Javier Pereda

Ante el alarmante aumento de la incidencia de enfermedades mentales en la población general, especialmente entre los jóvenes, la propuesta "FarmaSalud Mental" busca sensibilizar a los estudiantes del Grado de Farmacia sobre la importancia de la salud mental y empoderarlos como protagonistas activos en la búsqueda de soluciones. Este proyecto se desarrolla en los seminarios de la asignatura de Fisiopatología, en tercer curso, y se concibe como un espacio de acción inmediata y colaborativa. Los participantes abordan los desafíos de la salud mental desde diversas perspectivas, presentando propuestas que contribuyan al abordaje del tema y analizando su estado emocional antes y después del ejercicio. Este proyecto se realizó durante los cursos 22-23 y 23-24, y en sus resultados se destaca el impacto positivo de esta intervención en el aprendizaje y la gestión de los problemas emocionales del alumnado, así como en la integración de los ODS. Las propuestas presentadas refuerzan la percepción del papel activo y relevante de los futuros farmacéuticos en la promoción de la salud mental, subrayando la importancia de adoptar enfoques interdisciplinares y colaborativos para mejorar el bienestar general de la sociedad.

The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs. We therefore performed an extensive literature analysis to evaluate the clinical utility of miRNAs with a confirmed direct relationship with treatment response to ICIs. As a result of this systematic review, we have stratified the miRNA landscape into (i) miRNAs whose levels directly modulate response to ICIs, (ii) miRNAs whose expression is modulated by ICIs, and (iii) miRNAs that directly elicit toxic effects or participate in immune-related adverse events (irAEs) caused by ICIs.

Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension.

Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.

Pro-inflammatory cytokines like interleukin-1β (IL-1β) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1β on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1β and used Atomic Force Microscopy to unveil that IL-1β significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1β stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1β may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1β-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1β provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair.

The contribution of epithelial-to-mesenchymal transition (EMT) to the profibrotic stiff microenvironment and myofibroblast accumulation in pulmonary fibrosis remains unclear. We examined EMT-competent lung epithelial cells and lung fibroblasts from control (fibrosis-free) donors or patients with idiopathic pulmonary fibrosis (IPF), which is a very aggressive fibrotic disorder. Cells were cultured on profibrotic conditions including stiff substrata and TGF-β1, and analyzed in terms of morphology, stiffness, and expression of EMT/myofibroblast markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast phenotype on TGF-β1 stimulation. Yet IPF myofibroblasts exhibited higher stiffness and expression of fibrillar collagens than control fibroblasts, concomitantly with enhanced FAK^Y397 activity. FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAK^Y397 hyperactivation may underlie the aberrant mechanobiology of IPF fibroblasts. In contrast, cells undergoing EMT failed to reach the values exhibited by IPF myofibroblasts in all parameters examined. Likewise, EMT could be distinguished from nonactivated control fibroblasts, suggesting that EMT does not elicit myofibroblast precursors either. Our data suggest that EMT does not contribute directly to the myofibroblast population, and may contribute to the stiff fibrotic microenvironment through their own stiffness but not their collagen expression. Our results also support that targeting FAK^Y397 may rescue normal mechanobiology in IPF.

Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a standard therapy for a subset of non-small cell lung cancer (NSCLC) patients with lung adenocarcinomas (LADs) harboring EGFR kinase domain mutations; however, EGFR TKI therapy shows limited efficacy due to de novo and acquired resistance. Consequently, formulating strategies to potentiate the efficacy of EGFR TKI is of great interest. In EGFR TKI sensitive cells harboring EGFR mutation, it has been shown that EGFR inhibition induces autophagy to protect the cells from metabolic stress. Hydroxychloroquine (HQ), an inhibitor of autophagy, has been shown to potentiate EGFR TKIs in preclinical models, however, preliminary results from recent phase II clinical trials shows no added benefits to the development of resistance to erlotinib in patients with EGFR mutant NSCLC. The result suggests additional layers of mechanisms in controlling autophagy in EGFR mutated NSCLC. Furthermore, little is known about genomic alterations affecting these autophagy genes in lung cancer samples. The meta-analysis of The Cancer Genome Atlas (TCGA) database shows that essential genes for autophagic flux such as ATG5 and ATG7 tend to reduce their expression levels and/or are deleted in a significant proportion of LAD patients, suggesting a more complex scenario where the presence of these genetic alterations may lead to a structurally deficient autophagy. Besides, the detailed CNV analysis of the Cancer Cell Line Encyclopedia (CCLE) dataset suggests that a small subset of NSCLC cell lines may have lost ATG7 locus at chromosome 3. Our validation study showed that, as expected, EGFR-mutant H1650 cells exhibit an intragenic deletion at ATG7 and lack of protein expression. Moreover, functional assays of autophagic flow by western blot and confocal microscopy demonstrated that ATG7-deficient H1650 cells are not able to activate autophagy, whereas infection with lentivirus expressing ectopic ATG7 reconstituted autophagic flux and sensitivity to autophagy inhibitors including HQ. Taken together, our results suggest that genomic biomarkers based on autophagy genes could allow stratification of tumors, and selection of those candidates who could benefit from anti-autophagy therapy. Citation Format: Ines Pulido, Juan L. Pascual, Margaret Soucheray, Maria L. Rodriguez, Daniel T. Crespo, Salvador Aparisi, Joan A. Sirerol, Salvador Mena, Javier Pereda, Fatima Al-shahrour, Angel L. Ortega, Takeshi Shimamura, Julian Carretero. Genomic alterations of autophagy genes disrupts autophagic flux in human lung adenocarcinomas. []. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl): nr 753. doi:10.1158/1538-7445.AM2015-753

In addition to its expression in stem cells and many cancers, telomerase activity is transiently induced in murine bleomycin (BLM)–induced pulmonary fibrosis with increased levels of telomerase transcriptase (TERT) expression, which is essential for fibrosis. To extend these observations to human chronic fibrotic lung disease, we investigated the expression of telomerase activity in lung fibroblasts from patients with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). The results showed that telomerase activity was induced in more than 66% of IPF lung fibroblast samples, in comparison with less than 29% from control samples, some of which were obtained from lung cancer resections. Less than 4% of the human IPF lung fibroblast samples exhibited shortened telomeres, whereas less than 6% of peripheral blood leukocyte samples from patients with IPF or hypersensitivity pneumonitis demonstrated shortened telomeres. Moreover, shortened telomeres in late-generation telomerase RNA component knockout mice did not exert a significant effect on BLM-induced pulmonary fibrosis. In contrast, TERT knockout mice exhibited deficient fibrosis that was independent of telomere length. Finally, TERT expression was up-regulated by a histone deacetylase inhibitor, while the induction of TERT in lung fibroblasts was associated with the binding of acetylated histone H3K9 to the TERT promoter region. These findings indicate that significant telomerase induction was evident in fibroblasts from fibrotic murine lungs and a majority of IPF lung samples, whereas telomere shortening was not a common finding in the human blood and lung fibroblast samples. Notably, the animal studies indicated that the pathogenesis of pulmonary fibrosis was independent of telomere length.