Inhibition of murine colorectal cancer metastasis by targeting M2-TAM through STAT3/NF-kB/AKT signaling using macrophage 1-derived extracellular vesicles loaded with oxaliplatin, retinoic acid, and Libidibia ferrea.

Colorectal cancer is still unmanageable despite advances in target therapy. However, extracellular vesicles (EVs) have shown potential in nanomedicine as drug delivery systems, especially for modulating the immune cells in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), alone or in combination (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines and prevent metastasis in mice of allograft and peritoneal colorectal cancer models. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or particularly M1EV4 downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastasis in the peritoneum, liver, and lungs. STAT3, NF-kB, and AKT were the major genes downregulated by of M1EV systems. Tumor-associated macrophages (TAMs) shifted from an M2 phenotype (CD163) to an M1 phenotype (CD68) reducing levels of IL-10, TGF-ß and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR1, survivin, vimentin, and PD-L1 after treatment with systems of M1EVs. The study shows that EVs from M1 antitumor macrophages can transport drugs and enhance their immunomodulatory and antitumor activity by modulating pathways associated with cell proliferation, migration, survival, and drug resistance.

Use of sisal industrial waste (Agave sisalana Perrine) in sustainable and multifunctional cosmetic products.

OBJECTIVE: Sisal is a common stiff fibre produced around the world, corresponding to approximately 70% of the commercial production of all fibres of this type. The fibres are extracted from the leaves of Agave sisalana, from which approximately 4% of their weight is obtained, with the remaining 96% considered to be residues from the process of the sisal industry. The objective of this work was to obtain a polyphenol-enriched extract from the A. sisalana residue by ultrasonically assisted extraction, characterize it chemically, evaluate in vitro antioxidant activity, and develop safe and stable photoprotective formulations for future application in cosmetic preparations. METHODS: Ultrasonic extraction of solid plant material was performed using 50% ethanol/water (v/v). The extract was chemically characterized by high-performance liquid chromatography equipment associated with classical molecular networking and evaluated for in vitro antioxidant activity by different methodologies. Ten formulations were prepared, varying the component concentrations and the shear time. The 1.0% sisal extract was incorporated into the most stable formulations, and preliminary and accelerated stability were evaluated. The emulsions were investigated for safety by assessment of primary accumulated dermal irritability and sensitization and a dermatological clinical study of phototoxicity and photosensitization. The photoprotective formulations containing or not containing the extract that were stable after 90 days had their in vivo sun protection factor (SPF), UVA protection factor, critical wavelength, and protection against visible and blue light determined. RESULTS: Ultrasound extraction using 50% ethanol/water (EH 50) as an extractor vehicle showed the best yield. The extract exhibited a concentration of phenolic compounds (77.93 mg of equivalent to the standard gallic acid/g) and showed in vitro antioxidant activity. Emulsions without and with 1.0% sisal extract remained stable and safe. The addition of the extract to the photoprotective formulation statistically increased the SPF when compared to the formulation without the extract and offered protection against UVA radiation, critical wavelengths, and absorption of visible and blue light. CONCLUSION: Based on the findings, the solid residue of A. sisalana may be indicated as a component of photoprotective and antioxidant cosmetic formulations.

OBJECTIF: Le sisal est une fibre rigide courante produite dans le monde entier, correspondant à environ 70 % de la production commerciale de toutes les fibres de ce type. Les fibres sont extraites des feuilles d'Agave sisalana dont environ 4 % du poids est obtenu, les 96 % restants étant considérés comme des résidus du procédé de l'industrie du sisal. L'objectif de ce projet était d'obtenir un extrait du résidu d'A. sisalana enrichi en polyphénols par extraction assistée par ultrasons (EAU), de le caractériser chimiquement, d'évaluer l'activité antioxydante in vitro et de développer des formulations photoprotectrices sûres et stables pour une application future dans des préparations cosmétiques. MÉTHODES: L'extraction ultrasonique de la matière végétale solide a été effectuée avec une solution à 50 % d'éthanol/eau (v/v). L'extrait a été chimiquement caractérisé avec un équipement de chromatographie en phase liquide à haute performance associé à un réseau moléculaire (RM) classique, puis évalué pour l'activité antioxydante in vitro par différentes méthodologies. Dix formulations ont été préparées en variant les concentrations des composants et le temps de cisaillement. L'extrait de sisal à 1,0 % a été incorporé dans les formulations les plus stables et la stabilité préliminaire et accélérée a été évaluée. La sécurité d'emploi des émulsions a été étudiée en évaluant l'irritabilité et la sensibilisation cutanées accumulées primaires et l'étude clinique dermatologique de la phototoxicité et de la photosensibilisation. Le facteur de protection solaire in vivo, le facteur de protection UVA, la longueur d'onde critique et la protection contre la lumière visible et bleue ont été déterminées pour les formulations photoprotectrices contenant ou non l'extrait qui étaient stables après 90 jours. RÉSULTATS: L'extraction par ultrasons utilisant une solution à 50 % d'éthanol/eau (EH 50) comme véhicule d'extraction a menée au meilleur rendement. L'extrait a présenté une concentration de composés phénoliques (77,93 mg d'EAG/g) et une activité antioxydante in vitro. Les émulsions sans et avec 1,0 % d'extrait de sisal sont restées stables et sans danger. L'ajout de l'extrait à la formulation photoprotectrice a statistiquement augmenté le SPF par rapport à la formulation sans extrait et a offert une protection contre les rayonnements UVA, la longueur d'onde critique et l'absorption de la lumière visible et bleue. CONCLUSION: D'après ces résultats, les résidus solides d'A. sisalana peuvent être indiqués comme composant des formulations cosmétiques photoprotectrices et antioxydantes.

A New Ferulic Acid-Nicotinamide Cocrystal With Improved Solubility and Dissolution Performance.

Among the various strategies for increasing aqueous solubility of pharmaceutical substances, cocrystals have been emerging as a promising alternative. The ferulic acid (FEA) is a molecule with limited aqueous solubility, but with an interesting pharmacological activity, highlighting its antitumor potential. This study presents the characterization and physicochemical properties of a new cocrystal based on FEA and nicotinamide (NIC). The FEA-NIC cocrystal was obtained by solvent evaporation technique and physicochemically characterized by differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance and scanning electron microscopy. The content determination and dissolution profile in different media were analyzed by high-performance liquid chromatography. The results obtained with the characterization techniques indicated the obtainment of an anhydrous cocrystal of FEA and NIC at a 1:1 molar ratio. The method was reproducible and obtained a high yield, of approximately 99%. In addition, a 70% increase in the FEA solubility in the cocrystal and a better dissolution performance than the physical mixture in pH 6.8 were achieved.