Tratamiento de la enfermedad inflamatoria intestinal mediante terapia biológica

La Enfermedad de Crohn (EC) y la Colitis ulcerosa (CU) constituyen la denominada Enfermedad Inflamatoria Intestinal (EII). Los objetivos del tratamiento son controlar la enfermedad activa, mantener la remisión a largo plazo y evitar complicaciones. El tratamiento de estas enfermedades ha avanzado en los últimos años, gracias a lo cual se dispone de alternativas a los fármacos convencionales. Dentro de dichas alternativas se encuentran los tratamientos biológicos, objeto de estudio de este trabajo mediante una revisión bibliográfica de estudios publicados. Los tratamientos biológicos van dirigidos contra diferentes factores inmunológicos e inflamatorios implicados en la enfermedad. Los más utilizados en la práctica clínica son infliximab, adalimumab, golimumab y vedolizumab, otros siguen en estudio. Además están en investigación nuevas técnicas como el uso de células madre y microARN. El tratamiento de la EII es un campo de investigación en constante crecimiento y con resultados alentadores para un futuro

Current status of terpenoids as inflammasome inhibitors

Increasing evidence supports NLRP3 inflammasome as a new target to control inflammation. Dysregulation of NLRP3 inflammasome has been reported to be involved in the pathogenesis of several human inflammatory diseases. However, no NLRP3 inflammasome inhibitors are available in clinic. Terpenoids are natural products with multi-target activities against inflammation. Recent studies have revealed that these compounds are capable of inhibiting the activation of NLRP3 inflammasome in several mouse models of NLRP3 inflammasome-related pathogenesis. Thus, terpenoids represent an interesting pharmacological approach for the treatment of inflammatory diseases as they are endowed with a dual mechanism of inhibition of NF-KB transcription factor and inflammasome activation, both critically involved in their anti-inflammatory effects. This work provides an overview of the current knowledge on the therapeutic potential of terpenoids as NLRP3 inflammasome inhibitors.This work 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 SH and grant RTI2018-094356-B-C21 from Ministerio de Economía y Competitividad to LGC, IC and BH. LGC received a predoctoral fellowship award from the Spanish Ministry of Education, Culture and Sports (FPU17/03519).S

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

Synthesis of Quinoline and Dihydroquinoline Embelin Derivatives as Cardioprotective Agents

A set of new dihydroquinoline embelin derivatives was obtained from the reaction of the natural benzoquinone embelin (1) with anilines and aromatic aldehydes in the presence of AgOTf. The synthesis of these compounds involves the formation of a Knoevenagel adduct, followed by nucleophilic addition of aniline and subsequent electrocyclic ring closure. The scope of the reaction regarding the aldehydes and anilines was determined. Quinoline derivatives were also obtained from the corresponding dihydroquinolines under oxidation with DDQ. The cardioprotective activity of the synthesized compounds was screened using a doxorubicin-induced cardiotoxicity model in H9c2 cardiomyocytes. Some structure-activity relationships were outlined, and the best activities were achieved with quinoline-embelin derivatives having a 4-nitrophenyl group attached at the pyridine ring. The obtained results indicated that embelin derivatives 4i, 6a, 6d, 6k, and 6m could have potential as cardioprotective agents, as they attenuated a DOX-induced cardiotoxicity effect acting on oxidative stress and apoptosis.We gratefully acknowledge the financial support from the Spanish MICIU RTI2018-094356-B-C21 to A.E.B., I.C., and B.H. and Agencia Canaria de Investigación, Innovación y Sociedad de la Información Pro ID 2021010037 to A.E.B. These projects are also cofunded by the European Regional Development Fund (FEDER). We thank Dr. A. Tapia and G. Feresin for providing the natural embeline. We are grateful to Instituto de Salud Carlos III for financial support to S.H.S

NLRP3 inflammasome as anew target for anti-inflammatory activity of terpenes

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 02-03-2023Los productos naturales desempeñan un papel destacado en la búsqueda de nuevos agentes bioactivos en distintas áreas terapéuticas, entre las que destaca la inflamación. En concreto, diterpenos y triterpenos han mostrado gran potencial como agentes antiinflamatorios a través de la inhibición de vías de señalización clásicas implicadas en inflamación, como la activación del factor de transcripción NF-kB y de MAPKs. En los últimos años, se ha descrito la participación del inflamasoma NLRP3 en la regulación de la respuesta inflamatoria. Este inflamasoma es un complejo multiproteico formado por la proteínaNLRP3, la molécula adaptadora ASC y la proteína efectora caspasa-1. La activación de NLRP3desencadena la liberación de citoquinas proinflamatorias (IL-1b e IL-18) y la muerte celularpor piroptosis, estando implicado en el proceso patogénico de gran diversidad de enfermedades inflamatorias crónicas. Por todo ello, el inflamasoma NLRP3 se considera un adiana emergente en el tratamiento de estas patologías, no existiendo en la clínica actual agentes terapéuticos que inhiban su activación. En este contexto, los terpenos se postulan como agentes prometedores capaces de modular su actividad. El objetivo de esta Tesis Doctoral ha sido la identificación de nuevos compuestos antiinflamatorios, en particular, diterpenos de tipo labdano y triterpenos de tipo friedelano, como inhibidores de la vía del inflamasoma NLRP3...Natural products represent a successful source in the search for new bioactive agents in different therapeutic areas, especially in inflammation. Particularly, diterpenes and triterpenes have shown great potential as anti-inflammatory agents through inhibition of classical inflammatory pathways such as the nuclear factor NF-κB and MAPKs activation. In recent years, the involvement of the NLRP3 inflammasome in the regulation of the inflammatory response has been described. NLRP3 inflammasome is a multiprotein complex constituted by the sensor protein NLRP3, the adaptor molecule ASC and the effector proteincaspase-1. NLRP3 activation triggers the secretion of proinflammatory cytokines IL-1β andIL-18 and pyroptotic cell death, being involved in the pathogenesis of diverse chronic inflammatory diseases. Consequently, the NLRP3 inflammasome is considered a noveltarget in the treatment of these pathologies, although no therapeutic agents are available in clinic to inhibit its activation. In this context, terpenes have emerged as promising NLRP3 modulators.The aim of this Doctoral Thesis has been the identification of novel antiinflammatory compounds, particularly labdane diterpenes and friedelane triterpenes, as NLRP3 inflammasome inhibitors...Depto. de Farmacología, Farmacognosia y BotánicaFac. de FarmaciaTRUEunpu

Dehydroisohispanolone as a Promising NLRP3 Inhibitor Agent: Bioevaluation and Molecular Docking.

Dehydroisohispanolone (DIH), is a labdane diterpene that has exhibited anti-inflammatory activity via inhibition of NF-κB activation, although its potential effects on inflammasome activation remain unexplored. This study aims to elucidate whether DIH modulates NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in macrophages. Our findings show that DIH inhibited NLRP3 activation triggered by Nigericin (Nig), adenosine triphosphate (ATP) and monosodium urate (MSU) crystals, indicating broad inhibitory effects. DIH significantly attenuated caspase-1 activation and secretion of the interleukin-1β (IL-1β) in J774A.1 cells. Interestingly, the protein expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), pro-caspase-1 and pro-IL-1β were not affected by DIH treatment. Furthermore, we found that DIH pretreatment also inhibited the lipopolysaccharide (LPS)-induced NLRP3 inflammasome priming stage. In addition, DIH alleviated pyroptosis mediated by NLRP3 inflammasome activation. Similar results on IL-1β release were observed in Nig-activated bone marrow-derived macrophages (BMDMs). Covalent molecular docking analysis revealed that DIH fits well into the ATP-binding site of NLRP3 protein, forming a covalent bond with Cys415. In conclusion, our experiments show that DIH is an effective NLRP3 inflammasome inhibitor and provide new evidence for its application in the therapy of inflammation-related diseases.We are grateful to Instituto de Salud Carlos III for financial support to S.H. (PI17CIII/00012, PI20CIII/00018). We gratefully acknowledge the financial support from the Spanish MICIU RTI2018-094356-B-C21 to A.E.-B., I.C., B.d.l.H., Á.A. and L.G.-C., Agencia Canaria de Investigación, Innovación y Sociedad de la Información Pro ID 2021010037 to A.E.-B. These projects are also co-funded by the European Regional Development Fund (FEDER). L.G.-C. received a predoctoral fellowship award from the Spanish Ministry of Education, Culture and Sports (FPU17/03519). Á.A. thanks the Cabildo de Tenerife (Agustín de Betancourt Program).S

Dehydrohispanolone Derivatives Attenuate the Inflammatory Response through the Modulation of Inflammasome Activation

The NLRP3 inflammasome plays a critical role in inflammation-mediated human diseases and represents a promising drug target for novel anti-inflammatory therapies. Hispanolone is a labdane diterpenoid isolated from the aerial parts of Ballota species. This diterpenoid and some derivatives have demonstrated anti-inflammatory effects in classical inflammatory pathways. In the present study, a series of dehydrohispanolone derivatives (1-19) was synthesized, and their anti-inflammatory activities toward NLRP3 inflammasome activation were evaluated. The structures of the dehydrohispanolone analogues produced were elucidated by NMR spectroscopy and mass spectrometry. Four derivatives significantly inhibited IL-1β secretion, with 15 and 18 being the most active (IC50 = 18.7 and 13.8 μM, respectively). Analysis of IL-1β and caspase-1 expression revealed that the new diterpenoids 15 and 18 are selective inhibitors of the NLRP3 inflammasome, reinforcing the previously demonstrated anti-inflammatory properties of hispanolone derivatives.This study was supported by grant PI17/00012 from Instituto de Salud Carlos III to S. Hortelano and grant RTI2018-094356-B-C21 from Ministerio de Ciencia, Innovación y Universidades (MICIU) to AEB and BH, grant Pro ID 2017010071 from Agencia Canaria de Investigación, Innovación y Sociedad de la Información (ACIISI) to AEB. These projects are also co-funded by the European Regional Development Fund (FEDER). LGC received a predoctoral fellowship award from the Spanish Ministry of Education, Culture and Sports (FPU17/03519). Á.A. and S.O.R. thank the Cabildo de Tenerife (Agustín de Betancourt Program).S

Atlas interactivo de Fitoterapia

Este proyecto pretende crear un Atlas de Fitoterapia actualizado, mediado por recursos digitales y multimedia; elaborado por un equipo interdisciplinar y colaborativo, capaz de mejorar la enseñanza y aprendizaje de los estudiantes de farmacia y la adquisición de habilidades para su desarrollo profesional futuro