@article {710, title = {Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.}, journal = {Genes (Basel)}, volume = {12}, year = {2020}, month = {2020 12 31}, abstract = {

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients{\textquoteright} quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

}, keywords = {Animals, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Expression Regulation, Gene ontology, Humans, Metabolic Networks and Pathways, Mice, Mice, Nude, Microarray Analysis, Molecular Sequence Annotation, Principal Component Analysis, Signal Transduction, Skin, Skin Transplantation, Skin Ulcer, Streptozocin, Tissue Engineering, Transcriptome, Transplantation, Heterologous, Wound Healing}, issn = {2073-4425}, doi = {10.3390/genes12010047}, author = {Le{\'o}n, Carlos and Garcia-Garcia, Francisco and Llames, Sara and Garc{\'\i}a-P{\'e}rez, Eva and Carretero, Marta and Arriba, Mar{\'\i}a Del Carmen and Dopazo, Joaquin and Del Rio, Marcela and Escamez, Maria Jos{\'e} and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a} } @article {516, title = {IL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB.}, journal = {Stem Cell Rev Rep}, volume = {8}, year = {2012}, month = {2012 Sep}, pages = {905-16}, abstract = {

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX(3)CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.

}, keywords = {Cell Adhesion, Cell Movement, Cell Proliferation, Chemokines, Chemotaxis, Leukocyte, Collagen, Fibronectins, Gene Expression Profiling, Gene Knockdown Techniques, HEK293 Cells, Humans, I-kappa B Kinase, Inflammation Mediators, Intercellular Signaling Peptides and Proteins, Interleukin-1beta, Laminin, Leukocytes, Mesenchymal Stem Cells, NF-kappa B, Oligonucleotide Array Sequence Analysis, RNA Interference, Signal Transduction}, issn = {2629-3277}, doi = {10.1007/s12015-012-9364-9}, author = {Carrero, Rub{\'e}n and Cerrada, Inmaculada and Lled{\'o}, Elisa and Dopazo, Joaquin and Garcia-Garcia, Francisco and Rubio, Mari-Paz and Trigueros, C{\'e}sar and Dorronsoro, Akaitz and Ruiz-Sauri, Amparo and Montero, Jos{\'e} Anastasio and Sep{\'u}lveda, Pilar} } @article {531, title = {Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.}, journal = {BMC Med Genomics}, volume = {4}, year = {2011}, month = {2011 Dec 30}, pages = {86}, abstract = {

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion

RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.

CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

}, keywords = {Animals, Cell Proliferation, Cell Survival, Cholesterol, Down-Regulation, Female, Gene Expression Regulation, Gene Knockout Techniques, Insulin Resistance, Insulin-Secreting Cells, Mice, obesity, Oxidation-Reduction, Phosphorylation, PPAR gamma, Signal Transduction, Transcription, Genetic, Transforming Growth Factor beta}, issn = {1755-8794}, doi = {10.1186/1755-8794-4-86}, author = {Vivas, Yurena and Martinez-Garcia, Cristina and Izquierdo, Adriana and Garcia-Garcia, Francisco and Callejas, Sergio and Velasco, Ismael and Campbell, Mark and Ros, Manuel and Dopazo, Ana and Dopazo, Joaquin and Vidal-Puig, Antonio and Medina-Gomez, Gema} } @article {532, title = {Early transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions.}, journal = {Plant Physiol}, volume = {156}, year = {2011}, month = {2011 Jul}, pages = {1439-56}, abstract = {

The early transcriptional defense responses and reactive oxygen species (ROS) production in Arabidopsis (Arabidopsis thaliana) cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen ((1)O(2)). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical or hydrogen peroxide. The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the (1)O(2) sensor green reagent and 2{\textquoteright},7{\textquoteright}-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of (1)O(2) but not of hydrogen peroxide. Furthermore, the in vivo photodamage of the D1 protein of photosystem II indicated that the photogeneration of (1)O(2) took place within the photosystem II reaction center. Functional enrichment analyses identified transcripts that are key components of the ROS signaling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the fluorescent mutant family of Arabidopsis, a producer of (1)O(2) in plastids. Intriguingly, a high correlation was also observed with ABA deficient1 and more axillary growth4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. abscisic acid and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.

}, keywords = {Arabidopsis, Blotting, Western, Cell Culture Techniques, Cells, Cultured, Chloroplasts, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Plant, Hydrogen Peroxide, Light, mutation, Oligonucleotide Array Sequence Analysis, Photosystem II Protein Complex, Plant Growth Regulators, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction, Stress, Physiological, Transcription, Genetic}, issn = {1532-2548}, doi = {10.1104/pp.111.177766}, author = {Gonz{\'a}lez-P{\'e}rez, Sergio and Guti{\'e}rrez, Jorge and Garcia-Garcia, Francisco and Osuna, Daniel and Dopazo, Joaquin and Lorenzo, Oscar and Revuelta, Jos{\'e} L and Arellano, Juan B} }