Search Results (41)

Introduction: Olives have been used in traditional Mediterranean medicine for thousands of years to address the causes of inflammation, ageing and cognitive health. Traditional preparations of olive include olive oil and olive leaf extract, which are major components of diets that contribute to maintaining cognitive function and reducing neurodegenerative disease risk. Aims of the study: This systematic review aimed to synthesise experimental and limited human evidence on olive biophenols in neurodegenerative disease models, identify the most studied compounds, characterise their mechanisms of action, and evaluate key translational barriers. Materials and methods: Following PRISMA 2020 guidelines and registered with PROSPERO (CRD420251252252), primary studies investigating the effects of well-characterised olive biophenols in neurodegenerative relevant in vitro, in vivo, or human models were systematically reviewed. Each study was assessed for its design, experimental model, mechanistic outcomes and reported limitations. Risk of bias was evaluated using validated tools (SYRCLE/OHAT/ToxR) appropriate for preclinical and experimental study designs. Results: Among the 25 studies, 7 (28.0%) examined oleuropein or oleuropein aglycone, 10 (40.0%) focused on hydroxytyrosol or its derivatives, and 9 (36.0%) investigated oleocanthal. Most studies employed in vivo animal models (57.7%), predominantly transgenic mouse models of AD and toxin-induced PD models. Oleuropein-based studies reported inhibition of amyloid-β and α-synuclein aggregation with behavioural improvements. Hydroxytyrosol primarily exerted antioxidant and anti-inflammatory effects with modest cognitive benefits. Oleocanthal showed the most consistent anti-amyloid and anti-tau activity, including enhanced amyloid-β clearance across the blood–brain barrier. Most studies show a moderate risk of bias due to incomplete reporting, randomisation and blinding. Conclusions: Olive biophenols demonstrate consistent neuroprotective effects in preclinical models; however, translation to clinical application remains limited by pharmacokinetic constraints, methodological heterogeneity, and insufficient human evidence. Full article

Natural anthraquinones possess a wide range of biological activities, including antibacterial, antiviral, antitumor, and antioxidant effects. However, studies on their ability to inhibit amyloid protein aggregation remain relatively limited. In this study, we used insulin as a model protein to investigate the anti-amyloidogenic potential of several natural anthraquinones. Specifically, the inhibitory mechanisms of five anthraquinones (emodin, anthraflavin, aloe-emodin, alizarin, and purpurin) on insulin amyloid fibrillation were explored in both dilute and crowded environments (PEG 2000 and PEG 4000). Multidisciplinary analytical results demonstrated that all five anthraquinones could effectively inhibit insulin amyloid fibrillation in both dilute and crowded environments. Simultaneously, crowded agents themselves also exhibited inhibitory effects on insulin amyloid aggregation. However, the inhibitory efficacy of anthraquinones was weaker in crowded environments than in dilute solutions, indicating that although crowded agents themselves suppressed insulin aggregation, they may interfere with the regulatory roles of anthraquinones on insulin aggregation behavior. Interestingly, purpurin showed stronger inhibitory activity in crowded environments compared to dilute solutions. Furthermore, fluorescence spectral analysis suggested that the quenching mechanism of insulin by all these anthraquinones was identified as static quenching mode. Molecular simulation studies revealed that anthraquinones could bind to the aggregation-prone regions of insulin via hydrogen bonding and hydrophobic interactions, thereby inhibiting insulin amyloid aggregation. Notably, the inhibitory capacity of these compounds was correlated with their structural features and the binding affinities to insulin. Collectively, this study explored the anti-amyloid activity of anthraquinones, which held significant research value for the development of potential therapeutic agents for amyloid-associated proteinopathies. Full article

Late-life Alzheimer’s disease (AD) is increasingly defined by biomarkers, yet in adults aged ≥65 years the relationship between amyloid positivity and near-term cognitive decline is often discordant. Amyloid PET robustly detects fibrillar plaque burden, but it incompletely captures dynamic and potentially neurotoxic amyloid processes, particularly soluble assemblies and oligomer-related “activity.” This review rethinks the late-life AD spectrum by integrating four clinical lenses that frequently drive real-world interpretive uncertainty: (1) amyloid PET positivity as a measure of fibrillar plaque presence and magnitude; (2) plasma amyloid-β oligomerization tendency measured by the multimer detection system (MDS-OAβ) as an activity-oriented (i.e., a dynamic readout hypothesized to reflect ongoing processes rather than cumulative lesion burden), process-linked readout that may decouple from plaque burden; (3) postoperative delirium (POD) as a time-anchored stress-test phenotype revealing vulnerability and reduced resilience under systemic insults; and (4) drug-linked biomarker trajectories, contrasting rapid plaque removal by anti-amyloid monoclonal antibodies with observational signals raising the hypothesis that Ginkgo biloba may be associated with oligomer-related biology and, in some contexts, differences in longitudinal amyloid accumulation trajectories in the absence of observed immediate plaque reduction. We propose a pragmatic multi-axis framework—plaque burden, amyloid activity, downstream engagement, and vulnerability/resilience—to contextualize late-life discordances such as PET positivity without decline, PET negativity with elevated MDS-OAβ, delirium-associated decompensation, and clinical change without rapid PET decline. This synthesis highlights testable predictions and prioritizes longitudinal, multi-marker studies to determine whether activity-oriented biomarkers and stress phenotypes can refine late-life risk stratification beyond plaque-centered models. Full article

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by progressive neuronal loss, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, cholinergic dysfunction, and gut–brain axis dysregulation. Despite advances in anti-amyloid therapeutics, current interventions provide only modest symptomatic relief and face limitations in accessibility, cost, and long-term efficacy. Plant-derived bioactive compounds, rooted in traditional medicine systems such as Ayurveda and Traditional Chinese Medicine, have gained increasing attention as multi-target therapeutic agents due to their pleiotropic actions, relative safety, and ability to cross the blood–brain barrier. This review synthesizes mechanistic and translational evidence on major phytochemicals, including withanolides (Withania somnifera), curcumin (Curcuma longa), ginkgolides and bilobalide (Ginkgo biloba), bacosides (Bacopa monnieri), ginsenosides (Panax ginseng), crocin/safranal (Crocus sativus), epigallocatechin-3-gallate (Camellia sinensis), rosmarinic acid (Salvia officinalis, Melissa officinalis), and asiaticosides (Centella asiatica). These compounds exert neuroprotective effects by inhibiting Aβ aggregation, reducing tau phosphorylation, scavenging reactive oxygen species, attenuating NF-κB-mediated inflammation, modulating cholinergic signaling, enhancing synaptic plasticity via brain-derived neurotrophic factor/cAMP response element-binding protein (BDNF/CREB) activation, and regulating gut microbiota. Multi-target approach analyses underscore their synergistic potential in targeting interconnected AD pathways. However, translation remains hindered by poor oral bioavailability, rapid metabolism, and variability in clinical outcomes. Advances in delivery platforms, including liposomes, bilosomes, solid lipid nanoparticles, and nanostructured lipid carriers, are improving stability, blood–brain penetration, and therapeutic efficacy in preclinical models. Collectively, plant-derived phytochemicals serve as promising, affordable, and multi-modal candidates for reshaping AD management, bridging traditional knowledge with modern therapeutic innovation. Full article

Alzheimer’s disease continues to be one of the most urgent neurodegenerative conditions, with acetylcholinesterase (AChE) inhibitors serving as a fundamental component of contemporary treatment approaches. Growing evidence underscores that marine ecosystems are a rich source of structurally varied and biologically active natural products exhibiting anticholinesterase properties. This review presents a thorough synthesis of marine-derived metabolites—including those sourced from bacteria, fungi, sponges, algae, and other marine life—that demonstrate inhibitory effects against AChE and butyrylcholinesterase (BuChE). Numerous compounds, such as meroterpenoids, alkaloids, peptides, and phlorotannins, not only show nanomolar to micromolar inhibitory activity but also reveal additional neuroprotective characteristics, including antioxidant effects, anti-amyloid properties, and modulation of neuronal survival pathways. Despite these encouraging findings, the transition to clinical applications is hindered by a lack of comprehensive pharmacokinetic, toxicity, and long-term efficacy studies. The structural variety of marine metabolites provides valuable frameworks for the development of next-generation cholinesterase inhibitors. Further interdisciplinary research is essential to enhance their therapeutic potential and facilitate their incorporation into strategies for addressing Alzheimer’s disease and related conditions. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) pathology, synaptic degeneration, impaired neurogenesis, and chronic neuroinflammation. KBN2202, a small-molecule salicylic acid derivative [2-[(2-naphthalen-1-yloxy)ethyl]amino]-4-hydroxybenzoic acid], was investigated for its potential as a multi-target therapeutic agent in advanced-stage AD. To this end, 9-month-old 5xFAD mice with established AD-like pathology received daily oral KBN2202 (5 or 20 mg/kg) or vehicle for 12 weeks. KBN2202 demonstrated broad histopathological benefits. It preserved hippocampal CA1 cytoarchitecture and increased dendritic length in cortical neurons. Neurogenic activity was also enhanced, with elevated doublecortin (DCX) expression in the subventricular zone (SVZ). At the molecular level, KBN2202 reduced amyloid precursor protein C-terminal fragments (APP-CTFs), key intermediates in amyloidogenic processing, and histological staining confirmed a significant reduction in fibrillar and diffuse Aβ plaque burden in the cortex and hippocampus. Furthermore, KBN2202 attenuated astrocytic and microglial activation, indicating suppression of chronic neuroinflammation. In behavioral assessments, KBN2202 significantly improved recognition memory in the novel object recognition (NOR) test, while Y-maze performance remained unchanged. Overall, the compound exhibited robust neuroprotective, pro-neurogenic, anti-amyloid, and anti-inflammatory effects. These findings support the therapeutic potential of KBN2202 as a multi-functional candidate for symptomatic-stage AD. Full article

Blocking the MAPK pathway is a strategy to stop cancer cells proliferation. Despite all the successes, the acquisition of drug resistance by cells, as well as the mutational status of the downstream protein KRAS, reduces the tumor response to therapy. Ribonuclease binase from Bacillus pumilus is among the agents that block this pathway through direct interaction with EGFR and RAS. The present study is aimed at the design, optimization, and characterization of a novel complex based on antitumor binase immobilized on microgranular clinoptilolite-containing rock to ensure its prolonged release in the gastrointestinal tract. A set of modern methods including transmission electron microscopy, scanning electron microscopy, and computed tomography was used to characterize the granularity, porosity and elemental composition of the carrier. The size of binase particles, measured by atomic force microscopy at 7 nm, allows enzyme penetration into meso- and macropores of the carrier. Calorimetric results confirm that binase is stable at high temperatures, even exceeding those in the body, and retains catalytic activity in the model fluids of the gastrointestinal tract. The parameters for processing a natural clinoptilolite-containing rock and the conditions for binase sorption were selected. The gradual release of the enzyme from the carrier lasts over 20 h, which provides cytotoxicity towards human adenocarcinoma cells during movement through the gastrointestinal tract. Thus, for the first time a promising long-acting complex with antitumor and detoxifying properties was successfully created. Full article

Alzheimer’s disease (AD), the most frequent neurodegenerative disorder worldwide, is characterized by two key pathological features: extracellular amyloid beta plaques and intracellular highly phosphorylated tau protein aggregates known as neurofibrillary tangles. While in the last decades intensive research related to anti-amyloid disease-modifying therapies for AD was conducted, there has been less interest in treatments targeting tau protein. However, this paradigm is slowly changing, as recent studies have shown the increasing importance of tau protein in the onset and evolution of AD. In this context, this review aims to offer a practical overview of currently available therapies targeting tau protein and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and tau-related kinase dysregulations, considering their role in physiological versus AD conditions. Subsequently, the most relevant classes of drugs modulating tau protein formation, aggregation, and post-translational modifications are presented, with appropriate examples from clinical trials. Finally, unexplored research directions regarding tau-targeting therapies are discussed, with active and passive immunotherapies a promising research direction. Therapies targeting tau protein are a valuable treatment modality in AD, with current drug classes expected to diversify soon. Full article

This study systematically reviews the non-traditional pharmacological effects of diclofenac, a well-known nonsteroidal anti-inflammatory drug, to explore its potential for drug repositioning beyond its established analgesic and anti-inflammatory applications. A comprehensive literature search was conducted using the PubMed, Scopus and Web of Science databases, covering studies from 1981 to 2025. It was revealed that over 94% of records in Scopus and Web of Science are duplicated in PubMed, so the latter was used for the search in our study. After duplicate removal and independent screening, 89 from 1123 retrieved studies were selected for the search. The analysis revealed a broad spectrum of diclofenac’s non-traditional pharmacological activities, including neuroprotective, antiamyloid, anticancer, antiviral, immunomodulatory, antibacterial, antifungal, anticonvulsant, radioprotective, and antioxidant properties, primarily identified through preclinical In vitro and In vivo studies. These effects are mediated through diverse molecular pathways beyond cyclooxygenase inhibition, such as modulation of neurotransmitter release, apoptosis, and cellular proliferation. Diclofenac showed potential for repositioning in oncology, neurodegenerative disorders, infectious diseases, and immune-mediated conditions. Its hepatotoxicity and cardiovascular risks necessitate strategies like advanced drug formulations, dose optimization, and personalized medicine to enhance safety. Large-scale randomized clinical trials are essential to validate these findings and ensure safe therapeutic expansion. Full article

Alzheimer′s disease (AD) is a chronic neurodegenerative disorder that leads to memory loss and changes in mental and behavioral functions in elderly individuals. A major pathological feature of AD is the aggregation of amyloid-beta (Aβ) peptides, along with oxidative stress, inducing neurocellular apoptosis in the brain. Gobaishi (Galla chinensis), a traditional herbal medicine, has gained considerable attention for its constituents and potent therapeutic properties, particularly its strong inhibitory activity against Aβ fibril formation. In this study, we investigated the anti-Aβ aggregation effects of Gobaishi and its active constituents. We isolated two compounds by employing Thioflavin T (ThT) assay-guided fractionation, which were identified through various spectroscopic methods as pentagalloyl glucose (PGG) and methyl gallate (MG). Evaluation of their anti-Aβ aggregation effects revealed that PGG and MG contribute 1.5% and 0.7% of the activity of Gobaishi, respectively. In addition, PGG demonstrated significantly stronger DPPH radical scavenging activity (EC₅₀ = 1.16 µM) compared to MG (EC₅₀ = 6.44 µM). At a concentration of 30 µM, PGG significantly reduced the Aβ-induced cytotoxicity in SH-SY5Y cell lines compared to MG. Based on these findings, both Gobaishi and its active compound PGG are proposed as promising candidates for further investigation as potent anti-amyloidogenic agents in AD management. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, marked by cognitive impairment. Currently, the available treatment provides only symptomatic relief and there is a great need to design and formulate new drugs to stabilize AD. In the search for a new anti-Alzheimer’s drug, 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione (THTT), a tetrahydro-2H-1,3,5-thiadiazine-2-thione derivative, was investigated against a scopolamine-induced Alzheimer’s model. The selected test compound was administered intraperitoneally in three doses (15 mg/kg, 30 mg/kg, and 45 mg/kg). The test compound exhibited an IC50 value of 69.41 µg/mL, indicating its ability to inhibit the acetylcholinesterase enzyme. An antioxidant DPPH assay revealed that the IC50 value of the test compound was 97.75 µg/mL, which shows that the test compound possesses antioxidant activity. The results of behavior tests including the Y-maze and elevated plus maze (EPM) show that the test compound improved short-term memory and spatial memory, respectively. Furthermore, in the Morris water maze (MWM) and light/dark model, the test compound shows improvements in learning and memory. Moreover, the results of histological studies show that the test compound can protect the brain against the harmful effects of scopolamine. Overall, the findings of our investigation suggest that our chosen test compound has disease-modifying and neuroprotective activities against the scopolamine-induced Alzheimer’s model. The test compound may be beneficial, subject to further elaborate investigation for anti-amyloid disease-modifying properties in AD. Full article

An innovative biosensing strategy for the diagnosis of Alzheimer’s disease (AD) in human sera has been developed. The technology relied on a silicon flat substrate that was functionalized to perform a phage display detection of anti-amyloid beta (Aβ) antibodies, as AD markers, among the pool of IgGs of human sera. The substrate was derivatized with an interface able to bind and orient the IgGs for the detection operated by an engineered selective probe phage. The interface chemistry and its discrimination activity of healthy and AD sera have been fully characterized. Full article

Diseases of the central nervous system, which once occupied a large component of the pharmaceutical industry research and development portfolio, have for many years played a smaller part in major pharma pipelines—primarily due to the well cited challenges in target validation, valid translational models, and clinical trial design. Unfortunately, this decline in research and development interest has occurred in tandem with an increase in the medical need—in part driven by the success in treating other chronic diseases, which then results in a greater overall longevity along with a higher prevalence of diseases associated with ageing. The lead modality for drug agents targeting the brain remains the traditionally small molecule, despite potential in gene-based therapies and antibodies, particularly in the hugely anticipated anti-amyloid field, clearly driven by the additional challenge of effective distribution to the relevant brain compartments. However, in recognition of the growing disease burden, advanced therapies are being developed in tandem with improved delivery options. Hence, methodologies which were initially restricted to systemic indications are now being actively explored for a range of CNS diseases—an important class of which include the protein degradation technologies. Full article

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood–brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, β-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Since current treatment is aimed at preventing symptoms such as dementia and disability, the search for causative therapy that would be helpful in preventing and treating post-ischemic neurodegeneration of Alzheimer’s disease proteinopathy is ongoing. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects. Notably, in many preclinical studies, flavonoids and phenolic acids, the main components of honey, were also effective when administered after ischemia, suggesting their possible use in promoting recovery in stroke patients. This review provides new insight into honey’s potential to prevent brain ischemia as well as to ameliorate damage in advanced post-ischemic brain neurodegeneration. Full article

Tetrahydrocurcumin (THC) is a metabolite of curcumin (CUR). It shares many of CUR’s beneficial biological activities in addition to being more water-soluble, chemically stable, and bioavailable compared to CUR. However, its mechanisms of action have not been fully elucidated. This paper addresses the preventive role of THC on various brain dysfunctions as well as its effects on brain redox processes, traumatic brain injury, ischemia-reperfusion injury, Alzheimer’s disease, and Parkinson’s disease in various animal or cell culture models. In addition to its strong antioxidant properties, the effects of THC on the reduction of amyloid β aggregates are also well documented. The therapeutic potential of THC to treat patterns of mitochondrial brain dysmorphic dysfunction is also addressed and thoroughly reviewed, as is evidence from experimental studies about the mechanism of mitochondrial failure during cerebral ischemia/reperfusion injury. THC treatment also results in a dose-dependent decrease in ERK-mediated phosphorylation of GRASP65, which prevents further compartmentalization of the Golgi apparatus. The PI3K/AKT signaling pathway is possibly the most involved mechanism in the anti-apoptotic effect of THC. Overall, studies in various animal models of different brain disorders suggest that THC can be used as a dietary supplement to protect against traumatic brain injury and even improve brain function in Alzheimer’s and Parkinson’s diseases. We suggest further preclinical studies be conducted to demonstrate the brain-protective, anti-amyloid, and anti-Parkinson effects of THC. Application of the methods used in the currently reviewed studies would be useful and should help define doses and methods of THC administration in different disease conditions. Full article