Search Results (256)

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerations with primary degeneration of rod photoreceptors followed by secondary cone loss. We investigated whether downregulating Nrl (neural retina leucine zipper), a key transcription factor specifying rod fate, can reprogram rods into a more resilient state. In a transgenic Nrl^N/N mouse in which Nrl was markedly downregulated, the rod phenotype became more like a rod precursor, particularly in the inferior retina. Crossing Nrl^N/N mice with two rod degeneration models, rd1 (Pde6b^rd1/rd1) and rhodopsin P23H knock-in (Rho^P23H/P23H) mice, showed significantly improved photoreceptor survival in double-mutant mice. In addition, AAV-mediated delivery of shRNA targeting Nrl mRNA substantially enhanced photoreceptor survival in rd10 (Pde6b^rd10/rd10) mice. These findings demonstrate that downregulation of Nrl reprograms rods and confers broad resistance to degeneration across multiple RP models. AAV-mediated Nrl knockdown represents a promising mutation-independent therapeutic strategy for autosomal recessive and dominant forms of RP. Full article

GJB2-associated hearing loss is the most common form of non-syndromic hereditary deafness worldwide. However, it exhibits significant heterogeneity in terms of both clinical presentation and biological basis. This review focuses on mechanism-oriented therapeutic strategies for GJB2-associated hearing loss, investigating how different types of GJB2 variants correspond to distinct clinical phenotypes and underlying pathogenic mechanisms, and aims to determine appropriate treatments. Current evidence suggests that GJB2-associated hearing loss is not solely caused by channel dysfunction resulting from gap junction defects, but rather the result of multiple pathological processes, including impaired GJB2 transcriptional regulation, cochlear developmental abnormalities, sensory epithelial degeneration and secondary damage pathways such as inflammation. Consequently, emerging therapeutic approaches can be viewed as interventions targeting specific mechanisms, including gene therapy, restoration of protein transport and pharmacological modulation of damage to the cochlear microenvironment. Overall, this review highlights the importance of aligning therapeutic strategies with specific GJB2 variants, underlying pathogenic mechanisms, and the developmental window during which cochlear injury remains biologically reversible. Full article

Background and Objectives: Neovascular age-related macular degeneration (nAMD), including typical nAMD (tAMD) and polypoidal choroidal vasculopathy (PCV), is a leading cause of visual impairment. This study investigated the real-world short-term outcomes of faricimab, a bispecific antibody targeting Ang-2 and VEGF-A, in patients with treatment-naïve or -refractory nAMD. Materials and Methods: This retrospective study analyzed treatment-naïve or -refractory nAMD eyes receiving one, two, or three monthly intravitreal faricimab injections. Primary outcomes were changes in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) one month after the last injection. Secondary outcomes included the dry macula rate (absence of subretinal and intraretinal fluid) and subgroup comparisons between tAMD and PCV. Results: After a single injection, both treatment-naïve (n = 76) and -refractory (n = 44) eyes showed significant CFT reduction (p < 0.0001) but no significant BCVA improvement (p > 0.05). Dry macula was achieved in 63.2% of treatment-naïve and 71.4% of treatment-refractory eyes. In 38 treatment-naïve eyes receiving three injections, both CFT and BCVA significantly improved from baseline (p < 0.001 and p = 0.02, respectively), with a 94.7% dry macula rate. Subgroup analysis of those receiving three injections revealed that PCV eyes exhibited significant visual improvement, whereas tAMD eyes did not. No serious systemic or ocular adverse events were observed over the short-term follow-up period. Conclusions: Intravitreal faricimab is effective for both treatment-naïve and -refractory nAMD in the short term. While anatomical improvements were comparable between subtypes, the PCV subgroup showed a trend toward greater visual improvement in this small cohort; however, this may be influenced by the significantly younger age of PCV patients. These findings are exploratory and require validation in larger, age-matched prospective studies. Full article

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory stress. This review synthesizes mechanistic and transcriptomic insights that position PROM1 as a central regulator of photoreceptor and RPE integrity, reframing Prom1 disease as a multi-compartment retinal disorder relevant to both inherited retinal dystrophies (IRDs) and atrophic age-related macular degeneration (aAMD). We develop a dual-axis conceptual model in which Prom1 dysfunction can initiate pathology in either the photoreceptors (OS morphogenesis failure) or the RPE, including impaired autophagic flux, lysosomal activity, defective phagocytosis, and Epithelial-Mesenchymal Transition (EMT)-like de-differentiation, with secondary cross-compartmental degeneration. Clinically, autosomal-dominant missense variants associate with macular or cone-rod dystrophy, whereas biallelic truncating/splice-site mutations drive early-onset rod–cone disease and panretinal/RPE atrophy, illustrating genotype–phenotype diversity. By integrating recent high-resolution transcriptomic data from Prom1-deficient RPE cells with long-standing insights into photoreceptor biology, we highlight converging pathways of degeneration that challenge a photoreceptor-centric view and unify disparate phenotypes within a single molecular framework. These insights broaden the therapeutic landscape, advancing gene augmentation and pathway-targeted strategies to preserve RPE integrity, sustain photoreceptor function, and modify disease course in PROM1-associated IRDs and atrophic AMD. Full article

The purpose of this study was to compare the retinal gene expression profiles in canines with Sudden Acquired Retinal Degeneration Syndrome (SARDS) and Cancer-Associated Retinopathy (CAR) and identify shared and distinct molecular pathways. Previously published SARDS and CAR canine retinal microarray data were used for the purposes of retinal transcriptomic pathway analysis, followed by KEGG and GO pathway enrichment analysis using DAVID and MetaCore tools. Gene expression patterns were analyzed to detect the most important signaling pathways. ProteinBERT deep-learning language model, and large language models (LLM-Grok 4, ChatGPT4o) were used for analytical prediction of possible drug targets. Both diseases showed significant upregulation in T-cell co-stimulation and complement activation pathways, including CD86, DLA-79, and C5AR1. Downregulated genes were enriched in pathways associated with visual perception and cardiomyocyte signaling. CAR exhibited upregulation of tumor-related chemokine signaling (e.g., CCR5, CXCR4), while SARDS showed pronounced enrichment in vascular inflammation pathways. Analysis of drug targets identified different classes of drugs, which could be potentially utilized for SARDS and CAR treatment. SARDS and CAR share immune-related molecular signatures but potentially differ in secondary mechanisms—vascular inflammation and endothelial activation in SARDS versus paraneoplastic mimicry in CAR. These data provide potential insight into the pathogenesis of SARDS as well as CAR, and identify potential diagnostic and therapeutic targets. Full article

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin—have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable. Full article

Group II introns are catalytic RNAs that combine self-splicing ribozyme activity with mobility and have played major roles in shaping organellar genome evolution. In green macroalgae of the genus Ulva, organellar genomes are highly compact, yet they harbor unusually diverse and dynamic repertoires of group II introns. To understand how organellar group II introns diversify and persist within compact organellar genomes, we performed a comparative analysis of mitochondrial and chloroplast group II introns across Ulva, integrating secondary structure reconstruction, intron occurrence patterns, and phylogenetic inference based on both conserved intron RNA regions and intron-encoded proteins (IEPs), including reverse transcriptase/maturase (RT/M) and LAGLIDADG homing endonuclease (LHE). A total of 168 mitochondrial and 123 chloroplast introns were identified and classified into 32 families belonging to seven major subgroups (IIA1-RT/M, IIA2-RT/M, IIB1-RT/M, IIB1-LHE, IIB2-RT/M, IIB2-LHE, and IIB-like). Most intron families retain the canonical six-domain architecture (DI–DVI), but four mitochondrial IIA families display a seven-domain configuration generated by the lineage-specific insertion of an additional stem-loop structure (DIIIa). Phylogenetic analyses revealed a high degree of congruence, supporting persistent coevolution between RNA scaffolds and their IEPs. Notably, the LHE-encoding families were scattered across distinct IIB lineages instead of forming a single clade, suggesting that at least two independent invasion events occurred within the IIB1 and IIB2 lineages. Analysis of intron occurrence frequency revealed an evolutionary continuum ranging from structurally intact and broadly distributed families to lineage-specific families exhibiting progressive scaffold degeneration, with the chloroplast infA-62 family representing a stably inherited lineage maintained through vertical transmission. These results suggest that organellar group II introns in Ulva evolve through coordinated scaffold remodeling, enzymatic replacement, and differential distribution patterns across genomic compartments, highlighting Ulva organellar genomes as a valuable comparative model for investigating the long-term evolution of mobile ribozymes within compact genomic environments. Full article

Background: Chronic Achilles tendon ruptures present a major surgical challenge due to tendon retraction, degeneration, and large defects. Autologous hamstring tendon grafts have emerged as a reliable reconstructive option, yet their biomechanical consequences remain poorly understood. This study investigated whether Achilles tendon reconstruction with semitendinosus and gracilis autografts alters the plantar flexor moment arm and whether such changes affect muscle strength. Methods: A cohort of 25 patients (mean age: 44.5 years) underwent minimally invasive endoscopic reconstruction using hamstring autografts. This secondary salvage procedure was performed in patients with neglected ruptures or failed primary treatment. Five patients were excluded from the original intervention group due to inadequate radiographic quality. Radiographic measurements of the Achilles tendon moment arm and isometric plantar flexor strength assessments were performed at 12 and 24 months postoperatively. Statistical analyses included paired t-tests, Wilcoxon signed-rank tests, and correlation analyses. Results: Results showed a significant shortening of the Achilles tendon moment arm after reconstruction compared with the preoperative imaging length (mean reduction: 6.6 mm; p < 0.0001). Despite this, plantar flexor strength in the operated limb improved significantly over time at 12 and 24 months (+388.6 N at 24 months; p = 0.0067) and did not correlate with the degree of moment arm shortening (p > 0.3). By 24 months, the operated limb demonstrated comparable or greater strength than the contralateral side, with nearly half of the patients achieving substantial clinically meaningful improvements. Conclusions: In conclusion, Achilles tendon reconstruction with hamstring autografts leads to consistent moment arm shortening, yet this does not impair long-term restoration of plantar flexor strength. A progressive rehabilitation program extending up to two years appears essential to optimize recovery and compensate for biomechanical alterations. Full article

Background/Objectives: An unexplainably high millimolar (~3 mM) concentration of adenosine triphosphate (ATP), herein designated as nucleoside triphosphate (NTP), exists in the crystalline lens even though all of the known functions of NTP combined require only micromolar (μM) concentrations. Since the lens is one of the most metabolically quiescent tissues in the body and the retina is one of the most metabolically active tissues in the body, we compared their phosphorus metabolomics and related metabolic indices that measure their metabolic health status. As such, the purpose of this report was to compare the NTP concentrations in lenticular and retinal tissues and the metabolic indices that include NTP as well as their phosphorus-31 spectral modulus (PSM). Methods: Known phosphatic metabolic profiles of rat lenses and retinas were compared and quantified in mole % phosphorus using phosphorus-31 nuclear magnetic resonance spectroscopy. Metabolic indices measuring health status, where ATP is a principal component, were calculated, including the PSM. Results: In this secondary analysis, the NTP concentration calculated in the lens was 41.0% of the total phosphate detected, whereas it was similarly 37.6% in the sensory retina. The PSM values were 1.28 for the lens and similarly 1.42 for the retina. Conclusions: Due to the lens tissue’s low quiescent metabolic activity, one might expect the NTP concentration to be lower in the lens than in the highly metabolically active retina: a similar difference is expected in the PSM. However, this was not the case with the mM concentrations of NTP in both the lens (≥2.3 mM) and the retina (2.4 mM). The similarly high mM NTP concentration coupled with the PSM-calculated measure of metabolic health in these tissues is a novel finding. The novel findings of such similarly high concentrations of NTP in these metabolically diverse eye tissues further support and are consistent with the hypothesized role of NTP as a hydrotrope, preventing protein aggregation resulting in age-related cataractogenesis and age-related macular degeneration. Full article

Eye diseases, such as glaucoma, diabetic retinopathy, and age-related macular degeneration, drive the growing need for reliable and scalable analyses of fundus and optical coherence tomography (OCT) images. Deep learning performs strongly in ocular structure segmentation. However, it typically relies on dense pixel-wise annotations, which are costly and difficult to obtain at scale. Weakly supervised learning (WSL) can reduce this burden by leveraging coarse labels, limited strong annotations, and unlabeled data. This systematic umbrella review synthesizes survey and review articles on weakly supervised deep learning for image segmentation, with a focus on ocular imaging (fundus and OCT/OCTA). After analyzing twenty-one secondary studies, the main finding reveals an “empty intersection”: WSL-focused segmentation surveys are often modality-agnostic. Conversely, ocular reviews are predominantly fully supervised and seldom offer quantitative evidence on annotation-effort savings or direct comparisons between weak and fully supervised methods on identical datasets. Across the included reviews, label-efficient strategies cluster around CAM/MIL formulations, sparse supervision (points/scribbles/boxes), pseudo-labelling/self-training, and semi-/self-supervised learning, implemented mainly with U-Net/DeepLab families and increasingly Transformer or hybrid backbones. These results provide a structured map of available WSL mechanisms and, critically, identify reproducible reporting gaps that currently prevent fair benchmarking in ocular segmentation. Therefore, this review supports the development of ocular-specific benchmarks and minimum reporting practices that link segmentation performance to annotation effort. Full article

Spinal cord injury (SCI) is a devastating neurological disorder that can result in permanent disability and reduced quality of life, characterized by heterogeneous injury mechanisms and limited tools for accurate early diagnosis and prognostic stratification. The clinical course of SCI is driven not only by the initial mechanical insult but also by complex secondary injury cascades involving neuroinflammation, axonal degeneration, demyelination, and maladaptive repair responses. Current diagnostic and prognostic approaches, which rely largely on neurological examination and imaging, provide limited insight into these dynamic molecular processes. In this context, extracellular vesicles (EVs) have emerged as a biologically compelling source of biomarkers for SCI. EVs are released by neurons, glial cells, endothelial cells, and immune cells and carry molecular cargo that reflects cellular stress, injury severity, and endogenous repair activity. Increasing evidence indicates that EV-associated proteins and regulatory microRNAs (miRNAs) encode injury-specific signatures related to neuronal and glial damage, inflammatory signaling, metabolic stress, and functional recovery potential. In this review, we summarize the current knowledge on EV biology in SCI and discuss emerging evidence supporting EV-derived proteins and miRNAs as promising tools for refining diagnosis and prognosis. Our aim is not only to consolidate established findings but also to highlight EV-based molecular signatures as a developing framework for precision biomarker discovery in SCI. Full article

In 2023, the terminology of metabolic dysfunction-associated steatotic liver disease (MASLD) was proposed. MASLD uses metabolic abnormalities as an inclusion criterion. On the other hand, sarcopenia is defined by decrease in muscle mass and muscle strength. Skeletal muscle can be affected by insulin resistance (IR), and it is the largest site of insulin-stimulated glucose disposal. In recent years, advances in treatment have extended the life expectancy of patients with chronic liver disease (CLD). Due to the aging population, aging-related primary sarcopenia is expected to increase. On the other hand, liver fibrosis is an important treatment target associated with the onset of serious adverse events and poor prognosis in MASLD. The liver is the central organ for nutrition and metabolism, and patients with CLD may develop secondary sarcopenia due to various nutritional and metabolic disorders unrelated to aging. There is a strong correlation between sarcopenia, muscle fatty degeneration, liver fibrosis and IR in MASLD. MASLD and sarcopenia have a bidirectional relationship, forming a vicious cycle. In this review, we will summarize the relationship between MASLD and sarcopenia based on the current knowledge. Full article

Cisplatin-induced ovarian damage is a significant concern for young women receiving chemotherapy. Although propolis, a polyphenol- and flavonoid-rich natural product, has been proposed as a protective agent, its effects on cisplatin-related ovarian injury remain insufficiently defined. This study aimed to investigate whether propolis mitigates cisplatin-induced ovarian toxicity. In this study, 36 adult female Wistar rats were randomly allocated into six groups: Control, Propolis (50 mg/kg), Propolis (100 mg/kg), Cisplatin (7 mg/kg), Cisplatin + Propolis (50 mg/kg), and Cisplatin + Propolis (100 mg/kg). Cisplatin was administered as a single intraperitoneal dose on day 1, while propolis was given orally by gavage once daily for 14 days. Biochemical, histopathological, and endoplasmic reticulum (ER)-stress-related parameters were evaluated. Histopathologically, cisplatin caused significant vascular congestion, hemorrhage, edema, and follicular degeneration (p < 0.01), accompanied by marked reductions in primordial, primary, secondary, and tertiary follicle counts and a significant increase in atretic follicles. Propolis co-administration significantly ameliorated these lesions and partially preserved follicular counts, particularly at the 100 mg/kg dose (p < 0.01). Cisplatin markedly increased malondialdehyde (MDA) levels and ER stress markers (GRP78, ATF6, and CHOP), while reducing glutathione (GSH). Propolis treatment ameliorated these changes, decreased TNF-α and caspase-3 levels, and attenuated oxidative, inflammatory, and apoptotic responses. Propolis exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and ER-stress-modulating effects that collectively counteract cisplatin-induced ovarian injury. Full article

Thyroid hormones (THs) are master controllers in the endocrine system and have drawn considerable attention from the research community due to their associations with neurodegenerative diseases as well. In this review article, we present a comprehensive summary of the physiological functions and pathogenic mechanisms of THs in the regulation of several representative neurodegenerative diseases. Our study particularly focuses on Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). AD is the most common cause of dementia, primarily caused by tau protein tangles inside nerve cells and β-amyloid plaques outside, which lead to nerve cell death and brain atrophy. PD is primarily a movement disorder. The degeneration of dopaminergic neurons in the brain impairs the brain’s control over muscle activity. MS is usually considered to be an autoimmune demyelinating disease, but it has been found that MS also presents with secondary neurodegenerative pathology, including axonal loss and neuronal damage. In this review, the effects of TH on the pathogeneses of AD, PD, and MS are discussed in detail, with a focus on the following potential mechanisms: neuroprotection, neurogenesis, oxidative stress, and inflammatory response. In addition, we conduct an in-depth review of the possible clinical applications of TH, TH analogs, and thyrotropin-releasing hormone (TRH) in the treatment of AD, PD, and MS based on recent preclinical and clinical studies. By integrating experimental, clinical, and epidemiological results on the effects of TH on neurodegeneration, the present review constructs a theoretical basis for the involvement of TH in the pathogeneses of these diseases in detail. We believe that this basis will be useful for clinical diagnosis and treatment. Full article

Background and Objectives: Acetabular fractures in elderly patients are increasing in incidence and are frequently associated with osteoporotic bone, fracture comminution, marginal impaction, and pre-existing joint degeneration. Open reduction and internal fixation (ORIF) alone in this population is associated with high rates of fixation failure, post-traumatic osteoarthritis, and secondary conversion to total hip arthroplasty (THA). Acute THA, with or without concomitant internal fixation, has emerged as an alternative strategy aimed at enabling early mobilization and reducing reoperation rates. Materials and Methods: We retrospectively reviewed a series of elderly patients who sustained an acetabular fracture and were treated with acute THA, either as a standalone procedure or combined with internal fixation. Demographic data, fracture patterns, surgical technique, implant choice, complications, and short-term clinical and radiographic outcomes were analyzed. Results: Acute THA allowed immediate or early weight bearing in all patients. Implant stability was achieved using a highly porous, multi-hole acetabular component with supplemental screw fixation and selective use of internal fixation to restore columnar stability when required. Complications were comparable to those reported in the contemporary literature for acute THA in acetabular fractures. Conclusions: In carefully selected elderly patients with acetabular fractures at high risk of failure after ORIF, acute THA with or without internal fixation represents a viable definitive treatment strategy, enabling early mobilization and avoiding the morbidity associated with delayed salvage arthroplasty. Full article