Photobiomodulation of Neurogenesis through the Enhancement of Stem Cell and Neural Progenitor Differentiation in the Central and Peripheral Nervous Systems.

Photobiomodulation (PBM) is the regulation of biological processes using light energy from sources such as lasers or light-emitting diodes. Components of the nervous system, such as the brain and peripheral nerves, are important candidate PBM targets due to the lack of therapeutic modalities for the complete cure of neurological diseases. PBM can be applied either to regenerate damaged organs or to prevent or reduce damage caused by disease. Although recent findings have suggested that neural cells can be regenerated, which contradicts our previous understanding, neural structures are still thought to have weaker regenerative capacity than other systems. Therefore, enhancing the regenerative capacity of the nervous system would aid the future development of therapeutics for neural degeneration. PBM has been shown to enhance cell differentiation from stem or progenitor cells to near-target or target cells. In this review, we have reviewed research on the effects of PBM on neurogenesis in the central nervous system (e.g., animal brains) and the peripheral nervous system (e.g., peripheral sensory neural structures) and sought its potential as a therapeutic tool for intractable neural degenerative disorders.

Screening of FDA-Approved Drugs Using a MERS-CoV Clinical Isolate from South Korea Identifies Potential Therapeutic Options for COVID-19.

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.

Enhanced mitochondrial membrane potential and ATP synthesis by photobiomodulation increases viability of the auditory cell line after gentamicin-induced intrinsic apoptosis.

Photobiomodulation (PBM) has been suggested to have a therapeutic effect on irreversible hearing loss induced by aminoglycosides, including gentamicin (GM). However, its intracellular mechanism(s) in GM-induced ototoxicity remain poorly understood. In the present study, we investigated the effect of PBM in GM-induced ototoxicity in auditory cells. We tried to characterize the downstream process by PBM, and the process that triggered the increased cell viability of auditory cells. As a result, the effects of PBM against GM-induced ototoxicity by increasing ATP levels and mitochondrial membrane potential was confirmed. These results suggest a theory to explain the therapeutic effects and support the use of PBM for aminoglycoside-induced hearing loss.

Light-emitting diode irradiation using 660 nm promotes human fibroblast HSP90 expression and changes cellular activity and morphology.

We evaluated changes in cell viability and morphology in response to low-level light irradiation and underlying variations in the levels of heat shock proteins (HSPs). Human fibroblasts were irradiated with a light-emitting diode (LED) array at 660 nm (50 mW for 15, 30, and 60 minutes). Cell viability and morphological changes were evaluated via epifluorescence analysis; we also assessed cell viability and length changes. The expression levels of adenosine triphosphate (ATP) and various HSPs (HSP27, 60, 70, and 90) were analyzed by immunohistochemical staining, Western blotting and microarray analysis. After LED irradiation, cellular viability and morphology changed. Of the several HSPs analyzed, the HSP90 level increased significantly, suggesting that this protein played roles in the morphological and cellular changes. Thus, low-level irradiation triggered cellular changes mediated by increased HSP90 expression; this may explain why skin irradiation enhances wound-healing.

Photobiomodulation promotes adenoviral gene transduction in auditory cells.

Gene therapy is the delivery of a therapeutic gene into target cells to treat disorders by replacing disease-causing mutated genes with healthy ones. Gene therapy of the inner ear has been recently described, with applications for sensorineural hearing loss. However, gene delivery to the location of the inner ear, and thus efficacy of therapy, is challenging. Photobiomodulation (PBM) with a low-level laser has been suggested to have a therapeutic effect and has the potential to augment gene therapy. To investigate whether PBM improves the rate of adenovirus (Ad)-mediated viral delivery, we compared low-level laser therapy (LLLT) and non-LLLT HEI-OC1 cells treated with an Ad viral vector carrying green fluorescent protein (GFP). Cultured HEI-OC1 cells were divided into six groups: no treatment control, LLLT only, 1 µL Ad-GFP, 3 µL Ad-GFP, 1 µL Ad-GFP + LLLT, and 3 µL Ad-GFP + LLLT (LLLT: 808 nm at 15 mW for 15 min). Cells were irradiated twice: at 2 h and again at 24 h. A nonparametric Mann-Whitney U test was used to statistically analyze differences between the control and treatment groups. The viral inoculations used in this study did not change the amount of viable HEI-OC1 cells (N = 4-8). The 1 µL Ad-GFP + LLLT and 3 µL Ad-GFP + LLLT groups showed an increased density of GFP-positive cells compared to 1 µL and 3 µL Ad-GFP cells (N = 5-8, 1 µL: p = 0.0159; 3 µL: p = 0.0168,). The quantitative analysis of the epifluorescence of the 1 µL Ad-GFP + LLLT, and 3 µL Ad-GFP + LLLT groups revealed increased GFP expression/cell compared to 1 µL and 3 µL Ad-GFP cells (N = 6-15, 1 µL: p = 0.0082; 3 µL: p = 0.0012). The RT-qPCR results were consistent (N = 4-5, p = 0.0159). These findings suggest that PBM may enhance the gene delivery of Ad-mediated viral transduction, and the combination of the two may be a promising tool for gene therapy for sensorineural hearing loss.

Photobiomodulation by laser therapy rescued auditory neuropathy induced by ouabain.

Auditory neuropathy is a hearing disorder caused by impaired auditory nerve function. The lack of information about the pathophysiology of this disease limits early diagnosis and further treatment. Laser therapy is a novel approach to enhance nerve growth or induce axonal regeneration. We induced auditory neural degeneration sparing the sensory epithelium with local ouabain application in an animal model and observed the rescue effect of photobiomodulation (PBM), showing recovered auditory function and favorable histologic outcome. Hearing was evaluated using the auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). Seven days after ouabain application, the animals were sacrificed to evaluate the morphological changes. DPOAE change was not observed in all groups after ouabain application indicating no changes of outer hair cell function. Ouabain application increased the ABR thresholds increase, while the use of ouabain plus laser produced lower threshold compared to the ouabain group. Hematoxylin and Eosin staining of cochlea mid-modiolar sections in animals treated with ouabain showed damaged spiral ganglion cells, neurofilaments, and post synaptic puncta. Ouabain plus laser group showed higher number of spiral ganglion cells, higher density of neurofilaments, and higher number post synaptic puncta counts compared with ouabain application group. Short-term application of ouabain caused spiral ganglion cell damage while sparing the inner and outer hair cells in gerbils. Photobiomodulation alleviated the hearing loss caused by ouabain induced auditory neuropathy. The results indicate the possible role of photobiomodulation therapy for inner ear diseases accompanied by spiral ganglion degeneration.

A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein.

The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-ß-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action.

Safety assessment of trans-tympanic photobiomodulation.

We evaluated functional and morphological changes after trans-tympanic laser application using several different powers of photobiomodulation (PBM). The left (L) ears of 17 rats were irradiated for 30 min daily over 14 days using a power density of 909.1 (group A, 5040 J), 1136.4 (group B, 6300 J), and 1363.6 (group C, 7560 J) mW/cm(2). The right (N) ears served as controls. The safety of PBM was determined by endoscopic findings, auditory brainstem response (ABR) thresholds, and histological images of hair cells using confocal microscopy, and light microscopic images of the external auditory canal (EAC) and tympanic membrane (TM). Endoscopic findings revealed severe inflammation in the TM of C group; no other group showed damage in the TM. No significant difference in ABR threshold was found in the PBM-treated groups (excluding the group with TM damage). Confocal microscopy showed no histological difference between the AL and AN, or BL and BN groups. However, light microscopy showed more prominent edema, inflammation, and vascular congestion in the TM of BL ears. This study found a dose-response relationship between laser power parameters and TM changes. These results will be useful for defining future allowance criteria for trans-tympanic laser therapies.

[Effects of aroma hand massage on pain, state anxiety and depression in hospice patients with terminal cancer].

PURPOSE: The purpose of this study was to examine the effects of aroma hand massage on pain, state anxiety and depression in hospice patients with terminal cancer. METHODS: This study was a nonequivalent control group pretest-posttest design. The subjects were 58 hospice patients with terminal cancer who were hospitalized. Twenty eight hospice patients with terminal cancer were assigned to the experimental group (aroma hand massage), and 30 hospice patients with terminal cancer were assigned to the control group (general oil hand massage). As for the experimental treatment, the experimental group went through aroma hand massage on each hand for 5 min for 7 days with blended oil-a mixture of Bergamot, Lavender, and Frankincense in the ratio of 1:1:1, which was diluted 1.5% with sweet almond carrier oil 50 ml. The control group went through general oil hand massage by only sweet almond carrier oil-on each hand for 5 min for 7 days. RESULTS: The aroma hand massage experimental group showed more significant differences in the changes of pain score (t=-3.52, p=.001) and depression (t=-8.99, p=.000) than the control group. CONCLUSION: Aroma hand massage had a positive effect on pain and depression in hospice patients with terminal cancer.