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C.P. Sabino, et al. Journal of Photochemistry & Photobiology, B: Biology 212 (2020) 111999 overexposure can promote either flash blindness or retinal lesions. The exact mechanisms underlying the antimicrobial effects of blue light are not yet completely understood but appear to involve the for- mation of short-lived reactive oxygen species (ROS) [92]. The most widely accepted view of the process posits that the photochemical mechanisms of aBL are based on light energy excitation of endogenous microbial intracellular light receptors (chromophores), such as por- phyrins and flavins. Once excited, these receptors undergo energy transfer processes that lead to the generation of cytotoxic ROS which react with intracellular components resulting in photodamage and cell death by oxidative stress [93]. Since endogenous photoreceptors appear to be absent in viruses, the mechanisms by which aBL affects these pathogens remains unclear. However, it is currently known that: 1) the use of exogenous photosensitizers improves the efficiency of inactiva- tion by blue light, and 2) the inactivation is more pronounced when viral particles are present in body fluids, e.g., saliva, feces, and blood plasma, which contain photosensitive substances [94,95]. Accordingly, antimicrobial blue light has been explored in the treatment of infectious diseases and as a disinfection adjuvant in healthcare settings. Clinical trials have revealed the efficiency of aBL in the treatment of acne, Helicobacter pylori gastrointestinal infections, and dental infections [87,96–98]. aBL was recently shown to rescue mice from methicillin-resistant Staphylococcus aureus (MRSA) and Pseudo- monas aeruginosa wound infections [99,100]. Oral anaerobic period- ontopathogenic bacteria (Porphyromonas gingivalis, Prevotella intermedia, and P. nigrescens) were also inhibited or completely eradicated under blue light irradiation [101,102]. In a recent bioinformatics study, SARS-CoV-2 infection was reported to be dependent on porphyrin, which it captures from human he- moglobin, resulting in altered heme metabolism [103]. However, the in silico methods used to obtain such results have been questioned by a commentary publication, putting into doubt wheter SARS-CoV-2 actu- ally interacts with heme metabolism and accumulates porphyrins [103]. If this thesis is experimentally proven to be correct, aBL might be able to kill SARS-CoV-2 by photoexcitation of its acquired porphyrins. Thus, experimental studies are required to verify the potential of aBL to prevent and control COVID-19. 8. Photobiomodulation Therapy Photobiomodulation (PBM) employs low levels of red or near-in- frared (NIR) light to treat and heal wounds and injuries, reduce pain and inflammation, regenerate damaged tissue, and protect tissue at risk of dying [104]. Instead of directly targeting viruses, PBM mainly acts on the host cells, which absorb light in the red and near-infrared spectral region [104]. Literature indicates that photons are absorbed by mul- tiple cellular chromophores, including mitochondrial enzymes, to trigger the biological effects of PBM [104–106]. Cytochrome c oxidase (i.e., unit IV in the mitochondrial respiratory chain) appears to play a main role in this process [104]. Other molecular chromophores include light and heat-sensitive ion channels (transient receptor potential) that, upon light activation, lead to changes in calcium concentrations. Na- nostructured water (interfacial water) is also likely to act as a chro- mophore. Upon irradiation, the mitochondrial membrane potential is raised and oxygen consumption and ATP generation are increased. Subsequent activation of signaling pathways and transcription factors leads to fairly long-lasting effects even after relatively brief exposure of the tissue to light [107]. In the early 1900s, Finsen reported that patients exposed to red light exhibited significantly better recovery from smallpox infections than unexposed counterparts [21]. Since then, PBM has been used in the treatment of acute lung injury, pulmonary inflammation, and models of acute respiratory distress syndrome (ARDS), due to its ability to sub- stantially reduce systemic inflammation while preserving lung function. [108–110]. There are currently 90 published papers on PBM concerning “acute lung injury” [110] OR “pulmonary inflammation” [111] OR photosensitizing agents in both RNA and DNA [66]. The formation of RNA-protein crosslinks may also be an important lesion involved in virus inactivation via aPDT [67]. Enveloped viruses are more prone to aPDT neutralization than those without an envelope, due to the role of PS in damaging envelope components [68,69]. Initial studies on viral inactivation by aPDT de- monstrated the importance of the PS reaching specific reaction sites, so- called “marked targets”, for efficient viral inactivation [70]. Other re- ports have confirmed the importance of PS binding on the efficiency of virus inactivation via aPDT, and the PS membrane partition coefficients can be used as a predictor of its virus inactivation efficacy [71,72]. Transmission electron microscopy data has revealed that low PS con- centrations degrade envelope surface glycoproteins blocking virus in- ternalization, while higher PS concentrations can destroy lipid mem- branes [73]. These results can be interpreted in terms of the current mechanistic understanding of photosensitized oxidation, specifically the important role of direct-contact reactions. Irreversible membrane damage occurs with the abstraction of a hydrogen atom from an un- saturated fatty acid by direct reaction with the triplet excited state of the PS. Subsequent formation of peroxyl and alkoxyl radicals leads to the build-up of truncated lipid aldehydes, which are ultimately re- sponsible for opening membrane pores [74]. The fact that irreversible damage occurs due to contact-dependent reactions, indicates that the damage can be confined within the nanometer location site of the PS [75]. In terms of the application of aPDT to treat COVID-19 patients, it is encouraging to note that this technique is already used to treat several respiratory diseases [76]. PDT has been used for decades to treat lung cancers and its successful application in the treatment of laryngeal papillomas has also been reported [77]. Geralde et al. recently de- monstrated that acute pneumonia caused by Streptococcus pneumoniae could be treated via inhalation of indocyanine green combined with extracorporeal administration of infrared light [78]. A prophylactic approach proposed by Soares et al. showed that aPDT can also be used to eliminate bacterial biofilms frequently associated with endotracheal tubes and that can lead to more severe stages of acute respiratory syndromes [79]. More recently, Schikora and colleagues reported suc- cesfull use of aPDT to disinfect oral and nasal cavity of patients in early stages of COVID-19 infection This approach can potentially lead to a temporary and moderate reduction of disease progression but cannot be regarded as a potential therapeutic procedure since aPDT is limited to local effects and COVID-19 is a systemic disease [80]. Considering that: 1) SARS-CoV2 is an enveloped RNA virus, 2) aPDT is efficient at neutralizing such viruses, and 3) light is already used to treat lung and airway-related infections, we propose that aPDT is a good candidate for treating COVID-19 or as an adjunct to disinfect biological fluids. Alternatively, photosensitizers could also be used to decontaminate liquids and surfaces or be incorporated into polymeric matrices such as plastics, fabrics, paper, and paints to produce photo- antimicrobial materials [53,58,81]. Allotropes of carbon such as full- erenes, carbon nanotubes, and graphene can also show light-activated antimicrobial effects, including the inactivation of viruses [69,82,83]. 7. Antimicrobial Blue Light Visible blue light exhibits microbicidal effects in the wavelength range of 405–470 nm [25,84–88]. High-intensity narrow-spectrum light at 405 nm has been used for continuous decontamination of inpatient and outpatient burn units and patient-occupied intensive care isolation rooms, as well as the treatment of surgical site infections in an ortho- pedic operating room [89–91]. Compared to UV-C, in general terms antimicrobial blue light (aBL) requires a much higher radiant exposure (or longer exposure times) to reach similar levels of microbial in- activation if irradiance of the light sources is similar. Even though aBL displays decreased deleterious effects on mammalian cells, one should avoid direct eye exposure because eye lens focuses visible light and 4PDF Image | A Light-based technologies for management of COVID-19 pandemic
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