Search Results (3,200)

Gliomas are the most common primary brain tumors, representing approximately 28% of all central nervous system tumors. These tumors are characterized by rapid progression and show a median survival of approximately 18 months. The therapeutic options consist of surgical resection followed by radiotherapy and chemotherapy. Despite the multidisciplinary approach and the biomolecular role of targeted therapies, the median progression-free survival is approximately 6–8 months. The incomplete tumor compliance with treatment is due to several factors such as the presence of the blood–brain barrier, the numerous pathways involved in tumor transformation, and the presence of intra-tumoral mutations. Among these, the interaction between the mutations of genes involved in tumor bio-energetic metabolism and the functional response of the tumor has become the protagonist of numerous studies. In this scenario, the main role is played by mitochondria, cellular organelles delimited by a double membrane and containing their own DNA (mtDNA), which participates in numerous cellular processes such as the regulation of cellular metabolism, cellular proliferation, and apoptosis and is also the main source of cellular energy production. Therefore, it is understood that the mitochondrion, specifically its functional alteration, is a leading figure in tumor transformation, including brain tumors. The acquisition of mutations in the mitochondrial DNA of tumor cells and the subsequent identification of the so-called mitochondria-related genes (MRGs), both functional (mutation of Complex I) and structural (mutations of Complex III/IV), have been seen to play an important role in metabolic reprogramming with increased proliferation, resistance to apoptosis, and the progression of tumorigenesis. This demonstrates that these mitochondrial alterations could have a role not only in the intrinsic tumor biology but also in the extrinsic one associated with the therapeutic response. We aim to summarize the main mitochondrial dysfunction interactions present in gliomas and how they might impact prognosis. Full article

The blood–brain barrier and glial cells, particularly astrocytes, interact with each other in neuroimmune diseases. In the inflammatory environment typical of these diseases, alterations in vascular endothelial cell surface molecules and weakened cell connections allow immune cells and autoantibodies to enter the central nervous system. Glial cells influence the adhesion of endothelial cells by changing their morphology and releasing various signaling molecules. Multiple sclerosis has been the most studied disease in relation to vascular endothelial and glial cell interactions, but these cells also significantly affect the onset and severity of other neuroimmune conditions, including demyelinating and inflammatory diseases. In this context, we present an overview of these interactions and highlight how they vary across different neuroimmune diseases. Full article

Finding new molecules to prevent the growth of antimicrobial resistance is a hot topic for scientists worldwide. It has been reported that some raw bioproducts containing Monascus polyketides have antimicrobial activities, but extensive studies on this effect have not been conducted. In this context, our studies aimed to evaluate the antimicrobial properties of six raw bioproducts containing three classes of microbial polyketides biosynthesized by three Monascus strains through solid-state biosynthesis. As a methodology, we performed in silico predictions using programs such as PyMOL v3.0.4 and employed ESI-MS techniques to provide evidence of the presence of the six studied compounds in our bioproducts. The results obtained in silico were validated through in vitro studies using the Kirby-Bauer diffusion method on bacteria and fungi. The test performed in silico showed that Monascorubramine has the highest affinity for both Gram-positive and Gram-negative bacteria, followed by yellow polyketides such as Ankaflavin and Monascin. The estimated pharmacokinetic parameters indicated high gastrointestinal absorption and the potential to cross the blood-brain barrier for all studied compounds. However, the compounds also inhibit most enzymes involved in drug metabolism, presenting some level of toxicity. The best in vitro results were obtained for S. aureus, with an extract containing yellow Monascus polyketides. Predictions made for E. coli were validated in vitro for P. aeruginosa, S. enterica, and S. marcescens, as well as for fungi. Significant antibacterial properties were observed during this study for C. albicans, S. aureus, and fungal dermatophytes for crude bioproducts containing Monascus polyketides. In conclusion, the antimicrobial properties of Monascus polyketides were validated both in silico and in vitro. However, due to their potential toxicity, these bioproducts would be safer to use as topical formulations. Full article

Drug delivery, tissue engineering, and cell promotion in biomedical fields heavily rely on the use of nanomaterials (NMs). When they penetrate cells, NPs undergo degradation and initiate the generation of reactive oxygen species (ROS) by causing changes in the structures of organelles linked to mitochondria. Inside the cell, the excess production of ROS can initiate a chain reaction, along with the autophagy process that helps maintain ROS balance by discarding unnecessary materials. At present, there is no effective treatment for Alzheimer’s disease (AD), a progressive neurodegenerative disease. The use of NMs for siRNA delivery could become a promising treatment for AD and other CNS disorders. Recent research demonstrates that the use of combined NPs can induce autophagy in cells. This article emphasizes the importance of the shape of siRNA-encapsulated NMs in determining their efficiency in delivering and suppressing gene activity in the central nervous system. Because of its strict selectivity against foreign substances, the blood–brain barrier (BBB) significantly hinders the delivery of therapeutic agents to the brain. Conventional chemotherapeutic drugs are significantly less effective against brain cancers due to this limitation. As a result, NMs have become a promising approach for targeted drug delivery, as they can be modified to carry specific ligands that direct them to their intended targets. This review thoroughly examines the latest breakthroughs in using NMs to deliver bioactive compounds across the BBB, focusing on their use in cancer treatments. The review starts by examining the structure and functions of the BBB and BBTB, and then emphasizes the benefits that NMs offer. Full article

Accumulating evidence suggests that multiple sclerosis (MS) is an environmentally influenced disorder with contributions from life-time exposure to factors including Epstein–Barr virus infection or shifts in microbiome, diet and lifestyle. One suggested factor is a deficiency in propionic acid, a short-chain fatty acid produced by gut bacteria that may contribute to the disease pathology both in animal models and in human cases of MS. Propionate appears to exert beneficial effects on the immune, peripheral and central nervous systems of people with MS (pwMS), showing immunoregulatory, neuroprotective and neurogenerative effects. These functions are crucial, given that MS is characterized by immune-mediated damage of myelin in the central nervous system. Accordingly, propionate supplementation or a modulated increase in its levels through the microbiome and diet may help counteract the pro-inflammatory state in MS by directly regulating immune system and/or by decreasing permeability of gut barrier and blood–brain barrier. This could potentially improve outcomes when used with immune-modulating therapy. However, while its broad effects are promising, further large clinical trials are necessary to evaluate its efficacy and safety in pwMS and clarify its role as a complementary therapeutic strategy. This review provides a comprehensive analysis of the evidence, challenges and limitations concerning propionic acid supplementation in MS. Full article

As some previously reported studies have proven that amodiaquine, in addition to its primary antimalarial activity, also has potential for new applications such as the inhibition of cholinesterases, in our study we focused on the evaluation of the influence of different substituents in the aminoquinoline part of the amodiaquine structure on the inhibition of human acetylcholinesterase and butyrylcholinesterase to investigate the possibility for their use as drugs for the treatment of AD. We synthesized a series of amodiaquine derivatives bearing H-, F-, CF₃-, NO₂-, CN-, CO₂H- or CH₃O- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants (K_i) in the nM and low μM range and with prominent selectivity (up to 300 times) for the inhibition of acetylcholinesterase. All compounds displayed an ability to chelate biometal ions Fe²⁺, Zn²⁺ and Cu²⁺ and an antioxidant power comparable to that of standard antioxidants. Most of the compounds were estimated to be able to cross the blood–brain barrier by passive transport and were nontoxic toward cells that represent the models of individual organs. Considering all these beneficial features, our study has singled out compound 5, the most potent AChE inhibitor with a CH₃O- on C(7) position, followed by 6 and 14, compounds without substituent or hydroxyl groups in the C(17) position, respectively, as the most promising compounds from the series which could be considered as potential multi-target drugs for the treatment of AD. Full article

In contrast to most other rhabdoviruses, which spread by insect vectors, the rabies virus (RABV) is a very unusual member of the Rhabdoviridae family, since it has evolved to be fully adapted to warm-blooded hosts and spread directly between them. There are differences in the immune responses to laboratory-attenuated RABV and wild-type rabies virus infections. Various investigations showed that whilst laboratory-attenuated RABV elicits an innate immune response, wild-type RABV evades detection. Pathogenic RABV infection bypasses immune response by antagonizing interferon induction, which prevents downstream signal activation and impairs antiviral proteins and inflammatory cytokines production that could eliminate the virus. On the contrary, non-pathogenic RABV infection leads to immune activation and suppresses the disease. Apart from that, through recruiting leukocytes into the central nervous system (CNS) and enhancing the blood–brain barrier (BBB) permeability, which are vital factors for viral clearance and protection, cytokines/chemokines released during RABV infection play a critical role in suppressing the disease. Furthermore, early apoptosis of neural cells limit replication and spread of avirulent RABV infection, but street RABV strains infection cause delayed apoptosis that help them spread further to healthy cells and circumvent early immune exposure. Similarly, a cellular regulation mechanism called autophagy eliminates unused or damaged cytoplasmic materials and destroy microbes by delivering them to the lysosomes as part of a nonspecific immune defense mechanism. Infection with laboratory fixed RABV strains lead to complete autophagy and the viruses are eliminated. But incomplete autophagy during pathogenic RABV infection failed to destroy the viruses and might aid the virus in dodging detection by antigen-presenting cells, which could otherwise elicit adaptive immune activation. Pathogenic RABV P and M proteins, as well as high concentration of nitric oxide, which is produced during rabies virus infection, inhibits activities of mitochondrial proteins, which triggers the generation of reactive oxygen species, resulting in oxidative stress, contributing to mitochondrial malfunction and, finally, neuron process degeneration. Full article

The accurate assessment of drug concentrations in biodistribution studies is crucial for evaluating the efficacy and toxicity of compounds in drug development. As the concentration of biologics in plasma can be higher than in tissue due to their potentially low volume of distribution, transcardiac perfusion is commonly employed to reduce the influence of excess drugs in residual blood. However, there is a lack of consistency in the literature on the conditions and methods of perfusion. To enhance blood removal during transcardiac perfusion, sodium nitrite (NaNO₂), a vasodilator, has been widely used with concentrations up to 5% in publications. However, we found that such high NaNO₂ could disrupt the BBB during perfusion, which should be avoided in experiments. In this study, we examined the impact of various vasodilators on blood–brain barrier integrity and vascular permeability using the ratio of FITC-Dextran to Texas Red-Dextran (FITC/Texas Red). Additionally, we optimized perfusion conditions—including euthanasia method and perfusion flow rate—based on hemoglobin levels and the FITC/Texas Red ratio in tissues. Despite the superiority of NaNO₂ in terms of solubility and cost over other vasodilators, we found that 2% NaNO₂ disrupted blood–brain barrier integrity, significantly altering the FITC/Texas Red ratio. In contrast, 100 mM NaNO₂ did not significantly affect this ratio. Moreover, under Ketamine/Xylazine (Ket/Xyl) anesthesia, which reduced blood clot formation compared to CO₂ euthanasia, 100 mM NaNO₂ achieved the lowest hemoglobin levels in the brain. Compared to other vasodilators and the PBS control group, 100 mM NaNO₂ decreased the tissue/plasma ratio (K_p,t) but not brain/plasma ratio (K_p,b) of hIgG1 and human transferrin. We have developed a method to efficiently evaluate blood–brain barrier integrity during transcardiac perfusion. The combination of Ket/Xyl anesthesia and 100 mM NaNO₂ effectively removes residual blood from tissues without significantly affecting blood vessel permeability. Full article

Cerebral hyperperfusion syndrome (CHS) is a serious post-procedural complication of carotid artery stenting (CAS). The pathophysiological mechanisms of CHS in the absence of arterial hypertension (AH) remain only partially understood. We performed a systematic literature search of the PubMed database using the terms »cerebral hyperperfusion syndrome«, »hypotension«, »hyperperfusion«, »stroke«, »intracranial hemorrhages«, »risk factors«, »carotid revascularization«, »carotid stenting«, »carotid endarterectomy«, »blood-brain barrier«, »endothelium«, »contrast encephalopathy«, and combinations. We present a case of a normotensive female patient who developed CHS post-CAS for symptomatic carotid stenosis while being hypotensive with complete recovery. We identified 393 papers, among which 65 were deemed relevant to the topic. The weighted average prevalence of CHS after CAS is 1.2% [0.0–37.7%] with that of intracranial hemorrhage (ICH) being 0.51% [0–9.3%]. Recently symptomatic carotid stenosis or contralateral carotid revascularization, urgent intervention, acute carotid occlusion, contralateral ≥70% stenosis, and the presence of leptomeningeal collaterals were associated with CHS. A prolonged hemodynamic instability after CAS conveys a higher risk for CHS. However, none of the articles mentioned isolated hypotension as a risk factor for CHS. Whereas mortality after ICH post-CAS ranges from 40 to 75%, in the absence of ICH, CHS generally carries a good prognosis. AH is not obligatory in CHS development. Even though impaired cerebral autoregulation and post-revascularization changes in cerebral hemodynamics seem to play a pivotal role in CHS pathophysiology, our case highlights the complexity of CHS, involving factors like endothelial dysfunction and sudden reperfusion. Further research is needed to refine diagnostic and management approaches for this condition. Full article

The interplay between functional food nutrients and neurosteroids has garnered significant attention for its potential to enhance stress resilience in health and/or disease. Several bioactive nutrients, including medicinal herbs, flavonoids, and bioavailable polyphenol-combined nanoparticles, as well as probiotics, vitamin D and omega-3 fatty acids, have been shown to improve blood–brain barrier (BBB) dysfunction, endogenous neurosteroid homeostasis and brain function. These nutrients can inhibit oxidative stress and neuroinflammation, which are linked to the pathogenesis of various neurological disorders. Interestingly, flavonoids exhibit dose-dependent effects, activating the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway at the physiological/low dose (neurohormesis). This leads to the upregulation of antioxidant phase II genes and proteins such as heme oxygenase-1 (HO-1) and sirtuin-1 (Sirt1), which are activated by curcumin and resveratrol, respectively. These adaptive neuronal response mechanisms help protect against reactive oxygen species (ROS) and neurotoxicity. Impaired Nrf2 and neurosteroid hormone signaling in the brain can exacerbate selective vulnerability to neuroinflammatory conditions, contributing to the onset and progression of neurodegenerative and psychiatric disorders, including Alzheimer’s disease, anxiety and depression and other neurological disorders, due to the vulnerability of neurons to stress. This review focuses on functional food nutrients targeting Nrf2 antioxidant pathway and redox resilience genes to regulate the neurosteroid homeostasis and BBB damage associated with altered GABAergic neurotransmission. By exploring the underlying molecular mechanisms using innovative technologies, we aim to develop promising neuroprotective strategies and personalized nutritional and neuroregenerative therapies to prevent or attenuate oxidative stress and neuroinflammation, ultimately promoting brain health. Full article

Mitragynine is an “atypic opioid” analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability. An optimized sequence of CPC, flash chromatography, and preparative HPLC methods was used to isolate the four identified BBB+ alkaloids. To improve the bioavailability of the isolated alkaloids, their cyclodextrin (CD) complexation behavior was investigated via affinity capillary electrophoresis using almost 40 CD derivatives. The apparent alkaloid–CD complex stability constants were determined and compared, and the most relevant CDs phase-solubility studies were also performed. Both the neutral and negatively charged derivatives were able to form complexes with all four kratom alkaloids. It was found that cavity size, substituent type, and degree of substitution also influenced complex formation. The negatively charged Sugammadex, Subetadex, and the sufoalkylated-beta-CD analogs were able to form the most stable complexes, exceeding 1000 M⁻¹. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids. Full article

Sturge–Weber syndrome (SWS) is a rare congenital neurocutaneous disorder typically caused by a somatic mosaic mutation in R183Q GNAQ. At-risk children present at birth with a capillary malformation port-wine birthmark. The primary diagnostic characteristic of the disorder includes leptomeningeal enhancement of the brain, which demonstrates abnormal blood vessels and results in impaired venous drainage and impaired local cerebral perfusion. Impaired cerebral blood flow is complicated by seizures resulting in strokes, hemiparesis and visual field deficits, hormonal deficiencies, behavioral impairments, and intellectual disability. Therefore, anti-seizure medication in combination with low-dose aspirin is a common therapeutic treatment strategy. Recently published data indicate that the underlying mutation in endothelial cells results in the hyperactivation of downstream pathways and impairment of the blood–brain barrier. Cannabidiol (CBD) has been used to treat medically refractory seizures in SWS due to its anti-seizure, anti-inflammatory, and neuroprotective properties. Pilot research suggests that CBD improves cognitive impairment, emotional regulation, and quality of life in patients with SWS. Recent preclinical studies also suggest overlapping molecular pathways in SWS and in CBD, suggesting that CBD may be uniquely effective for SWS brain involvement. This review aims to summarize early data on CBD’s efficacy for preventing and treating epilepsy and neuro-cognitive impairments in patients with SWS, likely molecular pathways impacted, and provide insights for future translational research to improve clinical treatment for patients with SWS. Full article

Silent information regulator sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase with potent anti-arterial aging activities. Its protective function in aging-related diseases has been extensively studied. In the microcirculation, SIRT1 plays a crucial role in preventing microcirculatory endothelial senescence by suppressing inflammation and oxidative stress while promoting mitochondrial function and optimizing autophagy. It suppresses hypoxia-inducible factor-1α (HIF-1α)-mediated pathological angiogenesis while promoting healthy, physiological capillarization. As a result, SIRT1 protects against microvascular dysfunction, such as diabetic microangiopathy, while enhancing exercise-induced skeletal muscle capillarization and energy metabolism. In the brain, SIRT1 upregulates tight junction proteins and strengthens their interactions, thus maintaining the integrity of the blood−brain barrier. The present review summarizes recent findings on the regulation of microvascular function by SIRT1, the underlying mechanisms, and various approaches to modulate SIRT1 activity in microcirculation. The importance of SIRT1 as a molecular target in aging-related diseases, such as diabetic retinopathy and stroke, is underscored, along with the need for more clinical evidence to support SIRT1 modulation in the microcirculation. Full article

Background/objectives: The blood–brain barrier (BBB) significantly limits the treatment of central nervous system disorders, such as schizophrenia, by restricting drug delivery to the brain. This study explores the potential of intranasal clozapine-loaded lipid nanocapsules (IN LNCs_Clo) as a targeted and effective delivery system to the brain. Methods: LNCs_Clo were prepared using the phase inversion technique and characterized in terms of size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. The pharmacokinetic, safety, and pharmacodynamic effects of LNCs_Clo were then evaluated in a rat model through intranasal (IN) administration and compared with those of oral and intravenous (IV) Clo solutions. Results: LNCs_Clo were prepared using a phase inversion technique, resulting in a nanocarrier with a particle size of 28.6 ± 3.6 nm, homogenous dispersion, and high EE% (84.66 ± 5.66%). Pharmacokinetic analysis demonstrated that IN LNCs_Clo provided enhanced Clo brain bioavailability, rapid CNS targeting, and prolonged drug retention compared to oral and intravenous routes. Notably, the area under the curve (AUC) for brain concentration showed more than two-fold and eight-fold increases with LNCs_Clo, compared to IV and oral solutions, respectively, indicating improved brain-targeting efficiency. Safety assessments indicated that LNCs_Clo administration mitigated Clo-associated metabolic side effects, such as hyperglycemia, insulin imbalance, and liver enzyme alterations. Additionally, pharmacodynamic studies showed that LNCs_Clo significantly improved antipsychotic efficacy and reduced schizophrenia-induced hyperactivity, while preserving motor function. Conclusions: These results highlight the potential of IN LNCs_Clo as a novel drug delivery system, offering improved therapeutic efficacy, reduced systemic side effects, and better patient compliance in the treatment of schizophrenia and potentially other CNS disorders. Full article

Elevated brain iron levels are characteristic of many neurodegenerative diseases. As an iron chelator with short biological half-life, deferiprone leads to agranulocytosis and neutropenia with a prolonged therapeutic course. Its inclusion in sustained-release dosage forms may reduce the frequency of administration. On the other hand, when administered by an alternative route of administration, such as the nasal route, systemic exposure to deferiprone will be reduced, thereby reducing the occurrence of adverse effects. Direct nose-to-brain delivery has been raised as a non-invasive strategy to deliver drugs to the brain, bypassing the blood–brain barrier. The aim of the study was to develop and characterize nanocomposite microspheres suitable for intranasal administration by combining nano- and microparticle-based approaches. Nanoparticles with an average particle size of 213 ± 56 nm based on the biodegradable polymer poly-ε-caprolactone were developed using the solvent evaporation method. To ensure the deposition of the particles in the nasal cavity and avoid exhalation or deposition into the small airways, the nanoparticles were incorporated into composite structures of sodium alginate obtained by spray drying. Deferiprone demonstrated sustained release from the nanocomposite microspheres and high iron-chelating activity. Full article