Search Results (1,602)

The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington’s disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 µM), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS. Full article

Inflammatory bowel disease (IBD) is increasingly recognized as a systemic inflammatory disorder associated with elevated long-term risk of ischemic stroke, even among younger individuals without traditional vascular risk factors. Although chronic inflammation, endothelial dysfunction, and hypercoagulability partially explain this association, the biological mechanisms linking intestinal inflammation to cerebral vascular injury remain incompletely defined. Extracellular vesicles (EVs), membrane-bound particles released by epithelial, immune cells and platelets, have emerged as potent mediators of intercellular communication in inflammatory states. In IBD, circulating EVs are enriched with pro-inflammatory cytokines, microRNAs, adhesion molecules, tissue factors, which are capable of promoting endothelial activation, blood–brain barrier disruption, immune-thrombosis and neuroinflammation. This review summarizes epidemiologic, vascular, and EV biology literature to propose a mechanistic framework in which EV-mediated signaling integrates intestinal inflammation with cerebrovascular vulnerability along the gut–vascular–brain axis. While direct causal evidence remains limited, converging mechanistic data supports biological plausibility and defines priorities for future experimental and translational investigation. Full article

Background: Neurodegenerative diseases are a major health problem, and the neuropsychiatric symptoms seen in these diseases adversely impact the lives of patients, families, and caregivers. Inappropriate aggressive behavior is a highly disruptive symptom and a leading cause of institutionalization. There are no approved drugs specifically for the treatment of problematic aggression, and the off-label use of antipsychotics has limited benefit with significant side effects and safety risks. This review discusses dysregulated arginine vasopressin (AVP) signaling in fear–threat circuitry as a key driver of inappropriate aggression. Because the AVP 1a receptor (V1aR) is the dominant subtype in the CNS, the selective antagonism of this receptor represents a well-rationalized target for the treatment of aggression across neurodegenerative, psychiatric, and neurodevelopmental disorders. Objectives: Our goal was to summarize the basis for using V1aR antagonists as a treatment for irritability and aggressive behavior. We describe its discovery, biosynthesis, receptor pharmacology, and CNS distribution, emphasizing V1aR localization in central fear–threat circuits. Translational evidence from animal studies, pharmacological neuroimaging, and lesion network mapping is presented. These data support the suggestion that heightened vasopressinergic tone biases socioemotional information processing toward negative valence, increasing threat sensitivity and the likelihood of inappropriate aggressive responses. Emerging clinical data support this framework. Highly selective, CNS-penetrant V1aR antagonists reduced aggressive behavior and had an excellent safety profile in phase 2 studies in Huntington’s disease and intermittent explosive disorder, with efficacy signals across caregiver-reported, clinician-rated, and incident-based measures. Furthermore, pharmacological neuroimaging showed that V1aR antagonism normalizes AVP-induced alterations in activity within fear–threat circuitry. Conclusions and Future Directions: Preclinical, translational, and clinical findings to date support V1aR antagonism as a promising strategy for treating pathological aggression across disorders. Additional experimental medicine studies and clinical trials are needed to conclusively establish efficacy in various disease populations, and we note the need for improved trial designs and analytical methods as part of the development process. Full article

Background: In Parkinson’s disease (PD), changes in the brain begin before clinical symptoms. We have previously shown that VGF precursor levels were reduced in a presymptomatic PD animal model. Objectives: In the present study, we investigated whether two VGF precursor-derived products, namely NAPP-129 protein and TLQP-62 peptide, also exhibit alterations using the same PD animal model. Methods: Specifically, rats were unilaterally injected in the substantia nigra with a viral vector overexpressing green fluorescent protein (N = 12) or α-synuclein (N = 13), the latter resulting in mild dopaminergic alterations without overt motor deficits. Results: NAPP-129 and TLQP-62 were investigated in the substantia nigra, striatum, and plasma by Western blotting or immunoassays using specific antibodies against NAPP and TLQP sequences, alongside other NERP-1- and AQEE-related products. Plasma samples of a Huntington’s disease mouse model were also analyzed. We found reductions in NAPP-129 and TLQP-62 levels in the substantia nigra along with a decrease in NAPP- and TLQP-like plasma immunoreactivity in α-synuclein-overexpressed rats, while the striatum was not affected. NERP-1- and AQEE-related products were not altered. No changes were found in the Huntington’s disease model. Conclusions: These findings indicate that NAPP-129 and TLQP-62 may enhance the sensitivity and specificity of biomarker-based strategies for PD. Full article

Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease. Full article

Exosomes (EXs) mediate intercellular communication in the tissue microenvironment. We previously demonstrated that endothelial progenitor cell-derived exosomes (EPC-EXs) from exercised mice protect neurons and cerebral endothelial cells from hypoxia- and hypertension- induced injury ex vivo, suggesting their therapeutic potential in hypertensive ischemic injury. Here, we investigated whether exercise-conditioned EPC-EXs (ET-EPC-EXs) confer protection against acute ischemic injury. Hypertensive transgenic mice were divided into donor and recipient groups. Donor mice underwent treadmill exercise to generate ET-EPC-EXs. Recipient mice was subjected to middle cerebral artery occlusion and received ET-EPC-EXs via tail vein injection (2 × 10⁸/100 μL saline) two hours after stroke onset. Cerebral blood flow (CBF) was assessed, and brains were collected on day two for histological and molecular analyses. Our data showed that ET-EPC-EXs were robustly taken up by cerebral cells, predominantly in the penumbra in the ipsilateral hemisphere. ET-EPC-EXs reduced cell death and microglia activation and restored tight-junction proteins. Moreover, ET-EPC-EX treatment preserved CBF and improved sensorimotor function on day two post-stroke. Mechanistically, ET-EPC-EXs suppressed p38 activation, accompanied by reduced matrix metalloproteinase-3 and cytochrome c levels in the ipsilateral brain. Collectively, these findings demonstrate that EPC-EXs from exercise mice improve sensorimotor functions and confer protection in hypertensive ischemic brain injury, likely through attenuation of neuroinflammation and preservation of vascular integrity via modulation of the p38 signaling. Full article

Neurodegenerative diseases such as Alzheimer’s (AD) and Huntington’s (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation. Full article

Neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies—such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications—aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading driver of hepatocellular carcinoma (HCC) worldwide. A substantial proportion of MASLD-related HCC arises in the noncirrhotic liver, highlighting critical gaps in current surveillance strategies that rely primarily on fibrosis stage to define risk. Although the annual incidence of HCC in noncirrhotic MASLD is low and does not justify universal surveillance, the extraordinary global prevalence of MASLD translates into a considerable absolute burden of cancer. Accumulating evidence demonstrates that HCC risk in MASLD is modulated not only by histologic severity but also by metabolic comorbidities, particularly type 2 diabetes mellitus, which can significantly amplify cancer risk even in pre-cirrhotic stages. From both clinical and health economic perspectives, these observations underscore the need for more complex and targeted surveillance approaches. This review synthesizes current epidemiologic data, metabolic and histologic modifiers of HCC risk, emerging biomarkers, and predictive models in MASLD, with a focus on noncirrhotic disease. We discuss how integrated, precision-based risk assessment may identify high-risk MASLD subgroups and enable targeted, cost-effective surveillance strategies to mitigate the growing burden of MASLD-associated HCC. Full article

Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer’s disease, Parkinson’s disease (PD), and Huntington’s disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease. Full article

Background: Squamous cell carcinoma of head and neck (SCCHN) is a devastating disease with high morbidity and mortality and the 6th most common cancer worldwide. The 5-year relative survival for advanced-stage disease is below 50%, stressing the need for chemoprevention. In the current study, we investigated the chemopreventive efficacy of the combination of resveratrol and epigallocatechin gallate (EGCG). Methods: We used the 4-Nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis model. C57BL/6 mice were exposed to drinking water containing 4-NQO for 10 weeks. From week 11, mice were treated with vehicle, resveratrol, EGCG and their combination until week 22. RNASeq, qPCR and in silico analysis were performed identifying differentially expressed genes and enriched pathways. Results: Resveratrol alone and in combination with EGCG significantly inhibited the number of visible lesions, whereas the number of microscopic lesions and lesion areas were significantly inhibited only by the combination. The expression of Ki-67 was also significantly inhibited in resveratrol and combination groups. Growth differentiation factor 15 (GDF15), Activation transcription factor 3 (ATF3) and several other genes associated with xenobiotic metabolism as significantly upregulated genes, with GDF15 being the most upregulated one. Furthermore, hallmarks of xenobiotic metabolism and several other anticancer pathways were enriched after treatment with resveratrol and the combination. Conclusions: Our data strongly demonstrate the chemopreventive potential of the combination of resveratrol and EGCG and pave the way for further clinical developments. Full article

This paper aims to present a non-destructive, optimized variational mode decomposition (VMD)-based ground-penetrating radar (GPR) method developed for identifying void defects in reinforced concrete (RC) structures. This study also presents an enhanced framework for defect detection in RC by integrating advanced spectrum analysis with deep learning techniques. A GPR investigation was conducted on an RC bridge deck with known structural defects to generate a representative dataset reflecting both intact and void-defective conditions. In addition to conventional spectral techniques such as fast Fourier transform (FFT), spectrogram, and scalogram, an optimized variational mode decomposition (VMD) method was implemented. The VMD approach decomposes GPR signals into intrinsic mode functions, enabling refined feature extraction beyond traditional spectral methods and allowing clear differentiation between intact and defective signals. The limited availability and quality of GPR small datasets have restricted the application of a functional 1D-CNN which generally requires at least several hundred datasets. To address this challenge, a data augmentation strategy is adopted. FFT-based features were successfully utilized to train a one-dimensional convolutional neural network (1D-CNN) for automated defect identification. The results demonstrate that both the advanced spectrum-based approach and the hybrid framework combining spectral analysis with deep learning significantly improve defect detection performance. Overall, the proposed methodology provides an effective and intelligent solution to support timely, data-driven decision-making for maintenance and safety assurance of bridge infrastructure. Full article

The 3-nitropropionic acid (NPA) promotes neurological alterations in the striatum, hippocampus and vicinal motor and pre-motor cortical areas, and in the cerebellum. The neurological alterations induced by systemic NPA administration resemble those found in Huntington’s disease. In previous works, we have shown that intraperitoneal (i.p.) administration of kaempferol can efficiently protect against striatum degeneration and against motor neurological dysfunctions induced by NPA. In this work, we show that i.p. administration of kaempferol also protects against the increase in pro-inflammatory cytokines that potentiate the activation of complement C3 protein (a biomarker of A1-type reactive astrocytes generation) and overproduction of neurotoxic amyloid β (Aβ) peptides in the cerebellum of rats treated with acute i.p. administration of NPA. In NPA-treated rats, large multipolar neurons of cerebellar nuclei and Purkinje neurons of the cerebellar cortex are the cells that are most intensely stained by anti-C3 and by anti-Aβ antibodies. In addition, we found that kaempferol also protects against the NPA-induced increase in phospho-tau 217 and phospho-tau 181 in the cerebellum, and our results pointed out that the NPA-induced phospho-tau 217 colocalizes with Aβ(1-42) more closely than phospho-tau 181, both in dentate nucleus and cerebellar cortex. Also, our results unveil another novel brain-protective action of i.p. kaempferol co-administration: namely, its ability to prevent microhemorrhages induced in the cerebellar nuclei area by acute NPA administration. In conclusion, the results of this work show a potent protection of kaempferol against the NPA-induced increase in degeneration biomarkers in the cerebellum. Full article

Nicotine damages the cardiovascular system in a variety of ways, from promoting inflammation to causing oxidative stress to prompting unnecessary autophagy. The alteration to the nervous system that yields nicotine dependence further exacerbates the negative impact that nicotine use has on public health. Nicotine use has also been found to cause alterations in exosome content, especially miRNA. Conversely, exosomes have also had promising results as treatments for nicotine-mediated alterations in protein and miRNA levels. However, although nicotine has been shown to both alter exosome content and exacerbate stroke outcomes, the relationship between these two functions is poorly understood. This review examines multiple sources to compare available data. Several factors in nicotine’s effect on exosome content were thus found that imply a correlation. Also, exosome contents are not only a viable biomarker for multiple conditions, including ischemic brain damage and tobacco use, but they are also able to influence the cells of test subjects, both as a treatment for ischemic stroke and as a regulator of healthy brain function in stroke-free test subjects. Taken together, previous evidence suggests that nicotine-mediated alterations in neuronal exosome content have an effect on the progression of stroke in nicotine users. Full article

Neurodegenerative diseases share a mitochondrial–immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII₂, CIII₂-CIV_n, or CI-CIII₂-CIV_n) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis, and Huntington’s models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes. Full article