RESUMEN

Oral Topiramate therapy is associated with systemic adverse effects including paresthesia,abdominal pain, and fluctuations in plasma levels. The purpose of this research was to develop an intranasal in situ gel based system comprising Topiramate polymeric nanoparticles and evaluate its potential both in vitro and in vivo. Poly (lactic-co-glycolic acid) (PLGA)nanoparticles prepared by nanoprecipitation method were added into the in situ gelling system of Poloxamer 407 and HPMC K4M. Selected formulation (TG5) was evaluated for physicochemical properties, nasal permeation and in vivo pharmacokinetics in rats. PLGAnanoparticles (O1) exhibited low particle size (~ 144.4 nm), good polydispersity index (0.202), negative zeta potential (-12.7 mV), and adequate entrapment efficiency (64.7%). Developed in situ gel showed ideal pH (6.5), good gelling time (35 s), gelling temperature(37℃), suitable viscosity (1335 cP)and drug content of 96.2%. In vitro drug release conformedto Higuchi release kinetics, exhibiting a biphasic pattern of initial burst release and sustained release for 24 h. Oral administration of the drug to Sprague-Dawley rats (G3) showed higher plasma Cmax(504 ng/ml, p < 0.0001) when compared to nasal delivery of in situ gel (G4) or solution (G5). Additionally, AUC0-α of G3 (8786.82 ng/ml*h) was considerably higher than othergroups. Brain uptake data indicates a higher drug level with G4 (112.47 ng /ml) at 12 h when compared to G3. Histopathological examination of groups; G1 (intranasal saline), G2(intranasal placebo), G3, G4, and G5 did not show any lesions of pathological significance. Overall, the experimental results observed were promising and substantiated the potential of developed in situ gel for intranasal delivery.

Asunto(s)

Administración Intranasal , Encéfalo , Geles , Nanopartículas , Mucosa Nasal , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas Sprague-Dawley , Topiramato , Animales , Topiramato/administración & dosificación , Topiramato/farmacocinética , Nanopartículas/química , Ratas , Administración Intranasal/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Masculino , Tamaño de la Partícula , Fructosa/administración & dosificación , Fructosa/farmacocinética , Fructosa/química , Portadores de Fármacos/química , Liberación de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Ácido Láctico/química , Ácido Láctico/administración & dosificación , Ácido Poliglicólico/química , Administración Oral

RESUMEN

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.

Asunto(s)

Inmunidad Mucosa , Inmunomodulación , Humanos , Animales , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Tejido Linfoide/inmunología , Vacunas/inmunología , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Administración Intranasal

RESUMEN

COVID-19 remains a severe condition for many including immunocompromised individuals. There remains a need for effective measures against this and other respiratory infections, which transmit via virus-laden droplets that reach the nasal or oral mucosae. Nasal sprays offer potential protection against viruses. Such formulations should preserve normal nasal mucociliary function. The antiviral barrier efficacy and effects on mucociliary function of astodrimer sodium nasal spray (AS-NS) were evaluated and compared with other available nasal sprays-low pH hydroxypropyl methylcellulose (HPMC-NS), iota-carrageenan (Carr-NS), nitric oxide (NO-NS), and povidone iodine (PI-NS). Assays simulated clinical conditions. Antiviral barrier function and cell viability were assessed in airway cell monolayers, while a model of fully differentiated human nasal epithelium (MucilAir™) was utilized to evaluate tissue integrity, cytotoxicity, cilia beating frequency, and mucociliary clearance. AS-NS reduced infectious virus in cell monolayers and demonstrated a benign cytotoxicity profile. In human nasal epithelium ex vivo, AS-NS had no impact on mucociliary function (cilia beating nor mucociliary clearance). Carr-NS, HPMC-NS, NO-NS and PI-NS demonstrated limited antiviral effects, while HPMC-NS caused inhibition of mucociliary function. Astodrimer sodium nasal spray demonstrates an acceptable nonclinical efficacy and safety profile as a barrier nasal spray against respiratory viral infection in the nasal cavity.

Asunto(s)

Depuración Mucociliar , Mucosa Nasal , Rociadores Nasales , SARS-CoV-2 , Humanos , Mucosa Nasal/virología , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , SARS-CoV-2/efectos de los fármacos , Depuración Mucociliar/efectos de los fármacos , Antivirales/farmacología , Antivirales/administración & dosificación , COVID-19/virología , COVID-19/metabolismo , Tratamiento Farmacológico de COVID-19 , Supervivencia Celular/efectos de los fármacos

RESUMEN

This study aimed to investigate the impact of different types of nasal inflammation on the regulation of entry-associated genes of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus 229E (HCoV-229E), and influenza virus, in the nasal epithelium. Subjects were classified into three groups: control, eosinophilic chronic rhinosinusitis (ECRS), and noneosinophilic CRS (NECRS) groups. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), alanyl aminopeptidase (ANPEP), dipeptidyl peptidase 4 (DPP4), and beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1), and beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) were selected as key entry-associated genes for SARS-CoV-2, HCoV-229E, MERS-CoV, and influenza, respectively, and were evaluated. Brushing samples obtained from each group and human nasal epithelial cells cultured using an air-liquid interface system were treated for 7 days with typical inflammatory cytokines and analyzed using real-time polymerase chain reaction. Western blot analysis and confocal microscopy were performed. The entry-associated genes showed distinct regulation patterns in response to each interleukin-4 (IL-4), interleukin-13 (IL-13), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Specifically, ACE2 significantly decreased in type 2 cytokines (IL-4 and IL-13), while TMPRSS2 significantly decreased in type 1 cytokines (TNF-α and IFN-γ). ANPEP significantly decreased in both types of cytokines. Remarkably, DPP4 significantly increased in type 2 cytokines and decreased in type 1 cytokines. Moreover, ST6GAL1 and ST3GAL4 significantly increased in type 2 cytokines and decreased in type 1 cytokines, particularly IFN-γ. These findings were supported by western blot analysis and confocal imaging results, especially for ACE2 and DPP4. The findings regarding differential regulation suggest that patients with ECRS, primarily mediated by type 2 inflammation, may have lower susceptibility to SARS-CoV-2 and HCoV-229E infections but higher susceptibility to MERS-CoV and influenza infections.

Asunto(s)

Citocinas , Mucosa Nasal , Internalización del Virus , Humanos , Citocinas/genética , Citocinas/metabolismo , Mucosa Nasal/virología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Sinusitis/virología , Sinusitis/genética , Sinusitis/inmunología , SARS-CoV-2/inmunología , Rinitis/virología , Rinitis/genética , Rinitis/inmunología , Regulación de la Expresión Génica , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , COVID-19/inmunología , COVID-19/virología , Coronavirus Humano 229E/genética , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología

RESUMEN

Allergic rhinitis (AR) is a chronic, non-infectious inflammatory condition of the nasal mucosa mediated by IgE. There is a need for the development of novel medications to treat this ailment. Isoorientin is a naturally occurring flavonoid that possesses antioxidant, anti--inflammatory, and various other advantageous characteristics. However, its potential effects on AR remain unclear. This study evaluates the therapeutic effects of isoorientin on ovalbumin (OVA)-induced allergic rhinitis (AR) in mice and explores the underlying mechanism. Our study revealed that isoorientin administration effectively decreased the frequency of nose rubbing and sneezing in AR mice. The groups treated with isoorientin showed a significant decrease in serum levels of IgE and histamine, with reductions of 40% and 30%, respectively. Isoorientin ameliorated inflammation of the nasal mucosa and restored the Th1/Th2 balance. In addition, isoorientin inhibited the activation of the NF-κB pathway in nasal tissues. In summary, Isoorientin alleviates OVA-stimulated AR in mice by restoring Th1/Th2 balance and blocking the NF-κB pathway. Thus, isoorientin exhibits promise as a natural therapeutic agent for allergic rhinitis.

Asunto(s)

Modelos Animales de Enfermedad , Inmunoglobulina E , Luteolina , Ratones Endogámicos BALB C , FN-kappa B , Mucosa Nasal , Ovalbúmina , Rinitis Alérgica , Balance Th1 - Th2 , Animales , Luteolina/farmacología , Ovalbúmina/inmunología , Ratones , Rinitis Alérgica/inmunología , Rinitis Alérgica/tratamiento farmacológico , Balance Th1 - Th2/efectos de los fármacos , Mucosa Nasal/inmunología , Mucosa Nasal/efectos de los fármacos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , FN-kappa B/metabolismo , Células Th2/inmunología , Femenino , Humanos , Alérgenos/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Células TH1/inmunología , Células TH1/efectos de los fármacos , Histamina/metabolismo , Histamina/sangre

RESUMEN

Staphylococcus aureus acts both as a colonizing commensal bacterium and invasive pathogen. Nasal colonization is associated with an increased risk of infection caused by the identical strain. In patients with atopic dermatitis (AD), the degree of S. aureus colonization is associated with the severity of the disease. Here, we comparatively analyzed the in vivo transcriptional profile of S. aureus colonizing the nose and non-diseased skin (non-lesional skin) as opposed to the diseased skin (lesional skin-defined here as infection) of 12 patients with AD. The transcriptional profile during the asymptomatic colonization of the nose closely resembled that of the lesional skin samples for many of the genes studied, with an elevated expression of the genes encoding adhesion-related proteins and proteases. In addition, the genes that modify and remodel the cell wall and encode proteins that facilitate immune evasion showed increased transcriptional activity. Notably, in a subgroup of patients, the global virulence regulator Agr (accessory gene regulator) and downstream target genes were inactive during nasal colonization but upregulated in the lesional and non-lesional skin samples. Taken together, our results demonstrate a colonization-like transcriptional profile on diseased skin and suggest a role for the peptide quorum sensing system Agr during the transition from asymptomatic nasal colonization to skin colonization/infection.

Asunto(s)

Dermatitis Atópica , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica , Piel , Infecciones Estafilocócicas , Staphylococcus aureus , Dermatitis Atópica/microbiología , Dermatitis Atópica/genética , Humanos , Staphylococcus aureus/genética , Piel/microbiología , Piel/metabolismo , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/genética , Femenino , Masculino , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Adulto , Transcriptoma , Infecciones Cutáneas Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/genética , Mucosa Nasal/microbiología , Transactivadores

RESUMEN

ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.

Asunto(s)

Administración Intranasal , Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Donepezilo , Liposomas , ARN Interferente Pequeño , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Donepezilo/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/farmacología , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Indanos/administración & dosificación , Indanos/farmacocinética , Péptidos beta-Amiloides/metabolismo

RESUMEN

SARS-CoV-2 infection induces the generation of virus-specific CD4+ and CD8+ effector and memory T cells. However, the contribution of T cells in controlling SARS-CoV-2 during infection is not well understood. Following infection of C57BL/6 mice, SARS-CoV-2-specific CD4+ and CD8+ T cells are recruited to the respiratory tract, and a vast proportion secrete the cytotoxic molecule granzyme B. Using depleting antibodies, we found that T cells within the lungs play a minimal role in viral control, and viral clearance occurs in the absence of both CD4+ and CD8+ T cells through 28 days postinfection. In the nasal compartment, depletion of both CD4+ and CD8+ T cells, but not individually, results in persistent, culturable virus replicating in the nasal epithelial layer through 28 days postinfection. Viral sequencing analysis revealed adapted mutations across the SARS-CoV-2 genome, including a large deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.

Asunto(s)

Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , COVID-19 , Ratones Endogámicos C57BL , SARS-CoV-2 , Replicación Viral , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , SARS-CoV-2/fisiología , SARS-CoV-2/inmunología , COVID-19/virología , COVID-19/inmunología , COVID-19/prevención & control , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD4-Positivos/metabolismo , Ratones , Pulmón/virología , Pulmón/inmunología , Humanos , Femenino , Mucosa Nasal/virología , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Granzimas/metabolismo

RESUMEN

INTRODUCTION: The olfactory and trigeminal system are closely interlinked. Existing literature has primarily focused on characterizing trigeminal stimulation through mechanical and chemical stimulation, neglecting thermal stimulation thus far. The present study aimed to characterize the intranasal sensitivity to heat and the expression of trigeminal receptors (transient receptor potential channels, TRP). METHODS: A total of 20 healthy participants (aged 21-27 years, 11 women) were screened for olfactory function and trigeminal sensitivity using several tests. Under endoscopic control, a thermal stimulator was placed in 7 intranasal locations: anterior septum, lateral vestibulum, interior nose tip, lower turbinate, middle septum, middle turbinate, and olfactory cleft to determine the thermal threshold. Nasal swabs were obtained in 3 different locations (anterior septum, middle turbinate, olfactory cleft) to analyze the expression of trigeminal receptors TRP: TRPV1, TRPV3, TRPA1, TRPM8. RESULTS: The thermal threshold differed between locations (p = 0.018), with a trend for a higher threshold at the anterior septum (p = 0.092). There were no differences in quantitative receptor expression (p = 0.46) at the different sites. The highest overall receptor RNA expression was detected for TRPV1 over all sites (p<0.001). The expression of TRPV3 was highest at the anterior septum compared to the middle turbinate or the olfactory cleft. The thermal sensitivity correlated with olfactory sensitivity and results from tests were related to trigeminal function like intensity ratings of ammonium, a questionnaire regarding trigeminal function, nasal patency, and CO2 thresholds. However, no correlation was found between receptor expression and psychophysical measures of trigeminal function. DISCUSSION: This study provided the first insights about intranasal thermal sensitivity and suggested the presence of topographical differences in thermal thresholds. There was no correlation between thermal sensitivity and trigeminal mRNA receptor expression. However, thermal sensitivity was found to be associated with psychophysical measures of trigeminal and olfactory function.

Asunto(s)

Mucosa Nasal , Canales Catiónicos TRPV , Humanos , Femenino , Adulto , Masculino , Mucosa Nasal/metabolismo , Adulto Joven , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Calor , Nervio Trigémino/fisiología , Nervio Trigémino/metabolismo , Umbral Sensorial/fisiología , Canales de Potencial de Receptor Transitorio/metabolismo , Canales de Potencial de Receptor Transitorio/genética , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/genética , Sensación Térmica/fisiología , Canal Catiónico TRPA1/metabolismo , Canal Catiónico TRPA1/genética

RESUMEN

The advancement of effective nasal mucoadhesive delivery faces challenges due to rapid mucociliary clearance (MCC). Conventional studies have employed mucoadhesive materials, mainly forming spherical nanoparticles, but these offer limited adhesion to the nasal mucosa. This study hypothesizes that a 2D nanoscale structure utilizing adhesive polyphenols can provide a superior strategy for countering MCC, aligning with the planar mucosal layers. We explore the use of tannic acid (TA), a polyphenolic molecule known for its adhesive properties and ability to form complexes with biomolecules. Our study introduces an unprecedented 2D nanopatch, assembled through the interaction of TA with green fluorescent protein (GFP), and cell-penetrating peptide (CPP). This 2D nanopatch demonstrates robust adhesion to nasal mucosa and significantly enhances immunoglobulin A secretions, suggesting its potential for enhancing nasal vaccine delivery. The promise of a polyphenol-enabled adhesive 2D nanopatch signifies a pivotal shift from conventional spherical nanoparticles, opening new pathways for delivery strategies through respiratory mucoadhesion.

Asunto(s)

Mucosa Nasal , Polifenoles , Taninos , Taninos/química , Polifenoles/química , Polifenoles/administración & dosificación , Mucosa Nasal/metabolismo , Mucosa Nasal/inmunología , Animales , Nanopartículas/química , Humanos , Péptidos de Penetración Celular/química , Proteínas Fluorescentes Verdes/metabolismo , Proteínas Fluorescentes Verdes/química , Adhesivos/química , Depuración Mucociliar/efectos de los fármacos , Inmunoglobulina A , Ratones

RESUMEN

The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.

Asunto(s)

Encéfalo , Canfanos , Lípidos , Nanopartículas , Rociadores Nasales , Ratas Sprague-Dawley , Animales , Nanopartículas/química , Ratas , Lípidos/química , Encéfalo/metabolismo , Canfanos/química , Canfanos/administración & dosificación , Canfanos/farmacología , Masculino , Administración Intranasal , Sistemas de Liberación de Medicamentos , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Tamaño de la Partícula

RESUMEN

PURPOSE: To compare short-term outcomes between membrane perforation and non-perforation patients after simultaneous external elevation with implantation. MATERIALS AND METHODS: In this retrospective observational study, 60 maxillary posterior tooth-loss patients with an insufficient amount of residual bone for direct implantation were enrolled. All patients underwent simultaneous external elevation and implantation, and were divided into perforation and non-perforation groups according to the postoperative Schneiderian membrane status. RESULTS: Of the 60 patients, 30 cases (35 implants) were assigned to the membrane perforation group, and 30 (44 implants) were allocated to the non-perforation group. There were no statistically significant differences in baseline data (p>0.05). In the perforation group, the mean vertical bone gain (VBG) at 6 and 12 months was 6.02±2.14 mm and 5.37±2.22 mm, resp., compared to 6.78±2.59 mm and 6.42±2.64 mm in the non-perforation group, resp. (both p>0.05). Preoperative median Schneiderian membrane thickness (SMT) in the perforation group was 0.77 mm, which was statistically significantly thinner than the 1.24 mm measure in the non-perforation group (p< 0.05); however, there was no statistically significant difference between two groups at 12 months postoperatively (0.80 mm vs 1.25 mm, p>0.05). The marginal bone loss at 1 year after implant restoration in the perforation and non-perforation groups was 0.16±0.10 mm and 0.22±0.12 mm, resp. During postoperative follow-up, the implant survival rate was 100% in the two groups. The incidence of postoperative nasal bleeding in the perforation group was statistically significantly higher compared with that in the non-perforation group (50% vs 16.7%, p<0.05), whereas no statistically significant differences were observed in the incidence of facial swelling, intraoral bleeding, wound dehiscence and acute/chronic sinusitis between the two groups (p>0.05). CONCLUSIONS: Schneiderian membrane perforation after simultaneous external elevation and implantation do not adversely affect short-term clinical and radiographic outcomes.

Asunto(s)

Implantación Dental Endoósea , Mucosa Nasal , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Mucosa Nasal/lesiones , Mucosa Nasal/patología , Resultado del Tratamiento , Adulto , Maxilar/cirugía , Anciano , Pérdida de Diente

RESUMEN

Studies on the immune-regulatory roles played by the commensal microbes residing in the nasal mucosa consider the contribution of antiviral immune responses. Here, we sought to identify the nasal microbiome, Staphylococcus epidermidis-regulated antiviral immune responses and the alteration of polyamine metabolites in nasal epithelium. We found that polyamines were required for the life cycle of influenza A virus (IAV) and depletion of polyamines disturbed IAV replication in normal human nasal epithelial (NHNE) cells. Inoculation of S. epidermidis also suppressed IAV infection and the concentration of polyamines including putrescine, spermidine, and spermine was completely attenuated in S. epidermidis-inoculated NHNE cells. S. epidermidis activated the enzyme involved in the production of ornithine from arginine and downregulated the activity of the enzyme involved in the production of putrescine from ornithine in nasal epithelium. S. epidermidis also induced the activation of enzymes that promote the extracellular export of spermine and spermidine in NHNE cells. Our findings demonstrate that S. epidermidis is shown to be able of creating an intracellular environment lacking polyamines in the nasal epithelium and promote the balance of cellular polyamines in favor of the host to restrict influenza virus replication.

Asunto(s)

Virus de la Influenza A , Mucosa Nasal , Poliaminas , Staphylococcus epidermidis , Simbiosis , Replicación Viral , Staphylococcus epidermidis/fisiología , Staphylococcus epidermidis/metabolismo , Humanos , Poliaminas/metabolismo , Virus de la Influenza A/fisiología , Mucosa Nasal/microbiología , Mucosa Nasal/virología , Mucosa Nasal/metabolismo , Gripe Humana/virología , Gripe Humana/metabolismo

RESUMEN

This article explores Human-Centered Artificial Intelligence (HCAI) in medical cytology, with a focus on enhancing the interaction with AI. It presents a Human-AI interaction paradigm that emphasizes explainability and user control of AI systems. It is an iterative negotiation process based on three interaction strategies aimed to (i) elaborate the system outcomes through iterative steps (Iterative Exploration), (ii) explain the AI system's behavior or decisions (Clarification), and (iii) allow non-expert users to trigger simple retraining of the AI model (Reconfiguration). This interaction paradigm is exploited in the redesign of an existing AI-based tool for microscopic analysis of the nasal mucosa. The resulting tool is tested with rhinocytologists. The article discusses the analysis of the results of the conducted evaluation and outlines lessons learned that are relevant for AI in medicine.

Asunto(s)

Inteligencia Artificial , Humanos , Mucosa Nasal/metabolismo

RESUMEN

BACKGROUND: Altered biosynthesis of eicosanoids is linked to type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), but their role in recalcitrant NPs is unclear. OBJECTIVES: We sought to identify endotypes that are linked to recalcitrant CRSwNP, based on eicosanoids, their biosynthetic enzymes, and receptors as well as cytokines and the presence of eosinophils and mast cells in recurrent NPs. METHODS: Mucosal tissue collected at the time of sinus surgery from 54 patients with CRSwNP and 12 non-CRS controls were analysed for leukotriene (LT) E4, prostaglandin (PG) D2, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 17 cytokines with ELISAs and Bio-Plex immunoassays. Patient subgroups were identified by cluster analysis and the probability of NP recurrence were tested with logistic regression analyses. Gene expressions were analysed with qPCR. Tryptase and eosinophil-derived neurotoxin (EDN) were measured with ELISAs as indications of the presence of mast cells and eosinophils, respectively. RESULTS: Clustering of patients showed that an inflammatory signature characterised by elevated LTE4, PGD2, 15(S)-HETE and IL-13 was associated with NP recurrence. Previous NP surgery as well as aspirin-exacerbated respiratory disease were significantly more common among these patients. Expression of cyclooxygenase 1 was the only gene associated with NP recurrence. Levels of EDN, but not tryptase, were significantly higher in patients with recurrent NPs. CONCLUSION: Distinguishing endotypes that include LTE4, PGD2, 15HETE and conventional biomarkers of type 2 inflammation could help predict recurrent nasal polyposis and thus identify cases of recalcitrant CRSwNP.

Asunto(s)

Biomarcadores , Ácidos Hidroxieicosatetraenoicos , Leucotrieno E4 , Pólipos Nasales , Prostaglandina D2 , Recurrencia , Rinitis , Sinusitis , Humanos , Sinusitis/metabolismo , Sinusitis/patología , Sinusitis/cirugía , Sinusitis/diagnóstico , Pólipos Nasales/metabolismo , Pólipos Nasales/patología , Pólipos Nasales/cirugía , Pólipos Nasales/genética , Femenino , Masculino , Leucotrieno E4/metabolismo , Persona de Mediana Edad , Enfermedad Crónica , Ácidos Hidroxieicosatetraenoicos/metabolismo , Adulto , Rinitis/metabolismo , Rinitis/patología , Rinitis/diagnóstico , Rinitis/cirugía , Biomarcadores/metabolismo , Prostaglandina D2/metabolismo , Pronóstico , Mucosa Nasal/metabolismo , Mucosa Nasal/patología , Eosinófilos/metabolismo , Eosinófilos/patología , Mastocitos/metabolismo , Mastocitos/patología , Rinosinusitis

RESUMEN

Epilepsy is a highly prevalent neurological disease and valproic acid (VPA) is used as a first-line chronic treatment. However, this drug has poor oral bioavailability, which requires the administration of high doses, resulting in adverse effects. Alternative routes of VPA administration have therefore been investigated, such as the nose-to-brain route, which allows the drug to be transported directly from the nasal cavity to the brain. Here, the use of nanostructured lipid carriers (NLC) to encapsulate drugs administered in the nasal cavity has proved advantageous. The aim of this work was to optimise a mucoadhesive formulation of VPA-loaded NLC for intranasal administration to improve the treatment of epilepsy. The Design of Experiment (DoE) was used to optimise the formulation, starting with component optimisation using Mixture Design (MD), followed by optimisation of the manufacturing process parameters using Central Composite Design (CCD). The optimised VPA-loaded NLC had a particle size of 76.1 ± 2.8 nm, a polydispersity index of 0.190 ± 0.027, a zeta potential of 28.1 ± 2.0 mV and an encapsulation efficiency of 85.4 ± 0.8%. The in vitro release study showed VPA release from the NLC of 50 % after 6 h and 100 % after 24 h. The in vitro biocompatibility experiments in various cell lines have shown that the optimised VPA-loaded NLC formulation is safe up to 75 µg/mL, in neuronal (SH-SY5Y), nasal (RPMI 2650) and hepatic (HepG2) cells. Finally, the interaction of the optimised VPA-loaded NLC formulation with nasal mucus was investigated and mucoadhesive properties were observed. The results of this study suggest that the use of intranasal VPA-loaded NLC may be a promising alternative to promote VPA targeting to the brain, thereby improving bioavailability and minimising adverse effects.

Asunto(s)

Administración Intranasal , Anticonvulsivantes , Encéfalo , Portadores de Fármacos , Lípidos , Nanoestructuras , Mucosa Nasal , Ácido Valproico , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacocinética , Ácido Valproico/química , Portadores de Fármacos/química , Lípidos/química , Humanos , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/química , Nanoestructuras/química , Nanoestructuras/administración & dosificación , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Liberación de Fármacos , Tamaño de la Partícula , Adhesividad , Animales , Supervivencia Celular/efectos de los fármacos

RESUMEN

Xylometazoline is a well-established nasal decongestant that has been used alone and in combination with dexpanthenol as an over the counter (OTC) medicine. Considering the possibility of further improvement of xylometazoline nasal formulations, hyaluronic acid (HA) was evaluated as an additional ingredient. The aim of this study was to investigate the permeation, mucosal retention, and mucoadhesion properties of a new xylometazoline-HA [Xylo-HA] formulation ex vivo and to explore the potential benefits of incorporating HA in the formulation in vitro. Sheep nasal mucosa was used in the ex vivo study, where Xylo-HA was compared with xylometazoline alone [Xylo-Mono], and in combination with dexpanthenol [Xylo-Dex] to understand the impact of formulation changes. The permeation of xylometazoline was generally low (Xylo-Mono 11.14 ± 4.75 %, Xylo-HA 14.57 ± 5.72 % and Xylo-Dex 11.00 ± 3.05 % of the applied dose). The steady state fluxes of xylometazoline were determined as 12.64 ± 3.52 µg/cm2h, 14.94 ± 3.38 µg/cm2h and 12.19 ± 2.05 µg/cm2h for Xylo-Mono, Xylo-HA and Xylo-Dex, respectively. No significant differences were observed between the formulations in the permeation nor mucosal retention studies (p > 0.05 for all), while Xylo-HA exhibited superior mucoadhesive proprieties (p < 0.05 for all). The effects on wound healing and barrier integrity of the three xylometazoline formulations were tested in vitro on HaCaT cells. To better elucidate the role of HA, an additional HA formulation without xylometazoline was prepared (HA-Mono). A scratch test was performed to evaluate wound healing, revealing that the test formulations did not achieve complete wound closure within 72 h and demonstrated a similar effect at the end of the testing period. To assess the effect on barrier integrity, cells were treated for 5 days with daily measurements of transepithelial electrical resistance (TEER). At the end of the experiment, Xylo-Dex showed a moderate 14 % increase in TEER, while Xylo-Mono did not significantly affect this parameter. TEER rose by 951 % in the Xylo-HA, and by 10497 % in the HA group, suggesting that incorporating HA led to enhanced barrier function. Further clinical studies are recommended to better understand the clinical implications and efficacy of the Xylo-HA formulation, with particular focus on the role of HA.

Asunto(s)

Ácido Hialurónico , Imidazoles , Mucosa Nasal , Animales , Ovinos , Imidazoles/administración & dosificación , Imidazoles/química , Imidazoles/farmacocinética , Imidazoles/farmacología , Ácido Hialurónico/química , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Descongestionantes Nasales/administración & dosificación , Administración Intranasal , Humanos , Química Farmacéutica/métodos , Permeabilidad , Composición de Medicamentos/métodos

RESUMEN

OBJECTIVE: Sinus membrane perforation is a common complication of sinus lift surgery. This review aimed to examine if anatomical factors such as the presence of septa and lateral wall thickness influence the risk of membrane perforation. METHODS: This study was registered on PROSPERO (CRD42023488259). PubMed, Embase, and Web of Science were searched for relevant studies published up to 26th June 2024. The outcome of interest was the risk of perforation based on presence of septa and lateral wall thickness. Random-effects meta-analysis was conducted with dichotomous data to obtain the odds ratio (OR) of perforation using Review Manager. RESULTS: Ten studies with 1865 patients undergoing 2168 "lateral" sinus lift procedures were included. The total incidence of Schneiderian membrane perforations was 19% (405 cases). Schneiderian membrane perforation was present in 169/425 cases (39.76%) with sinus septa and 184/1492 cases (12.33%) without septa. Meta-analysis showed that septa were significantly associated with an increased risk of perforation (OR: 4.03 95% CI: 1.77, 9.19) with high heterogeneity (I2 = 87%). The certainty of the evidence was very low. Data on lateral wall thickness and risk of perforation was too heterogeneous for a meta-analysis. Studies reported mixed results on the risk of perforation based on lateral wall thickness. CONCLUSIONS: Our results show, with very low-quality evidence, that the presence of septa significantly increases the risk of perforations during maxillary sinus lift surgery. Evidence on the association between lateral wall thickness and a risk of perforations during sinus lift surgery is conflicting, and no clear conclusions can be derived at this stage.

Asunto(s)

Seno Maxilar , Humanos , Seno Maxilar/cirugía , Seno Maxilar/diagnóstico por imagen , Elevación del Piso del Seno Maxilar/efectos adversos , Factores de Riesgo , Mucosa Nasal/lesiones

RESUMEN

An application of CO2/HCO3--free solution (Zero-CO2) did not increase intracellular pH (pHi) in ciliated human nasal epithelial cells (c-hNECs), leading to no increase in frequency (CBF) or amplitude (CBA) of the ciliary beating. This study demonstrated that the pHi of c-hNECs expressing carbonic anhydrase IV (CAIV) is high (7.64), while the pHi of ciliated human bronchial epithelial cells (c-hBECs) expressing no CAIV is low (7.10). An extremely high pHi of c-hNECs caused pHi, CBF and CBA to decrease upon Zero-CO2 application, while a low pHi of c-hBECs caused them to increase. An extremely high pHi was generated by a high rate of HCO3- influx via interactions between CAIV and Na+/HCO3- cotransport (NBC) in c-hNECs. An NBC inhibitor (S0859) decreased pHi, CBF and CBA and increased CBF and CBA in c-hNECs upon Zero-CO2 application. In conclusion, the interactions of CAIV and NBC maximize HCO3- influx to increase pHi in c-hNECs. This novel mechanism causes pHi to decrease, leading to no increase in CBF and CBA in c-hNECs upon Zero-CO2 application, and appears to play a crucial role in maintaining pHi, CBF and CBA in c-hNECs periodically exposed to air (0.04% CO2) with respiration.

Asunto(s)

Bicarbonatos , Dióxido de Carbono , Anhidrasa Carbónica IV , Cilios , Células Epiteliales , Mucosa Nasal , Humanos , Concentración de Iones de Hidrógeno , Dióxido de Carbono/metabolismo , Cilios/metabolismo , Bicarbonatos/metabolismo , Células Epiteliales/metabolismo , Mucosa Nasal/metabolismo , Mucosa Nasal/citología , Anhidrasa Carbónica IV/metabolismo , Anhidrasa Carbónica IV/genética , Células Cultivadas , Simportadores de Sodio-Bicarbonato/metabolismo , Simportadores de Sodio-Bicarbonato/genética

RESUMEN

Naegleria fowleri is a protozoan that causes primary amebic meningoencephalitis (PAM). The infection occurs when the trophozoites enter the nasal cavity, adhere to the nasal mucosa, invade the epithelium, and migrate until they reach the olfactory bulb. Like other pathogens, there is evidence that the adhesion of N. fowleri to host cells is an important factor in the process of cytopathogenicity and disease progression. However, the factors involved in the adhesion of the pathogen to the cells of the nasal epithelium have not been characterized. The objective of this study was to identify a protein on the surface of N. fowleri, which could act as adhesin to the mouse nasal epithelium in the PAM model. The interaction between proteins of extracts of N. fowleri and cells of the nasal epithelium of BALB/c mice was analyzed using overlay and Western blot assays. A 72-kDa band of N. fowleri interacted directly with epithelial cell proteins, this polypeptide band was purified and analyzed by mass spectrometry. Analysis revealed that polypeptide bands of 72 kDa contained peptides that matched the membrane protein, actin 1 and 2, and Hsp70. Moreover, the N. fowleri extracts resolved in 2D-SDS-PAGE showed that 72-kDa spot interacted with proteins of mouse epithelial cells, which include characteristics of the theoretical data of molecular weight and pH obtained in the analysis by mass spectrometry. Immunofluorescence tests showed that this protein is located on the surface of trophozoites and plays an important role in the adhesion of amoeba either in vitro or in vivo assays, suggesting that this protein contributes during the N. fowleri invasion and migration to the brain, causing primary amoebic meningoencephalitis.

Asunto(s)

Infecciones Protozoarias del Sistema Nervioso Central , Ratones Endogámicos BALB C , Naegleria fowleri , Mucosa Nasal , Proteínas Protozoarias , Trofozoítos , Animales , Ratones , Mucosa Nasal/parasitología , Proteínas Protozoarias/metabolismo , Infecciones Protozoarias del Sistema Nervioso Central/parasitología , Western Blotting , Adhesión Celular , Femenino , Amebiasis/parasitología