Search Results (1,279)

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article

Neurodegeneration and oxidative stress are central drivers of immune-mediated neuropathies. Capsaicin, the active ingredient in chili pepper and a direct agonist of the transient receptor potential vanilloid (TRPV1) channel, is used clinically to treat neuropathic pain. We previously demonstrated immunomodulatory and antioxidative effects of capsaicin in experimental autoimmune neuritis in vivo and Schwann cells (SC) in vitro. However, the molecular mechanisms underlying the maintenance of axonal integrity in dorsal root ganglion (DRG) and SC homeostasis remain unclear. In this study, we described the effects of capsaicin on DRG and SC in vitro under both naïve and S-Nitroso-N-acetyl-DL-penicillamine (SNAP)-induced oxidative stress conditions. Capsaicin induced an upregulation of the antioxidative cascade involving Nrf2, Ho-1, and Nqo1 in naïve DRG neurons and restored axonal growth under preventive and therapeutic settings. Preventive treatment enhanced catalase expression, whereas treatment increased regeneration-associated Gap43 and Atf3. Inhibition of TRPV1 with capsazepine partly attenuated the protective effect of axonal outgrowth, indicating TRPV1-mediated neuroprotection. In SC, capsaicin increased mitochondrial ATP production and spare respiratory capacity, inducing a transient Nrf2-dependent antioxidant response. Capsaicin suppressed expression of myelination markers under basal conditions but promoted expression of myelination- and repair-associated markers under oxidative stress. The findings support capsaicin as a regulator of neuronal and Schwann cell oxidative stress adaptation. Full article

Background/Objectives: To explore potential associations between pediatric obesity and retinal and anterior segment ocular structures using OCT and ocular biometry. This study was designed as an exploratory, hypothesis-generating analysis without a pre-specified primary endpoint; all findings should be interpreted accordingly. Methods: This retrospective cross-sectional study included 52 children (104 eyes): 27 obese children (body mass index (BMI) percentile ≥95%) and 25 healthy controls (BMI percentile 5–85%). Optical coherence tomography (OCT) and ocular biometry were used to assess retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), focal loss volume (FLV), global loss volume (GLV), Early Treatment Macular Map 5 (EMM5), corneal parameters, axial length (AL), anterior chamber depth (ACD), and white-to-white corneal diameter (WTOW). Group comparisons and cluster-robust bootstrap regression adjusted for inter-eye dependency, age, and sex; Bonferroni correction was applied. Results: Obese children showed nominally higher GCC average thickness, RNFL, and EMM5 values and shallower ACD; however, no parameter survived Bonferroni correction. ACD showed the most internally consistent exploratory pattern (unadjusted p = 0.006; adjusted p = 0.018; Bonferroni p = 0.249); however, this finding did not survive Bonferroni correction and should not be interpreted as a confirmed association. Other corneal and biometric parameters were not significantly different. Conclusions: Pediatric obesity may be associated with subtle ocular structural variations, but all findings are exploratory and hypothesis-generating. Larger prospective, pre-registered studies are needed to determine whether pediatric obesity is associated with structural ocular changes. Full article

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor maintenance factor. In adults, LGR5/LGR6–RSPO–WNT signaling sustains progenitor activity, and gustatory neurons are an important source of RSPO2; available genetic evidence is consistent with a neuron-derived contribution to the LGR5/LGR6 niche, and AAV-Cre-mediated neuron-specific ablation of Rspo2 in the petrosal ganglion led to near-complete loss of circumvallate taste buds. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is governed by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells, and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5⁺/KRT14⁺ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved questions include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the degree to which mouse-derived networks are conserved in human taste biology. Full article

Background/Objectives: Retinal optical coherence tomography (OCT) has emerged as a sensitive biomarker of neurodegeneration in multiple sclerosis (MS), yet eyes without overt optic neuritis (ON) are routinely pooled as “clinically unaffected” despite their heterogeneous histories. We evaluated whether never-ON eyes and fellow eyes after unilateral ON differ structurally and microvascularly using swept-source OCT (SS-OCT) and OCT angiography (OCTA). Methods: In this cross-sectional, single-center study, 126 clinically unaffected MS eyes—96 never-ON eyes and 30 fellow eyes after unilateral ON—were compared with 118 healthy control eyes. SS-OCT quantified ganglion cell–inner plexiform layer (GCIPL), peripapillary retinal nerve fiber layer (pRNFL), and macular RNFL (mRNFL) thickness, while OCTA measured superficial vascular plexus (SVP) vessel density. Between-group differences were assessed using generalized estimating equations with participant-level clustering, empirical (sandwich) standard errors, adjustment for age and sex, and false discovery rate correction. Results: Despite preserved visual acuity, both never-ON and fellow eyes showed structural retinal thinning relative to controls. GCIPL thickness followed a stepwise gradient—66.14 ± 4.31, 62.08 ± 7.03, and 58.03 ± 7.71 µm in controls, never-ON eyes, and fellow eyes, respectively (FDR-adjusted q = 0.020 for fellow vs. never-ON eyes)—and pRNFL and mRNFL showed a similar overall pattern. After false discovery rate correction, OCTA parameters did not differ significantly between groups. Conclusions: Clinically unaffected eyes in MS are not structurally normal, and fellow eyes after unilateral ON carry a greater burden of silent retinal damage than never-ON eyes. These two phenotypes should be analyzed separately in MS imaging research. Structural OCT measures, particularly GCIPL thickness, appear more sensitive than microvascular indices for detecting subclinical retinal involvement. Full article

Background/Objectives: Ganglion cells are the projection neurons of the retina, and there are multiple types that differ in their morphology, light responses and central projections. Parasol cells are one of the major retinal ganglion cell types in primates. The presynaptic bipolar cells have been well-characterized, but less is known about the amacrine cells that provide the majority of their inputs. The goal of this study was to identify the amacrine cells presynaptic to the OFF subtype of parasol cells. Methods: Central retinal tissue from an adult macaque was processed for serial block-face scanning EM, and a volume of images of the inner retina located 2 mm temporal to the center of the fovea was analyzed. Results: All the OFF parasol cells in the volume were reconstructed. All the synaptic inputs of two OFF parasol cells were analyzed. They received 80% or more of their input from amacrine cells and the remainder from bipolar cells, almost entirely from the Off diffuse type. Many of the presynaptic amacrine cells were reconstructed sufficiently to be classified as wide-field or narrow-field, and the latter type predominated. Five specific types of presynaptic amacrine cells were identified as AII, A4, knotty bistratified type 1, A13 and wiry type 1. Notably, the same types of amacrine cells are also presynaptic to OFF midget ganglion cells, another major type. Conclusions: These findings suggest that differences between the light responses of midget and parasol ganglion cells likely arise from differences in the presynaptic bipolar cell types. Full article

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite adequate IOP control, pointing to IOP-independent mechanisms of neurodegeneration. Oxidative stress—defined as an imbalance between the production of reactive oxygen species and the capacity of endogenous antioxidant defenses—has emerged as a central, multi-tiered contributor to glaucoma pathogenesis. In the anterior segment, chronic oxidative damage to the trabecular meshwork impairs aqueous humor outflow and drives IOP elevation. In addition, oxidative stress may impair ocular biomechanical integrity, including corneal hysteresis and lamina cribrosa, resulting in heightened susceptibility to IOP fluctuations. In the posterior segment, oxidative stress directly contributes to mitochondrial damage and vascular endothelial injury, leading to RGC apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway coordinates the principal endogenous antioxidant response, while nicotinamide adenine dinucleotide (NAD⁺) depletion links redox imbalance to metabolic vulnerability of RGCs. This narrative review synthesizes evidence published up to March 2026 on the molecular mechanisms of oxidative stress in glaucoma, the role of biomarkers in aqueous humor and systemic circulation, and the translational landscape of antioxidant-based neuroprotection—including nicotinamide, coenzyme Q10, alpha-lipoic acid, and Nrf2-activating compounds. We highlight gaps between preclinical promise and clinical evidence, and outline priorities for future randomized controlled trials. Full article

Photonic imaging technologies have profoundly transformed neuro-ophthalmic diagnostics by enabling non-invasive visualization of neurodegenerative processes at the retinal level. This review examines how advanced light-based modalities provide unprecedented insights into the structural, physiologic, and biologic relationships between the eye and brain in conditions such as optic neuritis, multiple sclerosis, and glaucoma. Optical coherence tomography has emerged as an essential tool for quantifying thinning of the retinal nerve fiber layer and ganglion cell layer, serving as reliable biomarkers of axonal loss and disease progression across multiple sclerosis subtypes and optic neuropathies. Detection of apoptosing retinal cells imaging enables real-time visualization of retinal ganglion cell apoptosis preceding irreversible structural damage, offering a critical window for early intervention in various neurodegenerative conditions, in particular, glaucoma. Two-photon microscopy with adaptive optics enables subcellular-resolution imaging of retinal neurons, microvascular dynamics, and inflammatory processes in vivo, facilitating the characterization of neurodegenerative mechanisms at unprecedented spatial scales and redefining neuro-ophthalmology by positioning the retina as an accessible extension of the central nervous system. This review critically examines how established and investigational photonic imaging modalities may support earlier disease detection, longitudinal monitoring, and biomarker development in neuro-ophthalmic and neurodegenerative disorders, with potential implications for more timely and targeted management strategies. Full article

Visceral pain is a central feature of chronic gastrointestinal disorders, yet the epithelial sensory mechanisms that shape afferent input before it enters pain-relevant neural pathways remain insufficiently integrated into current models. This review advances the concept that the intestinal epithelium is not only a barrier or endocrine interface, but also an active neuroepithelial regulatory layer positioned upstream of visceral sensory signaling. Neuropod-cell studies established that specialized epithelial cells can communicate rapidly with vagal neurons and preserve luminal stimulus identity through transmitter-selective coding. Enterochromaffin cells extend this framework as polymodal epithelial sensory transducers that detect chemical, microbial, neurohumoral, and mechanical cues, convert them into serotonergic afferent signaling, and can causally amplify visceral hypersensitivity in experimental models. Complementing these amplifying pathways, GUCY2C^high (guanylate cyclase C-enriched) neuropod-like epithelial cells reveal a pain-restraining mechanism that regulates dorsal root ganglion excitability and preserves linaclotide-responsive suppression of nociceptive output in preclinical systems. Together, these findings support an integrative model in which epithelial sensory circuits may act as filters of biological meaning, amplifiers of afferent gain, and brakes on aberrant nociceptive escalation. This framework does not replace neural, immune, or central mechanisms of visceral pain, but adds an upstream epithelial tier that may shape pain vulnerability, persistence, or treatment responsiveness in selected contexts. Defining the cellular logic, molecular mediators, and human relevance of these circuits will be essential for advancing neuroepithelial pain biology toward disease-relevant and therapeutic applications. Full article

Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the non-inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the Na_V1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. In addition to its antagonistic action at the AT1 receptor and its agonistic activation of peroxisome proliferator-activator-γ, TEL may also directly enhance I_Na, thereby modulating AP firing in a variety of excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation. Full article

Background and Objectives: Myopia is a rapidly growing global health burden driven primarily by axial elongation, which exerts mechanical stress on the inner retina, leading to progressive thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC). The sector-specific pattern of these changes across the full spectrum of myopia remains incompletely characterized. This study aimed to provide a comprehensive, sector-level analysis of RNFL and GCC changes across four myopia severity grades using optical coherence tomography angiography (OCTA), and to quantify their correlations with axial length (AL) and central foveal thickness (CFD). Materials and Methods: A total of 260 eyes of 130 participants were enrolled in a prospective cross-sectional study. Eyes were classified into four groups: emmetropia (EM, n = 74), low myopia (LM, n = 68), moderate myopia (MM, n = 64), and high myopia (HM, n = 54). All participants underwent cycloplegic refraction, AL measurement, and RTVue XR Avanti OCTA imaging. RNFL thickness was assessed across five peripapillary sectors, and GCC thickness across twelve macular zones. Between-group differences were analyzed using one-way ANOVA with Bonferroni post hoc correction or Kruskal–Wallis/Dunn-Bonferroni tests. Pearson correlations were used to assess associations among structural parameters, AL, and CFD. Results: Both the RNFL and GCC showed progressive, statistically significant thinning with increasing myopia severity. The superior RNFL was the only peripapillary sector that differentiated EM from LM (p = 0.039), with total thinning of 18.8 μm from EM to HM. The paratemporal GCC zone showed the earliest macular structural signal (EM vs. LM, p = 0.049). Temporal and nasal RNFL sectors showed relative preservation, with differences restricted to comparisons involving HM. AL correlated negatively with the RNFL and GCC across all sectors (r = −0.46 to −0.71), with the strongest correlation observed for the superior RNFL in HM (r = −0.71, p < 0.001). CFD demonstrated progressively stronger coupling with GCC thickness as myopia severity increased, peaking in HM (r = 0.72, p < 0.001). Conclusions: The RNFL and GCC thinning in myopia follows a progressive, sector-specific pattern driven by axial elongation. The superior RNFL and paratemporal GCC are the earliest structural indicators of inner retinal change, detectable already at the low-myopia grade. These findings support a neural-first model of myopia-related retinal remodeling and advocate for multiparametric, stage-targeted structural monitoring in clinical practice. Full article

Background: Sensorineural hearing loss (SNHL) is increasingly recognized as a disorder involving not only hair-cell damage but also selective degeneration of spiral ganglion neurons (SGNs). Recent single-cell, molecular, and functional studies have refined the classical type I/type II classification of SGNs by identifying distinct Ia, Ib, and Ic subtypes within type I neurons. This review aims to synthesize current evidence on how SGN vulnerability is shaped by the interaction between subtype identity, life stage, and injury context. Methods: We conducted a critical narrative review of recent studies on SGN heterogeneity and subtype-specific vulnerability across development, maturity, and aging, with particular attention to molecular profiling, functional studies, and emerging therapeutic strategies. Results: SGN degeneration in SNHL is not uniform. During development, the available evidence mainly supports the vulnerability of subtype specification, synaptogenesis, and activity-dependent maturation, rather than direct selective degeneration of mature Ia/Ib/Ic identities. In the mature cochlea, subtype-specific differences in synaptic architecture, ion-channel composition, and metabolic demand appear to shape responses to noise, ototoxic drugs, and ischemic stress, with Ic-related populations often showing greater vulnerability. During aging, cumulative mitochondrial dysfunction, oxidative stress, chronic inflammation, and declining neurotrophic support may progressively unmask differences in subtype resilience and contribute to age-related auditory decline. Conclusions: A lifespan-oriented and subtype-informed framework may improve the current understanding of selective SGN degeneration and support the development of more precise neuroprotective and reparative strategies for SNHL. Full article

Progranulin (PGRN) is a secreted protein composed of 7.5 granulin domains. The protein is implicated in various functions, including cell survival, inflammation, lysosomal homeostasis, tumorigenesis, and aging. Haploinsufficiency and complete loss of PGRN function cause the neurodegenerative disorders frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis type 11, respectively. In the nervous system, administration of exogenous PGRN has been shown to promote the survival of various nerve cell types under different pathological conditions and to stimulate neurite outgrowth in vitro and axonal regeneration in vivo. In the retina, PGRN dysfunction results in photoreceptor and retinal ganglion cell (RGC) loss, whereas PGRN administration promotes photoreceptor cell survival. In the present study, we analyzed whether a sustained intravitreal administration of PGRN promotes the survival of axotomized RGCs and the regrowth of the lesioned axons. To this end, we generated a PGRN-overexpressing clonal neural stem cell line and injected the cells into the vitreous cavity of a mouse optic nerve crush model. The progression of the lesion-induced degeneration of RGCs was studied at different time points after the nerve crush. The regeneration of the injured RGC axons into the distal optic nerve stump was analyzed one month after nerve lesioning. We found that the intravitreally administered PGRN slowed the degeneration of the injured RGCs for up to four months, the latest post-lesion interval analyzed. Furthermore, PGRN stimulated the regeneration of some RGC axons over long distances into the distal optic nerve stumps. Taken together, our results identify PGRN as a novel neurotrophic factor for retinal ganglion cells. Full article