Perfil transcriptómico de células epiteliales primarias de próstata humana inducidas a senescencia por estrés (SIPS)

The senescent cell is characterized by being arrested in the cell cycle, presenting resistance to apoptosis, and having various alterations in gene expression. Little is known about transcriptomic aberrations caused by senescence in prostate epithelial cells, there is partial evidence that these disturbances could contribute to the appearance and progression of multiple prostate diseases. In this work, the HPEC transcriptome was analyzed after SIPS induction in order to determine the alterations in the expression patterns of various transcripts such as mRNA, lncRNA, circRNA, and miRNA. Once the differential gene expression (DGE) analysis was determined, enrichment analysis of signaling pathways and ontological terms were performed to find the molecular, biological functions, and cellular components that are affected by alterations in gene expression. The results of these enrichments showed effects on signaling pathways such as Nrf2, TGF-β, VEGFA-VEGFR and IFNγ, ErbB, Hippo, MAPK, PI3K-Akt, and Wnt. These alterations are associated with processes such as carcinogenesis, metastasis, neoplasms onset and progression, decreased immune response and increased apoptotic resistance. Also, in HPEC induced to SIPS, the presence of 20 genes that have already been reported in other models as part of the nucleus of genes associated with senescence, was confirmed; and 9 genes of the 20 present the highest number of interactions and co-expression patterns. Besides, mRNA-miRNA and mRNA-miRNA-circRNA interaction networks were made to try to find the regulatory mechanisms that govern the expression of these genes. The alterations present in the HPEC transcriptome caused by senescence are associated with processes such as carcinogenesis, metastasis, onset and progression of neoplasms, decreased immune response and increased resistance to apoptosis.La célula senescente se caracteriza por encontrarse detenida en las fases iniciales del ciclo celular, presentar resistencia ante la apoptosis y por diversas alteraciones en la expresión génica. Poco se conoce acerca de las aberraciones transcriptómicas ocasionadas por la senescencia en células epiteliales de próstata, existe evidencia parcial de que estas perturbaciones podrían contribuir con la aparición y progresión de diversas enfermedades prostáticas. En este trabajo se analizó el transcriptoma de las células HPEC inducidas a senescencia por SIPS con el objetivo de determinar cuáles son las alteraciones en los patrones de expresión de diversos transcritos como mRNA, lncRNA, circRNA y miRNA. Una vez determinados los análisis de expresión diferencial génica se realizaron análisis de enriquecimiento de vías de señalización y términos ontológicos para conocer las funciones moleculares, biológicas y los componentes celulares que resultan afectados por las alteraciones en la expresión génica. Los resultados de esos enriquecimientos mostraron afectaciones en vías de señalización como como NRF2, TGF-β, VEGFA-VEGFR e IFNγ, ErbB, Hippo, MAPK, PI3K-Akt y Wnt. Asimismo, en las células HPEC inducidas SIPS se confirmó la presencia de 20 genes que ya han sido reportados en otros modelos como parte del núcleo de genes asociados a la senescencia. De ellos, 9 genes presentan la mayor cantidad de interacciones proteína – proteína y patrones de co-expresión. Además, se realizaron redes de interacción mRNA – miRNA y mRNA – mirRNA – CircRNA para tratar de encontrar los mecanismos de regulación que rigen la expresión de estos genes. Las alteraciones presentes en el transcriptoma de HPEC provocadas por la senescencia se asocian con procesos como carcinogénesis, metástasis, aparición y progresión de neoplasias, disminución de la respuesta inmunológica y aumento de resistencia a la apoptosi

Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR