IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus.

Intron-containing RNA expressed from the HIV-1 provirus activates type 1 interferon in primary human blood cells, including CD4+ T cells, macrophages, and dendritic cells. To identify the innate immune receptor required for detection of intron-containing RNA expressed from the HIV-1 provirus, a loss-of-function screen was performed with short hairpin RNA-expressing lentivectors targeting twenty-one candidate genes in human monocyte-derived dendritic cells. Among the candidate genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the interferon-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with nontargetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant 2-CARD domain-deletion or phosphomimetic point mutations, indicates that IFIH1 (MDA5) filament formation, dephosphorylation, and association with MAVS are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 (MDA5) and DDX58 (RIG-I) signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation. RNA-Seq showed that IFIH1 knockdown in dendritic cells globally disrupted the induction of IFN-stimulated genes by HIV-1. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 (MDA5), over two orders of magnitude, was revealed by formaldehyde cross-linking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is the innate immune receptor for intron-containing RNA from the HIV-1 provirus and that IFIH1 potentially contributes to chronic inflammation in people living with HIV-1, even in the presence of effective antiretroviral therapy.

Nose-to-Brain Drug Delivery and Physico-Chemical Properties of Nanosystems: Analysis and Correlation Studies of Data from Scientific Literature.

Background: In the last few decades, nose-to-brain delivery has been investigated as an alternative route to deliver molecules to the Central Nervous System (CNS), bypassing the Blood-Brain Barrier. The use of nanotechnological carriers to promote drug transfer via this route has been widely explored. The exact mechanisms of transport remain unclear because different pathways (systemic or axonal) may be involved. Despite the large number of studies in this field, various aspects still need to be addressed. For example, what physicochemical properties should a suitable carrier possess in order to achieve this goal? To determine the correlation between carrier features (eg, particle size and surface charge) and drug targeting efficiency percentage (DTE%) and direct transport percentage (DTP%), correlation studies were performed using machine learning. Methods: Detailed analysis of the literature from 2010 to 2021 was performed on Pubmed in order to build "NANOSE" database. Regression analyses have been applied to exploit machine-learning technology. Results: A total of 64 research articles were considered for building the NANOSE database (102 formulations). Particle-based formulations were characterized by an average size between 150-200 nm and presented a negative zeta potential (ZP) from -10 to -25 mV. The most general-purpose model for the regression of DTP/DTE values is represented by Decision Tree regression, followed by K-Nearest Neighbors Regressor (KNeighbor regression). Conclusion: A literature review revealed that nose-to-brain delivery has been widely investigated in neurodegenerative diseases. Correlation studies between the physicochemical properties of nanosystems (mean size and ZP) and DTE/DTP parameters suggest that ZP may be more significant than particle size for DTP/DTE predictability.

In vitro and in vivo studies of ocular topically administered NLC for the treatment of uveal melanoma.

Uveal melanoma is one of the most common and aggressive intraocular malignancies, and, due to its great capability of metastasize, it constitutes the most incident intraocular tumor in adults. However, to date there is no effective treatment since achieving the inner ocular tissues still constitutes one of the greatest challenges in actual medicine, because of the complex structure and barriers. Uncoated and PEGylated nanostructured lipid carriers were developed to achieve physico-chemical properties (mean particle size, homogeneity, zeta potential, pH and osmolality) compatible for the ophthalmic administration of (S)-(-)-MRJF22, a new custom-synthetized prodrug for the potential treatment of uveal melanoma. The colloidal physical stability was investigated at different temperatures by Turbiscan® Ageing Station. Morphology analysis and mucoadhesive studies highlighted the presence of small particles suitable to be topically administered on the ocular surface. In vitro release studies performed using Franz diffusion cells demonstrated that the systems were able to provide a slow and prolonged prodrug release. In vitro cytotoxicity test on Human Corneal Epithelium and Human Uveal Melanoma cell lines and Hen's egg-chorioallantoic membrane test showed a dose-dependent cytotoxic effect of the free prodrug on corneal cells, whose cytocompatibility improved when encapsulated into nanoparticles, as also confirmed by in vivo studies on New Zealand albino rabbits. Antiangiogenic capability and preventive anti-inflammatory properties were also investigated on embryonated eggs and rabbits, respectively. Furthermore, preliminary in vivo biodistribution images of fluorescent nanoparticles after topical instillation in rabbits' eyes, suggested their ability to reach the posterior segment of the eye, as a promising strategy for the treatment of choroidal uveal melanoma.

W/O/W Microemulsions for Nasal Delivery of Hydrophilic Compounds: A Preliminary Study.

The administration of hydrophilic therapeutics has always been a great challenge because of their low bioavailability after administration. For this purpose, W/O/W microemulsion resulted to be a potential successful strategy for the delivery of hydrophilic compounds, interesting for the nasal mucosal therapy. Herein, an optimized biphasic W/O microemulsion was designed, through a preliminary screening, and it was inverted in a triphasic W/O/W microemulsion, intended for the nasal administration. In order to enhance the mucosal retention, surface modification of the biphasic W/O microemulsion was performed adding didodecyldimethylammonium bromide, and then converting the system into a cationic triphasic W/O/W microemulsion. The developed samples were characterized in terms of droplet size, polydispersity, zeta potential, pH and osmolality. The physical long-term stability was analyzed storing samples at accelerated conditions (40 ± 2 °C and 75 ± 5 % RH) for 6 months in a constant climate chamber, following ICH guidelines Q1A (R2). In order to verify the potential retention on the nasal mucosa, the two triphasic systems were analyzed in terms of mucoadhesive properties, measuring the in vitro interaction with mucin over time. Furthermore, fluorescein sodium salt was selected as a model hydrophilic drug to be encapsulated into the inner core of the two triphasic W/O/W microemulsions, and its release was analyzed compared to the free probe solution. The cytocompatibility of the two platforms was assessed on two cell lines, human fibroblasts HFF1 and Calu-3 cell lines, chosen as pre-clinical models for nasal and bronchial/tracheal airway epithelium.

IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus.

Antiretroviral therapy (ART) suppresses HIV-1 viremia and prevents progression to AIDS. Nonetheless, chronic inflammation is a common problem for people living with HIV-1 on ART. One possible cause of inflammation is ongoing transcription from HIV-1 proviruses, whether or not the sequences are competent for replication. Previous work has shown that intron-containing RNA expressed from the HIV-1 provirus in primary human blood cells, including CD4+ T cells, macrophages, and dendritic cells, activates type 1 interferon. This activation required HIV-1 rev and was blocked by the XPO1 (CRM1)-inhibitor leptomycin. To identify the innate immune receptor required for detection of intron-containing RNA expressed from the HIV-1 provirus, a loss-of-function screen was performed with shRNA-expressing lentivectors targeting twenty-one candidate genes in human monocyte derived dendritic cells. Among the candidate genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the IFN-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with non-targetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant inhibitory CARD-deletion or phosphomimetic point mutations, indicates that IFIH1 filament formation, dephosphorylation, and association with MAVS, are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 and DDX58 (RIG-I) signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation. RNA-Seq showed that IFIH1-knockdown in dendritic cells globally disrupted the induction of IFN-stimulated genes. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 was revealed by formaldehyde crosslinking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is required for innate immune activation by intron-containing RNA from the HIV-1 provirus, and potentially contributes to chronic inflammation in people living with HIV-1.

The Therapeutic Potential of Novel Carnosine Formulations: Perspectives for Drug Development.

Carnosine (beta-alanyl-L-histidine) is an endogenous dipeptide synthesized via the activity of the ATP-dependent enzyme carnosine synthetase 1 and can be found at a very high concentration in tissues with a high metabolic rate, including muscles (up to 20 mM) and brain (up to 5 mM). Because of its well-demonstrated multimodal pharmacodynamic profile, which includes anti-aggregant, antioxidant, and anti-inflammatory activities, as well as its ability to modulate the energy metabolism status in immune cells, this dipeptide has been investigated in numerous experimental models of diseases, including Alzheimer's disease, and at a clinical level. The main limit for the therapeutic use of carnosine is related to its rapid hydrolysis exerted by carnosinases, especially at the plasma level, reason why the development of new strategies, including the chemical modification of carnosine or its vehiculation into innovative drug delivery systems (DDS), aiming at increasing its bioavailability and/or at facilitating the site-specific transport to different tissues, is of utmost importance. In the present review, after a description of carnosine structure, biological activities, administration routes, and metabolism, we focused on different DDS, including vesicular systems and metallic nanoparticles, as well as on possible chemical derivatization strategies related to carnosine. In particular, a basic description of the DDS employed or the derivatization/conjugation applied to obtain carnosine formulations, followed by the possible mechanism of action, is given. To the best of our knowledge, this is the first review that includes all the new formulations of carnosine (DDS and derivatives), allowing a decrease or complete prevention of the hydrolysis of this dipeptide exerted by carnosinases, the simultaneous blood-brain barrier crossing, the maintenance or enhancement of carnosine biological activity, and the site-specific transport to different tissues, which then offers perspectives for the development of new drugs.

Melatonin loaded hybrid nanomedicine: DoE approach, optimization and in vitro study on diabetic retinopathy model.

Melatonin (MEL) is a pleiotropic neurohormone of increasing interest as a neuroprotective agent in ocular diseases. Improving the mucoadhesiveness is a proposed strategy to increase the bioavailability of topical formulations. Herein, the design and optimization of MEL-loaded lipid-polymer hybrid nanoparticles (mel-LPHNs) using Design of Experiment (DoE) was performed. LPHNs consisted of PLGA-PEG polymer nanoparticles coated with a cationic lipid-shell. The optimized nanomedicine showed suitable size for ophthalmic administration (189.4 nm; PDI 0.260) with a positive surface charge (+39.8 mV), high encapsulation efficiency (79.8 %), suitable pH and osmolarity values, good mucoadhesive properties and a controlled release profile. Differential Scanning Calorimetry and Fourier-Transform Infrared Spectroscopy confirmed the encapsulation of melatonin in the systems and the interaction between lipids and polymer matrix. Biological evaluation in an in vitro model of diabetic retinopathy demonstrated enhanced neuroprotective and antioxidant activities of mel-LPHNs, compared to melatonin aqueous solution at the same concentration (0.1 and 1 µM). A modified Draize test was performed to assess the ocular tolerability of the formulation showing no signs of irritation. To the best our knowledge, this study reported for the first time the development of mel-LPHNs, a novel and safe hybrid platform suitable for the topical management of retinal diseases.

Fluorescent Nanosystems for Drug Tracking and Theranostics: Recent Applications in the Ocular Field.

The greatest challenge associated with topical drug delivery for the treatment of diseases affecting the posterior segment of the eye is to overcome the poor bioavailability of the carried molecules. Nanomedicine offers the possibility to overcome obstacles related to physiological mechanisms and ocular barriers by exploiting different ocular routes. Functionalization of nanosystems by fluorescent probes could be a useful strategy to understand the pathway taken by nanocarriers into the ocular globe and to improve the desired targeting accuracy. The application of fluorescence to decorate nanocarrier surfaces or the encapsulation of fluorophore molecules makes the nanosystems a light probe useful in the landscape of diagnostics and theranostics. In this review, a state of the art on ocular routes of administration is reported, with a focus on pathways undertaken after topical application. Numerous studies are reported in the first section, confirming that the use of fluorescent within nanoparticles is already spread for tracking and biodistribution studies. The first section presents fluorescent molecules used for tracking nanosystems' cellular internalization and permeation of ocular tissues; discussions on the classification of nanosystems according to their nature (lipid-based, polymer-based, metallic-based and protein-based) follows. The following sections are dedicated to diagnostic and theranostic uses, respectively, which represent an innovation in the ocular field obtained by combining dual goals in a single administration system. For its great potential, this application of fluorescent nanoparticles would experience a great development in the near future. Finally, a brief overview is dedicated to the use of fluorescent markers in clinical trials and the market in the ocular field.

Intranasal Administration of a TRAIL Neutralizing Monoclonal Antibody Adsorbed in PLGA Nanoparticles and NLC Nanosystems: An In Vivo Study on a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that progressively compromises cognitive functions. Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand (TRAIL), a proinflammatory cytokine belonging to the TNF superfamily, appears to be a key player in the inflammatory/immune orchestra of the AD brain. Despite the ability of an anti-TRAIL monoclonal antibody to reach the brain producing beneficial effects in AD mice, we attempted to develop such a TRAIL-neutralizing monoclonal antibody adsorbed on lipid and polymeric nanocarriers, for intranasal administration, in a valid approach to overcome issues related to both high dose and drug transport across the blood-brain barrier. The two types of nanomedicines produced showed physico-chemical characteristics appropriate for intranasal administration. As confirmed by enzyme-linked immunosorbent assay (ELISA), both nanomedicines were able to form a complex with the antibody with an encapsulation efficiency of ≈99%. After testing in vitro the immunoneutralizing properties of the nanomedicines, the latter were intranasally administered in AD mice. The antibody-nanocarrier complexes were detectable in the brain in substantial amounts at concentrations significantly higher compared to the free form of the anti-TRAIL antibody. These data support the use of nanomedicine as an optimal method for the delivery of the TRAIL neutralizing antibody to the brain through the nose-to-brain route, aiming to improve the biological attributes of anti-TRAIL-based therapy for AD treatment.

Soluplus® polymeric nanomicelles improve solubility of BCS-class II drugs.

The issue of poor aqueous solubility is often a great hitch in the development of liquid dosage forms for those drugs that the Biopharmaceutics Classification System (BCS) includes in classes II and IV. Among the possible technological solutions, inclusion of the drug molecule within polymeric micelles, and particularly nanomicelles, has been proposed in the last years as a valid strategy. Our attention has been recently attracted by Soluplus®, an amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer able to form small and stable nanomicelles. The aim of this study was to characterize Soluplus® nanomicelles to enhance the apparent solubility of three model APIs, categorized in BCS class II: ibuprofen (IBU), idebenone (IDE), and miconazole (MIC). Drug-loaded Soluplus® micelles with a mean size around 60-70 nm were prepared by two methods (direct dissolution or film hydration method). The prepared nanosystems were characterized in terms of mean particle size and Zeta potential, physical stability, drug solubility, and in vitro drug release. The solubility of the tested APIs was shown to increase linearly with the concentration of graft copolymer. Soluplus® can be easily submitted to membrane filtration (0.2 µm PES or PTFE membranes), showing the potential to be sterilized by this method. Freeze-drying enabled to obtain powder materials that, upon reconstitution with water, maintained the initial micelle size. Finally, viscosity studies indicated that these nanomicelles have potential applications where a bioadhesive material is advantageous, such as in topical ocular administration.

Drug Nanocrystals: Focus on Brain Delivery from Therapeutic to Diagnostic Applications.

The development of new drugs is often hindered by low solubility in water, a problem common to nearly 90% of natural and/or synthetic molecules in the discovery pipeline. Nanocrystalline drug technology involves the reduction in the bulk particle size down to the nanosize range, thus modifying its physico-chemical properties with beneficial effects on drug bioavailability. Nanocrystals (NCs) are carrier-free drug particles surrounded by a stabilizer and suspended in an aqueous medium. Due to high drug loading, NCs maintain a potent therapeutic concentration to produce desirable pharmacological action, particularly useful in the treatment of central nervous system (CNS) diseases. In addition to the therapeutic purpose, NC technology can be applied for diagnostic scope. This review aims to provide an overview of NC application by different administration routes, especially focusing on brain targeting, and with a particular attention to therapeutic and diagnostic fields. NC therapeutic applications are analyzed for the most common CNS pathologies (i.e., Parkinson's disease, psychosis, Alzheimer's disease, etc.). Recently, a growing interest has emerged from the use of colloidal fluorescent NCs for brain diagnostics. Therefore, the use of NCs in the imaging of brain vessels and tumor cells is also discussed. Finally, the clinical effectiveness of NCs is leading to an increasing number of FDA-approved products, among which the NCs approved for neurological disorders have increased.

Nanoencapsulation Strategies for Active Compounds Delivery.

Nanoencapsulation strategies, including the possibility to deliver natural compounds, synthetic molecules, or other actives (viruses) for the treatment of different human diseases, represent a hot topic of great interest [...].

Ulceras post anestésicas en niños: Dos casos clínicos / Post anesthesia ulcers in children: Two clinical cases

RESUMEN El siguiente articulo describe dos casos clínicos de ulceras traumáticas pos-anestesia en niños, luego de un tratamiento odontológico, en el cual se utilizó la infiltración de anestesia local, como parte del tratamiento terapéutico para la perdida de la sensibilidad del sector a tratar. Los efectos del anestésico continuaron al terminar el tratamiento, lo que estimuló por la falta de sensibilidad la curiosidad en los niños que se succionen o se muerdan el tejido blando, esto provocó lesiones graves en la mucosa oral. La importancia de estas lesiones pos-anestésicas radica en la prevención, es decir que el profesional que atienda pacientes pediátricos, debe prevenir y evitar estas lesiones graves autoinflingidas por el niño, dándole las recomendaciones verbalmente y por escrito a los padres.

ABSTRACT The following article describes two clinical cases of post-anesthesia traumatic ulcers in children, after dental treatment, in which infiltration of local anesthesia was used as part of the therapeutic treatment for the loss of sensitivity of the sector to be treated. The effects of the anesthetic continued at the end of the treatment, which stimulated curiosity in children to suck or bite the soft tissue due to lack of sensitivity, this caused serious lesions in the oral mucosa. The importance of these post-anesthetic injuries lies in prevention, that is, the professional who attends pediatric patients, must prevent and avoid these serious injuries self-inflicted by the child, giving the recommendations verbally and in writing to the parents.

Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection.

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n = 40), treated for COVID-19 as outpatients (n = 51), and in uninfected controls (n = 86), as well as in children with COVID-19 (n = 19), recovering from COVID-19 (n = 14), MIS-C (n = 11), recovering from MIS-C (n = 7), and pediatric controls (n = 17). Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls. Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males. Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.

Sorafenib Repurposing for Ophthalmic Delivery by Lipid Nanoparticles: A Preliminary Study.

Uveal melanoma is the second most common melanoma and the most common intraocular malignant tumour of the eye. Among various treatments currently studied, Sorafenib was also proposed as a promising drug, often administered with other compounds in order to avoid resistance mechanisms. Despite its promising cellular activities, the use of Sorafenib by oral administration is limited by its severe side effects and the difficulty to reach the target. The encapsulation into drug delivery systems represents an interesting strategy to overcome these limits. In this study, different lipid nanoparticulate formulations were prepared and compared in order to select the most suitable for the encapsulation of Sorafenib. In particular, two solid lipids (Softisan or Suppocire) at different concentrations were used to produce solid lipid nanoparticles, demonstrating that higher amounts were able to achieve smaller particle sizes, higher homogeneity, and longer physical stability. The selected formulations, which demonstrated to be biocompatible on Statens Seruminstitut Rabbit Cornea cells, were modified to improve their mucoadhesion, evaluating the effect of two monovalent cationic lipids with two lipophilic chains. Sorafenib encapsulation allowed obtaining a sustained and prolonged drug release, thus confirming the potential use of the developed strategy to topically administer Sorafenib in the treatment of uveal melanoma.

Quality by design tools reducing the gap from bench to bedside for nanomedicine.

Pharmaceutical nanotechnology research is focused on smart nano-vehicles, which can deliver active pharmaceutical ingredients to enhance their efficacy through any route of administration and in the most varied therapeutical application. The design and development of new nanopharmaceuticals can be very laborious. In recent years, the application of mathematics, statistics and computational tools is emerging as a convenient strategy for this purpose. The application of Quality by Design (QbD) tools has been introduced to guarantee quality for pharmaceutical products and improve translational research from the laboratory bench into applicable therapeutics. In this review, a collection of basic-concept, historical overview and application of QbD in nanomedicine are discussed. A specific focus has been put on Response Surface Methodology and Artificial Neural Network approaches in general terms and their application in the development of nanomedicine to monitor the process parameters obtaining optimized system ensuring its quality profile.

Essential Oil-Loaded NLC for Potential Intranasal Administration.

Complementary and alternative medicines represent an interesting field of research on which worldwide academics are focusing many efforts. In particular, the possibility to exploit pharmaceutical technology strategies, such as the nanoencapsulation, for the delivery of essential oils is emerging as a promising strategy not only in Italy but also all over the world. The aim of this work was the development of nanostructured lipid carriers (NLC) for the delivery of essential oils (Lavandula, Mentha, and Rosmarinus) by intranasal administration, an interesting topic in which Italian contributions have recently increased. Essential oil-loaded NLC, projected as a possible add-on strategy in the treatment of neurodegenerative diseases, were characterized in comparison to control formulations prepared with Tegosoft CT and Neem oil. Homogeneous (polydispersity index, PDI < 0.2) nanoparticles with a small size (<200 nm) and good stability were obtained. Morphological and physical-chemical studies showed the formation of different structures depending on the nature of the liquid oil component. In particular, NLC prepared with Lavandula or Rosmarinus showed the formation of a more ordered structure with higher cytocompatibility on two cell lines, murine and human fibroblasts. Taken together, our preliminary results show that optimized positively charged NLC containing Lavandula or Rosmarinus can be proposed as a potential add-on strategy in the treatment of neurodegenerative diseases through intranasal administration, due to the well-known beneficial effects of essential oils and the mucoadhesive properties of NLC.

Improving Cognition with Nutraceuticals Targeting TGF-ß1 Signaling.

Rescue of cognitive function represents an unmet need in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Nutraceuticals deliver a concentrated form of a presumed bioactive(s) agent(s) that can improve cognitive function alone or in combination with current approved drugs for the treatment of cognitive disorders. Nutraceuticals include different natural compounds such as flavonoids and their subclasses (flavan-3-ols, catechins, anthocyanins, and flavonols), omega-3, and carnosine that can improve synaptic plasticity and rescue cognitive deficits through multiple molecular mechanisms. A deficit of transforming growth factor-ß1 (TGF-ß1) pathway is an early event in the pathophysiology of cognitive impairment in different neuropsychiatric disorders, from depression to AD. In the present review, we provide evidence that different nutraceuticals, such as Hypericum perforatum (hypericin and hyperforin), flavonoids such as hesperidin, omega-3, and carnosine, can target TGF-ß1 signaling and increase TGF-ß1 production in the central nervous system as well as cognitive function. The bioavailability of these nutraceuticals, in particular carnosine, can be significantly improved with novel formulations (nanoparticulate systems, nanoliposomes) that increase the efficacy and stability of this peptide. Overall, these studies suggest that the synergism between nutraceuticals targeting the TGF-ß1 pathway and current approved drugs might represent a novel pharmacological approach for reverting cognitive deficits in AD patients.