Functional Photobiomodulation

Photobiomodulation (PBM) is a modulation of low-level laser irradiation or monochromatic light (LLL) on a biological function. ^1,2 A function can be classified into a normal function in its function-specific homeostasis (FSH), a negative-feedback response of a biosystem to maintain the function-specific conditions inside the biosystem so that the function is perfectly performed, and a dysfunctional function far from its FSH. A normal/dysfunctional FSH-specific stress disrupting the FSH is called a “successful/chronic stress”. PBM is then classified into direct PBM (dPBM), which may modulate a dysfunctional function, or a chronic stress and an indirect PBM (iPBM), which may upgrade a normal function. The recent PBM progress suggested the PBM studies should be carefully designed.

A normal function should be different from a dysfunctional one. First, a normal function resists internal/external disturbance under its threshold, but a dysfunctional function does not. Second, a normal function is better performed than all its dysfunctional counterparts, so that the Arndt–Schulz law, a nonlinear dose relationship commonly described as being U/J-shaped or inverted-U/J shaped, holds. The cellular proliferation in vitro in 10% fetal bovine serum (FBS) and 22.5 mM glucose is always normal. ² McDermott et al. found that the proliferation of SV40 transformed human corneal epithelial cells in 10% FBS and 17.5 mmol/L glucose was not different from in 38.0 mmol/L glucose, but that it was higher than in 5.0 mmol/L glucose. ³ Houreld et al. further found that the adenosine triphosphate (ATP) level and the complexes III and IV activities of human skin fibroblast (HSF) cells in 10% FBS and 17.0 mmol/L glucose were higher than those in 0 mmol/L glucose. ⁴ These results suggested that normal proliferation might resist glucose changes from 17.5 to 38.0 mmol/L, but that the proliferation in 10% FBS and 0 or 5.0 mmol/L glucose was dysfunctional. On the other hand, healthy/diabetic cells in vivo are normal/dysfunctional. Therefore, the cells in 10% FBS and 0/17.5 mmol/L glucose cannot be used as an in vitro cell model of health/diabetes. However, Houreld et al. ^4,5 and Masha et al. ⁶ used HSF cells in 10% FBS and 0/17 mmol/L glucose as a cell model of health/diabetes. Their data were not relevant for diabetes, but important for PBM. The ATP assessment ⁴ suggested that a dPBM at 5 mJ/cm² promoted the dysfunctional ATP level of HSF in 0 mmol/L glucose, but could not modulate the normal one in 17 mmol/L glucose, and an iPBM at 15 J/cm² upgraded the normal one in 17 mmol/L glucose, but could not modulate the dysfunctional one in 0 mmol/L glucose. These did not hold for the activity of complexes II and IX, ⁴ because the isolated mitochondria were not cultivated in their respective intracellular cultures.

A successful stress should be different from the corresponding chronic stress. First, a stressful stress can resist internal/external disturbance under its threshold, but a chronic stress cannot. Second, a successful stress is better performed than all its corresponding chronic stresses, so that the Arndt–Schulz Law, the Yerkes–Dodson law in psychology, or the nonlinear dose relationship, commonly described as being U/J-shaped or inverted-U/J shaped, holds. Self-limited conditions, ⁷ , antifragility, ⁸ hormesis, ⁹ and mitochondrial reactive oxygen species (mtROS) increased longevity in the nematode Caenorhabditis elegans ¹⁰ are examples of successful stress. A dPBM may modulate a chronic stress, but cannot modulate a successful stress. When adding LLL to eccentric exercises (EE) for the treatment of Achilles' tendinopathy, Stergioulas et al. ¹¹ found the LLL was effective, but Tumilty et al. ¹² did not. The EE load of Tumilty et al. ¹² was heavier than the one of Stergioulas et al. ¹¹ so that the former Achilles' tendinopathy became self-limited and could not be modulated with LLL. The gene expression assessment ⁶ suggested that genes upregulated in the electron transport chain of wounded HSF cells in 10% FBS and 17 mmol/L glucose, whose wound was self-limited, were more sparse than the ones in 0 mmol/L glucose, whose wound was a chronic stress.

Signal transduction pathways or gene expression in PBM studies should be associated with FSH. The signal transduction pathways or regulated genes maintaining a dysfunctional function are very dense, but the ones maintaining a normal function are very sparse. ^2,13 A normal function can resist the activation of other signal transduction pathways, but maintains the full activation of normal function-specific signal transduction pathways (NSPs). ² Therefore, nth-order normal function maintains synergistic activation of n NSPs. Although dPBM-induced mtROS keeps cells alive under stressful conditions ¹⁰ through cytochrome c oxidase photodynamic reaction, ¹⁴ the dPBM may promote the activation of one partially activated NSP so that it promotes the second-order functional phase transition from a dysfunctional function to its first-order normal function. ² The gene expression or pathway kinase activity assessment should be conducted only after the first-order normal function is established. However, few groups did this; therefore, their pathways were very dense. For example, the gene expression profiles of HSF cells in 5% FBS revealed that 111 genes were regulated by an LLL at 627 nm, and could be grouped into 10 functional categories among which only 7 were directly or indirectly involved in cell proliferation. ¹⁵ An iPBM may promote the full activation of m partially activated NSPs so that it promotes the first-order functional phase transition of a normal function from nth order to (n+m)th order. ² For an iPBM on the normal proliferation of NIH3T3 fibroblasts, ¹⁶ the iPBM-activated NSP is the platelet-derived growth factor (PDGF) C mediated pathway. Komine et al. ¹⁶ have studied the iPBM on messenger ribonucleic acid (mRNA) expression of PDGF-A, PDGF-B, PDGF-C, transforming growth factor-beta (TGF-β), basic fibroblast growth factor (bFGF), PDGF-α receptor, and TGF-β receptor, and found that the iPBM only increased PDGF-C mRNA expression, but could not affect the mRNA expression of other proteins.