Creación de tejido uretral mediante ingeniería tisular para la reparación de defectos uretrales complejos en un modelo experimental de hipospadias proximal en conejos

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Pediatría. Fecha de lectura: 16-12-202

Queratopigmentación intraestromal utilizando pigmentos minerales micronizados como método de tatuaje corneal en un modelo animal

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Cirugía: Fecha de lectura: 06-07-2015Purpose: To study the tolerance and biocompatibility of micronized mineral pigments for corneal cosmetic pigmentation in an experimental animal model. Methods: Corneal intralamellar keratopigmentation was performed in 28 New Zealand white rabbits using micronized mineral pigments. Prophylactic actions using intraoperative antibiotic prophylaxis and gamma radiation of the pigment mixtures were performed to avoid infection. Animals were examined regularly by slit lamp to detect any sign of inflammation, pigment diffusion, colour changes or neovascularization. Histopathological examination was performed to determine the level of pigment diffusion, the level of inflammation and the presence of neovascularization. Results: No pigment diffusion or changes in color, inflammation or neovascularization were detected in the eyes treated. Histopathological examination corroborated clinical results regarding inflammation. Pigmented corneas showed a good cosmetic appearance without signs of ocular toxicity. Conclusions: Micronized mineral pigments could be a valid alternative treatment for cosmetic keratopigmentation. Intralamellar keratopigmentacion technique presented good cosmetic appearance without adverse effects in the eyes treatedObjetivo: Estudiar la tolerancia y la biocompatibilidad de los pigmentos minerales micronizados para la pigmentación corneal cosmética en un modelo experimental animal. Métodos: Se procedió a la queratopigmentación intraestromal en 28 conejos blancos New Zealand, utilizando pigmentos minerales micronizados. Se tomaron medidas profilácticas preoperatorias utilizando radiación gamma de las mezclas de pigmentos y antibióticos intraoperatorias para evitar el riesgo de infección. Los animales fueron examinados regularmente en la lámpara de hendidura para detectar cualquier signo de inflamación, difusión del pigmento, cambios de color y/o neovascularización. Posteriormente se realizó un examen histopatológico para corroborar la presencia o ausencia de difusión de los pigmentos, valorar el grado de inflamación y la presencia o ausencia de neovascularización. Resultados: No se observaron signos de difusión del pigmento o cambios en el color en ningún caso. Tampoco hubo evidencia de inflamación postoperatoria tardía ni neovascularización en los ojos tratados. El examen histopatológico mostró los mismos resultados que el examen clínico en lámpara de hendidura, en relación con la inflamación y neovascularización. Las córneas pigmentadas mostraron un buen aspecto cosmético sin signos de toxicidad ocular. Conclusiones: Los pigmentos minerales micronizados podrían ser utilizados como alternativa válida para la queratopigmentación con fines cosméticos. La técnica de queratopigmentación intraestromal mostró un excelente resultado cosmético, sin efectos adversos derivados de la técnica o de los pigmentos utilizados en los ojos tratados

Labdane conjugates protect cardiomyocytes from doxorubicin-induced cardiotoxicity

The cardiovascular side effects associated with doxorubicin (DOX), a wide spectrum anticancer drug, have limited its clinical application. Therefore, to explore novel strategies with cardioprotective effects, a series of new labdane conjugates were prepared (6a-6c and 8a-8d) from the natural diterpene labdanodiol (1). These hybrid compounds contain anti-inflammatory privileged structures such as naphthalimide, naphthoquinone, and furanonaphthoquinone. Biological activity of these conjugates against DOX-induced cardiotoxicity was tested in vitro and the potential molecular mechanisms of protective effects were explored in H9c2 cardiomyocytes. Three compounds 6c, 8a, and 8b significantly improved cardiomyocyte survival, via inhibition of reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways (extracellular signal-regulated kinase and c-Jun N-terminal kinase) and autophagy mediated by Akt activation. Some structure-activity relationships were outlined, and the best activity was achieved with the labdane-furonaphthoquinone conjugate 8a having an N-cyclohexyl substituent. The findings of this study pave the way for further investigations to obtain more compounds with potential cardioprotective activity.This study was supported by Grant RTI2018‐094356‐BC21 from the Ministerio de Ciencia, Innovación y Universidades (MICIU) to A. E.‐B., I. C., L. G.‐C., and B. H.; Grant PI17/00012 and PI20/00018 from the Instituto de Salud Carlos III to S. H. These projects are also cofunded by the European Regional Development Fund (FEDER). A. A. and S. O.‐R. thank the Cabildo de Tenerife (Agustín de Betancourt Program).S

Efficient multicomponent synthesis of diverse antibacterial embelin-privileged structure conjugates

A library of embelin derivatives has been synthesized through a multicomponent reaction from embelin (1), aldehydes and privileged structures such as 4-hydroxycoumarin, 4-hydroxy-2H-pyran-2-one and 2-naphthol, in the presence of InCl3 as catalyst. This multicomponent reaction implies Knoevenagel condensation, Michael addition, intramolecular cyclization and dehydration. Many of the synthesized compounds were active and selective against Gram-positive bacteria, including one important multiresistant Staphylococcus aureus clinical isolate. It was found how the conjugation of diverse privileged substructure with embelin led to adducts having enhanced antibacterial activities.Fil: Martín Acosta, Pedro. Universidad de La Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; EspañaFil: Peña, Rosalyn. Universidad de La Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; EspañaFil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; ArgentinaFil: Tapia, Alejandro. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Lorenzo Castrillejo, Isabel. Hospital Universitario Nuestra Señora de la Candelaria; España. Universidad de La Laguna; España. Universidad Fernando Pessoa Canarias; EspañaFil: Machín, Félix. Hospital Universitario Nuestra Señora de la Candelaria; EspañaFil: Amesty, Ángel. Universidad de La Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; EspañaFil: Estévez Braun, Ana. Universidad de La Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; Españ

Endometrial Cancer

This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist is about cancers of the endometrium and uterus, including the epidemiology, risk factors, diagnosis, genetic risk, histology, grading and type categorization, management, and prognosis.https://escholarship.umassmed.edu/cancer_concepts/1013/thumbnail.jp

Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses

A series of nine derivatives (2⁻10) were prepared from the diterpene solidagenone (1) and their structures were elucidated by means of spectroscopic studies. Their ability to inhibit inflammatory responses elicited in peritoneal macrophages by TLR ligands was investigated. Compounds 5 and 6 showed significant anti-inflammatory effects, as they inhibited the protein expression of nitric oxide synthase (NOS-2), cyclooxygenase-2 (COX-2), and cytokine production (TNF-α, IL-6, and IL-12) induced by the ligand of TLR4, lipopolysaccharide (LPS), acting at the transcriptional level. Some structure⁻activity relationships were outlined. Compound 5 was selected as a representative compound and molecular mechanisms involved in its biological activity were investigated. Inhibition of NF-κB and p38 signaling seems to be involved in the mechanism of action of compound 5. In addition, this compound also inhibited inflammatory responses mediated by ligands of TLR2 and TLR3 receptors. To rationalize the obtained results, molecular docking and molecular dynamic studies were carried out on TLR4. All these data indicate that solidagenone derivative 5 might be used for the design of new anti-inflammatory agents.S

α-Hispanolol Induces Apoptosis and Suppresses Migration and Invasion of Glioblastoma Cells Likely via Downregulation of MMP-2/9 Expression and p38MAPK Attenuation

α-Hispanolol (α-H) is a labdane diterpenoid that has been shown to induce apoptosis in several human cancer cells. However, the effect of α-H in human glioblastoma cells has not been described. In the present work, we have investigated the effects of α-H on apoptosis, migration, and invasion of human glioblastoma cells with the aim of identifying the molecular targets underlying its mechanism of action. The results revealed that α-H showed significant cytotoxicity against human glioma cancer cell lines U87 and U373 in a concentration- and time-dependent manner. This effect was higher in U87 cells and linked to apoptosis, as revealed the increased percentage of sub-G1 population by cell cycle analysis and acquisition of typical features of apoptotic cell morphology. Apoptosis was also confirmed by significant presence of annexin V-positive cells and caspase activation. Pretreatment with caspase inhibitors diminishes the activities of caspase 8, 9, and 3 and maintains the percentage of viable glioblastoma cells, indicating that α-H induced cell apoptosis through both the extrinsic and the intrinsic pathways. Moreover, we also found that α-H downregulated the anti-apoptotic Bcl-2 and Bcl-xL proteins and activated the pro-apoptotic Bid and Bax proteins. On the other hand, α-H exhibited inhibitory effects on the migration and invasion of U87 cells in a concentration-dependent manner. Furthermore, additional experiments showed that α-H treatment reduced the enzymatic activities and protein levels of matrix metalloproteinase MMP-2 and MMP-9 and increased the expression of TIMP-1 inhibitor, probably via p38MAPK regulation. Finally, xenograft assays confirmed the anti-glioma efficacy of α-H. Taken together, these findings suggest that α-H may exert anti-tumoral effects in vitro and in vivo through the inhibition of cell proliferation and invasion as well as by the induction of apoptosis in human glioblastoma cells. This research describes α-H as a new drug that may improve the therapeutic efficacy against glioblastoma tumors.This study was supported by grant PI11/00036, PI14/00055, and PI17/00012 from the FIS, MPY 1410/09 from ISCIII and Spanish Ministry of Health (Instituto de Salud Carlos III; RD12/0036/0059) to SoH and by grants IERPY 1149/16 and IERPY-M 389/18 to AL. L JG was supported by FIS (FI12/00340). SaH was supported by IERPY 1149/16 from ISCIII.S

Expanding the Chemical Space of Withaferin A by Incorporating Silicon to Improve its Clinical Potential on Human Ovarian Carcinoma Cells

Ovarian cancer represents the seventh most commonly diagnosed cancer worldwide. Herein, we report on the development of a withaferin A (WA)-silyl ether library with 30 analogues reported for the first time. Cytotoxicity assays on human epithelial ovarian carcinoma cisplatin-sensitive and -resistant cell lines identified eight analogues displaying nanomolar potency (IC 50 ranging from 1 to 32 nM), higher than that of the lead compound and reference drug. This cytotoxic potency is also coupled with a good selectivity index on a nontumoral cell line. Cell cycle analysis of two potent analogues revealed cell death by apoptosis without indication of cell cycle arrest in G0/G1 phase. The structure-activity relationship and in silico absorption, distribution, metabolism, and excretion studies demonstrated that the incorporation of silicon and a carbonyl group at C-4 in the WA framework enhances potency, selectivity, and drug likeness. These findings reveal analogues 22, 23, and 25 as potential candidates for clinical translation in patients with relapsed ovarian cancer. </p

Evaluation of pharmacy-based HIV testing in a high-risk New York City community

Injection drug users (IDUs) face limited access to HIV testing and experience delayed HIV diagnoses. New York City (NYC) pharmacies play an important role in HIV prevention among IDUs through the Expanded Syringe Access Program (ESAP), which provides access to sterile syringes without a prescription. We examined in-pharmacy HIV testing among syringe/non-syringe customers in ESAP pharmacies in NYC