Search Results (722)

Treating brain cancer remains challenging due to the blood–brain barrier (BBB) and the systemic toxicity of chemotherapy. This study focuses on developing human serum albumin (HSA) nanoparticles modified with low-molecular-weight protamine (LMWP) to improve crossing the BBB and enable targeted delivery of curcumin and temozolomide (TMZ). Nanoparticle stability was enhanced by crosslinking with aldehyde groups from oxidized gellan (OG). The successful attachment of LMWP to HSA at the thiol group of Cys34 was confirmed through FT-IR and ¹H-NMR analyses. Most self-assembled nanoparticles were smaller than 200 nm in diameter. Curcumin showed higher encapsulation efficiency than TMZ. In vitro drug release was pH-dependent: curcumin released more at pH 7.4, while TMZ release was better at pH 4. Higher crosslinking degrees reduced drug release. Cytotoxicity assays on V79-4 (normal) and C6 (glioma) cell lines showed increased apoptosis and significantly lower IC₅₀ values for co-encapsulated formulations, indicating a synergistic effect. Curcumin’s antioxidant activity was maintained and protected from UV degradation by the polymer matrix. The parallel artificial membrane permeability assay (PAMPA) confirmed that the functionalized formulations with co-encapsulated drugs could cross the BBB. Hemocompatibility studies indicated a favorable profile for intravenous use. Full article

Background/Objectives: The intranasal (IN) route of administration is a promising non-invasive approach for brain targeting, bypassing the blood–brain barrier and enhancing bioavailability. Citalopram hydrobromide (CT), a widely prescribed sparingly water-soluble selective serotonin reuptake inhibitor (SSRI), faces challenges with oral and intravenous administration, including delayed onset, adverse effects, and patient compliance issues. Methods: This study aimed to develop a novel thermoresponsive polymeric micelle (PM) system based on Pluronic^® copolymers (Pluronic F127 and Poloxamer 188) improving CT’s solubility, stability, and nasal permeability for enhanced antidepressant efficacy. A preliminary study was conducted to select the optimized formulation. The preparation process involved using the thin-film hydration method, followed by freeze-drying. Comprehensive evaluations of optimized formulation characteristics included Z-average, polydispersity index (PdI), thermal behavior (lower critical solution temperature, LCST), encapsulation efficiency, X-ray powder diffraction (XRPD), thermodynamic solubility, and biological stability. Additionally, in vitro CT release and CT permeability in nasal conditions were studied. Stability under storage was also evaluated. Results: The optimized CT-PM formulation showed nanoscale micelle size (Z-average of 31.41 ± 0.99 nm), narrow size distribution (polydispersity index = 0.241), and a suitable thermal behavior for intranasal delivery (lower critical solution temperature (LCST) ~31 °C). Encapsulation efficiency reached approximately 90%, with an amorphous structure confirmed via XRPD, leading to a 95-fold increase in CT solubility. The formulation demonstrated appropriate biological and physical stability. In vitro studies showed a 25-fold faster CT release from optimized formulation compared to the initial CT, while CT-PM permeability in nasal conditions increased four-fold. Conclusions: This novel nanoscale thermosensitive formulation is a value-added strategy for nasal drug delivery systems, offering enhanced drug solubility, rapid drug release, stability, and improved permeability. This smart nanosystem represents a promising platform to overcome the limitations of conventional CT administration, improving therapeutic outcomes and patient compliance in depression management. Full article

Claudin 5 (Cldn5) is a critical tight junction protein essential for maintaining paracellular barrier integrity across endothelial and epithelial cells in barrier-forming tissues, including the blood–brain barrier and blood–retinal barrier. Cldn5 plays a central role in regulating vascular permeability, immune responses, and tissue homeostasis. The complex distribution and organ-specific regulation of Cldn5 underscore its potential as a promising therapeutic target. This review comprehensively analyzes the role of Cldn5 in endothelial and epithelial barrier function, its regulation of vascular permeability, and the discrepancies in the literature regarding its expression, regulation, and function in both physiological and pathological conditions across multiple organ systems, including the retina, brain, lung, heart, gut, kidney, liver, skin, and peripheral nerves, while emphasizing its tissue-specific expression patterns. We discuss how both reduced and excessive expressions of Cldn5 can disrupt barrier integrity and contribute to the pathogenesis of ischemic retinopathies, neuroinflammation, cardiovascular injury, and other forms of barrier dysfunction. Furthermore, we explore the dual role of Cldn5 as both a biomarker and a therapeutic target, highlighting emerging strategies such as RNA silencing, pharmacological stabilizers, and transcriptional modulators in controlling barrier leakage in disease conditions. Full article

Heat shock proteins (HSPs), a family of proteins including HSP27, HSP40, HSP60, HSP70, and HSP90, play critical roles in cellular processes and are often dysregulated in cancer. Heat Shock Factor 1 (HSF1) protein, the master regulator of HSP expression, is also a promising target for cancer therapy due to its involvement in tumorigenesis. This study is the first to investigate the potential of two novel curcumin analogs, MS13 (1,2-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) and MS17 (1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one), as modulators of these key targets. Employing molecular docking and molecular dynamics (MD) simulations, we investigated the interactions of MS13 and MS17 with HSF1 and the panel of HSPs. Both compounds demonstrated strong binding affinity for all the proteins, particularly for HSP70, exhibiting greater affinity compared to curcumin. Molecular docking revealed specific binding sites for both compounds on each target protein, which were further investigated using MD simulations. MS17 generally formed more stable complexes with HSP27, HSP40, HSP60, and HSP70, suggesting it might be a more potent modulator of these specific proteins. In contrast, MS13 displayed greater stability when bound to HSF1 and HSP90. These different variations could be attributed to variations in the chemical structures of MS13 and MS17, leading to distinct interactions with each protein’s binding site. MS13 and MS17 exhibit more advantageous ADMET profiles compared to curcumin, particularly in their predicted Blood–Brain Barrier (BBB) permeability and MS17’s superior passive membrane permeability and absorption. These findings highlight the potential of both MS13 and MS17 as promising leads for developing HSP modulators for cancer treatment. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disease that, beyond joint destruction, contributes to neuropsychiatric symptoms such as depression, anxiety, and cognitive impairment. These symptoms are often underrecognized despite their major impact on quality of life. Accumulating evidence suggests that pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), play a key role in this neuroimmune interface. This narrative review examined 16 clinical studies evaluating the effects of biologic therapies targeting TNF-α and IL-6 on mental health outcomes in RA. The total study population comprised 9939 patients, including 2467 treated with TNF-α inhibitors and 7472 with IL-6 or IL-6 receptor inhibitors. TNF-α inhibitors were associated with improved depressive symptoms and emotional well-being. IL-6 inhibitors demonstrated similar psychiatric benefits, particularly in patients with elevated IL-6 levels. The findings highlight that biological therapies in RA may influence not only physical symptoms but also mental health, likely through modulation of neuroimmune pathways including blood–brain barrier permeability, microglial activation, and HPA axis regulation. Future research is needed to clarify these effects in populations stratified by psychiatric comorbidity and inflammatory biomarkers. Clinical implications: Incorporating psychiatric symptom screening and considering neuroinflammatory profiles may help guide the selection of biologic therapy in RA, particularly in patients with comorbid depression or fatigue. Full article

This review aims to point out the main achievements in the cutting-edge field of aptamer nanotechnology and its applications in the most frequent neuro-oncological and neurodegenerative diseases. The article discusses the properties, advantages and drawbacks of aptamers (AP), and their design and selection by various SELEX methods, as well as the synergical advantages as theranostics of the aptamer-functionalized nanoparticles (Ap-NP). The Ap-nanoconjugates properties are compared to those of Ap and unconjugated NP. Moreover, the article comparatively analyzes the aptamer-based approaches vs. antibody-drug conjugates vs. exosome-based delivery systems vs. unconjugated NP, as targeted therapies in neurodegenerative diseases and gliomas. The review presents major challenges in Ap-NP conjugates’ clinical progress (concerning the in vivo enzymatic stability, blood–brain barrier (BBB) permeability, selective intracellular uptake in the brain parenchyma and target tissues, rapid renal clearance, off-target toxicity, immunogenicity, reproductible manufacturing) and the investigated developmental strategies to solve them. Furthermore, relevant examples and comparative insights regarding preclinically tested Ap and Ap-NP conjugates are presented for targeted delivery systems loaded with chemotherapeutical drugs or genes, Ap-siRNA chimeras and immunotherapeutical aptamers, which are evaluated in glioblastomas (GBM), amyloidogenic diseases and multiple sclerosis (MS); radiotherapy enhancers in GBM; aptasensors for diagnostic and bioimaging-guided therapy in GBM, MS and amyloidopathies. The review finally points out future research directions in order to accelerate the clinical translation and the real-world impact as theranostics of the most preclinically advanced Ap-NP conjugates in major neuro-oncological and neurodegenerative disorders. Full article

CD44, a structurally diverse cell-surface glycoprotein, plays a multifaceted and indispensable role in neural tissue across both physiological and pathological conditions. It orchestrates complex cell–extracellular matrix interactions and intracellular signaling through its variant isoforms and post-translational modifications and is broadly expressed in neural stem/progenitor cells, microglia, astrocytes, and selected neuronal populations. The interactions of CD44 with ligands such as hyaluronan and osteopontin regulate critical cellular functions, including migration, differentiation, inflammation, and synaptic plasticity. In microglia and macrophages, CD44 mediates immune signaling and phagocytic activity, and it is dynamically upregulated in neuroinflammatory diseases, particularly through pathways involving Toll-like receptor 4. CD44 expression in astrocytes is abundant during central nervous system development and in diseases, contributing to glial differentiation, reactive astrogliosis, and scar formation. Though its expression is less prominent in mature neurons, CD44 supports neural plasticity, circuit organization, and injury-induced repair mechanisms. Additionally, its expression at nervous system barriers, such as the blood–brain barrier, underscores its role in regulating vascular permeability during inflammation and ischemia. Collectively, CD44 emerges as a critical integrator of neural cell function and intercellular communication. Although the roles of CD44 in glial cells appear to be similar to those explored in other tissues, the expression of this molecule and its variants on neurons reveals peculiar functions. Elucidating the cell-type-specific roles and regulation of CD44 variants may offer novel therapeutic strategies for diverse neurological disorders. Full article

In recent years, the bidirectional regulatory mechanism of the bone-brain axis has become a hotspot for interdisciplinary research. In this paper, we systematically review the anatomical and functional links between bone and the central nervous system, focusing on the regulation of brain function by bone-derived signals and their clinical translational potential. At the anatomical level, the blood–brain barrier permeability mechanism and the unique structure of the periventricular organs establish the anatomical basis for bone-brain information transmission. Innovative discoveries indicate that the bone cell network (bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, and bone marrow monocytes) directly regulates neuroplasticity and the inflammatory microenvironment through the secretion of factors such as osteocalcin, lipid transporter protein 2, nuclear factor κB receptor-activating factor ligand, and fibroblast growth factor 23, as well as exosome-mediated remote signaling. Clinical studies have revealed a bidirectional vicious cycle between osteoporosis and Alzheimer’s disease: reduced bone density exacerbates Alzheimer’s disease pathology through pathways such as PDGF-BB, while AD-related neurodegeneration further accelerates bone loss. The breakthrough lies in the discovery that anti-osteoporotic drugs, such as bisphosphonates, improve cognitive function. In contrast, neuroactive drugs modulate bone metabolism, providing new strategies for the treatment of comorbid conditions. Additionally, whole-body vibration therapy shows potential for non-pharmacological interventions by modulating bone-brain interactions through the mechano-osteoclast signaling axis. In the future, it will be essential to integrate multiple groups of biomarkers to develop early diagnostic tools that promote precise prevention and treatment of bone-brain comorbidities. This article provides a new perspective on the mechanisms and therapeutic strategies of neuroskeletal comorbidities. Full article

Species of the Ferula genus are known for their traditional medicinal applications against diverse illnesses. Our previous study was the first to suggest the cholinesterase inhibitory activity of Ferula persica L. However, the neuroprotective efficacy of therapeutic molecules is often limited by their ability to cross the blood–brain barrier (BBB) and reach the brain. In the present study, the BBB permeability of the main molecules present in the aerial parts and roots of F. persica L. extracted under optimum conditions was assessed using two well-established methods: the parallel artificial membrane permeability assay (PAMPA) and the HBMEC cell culture in vitro model. The results demonstrated a high permeability of several neuroprotective compounds, such as apigenin, diosmetin, and α-cyperone. Additionally, the neuroprotective potential of F. persica extracts was evaluated using SH-SY5Y neuron-like cells exposed to different insults, including oxidative stress (H₂O₂), excitotoxicity (L-glutamate), and Aβ1-42 peptide toxicity. However, none of the obtained extracts provided significant protection. This study highlights the importance of in vitro cell culture models for a better understanding of BBB permeability mechanisms and reports the tentative identification of newly formed sulfated metabolites derived from the metabolism of ferulic acid, apigenin, and diosmetin by HBMEC cells. Full article

Blood–brain barrier (BBB) deterioration with increasing age is an important factor contributing to vascular dementia. Previous studies show that endothelial nitric oxide synthase (eNOS) facilitates vascular endothelial growth factor-mediated angiogenesis and increased vascular permeability. In contrast, recent work has shown that aged hemi-deficient hemizygous eNOS^+/− mice manifest BBB disruption in association with increased incidence of thromboembolic events in the brain. To unravel whether eNOS contributes to or protects against hypoxia-induced cerebrovascular damage, we compared chronic mild hypoxia (CMH)-induced cerebrovascular angiogenic remodeling and BBB breakdown in aged (20 months old) eNOS^+/− and wild-type (WT) mice. This revealed that CMH strongly enhanced eNOS expression in cerebral blood vessels with much lower levels in eNOS^+/− mice. eNOS hemi-deficiency resulted in greater CMH-induced BBB disruption, but unexpectedly, had no effect on endothelial proliferation. eNOS^+/− mice also displayed enhanced endothelial expression of the endothelial activation markers MECA-32, VCAM-1, and β3 integrin in cerebral blood vessels, indicating greater vascular inflammation, and this correlated with increased levels of microglial activation and demyelination. Taken together, our results support the concept that eNOS plays an important protective function in the aged brain by suppressing endothelial activation and maintaining cerebrovascular health. Full article

Background/Objectives: Gut microbial dysbiosis, leaky gut, and increased transepithelial translocation of commensal bacteria have been documented in multiple sclerosis (MS). Intrathecal IgGs specific for Akkermansia muciniphila, a gut bacterium, are increased in patients with MS and associated with clinical disability. Our objective here was to explore the putative involvement of intrathecal anti-A. muciniphila IgG in MS pathogenesis by characterizing patients with different anti-A. muciniphila IgG indices. Methods: Serum and intrathecal IgG specific for A. muciniphila and other gut bacteria, as well as routine cerebrospinal fluid (CSF) parameters, were measured in 61 patients with MS. Examination of these patients included immunophenotyping of CSF-infiltrating and paired circulating lymphocytes, intrathecal markers of neurodegeneration and inflammation, and a detailed characterization of demographic, clinical, and magnetic resonance imaging (MRI) features. Results: Plasma blasts (p < 0.01), B cells (p < 0.01), and Th2 cells (p < 0.01), which might be involved in antibody production, were increased in the CSF of these patients, as well as blood pro-inflammatory Th17 cells (p < 0.05). Anti-A. muciniphila IgG indices were negatively associated with blood-brain barrier (BBB) permeability and circulating monocytes (p < 0.001), and positively with brain lesion load (p < 0.01). Conclusions: The differences between patients with low and high anti-A. muciniphila IgG indexes regarding BBB permeability, CSF cell infiltrates, and pro-inflammatory peripheral immune cells, as well as imaging features, support a role of anti-A. muciniphila immune response in MS pathogenesis. Full article

Tumor necrosis factor (TNF) receptor-associated factor 7 (TRAF7) is a signal transducer in the TNF receptor superfamily. TRAF7 is unique among its superfamily in that it does not contain a TRAF-C domain but does contain WD-40 domains. TRAF7 interacts with mitogen-activated protein kinases (MAPK), which are known regulators of inflammation and shear stress response. Notably, these molecular interactions have profound implications for the function of brain endothelial cells (ECs), which are pivotal for sustaining the integrity of the blood–brain barrier (BBB), orchestrating neurovascular coupling (NVC), and modulating the vascular architecture. By directly influencing MAPK signaling pathways, particularly the shear stress-responsive MAPK kinase kinase 3 (MEKK3)–MAPK kinase 5 (MEK5)–extracellular-regulated protein kinase 5 (ERK5) cascade, TRAF7 contributes to vascular homeostasis, as exemplified by its role in phosphorylating ERK5. Such molecular events underpin the capacity of brain ECs to regulate substance exchange, adjust blood flow in response to neural activity, and maintain efficient cerebral perfusion, all of which are essential for preserving brain health and cognitive performance. By synthesizing the current evidence regarding TRAF7’s molecular functions and its impact on brain endothelial integrity, cerebrovascular aging, and exploring implications for therapeutic strategies targeting vascular dysfunction in the aging brain, this review fills a crucial gap in the literature. Given the limited number of original studies directly addressing these contexts, the review will integrate broader insights from related literature to provide a foundational overview for future research in this developing field. The culmination of this literature will provide a rationale for the development of novel TRAF7-targeted therapies to restore vascular integrity in the context of aging, which could maintain cognitive health. Although TRAF7 has been implicated in regulating endothelial permeability during inflammation, its precise functions in brain ECs and the subsequent effects on cerebrovascular structure and cognitive function remain to be fully elucidated. Full article

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood–brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets—including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites—that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody–drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases. Full article

Callistemon citrinus has shown antioxidant and anti-inflammatory properties in certain tissues. However, its impact on the brain remains unproven. This study investigates the effect of C. citrinus extract and phytosomes on the oxidative status of the brains of rats fed a high-fat–fructose diet (HFD). Fifty-four male Wistar rats were randomly divided into nine groups (n = 6). Groups 1, 2, and 3 received a standard chow diet; Group 2 also received the vehicle, and Group 3 was supplemented with C. citrinus extract (200 mg/kg). Groups 4, 5, 6, 7, 8, and 9 received a high-fat diet (HFD). Additionally, groups 5, 6, 7, 8, and 9 were supplemented with orlistat at 5 mg/kg, C. citrinus extract at 200 mg/kg, and phytosomes loaded with C. citrinus at doses of 50, 100, and 200 mg/kg, respectively. Administration was oral for 16 weeks. Antioxidant enzymes, biomarkers of oxidative stress, and fatty acid content in the brain were determined. A parallel artificial membrane permeability assay (PAMPA) was employed to identify compounds that can cross the intestinal and blood–brain barriers. The HFD group (group 4) increased body weight and adipose tissue, unlike the other groups. The brain fatty acid profile showed slight variations in all of the groups. On the other hand, group 4 showed a decrease in the activities of antioxidant enzymes SOD, CAT, and PON. It reduced GSH level, while increasing GPx activity as well as MDA, 4-HNE, and AOPP levels. C. citrinus extract and phytosomes restore the antioxidant enzyme activities and mitigate oxidative stress in the brain. C. citrinus modulates oxidative stress in brain tissue through 1.8-cineole and α-terpineol, which possess antioxidant and anti-inflammatory properties. Full article

Central nervous system (CNS) disorders present significant therapeutic challenges due to the limited regenerative capacity of neural tissues, resulting in long-term disability for many patients. Consequently, the development of novel therapeutic strategies is urgently warranted. Stem cell therapies show considerable potential for mitigating brain damage and restoring neural connectivity, owing to their multifaceted properties, including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Recent research has also identified exosomes—small vesicles enclosed by a lipid bilayer, secreted by stem cells—as a key mechanism underlying the therapeutic effects of stem cell therapies, and given their enhanced stability and superior blood–brain barrier permeability compared to the stem cells themselves, exosomes have emerged as a promising alternative treatment for CNS disorders. A key challenge in the application of both stem cell and exosome-based therapies for CNS diseases is the method of delivery. Currently, several routes are being investigated, including intracerebral, intrathecal, intravenous, intranasal, and intra-arterial administration. Intracerebral injection can deliver a substantial quantity of stem cells directly to the brain, but it carries the potential risk of inducing additional brain injury. Conversely, intravenous transplantation is minimally invasive but results in limited delivery of cells and exosomes to the brain, which may compromise the therapeutic efficacy. With advancements in catheter technology, intra-arterial administration of stem cells and exosomes has garnered increasing attention as a promising delivery strategy. This approach offers the advantage of delivering a significant number of stem cells and exosomes to the brain while minimizing the risk of additional brain damage. However, the investigation into the therapeutic potential of intra-arterial transplantation for CNS injury is still in its early stages. In this comprehensive review, we aim to summarize both basic and clinical research exploring the intra-arterial administration of stem cells and exosomes for the treatment of CNS diseases. Additionally, we will elucidate the underlying therapeutic mechanisms and provide insights into the future potential of this approach. Full article