Search Results (472)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier dysfunction, oxidative stress (OS), and neuroinflammation. Current treatments provide symptomatic relief, but do not halt the disease’s progression. OS plays a crucial role in AD pathogenesis by promoting Aβ accumulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the antioxidant response, influencing genes involved in OS mitigation, mitochondrial function, and inflammation. Dysregulation of NRF2 is implicated in AD, making it a promising therapeutic target. Emerging evidence suggests that adherence to a Mediterranean diet (MD), which is particularly rich in polyphenols from extra virgin olive oil (EVOO), is associated with improved cognitive function and a reduced risk of mild cognitive impairment. Polyphenols can activate NRF2, enhancing endogenous antioxidant defenses. This study employs a computational approach to explore the potential of bioactive compounds in EVOO to modulate NRF2-related pathways in AD. We analyzed transcriptomic data from AD and EVOO-treated samples to identify NRF2-associated genes, and used chemical structure-based analysis to compare EVOO’s bioactive compounds with known NRF2 activators. Enrichment analysis was performed to identify common biological functions between NRF2-, EVOO-, and AD-related pathways. Our findings highlight important factors and biological functions that provide new insight into the molecular mechanisms through which EVOO consumption might influence cellular pathways associated with AD via modulation of the NRF2 pathway. The presented approach provides a different perspective in the discovery of compounds that may contribute to neuroprotective mechanisms in the context of AD. Full article

Background: Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. Methods: We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. Results: PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα^−/− mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood–brain barrier (BBB) function, pointing to broader systemic toxicity. Conclusions: Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence suggests a crucial role of lipid signaling pathways in AD pathogenesis, particularly those mediated by autotaxin (ATX) and lysophosphatidic acid (LPA). ATX, an enzyme responsible for LPA production, has been implicated in neuroinflammatory processes, blood–brain barrier dysfunction, and neuronal degeneration. LPA signaling, through its interaction with specific G-protein-coupled receptors, influences neuroinflammation, synaptic plasticity, and tau pathology, all of which contribute to AD progression. This review synthesizes recent findings on the ATX/LPA axis in AD, exploring its potential as a biomarker and therapeutic target. Understanding the mechanistic links between ATX, LPA, and AD pathology may open new avenues for disease-modifying strategies. Full article

Post-traumatic stress disorder (PTSD) has traditionally been viewed as a psychiatric disorder of fear, memory, and emotional regulation. However, growing evidence implicates systemic and neuroinflammation as key contributors. Individuals with PTSD often exhibit elevated blood levels of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and C-reactive protein, indicating immune dysregulation. Dysfunctions in the hypothalamic–pituitary–adrenal (HPA) axis marked by reduced cortisol levels impair the body’s ability to regulate inflammation, allowing persistent immune activation. Circulating cytokines cross a weakened blood–brain barrier and activate microglia, which release additional inflammatory mediators. This neuroinflammatory loop can damage brain circuits critical to emotion processing including the hippocampus, amygdala, and prefrontal cortex, and disrupt neurotransmitter systems like serotonin and glutamate, potentially explaining PTSD symptoms such as hyperarousal and persistent fear memories. Rodent models of PTSD show similar inflammatory profiles, reinforcing the role of neuroinflammation in disease pathology. Bromo-epi-androsterone (BEA), a synthetic analog of dehydroepiandrosterone (DHEA), has shown potent anti-inflammatory effects in clinical trials, significantly reducing IL-1β, IL-6, and TNF-α. By modulating immune activity, BEA represents a promising candidate for mitigating neuroinflammation and its downstream effects in PTSD. These findings support the rationale for initiating clinical trials of BEA as a novel therapeutic intervention for PTSD. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuronal loss, α-synuclein aggregation, and chronic neuroinflammation. Recent evidence suggests that exosomal microRNAs (miRNAs)—small, non-coding RNAs encapsulated in extracellular vesicles—are key regulators of PD pathophysiology and promising candidates for biomarker development and therapeutic intervention. Exosomes facilitate intercellular communication, cross the blood–brain barrier, and protect miRNAs from degradation, rendering them suitable for non-invasive diagnostics and targeted delivery. Specific exosomal miRNAs modulate neuroinflammatory cascades, oxidative stress, and synaptic dysfunction, and their altered expression in cerebrospinal fluid and plasma correlates with disease onset, severity, and progression. Despite their translational promise, challenges persist, including methodological variability in exosome isolation, miRNA profiling, and delivery strategies. This review integrates findings from preclinical models, patient-derived samples, and systems biology to delineate the functional impact of exosomal miRNAs in PD. We propose mechanistic hypotheses linking miRNA dysregulation to molecular pathogenesis and present an interactome model highlighting therapeutic nodes. Advancing exosomal miRNA research may transform the clinical management of PD by enabling earlier diagnosis, molecular stratification, and the development of disease-modifying therapies. Full article

Background: Oligopeptides from sea cucumber eggs (SCEPs) are rarely studied for their neuroprotective effects. Methods: Therefore, we prepared SCEPs via simulated gastrointestinal digestion and then administered them to an Alzheimer’s disease (AD) mouse model via gavage. Behavior tests, gut–brain histopathology and fecal microbiota transplantation (FMT) experiments were conducted, and gut microbiota and metabolite short-chain fatty acids (SCFAs) were evaluated via 16sRNA gene sequencing and LC-MS. Results: The results showed that both the SCEP and FMT groups experienced improvements in the cognitive impairments of AD and showed reduced levels of Aβ, P-Tau, GFAP, and NFL in the brain, especially in the hippocampus. SCEP remodeled the gut microbiota, increasing the relative abundances of Turicibacter and Lactobacillus by 2.7- and 4.8-fold compared with the model at the genus level. In the SCEP and FMT treatments, four SCFA-producing bacteria obtained from gut microbiota profiling showed consistent trends, indicating that they may be involved in mediating the neuroprotective effects of SCEP. Mechanically, SCEP regulated the SCFA distribution in feces, blood, and the brain, greatly increased the content of SCFAs in the brain up to 2000 μg/mg, eased gut–brain barrier dysfunction, inhibited HDAC3 overexpression, and upregulated BDNF/NT3 levels. Conclusions: This study provides a promising candidate for preventing AD and a reference for applying SCEP. Full article

Blood–brain barrier (BBB) dysfunction is a hallmark of cerebral small vessel disease (cSVD). This study aimed to identify a mouse model that replicates BBB impairment and shares key cSVD risk factors. Transgenic db/db and LDLr^−/−.Leiden mice, both prone to obesity and hypertension, were compared to C57BL/6J controls. BBB leakage was assessed using DCE-MRI and sodium fluorescein (NaFl); cerebral blood flow (CBF) by MRI. Dyslipidemia and vascular inflammation were measured by plasma tests. Tight junction integrity, endothelial dysfunction (glucose transporter 1, GLUT-1) and neuroinflammation were evaluated with immunohistochemistry and PCR. Both transgenic models developed an obese phenotype with hyperinsulinemia, but only LDLr^−/−.Leiden mice showed human-like dyslipidemia. When fed a high-fat diet (HFD) or HFD plus cholesterol, LDLr^−/−.Leiden mice showed reduced CBF, endothelial dysfunction (lowered GLUT-1), elevated vascular inflammation (ICAM-1, VCAM-1, S-selectin), and BBB leakage, as evidenced by DCE-MRI and NaFl, together with reduced ZO-1 and claudin-5 expression. Contrastingly, db/db mice showed endothelial dysfunction without BBB leakage. Neuroinflammation (IBA-1, GFAP) was observed only in LDLr^−/−.Leiden groups, consistent with BBB disruption. These findings indicate that LDLr^−/−.Leiden mice, but not db/db mice, are a promising translational model for studying BBB dysfunction in cSVD, offering insights into disease mechanisms and a platform for therapeutic development. Full article

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by mitochondrial dysfunction, increased reactive oxygen species (ROS), α-synuclein (α-syn) and phosphorylated-tau protein (p-tau) aggregation, and dopaminergic neuron cell death. Current drug therapies only provide temporary symptomatic relief and fail to stop or reverse disease progression due to the severe side effects or the blood–brain barrier. This study aimed to investigate the neuroprotective effects of an intermittent heating approach, thermal cycling-hyperthermia (TC-HT), in an in vitro PD model using rotenone (ROT)-induced human neural SH-SY5Y cells. Our results revealed that TC-HT pretreatment conferred neuroprotective effects in the ROT-induced in vitro PD model using human SH-SY5Y neuronal cells, including reducing ROT-induced mitochondrial apoptosis and ROS accumulation in SH-SY5Y cells. In addition, TC-HT also inhibited the expression of α-syn and p-tau through heat-activated pathways associated with sirtuin 1 (SIRT1) and heat-shock protein 70 (Hsp70), involved in protein chaperoning, and resulted in the phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), which inhibit p-tau formation. These findings underscore the potential of TC-HT as an effective treatment for PD in vitro, supporting its further investigation in in vivo models with focused ultrasound (FUS) as a feasible heat-delivery approach. Full article

Epilepsy is one of the most prevalent chronic medical conditions that really can affect individuals at any age. A broader study of the pathogenesis of the epileptic condition will probably serve as the cornerstone for the development of new antiepileptic remedies that aim to treat epilepsy symptomatically as well as prevent the epileptogenesis process or regulate its progression. Cellular changes in the brain include oxidative stress, neuroinflammation, inflammatory cell invasion, angiogenesis, and extracellular matrix associated changes. The extensive molecular profiling of epileptogenic tissue has revealed details on the molecular pathways that might start and sustain cellular changes. In healthy brains, epilepsy develops because of vascular disruptions, such as blood–brain barrier permeability and pathologic angiogenesis. Key inflammatory mediators are elevated during epileptic seizures, increasing the risk of recurrent seizures and resulting in secondary brain injury. Prostaglandins and cytokines are well-known inflammatory mediators in the brain and, after seizures, their production is increased. These inflammatory mediators may serve as therapeutic targets in the clinical research of novel antiepileptic medications. The functions of inflammatory mediators in epileptogenesis are covered in this review. Oxidative stress also plays a significant role in the pathogenesis of various neurological disorders, specifically epilepsy. Antioxidant therapy seems to be crucial for treating epileptic patients, as it prevents neuronal death by scavenging excess free radicals formed during the epileptic condition. The significance of antioxidants in mitochondrial dysfunction prevention and the relationship between oxidative stress and inflammation in epileptic patients are the major sections covered in this review. Full article

Alzheimer’s disease (AD) impacts more than half a million people worldwide, with no cure available. The regulatory approval of three anti-amyloid monoclonal antibodies (mAbs), including aducanumab, lecanemab, and donanemab, has established immunotherapy as a therapeutic approach to modify disease progression. Its multifactorial pathology, which involves amyloid-β (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and cerebrovascular dysfunction, limits the efficacy of single-target therapies. The restricted blood–brain barrier (BBB) penetration and amyloid-related imaging abnormalities (ARIA), together with small treatment effects, demonstrate the necessity for advanced biologic therapies. Protein engineering advancements have created bispecific antibodies that bind to pathological proteins (e.g., Aβ, tau) and BBB shuttle receptors to boost brain delivery and dual therapeutic effects. This review combines existing information about antibody-based therapy in AD by focusing on bispecific antibody formats and their preclinical and clinical development, as well as biomarker-based patient selection and upcoming combination strategies. The combination of rationally designed bispecific antibodies with fluid and imaging biomarkers could show potential for overcoming existing therapeutic challenges and delivering significant clinical advantages. Full article

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article

The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood–brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus–immune–brain axis in long COVID and inform effective clinical management. Full article

Background: Huntington’s Disease (HD) remains without disease-modifying treatments, with existing therapies primarily targeting chorea symptoms and offering limited benefits. This study aims to identify druggable genes and potential biomarkers for HD, focusing on using RNA-Seq analysis to uncover molecular targets and improve clinical trial outcomes. Methods: We reanalyzed transcriptomic data from six independent studies comparing cortex samples of HD patients and healthy controls. The Propensity Score Matching (PSM) algorithm was applied to match cases and controls by age. Differential expression analysis (DEA) coupled with machine learning algorithms were coupled to identify differentially expressed genes (DEGs) and potential biomarkers in HD. Results: Our analysis identified 5834 DEGs, including 394 putative druggable genes involved in processes like neuroinflammation, metal ion dysregulation, and blood–brain barrier dysfunction. These genes’ expression levels correlated with CAG repeat length, disease onset, and progression. We also identified FTH1 as a promising biomarker for HD, with its expression downregulated in the prefrontal cortex and upregulated in peripheral blood in a CAG repeat-dependent manner. Conclusions: This study highlights the potential of FTH1 as both a biomarker and a therapeutic target for HD. Advanced bioinformatics approaches like RNA-Seq and PSM are crucial for uncovering novel targets in HD, paving the way for better therapeutic interventions and improved clinical trial outcomes. Further validation of FTH1′s role is needed to confirm its utility in HD. Full article

Plastics pollution is a critical global environmental issue, with growing concern over the increasing presence of nanoplastic particles. Plastics are major environmental pollutants that adversely affect human health, particularly when plastics from food sources enter the body and pose potential risks to reproductive health. Echinacea purpurea is an immunologically active medicinal plant containing phenolic acids and alkylamides. Nanoparticles present a promising approach to enhance the effectiveness, stability, and bioavailability of Echinacea purpurea ethanol extract (EE) active components. This study aimed to determine the protective effects of chitosan-silica-Echinacea purpurea nanoparticles (CSE) against reproductive injury induced by polystyrene nanoplastics (PS-NPs) in male rats. The results showed that CSE dose-dependently reduced oxidative damage and protected intestinal and reproductive health. Furthermore, CSE improved gut microbiota dysbiosis, preserved barrier integrity, and attenuated PS-NPs-induced inflammation in the colon, brain, and gonads. Inflammatory factors released from the gut can enter the bloodstream, cross the blood–brain barrier, and potentially modulate the hypothalamic–pituitary–gonadal (HPG) axis. CSE has also been shown to elevate neurotransmitter levels in the colon and brain, thereby repairing HPG axis dysregulation caused by PS-NPs through gut–brain communication and improving reproductive dysfunction. This study enhances our understanding of CSE in modulating the gut–brain and HPG axes under PS-NPs-induced damage. CSE demonstrates the capacity to provide protection and facilitate recovery by mitigating oxidative stress and inflammation, restoring gut microbiota balance, and preserving hormone levels in the context of PS-NPs-induced injury. Full article