Search Results (697)

Retinal ischemia is a key factor in the progression of vision-threatening ocular diseases, including central retinal artery/vein occlusion, exudative age-related macular degeneration (eAMD), and proliferative diabetic retinopathy. This study investigates the effects of paeoniflorin along with its related neuroprotective molecular pathways in the treatment of retinal ischemia. Free radical or ischemic-like damage was induced by incubating retinal pigment epithelium (RPE) cells for 24 h with 1 mM hydrogen peroxide (H₂O₂) or by subjecting retinal neuronal cells to 8 h of oxygen–glucose deprivation (OGD). Both treatments caused significant cell loss. Treatment with paeoniflorin significantly increased cell viability at 0.5 mM in both cell types. In a Wistar rat model of retinal ischemia and reperfusion (I/R) elicited by sustained high intraocular pressure (HIOP), pre-treatment with 0.5 mM paeoniflorin mitigated the ischemia-induced decline in ERG b-wave amplitude, reduction in whole and inner retinal thickness, loss of fluorogold-labeled retinal ganglion cells, and formation of apoptotic cells. Meanwhile, paeoniflorin effectively downregulated pro-neovascular mediators β-catenin, hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and the pro-inflammatory/angiogenic biomarker angiopoietin-2 (Ang-2), producing effects similar to the Wnt/β-catenin inhibitor (dickkopf-related protein 1), anti-angiogenic pigment epithelium-derived factor (PEDF), and anti-VEGF Avastin (bevacizumab). These findings suggest that paeoniflorin may protect against retinal ischemia through its anti-inflammatory, anti-neovascular/angiogenic, antioxidative, and neuroprotective properties. Full article

Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic β-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K/Akt and MAPK/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease. Full article

Various clinical studies aimed at modifying the progression of idiopathic Parkinson’s disease have been unsuccessful. Similarly, several nutritional trials using bioactive compounds have shown positive effects for patients but have also failed to slow or reduce the disease’s progression. This repeated failure is likely because these studies ignore the extremely slow neurodegenerative process, which unfolds over many years. The molecular mechanism behind the loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal system in idiopathic Parkinson’s disease remains unclear. This is a conceptual/theoretical review based mainly on mechanistic and preclinical evidence, with no direct clinical data. However, research suggests that aminochrome, an endogenous neurotoxin, may trigger the degeneration of these neurons through a single-neuron degeneration model. In this model, aminochrome selectively destroys individual neurons without spreading to neighboring cells. Aminochrome is produced during neuromelanin synthesis, a process that is normally harmless because protective enzymes like DT-diaphorase and glutathione transferase M2-2 neutralize aminochrome’s neurotoxic effects. Increasing the levels of these enzymes could offer neuroprotection. The KEAP1/NRF2 signaling pathway is critical for regulating antioxidant enzymes, such as DT-diaphorase and glutathione transferase M2-2. Importantly, specific bioactive compounds from food can activate this pathway, increasing the production of these protective enzymes. For instance, the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), along with astaxanthin—a compound present in cold-water fish like salmon—have been demonstrated to enhance enzyme expression. This connection leads to a compelling question: Could dietary interventions help prevent idiopathic Parkinson’s disease? Answering this will require further research. Full article

The cytoskeleton relies heavily on the dynamic nature of microtubules, regulated by post-translational modifications such as polyglutamylation and deglutamylation. Disruption of its internal balance, particularly through the absence of cytosolic carboxypeptidase 1 (CCP1), leads to cytoskeletal collapse and cell death. An example of this occurrence exists in the Purkinje Cell Degeneration (PCD) mouse, a direct animal model for childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) human disease. Both CONDCA patients and PCD mice suffer a dramatic degeneration of Purkinje cells. Intriguingly, lobe X appears less vulnerable to this insult. This study revealed in wild-type mice that lobe X expresses less Ccp1 compared to other lobes, correlating with its delayed degeneration in PCD mice. Further expression analysis of other deglutamylating enzymes (CCP4 and CCP6) and glutamylating enzymes (TTLL1) revealed distinctive patterns: Ccp4 showed minimal relevance in cerebellum, while Ccp6 displayed a compensatory increase during critical stages. Meanwhile, Ttll1 expression remained consistent across lobes, suggesting that the resistance of lobe X may be related to a more dynamic, hyperglutamylated cytoskeleton. Unraveling the neuroresistance mechanisms of Purkinje cells may help mitigate neuronal loss in CONDCA patients and may offer a glimmer of hope for alleviating the symptoms of other neurodegenerative diseases. Full article

Colorectal cancer remains one of the leading causes of cancer-related mortality both in Japan and worldwide. Oxaliplatin (L-OHP) is a key chemotherapeutic agent used in the treatment of colorectal and other malignancies; however, its clinical use is often limited by the development of oxaliplatin-induced peripheral neuropathy (OIPN). In this study, we investigated ergothioneine (EGT), a natural antioxidant abundant in mushrooms, for its potential to mitigate OIPN without compromising the antitumor efficacy of L-OHP. Using the SH-SY5Y neuroblastoma cell line and differentiated neurons, we assessed the effects of EGT on L-OHP-induced apoptosis, oxidative stress, and axonal degeneration. We further evaluated whether EGT interferes with the anticancer activity of L-OHP using cultured cancer cell lines and a tumor-bearing mouse model. EGT suppressed L-OHP-induced apoptosis in neuronal cells and preserved axonal structures in differentiated neurons. Importantly, EGT had no adverse effect on the antitumor efficacy of L-OHP, as evidenced by unchanged cancer cell proliferation, tumor volume, and body weight in treated mice. These findings suggest that EGT may be a promising adjuvant for preventing OIPN while maintaining the therapeutic benefits of L-OHP. Full article

Background: Currently, there are limited therapeutic or preventative strategies for neurodegenerative disorders due to the challenges in alleviating the progressive neuronal loss and neuroinflammation which are the primary characteristics of these diseases, ultimately leading to cell death and functional impairment. Cocoa-derived flavanols (Theobroma cacao) have been studied as potential bioactive compounds to modify and reverse various inflammation-associated diseases because of their remarkable antioxidant properties and capacity to modulate metabolic imbalance and reactive inflammatory responses. The faba bean (Vicia faba) extract obtained through nondenaturing biotechnological processes is a potent dopamine (DA) enhancer that has shown promising results as a neuroprotective agent against degeneration. Objective: This study will examine the synergistic effects of Neurofabine-C, a hybrid compound derived from cocoa and faba bean extracts, on various brain biomarkers in mice related to inflammatory, metabolic, and neurodegenerative processes. Methods: A triple-transgenic mouse model of neurodegeneration was treated with Neurofabine-C, and biomolecular data were obtained by performing biochemical and immunohistochemical analysis. Results: Neurofabine-C prevented neuronal degeneration (NeuN), mitigated the neuro-inflammatory processes triggered (decreased expression of reactive astrocytes (GFAP)), and induced an increase in neurogenesis in the treated cortical mice brain (PAX6). Epigenetic analysis revealed significant chromatin remodeling in the hippocampus. Neuroprotective genes, including FOXO3, ATM, and TRP73, were upregulated, whereas the expression of HIF1α and APOE decreased. In parallel, DNMT3A expression increased 20-fold, HDAC3 decreased by 60%, and global 5-methylcytosine levels increased four-fold. These coordinated changes suggest that Neurofabine-C promotes neuroprotective programs through enhanced DNA methylation and reduced histone deacetylation. Conclusions: The findings indicate that Neurofabine-C exhibits multiple neuroprotective mechanisms, making it a potent bioproduct for mitigating neuroinflammatory processes associated with neurodegenerative disorders. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons (DNs) and movement disorders. Low efficiency of pharmacotherapy requires improvement, e.g., using receptor agonists or antagonists as drugs. Our work aims to initiate these developments by studying the expression levels of genes encoding neurotransmitters, neuropeptides and hormone receptors in substantia nigra pars compacta (SNpc) cells and in isolated DNs in intact mice, and changes in expression of these genes in MPTP mouse models of PD at preclinical and clinical stages. Expression of all 12 studied genes was detected in the SNpc and only 10 in DNs—Cckar and Glp1r were undetectable. In intact mice, the expression of Drd2, Grin2b, Grm1 and Ntsr2 predominates in SNpc tissue, whereas that of Gria2, Chrnb2, Gper1, Igf1r is higher in DNs. In PD models, change in receptor gene expression was detected in DNs but not in SNpc tissue. In the preclinical PD, Drd2 expression increased and Gria2 decreased, whereas in a clinical model, Drd2, Grm1, Ntsr2 expression decreased. Thus, the above genes are expressed in DNs and other cells of SNpc; expression of some genes changes in PD models, which opens up prospects for development of therapy using receptor agonists and antagonists. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and progressive cognitive decline. Recent evidence has highlighted the role of blood–brain barrier (BBB) dysfunction in the early stages of AD pathology. Objective: We sought to explore the histological structure and physiological function of the blood–brain barrier, and to identify the shared pathological mechanisms between BBB disruption and Alzheimer’s disease progression. Methods: This narrative review was conducted through a comprehensive search of peer-reviewed literature from 1997 to 2024, using databases such as PubMed, Elsevier, Scopus, and Google Scholar. Results: Multiple histological and cellular components—including endothelial cells, pericytes, astrocytes, and tight junctions—contribute to BBB integrity. The breakdown of this barrier in AD is associated with chronic inflammation, oxidative stress, vascular injury, pericyte degeneration, astrocyte polarity loss, and dysfunction of nutrient transport systems like Glucose Transporter Type 1 (GLUT1). These alterations promote neuroinflammation, amyloid-β (Aβ) accumulation, and progressive neuronal damage. Conclusions: BBB dysfunction is not merely a consequence of AD but may act as an early and active driver of its pathogenesis. Understanding the mechanisms of BBB breakdown can lead to early diagnostic markers and novel therapeutic strategies aimed at preserving or restoring barrier integrity in Alzheimer’s disease. Full article

The ovary is among the earliest organs to undergo age-related degeneration, limiting the reproductive potential of elite horses and constraining the growth of the equine industry. Follicular development during estrus is a key determinant of fertility, yet the molecular mechanisms underlying its decline, particularly at the level of specific ovarian cell types, remain poorly understood in equids. Here, we constructed a single-cell transcriptomic atlas to investigate ovarian changes in Kazakh horses. Using single-cell RNA sequencing (scRNA-seq), we profiled 112,861 cells from follicle-containing and follicle-absent ovaries, identifying nine distinct ovarian cell types and their subtypes, each with distinct gene expression signatures. Functional enrichment analyses revealed cell type-specific engagement in biological pathways, including ECM–receptor interaction, PI3K-Akt signaling, and oxytocin signaling. Gene expression patterns indicated tightly regulated processes of ovarian activation and cell differentiation. Notably, stromal cells exhibited high expression of ROBO2, LOC111770199, and TMTC2, while smooth muscle cells (SMCs) were marked by elevated levels of CCL5, KLRD1, and NKG7. Moreover, cell–cell interaction analyses revealed robust signaling interactions among SMCs, endothelial cells, neurons, and proliferating (cycling) cells. Together, these findings provide a comprehensive single-cell transcriptomic map of normal and abnormal ovarian states during estrus in Kazakh horses, offering novel insights into the cellular mechanisms of follicular development and identifying potential diagnostic biomarkers and therapeutic targets for ovarian quiescence in equids. Full article

Although clomipramine (CLO) is widely used as a serotonin reuptake inhibitor, its subchronic administration during the early stages of brain development leads to depressive-like behaviors in adulthood. High doses of CLO have been linked to mitochondrial impairment and increased reactive oxygen species in cells and adult animals. It is unknown whether subchronic administration of this drug at early ages can induce oxidative stress (OS) in adulthood. The objective of this study was to evaluate OS and cellular damage in the prefrontal cortex and limbic system (hippocampus and amygdala) of rats exposed to CLO neonatally. Methods: Forty male Wistar rats were divided into experimental (EXP) and control (CTRL) groups. The EXP animals received CLO (15 mg/kg, twice daily, subcutaneously, postnatal days 5–35); the CTRL animals received saline. At 55 and 85 days of age, the brains were collected for biochemical assays and histological analysis. Results: Rats exposed to neonatal CLO presented significant reductions in reduced glutathione (GSH) and increases in oxidized glutathione (GSSG) and malondialdehyde in both studied regions, especially on day 85. The GSH/GSSG ratio decreased, indicating persistent OS. Histology revealed neuronal degeneration, pyknotic nuclei, cell shrinkage, and disorganized tissue, which progressed from days 55 to 85. Conclusions: Early exposure to CLO can cause long-lasting neurochemical and structural alterations in the brain regions associated with the regulation of emotions and some behavioral responses that can persist over time and affect behavior in adulthood. Full article

Methamphetamine (METH) is a highly addictive synthetic psychostimulant that can induce severe neurotoxicity, leading to neurodegeneration similar to neurodegenerative diseases. The endocytosis of glial cell line-derived neurotrophic factor (GDNF) and its family receptor alpha 1 (GFRα1), regulated by transmembrane receptor tyrosine kinase (RET), has been shown to resist neurodegeneration. Specifically, the endocytosis of GDNF-GFRα1 mediated by RET is crucial in protecting neurons. Although many molecular mechanisms of METH induced neurotoxicity have been explored, the obstacles to the neuroprotective effect of GDNF in the context of METH induced neurotoxicity are still unclear. In this study, an increase in cell apoptosis and GDNF expression was observed in the hippocampus of METH abusers. METH also induces cell degeneration, cytotoxicity, and GDNF expression and release in hippocampal neuronal (HT-22) cells in a concentration-dependent manner (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Meanwhile, after 24 h of exposure to METH (2mM), apoptosis, impaired endocytosis of GDNF-GFRα1, and decreased expression of RET were observed in HT-22 cells and organotypic hippocampal slices of mice. More notably, overexpression of RET weakened METH induced cell degeneration, apoptosis, and disruption of GDNF-GFRα1 endocytosis in HT-22 cells. This study suggests that RET is a key molecule for METH to disrupt GDNF-mediated neuroprotective signaling, and targeting RET-mediated endocytosis of GDNF-GFRα1 may be a potential therapeutic approach for METH induced neurotoxicity and neurodegeneration. Full article

Retinal vasculature is essential for maintaining visual function by supporting metabolically active neurons. However, the retina lacks redundant blood supply, rendering it highly susceptible to vascular dysfunction. Understanding mechanisms of retinal vascular abnormalities is critical for therapies that preserve vascular and neuronal integrity, yet progress has been hindered by limited models and genetic diversity. To address this gap, we examined the retinal vasculature in multiple aged strains from the BXD recombinant inbred mouse panel, a genetically diverse, tractable, and physiologically relevant platform for uncovering novel genetic drivers and disease mechanisms. We identified BXD32 as a striking outlier with dramatically reduced vessel density. Using optical coherence tomography, optical coherence tomography angiography, and histological analyses, we comprehensively characterized retinal vasculature and structural integrity of BXD32 mice during aging. We found progressive, age-dependent vascular dysfunction and degeneration, beginning in the deep capillary plexus and advancing to the intermediate and superficial layers. These changes were accompanied by neuronal degeneration, including photoreceptor loss and thinning of the ganglion cell complex. Our findings establish BXD32 as a spontaneous and genetically tractable model of inherited retinal neurovascular degeneration and provide a foundation for future studies to identify causative genetic loci and underlying molecular mechanisms. Full article

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by progressive degeneration of motor neurons and accumulation of TAR DNA-binding protein 43 (TDP-43) in the brain. Increasing evidence indicates that aberration in lipid synthesis or regulation underlies neuronal dysfunction and degeneration. Phosphatidylethanolmine (PE) is an abundant phospholipid in the brain and is synthesized by the SELENOI gene. SELENOI is important in motor neuron development and function, as demonstrated in hereditary spastic paraplegia, a neurological disorder in which SELENOI is mutated. Despite this, virtually nothing was known about SELENOI in the context of ALS neuropathology. We therefore undertook a comprehensive assessment of PE in ALS brain tissues, using sophisticated liquid chromatography-mass spectrometry, and investigated how SELENOI regulates TDP-43 expression. PE levels were significantly decreased in the disease-affected motor cortex of ALS compared to controls and were inversely associated with disease duration. In contrast, PE levels were unaltered in the disease-unaffected cerebellum. Consistent with this, SELENOI expression was dysregulated only in the motor cortex of ALS. The correlation between SELENOI and TDP-43 was also lost in the motor cortex of ALS. A knockdown of SELENOI expression in neuronal cells caused an upregulation of TDP-43 expression. When put together, these results suggest that SELENOI dysregulation may contribute to TDP-43 pathology in ALS brain. Our study has provided new insights into an unrecognized pathway in ALS brain and revealed new targets for controlling TDP-43 pathology in ALS brain. Full article