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Dermal and transdermal drug delivery represents an important strategy to target drugs towards the site of action or to noninvasively enhance treatment activity, circumventing the hepatic first passage and reducing toxicity [...]

An increasing number of innovative therapies have emerged in the field of wound healing. Nanostructured systems have been used to improve wound healing at different stages. The drug itself may be formulated at a nanoscale such that it can function as its own “carrier” or nanomaterials may be used as drug delivery vehicles. The present work covers the latest advancements on innovative nano‐based organic and inorganic materials. These novel drug delivery systems possess high stability, large surface area and tunable compositions and have demonstrated their wound‐healing properties using in vitro and in vivo models. Key areas in the development of new systems for wound care are the assessment of biological compatibility, the evaluation of anti‐microbial activity and the in vivo efficacy assessment using full‐thickness skin models. Due to the multifactorial nature of chronic wound occurrence robust models should support the investigation of new materials in order to elucidate mechanisms involved in the sequence of physiologic processes that take place at wound healing. Although several nanoparticles have been successfully tested both in vitro and in vivo, researchers are still investigating the approaches to implementing large scale production of nanotechnological platforms to wound healing treatments. Several nanomaterials have been employed in wound healing in each type of healing phase (Hemostasis, Inflammation, Proliferation, Remodeling). The rationale for using each material strongly depends on the phase but also the duration of the therapeutic effect, dose, deepness and mechanism of action. NPs, nanoparticles.

Tomato producing and processing industries present undoubted potential for industrial discarded products valorization whether due to the overproduction of fresh tomatoes or to the loss during processing. Although tomato by-products are not yet considered a raw material, several studies have suggested innovative and profitable applications. It is often referred to as “tomato pomace” and is quite rich in a variety of bioactive compounds. Lycopene, vitamin C, β-carotene, phenolic compounds, and tocopherol are some of the bioactives herein discussed. Tomato by-products are also rich in minerals. Many of these compounds are powerful antioxidants with anti-inflammatory properties besides modulating the immune system. Several researchers have focused on the possible application of natural ingredients, especially those extracted from foods, and their physiological and pharmacological effects. Herein, the effects of processing and further applications of the bioactive compounds present in tomato by-products were carefully reviewed, especially regarding the anti-inflammatory and anti-cancer effects. The aim of this review was thus to highlight the existing opportunities to create profitable and innovative applications for tomato by-products in health context.

When the first cases of HIV infection appeared in the 1980s, AIDS was a deadly disease without any therapeutic alternatives. Currently, there is still no cure for most cases mainly due to the multiple tissues that act as a reservoir for this virus besides the high viral mutagenesis that leads to an antiretroviral drug resistance. Throughout the years, multiple drugs with specific mechanisms of action on distinct targets have been approved. In this review, the most recent phase III clinical studies and other research therapies as advanced antiretroviral nanodelivery systems will be here discussed. Although the combined antiretroviral therapy is effective in reducing viral loading to undetectable levels, it also presents some disadvantages, such as usual side effects, high frequency of administration, and the possibility of drug resistance. Therefore, several new drugs, delivery systems, and vaccines have been tested in pre-clinical and clinical trials. Regarding drug delivery, an attempt to change the route of administration of some conventional antiretrovirals has proven to be successful and surpassed some issues related to patient compliance. Nanotechnology has brought a new approach to overcoming certain obstacles of formulation design including drug solubility and biodistribution. Overall, the encapsulation of antiretroviral drugs into nanosystems has shown improved drug release and pharmacokinetic profile.

Rheumatoid arthritis (RA) is an autoimmune disorder whose treatment is mostly restricted to pain and symptom management and to the delay of joint destruction. Mesenchymal stem/stromal cells from the umbilical cord tissue (UC-MSCs) have previously been proven to be immunomodulatory and more efficient than bone marrow-derived MSCs in causing remission of local and systemic arthritic manifestations . Given the paracrine nature of UC-MSC activity, their application as active substances can be replaced by their secretome, thus avoiding allogeneic rejection and safety issues related to unwanted grafting. In this work, we aimed at demonstrating the viability of applying the 3D-primed UC-MSC secretome for the amelioration of arthritic signs. A proteomic analysis was performed to both, media conditioned by UC-MSC monolayer (CM2D) and 3D cultures (CM3D). The analysis of relevant trophic factors confirmed secretome profiles with very significant differences in terms of therapeutic potential. Whereas, CM3D was characterised by a prevailing expression of anti-inflammatory cytokines such as IL-10 and LIF, along with trophic factors involved in different mechanisms leading to tissue regeneration, such as PDGF-BB, FGF-2, I-309, SCF, and GM-CSF; CM2D presented relatively higher levels of IL-6, MCP-1, and IL-21, with recognised pro-inflammatory roles in joint disease and pleiotropic effects in the progression of rheumatoid arthritis (RA). Accordingly, different motogenic effects over mouse chondrocytes and distinct capacities of inducing glycosaminoglycan synthesis were observed between CM3D and CM2D. Finally, the evaluation of arthritic manifestations , using an adjuvant-induced model for arthritis (AIA), suggested a significantly higher therapeutic potential of CM3D over CM2D and even UC-MSCs. Histological analysis confirmed a faster remission of local and systemic arthritic manifestations of CM3D-treated animals. Overall, the results show that the use of UC-MSC CM3D is a viable and better strategy than direct UC-MSC administration for counteracting AIA-related signs. This strategy represents a novel MSC-based but nonetheless cell-free treatment for arthritic conditions such as those characterising RA.

Ultradeformable vesicles (UDV) have recently become a promising tool for the development of improved and innovative dermal and transdermal therapies. The aim of this work was to study three related UDV: transfersomes, ethosomes, and transethosomes for the incorporation of actives of distinct polarities, namely, vitamin E and caffeine, and to evaluate the effect of the carrier on skin permeation and penetration. These actives were incorporated in UDV formulations further characterized for vesicles imaging by transmission electron microscopy; mean vesicle size and polydispersity index by photon correlation spectroscopy; zeta potential by laser-Doppler anemometry; deformability by pressure-driven transport; and incorporation efficiency (IE) after actives quantification by high-performance liquid chromatography. Topical delivery studies were performed in order to compare UDV formulations regarding the release, skin permeation, and penetration profiles. All UDV formulations showed size values within the expected range, except transethosomes prepared by \"transfersomal method\", for which size was smaller than 100 nm in contrast to that obtained for vesicles prepared by \"ethosomal method\". Zeta potential was negative and higher for formulations containing sodium cholate. The IE was much higher for vitamin E- than caffeine-loaded UDV as expected. For flux measurements, the following order was obtained: transethosomes (TE) > ethosomes (E) ≥ transfersomes (T). This result was consistent with the release and skin penetration profiles for Vitamin E-loaded UDV. However, the releasing results were totally the opposite for caffeine-loaded UDV, which might be explained by the solubility and thermodynamic activity of this active in each formulation instead of the UDV deformability attending to the higher non-incorporated fraction of caffeine. Anyway, a high skin penetration and permeation for all caffeine-loaded UDV were obtained. Transethosomes were more deformable than ethosomes and transfersomes due to the presence of both ethanol and surfactant in their composition. All these UDV were suitable for a deeper skin penetration, especially transethosomes.

Green tomatoes, a by-product of agro-food industry, are rich in the glycoalkaloid alpha-tomatine. This compound presents health benefits including anti-inflammatory and fungicide properties. Subcritical water extraction (SWE), a green and sustainable process, was used to obtain a tomatine-rich extract from fresh or frozen tomatoes. SWE extracted ca 200 mg tomatine/100 g tomato, an amount higher than conventional methods, at a temperature of 190°C and a residence time of 15 min. Green tomatoes' SWE extracts were characterized in terms of their composition and antioxidant activity. The phenolic content obtained was approximately 200 mg of gallic acid equivalents/100 g tomatoes, and the saponin content was 1000 mg of tomatine equivalents/100 g tomatoes. Total carbohydrate content was different between fresh and frozen tomatoes, 1812 mg of D(+)- glucose equivalents/100 g tomatoes versus 1269 mg/100 g, respectively. In terms of antioxidant activity, a value around 100 mg of Trolox equivalents/100 g of tomatoes was obtained in the 2,2-diphenyl-1-picrylhydrazyl assay, whereas a value of 558 mg of Trolox equivalents/100 mg fresh tomatoes versus 452 mg of Trolox equivalents/100 g frozen tomatoes was obtained by cupric ion reducing antioxidant capacity assay. SWE extraction proved to be a valuable method to extract glycoalkaloids from green tomatoes. The obtained extracts have the potential to be used as ingredients and actives in the cosmetic and pharmaceutical industries.

Acute gastric mucosal injury is a common disorder of the gastrointestinal tract and the search for new therapeutics is ongoing. The aim of this study is to update and expand the information related to the most widely used rat models of acute gastric ulcer, the ethanol‐induced ulcer and the indomethacin‐induced ulcer. These two models are compared in terms of macroscopic and microscopic features. Experimentally, ethanol was given orally in a single dose and indomethacin was subcutaneously injected into male Wistar rats. After ulcerative challenges, the stomachs were removed and visually inspected. Anti‐ulcerative drugs were used to validate the models. Histological analysis of the stomachs determined the microscopic score. The methodology used for model evaluation applied to macroscopic and microscopic gastric lesions. With these methods it was possible to induce lesions in the gastric mucosa. Microscopic evaluation permitted assessment of the inflammatory and apoptotic impact in the mucosa not observable by macroscopic evaluation. Groups of animals were treated with two standard drugs: sulcralfate suspension or lansoprazole solution. Both drugs reduced macroscopic and microscopic lesions, particularly the hemorrhagic ones. Both models induced acute gastric mucosal injury and no single evaluation method can address all the aspects of the pathology of gastric lesions. As a complement to macroscopic evaluation, microscopy appears to be a relevant tool to selectively identify specific aspects of the development of mucosal injury, quantify the extent of lesions, and contribute to an appropriate interpretation of results. The score systems established here offer a reliable method for testing antiulcer drugs.

Introduction The secretion of trophic factors by mesenchymal stromal cells has gained increased interest given the benefits it may bring to the treatment of a variety of traumatic injuries such as skin wounds. Herein, we report on a three-dimensional culture-based method to improve the paracrine activity of a specific population of umbilical cord tissue-derived mesenchymal stromal cells (UCX®) towards the application of conditioned medium for the treatment of cutaneous wounds. Methods A UCX® three-dimensional culture model was developed and characterized with respect to spheroid formation, cell phenotype and cell viability. The secretion by UCX® spheroids of extracellular matrix proteins and trophic factors involved in the wound-healing process was analysed. The skin regenerative potential of UCX® three-dimensional culture-derived conditioned medium (CM3D) was also assessed in vitro and in vivo against UCX® two-dimensional culture-derived conditioned medium (CM2D) using scratch and tubulogenesis assays and a rat wound splinting model, respectively. Results UCX® spheroids kept in our three-dimensional system remained viable and multipotent and secreted considerable amounts of vascular endothelial growth factor A, which was undetected in two-dimensional cultures, and higher amounts of matrix metalloproteinase-2, matrix metalloproteinase-9, hepatocyte growth factor, transforming growth factor β1, granulocyte-colony stimulating factor, fibroblast growth factor 2 and interleukin-6, when compared to CM2D. Furthermore, CM3D significantly enhanced elastin production and migration of keratinocytes and fibroblasts in vitro . In turn, tubulogenesis assays revealed increased capillary maturation in the presence of CM3D, as seen by a significant increase in capillary thickness and length when compared to CM2D, and increased branching points and capillary number when compared to basal medium. Finally, CM3D-treated wounds presented signs of faster and better resolution when compared to untreated and CM2D-treated wounds in vivo . Although CM2D proved to be beneficial, CM3D-treated wounds revealed a completely regenerated tissue by day 14 after excisions, with a more mature vascular system already showing glands and hair follicles. Conclusions This work unravels an important alternative to the use of cells in the final formulation of advanced therapy medicinal products by providing a proof of concept that a reproducible system for the production of UCX®-conditioned medium can be used to prime a secretome for eventual clinical applications.

Biogenic silver nanoparticles (AgNP) are among the fastest-growing nanomaterials due to the simplicity, efficiency, and sustainability of their biosynthesis using phytochemicals as reducing and coating agents. The agro-food industry generates large quantities of organic waste, a renewable source of biomolecules for AgNP biosynthesis. The main objective of this work was to prepare and characterize biogenic AgNP using a green tomato waste extract (TE) obtained by subcritical water extraction. To the best of our knowledge, this is the first report on the use of such an extract in the synthesis of AgNP. The effects of the TE and AgNO3 concentrations, reaction time, pH, and temperature on AgNP physico-chemical characteristics and on in vitro cytotoxicity against HaCaT and THP-1 cells were assessed. Antimicrobial activity was determined in vitro and ex vivo. The wound-healing capability of AgNP was evaluated in vivo in an incisional wound mouse model. The developed AgNP have a Surface Plasmon Resonance (SPR) band between 402 and 406 nm and a size of ±60 nm, and they are negatively charged (−42 mV) and spherical. In vitro and ex vivo studies prove that AgNP do not compromise skin cells and can decrease cutaneous irritation. The AgNP formulated in a gel revealed similar wound-healing properties to a commercial silver-containing topical ointment. Overall, the biogenic synthesis of AgNP employing an extract of agricultural waste obtained by an eco-friendly method is simple and cost-effective and presents the potential for application in skin disease management.