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Review

Sunlight Exposure and Phototherapy: Perspectives for Healthy Aging in an Era of COVID-19

1
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
2
Liver Transplantation Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
3
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
4
Faculty of Nursing, Josai International University, Togane 283-8555, Japan
5
Kazusa Institute for Drug Discovery, Josai International University, Togane 283-8555, Japan
6
Nobeoka Medical Check Center, Fukuoka Institution of Occupational Health, Nobeoka 882-0872, Japan
*
Authors to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2021, 18(20), 10950; https://doi.org/10.3390/ijerph182010950
Submission received: 25 August 2021 / Revised: 12 October 2021 / Accepted: 13 October 2021 / Published: 18 October 2021
(This article belongs to the Special Issue Active and Healthy Ageing)

Abstract

:
Most humans depend on sunlight exposure to satisfy their requirements for vitamin D3. However, the destruction of the ozone layer in the past few decades has increased the risk of skin aging and wrinkling caused by excessive exposure to ultraviolet (UV) radiation, which may also promote the risk of skin cancer development. The promotion of public health recommendations to avoid sunlight exposure would reduce the risk of skin cancer, but it would also enhance the risk of vitamin D3 insufficiency/deficiency, which may cause disease development and progression. In addition, the ongoing global COVID-19 pandemic may further reduce sunlight exposure due to stay-at-home policies, resulting in difficulty in active and healthy aging. In this review article, we performed a literature search in PubMed and provided an overview of basic and clinical data regarding the impact of sunlight exposure and vitamin D3 on public health. We also discuss the potential mechanisms and clinical value of phototherapy with a full-spectrum light (notably blue, red, and near-infrared light) as an alternative to sunlight exposure, which may contribute to combating COVID-19 and promoting active and healthy aging in current aged/superaged societies.

1. Introduction: Impact of Sunlight on Active and Healthy Aging

Sunlight exposure, water, and carbon dioxide are essential for the release of oxygen into the atmosphere and the growth of plants, trees, and their organic products by photosynthesis [1]. Animals can survive by breathing fresh air and eating plant/animal-based foods. In other words, photosynthesis is essential to all life on Earth, including humans. In addition to the role of photosynthesis in the supply of fresh air and food products, there are many benefits of sunlight exposure in our biological activities for active and healthy aging. The first description of the benefits of sunlight exposure was found in a book written by Hippocrates of Kos (460–377 BCE), the father of modern medicine [2]. He described the impact of sunlight exposure on wounds, tetanus, bone fracture, obesity, and mood disorders [3]. In her book Notes of Nursing: What it is and What it is Not, Florence Nightingale (1820–1910), the founder of modern nursing, also mentioned that light is one of five essential points for the health of houses, in addition to pure air, pure water, drainage and cleanliness [4].
One of the potential mechanisms underlying the association between sunlight exposure and public health is the biosynthesis of vitamin D3, which is known as the “sunshine vitamin.” Most humans depend on sunlight exposure to satisfy their requirements for vitamin D3; otherwise, it can be obtained from vitamin D-rich diets (e.g., oily fish, red meat, liver, egg yolks, mushroom) or supplements (e.g., cod liver oil) [5]. Briefly, solar ultraviolet B (UV-B; 280–315 nm) photons are absorbed by 7-dehydrocholesterol (7-DHC) in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 (25(OH)D3; calcidiol) followed by conversion into its biologically active form, 1α, 25-dihydroxyvitamin D3 (1,25(OH)2D3; calcitriol), in the kidney [6]. However, too much UV radiation (UV-A; 315–400 nm and UV-B) has reached Earth. UV-A and UV-B contribute to skin aging and wrinkling and promote the development of skin cancer [7], leading to the promotion of many public health recommendations to avoid excessive sunlight exposure. The avoidance of excessive sunlight exposure may reduce the risk of skin cancer, but insufficient sunlight exposure can cause vitamin D3 insufficiency, which is associated with many diseases, such as osteoporosis, rickets, psychiatric disorders, infections, allergies, autoimmune diseases, cardiovascular diseases, metabolic syndrome and cancers [8,9,10]. In addition, aging may also affect the formation of 1,25(OH)2D3 due to age-related reductions of renal function [11]. How to solve this dilemma (benefit vs. disadvantage of sunlight exposure) is an important issue for achieving active and healthy aging in current aged and superaged societies [12,13,14,15]. Furthermore, the current outbreak of COVID-19 has caused worldwide health and economic burdens. Many studies have discussed the association between sunlight exposure and the global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vitamin D3 has been considered one of the contributing factors for the prevention of COVID-19 [16,17,18,19]. In addition, the direct impact of solar UV-A/-B or artificial UV-C (100–280 nm) radiation on the inactivation of SARS-CoV-2 has been reported [20,21]. UV-C radiation may induce viral genome damage without apparent changes in viral morphology, resulting in the inactivation of SARS-CoV-2 [21].
In this review article, we summarize the impact of sunlight exposure and vitamin D3 on public health and identify the risk factors and potential mechanisms of COVID-19 and severe illness. This work is based on a literature search in PubMed until 27 September 2021 using the search terms “sunlight and vitamin D and health [Filter applied: Review] (n = 518)”, “sun exposure and public health [found by citation matching] (n = 8)”, “vitamin D biosynthesis and aging (ageing) [Filter applied: Review] (n = 551)”, “sunlight and COVID-19 (n = 301)”, “COVID-19 and UV and latitude (n = 6)”, “UV radiation and COVID-19 (n = 221)”, “phototherapy and COVID-19 (n = 111)”, “founder of phototherapy and dermatology (n = 9)”, “phototherapy and psychiatry (Filter applied: Review) (n = 162)”, “phototherapy and sleep disorder (n = 677)”, “phototherapy and Alzheimer’s disease and dementia (Filter applied: Review) (n = 38)”, “ COVID-19 and risk factors and obesity and diabetes (n = 645)”, “COVID-19 and vitamin D deficiency (n = 369)”, “COVID-19 and angiotensin and ACE2 (n = 4708)”, “COVID-19 and angiotensin and ACE2 and vitamin D (n = 51)”, “COVID-19 and adipokines (n = 38)”, “COVID-19 and alarmins (n = 36)”, “angiotensin and alarmins (n = 14)”, “COVID-19 and oxidative stress and antioxidants (n = 221)”, “COVID-19 and gut dysbiosis (n = 124)”, “COVID-19 and fecal (fecal) microbiota transplantation (n = 37)”, “sunlight and gut dysbiosis (n = 4)”, “visible light and opsins (Filter applied: Review) (n = 556)”, “visible light and opsins and lung (n = 14)”, “visible light and opsins and adipose tissues (n = 6)”, or “opsins and cancer (n = 176)”. We then integrate our previous and present data and discuss the potential mechanisms and clinical value of phototherapy with full-spectrum light (notably blue, red, and near-infrared light) as an alternative to sunlight exposure for contributing to active and healthy aging, notably in the era of COVID-19.

2. Phototherapy for Active and Healthy Aging: History and Current Applications

The first published application of phototherapy was conducted by Niels Ryberg Finsen (1860–1904), who developed a carbon arc lamp for the treatment of skin tuberculosis (lupus vulgaris), and his clinical contribution in dermatology was awarded the Nobel Prize in Physiology or Medicine in 1903 [22]. The mechanism of action of Finsen’s carbon arc lamp for the treatment of skin tuberculosis has not been fully elucidated, but evidence suggests the impact of violet/blue (400–470 nm) light on antimicrobial activity [23]. In addition to the application of phototherapy in skin diseases, phototherapy has been widely applied for many diseases, including mental disorders [24,25], sleep disorders [26,27], and neurological disorders [28,29]. In addition, phototherapy is suitable for shift workers, such as rotating night-shift hospital workers who have a higher risk of vitamin D3 insufficiency/deficiency [30]. Well-designed studies using phototherapy for shift workers have been conducted at the National Aeronautics and Space Administration (NASA), and treatment subjects have reported better sleep, performance, and physical and mental well-being than control subjects due to the adjustment of circadian rhythms [31,32,33].
In our previous study, we demonstrated lower expression of vitamin D3 (calcidiol and calcitriol) in nonalcoholic steatohepatitis (NASH), and phototherapy with full-spectrum light (color temperature 5500 K, color rendition index >90 Ra, distance from animals and light 45 cm, exposure value 600–750 l×, Chang Gung Biotechnology, Taipei, Taiwan) 12 h/day for 6 weeks could elevate vitamin D3 levels, resulting in the amelioration of NASH progression in rats [34]. In this study, we demonstrated the altered expression of vitamin D3 and lipid transfer/metabolic proteins, such as apolipoprotein E (apoE) and adiponectin, by phototherapy with full-spectrum light [34]. However, the intensities of UV-A (315–400 nm, Figure 1) and UV-B (280–315 nm, [35]) are fairly low and comparable to normal light. UV-B irradiation is indispensable for the photoconversion of 7-DHC to previtamin D3 in the skin [36], and a long duration of light exposure (12 h/day) may trigger this reaction both in the control and phototherapy groups. However, the serum levels of calcidiol and calcitriol in the phototherapy group were significantly higher than those in the control group [34]. Interestingly, our preliminary study revealed elevated CYP27B1, which generates active vitamin D3 [37] in human keratinocyte HaCaT cells pretreated with 7-DHC (25 μM) for 24 h followed by 3 h irradiation with red (660 nm) or near-infrared light (730 nm) (Figure 2). Therefore, phototherapy with full-spectrum light may play a certain role in vitamin D3 metabolism partly through the induction of CYP27B1 for active vitamin D3 generation. In support of our observations, a recent review article mentioned the fundamental role of red and near-infrared light in improved health status induced by sunlight exposure [38]. The impact of visible or non-infrared light on vitamin D3 biosynthesis should be further explored using full-spectrum light with UV cut-off filters. In addition to the clinical impact of phototherapy in terms of the elevated vitamin D3 in NASH patients [35], we and our collaborator have demonstrated the therapeutic potential of phototherapy in experimental animal models of colitis [39] peritonitis [40], and food allergies [41]. Although the mode of action of phototherapy with full-spectrum light has not been fully elucidated, it may regulate proinflammatory cytokine signaling and oxidative stress and maintain optimal levels of vitamin D3 and healthy microbiota composition. Interestingly, accumulating evidence suggests the impact of microbiota on circadian rhythms and human health [42]. These evidences suggest the therapeutic potential of phototherapy with full-spectrum light in many diseases associated with vitamin D3 insufficiency/deficiency, circadian rhythm disruption and gut dysbiosis.

3. Risk Factors and Potential Mechanisms of Severity and Mortality of COVID-19

There are many risk factors associated with the severity and mortality of COVID-19, including aging, overweight-obesity, hypertension, diabetes, and lung, cardiovascular, and kidney diseases [43]. In addition, many studies have observed an association between vitamin D3 insufficiency/deficiency and COVID-19, suggesting the therapeutic potential of vitamin D3 supplementation for the prevention and treatment of SARS-CoV-2 infection [44,45,46,47,48]. One of the potential mechanisms behind SARS-CoV-2 infection is the altered expression of receptors for virus entry, such as angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4, also known as CD26), in patients with the mentioned risk factors [49,50,51,52]. Although a recent molecular docking study did not support the effective interaction between DPP4 and SARS-CoV-2 spike protein for virus entry [53], blockade of ACE2 and DPP4 has been proposed as a preventive strategy for COVID-19 [54,55] (Figure 3a). Another possibility is that SARS-CoV-2 infection could reduce ACE2 expression due to attachment of the SARS-CoV-2 spike protein, resulting in induction of the ACE/angiotensin II (Ang-II)/angiotensin type I receptor (AT1R) axis, which is associated with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, the development of drugs that enhance ACE2 activity may be a promising approach for the treatment of COVID-19 and severe illness [56]. In terms of the above renin-angiotensin system (RAS), vitamin D3 supplementation could modulate unbalanced RAS and ACE2 downregulation, resulting in induction of the ACE2/Ang-(1–7)/Mas receptor (MasR) axis for protection against ALI/ARDS [57] (Figure 3b).
In addition, adipose tissues are one of the largest endocrine organs and a source of proinflammatory mediators and adipokines, which may create chronic low-grade inflammatory preconditioning [58,59]. Therefore, preexisting chronic inflammation and further inflammatory responses against virus infection lead to extreme systemic inflammation known as a cytokine storm, resulting in the increased severity and mortality of SARS-CoV-2 infection [60]. These COVID-19 patients with poor outcomes have been associated with gut dysbiosis [61]. Interestingly, a recent study pointed to the therapeutic potential of oral Ang-(1–7) peptide in obese mice by modulating the intestinal microbiota (reduction in Firmicutes/Bacteroidetes ratio), suggesting the involvement of RAS in obesity, gut dysbiosis, COVID-19, and ALI/ARDS [62].
Recent studies have pointed to the significance of early detection of danger signals for the classification of COVID-19 patients as being at high risk of mortality. Alarmins are possible danger signals associated with COVID-19 and comorbidities [63], and S100A8/A9, high mobility group box 1 (HMGB1), and histones are considered potential therapeutic targets [64,65,66]. The elevation of S100A8/A9 and HMGB1 by Ang-II suggests the involvement of alarmins in unbalanced RAS [67,68], and the ACE2/Ang-(1–7)/MasR axis could suppress HMGB1 signaling [69]. Although there is no application of alarmin blockade in COVID-19 and comorbidities, previous studies have suggested the therapeutic potential of neutralizing antibodies against S100A8/A9, HMGB1, or histones for the inhibition of pulmonary fibrosis and sepsis-associated ALI/ARDS [70,71,72,73]. The suppression of oxidative stress is also a potential strategy for the treatment of COVID-19, and our previous study demonstrated the induction of nuclear factor-erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant responses, such as heme oxygenase-1 (HO-1), superoxide dismutase 1 (SOD1) and SOD2, by phototherapy with full-spectrum light [41]. Some potential antioxidants, such as vitamin C, glutathione, melatonin, and α-lipoic acid, have also been proposed for clinical applications in COVID-19 [74,75,76,77].

4. Hypothesis: Potential Impact of Phototherapy with Full-Spectrum Light on the COVID-19 Pandemic

Based on the current understanding of risk factors, prognostic factors, and mechanisms of action of SARS-CoV-2, one of the promising strategies for the prevention of infection and recovery from severe illness may be the maintenance of optimal levels of vitamin D3 and the reduction in risk factors. However, a recent randomized clinical trial with a single oral dose of vitamin D3 (200,000 IU) did not reduce the hospital length of stay in patients with moderate to severe COVID-19 [78]. Furthermore, a Mendelian randomization study did not reveal evidence to support an association between calcidiol levels and COVID-19 susceptibility, severity, or hospitalization [79]. On the other hand, another randomized clinical trial with daily oral vitamin D3 (5000 IU) for two weeks reduced the time to recovery for symptoms such as cough and gustatory sensory loss among mild to moderate COVID-19 patients with suboptimal vitamin D3 status [80]. Another large-scale population-based cohort study observed that patients on vitamin D3 supplementation who achieved serum 25(OH)D3 levels ≥30 ng/mL had a lower risk of SARS-CoV-2 infection, severity, and mortality than unsupplemented controls [81]. These clinical trials suggest that vitamin D3 supplementation may be effective for the prevention of SARS-CoV-2 infection and the treatment of symptoms, but deciding the dose and duration of vitamin D3 supplementation must be an important point for achieving better COVID-19 outcomes. Most importantly, misuse of vitamin D3 supplementation may rarely cause vitamin D intoxication, leading to hypercalcemia and serious kidney, heart, and neurological problems [82,83]. On the other hand, there is no risk of vitamin D intoxication even through excessive exposure to sunlight [84].
Although there is no direct evidence that phototherapy could prevent or ameliorate SARS-CoV-2 infection or COVID-19 comorbidities, previous and present observations have suggested the potential of phototherapy with full-spectrum light in COVID-19. Furthermore, there are several advantages of phototherapy with full-spectrum light for the prevention and treatment of COVID-19. First, phototherapy with full-spectrum light would be a safe strategy to satisfy vitamin D3 without the risk of vitamin D intoxication because it would be expected to generate sufficient vitamin D3 under the appropriate exposure regimen (12 h/day for 6–9 weeks) [34,41]; i.e., a single exposure would not produce sufficient vitamin D3, and multiple standard-dose exposures (exposure value 600–750 l×) over a period of time would be required. Second, phototherapy with full-spectrum light would ameliorate the adipose tissue dysfunction, which causes insulin resistance, proinflammatory cytokine release, and altered adipokine production [34]. Reduced expression of adiponectin is a risk factor of metabolic syndrome, and a recent case-control study pointed to the link between obesity and COVID-19 respiratory failure in terms of adiponectin levels [85]. Our previous study demonstrated the elevation of adiponectin by phototherapy with full-spectrum light [34]. A recent study also pointed to the involvement of apoE in virus (SARS-CoV-2) entry by hijacking the metabolic pathway of apoE [86]. Third, phototherapy with full-spectrum light reduces circulating levels of alarmins, such as histone H1 and HMGB1 (Figure 4), which reflect the severity of inflammatory responses [35]. A similar elevation of alarmins was confirmed in septic mice [71,72] and in rats undergoing rejection [87,88], resulting in local and systemic inflammation. The suppression of oxidative stress by the Nrf2-mediated antioxidant response may be a potential mechanism of phototherapy with full-spectrum light. Fourth, phototherapy with full-spectrum light can improve gut dysbiosis by modulating the Firmicutes/Bacteroidetes ratio [41]. Elevation of the Firmicutes/Bacteroidetes ratio was reported in COVID-19 patients and was reduced in the recovery state [89]. In our recent study, we identified the genus Lachnospiraceae_NK4A136_group (phylum Firmicutes) as a food allergy-associated bacteria [41], and a recent study pointed to the existence of gut-associated bacteria, such as the family Lachnospiraceae in the lung microbiota of patients with ARDS [90]. Interestingly, recent studies introduced the therapeutic potential of fecal microbiota transplantation (FMT) for recurrent Clostridium difficile infection patients with COVID-19 [91,92]. In addition, a clinical trial (NCT04824222) to assess the impact of FMT on reducing the risk of disease progression as a supplement to standard COVID-19 treatment is ongoing [92]. On the other hand, Parabacteroides goldsteinii (phylum Bacteroidetes) was identified as a beneficial bacterial species enriched by phototherapy with full-spectrum light [41]. Gut commensal Parabacteroides goldsteinii plays an important role in the anti-obesity effect of polysaccharides isolated from Hirsutella sinensis [93], a traditional Chinese medicine known to possess various pharmacological properties, including the attenuation of pulmonary inflammation and fibrosis [94]. Recently, the same group demonstrated the prevention of chronic obstructive pulmonary syndrome (COPD) by lipopolysaccharide derived from Parabacteroides goldsteinii [95], suggesting the therapeutic potential of phototherapy with full-spectrum light in COVID-19 in part through the induction of beneficial bacteria, such as Parabacteroides goldsteinii. Finally, our preliminary data suggest the impact of phototherapy with full-spectrum light on altered expression of ACE2 and DPP4 (CD26), receptors for SARS-CoV-2 entry in inflamed colon tissues (Figure 5). Due to the large distribution of ACE2 and DPP4 (CD26) in the human body, SARS-CoV-2 may infect other tissues aside from the lungs [50,96], and diarrhea is a common presenting symptom in COVID-19 patients [97].
Taken together, phototherapy with full-spectrum light induces vitamin D3 biosynthesis, alters adipokine production (elevated adiponectin), modulates microbiota composition (reduction in the Firmicutes/Bacteroidetes ratio and induction of beneficial bacteria, i.e., Parabacteroides goldsteinii), and reduces many risk factors (e.g., alarmins, proinflammatory cytokines, and oxidative stress markers) associated with COVID-19 and severe illness (Figure 6).

5. Summary and Future Directions for Active and Healthy Aging

Sunlight exposure and appropriate exercise may be the best ways to maintain healthy conditions. However, vitamin D3 biosynthesis depends on the strength of UV radiation, its exposure time as well as skin color (the type of melanin) [98,99]. Therefore, optimal conditions for vitamin D3 biosynthesis may be different in each individual, and seasonal changes in sunlight exposure may also affect it. We also need to consider the adverse effects (skin aging, wrinkling, and skin cancer development) caused by excessive UV exposure. In addition, many people, such as night-shift workers, elderly people with difficulty walking, and people who are hospitalized, may be limited to receiving enough benefits from sunlight. In current aged/superaged societies and an ongoing global pandemic of COVID-19, we need to consider ways to enhance our immunity to maintain suitable health. Notably, the stay-at-home policy may reduce the time for outdoor activities, resulting in vitamin D3 insufficiency/deficiency [100] and an increased incidence of bone fractures in the elderly [101]. In addition to sunlight exposure and vitamin D3 supplementation, phototherapy with full-spectrum light is an alternative approach to stimulate vitamin D3 biosynthesis with minimal risk of skin damage and adjust circadian rhythms, which are quite important for biological, physiological, and immunological activities in all living organisms. To achieve healthy aging, the age-dependent decline in vitamin D3 biosynthesis should be actively adjusted by vitamin D3 supplementation and phototherapy with full-spectrum light, which may reduce the risk of various diseases, such as osteoporosis, metabolic syndromes, allergies, infectious disorders, mental/neurological disorders and cancers (Figure 7a). In the case of vitamin D3 supplementation, we may need to carefully evaluate the optimal dose of vitamin D3 to reduce the risk of vitamin D intoxication and relative complications. To further explore the clinical impact of phototherapy with full-spectrum light, we set up a phototherapy room for patients (Figure 7b). Although we have no data to demonstrate the involvement of vitamin D3, we have confirmed some beneficial effects of phototherapy, such as the reduction in total bilirubin in a patient with severe jaundice after liver transplantation (data not shown). Although further small and large cohort studies are necessary, phototherapy with full-spectrum light could be a reasonable approach with a low potential risk of adverse events, and we highly recommend changing the indoor light environment to full-spectrum light at homes and public spaces, such as schools, working places, clinics, and hospitals as well as nursing homes. The cost of full-spectrum light (roughly three times higher than normal light) may be a critical issue, but there are many beneficial impacts of phototherapy with full-spectrum light, including the generation of sufficient vitamin D3 and the maintenance of healthy gut microbiota composition as well as suitable circadian rhythm. All of these are indispensable for achieving active and healthy aging in current aged/superaged societies.

6. Conclusions

In conclusion, we propose phototherapy with full-spectrum light as one of the potential strategies to prevent disease progression associated with vitamin D3 insufficiency/deficiency, and it may lead us to achieve active and healthy aging in the era of COVID-19.
Recently, the impact of blue light (450, 454, and 470 nm) on SARS-CoV-2 inactivation was reported [102]. Furthermore, a recent case report suggested the therapeutic potential of phototherapy with a red light (630 + 660 nm) for the alleviation of respiratory symptoms, pulmonary inflammation, and hypoxia [103]. The beneficial effect of red light (660 nm) was also confirmed in an experimental model of sepsis-associated ALI [104]. Although most peripheral tissues, except the eye and skin, are not normally reached by light, accumulating evidence suggests the direct and indirect impacts of visible light on cell behavior and biological activities through opsin (OPN) receptors [105]. For example, OPN3 and OPN4 are expressed in the aorta and pulmonary arteries, and blue light exposure induces vasorelaxation [106,107]. The expression of OPN3 and OPN4 in airway smooth muscle [108] also suggested the impact of blue light exposure on vasorelaxation for the treatment of pulmonary disorders caused by COVID-19. On the other hand, blue light exposure has been shown to suppress melatonin, resulting in a negative impact on sleep quality [109]. In addition, the impact of light on adipose tissues and lipid homeostasis has been reported. Briefly, specific wavelength, especially green light (505 nm), enhanced OPN2 expression in mature 3T3-L1 adipocytes and decreased lipid droplets [110]. Ondrusova K et al. demonstrated the expression of OPN3 in subcutaneous white adipose tissues, and daily exposure of differentiated 3T3-L1 adipocytes to blue light resulted in decreased lipid droplet size [111]. A recent study demonstrated the expression of OPN3 in brown adipose tissues and its impact on the regulation of glucose metabolism and mitochondrial respiration in brown adipocytes [112]. The direct exposure of brown adipose tissues to white light (465 + 565 nm) increased thermogenic capacity in an OPN3-dependent manner, suggesting the potential of phototherapy for obesity and obesity-associated metabolic disorders [112]. Furthermore, the OPN1SW (opsin 1, shortwave sensitive), OPN2, OPN3, and OPN4 genes are widely found and differentially expressed in human brain areas and potentially regulate the circadian photoentrainment of the central biological clock [105]. The impact of OPN3 or OPN4 on tumor cell activities, such as drug sensitivity, growth, and metastasis, has been reported in hepatocellular carcinoma, colon cancer, and lung adenocarcinoma [113,114,115,116], and blue light (465 nm) exposure suppresses tumor growth by inducing autophagy [114]. Taken together, these observations suggest the possible broad impacts of phototherapy with full-spectrum light on biological, physiological, and immunological activities in multiple organs, tissues, and cells.
Further investigations, including the screening of optimal conditions of phototherapy, such as light strength, effective wavelength, and the duration of exposure, should be considered in future preclinical and clinical trials.

Author Contributions

Conceptualization, T.N. and S.G.; investigation, K.-C.C., C.-C.C., P.-J.C., C.-Y.L., and L.-W.H.; resources, T.N., C.-C.C., N.O., T.G., C.-L.C., and S.G.; data curation, T.N.; writing—original draft preparation, T.N.; writing—review and editing, T.N., K.-C.C., N.O., T.G., and S.G.; visualization, T.N.; supervision, S.G.; project administration, T.N.; funding acquisition, T.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Technology (MOST109-2320-B-182-014 to T.N.) and Chang Gung Medical Foundation (CMRPD8I0011, CMRPD8I0012, and CMRPG8I0013 to T.N.). The APC was funded by Josai International University.

Institutional Review Board Statement

Our experimental design was reviewed and approved by the Institutional Animal Care and Use Committee (approval no. 2018122119) of Kaohsiung Chang Gung Memorial Hospital.

Informed Consent Statement

Not applicable.

Data Availability Statement

No datasets were generated or analyzed during the current study.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

References

  1. Rojstaczer, S.; Sterling, S.M.; Moore, N.J. Human appropriation of photosynthesis products. Science 2001, 294, 2549–2552. [Google Scholar] [CrossRef]
  2. Yapijakis, C. Hippocrates of Kos, the father of clinical medicine, and Asclepiades of Bithynia, the father of molecular medicine. Review. In Vivo 2009, 23, 507–514. [Google Scholar]
  3. Hippocrates on Airs, Waters, and Paces. Available online: http://classics.mit.edu//Hippocrates/airwatpl.html (accessed on 3 August 2021).
  4. Nightingale, F. Notes of Nursing: What It Is and What It Is Not; Harrison: London, UK, 1859.
  5. Grant, W.B.; Holick, M.F. Benefits and requirements of vitamin D for optimal health: A review. Altern. Med. Rev. J. Clin. Ther. 2005, 10, 94–111. [Google Scholar]
  6. Holick, M.F. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am. J. Clin. Nutr. 2004, 80, 1678S–1688S. [Google Scholar] [CrossRef] [Green Version]
  7. Gordon, J.R.; Brieva, J.C. Images in clinical medicine. Unilateral dermatoheliosis. N. Engl. J. Med. 2012, 366, e25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Wacker, M.; Holick, M.F. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinology 2013, 5, 51–108. [Google Scholar] [CrossRef] [Green Version]
  9. Hoel, D.G.; de Gruijl, F.R. Sun Exposure Public Health Directives. Int. J. Environ. Res. Public Health 2018, 15, 2794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Alfredsson, L.; Armstrong, B.K.; Butterfield, D.A.; Chowdhury, R.; de Gruijl, F.R.; Feelisch, M.; Garland, C.F.; Hart, P.H.; Hoel, D.G.; Jacobsen, R.; et al. Insufficient Sun Exposure Has Become a Real Public Health Problem. Int. J. Environ. Res. Public Health 2020, 17, 5014. [Google Scholar] [CrossRef]
  11. Gallagher, J.C. Vitamin D and aging. Endocrinol. Metab. Clin. N. Am. 2013, 42, 319–332. [Google Scholar] [CrossRef] [Green Version]
  12. Reichrath, J. Skin cancer prevention and UV-protection: How to avoid vitamin D-deficiency? Br. J. Dermatol. 2009, 161 (Suppl. S3), 54–60. [Google Scholar] [CrossRef] [PubMed]
  13. Lucas, R.M. An epidemiological perspective of ultraviolet exposure—Public health concerns. Eye Contact Lens 2011, 37, 168–175. [Google Scholar] [CrossRef]
  14. Reichrath, J.; Reichrath, S. Hope and challenge: The importance of ultraviolet (UV) radiation for cutaneous vitamin D synthesis and skin cancer. Scand. J. Clin. Lab. Investig. Suppl. 2012, 243, 112–119. [Google Scholar] [CrossRef]
  15. Reichrath, J. Lessons Learned from Paleolithic Models and Evolution for Human Health: A Snap Shot on Beneficial Effects and Risks of Solar Radiation. Adv. Exp. Med. Biol. 2020, 1268, 3–15. [Google Scholar] [CrossRef]
  16. Whittemore, P.B. COVID-19 fatalities, latitude, sunlight, and vitamin D. Am. J. Infect. Control 2020, 48, 1042–1044. [Google Scholar] [CrossRef] [PubMed]
  17. Walrand, S. Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor. Sci. Rep. 2021, 11, 1981. [Google Scholar] [CrossRef] [PubMed]
  18. Chen, S.; Prettner, K.; Kuhn, M.; Geldsetzer, P.; Wang, C.; Barnighausen, T.; Bloom, D.E. Climate and the spread of COVID-19. Sci. Rep. 2021, 11, 9042. [Google Scholar] [CrossRef]
  19. Sharun, K.; Tiwari, R.; Dhama, K. COVID-19 and sunlight: Impact on SARS-CoV-2 transmissibility, morbidity, and mortality. Ann. Med. Surg. 2021, 66, 102419. [Google Scholar] [CrossRef]
  20. Nicastro, F.; Sironi, G.; Antonello, E.; Bianco, A.; Biasin, M.; Brucato, J.R.; Ermolli, I.; Pareschi, G.; Salvati, M.; Tozzi, P.; et al. Solar UV-B/A radiation is highly effective in inactivating SARS-CoV-2. Sci. Rep. 2021, 11, 14805. [Google Scholar] [CrossRef] [PubMed]
  21. Lo, C.W.; Matsuura, R.; Iimura, K.; Wada, S.; Shinjo, A.; Benno, Y.; Nakagawa, M.; Takei, M.; Aida, Y. UVC disinfects SARS-CoV-2 by induction of viral genome damage without apparent effects on viral morphology and proteins. Sci. Rep. 2021, 11, 13804. [Google Scholar] [CrossRef]
  22. Grzybowski, A.; Pietrzak, K. From patient to discoverer—Niels Ryberg Finsen (1860-1904)—The founder of phototherapy in dermatology. Clin. Dermatol. 2012, 30, 451–455. [Google Scholar] [CrossRef]
  23. Enwemeka, C.S.; Bumah, V.V.; Masson-Meyers, D.S. Light as a potential treatment for pandemic coronavirus infections: A perspective. J. Photochem. Photobiol. B Biol. 2020, 207, 111891. [Google Scholar] [CrossRef]
  24. Stumpf, W.E.; Privette, T.H. Light, vitamin D and psychiatry. Role of 1,25 dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes. Psychopharmacology 1989, 97, 285–294. [Google Scholar] [CrossRef]
  25. Tseng, P.T.; Chen, Y.W.; Tu, K.Y.; Chung, W.; Wang, H.Y.; Wu, C.K.; Lin, P.Y. Light therapy in the treatment of patients with bipolar depression: A meta-analytic study. Eur. Neuropsychopharmacol. 2016, 26, 1037–1047. [Google Scholar] [CrossRef] [PubMed]
  26. Jurvelin, H.; Jokelainen, J.; Takala, T. Transcranial bright light and symptoms of jet lag: A randomized, placebo-controlled trial. Aerosp. Med. Hum. Perform. 2015, 86, 344–350. [Google Scholar] [CrossRef] [PubMed]
  27. van Maanen, A.; Meijer, A.M.; van der Heijden, K.B.; Oort, F.J. The effects of light therapy on sleep problems: A systematic review and meta-analysis. Sleep Med. Rev. 2016, 29, 52–62. [Google Scholar] [CrossRef] [PubMed]
  28. Aarts, M.P.; Aries, M.B.; Diakoumis, A.; van Hoof, J. Shedding a Light on Phototherapy Studies with People having Dementia: A Critical Review of the Methodology from a Light Perspective. Am. J. Alzheimers Dis. Other Dement. 2016, 31, 551–563. [Google Scholar] [CrossRef]
  29. Figueiro, M.G. Light, sleep and circadian rhythms in older adults with Alzheimer’s disease and related dementias. Neurodegener. Dis. Manag. 2017, 7, 119–145. [Google Scholar] [CrossRef] [Green Version]
  30. Rizza, S.; Pietroiusti, A.; Farcomeni, A.; Mina, G.G.; Caruso, M.; Virgilio, M.; Magrini, A.; Federici, M.; Coppeta, L. Monthly fluctuations in 25-hydroxy-vitamin D levels in day and rotating night shift hospital workers. J. Endocrinol. Investig. 2020, 43, 1655–1660. [Google Scholar] [CrossRef]
  31. Stewart, K.T.; Hayes, B.C.; Eastman, C.I. Light treatment for NASA shiftworkers. Chronobiol. Int. 1995, 12, 141–151. [Google Scholar] [CrossRef]
  32. Eastman, C.I.; Boulos, Z.; Terman, M.; Campbell, S.S.; Dijk, D.J.; Lewy, A.J. Light treatment for sleep disorders: Consensus report. VI. Shift work. J. Biol. Rhythm. 1995, 10, 157–164. [Google Scholar] [CrossRef]
  33. Samel, A.; Gander, P. Bright light as a chronobiological countermeasure for shiftwork in space. Acta Astronaut. 1995, 36, 669–683. [Google Scholar] [CrossRef]
  34. Nakano, T.; Cheng, Y.F.; Lai, C.Y.; Hsu, L.W.; Chang, Y.C.; Deng, J.Y.; Huang, Y.Z.; Honda, H.; Chen, K.D.; Wang, C.C.; et al. Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J. Hepatol. 2011, 55, 415–425. [Google Scholar] [CrossRef]
  35. Goto, S.; Nakano, T.; Chen, C.L.; Chiu, K.W.; Hsu, L.W.; Chen, I.H.; Huang, K.T.; Chen, D.W.; Goto, T.; Omori, N.; et al. Application of Artificial Sunlight for the Elderly as a Possible Environmental Nursing Practice. POJ Nurs. Pract. Res. 2018, 2, 1–5. [Google Scholar] [CrossRef]
  36. MacLaughlin, J.A.; Anderson, R.R.; Holick, M.F. Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Science 1982, 216, 1001–1003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Seifert, M.; Tilgen, W.; Reichrath, J. Expression of 25-hydroxyvitamin D-1alpha-hydroxylase (1alphaOHase, CYP27B1) splice variants in HaCaT keratinocytes and other skin cells: Modulation by culture conditions and UV-B treatment in vitro. Anticancer Res. 2009, 29, 3659–3667. [Google Scholar] [PubMed]
  38. Heiskanen, V.; Pfiffner, M.; Partonen, T. Sunlight and health: Shifting the focus from vitamin D3 to photobiomodulation by red and near-infrared light. Ageing Res. Rev. 2020, 61, 101089. [Google Scholar] [CrossRef] [PubMed]
  39. Hiratsuka, T.; Inomata, M.; Goto, S.; Oyama, Y.; Nakano, T.; Chen, C.L.; Shiraishi, N.; Noguchi, T.; Kitano, S. Phototherapy with artificial light suppresses dextran sulfate sodium-induced colitis in a mouse model. J. Gastroenterol. Hepatol. 2014, 29, 749–756. [Google Scholar] [CrossRef]
  40. Hara, T.; Hiratsuka, T.; Etoh, T.; Itai, Y.; Kono, Y.; Shiroshita, H.; Shiraishi, N.; Inomata, M. Intraperitoneal Phototherapy Suppresses Inflammatory Reactions in a Surgical Model of Peritonitis. J. Surg. Res. 2020, 252, 231–239. [Google Scholar] [CrossRef]
  41. Chen, P.J.; Nakano, T.; Lai, C.Y.; Chang, K.C.; Chen, C.L.; Goto, S. Daily full spectrum light exposure prevents food allergy-like allergic diarrhea by modulating vitamin D3 and microbiota composition. NPJ Biofilms Microbiomes 2021, 7, 41. [Google Scholar] [CrossRef]
  42. Pearson, J.A.; Wong, F.S.; Wen, L. Crosstalk between circadian rhythms and the microbiota. Immunology 2020, 161, 278–290. [Google Scholar] [CrossRef]
  43. Cueto-Manzano, A.M.; Espinel-Bermudez, M.C.; Hernandez-Gonzalez, S.O.; Rojas-Campos, E.; Nava-Zavala, A.H.; Fuentes-Orozco, C.; Balderas-Pena, L.M.A.; Gonzalez-Ojeda, A.; Cortes-Sanabria, L.; Mireles-Ramirez, M.A.; et al. Risk factors for mortality of adult patients with COVID-19 hospitalised in an emerging country: A cohort study. BMJ Open 2021, 11, e050321. [Google Scholar] [CrossRef]
  44. Mohan, M.; Cherian, J.J.; Sharma, A. Exploring links between vitamin D deficiency and COVID-19. PLoS Pathog. 2020, 16, e1008874. [Google Scholar] [CrossRef] [PubMed]
  45. Zemb, P.; Bergman, P.; Camargo, C.A., Jr.; Cavalier, E.; Cormier, C.; Courbebaisse, M.; Hollis, B.; Joulia, F.; Minisola, S.; Pilz, S.; et al. Vitamin D deficiency and the COVID-19 pandemic. J. Glob. Antimicrob. Resist. 2020, 22, 133–134. [Google Scholar] [CrossRef]
  46. Radujkovic, A.; Hippchen, T.; Tiwari-Heckler, S.; Dreher, S.; Boxberger, M.; Merle, U. Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients 2020, 12, 2757. [Google Scholar] [CrossRef] [PubMed]
  47. Weir, E.K.; Thenappan, T.; Bhargava, M.; Chen, Y. Does vitamin D deficiency increase the severity of COVID-19? Clin. Med. 2020, 20, e107–e108. [Google Scholar] [CrossRef] [PubMed]
  48. Pereira, M.; Dantas Damascena, A.; Galvao Azevedo, L.M.; de Almeida Oliveira, T.; da Mota Santana, J. Vitamin D deficiency aggravates COVID-19: Systematic review and meta-analysis. Crit. Rev. Food Sci. Nutr. 2020, 1–9, epub ahead of print. [Google Scholar] [CrossRef]
  49. Drucker, D.J. Coronavirus Infections and Type 2 Diabetes-Shared Pathways with Therapeutic Implications. Endocr. Rev. 2020, 41, 457–470. [Google Scholar] [CrossRef]
  50. Radzikowska, U.; Ding, M.; Tan, G.; Zhakparov, D.; Peng, Y.; Wawrzyniak, P.; Wang, M.; Li, S.; Morita, H.; Altunbulakli, C.; et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy 2020, 75, 2829–2845. [Google Scholar] [CrossRef]
  51. Zamorano Cuervo, N.; Grandvaux, N. ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities. eLife 2020, 9, e61390. [Google Scholar] [CrossRef]
  52. Bassendine, M.F.; Bridge, S.H.; McCaughan, G.W.; Gorrell, M.D. COVID-19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) in disease severity? J. Diabetes 2020, 12, 649–658. [Google Scholar] [CrossRef]
  53. Cameron, K.; Rozano, L.; Falasca, M.; Mancera, R.L. Does the SARS-CoV-2 Spike Protein Receptor Binding Domain Interact Effectively with the DPP4 (CD26) Receptor? A Molecular Docking Study. Int. J. Mol. Sci. 2021, 22, 7001. [Google Scholar] [CrossRef] [PubMed]
  54. Irani, A.H.; Steyn-Ross, D.A.; Steyn-Ross, M.L.; Voss, L.; Sleigh, J. The molecular dynamics of possible inhibitors for SARS-CoV-2. J. Biomol. Struct. Dyn. 2021, 1–10, epub ahead of print. [Google Scholar] [CrossRef] [PubMed]
  55. Rhee, S.Y.; Lee, J.; Nam, H.; Kyoung, D.S.; Shin, D.W.; Kim, D.J. Effects of a DPP-4 Inhibitor and RAS Blockade on Clinical Outcomes of Patients with Diabetes and COVID-19. Diabetes Metab. J. 2021, 45, 251–259. [Google Scholar] [CrossRef] [PubMed]
  56. Zhang, X.; Li, S.; Niu, S. ACE2 and COVID-19 and the resulting ARDS. Postgrad. Med. J. 2020, 96, 403–407. [Google Scholar] [CrossRef]
  57. Malek Mahdavi, A. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19. Rev. Med. Virol. 2020, 30, e2119. [Google Scholar] [CrossRef]
  58. Unamuno, X.; Gomez-Ambrosi, J.; Rodriguez, A.; Becerril, S.; Fruhbeck, G.; Catalan, V. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur. J. Clin. Investig. 2018, 48, e12997. [Google Scholar] [CrossRef] [Green Version]
  59. Landecho, M.F.; Marin-Oto, M.; Recalde-Zamacona, B.; Bilbao, I.; Fruhbeck, G. Obesity as an adipose tissue dysfunction disease and a risk factor for infections—Covid-19 as a case study. Eur. J. Intern. Med. 2021. [Google Scholar] [CrossRef]
  60. Rajpal, A.; Rahimi, L.; Ismail-Beigi, F. Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes. J. Diabetes 2020, 12, 895–908. [Google Scholar] [CrossRef]
  61. Ferreira, C.; Viana, S.D.; Reis, F. Is Gut Microbiota Dysbiosis a Predictor of Increased Susceptibility to Poor Outcome of COVID-19 Patients? An Update. Microorganisms 2020, 9, 53. [Google Scholar] [CrossRef]
  62. Machado, A.S.; Oliveira, J.R.; Lelis, D.d.F.; Guimarães, V.H.D.; de Paula, A.M.B.; Guimaraes, A.L.S.; Brandi, I.V.; de Carvalho, B.M.A.; da Costa, D.V.; Vieira, C.R.; et al. Oral angiotensin-(1-7) peptide modulates intestinal microbiota improving metabolic profile in obese mice. Protein Pept. Lett. 2021. epub ahead of print. [Google Scholar] [CrossRef]
  63. Di Salvo, E.; Di Gioacchino, M.; Tonacci, A.; Casciaro, M.; Gangemi, S. Alarmins, COVID-19 and comorbidities. Ann. Med. 2021, 53, 777–785. [Google Scholar] [CrossRef]
  64. Chen, L.; Long, X.; Xu, Q.; Tan, J.; Wang, G.; Cao, Y.; Wei, J.; Luo, H.; Zhu, H.; Huang, L.; et al. Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients. Cell. Mol. Immunol. 2020, 17, 992–994. [Google Scholar] [CrossRef]
  65. Sivakorn, C.; Dechsanga, J.; Jamjumrus, L.; Boonnak, K.; Schultz, M.J.; Dorndorp, A.M.; Phumratanaprapin, W.; Ratanarat, R.; Naorungroj, T.; Wattanawinitchai, P.; et al. High Mobility Group Box 1 and Interleukin 6 at Intensive Care Unit Admission as Biomarkers in Critically Ill COVID-19 Patients. Am. J. Trop. Med. Hyg. 2021, 105, 73–80. [Google Scholar] [CrossRef]
  66. Shaw, R.J.; Abrams, S.T.; Austin, J.; Taylor, J.M.; Lane, S.; Dutt, T.; Downey, C.; Du, M.; Turtle, L.; Baillie, J.K.; et al. Circulating histones play a central role in COVID-19-associated coagulopathy and mortality. Haematologica 2021, 106, 2493–2498. [Google Scholar] [CrossRef]
  67. Wu, Y.; Li, Y.; Zhang, C.; A, X.; Wang, Y.; Cui, W.; Li, H.; Du, J. S100a8/a9 released by CD11b+Gr1+ neutrophils activates cardiac fibroblasts to initiate angiotensin II-Induced cardiac inflammation and injury. Hypertension 2014, 63, 1241–1250. [Google Scholar] [CrossRef] [Green Version]
  68. Zhang, L.; Zhang, B.; Yu, Y.; Wang, J.; Wu, J.; Su, Y.; Jiang, H.; Zou, Y.; Ge, J. Angiotensin II Increases HMGB1 Expression in the Myocardium Through AT1 and AT2 Receptors When Under Pressure Overload. Int. Heart J. 2021, 62, 162–170. [Google Scholar] [CrossRef] [PubMed]
  69. Rabie, M.A.; Abd El Fattah, M.A.; Nassar, N.N.; Abdallah, D.M.; El-Abhar, H.S. Correlation between angiotensin 1-7-mediated Mas receptor expression with motor improvement, activated STAT3/SOCS3 cascade, and suppressed HMGB-1/RAGE/NF-kappaB signaling in 6-hydroxydopamine hemiparkinsonian rats. Biochem. Pharmacol. 2020, 171, 113681. [Google Scholar] [CrossRef] [PubMed]
  70. Araki, K.; Kinoshita, R.; Tomonobu, N.; Gohara, Y.; Tomida, S.; Takahashi, Y.; Senoo, S.; Taniguchi, A.; Itano, J.; Yamamoto, K.I.; et al. The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. J. Mol. Med. 2021, 99, 131–145. [Google Scholar] [CrossRef]
  71. Wang, H.; Yang, H.; Tracey, K.J. Extracellular role of HMGB1 in inflammation and sepsis. J. Intern. Med. 2004, 255, 320–331. [Google Scholar] [CrossRef] [PubMed]
  72. Kusano, T.; Chiang, K.C.; Inomata, M.; Shimada, Y.; Ohmori, N.; Goto, T.; Sato, S.; Goto, S.; Nakano, T.; Kawamoto, S.; et al. A novel anti-histone H1 monoclonal antibody, SSV monoclonal antibody, improves lung injury and survival in a mouse model of lipopolysaccharide-induced sepsis-like syndrome. BioMed Res. Int. 2015, 2015, 491649. [Google Scholar] [CrossRef] [Green Version]
  73. Deng, Q.; Pan, B.; Alam, H.B.; Liang, Y.; Wu, Z.; Liu, B.; Mor-Vaknin, N.; Duan, X.; Williams, A.M.; Tian, Y.; et al. Citrullinated Histone H3 as a Therapeutic Target for Endotoxic Shock in Mice. Front. Immunol. 2019, 10, 2957. [Google Scholar] [CrossRef]
  74. Farjana, M.; Moni, A.; Sohag, A.A.M.; Hasan, A.; Hannan, M.A.; Hossain, M.G.; Uddin, M.J. Repositioning Vitamin C as a Promising Option to Alleviate Complications associated with COVID-19. Infect. Chemother. 2020, 52, 461–477. [Google Scholar] [CrossRef]
  75. Karkhanei, B.; Talebi Ghane, E.; Mehri, F. Evaluation of oxidative stress level: Total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19. New Microbes New Infect. 2021, 42, 100897. [Google Scholar] [CrossRef] [PubMed]
  76. Esmaeili Gouvarchin Ghaleh, H.; Hosseini, A.; Aghamollaei, H.; Fasihi-Ramandi, M.; Alishiri, G.; Saeedi-Boroujeni, A.; Hassanpour, K.; Mahmoudian-Sani, M.R.; Farnoosh, G. NLRP3 inflammasome activation and oxidative stress status in the mild and moderate SARS-CoV-2 infected patients: Impact of melatonin as a medicinal supplement. Z. Fur Naturforschung. C J. Biosci. 2021. epub ahead of print. [Google Scholar] [CrossRef]
  77. Rochette, L.; Ghibu, S. Mechanics Insights of Alpha-Lipoic Acid against Cardiovascular Diseases during COVID-19 Infection. Int. J. Mol. Sci. 2021, 22, 7979. [Google Scholar] [CrossRef] [PubMed]
  78. Murai, I.H.; Fernandes, A.L.; Sales, L.P.; Pinto, A.J.; Goessler, K.F.; Duran, C.S.C.; Silva, C.B.R.; Franco, A.S.; Macedo, M.B.; Dalmolin, H.H.H.; et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA 2021, 325, 1053–1060. [Google Scholar] [CrossRef] [PubMed]
  79. Butler-Laporte, G.; Nakanishi, T.; Mooser, V.; Morrison, D.R.; Abdullah, T.; Adeleye, O.; Mamlouk, N.; Kimchi, N.; Afrasiabi, Z.; Rezk, N.; et al. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study. PLoS Med. 2021, 18, e1003605. [Google Scholar] [CrossRef] [PubMed]
  80. Sabico, S.; Enani, M.A.; Sheshah, E.; Aljohani, N.J.; Aldisi, D.A.; Alotaibi, N.H.; Alshingetti, N.; Alomar, S.Y.; Alnaami, A.M.; Amer, O.E.; et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients 2021, 13, 2170. [Google Scholar] [CrossRef] [PubMed]
  81. Oristrell, J.; Oliva, J.C.; Casado, E.; Subirana, I.; Dominguez, D.; Toloba, A.; Balado, A.; Grau, M. Vitamin D supplementation and COVID-19 risk: A population-based, cohort study. J. Endocrinol. Investig. 2021, 1–13, epub ahead of print. [Google Scholar] [CrossRef]
  82. Asif, A.; Farooq, N. Vitamin D Toxicity; StatPearls Publishing: Treasure Island, FL, USA, 2021. [Google Scholar]
  83. Caglar, A.; Tugce Caglar, H. Vitamin D intoxication due to misuse: 5-year experience. Arch. Pediatr. 2021, 28, 222–225. [Google Scholar] [CrossRef]
  84. Holick, M.F.; Chen, T.C.; Lu, Z.; Sauter, E. Vitamin D and skin physiology: A D-lightful story. J. Bone Miner. Res. 2007, 22 (Suppl. S2), V28–V33. [Google Scholar] [CrossRef]
  85. Kearns, S.M.; Ahern, K.W.; Patrie, J.T.; Horton, W.B.; Harris, T.E.; Kadl, A. Reduced adiponectin levels in patients with COVID-19 acute respiratory failure: A case-control study. Physiol. Rep. 2021, 9, e14843. [Google Scholar] [CrossRef]
  86. Yin, Y.W.; Sheng, Y.J.; Wang, M.; Ma, Y.Q.; Ding, H.M. Interaction of serum proteins with SARS-CoV-2 RBD. Nanoscale 2021, 13, 12865–12873. [Google Scholar] [CrossRef]
  87. Nakano, T.; Chen, C.L.; Goto, S. Nuclear antigens and auto/alloantibody responses: Friend or foe in transplant immunology. Clin. Dev. Immunol. 2013, 2013, 267156. [Google Scholar] [CrossRef] [Green Version]
  88. Nakano, T.; Goto, S.; Lai, C.Y.; Hsu, L.W.; Tseng, H.P.; Chen, K.D.; Chiu, K.W.; Wang, C.C.; Cheng, Y.F.; Chen, C.L. Induction of antinuclear antibodies by de novo autoimmune hepatitis regulates alloimmune responses in rat liver transplantation. Clin. Dev. Immunol. 2013, 2013, 413928. [Google Scholar] [CrossRef] [Green Version]
  89. Kim, H.N.; Joo, E.J.; Lee, C.W.; Ahn, K.S.; Kim, H.L.; Park, D.I.; Park, S.K. Reversion of Gut Microbiota during the Recovery Phase in Patients with Asymptomatic or Mild COVID-19: Longitudinal Study. Microorganisms 2021, 9, 1237. [Google Scholar] [CrossRef]
  90. Dickson, R.P.; Schultz, M.J.; van der Poll, T.; Schouten, L.R.; Falkowski, N.R.; Luth, J.E.; Sjoding, M.W.; Brown, C.A.; Chanderraj, R.; Huffnagle, G.B.; et al. Lung Microbiota Predict Clinical Outcomes in Critically Ill Patients. Am. J. Respir. Crit. Care Med. 2020, 201, 555–563. [Google Scholar] [CrossRef] [PubMed]
  91. Nejadghaderi, S.A.; Nazemalhosseini-Mojarad, E.; Asadzadeh Aghdaei, H. Fecal microbiota transplantation for COVID-19; a potential emerging treatment strategy. Med. Hypotheses 2021, 147, 110476. [Google Scholar] [CrossRef] [PubMed]
  92. Bilinski, J.; Winter, K.; Jasinski, M.; Szczes, A.; Bilinska, N.; Mullish, B.H.; Malecka-Panas, E.; Basak, G.W. Rapid resolution of COVID-19 after faecal microbiota transplantation. Gut 2021. epub ahead of print. [Google Scholar] [CrossRef]
  93. Wu, T.R.; Lin, C.S.; Chang, C.J.; Lin, T.L.; Martel, J.; Ko, Y.F.; Ojcius, D.M.; Lu, C.C.; Young, J.D.; Lai, H.C. Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti-obesity effects of polysaccharides isolated from Hirsutella sinensis. Gut 2019, 68, 248–262. [Google Scholar] [CrossRef]
  94. Huang, T.T.; Lai, H.C.; Ko, Y.F.; Ojcius, D.M.; Lan, Y.W.; Martel, J.; Young, J.D.; Chong, K.Y. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo. Sci. Rep. 2015, 5, 15282. [Google Scholar] [CrossRef] [Green Version]
  95. Lai, H.C.; Lin, T.L.; Chen, T.W.; Kuo, Y.L.; Chang, C.J.; Wu, T.R.; Shu, C.C.; Tsai, Y.H.; Swift, S.; Lu, C.C. Gut microbiota modulates COPD pathogenesis: Role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut 2021. epub ahead of print. [Google Scholar] [CrossRef]
  96. Li, M.Y.; Li, L.; Zhang, Y.; Wang, X.S. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect. Dis. Poverty 2020, 9, 45. [Google Scholar] [CrossRef]
  97. D’Amico, F.; Baumgart, D.C.; Danese, S.; Peyrin-Biroulet, L. Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2020, 18, 1663–1672. [Google Scholar] [CrossRef] [PubMed]
  98. Darling, A.; Ahmadi, K.R.; Ward, K.A.; Harvey, N.C.; Couto Alves, A.; Dunn-Walters, D.K.; Lanham-New, S.A.; Cooer, C.; Blackbourn, D.J. Vitamin D concentration, body mass index, ethnicity and SARS-CoV-2/COVID-19: Initial analysis of the first-reported UK Biobank Cohort positive cases (n 1474) compared with negative controls (n 4643). Proc. Nutr. Soc. 2021, 80, E17. [Google Scholar] [CrossRef]
  99. Sidiropoulou, P.; Docea, A.O.; Nikolaou, V.; Katsarou, M.S.; Spandidos, D.A.; Tsatsakis, A.; Calina, D.; Drakoulis, N. Unraveling the roles of vitamin D status and melanin during COVID-19 (Review). Int. J. Mol. Med. 2021, 47, 92–100. [Google Scholar] [CrossRef]
  100. DeLuccia, R.; Clegg, D.; Sukumar, D. The implications of vitamin D deficiency on COVID-19 for at-risk populations. Nutr. Rev. 2021, 79, 227–234. [Google Scholar] [CrossRef] [PubMed]
  101. Umeda-Raffa, S.; Pergolizzi, J.V., Jr.; Raffa, R.B. Bone fractures during the time of coronavirus. J. Clin. Pharm. Ther. 2021, 46, 543–546. [Google Scholar] [CrossRef] [PubMed]
  102. Zupin, L.; Gratton, R.; Fontana, F.; Clemente, L.; Pascolo, L.; Ruscio, M.; Crovella, S. Blue photobiomodulation LED therapy impacts SARS-CoV-2 by limiting its replication in Vero cells. J. Biophotonics 2021, 14, e202000496. [Google Scholar] [CrossRef]
  103. Pelletier-Aouizerate, M.; Zivic, Y. Early cases of acute infectious respiratory syndrome treated with photobiomodulation, diagnosis and intervention: Two case reports. Clin. Case Rep. 2021, 9, 2429–2437. [Google Scholar] [CrossRef]
  104. Costa, S.G.; Barioni, E.D.; Ignacio, A.; Albuquerque, J.; Camara, N.O.S.; Pavani, C.; Vitoretti, L.B.; Damazo, A.S.; Farsky, S.H.P.; Lino-Dos-Santos-Franco, A. Beneficial effects of Red Light-Emitting Diode treatment in experimental model of acute lung injury induced by sepsis. Sci. Rep. 2017, 7, 12670. [Google Scholar] [CrossRef]
  105. Moraes, M.N.; de Assis, L.V.M.; Provencio, I.; Castrucci, A.M.L. Opsins outside the eye and the skin: A more complex scenario than originally thought for a classical light sensor. Cell Tissue Res. 2021. [Google Scholar] [CrossRef]
  106. Sikka, G.; Hussmann, G.P.; Pandey, D.; Cao, S.; Hori, D.; Park, J.T.; Steppan, J.; Kim, J.H.; Barodka, V.; Myers, A.C.; et al. Melanopsin mediates light-dependent relaxation in blood vessels. Proc. Natl. Acad. Sci. USA 2014, 111, 17977–17982. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Barreto Ortiz, S.; Hori, D.; Nomura, Y.; Yun, X.; Jiang, H.; Yong, H.; Chen, J.; Paek, S.; Pandey, D.; Sikka, G.; et al. Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition. Am. J. Physiol. Lung Cell. Mol. Physiol. 2018, 314, L93–L106. [Google Scholar] [CrossRef] [PubMed]
  108. Yim, P.D.; Gallos, G.; Perez-Zoghbi, J.F.; Zhang, Y.; Xu, D.; Wu, A.; Berkowitz, D.E.; Emala, C.W. Airway smooth muscle photorelaxation via opsin receptor activation. Am. J. Physiol. Lung Cell. Mol. Physiol. 2019, 316, L82–L93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Tahkamo, L.; Partonen, T.; Pesonen, A.K. Systematic review of light exposure impact on human circadian rhythm. Chronobiol. Int. 2019, 36, 151–170. [Google Scholar] [CrossRef] [Green Version]
  110. Park, P.J.; Cho, J.Y.; Cho, E.G. Specific visible radiation facilitates lipolysis in mature 3T3-L1 adipocytes via rhodopsin-dependent beta3-adrenergic signaling. Eur. J. Cell Biol. 2017, 96, 301–311. [Google Scholar] [CrossRef]
  111. Ondrusova, K.; Fatehi, M.; Barr, A.; Czarnecka, Z.; Long, W.; Suzuki, K.; Campbell, S.; Philippaert, K.; Hubert, M.; Tredget, E.; et al. Subcutaneous white adipocytes express a light sensitive signaling pathway mediated via a melanopsin/TRPC channel axis. Sci. Rep. 2017, 7, 16332. [Google Scholar] [CrossRef] [Green Version]
  112. Sato, M.; Tsuji, T.; Yang, K.; Ren, X.; Dreyfuss, J.M.; Huang, T.L.; Wang, C.H.; Shamsi, F.; Leiria, L.O.; Lynes, M.D.; et al. Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes. PLoS Biol. 2020, 18, e3000630. [Google Scholar] [CrossRef] [Green Version]
  113. Jiao, J.; Hong, S.; Zhang, J.; Ma, L.; Sun, Y.; Zhang, D.; Shen, B.; Zhu, C. Opsin3 sensitizes hepatocellular carcinoma cells to 5-fluorouracil treatment by regulating the apoptotic pathway. Cancer Lett. 2012, 320, 96–103. [Google Scholar] [CrossRef]
  114. Yoshimoto, T.; Morine, Y.; Takasu, C.; Feng, R.; Ikemoto, T.; Yoshikawa, K.; Iwahashi, S.; Saito, Y.; Kashihara, H.; Akutagawa, M.; et al. Blue light-emitting diodes induce autophagy in colon cancer cells by Opsin 3. Ann. Gastroenterol. Surg. 2018, 2, 154–161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Xu, C.; Wang, R.; Yang, Y.; Xu, T.; Li, Y.; Xu, J.; Jiang, Z. Expression of OPN3 in lung adenocarcinoma promotes epithelial-mesenchymal transition and tumor metastasis. Thorac. Cancer 2020, 11, 286–294. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Wang, Q.; Zhang, T.; Chang, X.; Wang, K.; Lee, M.H.; Ma, W.Y.; Liu, K.; Dong, Z. Targeting Opsin4/Melanopsin with a Novel Small Molecule Suppresses PKC/RAF/MEK/ERK Signaling and Inhibits Lung Adenocarcinoma Progression. Mol. Cancer Res. MCR 2020, 18, 1028–1038. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Comparison of the spectrum data in (a) sunlight (in September, noon, through the window, exposure value 6500 l×), (b) normal light (blue, color rendition index 81, exposure value 780 l×) and (b) full-spectrum light (magenta, color rendition index 94, exposure value 750 l×). Spectral irradiance of the light spectrum was measured by an illuminance spectrophotometer (CL-500A, Konica Minolta, Inc., Tokyo, Japan).
Figure 1. Comparison of the spectrum data in (a) sunlight (in September, noon, through the window, exposure value 6500 l×), (b) normal light (blue, color rendition index 81, exposure value 780 l×) and (b) full-spectrum light (magenta, color rendition index 94, exposure value 750 l×). Spectral irradiance of the light spectrum was measured by an illuminance spectrophotometer (CL-500A, Konica Minolta, Inc., Tokyo, Japan).
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Figure 2. Impact of blue, red, or near-infrared (near-IR) light on the expression of CYP27B1. The human keratinocyte cell line HaCaT was preincubated with 7-dehydrocholesterol (7-DHC, 25 μM) for 24 h, and the cells were irradiated with blue light (470 nm, exposure value 3300 l×), red light (660 nm, exposure value 1600 l×), or near-IR light (730 nm, exposure value 74 l×) for 3 h at 37 °C in 5% CO2/95% air. Twenty-four hours after irradiation, the cells were harvested, and the expression level of CYP27B1 was evaluated by quantitative real-time PCR. Values are presented as the means ± SD of two independent experiments. *, ** p < 0.05 and 0.01 vs. control without light irradiation (n = 4), respectively (Student’s t-test).
Figure 2. Impact of blue, red, or near-infrared (near-IR) light on the expression of CYP27B1. The human keratinocyte cell line HaCaT was preincubated with 7-dehydrocholesterol (7-DHC, 25 μM) for 24 h, and the cells were irradiated with blue light (470 nm, exposure value 3300 l×), red light (660 nm, exposure value 1600 l×), or near-IR light (730 nm, exposure value 74 l×) for 3 h at 37 °C in 5% CO2/95% air. Twenty-four hours after irradiation, the cells were harvested, and the expression level of CYP27B1 was evaluated by quantitative real-time PCR. Values are presented as the means ± SD of two independent experiments. *, ** p < 0.05 and 0.01 vs. control without light irradiation (n = 4), respectively (Student’s t-test).
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Figure 3. Risk factors and current strategies for the (a) prevention and (b) treatment of COVID-19 and severe illness. ACE2: angiotensin-converting enzyme 2, ALI: acute lung injury, Ang-(1–7): angiotensin 1–7, Ang-II: angiotensin II, AT1R: angiotensin type I receptor, ARDS: acute respiratory distress syndrome, DPP4: dipeptidyl peptidase 4, FMT: fecal microbiota transplantation, MasR: Mas receptor.
Figure 3. Risk factors and current strategies for the (a) prevention and (b) treatment of COVID-19 and severe illness. ACE2: angiotensin-converting enzyme 2, ALI: acute lung injury, Ang-(1–7): angiotensin 1–7, Ang-II: angiotensin II, AT1R: angiotensin type I receptor, ARDS: acute respiratory distress syndrome, DPP4: dipeptidyl peptidase 4, FMT: fecal microbiota transplantation, MasR: Mas receptor.
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Figure 4. Elevation of circulating alarmins during inflammatory responses. BALB/c mice (n = 12) were sensitized with ovalbumin (OVA)/alum followed by intragastric ingestion of OVA for the development of a mouse model of food allergy (FA) [35]. Circulating levels of (a) histone H1 and (b) high mobility group box 1 (HMGB1) were quantified using an enzyme-linked immunosorbent assay (ELISA) as previously described [87,88]. Values are presented as the means ± SD of four to six individuals in each group. Phototherapy with full-spectrum light (n = 6) ameliorated FA-like allergic diarrhea in FA mice (n = 6), with significant suppression of circulating histone H1 and HMGB1 released from damaged cells or actively secreted from immune cells (e.g., macrophages, dendritic cells, mast cells). *, ** p < 0.05 and 0.01 vs. control (n = 4) or phototherapy group, respectively (Student’s t-test).
Figure 4. Elevation of circulating alarmins during inflammatory responses. BALB/c mice (n = 12) were sensitized with ovalbumin (OVA)/alum followed by intragastric ingestion of OVA for the development of a mouse model of food allergy (FA) [35]. Circulating levels of (a) histone H1 and (b) high mobility group box 1 (HMGB1) were quantified using an enzyme-linked immunosorbent assay (ELISA) as previously described [87,88]. Values are presented as the means ± SD of four to six individuals in each group. Phototherapy with full-spectrum light (n = 6) ameliorated FA-like allergic diarrhea in FA mice (n = 6), with significant suppression of circulating histone H1 and HMGB1 released from damaged cells or actively secreted from immune cells (e.g., macrophages, dendritic cells, mast cells). *, ** p < 0.05 and 0.01 vs. control (n = 4) or phototherapy group, respectively (Student’s t-test).
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Figure 5. Elevation of (a) angiotensin-converting enzyme 2 (ACE2) and (b) dipeptidyl peptidase 4 (DPP4) in inflamed colon tissues. Colon tissues were obtained from naïve mice (n = 4), food allergy (FA) mice (n = 4), and FA mice with phototherapy (n = 6) [35], and colonic levels of ACE2 and DPP4 were evaluated by quantitative real-time PCR. Values are presented as the means ± SD of four individuals in each group. Although there was a large variation in expression profiles due to the different intensities of inflammation in each FA mouse, we confirmed the tendency to increase colonic levels of ACE2 and DPP4, key receptors for SARS-CoV-2 entry, in FA. On the other hand, phototherapy with full-spectrum light suppressed these expression levels, suggesting the preventive potential of phototherapy in COVID-19. * p < 0.05 vs. control or phototherapy group (Student’s t-test).
Figure 5. Elevation of (a) angiotensin-converting enzyme 2 (ACE2) and (b) dipeptidyl peptidase 4 (DPP4) in inflamed colon tissues. Colon tissues were obtained from naïve mice (n = 4), food allergy (FA) mice (n = 4), and FA mice with phototherapy (n = 6) [35], and colonic levels of ACE2 and DPP4 were evaluated by quantitative real-time PCR. Values are presented as the means ± SD of four individuals in each group. Although there was a large variation in expression profiles due to the different intensities of inflammation in each FA mouse, we confirmed the tendency to increase colonic levels of ACE2 and DPP4, key receptors for SARS-CoV-2 entry, in FA. On the other hand, phototherapy with full-spectrum light suppressed these expression levels, suggesting the preventive potential of phototherapy in COVID-19. * p < 0.05 vs. control or phototherapy group (Student’s t-test).
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Figure 6. Proposed mechanisms of phototherapy with full-spectrum light for the prevention and treatment of COVID-19. Phototherapy may induce (1) vitamin D3 biogenesis and (2) adiponectin, which are associated with both prevention and treatment of COVID-19 in terms of the reduction in COVID-19 risk factors (Figure 1). (3) The elevation of circulating alarmins and oxidative stress markers during inflammatory responses may be inhibited by phototherapy, partly through the induction of Nrf2-mediated antioxidant responses. (4) Gut dysbiosis (an elevated Firmicutes/Bacteroidetes ratio) may be modulated by phototherapy and may induce the beneficial bacteria Parabacteroides goldsteinii. (5) Phototherapy may reduce ACE2 expression, resulting in a reduced risk of virus (SARS-CoV-2) infection. For treatment, vitamin D3 may induce the ACE2/Ang-(1–7)/MasR axis and inhibit Ang-II-induced alarmin elevation, oxidative stress responses, and gut dysbiosis, which are associated with poor outcomes in COVID-19. ACE2: angiotensin-converting enzyme 2, Ang-(1–7): angiotensin 1–7, Ang-II: angiotensin II, AT1R: angiotensin type I receptor, MasR: Mas receptor, Nrf2: nuclear factor-erythroid 2-related factor 2.
Figure 6. Proposed mechanisms of phototherapy with full-spectrum light for the prevention and treatment of COVID-19. Phototherapy may induce (1) vitamin D3 biogenesis and (2) adiponectin, which are associated with both prevention and treatment of COVID-19 in terms of the reduction in COVID-19 risk factors (Figure 1). (3) The elevation of circulating alarmins and oxidative stress markers during inflammatory responses may be inhibited by phototherapy, partly through the induction of Nrf2-mediated antioxidant responses. (4) Gut dysbiosis (an elevated Firmicutes/Bacteroidetes ratio) may be modulated by phototherapy and may induce the beneficial bacteria Parabacteroides goldsteinii. (5) Phototherapy may reduce ACE2 expression, resulting in a reduced risk of virus (SARS-CoV-2) infection. For treatment, vitamin D3 may induce the ACE2/Ang-(1–7)/MasR axis and inhibit Ang-II-induced alarmin elevation, oxidative stress responses, and gut dysbiosis, which are associated with poor outcomes in COVID-19. ACE2: angiotensin-converting enzyme 2, Ang-(1–7): angiotensin 1–7, Ang-II: angiotensin II, AT1R: angiotensin type I receptor, MasR: Mas receptor, Nrf2: nuclear factor-erythroid 2-related factor 2.
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Figure 7. Roadmap for active and healthy aging. (a) Sunlight exposure is fundamental for our health, including infants to elderly individuals. Vitamin D3 levels decline in the aging process as well as due to insufficient sunlight exposure and stay-at-home policies in the era of COVID-19, resulting in an increased risk of various diseases (red arrow) associated with vitamin D3 insufficiency/deficiency, elevation of circulating alarmins, and gut dysbiosis. In addition to sunlight exposure and vitamin D3 supplementation, phototherapy may maintain the vitamin D3 concentration required for biological, physiological, and immunological activities, resulting in the achievement of active and healthy aging. (b) Sunlight and phototherapy as an alternative to sunlight exposure. A ward equipped with full-spectrum light (color temperature 5500 K, color rendition index >90 Ra, Chang Gung Biotechnology, Taipei, Taiwan) was used for the clinical application of phototherapy.
Figure 7. Roadmap for active and healthy aging. (a) Sunlight exposure is fundamental for our health, including infants to elderly individuals. Vitamin D3 levels decline in the aging process as well as due to insufficient sunlight exposure and stay-at-home policies in the era of COVID-19, resulting in an increased risk of various diseases (red arrow) associated with vitamin D3 insufficiency/deficiency, elevation of circulating alarmins, and gut dysbiosis. In addition to sunlight exposure and vitamin D3 supplementation, phototherapy may maintain the vitamin D3 concentration required for biological, physiological, and immunological activities, resulting in the achievement of active and healthy aging. (b) Sunlight and phototherapy as an alternative to sunlight exposure. A ward equipped with full-spectrum light (color temperature 5500 K, color rendition index >90 Ra, Chang Gung Biotechnology, Taipei, Taiwan) was used for the clinical application of phototherapy.
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Nakano, T.; Chiang, K.-C.; Chen, C.-C.; Chen, P.-J.; Lai, C.-Y.; Hsu, L.-W.; Ohmori, N.; Goto, T.; Chen, C.-L.; Goto, S. Sunlight Exposure and Phototherapy: Perspectives for Healthy Aging in an Era of COVID-19. Int. J. Environ. Res. Public Health 2021, 18, 10950. https://doi.org/10.3390/ijerph182010950

AMA Style

Nakano T, Chiang K-C, Chen C-C, Chen P-J, Lai C-Y, Hsu L-W, Ohmori N, Goto T, Chen C-L, Goto S. Sunlight Exposure and Phototherapy: Perspectives for Healthy Aging in an Era of COVID-19. International Journal of Environmental Research and Public Health. 2021; 18(20):10950. https://doi.org/10.3390/ijerph182010950

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Nakano, Toshiaki, Kuei-Chen Chiang, Chien-Chih Chen, Po-Jung Chen, Chia-Yun Lai, Li-Wen Hsu, Naoya Ohmori, Takeshi Goto, Chao-Long Chen, and Shigeru Goto. 2021. "Sunlight Exposure and Phototherapy: Perspectives for Healthy Aging in an Era of COVID-19" International Journal of Environmental Research and Public Health 18, no. 20: 10950. https://doi.org/10.3390/ijerph182010950

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