Search Results (363)

With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as Cryptococcus neoformans. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis. 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 low effectiveness of various brain cancer treatment methods is due to a number of significant challenges. Most of them are unable to penetrate the blood–brain barrier (BBB) when drugs are administered systemically through the bloodstream. Nanoscale particles play a special role among materials capable of binding drug molecules and successfully crossing the BBB. Biopolymeric nanoparticles (NPs) demonstrate excellent biocompatibility and have the remarkable ability to modify the environment surrounding tumor cells, thereby potentially improving cellular uptake of delivery agents. In our research, nanoscale polyelectrolyte complexes (PECs) ranging in size from 56 to 209 nm were synthesized by ionic interaction of the oppositely charged polysaccharides pectin and chitosan. The structural characteristics of these complexes were carefully characterized by infrared (FTIR) and Raman spectroscopy. The immobilization efficiency of antitumor drugs was comprehensively evaluated using UV spectrophotometry. The cytotoxicity of the NPs was evaluated in the U87-MG cell line. The preliminary data indicate a significant decrease in the metabolic activity of these tumor cells. Important details on the interaction of the NPs with an endothelial layer structurally similar to the BBB were obtained by simulating the BBB using a model based on human blood vessels. Our studies allowed us to establish a significant correlation between the kinetic parameters of drug immobilization and the ratio of biopolymer concentrations in the initial compositions, which provides valuable information for future optimization of drug delivery system design. Full article

Background: The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) but also limits drug delivery. Insufficient knowledge of how the CNS promotes the onset and maintenance of peripheral neuropathic pain limits therapeutic methods for the treatment of persistent neuropathic pain. Thus, this study aimed to evaluate the ability of a novel combination of Palmitoylethanolamide (PEA) and Equisetum arvense L. (Equisetum A.L.) to cross the BBB and modulate nociceptive pathways. Methods: Using a humanised in vitro BBB tri-culture model, the permeability, cytotoxicity, and integrity of the barrier were assessed after exposure to two different PEA forms, PEA ultramicronized (PEA-um) and PEA80mesh, Equisetum A.L., and a combination of the last two samples. The samples exhibited no cytotoxicity, maintained tight junction integrity, and efficiently crossed the blood–brain barrier (BBB), with the combination displaying the highest permeability. The eluate from the BBB model was then used to stimulate the co-culture of CCF-STTG1 astrocytes and SH-SY5Y neurons pre-treated with H₂O₂ 200 µM. Results: Treatment with the combination significantly increased cell viability (1.8-fold, p < 0.05), reduced oxidative stress (2.5-fold, p < 0.05), and decreased pro-inflammatory cytokines (TNFα, IL-1β) compared to single agents. Mechanistic analysis revealed modulation of key targets involved in pain pathways, including decreased FAAH and NAAA activity, increased levels of endocannabinoids (AEA and 2-AG), upregulation of CB2 receptor expression, enhanced PPARα activity, and reduced phosphorylation of PKA and TRPV1. Conclusions: These findings suggest that the combination of PEA and Equisetum A.L. effectively crosses the BBB and exerts combined anti-inflammatory and analgesic effects at the CNS level, suggesting a possible role in modulating neuroinflammatory and nociception responses. Full article

Neurodegenerative diseases affect millions worldwide and present an urgent challenge due to the aging of the population. Drug delivery to the brain is limited by the blood–brain barrier (BBB), inspiring the development of nanotransporters like phytosomes. This study aimed to develop phosphatidylcholine (PC)-based phytosomes incorporating macroalgae extracts. Some of them were functionalized with PEG and ApoE to enhance BBB passage. The phytosomes were characterized by the encapsulation rate, size, polydispersity index (PDI), zeta potential, and stability, with BBB passage tested in an in vitro model (transwell hCMEC/D3 cell model). The phytosomes showed high stability and effective extract binding (74.9–80.3%) over four weeks. Although ApoE functionalization did not significantly improve BBB crossing, all nanotransporters successfully traversed the BBB in the model. Full article

The blood–brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including neurodegenerative disorders, brain tumors, and psychiatric conditions. Many chemical drugs and biopharmaceuticals are unable to cross the BBB, and conventional drug delivery methods often fail to achieve sufficient brain concentrations, leading to reduced therapeutic efficacy and increased risk of systemic toxicity. In recent years, targeted drug delivery strategies have emerged as promising approaches to overcome the BBB and enhance the delivery of therapeutic agents to the brain. Among these, receptor-mediated transcytosis (RMT) and transporter-mediated transcytosis (TMT) are two of the most extensively studied mechanisms for transporting drugs across brain endothelial cells into the brain parenchyma. Advances in materials science and nanotechnology have facilitated the development of multifunctional carriers with optimized properties, improving drug targeting, stability, and release profiles within the brain. This review summarizes the physiological structure of the BBB and highlights recent innovations in RMT- and TMT-mediated brain drug delivery systems, emphasizing their potential not only to overcome current challenges in CNS drug development, but also to pave the way for next-generation therapies that enable more precise, effective, and personalized treatment of brain-related diseases. Full article

VEXAS syndrome and Alzheimer’s disease (AD), though distinct in clinical manifestations, share overlapping pathophysiological mechanisms, including systemic inflammation, protein misfolding, and vascular dysfunction. VEXAS syndrome, a rare autoinflammatory disorder characterized by somatic UBA1 mutations, systemic inflammation, and hematologic abnormalities, presents primarily in older males. Meanwhile, AD, the leading cause of dementia, involves progressive neurodegeneration driven by amyloid-beta plaques, tau tangles, and chronic neuroinflammation. This article explores potential connections between the two conditions, focusing on inflammation, neurovascular changes and cellular stress. Systemic inflammation observed in VEXAS syndrome may potentiate neuroinflammatory processes in Alzheimer’s disease (AD), as circulating proinflammatory cytokines have the capacity to cross the blood–brain barrier (BBB), thereby inducing glial activation and promoting neuroinflammation. Additionally, coexisting vascular dysfunctions characteristic of both conditions may synergistically contribute to accelerated cognitive decline. Both conditions involve disruption of the ubiquitin–proteasome system, with UBA1 mutations being specific to VEXAS. Given the established role of UBA1 in maintaining neuronal homeostasis, investigating the overlapping and distinct molecular mechanisms may provide valuable insights into their pathophysiology. The review underscores the need for further research to elucidate these links and improve therapeutic strategies, especially for individuals affected by both disorders. Full article

GBM is the most common and aggressive primary brain tumor in adults, characterized by low survival rates, high recurrence, and resistance to conventional therapies. Traditional diagnostic and therapeutic methods remain limited due to the difficulty in permeating the blood–brain barrier (BBB), diffuse tumor cell infiltration, and tumor heterogeneity. In recent years, nano-based technologies have emerged as innovative approaches for the detection and treatment of GBM. A wide variety of nanocarriers, including dendrimers, liposomes, metallic nanoparticles, carbon nanotubes, carbon dots, extracellular vesicles, and many more demonstrate the ability to cross the BBB, precisely deliver therapeutic agents, and enhance the effects of radiotherapy and immunotherapy. Surface functionalization, peptide modification, and cell membrane coating improve the targeting capabilities of nanostructures toward GBM cells and enable the exploitation of their photothermal, magnetic, and optical properties. Furthermore, the development of miRNA nanosponge systems offers the simultaneous inhibition of multiple tumor growth mechanisms and the modulation of the immunosuppressive tumor microenvironment. This article presents current advancements in nanotechnology for GBM, with a particular focus on the characteristics and advantages of specific groups of nanoparticles, including their role in radiosensitization. Full article

Spinal cord injury (SCI) is a prevalent central nervous system disorder that causes significant disability and mortality. Unfortunately, due to the complex pathophysiological mechanisms involved, there remains a critical paucity of effective therapeutic interventions capable of achieving neural tissue regeneration and functional recovery enhancement in SCI patients. The advancements in extracellular vesicles (EVs) as a cell-free therapy for SCI have displayed notable benefits. These include their small size, low immunogenicity, capacity to target specific areas, and ability to cross the blood‒brain barrier (BBB). EVs offer the potential to not only repair tissue damage and stimulate regeneration but also effectively deliver and release them at the site of SCI when combined with diverse biomaterials. This review explores the biological role and importance of EVs in treating SCI, highlighting the combined use of modified EVs with different biomaterials and their potential for future applications. It presents new and hopeful treatment approaches for individuals afflicted with SCI. Full article

Neuronal apoptosis is an early and critical pathological hallmark of many chronic neurodegenerative diseases, often occurring silently long before the appearance of overt clinical symptoms. In this study, we engineered astrocytes utilizing a dual-biomarker recognition synNotch system (dual-synNotch). This system is designed to specifically identify neuronal apoptosis through the ‘AND Gate’ activation mechanism, which is triggered by the simultaneous sensing of the apoptotic signal phosphatidylserine (PS) and the neuronal signal ganglioside Gt1b. Upon detection of these neuronal apoptotic signals, the synNotch receptors are activated, inducing the expression of two key molecules: secreted Gaussia luciferase (GLuc), a highly detectable reporter that can cross the blood–brain barrier (BBB), and brain-derived neurotrophic factor (BDNF), a neuroprotective molecule that promotes neuronal survival by inhibiting apoptosis and enhancing memory and cognitive function. This engineered system effectively converts and amplifies early, imperceptible neuronal apoptotic signals into detectable outputs, enabling convenient in vitro monitoring and diagnosis. Therefore, it represents a promising strategy for the early detection and intervention of neurodegenerative diseases associated with neuronal apoptosis. Full article

Background/Objectives: Alzheimer’s disease (AD) is the most common type of dementia, characterized by complex processes such as neuro-inflammation, oxidative damage, synaptic loss, and neuronal death. Carotenoids are among the potential therapeutic molecules that have attracted attention due to their neuroprotective properties, but their efficacy is limited mainly by their capacity to cross the blood–brain barrier (BBB). Results: The results showed that T. chuii extracts could protect neuronal cells from neurotoxic damage, especially against L-glutamate and H₂O₂. Moreover, the BBB permeability and the intestinal transport analyses revealed that fucoxanthinol, crocoxanthin, diatoxanthin, neoxanthin, violaxanthin, and prasinoxanthin have diverse permeabilities depending on the incubation time and the cell model used. Fucoxanthinol was the carotenoid with the highest and similar permeability in HBMEC cells (4.41%, 5.13%, and 18.94% at 2, 4, and 24 h, respectively) and Caco-2 cells (7.01%, 8.63%, and 18.36% at the same times), while crocoxanthin, diatoxanthin, and neoxanthin showed different kinetics. Methods: The neuroprotective potential of two extracts obtained from Tetraselmis chuii microalga were evaluated against Aβ1-42-, L-glutamate-, and H₂O₂-induced toxicities in SH-SY5Y cells. In addition, the BBB permeability and the intestinal transepithelial transport of the main carotenoids present in the extracts were evaluated and compared using two cell culture models, HBMEC and Caco-2 cells. For that aim, the transport of the bioactive molecules across the barriers was evaluated using UHPLC-q-TOF-MS after 2, 4, and 24 h of incubation. Conclusions: These findings indicate that T. chuii is a promising natural source of bioactive compounds to develop functional foods against neurodegenerative diseases. Full article

Neurological diseases, including neurodegenerative disorders and stroke, represent significant medical challenges due to their complexity and the limitations of current treatment approaches. This review explores the potential of stem cell (SC)-derived exosomes (Exos) as a transformative therapeutic strategy for these diseases. Exos, especially those derived from SCs, exhibit natural targeting ability, biocompatibility, and the capacity to cross the blood–brain barrier (BBB), making them ideal vehicles for drug delivery. This review provides an in-depth discussion of the properties and advantages of SC-Exos. It highlights their potential synergistic benefits in therapeutic approaches to treat neurological diseases. This article discusses the mechanisms of action of SC-Exos, highlighting their ability to target specific cells, modulate disease pathways, and provide controlled release of therapeutic agents. Applications in specific neurological disorders have been investigated, demonstrating the potential to improve outcomes in conditions such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and stroke. Moreover, Exos-coated nanoparticles (NPs) combine the natural properties of Exos with the multifunctionality of NPs. This integration takes advantage of exosome membrane biocompatibility and targeting capabilities while preserving NPs’ beneficial features, such as drug loading and controlled release. As a result, Exos-coated NPs may enhance the precision, efficacy, and safety of therapeutic interventions. In conclusion, SC-Exos represent a promising and innovative approach to treating neurological diseases. Full article

Background/Objectives: The development of effective therapies for brain disorders is highly correlated with the ability of drugs or nanosystems to cross the blood–brain barrier (BBB), which has been limited. Recently, carbon dots (CDs) have been receiving attention to be used as BBB-crossing theranostic agents due to their inherent advantages, such as low size, excellent biocompatibility, high quantum yield (QY), tunable fluorescence, high drug loading, and relatively easy synthesis at low cost. The aim of this study was to design CDs with precisely controlled fluorescence properties for advanced bioimaging and an in-depth assessment of BBB permeability. Methods: CDs were synthesized using a microwave-assisted approach, optimized through microwaves’ irradiation time, and employing citric acid, urea, and sodium fluoride as precursors. The optimized sample was labeled as NF-CD. Results: A comprehensive physicochemical, photoluminescence, and biological characterization revealed the ability of NF-CD to diffuse across a neuromimetic-BBB model, mainly due to their small size (average diameter of 4.0 ± 1.1 nm), exhibiting excitation-dependent fluorescence in the blue and green wavelengths, high biocompatibility and QY, and exceptional photostability. Conclusions: Owing to the exceptional fluorescence characteristics and biological compatibility, NF-CD presents promising opportunities in theranostic applications, particularly in brain-targeted bioimaging, nanocarrier-based drug and immunotherapy delivery, early-stage diagnostics, and personalized medicine. NF-CD’s ability to cross the BBB further underscores the relevance of pioneering nanomaterial-based strategies for neurological disorder diagnostics and precision-targeted therapeutic interventions. Overall, this research contributes to the broader field of nanotechnology-driven biomedical advancements, fostering innovations in neurological diagnostics and therapeutic delivery systems. Full article

Extracellular vesicles (EVs) have been explored as promising vehicles for drug delivery. One of the most valuable features of EVs is their ability to cross physiological barriers, particularly the blood–brain barrier (BBB). This significantly enhances the development of EV-based drug delivery systems for the treatment of CNS disorders. The present review focuses on the factors and techniques that contribute to the successful delivery of EV-based therapeutics to the brain. Here, we discuss the major methods of brain targeting which includes the utilization of different administration routes, capitalizing on the biological origins of EVs, and the modification of EVs through the addition of specific ligands on to the surface of EVs. Finally, we discuss the current challenges in large-scale EV production and drug loading while highlighting future perspectives regarding the application of EV-based therapeutics for brain delivery. Full article

Background: The blood–brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone^®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood–brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT). Full article