Search Results (4,174)

Although oxidative stress plays a critical role in age-related macular degeneration (AMD) progression, natural product–derived single compounds against AMD remain largely unexplored. We investigated the protective effects and underlying mechanism of α-iso-cubebene against AMD-like retinal injury. Alterations in key phenotypes for AMD were analyzed in AMD-mimicking models using ARPE-19 cells co-treated with blue light (BL) and N-retinylidene-N-retinylethanolamine (A2E), as well as BL-exposed BALB/c mice. In BL+A2E-treated ARPE-19 cells, α-iso-cubebene reduced intracellular reactive oxygen species (ROS) and nitric oxide (NO) production and restored superoxide dismutase (SOD) activity and nuclear factor erythroid 2–related factor 2 (Nrf2), suggesting enhancement of the antioxidant defense system. Furthermore, α-iso-cubebene improved cell viability, reduced apoptotic cell populations, and regulated apoptosis-related signaling pathways under oxidative stress conditions. It also attenuated cyclooxygenase-2 (COX-2)-mediated inducible nitric oxide synthase (iNOS) signaling and was associated with reduced inflammasome-related signaling. Importantly, these protective effects were consistently observed regarding the protection of histopathological structure and normalization of inflammatory cytokines in the retina of BL-exposed BALB/c mice. Collectively, our results demonstrate that α-iso-cubebene, as a potential therapeutic candidate, alleviates AMD-like retinal injury and was associated with enhanced antioxidant responses and reduced inflammatory and apoptotic signaling markers. Full article

Background/Objectives: The efficacy of lenvatinib after different first-line immune checkpoint inhibitor (ICI)-based regimens for hepatocellular carcinoma (HCC) remains unclear. Materials and Methods: In this retrospective single-center study, we analyzed 56 patients with unresectable HCC who received lenvatinib as second-line therapy after atezolizumab plus bevacizumab (Atz/Bev; n = 41) or durvalumab plus tremelimumab (Dur/Tre; n = 15). Antitumor response was evaluated using RECIST v1.1 and modified RECIST (mRECIST). Results: Patients in the Dur/Tre group demonstrated significantly lower disease control rates (46.7% vs. 82.9%, p = 0.014) and shorter progression-free survival (PFS) (median, 56 vs. 210 days; p = 0.015) during prior ICI therapy, indicating more refractory disease. Despite this, lenvatinib demonstrated clinically meaningful antitumor activity after both Atz/Bev and Dur/Tre. Objective response rates were 12.2% vs. 26.7% by RECIST v1.1 and 41.5% vs. 60.0% by mRECIST in the Atz/Bev and Dur/Tre groups, respectively. Similar findings were observed in the Child–Pugh class A subgroup, in which mRECIST response rates were numerically higher in the Dur/Tre group. PFS and overall survival (OS) after lenvatinib initiation were comparable between groups. Objective responses were observed even in patients with progressive disease during prior ICI therapy. Multivariate analysis identified ECOG performance status and mALBI grade, but not prior ICI regimen or antitumor response, as independent prognostic factors for OS. Conclusions: Lenvatinib demonstrated clinically meaningful efficacy after both Atz/Bev and Dur/Tre, and no significant association was observed between prior ICI response and subsequent lenvatinib efficacy. These findings suggest that resistance to immunotherapy does not necessarily confer resistance to lenvatinib in patients with unresectable HCC. The observed differences in response patterns according to prior treatment exposure warrant further investigation and may have implications for treatment sequencing in the current ICI era. However, these findings should be considered hypothesis-generating and require validation in larger multicenter studies. Full article

Background/Objectives: Migraine is a common neurovascular disorder associated with substantial disability. Increasing evidence suggests that hypoxia-related signaling, endothelial dysfunction, and nitric oxide metabolism contribute to its pathophysiology. This study investigated the relationships between hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor A (VEGF-A), and arginine pathway metabolites in chronic migraine. Methods: In this observational study, fasting ethylenediaminetetraacetic acid (EDTA) plasma samples were obtained from 28 patients with chronic migraine and 28 healthy controls. Arginine, citrulline, and ornithine concentrations were quantified by liquid chromatography–tandem mass spectrometry, whereas HIF-1α and VEGF-A were measured using enzyme-linked immunosorbent assays. Group comparisons, receiver operating characteristic analyses, and Firth penalized logistic regression models were performed. Results: Patients with chronic migraine exhibited significantly higher VEGF-A and HIF-1α concentrations than controls (both FDR-adjusted p ≤ 0.001). VEGF-A demonstrated excellent discrimination of migraine status (AUC = 0.973), whereas HIF-1α showed good discriminatory performance (AUC = 0.794). The arginine-to-citrulline ratio was higher (FDR-adjusted p = 0.032) and ornithine concentrations were lower (FDR-adjusted p = 0.043) in migraine patients. In multivariable analyses, VEGF-A (OR = 14.46), HIF-1α (OR = 5.83), and ornithine (OR = 0.28) remained independently associated with migraine status. Conclusions: Chronic migraine was associated with elevated circulating HIF-1α and VEGF-A concentrations together with alterations in arginine metabolism. These exploratory findings suggest that hypoxia-responsive signaling, endothelial activation, and nitric oxide-related metabolic pathways may represent interconnected biological processes associated with chronic migraine. Larger longitudinal and externally validated studies are required to confirm these observations and clarify their potential clinical relevance. Full article

Endothelial VEGFR-2 plays a central role in vascular remodeling during intestinal inflammation, yet its activation during the early stages of colitis remains poorly characterized. Because Akt is a major downstream effector of VEGFR-2 signaling and a key mediator of endothelial responses, we investigated whether VEGFR-2 phosphorylation and Akt activation occur during the early phase of TNBS-induced colitis before the development of extensive mucosal injury. Acute colitis was induced in adult female Wistar rats by intracolonic administration of TNBS. Colonic tissues were collected on days 2, 4, and 6 after induction. Histological analyses and macrophage (CD68⁺ cells) infiltration were performed to characterize disease progression. VEGFR-2 expression and phosphorylation at Tyr1175 were evaluated on day 4 by Western blot, immunoprecipitation, and immunofluorescence. Akt activation was also assessed. TNBS-induced colitis is characterized by histological injury and increased CD68⁺ macrophage infiltration on day 4, with severe tissue damage observed on day 6. On day 4, colitis is associated with increased endothelial VEGFR-2 expression, enhanced VEGFR-2 phosphorylation at Tyr1175, and Akt activation. Early TNBS-induced colitis is associated with endothelial VEGFR-2 phosphorylation and Akt activation before the onset of extensive mucosal destruction on day 6. These findings support activation of the VEGFR-2/Akt signaling axis as an early vascular response during intestinal inflammation and suggest its potential contribution to disease progression. Full article

Diabetic wounds are a common complication of diabetes mellitus (DM), with healing often impaired by ferroptosis and persistent inflammation. This study investigated the effects of Ginkgo biloba flower extract (GBF) on diabetic wound healing by focusing on inflammation and ferroptosis. Chemical composition analysis identified 123 compounds in GBF containing 73 active ingredients of flavonoids and 12 terpenoids. In vivo, GBF treatment significantly accelerated the wound healing process in diabetic rats, and GBF promoted epithelial regeneration and collagen deposition by increasing the expression of CD31 and VEGF. It also enhanced the formation of new blood vessels. Mechanistically, GBF could inhibit the inflammatory response by reducing the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and inhibit the oxidative stress-induced ferroptosis by increasing the levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4). Proteomics analysis further confirmed its regulatory effects on inflammation and iron metabolism pathways. In vitro, GBF promoted the survival and migration of rat skin fibroblasts (RS1) while reducing the levels of reactive oxygen species (ROS) and Fe²⁺ in erastin-induced ferroptosis cells. In conclusion, GBF promotes diabetic wound healing by inhibiting ferroptosis and inflammation. Full article

Background and Objectives: Despite recent advancement, neovascular age-related macular degeneration (nAMD) remains a leading cause of irreversible vision loss. Undertreatment, fewer anti-VEGF injections and longer intervals than in clinical trials have been associated with sub-optimal visual outcomes. Visit-based regimens (Treat-and-Extend, PRN) may permit intervals of unrecognized retinal fluid between office visits. A home OCT system with near-daily self-imaging provides frequent structural retinal information between office visits that can support early detection of persistent or recurring fluid. The objective was to evaluate the duration and magnitude of fluid exposure between standard care visits and estimate the potential to shorten that exposure. Materials andMethods: Ad hoc analysis of three cohorts of treatment naïve and experienced nAMD eyes managed by standard care while participating in observational studies of the home OCT system, with treating physicians masked to home OCT data. AI-based analysis of fluid volume, rate of change and time of fluid onset was performed. Results: Data from 209 participants, mean age 76.4 years, 53% female, who performed 10,110 scans (6.0 scans/week) were analyzed. An amount of 119 eligible eyes provided data from 185 standard care intervals. Persistent or recurring fluid was identified in 121 (65%) intervals, on average 32 days prior to the next office visit. Of these, 84 (69%) had potential visit advancement within labeled minimal treatment intervals of 19 days. Mean fluid volume at the earliest possible notification was 26 nL and recurrence rate averaged 4.4 nL/day. Conclusions: A substantial proportion of patients experience unrecognized disease activity between visits. Home OCT monitoring provides adjunctive information to support early detection of fluid and may facilitate timely clinical evaluation. In this context, such monitoring may be considered reasonable and necessary to inform management of nAMD within established standards of care, while not replacing clinician-directed diagnosis or treatment decisions. Full article

Everolimus is approved for the treatment of advanced renal cell carcinoma after VEGF-targeted therapy, metastatic HR-positive/HER2-negative breast cancer in combination with exemestane, and other oncologic indications. However, an intravenous option has not been developed, largely due to its pronounced hydrophobicity and limited oral bioavailability of approximately 15–20%. In this study, we report the development of Sapu003, a novel intravenous Everolimus7 formulation enabled through the Deciparticle™ platform. A diverse library of mPEG-based block copolymers was evaluated for their ability to encapsulate Everolimus and self-assemble into stable nanoparticle structures. mPEG-Chol was ultimately selected based on its favorable biocompatibility characteristics. In addition to Everolimus, mPEG-Chol and related analogs demonstrated broad formulation compatibility with multiple hydrophobic therapeutics, including Sirolimus, Tacrolimus, Cyclosporine, as well as representative peptides and polyketides. Clinical manufacturing was conducted in a cGMP environment over a 7-day production cycle. Production was carried out under amber light using light-protective vials to reduce drug degradation. The bulk material was sterile-filtered, and subsequent fill/finish/lyophilization operations were performed under temperature-controlled conditions with high precision in fill accuracy (≥98%). After reconstitution, the final product yielding uniform Deciparticles™ that met predefined sterility and particle size criteria. Stability studies demonstrated that the formulation remained stable for at least one month at 5 °C and retained acceptable in-use stability for at least 24 h at room temperature. The process was successfully scaled beyond 10 g, supporting an ongoing Phase 1b open-label dose escalation clinical study of Sapu003 in combination with exemestane in patients with advanced mTOR-sensitive solid tumors (NCT07369505). In vivo evaluation demonstrated strong antitumor efficacy following intravenous administration (QW × 3), with tumor growth inhibition reaching 97–98% in the U-87MG glioblastoma xenograft model. No evidence of phlebitis was observed with repeated tail vein dosing. In this model, Sapu003 dosed weekly showed superior tumor suppression compared with oral Everolimus. Collectively, screening of a mPEG-block copolymer library identified mPEG-Chol as a lead excipient capable of consistently forming stable Deciparticles™ with sub-20 nm mean particle size. The resulting intravenous Everolimus formulation demonstrated scalable manufacturing, favorable stability, and potent antitumor activity in preclinical models, supporting further clinical evaluation of Sapu003 in advanced solid tumors. Full article

Background: Colorectal cancer (CRC) remains a leading cause of mortality worldwide, with a significant proportion of patients presenting with metastatic disease (mCRC). While molecularly targeted therapies, including anti-EGFR and anti-VEGF agents, have improved survival outcomes, their efficacy is often limited by drug resistance, toxicity, and high costs. There is a growing need for sustainable strategies to enhance therapeutic efficacy. Methods: This review explores the emerging role of plant-derived compounds as synergistic adjuvants. Specifically, PubMed, Scopus, and Web of Science were searched for English-language articles published between January 2004 and June 2026, using combination of terms related to colorectal cancer, metastatic disease, anti-EGFR/anti-VEGF targeted therapy, phytochemicals/natural products, and gut microbiota; both primary studies and reviews were eligible. Results: Targeted therapies such as cetuximab and bevacizumab are the standard of care but face challenges related to RAS/BRAF mutations and primary tumour location. Clinical data demonstrate that while cetuximab improves overall survival in patients with RAS wild-type, left-sided tumours (median OS 31 vs. 26 months; HR 0.76, p = 0.012), progression-free survival remains comparable to that of bevacizumab. Concurrently, natural products like Vitis vinifera, Dendrobium candidum, and quercetin demonstrate significant preclinical potential in inhibiting angiogenesis, inducing apoptosis, and modulating the tumour microenvironment. The gut microbiome, particularly Fusobacterium nucleatum (whose reported prevalence varies widely across cohorts and reaches up to ~98% of CRC tissues only in selected series), has emerged as a key factor in chemoresistance. It should be emphasised that the great majority of the phytochemical-targeted therapy combinations discussed here are currently supported primarily by preclinical (in vitro and animal) studies rather than by clinical trials. Conclusions: Integrating evidence-based phytochemicals with conventional targeted therapies is a mechanistically compelling and potentially sustainable strategy that may enhance therapeutic efficacy, help overcome resistance, and mitigate adverse effects in mCRC management. However, because current support is largely preclinical, these combinations should be regarded as hypothesis-generating and require validation in prospective, biomarker-stratified clinical trials before clinical adoption. Full article

Oral mucosal repair is a redox-regulated process that may be impaired by diabetes, chronic inflammation, infection, and chemotherapy- or radiotherapy-induced oral mucositis. Reactive oxygen species (ROS) support host defense, epithelial migration, angiogenesis, extracellular matrix remodeling, and adaptive repair when their production is transient and compartmentalized. In contrast, persistent ROS promote lipid, protein, and DNA oxidation, mitochondrial dysfunction, and extracellular matrix damage. Photobiomodulation (PBM) is increasingly used to support oral tissue repair, but its effects should be interpreted as dose- and context-dependent redox modulation rather than as simple antioxidant activity. This narrative review synthesizes oxidative stress biomarkers and redox-sensitive pathways relevant to oral mucosal repair and PBM, including oxidant–antioxidant balance, lipid and protein oxidation, oxidative DNA damage, antioxidant defense, thiol/disulfide homeostasis, mitochondrial and NADPH oxidase-derived ROS, Nrf2/HO-1, NF-κB, HIF-1α/VEGF, MAPK/ERK, PI3K/Akt, and MMP/TIMP signaling. The review emphasizes the distinction between transient mitochondrial ROS/nitric oxide signaling and sustained NADPH oxidase-driven oxi-inflammatory stress. It proposes a practical redox-guided framework for biomarker selection, PBM response interpretation, and future study design, while noting that this framework remains conceptual and is not yet a validated clinical decision algorithm. Full article

Background: Hypoxic–ischaemic brain injury (HI) is a major contributor to neurological deficits following stroke. Understanding what happens to the smallest functional and structural unit of the central nervous system in the face of oxygen and nutrient deprivation is essential to fully comprehend the pathogenesis of diseases and disorders associated with HI, such as ischaemic stroke. Aim: The aim of this study was to develop a robust in vitro tool for initial screening of potential therapeutics and identification of diagnostic markers of brain hypoxic injury. Methods: This study details and validates a comprehensive protocol for modelling HI using differentiated SH-SY5Y neuroblastoma cells (Neuron-like Cells, NLCs). First, we optimized the differentiation process and confirmed the maturity and purity of NLCs via standard molecular markers. The NLCs exhibited functional excitotoxicity, demonstrating a graded cell death response to N-methyl-D-aspartate (NMDA), thus validating their functional application. To simulate HI, we initially optimized the oxygen-glucose deprivation (OGD) treatment using graded concentrations of CoCl₂ (0.125 mM to 2 mM) in glucose-free media. The validated NLCs were then subjected to the refined OGD protocol (1 mM CoCl₂ in glucose-free media) for 3 h, followed by various periods of reoxygenation (1 h, 3 h, 6 h, 12 h, 18 h, and 24 h). Result: Bulk RNA-sequencing revealed a distinct temporal transcriptional response to HI. Injury-associated genes, including heat shock proteins and stress markers, were significantly (p < 0.05) upregulated at 3 h of reoxygenation, peaked at 6 h, and declined thereafter, remaining above baseline at 24 h. Upstream regulator analysis identified IL-1β, TNF-α, and HIF-1α as key drivers during OGD, with additional regulators emerging during reoxygenation. TNF-α and β-oestradiol were consistently identified across time points, while TGF-β1 and NTRK1 became prominent during peak injury and later phases. Analysis of secreted factors showed increased release of inflammatory (TNF-α) and neurotrophic (β-NGF, BDNF, VEGF) mediators with reoxygenation, while maximal cell death occurred at 24 h. Conclusions: This study identifies a transient, time-dependent transcriptional cascade following hypoxic–ischaemic injury, highlighting a critical window for early neuronal response. The model provides a reproducible platform for studying neuronal injury and recovery, and identifies known (TNF-α, IL-β, and HIF-1α), context-specific (NTRK1 and TGF-β) and novel (β-oestradiol) regulators of the injury response with potential relevance for therapeutic targeting. Full article

Platelet-rich fibrin (PRF) has been widely used in regenerative dentistry because of its potential to support tissue regeneration. Recently, modifications in PRF preparation protocols and tube surface characteristics have attracted attention because of their possible influence on fibrin organization and biologic activity. The present in vitro study aimed to evaluate the effects of nano-hydroxyapatite platelet-rich fibrin (HA-PRF) on gingiva-derived mesenchymal stem cells (GMSCs) by comparing it with leukocyte platelet-rich fibrin (L-PRF) and titanium platelet-rich fibrin (T-PRF). Gingival tissue and venous blood samples were obtained from a systemically healthy male volunteer. PRF membranes were prepared using conventional glass tubes, nano-hydroxyapatite-coated tubes, and titanium tubes. GMSCs were isolated, characterized, and cultured with PRF membranes. Cell viability and metabolic activity were evaluated using MTT analysis. Apoptosis and necrosis rates were assessed by Annexin V/PI flow cytometry. VEGF and TGF-β1 release levels were determined by ELISA, whereas IL-1β, IL-6, and TNF-α gene expression levels were analyzed using qRT-PCR. The HA-PRF and L-PRF groups demonstrated higher cell viability values compared with the T-PRF group on day 7. Annexin V/PI analysis revealed no statistically significant differences between the groups in terms of apoptosis and necrosis. Growth factor release and cytokine gene expression profiles demonstrated time-dependent biologic responses in all PRF membranes. Within the limitations of this study, HA-PRF showed no evidence of cytotoxicity and demonstrated biologic responses comparable to those observed with conventional L-PRF. Both HA-PRF and L-PRF generally exhibited more favorable cellular responses than T-PRF under the present experimental conditions. Full article

There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma and whether these vesicles can be selectively targeted using a glycan-binding affinity resin. Large (100–500 nm) and small (40–200 nm) EVs were isolated from post-acute COVID-19 plasma and analyzed by nanoparticle flow cytometry to assess surface glycosylation. Small EV capture assays were performed using Galanthus nivalis agglutinin (GNA) affinity resin. Plasma miRNA profiles before and after GNA treatment were evaluated using NanoString nCounter analysis, and potential downstream pathway effects were computationally inferred using validated miRNA–mRNA interactions and PROGENy. Mannose-positive large EVs were significantly increased in Long COVID compared to recovered controls (p < 0.05). GNA-mediated small EV capture correlated with mannose-positive EV abundance (r = 0.341, p < 0.05), and seven miRNAs were significantly reduced following treatment. Computational pathway analysis suggested modulation of key signaling pathways, including JAK-STAT, Estrogen, VEGF, and PI3K. These findings suggest a glycan-associated EV signature in Long COVID and support further investigation of lectin-based capture as a potential strategy to target vesicle-associated molecular cargo. Full article

Background and Objectives: Seroma formation is the most common postoperative complication following mastectomy and axillary dissection, negatively affecting wound healing and delaying adjuvant therapy. Despite numerous surgical and pharmacological approaches, no universally effective strategies have been established. This study aimed to comparatively evaluate the effects of porcine dermal collagen (PDC), tranexamic acid (TXA), and thymoquinone (TQ) on seroma formation and tissue repair. Materials and Methods: A randomized controlled experimental study was conducted using 40 female Wistar albino rats that underwent modified radical mastectomy and axillary dissection. All surgical and postoperative procedures were performed in accordance with the institutional animal welfare and ethical guidelines, including postoperative analgesic administration. The animals were divided into four groups: control, PDC, TXA, and TQ (n = 10 each). Seroma volume was measured on postoperative day 14. Histopathological evaluation, immunohistochemical analysis (FGF2, VEGF, TGF-β1, p53), and quantitative real-time PCR were performed to assess tissue remodeling and molecular responses. Results: All treatment groups demonstrated a significant reduction in seroma volume compared to the control group, with the most pronounced decrease observed in the TQ and TXA groups (p < 0.0001), while PDC showed a moderate effect (p < 0.01). Histopathological analysis revealed increased collagen deposition and fibrin formation in the PDC and TQ groups, whereas TXA exhibited a more limited remodeling profile than the others. Immunohistochemical and molecular analyses showed significant upregulation of VEGF across all groups, with broader and more consistent increases in the PDC and TQ groups. TGF-β1 and FGF2 expression demonstrated region-specific increases, particularly in the thoracic tissue. p53 expression remained relatively stable in the TXA group but was elevated in specific regions in the PDC and TQ groups. Importantly, the increased inflammatory infiltration, edema, vascular proliferation, and fibrin deposition observed in the TQ group may reflect not only active tissue remodeling processes but also prolonged inflammatory activation and enhanced fibrotic responses and should therefore be interpreted cautiously. Conclusions: PDC, TXA, and TQ differentially modulate postoperative seroma formation via distinct biological mechanisms. While TXA primarily exerts a targeted anti-seroma effect and PDC enhances extracellular matrix stabilization, TQ is associated with broader angiogenic, inflammatory, and tissue remodeling responses within this preclinical rat model. These findings should be considered exploratory and hypothesis-generating, and additional mechanistic studies and clinical investigations are necessary before definitive therapeutic conclusions can be established regarding the use of TQ in human breast surgery settings. Full article

Photobiomodulation (PBM) is a non-invasive therapeutic strategy that uses red and near-infrared (NIR) light in the 590–950 nm range to modulate the cellular and molecular pathways involved in retinal homeostasis. At the molecular level, PBM acts primarily through photon absorption by cytochrome c oxidase (CcO, complex IV of the mitochondrial electron transport chain), whose four metal centres—two copper (CuA and CuB) and two heme groups (heme a and heme a₃)—absorb light across approximately 600–1000 nm. Photon capture promotes photodissociation of inhibitory nitric oxide (NO) from the binuclear CuB–heme a₃ centre, accelerates electron transfer, restores the proton-motive force and increases ATP synthesis. These primary events trigger a coordinated molecular programme that includes (i) transient mitochondrial reactive oxygen species (ROS) bursts that activate the Nrf2/Keap1/ARE axis and upregulate phase II antioxidant enzymes (HO-1, NQO1, GCLC, SOD2, catalase, GPx); (ii) calcium- and cAMP-dependent secondary signalling that converges on PI3K/Akt, MAPK/ERK, AMPK and mTOR pathways; (iii) suppression of NF-κB-driven cytokine production (TNF-α, IL-1β, IL-6) and of NLRP3 inflammasome activation; (iv) downregulation of the HIF-1α/VEGF axis, particularly at 590 nm; (v) anti-apoptotic remodelling of the Bcl-2/Bax ratio with reduced cytochrome c release and caspase-3/9 activation; and (vi) PGC-1α/TFAM/NRF1-driven mitochondrial biogenesis, alongside restoration of fission/fusion homeostasis (Drp1, Mfn1/2, Opa1) and PINK1/Parkin-mediated mitophagy. Wavelength specificity has a defined molecular basis: 590 nm modulates VEGF signalling and RPE pump activity, 660 nm interacts with the CuB centre and enhances O₂ binding at CcO, and 850 nm is absorbed by CuA and supports electron entry into complex IV. A second molecular axis is the bidirectional crosstalk between PBM and the circadian system: mitochondrial respiration, ATP turnover and CcO activity oscillate over the 24 h cycle under the control of the BMAL1/CLOCK and PER/CRY core machinery, the NAD⁺/SIRT1–SIRT3 axis and REV-ERBα. Preliminary preclinical and human observations suggest that NIR-induced bioenergetic and functional gains may be coupled to this rhythm, with greater benefit reported when light is delivered in the morning window (≈08:00–11:00); this time dependence should be regarded as an emerging hypothesis rather than an established clinical principle. The clinical evidence is unevenly developed across indications. It is most robust for non-exudative age-related macular degeneration, where multiwavelength PBM (590/660/850 nm; Valeda Light Delivery System) has shown disease-modifying potential in randomized controlled trials (LIGHTSITE I–III and the LIGHTSITE IIIB extension), with sustained BCVA gains and reduced incidence of geographic atrophy over 24 months and beyond. Evidence for retinitis pigmentosa, central serous chorioretinopathy and, with red-light monotherapy, childhood myopia is at present limited to small or short-term studies and remains preliminary. This narrative review synthesizes the molecular machinery engaged by PBM, integrates clinical findings across retinal diseases and discusses how chronotherapeutic delivery of light, aligned with the molecular clock, may further optimize therapeutic efficacy. Full article

Objective: This study aimed to evaluate the predictability of baseline optical coherence tomography angiography (OCTA) metrics utilizing a specialized capillary–large vessel segmentation analysis framework in patients with diabetic macular edema (DME) undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy. Methods: Forty-two treatment-naïve eyes with DME receiving three monthly loading anti-VEGF injections were included. Superficial capillary plexus (SCP) images from 3 × 3 mm OCTA scans were processed to isolate the capillary network from the large vessels via image processing. Vessel density and skeleton density were extracted for the total, large-vessel, and capillary components. Multiple linear and logistic regression models were used to identify independent predictors of post-treatment best-corrected visual acuity (BCVA) and “good visual outcome” (≥3-line improvement or final BCVA of 20/40 or better). Results: Following three monthly anti-VEGF injections, the mean BCVA significantly improved from 0.57 ± 0.36 to 0.37 ± 0.30 LogMAR (p < 0.0001), and the mean central retinal thickness decreased from 424.3 ± 117.7 μm to 316.9 ± 84.7 μm (p < 0.0001). The proportion of patients who achieved a good visual outcome was 73.8%. Baseline central retinal thickness was associated with baseline BCVA (p = 0.049) but not predictive of post-treatment BCVA (p = 0.38) or good visual outcomes (p = 0.79). Baseline capillary vessel density was identified as a significant independent predictor of post-treatment BCVA (p = 0.024), whereas total and large-vessel metrics were not. Capillary vessel density was also the only significant predictor of good visual outcomes (p = 0.044). Conclusions: Baseline capillary vessel density is a robust predictor of visual prognosis after anti-VEGF therapy in patients with DME, underscoring the importance of capillary network integrity in functional recovery. Full article