglio, F., Voigt, A. M., Bachmann, P., Safi, T., Pfeiffer, N., & Gericke, A. (2023). Oxidative stress in the eye and its role in the pathophysiology of ocular diseases. Redox biology, 68, 102967. Grimwood, S. J. (2024). Profiling the Physiological and Psychological Effectiveness of Singlet Oxygen in the Management of Chronic Obstructive Pulmonary Disease (COPD) (Doctoral dissertation, University of Derby (United Kingdom)). (a) Price, D. D., Finniss, D. G., & Benedetti, F. (2008). A comprehensive review of the placebo effect: recent advances and current thought. Annu. Rev. Psychol., 59(1), 565-590. (b) Enck, P., Benedetti, F., & Schedlowski, M. (2008). New insights into the placebo and nocebo responses. Neuron, 59(2), 195-206. (a) Colloca, L., & Barsky, A. J. (2020). Placebo and nocebo effects. New England Journal of Medicine, 382(6), 554-561. (b) Benedetti, F., & Amanzio, M. (2013). Mechanisms of the placebo response. Pulmonary pharmacology & therapeutics, 26(5), 520-523. Liu, S., Pi, J., & Zhang, Q. (2022). Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway. Redox biology, 54, 102389.