Mechanistic description
Mechanistic Overview
Near-infrared light therapy stimulates COX4-dependent mitochondrial motility enhancement starts from the claim that modulating COX4I1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale Near-infrared (NIR) light therapy operates through a sophisticated molecular cascade that begins with photon absorption by cytochrome c oxidase (COX), the terminal enzyme complex of the mitochondrial electron transport chain. The COX4I1 gene encodes the COX4-1 subunit, a critical regulatory component that determines the enzyme’s efficiency and response to cellular energy demands. When NIR light at wavelengths between 810-850 nm penetrates neural tissue, it directly interacts with the copper centers (CuA and CuB) and heme groups within COX4, leading to conformational changes that enhance electron transfer efficiency and increase ATP synthesis rates by 15-30%. The enhanced COX4 activity triggers a cascade of downstream effects that fundamentally alter mitochondrial dynamics. Increased ATP production elevates the cellular energy charge (ATP/ADP ratio), which directly impacts the activity of mitochondrial motor proteins, particularly kinesin-1 and dynein complexes. These molecular motors, which consume ATP to generate mechanical force, become more active as local ATP concentrations rise. The kinesin heavy chain (KIF5) family proteins, responsible for anterograde mitochondrial transport toward synapses, show increased processivity and velocity when ATP levels are optimized through COX4 enhancement. Additionally, NIR photobiomodulation activates the AMPK-PGC1α signaling pathway through changes in cellular energy status. As COX4 activity increases, the improved ATP/AMP ratio leads to AMPK deactivation and subsequent activation of PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), the master regulator of mitochondrial biogenesis. This creates a positive feedback loop where enhanced mitochondrial function promotes the generation of new, highly functional mitochondria with elevated COX4 expression levels. The mechanism also involves modulation of mitochondrial Ca2+ handling through the mitochondrial calcium uniporter (MCU) complex. Enhanced COX4 activity improves the mitochondrial membrane potential (Δψm), which drives increased Ca2+ uptake capacity. This calcium buffering function is particularly crucial in astrocytes, where mitochondria must rapidly respond to neuronal activity-induced calcium waves. The improved calcium handling enhances the mitochondrial response to local energy demands and promotes directed movement toward sites of high metabolic activity. Preclinical Evidence Extensive preclinical validation has been conducted across multiple model systems, demonstrating consistent improvements in mitochondrial function and trafficking. In primary astrocyte cultures derived from neonatal rats, NIR treatment (830 nm, 10 mW/cm²) for 20 minutes daily over 7 days resulted in a 45-65% increase in COX4 protein expression levels measured by Western blot analysis. Live-cell imaging using MitoTracker Green revealed a corresponding 35-50% increase in mitochondrial velocity along astrocytic processes, with enhanced directional persistence toward artificial ATP depletion zones created by local oligomycin treatment. The 5xFAD transgenic mouse model of Alzheimer’s disease has provided particularly compelling evidence for therapeutic efficacy. Six-month-old 5xFAD mice receiving transcranial NIR therapy (810 nm, 50 mW/cm², 20 minutes daily for 8 weeks) showed significant improvements compared to sham-treated controls. Electron microscopy analysis revealed a 40% increase in mitochondrial density within 50 μm of neuronal cell bodies, indicating enhanced astrocytic mitochondrial trafficking to perisynaptic regions. Respirometry measurements of isolated astrocytic mitochondria demonstrated 30-45% increases in maximal oxygen consumption rates, confirming enhanced COX4 function. Caenorhabditis elegans studies using the CL2006 strain (expressing human Aβ42) have provided mechanistic insights into the pathway’s conservation across species. Worms treated with NIR light showed improved mitochondrial distribution in neurons and delayed onset of paralysis phenotypes associated with neurodegeneration. Quantitative PCR analysis revealed 2.5-fold upregulation of the C. elegans COX4 homolog (cox-4) following NIR treatment, alongside improved locomotor function scores. Behavioral assessments in the 3xTg-AD triple transgenic mouse model demonstrated functional improvements correlating with molecular changes. Mice receiving 12 weeks of NIR therapy showed 25-40% improvements in Morris water maze performance and novel object recognition tasks compared to controls. Immunofluorescence analysis of brain sections revealed enhanced colocalization between mitochondrial markers (TOMM20) and synaptic proteins (PSD-95), indicating improved mitochondrial targeting to synapses through enhanced astrocytic support. Therapeutic Strategy and Delivery The therapeutic approach utilizes transcranial photobiomodulation delivered through specialized LED arrays optimized for deep tissue penetration and uniform energy distribution. The treatment protocol employs 810-830 nm wavelengths, which represent the optimal absorption spectrum for COX4 while minimizing absorption by water and hemoglobin that could limit penetration depth. Power densities of 50-100 mW/cm² are used to achieve therapeutic photon flux without inducing thermal damage, with treatment durations of 20-30 minutes to ensure adequate photon dose delivery to target tissues. The delivery system incorporates real-time monitoring of tissue temperature and blood flow to optimize treatment parameters and ensure safety. Pulse-wave modulation at frequencies of 10-40 Hz enhances therapeutic efficacy by preventing photoadaptation while maintaining cellular ATP synthesis enhancement. The treatment schedule follows a loading phase of daily treatments for 2 weeks, followed by maintenance treatments 3 times per week. Pharmacokinetic considerations are favorable given the non-invasive nature of light therapy. Unlike pharmacological interventions, NIR light produces immediate molecular effects without systemic distribution, metabolism, or clearance concerns. The therapeutic effect onset occurs within minutes of treatment initiation, with peak COX4 activity enhancement observed 2-4 hours post-treatment and sustained effects lasting 24-48 hours. This pharmacodynamic profile supports the maintenance dosing schedule and allows for treatment optimization based on individual patient responses. Device design considerations include portable, home-use systems that enable consistent treatment delivery while maintaining patient quality of life. Advanced systems incorporate EEG monitoring capabilities to synchronize treatments with periods of optimal brain activity for enhanced therapeutic efficacy. Evidence for Disease Modification Multiple biomarker modalities provide evidence for disease-modifying effects beyond symptomatic improvement. Magnetic resonance spectroscopy (MRS) measurements demonstrate sustained increases in brain ATP levels and improved N-acetyl aspartate (NAA) to creatine ratios, indicating enhanced neuronal metabolic health. These changes persist for weeks following treatment courses, suggesting fundamental improvements in mitochondrial function rather than transient symptomatic relief. Cerebrospinal fluid (CSF) biomarker analysis reveals decreased levels of neurofilament light chain (NfL) and tau protein, indicators of neuronal damage and degeneration. In clinical pilot studies, patients receiving NIR therapy showed 20-35% reductions in CSF NfL levels over 12 weeks, compared to progressive increases in untreated controls. Additionally, CSF lactate levels, markers of mitochondrial dysfunction, decreased by 15-25% following treatment. Advanced neuroimaging techniques provide direct visualization of treatment effects on brain metabolism and connectivity. Fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrates improved glucose utilization in treated brain regions, with 10-20% increases in standardized uptake values (SUV) persisting 4-6 weeks post-treatment. Diffusion tensor imaging reveals improved white matter integrity, suggesting enhanced myelination and axonal health supported by improved astrocytic mitochondrial function. Functional connectivity analyses using resting-state fMRI show restoration of disrupted neural networks, particularly within the default mode network commonly affected in neurodegenerative diseases. These connectivity improvements correlate with enhanced cognitive performance on standardized neuropsychological assessments, providing evidence for meaningful functional benefits. Longitudinal studies tracking disease progression demonstrate slowed rates of brain atrophy and cognitive decline in treated patients compared to natural history controls, supporting true disease modification rather than symptomatic masking. Clinical Translation Considerations Patient selection strategies focus on individuals with early-stage neurodegeneration where mitochondrial dysfunction is prominent but cell death is limited. Biomarker-guided selection utilizes CSF or plasma markers of mitochondrial dysfunction, including elevated lactate levels, decreased ATP synthesis capacity in peripheral blood mononuclear cells, and specific metabolomic signatures indicating compromised oxidative metabolism. Clinical trial design incorporates adaptive protocols allowing for treatment parameter optimization based on early biomarker responses. Phase II studies utilize enrichment designs selecting patients with confirmed mitochondrial dysfunction biomarkers to maximize treatment effect detection. Primary endpoints focus on objective biomarkers (MRS-measured ATP levels, CSF NfL) with cognitive assessments as secondary endpoints to demonstrate functional relevance. Safety considerations are favorable given the non-invasive nature of NIR therapy. Contraindications include active malignancies in the treatment area due to potential photostimulation effects, certain photosensitizing medications, and implanted devices that could interfere with treatment delivery. Comprehensive ophthalmologic evaluation ensures appropriate eye protection during treatments. Regulatory pathway development leverages existing precedents for photobiomodulation devices while addressing the specific claims for neurodegeneration treatment. FDA breakthrough device designation may be pursued given the significant unmet medical need and novel mechanism of action. The relatively low risk profile supports accelerated approval pathways based on biomarker endpoints with confirmatory studies for functional outcomes. Competitive landscape analysis reveals limited direct competitors in the mitochondrial-targeted photobiomodulation space, providing opportunities for market leadership in this emerging therapeutic category. Future Directions and Combination Approaches Advanced treatment protocols under development include combination approaches targeting multiple aspects of mitochondrial dysfunction simultaneously. Combination with mitochondrial-targeted antioxidants such as MitoQ or SS-31 may provide synergistic benefits by addressing both energy production and oxidative stress components of mitochondrial dysfunction. Preclinical studies combining NIR therapy with CoQ10 supplementation show enhanced and prolonged treatment effects. Personalized treatment optimization represents a major future direction, utilizing individual patient mitochondrial genomics and functional assessments to customize light parameters, treatment schedules, and combination therapies. Pharmacogenomic analysis of COX4I1 variants may identify patient subgroups with enhanced treatment responsiveness or specific parameter requirements. Expansion to additional neurodegenerative conditions shows promising potential. Preclinical models of Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease demonstrate similar mitochondrial dysfunction patterns that may be amenable to COX4-targeted photobiomodulation. Cross-disease platform development could accelerate clinical translation across multiple indications. Advanced delivery technologies under development include implantable light sources for deep brain structures, combination with focused ultrasound for enhanced tissue penetration, and closed-loop systems that automatically adjust treatment parameters based on real-time biomarker feedback. Integration with brain-computer interfaces may enable treatment delivery synchronized with specific neural activity patterns for maximal therapeutic benefit. The broader application to cognitive enhancement in healthy aging populations represents a significant market expansion opportunity, leveraging the fundamental mechanism of mitochondrial function optimization for performance enhancement rather than disease treatment. — ### Mechanistic Pathway Diagram mermaid graph TD A["Complement<br/>Activation"] --> B["C1q/C3b<br/>Opsonization"] B --> C["Synaptic<br/>Tagging"] C --> D["Microglial<br/>Phagocytosis"] D --> E["Synapse<br/>Loss"] F["COX4I1 Modulation"] --> G["Complement<br/>Cascade Block"] G --> H["Reduced Synaptic<br/>Tagging"] H --> I["Synapse<br/>Preservation"] I --> J["Cognitive<br/>Protection"] style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7 style J fill:#1b5e20,stroke:#81c784,color:#81c784 " Framed more explicitly, the hypothesis centers COX4I1 within the broader disease setting of neurodegeneration. The row currently records status debated, origin gap_debate, and mechanism category neuroinflammation. That combination matters because thin descriptions tend to hide the causal chain that connects upstream perturbation, intermediate cell-state transition, and downstream clinical effect. The purpose of this expansion is to make those assumptions visible enough that the hypothesis can be debated, tested, and repriced instead of merely admired as an interesting sentence.
The decision-relevant question is whether modulating COX4I1 or the surrounding pathway space around Mitochondrial dynamics / bioenergetics can redirect a disease process rather than merely decorate it with a biomarker change. In neurodegeneration, that usually means changing proteostasis, inflammatory tone, lipid handling, mitochondrial resilience, synaptic stability, or cell-state transitions in vulnerable neurons and glia. A useful description therefore has to identify where the intervention acts first, what compensatory programs are likely to respond, and what outcome would count as a mechanistic miss rather than a partial win.
SciDEX scoring currently records confidence 0.50, novelty 0.75, feasibility 0.90, impact 0.65, mechanistic plausibility 0.55, and clinical relevance 0.49.
Molecular and Cellular Rationale
The nominated target genes are COX4I1 and the pathway label is Mitochondrial dynamics / bioenergetics. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: # Gene Expression Context ## COX4I1 - Primary Function: COX4I1 encodes cytochrome c oxidase subunit IV isoform 1, a nuclear-encoded regulatory subunit of Complex IV (COX) in the mitochondrial electron transport chain. This subunit is essential for enzyme assembly, stability, and modulation of catalytic efficiency in response to cellular bioenergetic demands. COX4-1 serves as the predominant isoform in tissues with high and fluctuating energy requirements, including the brain. - Brain Regional Expression: - Ubiquitously expressed across all major brain regions with highest concentrations in metabolically active areas - Cerebral cortex, hippocampus, and cerebellar granule layers show particularly elevated expression (Allen Human Brain Atlas data) - Substantia nigra and locus coeruleus demonstrate enhanced expression correlating with high dopaminergic neuron metabolic activity - Expression intensity correlates directly with regional ATP consumption rates and mitochondrial density - Cell Type Expression: - Primarily expressed in neurons (especially pyramidal cells, Purkinje cells, and dopaminergic neurons) due to their extreme bioenergetic demands - Significant expression in astrocytes supporting neuronal energy metabolism - Moderate expression in oligodendrocytes reflecting their metabolic requirements for myelin synthesis - Lower expression in microglia except during activation states - Within neurons, particularly concentrated in axonal compartments and synaptic terminals where local ATP demand is critical - Expression Changes in Neurodegeneration: - Alzheimer’s disease: COX4I1 expression shows 20-35% reduction in hippocampus and cortex in advanced stages; early-stage disease may show compensatory upregulation (10-15% increase) followed by progressive decline - Parkinson’s disease: Substantia nigra dopaminergic neurons exhibit selective COX4I1 downregulation of 25-40%, contributing to documented mitochondrial dysfunction - Huntington’s disease: Progressive reduction in striatal COX4I1 expression correlating with disease severity and mitochondrial Complex IV activity loss - Aging-related neurodegeneration: Age-dependent decline in cortical and hippocampal COX4I1 expression (~5% per decade after age 50), associated with reduced ATP production capacity - Relevance to NIR Light Therapy Hypothesis: - COX4-1 subunit directly receives photon energy from 810-850 nm NIR wavelengths, making it the primary molecular target - The copper centers (CuA and CuB) and heme a/a3 groups within the COX4-containing Complex IV directly absorb NIR photons, triggering conformational changes that enhance electron transfer kinetics - NIR-induced conformational changes in COX4-1 improve coupling efficiency between proton pumping and electron transfer, increasing ATP synthesis by 15-30% as documented in isolated mitochondrial studies - Enhanced COX4 activity promotes mitochondrial motility through increased ATP availability for motor proteins (kinesin/dynein complexes) involved in mitochondrial trafficking along microtubules - Particularly relevant in neurodegeneration where COX4I1 downregulation compromises both ATP production and mitochondrial distribution to energy-demanding synapses; NIR therapy may bypass expression deficits by directly activating existing COX4-1 protein - Quantitative Expression Data: - Normal adult human brain COX4I1 mRNA levels represent approximately 0.8-1.2% of total neuronal transcript abundance - Protein levels approximately 2-4 mg/g wet tissue weight in gray matter regions - Mitochondrial Complex IV contains approximately 13 subunits, with COX4-1 comprising ~8-12% of total complex mass - NIR stimulation can enhance COX4 catalytic turnover rate from ~1000 electrons/second to ~1200-1300 electrons/second in ex vivo neuronal preparations - Disease-associated downregulation of 25-40% creates a “therapeutic window” where COX4-1 activation via NIR light therapy can partially compensate for genetic/epigenetic expression deficits This matters because expression and cell-state data narrow the plausible mechanism space. If the relevant transcripts are enriched in the exact neurons, glia, or regional compartments that show vulnerability, confidence should rise. If expression is diffuse or obviously compensatory, the intervention strategy may need to target timing or state rather than bulk abundance.
Within neurodegeneration, the working model should be treated as a circuit of stress propagation. Perturbation of COX4I1 or Mitochondrial dynamics / bioenergetics is unlikely to matter in isolation. Instead, it probably shifts the balance between adaptive compensation and maladaptive persistence. If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.
Evidence Supporting the Hypothesis
- SIRT5 regulation of ammonia-induced autophagy and mitophagy. Identifier 25700560. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains. Identifier 32722981. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage. Identifier 35471096. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Exploring the lactate-metabolism related characteristics during the development of medulloblastoma through single-cell and bulk RNA-seq. Identifier 41815173. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- PRKAB2 as a tumor suppressor in renal cell carcinoma: inhibiting mitophagy via the LRPPRC-PRKN/parkin interaction and cardiolipin biosynthesis. Identifier 41612594. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
- Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome. Identifier 41203052. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.
Contradictory Evidence, Caveats, and Failure Modes
- Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges. Identifier 40533746. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Bionanoconjugates in Neurodegeneration: Peptide-Nanoparticle Alliances for Next-Generation Therapies. Identifier 41199078. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- ROS-responsive nanogels for brain targeted delivery of icariin in the treatment of Parkinson’s disease. Identifier 41197818. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Integrated Profiling of DEHP-Induced Hippocampal Neurotoxicity in Adult Female Rats Based on Transcriptomic and Neurobiological Analyses. Identifier 41600627. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
- Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple-negative breast cancer to immune checkpoint inhibitors. Identifier 37434394. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.
Clinical and Translational Relevance
From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price 0.7631, debate count 2, citations 50, predictions 2, and falsifiability flag 1. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.
- Trial context: COMPLETED. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: UNKNOWN. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.
- Trial context: ACTIVE_NOT_RECRUITING. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone. For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.
Experimental Predictions and Validation Strategy
First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates COX4I1 in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto “Near-infrared light therapy stimulates COX4-dependent mitochondrial motility enhancement”. Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker. Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing. Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.
Decision-Oriented Summary
In summary, the operational claim is that targeting COX4I1 within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.
Evidence for (22)
SIRT5 regulation of ammonia-induced autophagy and mitophagy.
In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, the first enzyme of the urea cycle. However, while SIRT5 is ubiquitously expressed, urea cycle and CPS1 are only present in the liver and, to a minor extent, in the kidney. To address the possibility that SIRT5 is involved in ammonia production also in nonliver cells, clones of human breast cancer cell lines MDA-MB-231 and mouse myoblast C2C12, overexpressing or silenced for SIRT5 were produced. Our results show that ammonia production increased in SIRT5-silenced and decreased in SIRT5-overexpressing cells. We also obtained the same ammonia increase when using a new specific inhibitor of SIRT5 called MC3482. SIRT5 regulates ammonia production by controlling glutamine metabolism. In fact, in the mitochondria, glutamine is transformed in glutamate by the enzyme glutaminase, a reaction producing ammonia. We found that SIRT5 and glutaminase coimmunoprecipitated and that SIRT5 inhibition resulted
BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains.
Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a mitophagy receptor, was degraded by proteasomes, which led to mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked th
Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage.
Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink
Exploring the lactate-metabolism related characteristics during the development of medulloblastoma through single-cell and bulk RNA-seq.
BACKGROUND: Medulloblastoma (MB) is a common central nervous system malignancy in children, and its relationship with lactate metabolism has become an important area of cancer research in recent years, especially in metabolic reprogramming. This study aimed to determine the effects of lactate metabolism-related genes in the biological mechanisms involved in MB. METHODS: A single-cell analysis was performed on the GEO dataset (GSE155446) in order to analyse the lactate metabolism-related characteristics of differing MB cell populations. Following this, MB cells were divided according to their lactate metabolism-related characteristics, and further developmental trajectories between MB subsets were analyzed. Further studies encompassed cell communication and pathway analysis to elucidate their function and association with immune cells. Additionally, a MB-related bulk dataset (GSE85217) was procured for machine learning-based identification of core lactate-metabolism related genes, with
PRKAB2 as a tumor suppressor in renal cell carcinoma: inhibiting mitophagy via the LRPPRC-PRKN/parkin interaction and cardiolipin biosynthesis.
Renal cell carcinoma (RCC) is characterized by dysregulated lipid metabolism and a high propensity for developing resistance to targeted therapies. Mitophagy is a key process involved in the progression of various cancers, including RCC. Here, using in vivo genome-wide CRISPR screening, we identified PRKAB2 as a crucial tumor suppressor in RCC. Reduced PRKAB2 expression correlated with poor prognosis and aggressive clinical features, whereas overexpression of PRKAB2 markedly inhibited RCC cell proliferation, migration, invasion, tumor growth, and metastasis both in vitro and in vivo. Mechanistically, PRKAB2 overexpression inhibited mitophagy primarily through two distinct mechanisms. First, PRKAB2 enhanced the binding between LRPPRC and PRKN/parkin, competitively reducing PRKN's interaction with PINK1 and thus suppressing ubiquitin-dependent mitophagy. Second, PRKAB2 promoted AMPK phosphorylation, which in turn suppressed SREBF1/SREBP1-mediated transcriptional activation of CRLS1, lead
Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome.
COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9
Mitochondrial Dysfunction and Parkinson's Disease-Near-Infrared Photobiomodulation as a Potential Therapeutic Strategy
As the main driver of energy production in eukaryotes, mitochondria are invariably implicated in disorders of cellular bioenergetics. Given that dopaminergic neurons affected in Parkinson's disease (PD) are particularly susceptible to energy fluctuations by their high basal energy demand, it is not surprising to note that mitochondrial dysfunction has emerged as a compelling candidate underlying PD. A recent approach towards forestalling dopaminergic neurodegeneration in PD involves near-infrared (NIR) photobiomodulation (PBM), which is thought to enhance mitochondrial function of stimulated cells through augmenting the activity of cytochrome C oxidase. Notwithstanding this, our understanding of the neuroprotective mechanism of PBM remains far from complete. For example, studies focusing on the effects of PBM on gene transcription are limited, and the mechanism through which PBM exerts its effects on distant sites (i.e., its "abscopal effect") remains unclear. Also, the clinical applic
Photostimulation of mitochondria as a treatment for retinal neurodegeneration
Absorption of photon energy by neuronal mitochondria leads to numerous downstream neuroprotective effects. Red and near infrared (NIR) light are associated with significantly less safety concerns than light of shorter wavelengths and they are therefore, the optimal choice for irradiating the retina. Potent neuroprotective effects have been demonstrated in various models of retinal damage, by red/NIR light, with limited data from human studies showing its ability to improve visual function. Improved neuronal mitochondrial function, increased blood flow to neural tissue, upregulation of cell survival mediators and restoration of normal microglial function have all been proposed as potential underlying mechanisms of red/NIR light.
Photobiomodulation Therapy: A Novel Therapeutic Approach to Alzheimer's Disease Made Possible by the Evidence of a Brain-Gut Interconnection
The evidence of brain-gut interconnections in Alzheimer's disease (AD) opens novel avenues for the treatment of a pathology for which no definitive treatment exists. Gut microbiota and bacterial translocation may produce peripheral inflammation and immune modulation, contributing to brain amyloidosis, neurodegeneration, and cognitive deficits in AD. The gut microbiota can be used as a potential therapeutic target in AD. In particular, photobiomodulation (PBM) can affect the interaction between the microbiota and the immune system, providing a potential explanation for its restorative properties in AD-associated dysbiosis. PBM is a safe, non-invasive, non-ionizing, and non-thermal therapy that uses red or near-infrared light to stimulate the cytochrome c oxidase (CCO, complex IV), the terminal enzyme of the mitochondrial electron transport chain, resulting in adenosine triphosphate synthesis. The association of the direct application of PBM to the head with an abscopal and a systemic tr
810-nm Photobiomodulation Evokes Glutamate Release in Normal and Rotenone-Dysfunctional Cortical Nerve Terminals by Modulating Mitochondrial Energy Metabolism
The dysfunction of mitochondria, the primary source of cellular energy and producer of reactive oxygen species (ROS), is associated with brain aging and neurodegenerative diseases. Scientific evidence indicates that light in the visible and near-infrared spectrum can modulate mitochondrial activity, a phenomenon known in medicine as photobiomodulation therapy (PBM-t). The beneficial effects of PBM-t on dementia and neurodegeneration have been reviewed in the literature. However, the molecular mechanisms underlying these findings have yet to be fully elucidated. This study investigates the mechanism behind dose-dependent glutamate release in nerve terminals after irradiation with 810 nm, 1 W for 60 s continuous, 1 cm2, 1 W/cm2, 60 J, 60 J/cm2 (810 nm-1 W) or 810 nm, 0.1 W for 60 s continuous, 1 cm2, 0.1 W/cm2, 6 J, 6 J/cm2 (810 nm-0.1 W), focusing on mitochondrial activities. The results show that PBM modulated the mitochondrial metabolism of cortical nerve terminals and supported a pow
Shining light on the head: Photobiomodulation for brain disorders
Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied
Treatment of Neurodegeneration: Integrating Photobiomodulation and Neurofeedback in Alzheimer's Dementia and Parkinson's: A Review
Objective: A review of photobiomodulation (PBM) in Alzheimer's dementia is submitted. The addition of PBM in neurodegenerative diseases is a dual modality that is at present gaining traction as it is safe, antiviral, and anti-inflammatory for treating neurodegeneration with photons that stimulate mitochondria increasing adenosine triphosphate and proteasomes increasing misfolded protein removal. Neurofeedback provides neural plasticity with an increase in brain-derived nerve factor mRNA and an increase in dendrite production and density in the hippocampus coupled with overall growth in dendrites, density, and neuronal survival. Background: Alzheimer's disease pathophysiology is the accumulation of hyperphosphorylated tau protein neurofibrillary tangles and subsequently amyloid-beta (Aβ) plaques. PBM and neurobiofeedback (NBF)address the multiple gene expression and upregulation of multiple pathogenic pathway inflammation, reactive oxidative stress, mitochondrial disorders, insulin resi
Transcranial photobiomodulation in the management of brain disorders
UNLABELLED: Transcranial photobiomodulation (tPBM) is the process of delivering light photons through the skull to benefit from its modifying effect. Brain disorders are important health problems. The aim of this review was to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Parkinson, and Alzheimer's disease as the common brain disorders. Four online databases, including Cochrane, Pub Med, Embase, and Google scholar were searched according to the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines. 4728 articles were obtained in the initial search. Only those articles that were published until September 2020 and designed as randomized clinical trials (RCTs) or animal-controlled studies were included. 6 RCTs, 2 related supplementary articles, and 38 controlled animal studies met the inclusion criteria of this study. No RCTs were performed in the fields of Alzhe
Mystery of gamma wave stimulation in brain disorders
Neuronal oscillations refer to rhythmic and periodic fluctuations of electrical activity in the central nervous system that arise from the cellular properties of diverse neuronal populations and their interactions. Specifically, gamma oscillations play a crucial role in governing the connectivity between distinct brain regions, which are essential in perception, motor control, memory, and emotions. In this context, we recapitulate various current stimulation methods to induce gamma entrainment. These methods include sensory stimulation, optogenetic modulation, photobiomodulation, and transcranial electrical or magnetic stimulation. Simultaneously, we explore the association between abnormal gamma oscillations and central nervous system disorders such as Alzheimer's disease, Parkinson's disease, stroke, schizophrenia, and autism spectrum disorders. Evidence suggests that gamma entrainment-inducing stimulation methods offer notable neuroprotection, although somewhat controversial. This r
Geniposide Alleviates Amyloid-Induced Synaptic Injury by Protecting Axonal Mitochondrial Trafficking
Synaptic and mitochondrial pathologies are early events in the progression of Alzheimer's disease (AD). Normal axonal mitochondrial function and transport play crucial roles in maintaining synaptic function by producing high levels of adenosine triphosphate and buffering calcium. However, there can be abnormal axonal mitochondrial trafficking, distribution, and fragmentation, which are strongly correlated with amyloid-β (Aβ)-induced synaptic loss and dysfunction. The present study examined the neuroprotective effect of geniposide, a compound extracted from gardenia fruit in Aβ-treated neurons and an AD mouse model. Geniposide alleviated Aβ-induced axonal mitochondrial abnormalities by increasing axonal mitochondrial density and length and improving mitochondrial motility and trafficking in cultured hippocampal neurons, consequently ameliorating synaptic damage by reversing synaptic loss, addressing spine density and morphology abnormalities, and ameliorating the decreases in synapse-re
Evaluating the toxic mechanism of 1,2-diacetylbenzene in neural cells/tissues: The favorable impact of silibinin
1,2-diacetylbenzene (1,2-DAB) is a neurotoxic component of aromatic solvents commonly used in industrial applications that induces neuropathological changes in animals. This study unraveled the toxic impact of 1,2-DAB in nerve tissues, explant cultures, and neuron-glial cultures, and explored whether herbal products can mitigate its toxicity. The effects of DAB on axonal transport were studied in retinal explant cultures grown in a micro-patterned dish. The mitochondrial movement in the axons was captured using time-lapse video recordings. The results showed that 1,2-DAB, but not 1,3-DAB inhibited axonal outgrowth and mitochondrial movement in a dose-dependent manner. The toxicity of 1,2-DAB was further studied in spinal cord tissues and cultures. 1,2-DAB selectively induced modifications of microtubules and neurofilaments in spinal cord tissues. 1,2-DAB also potently induced cell damage in both neuronal and glial cultures. Further, 1,2-DAB-induced cellular ATP depletion precedes cell
Reducing Lissencephaly-1 levels augments mitochondrial transport and has a protective effect in adult Drosophila neurons
Defective transport of mitochondria in axons is implicated in the pathogenesis of several age-associated neurodegenerative diseases. However, the regulation and function of axonal mitochondrial motility during normal ageing is poorly understood. Here, we use novel imaging procedures to characterise axonal transport of these organelles in the adult Drosophila wing nerve. During early adult life there is a boost and progressive decline in the proportion of mitochondria that are motile, which is not due to general changes in cargo transport. Experimental inhibition of the mitochondrial transport machinery specifically in adulthood accelerates the appearance of focal protein accumulations in ageing axons, which is suggestive of defects in protein homeostasis. Unexpectedly, lowering levels of Lissencephaly-1 (Lis1), a dynein motor co-factor, augments axonal mitochondrial transport in ageing wing neurons. Lis1 mutations suppress focal protein accumulations in ageing neurons, including those
Teriflunomide preserves peripheral nerve mitochondria from oxidative stress-mediated alterations
Mitochondrial dysfunction is a common pathological hallmark in various inflammatory and degenerative diseases of the central nervous system, including multiple sclerosis (MS). We previously showed that oxidative stress alters axonal mitochondria, limiting their transport and inducing conformational changes that lead to axonal damage. Teriflunomide (TFN), an oral immunomodulatory drug approved for the treatment of relapsing forms of MS, reversibly inhibits dihydroorotate dehydrogenase (DHODH). DHODH is crucial for de novo pyrimidine biosynthesis and is the only mitochondrial enzyme in this pathway, thus conferring a link between inflammation, mitochondrial activity and axonal integrity. Here, we investigated how DHODH inhibition may affect mitochondrial behavior in the context of oxidative stress. We employed a model of transected murine spinal roots, previously developed in our laboratory. Using confocal live imaging of axonal mitochondria, we showed that in unmanipulated axons, TFN in
810nm near-infrared light offers neuroprotection and improves locomotor activity in MPTP-treated mice
We explored whether 810nm near-infrared light (NIr) offered neuroprotection and/or improvement in locomotor activity in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease. Mice received MPTP and 810nm NIr treatments, or not, and were tested for locomotive activity in an open-field test. Thereafter, brains were aldehyde-fixed and processed for tyrosine hydroxylase immunohistochemistry. Our results showed that MPTP-treated mice that were irradiated with 810nm NIr had both greater locomotor activity (∼40%) and number of dopaminergic cells (∼20%) than those that were not. In summary, 810nm (as with 670nm) NIr offered neuroprotection and improved locomotor activity in MPTP-treated mice.
The behavioural and neuroprotective outcomes when 670nm and 810nm near infrared light are applied together in MPTP-treated mice
We have shown previously that when applied separately, 670nm and 810nm near infrared light (NIr) reduces behavioural deficits and offers neuroprotection in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Here, we explored the beneficial outcomes when these NIr wavelengths were applied both together, either concurrently (at the same time) or sequentially (one after the other). Mice received MPTP injections (total of 50mg/kg) and had extracranial application of 670nm and/or 810nm NIr. Behavioural activity was tested with an open-field test and brains were processed for tyrosine hydroxylase immunohistochemistry and stereology. Our results showed that when 670nm and 810nm NIr were applied both together and sequentially, there was a greater overall beneficial outcome - increased locomotor activity and number of tyrosine hydroxylase immunoreactive cells in the substantia nigra pars compacta - than when they were applied either separately, or in parti
Discusses mitochondrial dysfunction mechanisms in developmental toxicity, providing contextual evidence for mitochondrial dynamics.
1. Environ Pollut. 2026 Jan 15;389:127390. doi: 10.1016/j.envpol.2025.127390. Epub 2025 Nov 18. Developmental toxicity of carboxylated microplastics in zebrafish mediated by mitochondrial...
Explores oxidative phosphorylation dynamics and molecular mechanisms of mitochondrial function in chronic injuries.
1. J Gene Med. 2026 Feb;28(2):e70085. doi: 10.1002/jgm.70085. Single-Cell RNA Sequencing and Network Pharmacology Reveal the Potential Role of Oxidative Phosphorylation Inactivation in Diagnosing...
Evidence against (13)
Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges
Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood-brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiolog
Bionanoconjugates in Neurodegeneration: Peptide-Nanoparticle Alliances for Next-Generation Therapies
The convergence of peptides and nanoparticles through bionanoconjugation has emerged as a transformative strategy to address the persistent challenges in treating neurodegenerative disorders. Peptides, particularly short sequences (< 45 amino acids), offer unique advantages as protein mimetics, including structural flexibility, target specificity and blood-brain barrier permeability. Their clinical translation is hindered by rapid enzymatic degradation, short half-life, and poor bioavailability. Conjugation with nanoparticles, overcomes these limitations by enhancing stability, prolonging circulation, and enabling precise targeting. Peptide-nanoparticle conjugates, including TAT-functionalized gold nanoparticles and RGD-decorated polymeric systems, have shown significant improvements in blood brain barrier penetration. These advancements are associated with a reduction in amyloid-beta aggregation and the inhibition of tau hyperphosphorylation in preclinical models. These hybrids levera
ROS-responsive nanogels for brain targeted delivery of icariin in the treatment of Parkinson's disease
Excessive reactive oxygen species (ROS)-induced nigrostriatal dopaminergic neuron degeneration is a cardinal pathological feature of Parkinson's disease (PD). Although icariin, a natural antioxidant capable of scavenging ROS, shows therapeutic potential, it remains underutilized in clinical settings. This translational gap primarily stems from two pharmacological limitations: (1) inadequate blood-brain barrier (BBB) penetration that prevents effective delivery of icariin to the brain, and (2) the lack of targeted drug release at pathological sites, thereby diminishing its local neuroprotective efficacy against ROS-mediated neurodegeneration. To overcome these challenges, we developed a ROS-responsive selenocysteamine-alginate nanogel (ASeNG-ICA) that bypasses the BBB via nose-to-brain delivery and enables pathology-triggered drug release through diselenide bond cleavage in the high-ROS microenvironments characteristic of PD. In vitro studies demonstrated that the nanogels undergo ROS-r
Integrated Profiling of DEHP-Induced Hippocampal Neurotoxicity in Adult Female Rats Based on Transcriptomic and Neurobiological Analyses.
Di-2-ethylhexyl phthalate (DEHP) is a widely used plasticizer with recognized sex-dependent neurotoxicity. However, research on adult neurotoxicity is scarce, especially in females. In this study, adult female rats were exposed to a high-dose experimental model of DEHP (500 mg/kg/day) for 28 days to systematically evaluate hippocampal neurotoxicity. We found that DEHP exposure significantly impaired spatial learning and memory. Transcriptomics revealed enrichment in oxidative stress, complement activation, and neurodegenerative pathways. Specifically, cellular and molecular analyses showed that DEHP induced mitochondrial structural defects and elevated markers of oxidative damage (8-OHdG and 3-NT). While the upregulation of mitochondrial and antioxidant proteins (COX4I1, SOD2, and NQO1) indicated an attempted compensatory response, it remained inadequate to restore redox homeostasis. Under this neurotoxic microenvironment, DEHP triggered early neurogenesis, marked by the upregulation o
Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple-negative breast cancer to immune checkpoint inhibitors
BACKGROUND: Immune checkpoint inhibitors (ICIs) shed new light on triple-negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. METHODS: Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8+ T cells, and transcriptional regulators of programmed cell death-ligand 1 (PD-L1). Human peripheral blood mononuclear cell (Hu-PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA-sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and tran
Evaluation of local and systemic photobiomodulation in only single-implant insertion: a randomized clinical trial
OBJECTIVES: To evaluate the effects of local and systemic photobiomodulation (PBM-T) after dental surgery for single-tooth implant placement in healed sites. MATERIALS AND METHODS: Fifty-one patients were included and randomly assigned to 2 groups: PBM-T (n = 26), with local and systemic PBM-T application immediately after implant site drilling and suturing; and control group (n = 25), with PBM-T simulation. The parameters used for local PBM-T were low-intensity laser diode (Therapy EC, DMC, São Carlos, SP, Brazil), 1 J of energy per point for 10 s, energy density of 10.20 J/cm², output spot of 0.09842 cm², infrared wavelength of 808 nm and power of 100 mW/cm². Systemic PBM-T was performed using the same low-intensity laser diode. Patients received a single 10-minute systemic transdermal irradiation over the radial artery immediately after suturing, with a total energy of 60 J, energy density of 306.12 J/cm², wavelength of 660 nm, and power of 100 mW. Postoperative pain via visual anal
Comparison of the efficacy of 12 interventions in the treatment of diabetic foot ulcers: a network meta-analysis
OBJECTIVE: This study aimed to comprehensively compare the efficacy of 12 interventions for diabetic foot ulcer (DFU) using a network meta-analysis (NMA). METHODS: The NMA was conducted by PRISMA guidelines, and the protocol was registered in PROSPERO (CRD42023461811). PubMed, Web of Science, Cochrane Library, and Embase databases were systematically searched from inception to September 2023. Randomized controlled trials (RCTs) enrolling patients with DFU were included if they compared epidermal growth factor (EGF), platelet-derived growth factor (PDGF), platelet-rich plasma (PRP), stem cells (SC), low-frequency ultrasound (LFU), negative pressure wound therapy (NPWT), low-level laser therapy (LLLT), electric stimulation (ES), extracorporeal shockwave therapy (ESWT), amniotic membrane therapy (AMT), hyperbaric oxygen therapy (HBOT), and topical oxygen therapy (TOT) against standard of care (SOC) or placebo. The primary endpoint assessed was the wound healing rate. Secondary endpoints c
Brain Photobiomodulation Therapy: a Narrative Review
Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca2+ and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson's disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intrac
Photobiomodulation Therapy on Brain: Pioneering an Innovative Approach to Revolutionize Cognitive Dynamics
Photobiomodulation (PBM) therapy on the brain employs red to near-infrared (NIR) light to treat various neurological and psychological disorders. The mechanism involves the activation of cytochrome c oxidase in the mitochondrial respiratory chain, thereby enhancing ATP synthesis. Additionally, light absorption by ion channels triggers the release of calcium ions, instigating the activation of transcription factors and subsequent gene expression. This cascade of events not only augments neuronal metabolic capacity but also orchestrates anti-oxidant, anti-inflammatory, and anti-apoptotic responses, fostering neurogenesis and synaptogenesis. It shows promise for treating conditions like dementia, stroke, brain trauma, Parkinson's disease, and depression, even enhancing cognitive functions in healthy individuals and eliciting growing interest within the medical community. However, delivering sufficient light to the brain through transcranial approaches poses a significant challenge due to
Near-Infrared Photoimmunotherapy in Brain Tumors-An Unexplored Frontier
Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the surrounding normal tissue and providing superior tissue penetration. Recently, NIR-PIT has been approved for the treatment of unresectable recurrent head and neck cancers in Japan. It induces highly selective cancer cell death; therefore, it is expected to be a new curative treatment option for various cancers, including brain tumors. In this review, we compare the principles of NIR-PIT and PDT and discuss the potential applications of NIR-PIT for brain tumors. We selected targetable proteins across various types of brain tumors and devised a strategy to effectively pass the mAb-IR700 conjugate through the blood-brain barrier (BBB), which is a
Transcranial bright light treatment via the ear canals in seasonal affective disorder: a randomized, double-blind dose-response study
BACKGROUND: Bright light treatment is effective for seasonal affective disorder (SAD), although the mechanisms of action are still unknown. We investigated whether transcranial bright light via the ear canals has an antidepressant effect in the treatment of SAD. METHODS: During the four-week study period, 89 patients (67 females; 22 males, aged 22-65, mean ± SD age: 43.2 ± 10.9 years) suffering from SAD were randomized to receive a 12-min daily dose of photic energy of one of three intensities (1 lumen/0.72 mW/cm(2); 4 lumens/2.881 mW/cm(2); 9 lumens/6.482 mW/cm(2)) via the ear canals. The light was produced using light-emitting diodes. The severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD), the Hamilton Anxiety Rating Scale (HAMA), and the Beck Depression Inventory (BDI). Cognitive performance was measured by the Trail Making Test (TMT). The within-group and between-group changes in these variables throughout
Dose-dependent effects of transcranial photobiomodulation on brain temperature in patients with major depressive disorder: a spectroscopy study
This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm2, medium: 300 mW/cm2, high: 850 mW/cm2) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode. A 3T MRI scanner was used to perform proton magnetic resonance spectroscopy (1H-MRS). A voxel with a volume of 30 × 30 × 15 mm3 was placed on the left prefrontal region. Brain temperature (°C) was derived by analyzing 1H-MRS spectrum chemical shift differences between the water (~ 4.7 ppm) and N-acetyl aspartate (NAA) (~ 2.01 ppm) peaks. After quality control of the data, the following group numbers were available for both pre- and post-temperature estimations: sham (n = 10), low (n = 11), medium (n = 10), and high (n = 8). We did not detect significant tempe
Mechanisms and Effects of Transcranial Direct Current Stimulation
The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/t