6,797 research outputs found

    Research progress in brain-targeted nasal drug delivery

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    The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood–brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract)

    Oxidation alters IL-33 function:new insights in the biology of different forms of IL-33 and their relevance for COPD

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    In recent decades, the perception of the epithelium lining the airways has drastically changed from that of a physical barrier that mediates mucociliary transport to a multifunctional tissue that is actively involved in initiating and regulating tissue inflammation and remodelling [1, 2]. The airway epithelium produces a range of mediators, including chemokines, cytokines, growth factors and lipid mediators, to mediate these effects. Among these, the alarmin cytokines interleukin (IL)-33, thymic stromal lymphopoietin (TSLP) and IL-25 were found to regulate type 2 responses through effects on immune cells such as T helper type 2 (Th2) lymphocytes and type 2 innate lymphocytes (ILC2) [3]. Epithelial cells were recognised as source of these alarmin cytokines following exposure to a range of (environmental) triggers, including respiratory viruses, parasites, air pollutants and cigarette smoke, as well as allergens. These insults all have in common that they provoke a danger signal to the immune system upon damaging the epithelial layer. Based on their role in directing immune responses, alarmin cytokines have attracted attention as targets for a novel set of biologicals in the treatment of inflammatory lung diseases. Promising results were reported from clinical studies in which TSLP and IL-33 were targeted for the treatment of exacerbations of asthma and COPD [4]

    Platelet-activating factor receptor in health and disease.

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    Background Platelet-activating factor receptor (PAFR) expression has been linked to anthropogenic particulate matter (PM). Traffic-related air pollution (TRAP) now accounts for the majority of this PM. PAFR expression has also been linked to an increased risk of infection from Streptococcus pneumoniae (S. pneumoniae). Children with asthma and sickle cell disease (SCD) have a significantly increased risk of morbidity and mortality from invasive pneumococcal disease (IPD). PAFR expression has not yet been investigated in relation to TRAP-generated PM, nor has constitutive expression been investigated in these children at increased risk of IPD. Methods PM10 was collected from roadside traffic using the Cyclone device. A549 cells were exposed to the collected PM10 and flow cytometry was undertaken to measure PAFR expression by median fluorescence intensity (MFI). Exposed A549 cells also underwent assays to determine bacterial adhesion (colony-forming units, CFU) using D39 S. pneumoniae species. In both experiments, Dulbecco’s phosphate buffered saline (DPBS) was used as a control. In a separate study, children aged 1 – 17 years were recruited into 4 groups: 2 disease groups (children with asthma, and those with SCD); and 2 control groups (healthy children, and children with atopy but not asthma). Nasal epithelial cells were collected and PAFR expression (MFI) measured by flow cytometry. 24-hour PM10 pollution (μg/m3) data were also collected for each participant. Results TRAP-related PM caused a significant increase in PAFR expression in A549 cells when exposed to a concentration of 10 ug/ml (p < 0.05). Bacterial adhesion (CFU) was significantly raised in A549 cells exposed to TRAP PM verses the control wells (p < 0.05). In children, PAFR expression in SCD was notably raised when compared to all other groups (p < 0.001). There was no 7 significant difference in the PAFR expression in those with asthma versus the control groups. 24% of the children within the study demonstrated exposure to PM10 levels above the WHO daily safety limit. Conclusion PAFR expression and subsequent bacterial adhesion is increased following exposure to TRAP. PAFR is shown to be constitutively raised in those with SCD and this may explain some of the reported risk from IPD. Air pollution levels in London remain above safe limits despite public health initiatives trying to decrease them

    Otitis media: recent advances in otitis media vaccine development and model systems

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    Otitis media is an inflammatory disorder of the middle ear caused by airways-associated bacterial or viral infections. It is one of the most common childhood infections as globally more than 80% of children are diagnosed with acute otitis media by 3 years of age and it is a common reason for doctor’s visits, antibiotics prescriptions, and surgery among children. Otitis media is a multifactorial disease with various genetic, immunologic, infectious, and environmental factors predisposing children to develop ear infections. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common culprits responsible for acute otitis media. Despite the massive global disease burden, the pathogenesis of otitis media is still unclear and requires extensive future research. Antibiotics are the preferred treatment to cure middle ear infections, however, the antimicrobial resistance rate of common middle ear pathogens has increased considerably over the years. At present, pneumococcal and influenza vaccines are administered as a preventive measure against otitis media, nevertheless, these vaccines are only beneficial in preventing carriage and/or disease caused by vaccine serotypes. Otitis media caused by non-vaccine serotype pneumococci, non-typeable H. influenza, and M. catarrhalis remain an important healthcare burden. The development of multi-species vaccines is an arduous process but is required to reduce the global burden of this disease. Many novel vaccines against S. pneumoniae, non-typeable H. influenza, and M. catarrhalis are in preclinical trials. It is anticipated that these vaccines will lower the disease burden and provide better protection against otitis media. To study disease pathology the rat, mouse, and chinchilla are commonly used to induce experimental acute otitis media to test new therapeutics, including antibiotics and vaccines. Each of these models has its advantages and disadvantages, yet there is still a need to develop an improved animal model providing a better correlated mechanistic understanding of human middle ear infections, thereby underpinning the development of more effective otitis media therapeutics. This review provides an updated summary of current vaccines against otitis media, various animal models of otitis media, their limitations, and some future insights in this field providing a springboard in the development of new animal models and novel vaccines for otitis media

    Development of hydrogel cavities of tuneable stiffness for the growth of epithelial crypts

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    Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2023-2024. Tutor/Director: Jordi Comelles PujadasDepending on their function, the epithelial cell monolayers that line the inner surfaces of organs adopt a variety of three-dimensional shapes. Traditional studies in vitro have been using mainly flat cell culture dishes, overseeing the impact of these in vivo shapes in tissue function. Recent research has begun to address this issue, by trying to mimic the 3D structures found in tissues. However, those novel culture platforms still have some limitations, especially in cases where the architecture must correspond with the original tissue’s stiffness. Tissues have a quite low physiological rigidity, and most of the microfabrication techniques used nowadays need quite firm materials to achieve the desired 3D structures without issue. A type of structure difficult to fabricate using soft materials are invaginations, which can be found in vivo in kidneys, lungs, and the small intestine. Low rigidity substrates are typically characterized by high deformability and lack of structural support, which can result in unprecise final features due to distortions of the material during the microfabricating process. In this project, 3D cavities have been fabricated into polyacrylamide (PA), a material which allows the tuneability of its rigidity by changing the proportion of acrylamides during the synthesis of the prepolymer solution. Replica moulding has been employed to acquire these structures. The invaginations successfully recreated key aspects of the in vivo environment, both with their shape and stiffness, and multiple copies were created easily, enabling precise characterization. Finally, after the assessment of the mechanical properties and the architectural features of the microcavities, the functionalization of the samples was successful, confirming the suitability of the resulting scaffold as a model to study epithelial growth, morphology, and conformity in these inward bended structures

    Nasal polyps show decreased mucociliary transport despite vigorous ciliary beating

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    Objective: Mucociliary transport function in the airway mucosa is essential for maintaining a clean mucosal surface. This function is impaired in upper and lower airway diseases. Nasal polyps are a noticeable pathological feature that develop in some of the patients with chronic rhinosinusitis. Like ordinary nasal mucosae, nasal polyps have a ciliated pseudostratified epithelium with vigorous ciliary beating. We measured ex vivo Mucociliary Transport Velocity (MCTV) and Ciliary Beat Frequency (CBF) and explored the expressions of Planar Cell Polarity (PCP) proteins in nasal polyps in comparison with turbinate mucosae. Methods: Inferior turbinates and nasal polyps were surgically collected from patients with chronic rhinosinusitis. Ex vivo MCTV and CBF were measured using a high-speed digital imaging system. Expressions of PCP proteins were explored by fluorescence immunohistochemistry and quantitative RT-PCR. Results: The MCTV of nasal polyps was significantly lower than that of the turbinates (7.43 ± 2.01 vs. 14.56 ± 2.09 mm/s; p = 0.0361), whereas CBF did not differ between the two tissues. The MCTV vector was pointed to the posteroinferior direction in all turbinates with an average inclination angle of 41.0 degrees. Immunohistochemical expressions of Dishevelled-1, Dishevelled-3, Frizzled3, Frizzled6, Prickle2 and Vangl2 were lower in the nasal polyps than in the turbinates. Confocal laser scanning microscopy showed that Frizzled3 was localized along the cell junction on the apical surface. The expression levels of mRNAs for Dishevelled-1, Dishevelled-3 and Frizzled3 in the nasal polyps were also decreased in comparison with the turbinates. Conclusion: These results indicate that muco ciliary transport in nasal polyps is impaired although vigorous ciliary beating is maintained, and that the impairment may be caused by a decrease in Dishevelled/Frizzled proteins and resultant PCP disarrangement. Level of evidence: Level 3

    Acute and Chronic Bronchitis in Childhood: Cystic Fibrosis

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    The chapter discusses the problems of clinical diagnosis, treatment, and follow-up of children with acute and chronic bronchitis. All clinical types of acute bronchitis are covered. Special focus is paid on cystic fibrosis—diagnosis, clinical features, and treatment. Affecting the lower respiratory tract (bronchi and bronchioles) is a very common phenomenon in childhood, most often with a viral etiology, sometimes bacterial, atypical, allergic, etc. Children’s bronchi have a small amount of cartilaginous tissue, mainly smooth muscle tissue, and react to various triggers with bronchial spasm and increased mucus secretion. A significant part of pediatric pathology in early childhood is acute inflammatory diseases of the lower respiratory tract

    Identification of a novel RPGR mutation associated with retinitis pigmentosa and primary ciliary dyskinesia in a Slovak family: a case report

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    BackgroundThe mutations in the RPGR (retinitis pigmentosa GTPase regulator) gene are the most common cause of X-linked retinitis pigmentosa (XLRP), a rare genetic disorder affecting the photoreceptor cells in the retina. Several reported cases identified this gene as a genetic link between retinitis pigmentosa (RP) and primary ciliary dyskinesia (PCD), characterised by impaired ciliary function predominantly in the respiratory tract. Since different mutations in the same gene can result in various clinical manifestations, it is important to describe a correlation between the gene variant and the observed phenotype.MethodsTwo young brothers from a non-consanguineous Slovak family with diagnosed retinal dystrophy and recurrent respiratory infections were examined. Suspected PCD was diagnosed based on a PICADAR questionnaire, nasal nitric oxide analysis, transmission electron microscopy, high-speed video microscopy analysis, and genetic testing.ResultsWe identified a novel frameshift RPGR mutation NM_001034853: c.309_310insA, p.Glu104Argfs*12, resulting in a complex X-linked phenotype combining PCD and RP. In our patients, this mutation was associated with normal ultrastructure of respiratory cilia, reduced ciliary epithelium, more aciliary respiratory epithelium, shorter cilia, and uncoordinated beating with a frequency at a lower limit of normal beating, explaining the clinical manifestation of PCD in our patients.ConclusionThe identified novel pathogenic mutation in the RPGR gene expands the spectrum of genetic variants associated with the X-linked PCD phenotype overlapping with RP, highlighting the diversity of mutations contributing to the disorder. The described genotype–phenotype correlation can be useful in clinical practice to recognise a broader spectrum of PCD phenotypes as well as for future research focused on the genetic basis of PCD, gene interactions, the pathways implicated in PCD pathogenesis, and the role of RPGR protein for the proper functioning of cilia in various tissues throughout the body

    A comprehensive study on nanoparticle drug delivery to the brain: application of machine learning techniques

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    The delivery of drugs to specific target tissues and cells in the brain poses a significant challenge in brain therapeutics, primarily due to limited understanding of how nanoparticle (NP) properties influence drug biodistribution and off-target organ accumulation. This study addresses the limitations of previous research by using various predictive models based on collection of large data sets of 403 data points incorporating both numerical and categorical features. Machine learning techniques and comprehensive literature data analysis were used to develop models for predicting NP delivery to the brain. Furthermore, the physicochemical properties of loaded drugs and NPs were analyzed through a systematic analysis of pharmacodynamic parameters such as plasma area under the curve. The analysis employed various linear models, with a particular emphasis on linear mixed-effect models (LMEMs) that demonstrated exceptional accuracy. The model was validated via the preparation and administration of two distinct NP formulations via the intranasal and intravenous routes. Among the various modeling approaches, LMEMs exhibited superior performance in capturing underlying patterns. Factors such as the release rate and molecular weight had a negative impact on brain targeting. The model also suggests a slightly positive impact on brain targeting when the drug is a P-glycoprotein substrate
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