Defective Induction of COX-2 Expression by Psoriatic Fibroblasts Promotes Pro-inflammatory Activation of Macrophages

Fibroblasts play an important role as members of the innate immune system through the secretion of COX-2-derived inflammatory mediators such as prostaglandin E2 (PGE2). However, it has been described that dermal fibroblasts behave like mesenchymal stem cells reducing lymphocyte recruitment and dendritic cell activation through PGE2 release. As the role of fibroblasts in psoriasis remains poorly characterized, in the present study we have evaluated the possible influence of PGE2 derived from dermal fibroblasts as modulator of the immune response in psoriatic skin. Our results indicate that under inflammatory conditions, psoriatic fibroblasts showed defective induction of COX-2, which resulted in diminished production of PGE2, in contrast to healthy fibroblasts. This phenotype correlated with deficient c-Jun N-terminal kinase (JNK) activation, in accordance with the hypothesis that alterations in members of the JNK pathway are associated with psoriasis. Furthermore, conditioned medium from psoriatic fibroblasts promoted the polarization of monocytic cells toward a pro-inflammatory profile, effect that was mimicked in healthy fibroblasts after pre-incubation with indomethacin. These results are consistent with a prominent role of dermal fibroblasts in the regulation of inflammatory response through the participation of COX-derived metabolites. This resolutive behavior seems to be defective in psoriatic fibroblasts, offering a possible explanation for the chronification of the disease and for the exacerbation triggered by nonsteroidal anti-inflammatory drugs (NSAIDS) such as indomethacin

Adenosine A(2A) and A(2B) Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A2B receptors, human epidermal keratinocytes also express A2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists, we showed that physiological concentrations of adenosine activate A2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling. In contrast, the selective activation of A2A receptors by CGS-21680 induces keratinocyte proliferation via p38–mitogen-activated protein kinase activation. Adenosine and selective A2A and A2B agonists presented anti-inflammatory profiles independent of adenosine receptors but mediated by membrane phosphatase activation. Finally, keratinocyte exposure to diverse inflammatory cytokines altered adenosine receptor expression by reducing A2B and increasing A2A, a pattern also observed in psoriatic epidermis. Because increased epidermal turnover and inflammatory response are characteristics of psoriatic disease, further studies are needed to assess the role and consequences of the altered adenosine receptor expression in lesional and nonlesional psoriatic keratinocytes.We thank Laura Catalán for her technical assistance in the immunoblotting analysis. This work was supported by the Spanish Ministry of Economy and Competitiveness, ISCIII, FEDER (SAF2009-10347 and RETICEF RD07/0013/ 2011), the University of Valencia (AEVI 2015-16) and the Spanish Conselleria Valenciana d’Educació (Prometeo 2010-047). Rosa M. Andrés was the recipient of a research fellowship from the Spanish Conselleria Valenciana d’Educació

Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine

[EN] A new hybrid organic-inorganic material for sensing spermine (Spm) and spermidine (Spd) has been prepared and characterized. The material is based on MCM-41 particles functionalized with an N-hydroxysuccinimide derivative and loaded with Rhodamine 6G. The cargo is kept inside the porous material due to the formation of a double layer of organic matter. The inner layer is covalently bound to the silica particles, while the external layer is formed through hydrogen and hydrophobic interactions. The limits of detection determined by fluorimetric titration are 27 mu M and 45 mu M for Spm and Spd, respectively. The sensor remains silent in the presence of other biologically important amines and is able to detect Spm and Spd in both aqueous solution and cells.This research was funded by Spanish Government (RTI2018-100910-B-C42 and RTI2018100910-B-C44 (MCUI/AEI/FEDER, UE) and grant GRISOLIAP/2019/023.Barros, M.; López-Carrasco, A.; Amorós, P.; Gil Grau, S.; Gaviña, P.; Parra Alvarez, M.; El Haskouri, J.... (2021). Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine. Nanomaterials. 11(3):1-12. https://doi.org/10.3390/nano1103081811211

Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex

[EN] A two-photon fluorescent probe based on a ruthenium(II) vinyl complex is capable of selectively detecting carbon monoxide in cells and ex vivo using mice with a subcutaneous air pouch as a model for inflammation. This probe combines highly selective and sensitive ex vivo detection of endogenous CO in a realistic model with facile, inexpensive synthesis, and displays many advantages over the widely used palladium-based systems.The authors thank the Spanish government (Project MAT2015-64139-C4-1), the Generalitat Valencia (Project PROME-TEOII/2014/047), CIBER-BBN, IC Global Engagements fund, Santander Mobility Award. C.T. is grateful to the Spanish Ministry of Science and Innovation, A.T. thanks the Leverhulme Trust (RPG-2012-634) and J.A.R. thanks the EPSRC, for PhD studentships.De La Torre-Paredes, C.; Toscani, A.; Marín-Hernández, C.; Robson, JA.; Terencio, MC.; White, AJ.; Alcaraz, MJ.... (2017). Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex. Journal of the American Chemical Society. 139(51):18484-18487. https://doi.org/10.1021/jacs.7b11158S18484184871395

Peptide-Capped Mesoporous Nanoparticles: Toward a more Efficient Internalization of Alendronate

This is the peer reviewed version of the following article: E. Añón, A. M. Costero, P. Amorós, J. El Haskouri, R. Martínez-Mánez, M. Parra, S. Gil, P. Gaviña, M. C. Terencio, M. Alfonso, ChemistrySelect 2020, 5, 3618., which has been published in final form at https://doi.org/10.1002/slct.202000417. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Osteoporosis is an illness which appears when the osteoblast/osteoclast activities are unbalanced taking place bone resorption (caused by osteoclasts) in higher extension than bone formation (induced by osteoblasts). Alendronate is one of the most used drugs for osteoporosis treatment despite its scarce bioavailability. Here we present the synthesis and characterization of mesoporous gated nanoparticles (two sets) for the controlled release of alendronate. The first set of nanoparticles (S1) were loaded with sulforhodamine B and capped with a peptide that could be selectively hydrolyzed by cathepsin K enzyme (overexpressed in osteoclasts). The second set (S2) was functionalized with aminopropyl moieties, loaded with nitrobenzofurazan labelled alendronate and capped with the same peptide. Both nanoparticles were internalized by RAW 264.7 macrophages (which could differentiate in osteoclasts) and were able to release its entrapped cargo in the presence of cathepsin K added in the macrophage lysates. Using S2 nanoparticles 4.2% of the total alendronate amount in contact with the cells is liberated inside them and could produce its therapeutic effect.We thank the Spanish Government (RTI2018-100910-B-C41, RTI2018-100910-B-C42 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (PROMETEU/2018/024) for support. SCSIE (Universitat de Valencia) is gratefully acknowledged for all the equipment employed. 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