Search Results (108)

Cells respond to metabolic and environmental challenges through the integrated stress response (ISR), a cellular process that maintains homeostasis under diverse stressors. ATF4 is a key player in this ISR, as it is activated via the PERK–eIF2α–ATF4 pathway. ATF4 induction can elicit adaptive responses, including the regulation of genes involved in metabolism and autophagy, to maintain homeostasis. However, ATF4 activation can also induce apoptosis, leading to a wide spectrum of diseases, including metabolic, neurologic, and ocular pathologies. This duality reflects the highly context-dependent nature of ATF4 signaling. This review aims to synthesize the role of ATF4 in metabolic dysfunction, neurodegenerative diseases, and ocular pathology; the mechanisms underlying its protective versus pathologic effects; and future directions to refine ATF4’s potential as a clinical therapeutic target across different diseases. Full article

Age-related cognitive impairment represents a critical stage in the continuum of neurodegenerative disorders, including Alzheimer’s disease (AD), highlighting the need for objective and non-invasive physiological indicators of early neurological change. This study investigates the simultaneous analysis of microsaccadic eye movements and pupil size variations as ocular biomarkers associated with age-related cognitive impairment using eye-tracking technology. A total of 70 participants were recruited and categorized into three age groups: individuals in their 20s, 60s, and 70s. Participants in their 70s were further categorized based on MMSE-K scores into cognitively normal (≥24) and impaired (≤23) subgroups. Quantitative analyses showed a significant age-related increase in microsaccade frequency along both axes, with significantly higher microsaccade frequencies (p < 0.01) among individuals with lower cognitive scores within the same age group. Pupil size variation, including constriction and dilation rates, declined with age, while response speed remained relatively unchanged across all age groups. These findings highlight a clear association between age related-cognitive decline and involuntary ocular responses. The proposed dual-biomarker method offers a non-invasive and quantitative framework that may complement traditional cognitive screening tools. Future studies involving larger cohorts and clinically diagnosed AD populations are required to determine the diagnostic utility of these ocular biomarkers. Full article

The G-protein-coupled receptor cannabinoid receptor 2 (CB₂R) initiates a key signaling pathway in mammalian physiology and pathophysiology. CB₂R signaling holds significant therapeutic potential in ameliorating many pathologies, particularly in inflammatory conditions, neurodegenerative disorders, fibroproliferative and ocular diseases. CB2 modulators have been studied for their anti-inflammatory and tissue protective effects in preclinical animal models of cardiovascular, gastrointestinal, liver, kidney, lung and neurodegenerative disorders with numerous compounds undergoing clinical evaluation. Existing ligands can be classified as endocannabinoids, cannabinoid-like natural products and synthetic CB₂R ligands. A genetically encoded G-protein-coupled receptor activation-based (GRAB) sensor for CB₁R—GRAB_eCB2.0 was developed recently. This current study extends the sensor’s development to allow for a GPCR activation-based sensor for CB₂R. The sensor, GRAB-CB2, will facilitate the evaluation of pharmacological characteristics and responses of various functionally selective and indiscriminate cannabinoid ligands acting on CB2. Full article

Background: Glaucoma is a neurodegenerative disease and the second leading cause of irreversible blindness in developed countries. It is characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve axons, leading to permanent vision impairment. Although elevated intraocular pressure (IOP) is the main recognized risk factor, recent evidence suggests that ocular and gut microbiota may play a significant role in the onset and progression of glaucoma. Objectives: This study aimed to characterize ocular and gut microbiota alterations in patients with different types of glaucoma. Methods: Five searches were conducted between June and September 2025 using selected keywords. A total of 121 articles were identified, of which 14 met the inclusion criteria following the PRISMA 2020 guidelines. Results: Findings indicate a Mendelian genetic predisposition influencing microbiota composition associated with glaucoma development. Patients treated with benzalkonium chloride (BAK) showed increased Gram-negative and Alphaproteobacteria on the ocular surface, along with enhanced lipopolysaccharide synthesis. Compared with controls, glaucoma patients exhibited reduced Corynebacterium mastiditis and Actinobacteria and increased Firmicutes, Proteobacteria, and Verrucomicrobiota. Dysbiosis was more pronounced in patients with concurrent dry eye disease, characterized by higher Gram-negative taxa and pro-inflammatory microbial activity. Conclusions: Significant differences in ocular and gut microbiota were observed between glaucoma patients and controls, as well as among glaucoma subtypes such as pseudoexfoliation and primary open-angle glaucoma. Age-related dysbiosis and epigenetic factors appear to contribute to disease development. Microbiota profiling may offer new opportunities for improved prediction, management, and treatment of glaucoma. Full article

Ocular diseases, including glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), remain major global causes of irreversible vision loss. Despite advances in clinical management, current therapies insufficiently address the shared metabolic, inflammatory, vascular, and neurodegenerative mechanisms underlying these conditions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, have emerged as multi-target candidates for ocular therapeutics due to their pleiotropic anti-inflammatory, antioxidant, vasculoprotective, and neuroprotective properties. Preclinical studies consistently demonstrate that GLP-1RAs preserve blood–retina barrier integrity, suppress pathological angiogenesis, mitigate oxidative and inflammatory stress, and protect retinal neurons from degeneration. Complementary clinical and real-world evidence shows a robust and reproducible reduction in glaucoma risk among GLP-1RA users across diabetic and non-diabetic populations. By contrast, findings for DR and AMD are more heterogeneous and appear context-dependent, with potential benefits most evident in early or non-exudative disease stages. Emerging safety considerations—including reports of nonarteritic anterior ischemic optic neuropathy and early DR worsening in the setting of rapid glycemic improvement—highlight the need for careful interpretation, individualized risk assessment, and appropriate ophthalmic monitoring. This review synthesizes molecular mechanisms, experimental data, clinical and pharmacoepidemiologic evidence, and safety signals to critically evaluate the therapeutic potential of GLP-1RAs in ocular disease. We also outline key translational challenges, including the need for ocular-targeted delivery strategies, prospective ophthalmology-specific trials, and precision-medicine approaches to determine when and how GLP-1RAs can be safely advanced as disease-modifying treatments in ophthalmology. Full article

Chronic diseases such as cancer, cardiovascular disorders, neurodegenerative conditions, chronic respiratory diseases, autoimmune disorders, chronic kidney disease, persistent infectious diseases, diabetes, and ocular inflammation remain leading causes of morbidity and mortality worldwide. Their complex pathophysiologies and the limitations of conventional therapies underscore the urgent need for advanced drug delivery platforms that enhance therapeutic efficacy while minimizing off-target effects and systemic toxicity leading to adverse reactions. Nanomedicine has emerged as a transformative approach, with chitosan-based nanocarriers offering advantages due to their biocompatibility, biodegradability, mucoadhesive properties, and ability to be physic-chemically modified. These nanocarriers improve solubility, stability, bioavailability, and the therapeutic index of drugs, while enabling controlled release, targeted delivery, and immune modulation. This review highlights recent advances in chitosan-based nanomedicine for the management of chronic disease. We discuss methods of synthesis such as ionic gelation and electrospray, functionalization approaches, and immunomodulatory roles that expand therapeutic potential. The evidence emphasizes that chitosan nanocarriers are a versatile, safe, and effective platform which can be used to improve clinical results, reduce adverse effects, and advance the science of personalized medicine. Full article

Oxidative stress, caused by an imbalance between the production of reactive oxygen species and endogenous antioxidant capacity, is a key etiological factor in numerous pathologies, including neurodegenerative and cardiovascular diseases. The limited clinical efficacy of conventional antioxidants is primarily due to their insufficient accumulation within the mitochondria, the main site of intracellular ROS generation. This article reviews the design and application of Mitochondria-Targeted Antioxidants, which represent a major advance in precision medicine. The design of these compounds involves linking an antioxidant “payload” to a lipophilic cation, such as the triphenylphosphonium group. This positive charge leverages the negative electrochemical gradient across the inner mitochondrial membrane to drive the antioxidant into the organelle. This mechanism allows the drug to reach concentrations over 100 times higher than non-targeted alternatives. The discussion encompasses the structure-activity analysis of the carrier, the payload (e.g., quinone derivatives), and the linker, which determine optimal subcellular partitioning and scavenging efficiency. Preclinical data highlight the therapeutic potential of this approach, showing strong neuroprotection in models of Parkinson’s and Alzheimer’s diseases, as well as improved outcomes in cardiovascular and ocular health. By restoring redox balance specifically within the mitochondria, these targeted therapies offer a more effective way to treat chronic oxidative damage. Full article

Influenza is typically framed as an acute respiratory infection, yet accumulating evidence suggests that—like SARS-CoV-2—it may trigger persistent, multi-organ morbidity consistent with a post-acute infection syndrome (“long flu”). Leveraging the nationwide FinnGen registry infrastructure, we conducted a temporally stratified disease-wide association study (DWAS) to map antecedent risk factors and long-term sequelae following clinically diagnosed influenza and COVID-19. We assembled an exposed cohort comprising 9204 individuals with influenza (ICD-10 J09–J11) and 4258 individuals with COVID-19 (ICD-10 U072) recorded in specialist inpatient/outpatient care between 1998 and 2021, and an unexposed comparator cohort of 420,005 individuals with no recorded influenza or pneumonia (J09–J18) across their available medical history. Across harmonized clinical endpoints, we fitted age- and sex-adjusted Cox proportional hazards models and controlled for multiple testing using a stringent false discovery rate threshold (FDR-adjusted p < 0.001), further interrogating temporal persistence within 1-, 5-, and 15-year windows. The DWAS revealed that both infections are associated with broad, system-spanning disease signatures extending beyond the respiratory tract, including circulatory, neurological, metabolic, musculoskeletal, digestive, mental/behavioural, ocular, and oncologic endpoints. Predisposition analyses demonstrated that infection risk is concentrated in individuals with substantial pre-existing multimorbidity, most prominently cardiovascular disease, alongside cardiometabolic, respiratory, renal, neuropsychiatric, and inflammatory conditions. Post-infection analyses identified a durable burden of incident multi-system morbidity after influenza, with particularly robust and persistent cardiovascular and neurological signatures—encompassing thromboembolic disease and major adverse cardiovascular outcomes, as well as migraine, neurodegenerative disorders, and depression—together with metabolic and renal sequelae that, in subsets, extended across multi-year horizons. Collectively, these longitudinal findings reframe influenza as a systemic event embedded within a chronic disease continuum, motivate recognition of “long flu” as a clinically meaningful post-viral risk landscape, and support intensified prevention and risk-stratified surveillance strategies alongside analogous efforts for long COVID. Full article

Mitochondrial dysfunction represents a central hallmark of aging and a broad spectrum of chronic diseases, ranging from metabolic to neurodegenerative and ocular disorders. Nicotinamide riboside (NR), a vitamin B₃ derivative and efficient precursor of NAD⁺ (nicotinamide adenine dinucleotide), and berberine (BBR), an isoquinoline alkaloid widely investigated in metabolic regulation, have independently emerged as promising mitochondrial modulators. NR enhances cellular NAD⁺ pools, thereby activating sirtuin-dependent pathways, stimulating PGC-1α–mediated mitochondrial biogenesis, and triggering the mitochondrial unfolded protein response (UPR^mt). BBR, by contrast, primarily activates AMPK (AMP-activated protein kinase) and interacts with respiratory complex I, improving bioenergetics, reducing mitochondrial reactive oxygen species, and promoting mitophagy and organelle quality control. Importantly, despite distinct upstream mechanisms, NR and BBR converge on shared signaling pathways that support mitochondrial health, including redox balance, metabolic flexibility, and immunometabolic regulation. Unlike previous reviews addressing these compounds separately, this article integrates current preclinical and clinical findings to provide a unified perspective on their converging actions. We critically discuss translational opportunities as well as limitations, including heterogeneous clinical outcomes and the need for robust biomarkers of mitochondrial function. By outlining overlapping and complementary mechanisms, we highlight NR and BBR as rational combinatorial strategies to restore mitochondrial resilience. This integrative perspective may guide the design of next-generation clinical trials and advance precision approaches in mitochondrial medicine. Full article

Objectives: Glaucoma is an age-related neurodegenerative disease, characterized by retinal ganglion cell loss and progressive visual field deterioration. Beyond intraocular pressure (IOP), vascular and metabolic dysregulation contributes to optic nerve head (ONH) ischemia and neuronal vulnerability. Nutritional factors with antioxidative and vasodilatory properties may help preserve ocular perfusion. This study investigated the acute and subacute effects of a single dose of a dietary supplement containing red ginger extract (Zingiber officinale var. rubra), lutein, and vitamin B6 on ONH blood flow in patients with open-angle glaucoma (OAG). Methods: A retrospective self-controlled study was conducted at Tohoku University Hospital between August 2023 and March 2025. ONH blood flow was quantified using a laser speckle flowgraphy (LSFG) baseline one hour after and one month after continuous oral supplementation in patients with OAG. Systemic parameters, ocular biometry, and concomitant glaucoma medications were recorded in medical charts. Relative mean blur rate (MBR) changes were analyzed using a linear mixed-effects model, accounting for repeated measures and inter-eye correlations. Results: Nineteen glaucoma patients (38 eyes) were included in the acute phase and 13 patients (26 eyes) completed the one-month follow-up. After adjusting for age and sex, a single oral dose of red ginger extract significantly increased the relative MBR at 1 h (106.9 ± 3.1%; p < 0.05), and this enhancement increased after 1 month of continuous intake (115.4 ± 6.7%; p < 0.05). Greater ONH perfusion was particularly prominent in eyes with shorter axial length. Conclusions: Oral supplementation was associated with acute and short-term increases in ONH blood flow in glaucomatous eyes. Although this study was a retrospective study without a placebo-controlled comparison group, our findings offer hypothesis-generating evidence that nutritional interventions may support ocular perfusion alongside conventional glaucoma management. Future prospective randomized controlled trials are required to confirm these associations. Full article

Background: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development. Methods: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications. Results: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF—cenegermin and recombinant CNTF—Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance. Conclusions: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance. Full article

Redox unbalance, a molecular trait common to neurodegenerative conditions and para-physiological processes like aging, is a critical factor in disease development and in exacerbating progression. The mechanism by which redox imbalance perturbs cellular homeostasis is strongly linked to the activity and function of the ubiquitin–proteasome system (UPS). The UPS, along with autophagy, is the primary intracellular proteolytic system, regulating targeted proteolysis and removing damaged proteins. Consequently, the UPS serves also as the first line of defense for cellular recovery following exposure to redox stressors. Paradoxically, the composition and function of the UPS can also be negatively targeted by redox unbalance through a vicious cycle. The alterations in redox balance and UPS biological mechanisms are involved in the etiopathogenesis of chronic eye disorders. These disorders encompass a diverse repertoire of pathologies affecting the retinal layers (e.g., age-related macular degeneration, diabetic retinopathy) and the optic nerve (e.g., glaucoma). Nowadays, the comprehension of the interplay between proteostasis and oxidative redox status remains pivotal for identifying new therapeutic approaches. Encouragingly, a number of anti-oxidant compounds have been reported to modulate proteasome activity against redox insults in vitro and in vivo. Furthermore, these compounds provide cytoprotective roles in both in vitro and animal models of eye diseases. Therefore, this review highlights recent research on the interplay of the UPS with oxidative stress in physio-pathological conditions, focusing on the onset and progression of ocular diseases, thereby providing new insights into UPS-oxidative stress interaction. Full article

Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative condition with increasing global prevalence. As early diagnosis becomes critical for timely symptomatic management, noninvasive and easily accessible biomarkers are needed. Given the shared embryologic origins between the eye and the brain, ocular imaging has emerged as a promising diagnostic technique. This review summarizes the associations between AD, ocular imaging and fluid biomarkers in the anterior and posterior segment. We also describe the underlying pathophysiology that explains the connections between each ocular structure and the brain in the context of AD. Optical coherence tomography (OCT), OCT angiography, and fundus photography are the most common imaging modalities utilized in AD research. However, these techniques may or may not be feasible in primary care or neurologic clinical settings. Compared to plasma biomarker analysis, which is minimally invasive and nearing clinical implementation, ocular biomarkers remain primarily valuable in research investigations. Full article

Glaucoma is a major ocular neurodegenerative disease and a leading cause of irreversible blindness worldwide, with prevalence projected to exceed 110 million by 2040. Although lowering intraocular pressure (IOP) remains the only proven treatment, glaucoma arises from a complex interplay of genetic, local, and systemic factors—including oxidative stress, vascular dysregulation, mitochondrial dysfunction, and neuroinflammation. Emerging evidence suggests that modifiable lifestyle factors may influence these pathogenic pathways. In this review, higher dietary nitrate from leafy greens is consistently associated with lower primary open-angle glaucoma risk, aligning with nitric-oxide-mediated endothelial support and more stable ocular perfusion pressure. Flavonoids (anthocyanins and flavanols), carotenoids (lutein/zeaxanthin), and B vitamins have strong biological rationale for glaucoma prevention but have limited support from long-term, large population-based studies. The effect of polyunsaturated fats on glaucoma remains inconsistent and warrants source-(plant vs. animal) and substitution-based analyses. Consistent protective effects of aerobic exercise and high-quality sleep may be associated with favorable metabolic profiles and ocular perfusion, potentially mitigating retinal ganglion cell loss. Conversely, smoking and alcohol use are frequently coupled with poorer diet quality (e.g., lower vegetable intake) and heightened oxidative stress, which may exacerbate glaucomatous neurodegeneration. However, much of the current literature is constrained by cross-sectional designs, reliance on self-reported food frequency questionnaires, and insufficient use of structural endpoints such as retinal nerve fiber layer imaging. This review focuses on the potential of lifestyle modification and future directions in prevention and treatment strategies for glaucoma, highlighting the need for large-scale, multi-ethnic, genotype-stratified longitudinal studies and randomized controlled trials to establish causality and define optimal intervention strategies. Full article