Immune checkpoints inhibitors for cancer treatment

El cáncer consigue escapar a la respuesta inmune de nuestro organismo gracias a las denominadas señales coinhibidoras. Las células cancerosas, tras ser detectadas por los linfocitos, son capaces de expresar en su superficie receptores de membrana que interaccionan con otros receptores en las células T desencadenando la inhibición de la respuesta inmune. Con el fin de evitar esto, se han desarrollado los inhibidores de la coestimulación inmune, anticuerpos monoclonales que bloquean dichas moléculas de superficie impidiendo su interacción y pudiéndose entonces desarrollar una respuesta inmune completa. El objetivo de este trabajo es analizar las dianas moleculares de estos fármacos, las rutas coinhibitorias, el estado actual de la terapéutica de los mismos y las diferentes vías de investigación que presumen el descubrimiento de nuevos inhibidores de la coestimulación.Cancer is able to escape from de immune response because of signals called coinhibitory signals. After cancer’s cells are detected by lymphocytes, they modulate the expression of surface receptors which interact with T cells spreading the inhibition of the immune response. To avoid that, immune checkpoints inhibitors have been developed. They are monoclonal antibodies that try to blockage these surface receptors, resulting on no inhibitory interaction between T cells and cancer cells and developing a complete immune response. The aim of this review is to analyse molecular targets, coinhibition pathways, the therapeutic usage of these drugs and the new research lines that promise the finding of new immune checkpoints inhibitors.Fac. de FarmaciaTRUEunpu

Tacrolimus prevents TWEAK-induced PLA2R expression in cultured human podocytes

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawalThis research was funded by Instituto de Salud Carlos III FIS PI15/00298, PI16/02057, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, Sociedad Española de Nefrología, EUTOX, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM, Fundacion Renal Iñigo Alvarez de Toledo (FRIAT) and Grant Fondecyt (Conicyt Chile) 1160465

MAP3K kinases and kidney injury

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexploredLas proteínas quinasas activadas por mitógenos (MAP quinasas) son quinasas conectadas funcionalmente que regulan procesos celulares clave involucrados en la enfermedad renal como la supervivencia, la muerte, la diferenciación y la proliferación. El típico módulo MAP quinasa está compuesto por una cascada de 3 quinasas: una MAP quinasa quinasa quinasa (MAP3K) que fosforila y activa una MAP quinasa quinasa (MAP2K) que, a su vez, fosforila una MAP quinasa (MAPK). Si bien el papel de las MAPK como ERK, p38 y JNK se ha caracterizado bien en las lesiones renales experimentales, se sabe mucho menos acerca de las quinasas apicales en la cascada, las MAP3K. Hay 24 MAP3K (MAP3K1 a MAP3K21, más RAF1, BRAF y ARAF). En este trabajo revisamos el conocimiento actual sobre la participación de MAP3K en la enfermedad renal no maligna y las herramientas terapéuticas disponibles. Existe evidencia intervencionista experimental in vivo que respalda claramente el papel de MAP3K5 (ASK1) y MAP3K14 (NIK) en la patogenia de la enfermedad renal experimental. De hecho, el inhibidor de ASK1, selonsertib, ha sido estudiado en ensayos clínicos en la enfermedad renal diabética. Además, aunque la MAP3K7 (MEKK7, TAK1) es necesaria para el desarrollo renal, la inhibición de MAP3K7 en el adulto protegió de la lesión renal aguda y crónica experimental; e inhibir MAP3K8 (TPL2/Cot) protegió de la lesión renal aguda. Por el contrario, MAP3K15 (ASK3) puede proteger de la hipertensión y los inhibidores de BRAF, en uso clínico, pueden inducir lesión renal aguda y síndrome nefrótico. Dado su papel como reguladores de los primeros pasos de la señalización intracelular, las MAP3K son posibles dianas terapéuticas en la lesión renal, como se ha demostrado para algunas de ellos. Sin embargo, el papel de la mayoría de las MAP3K en la enfermedad renal no ha sido exploradoGrant support: Instituto de Salud Carlos III (ISCIII) and FEDER– Fonds Européen de Développement Économique et Régional (FEDER) funds EUTOX, CP14/00133, PI15/00298, PI16/01900,PI16/02057, PI18/01366, Sociedad Española de Nefrologia, Fun-dación Renal Iñigo Alvarez de Toledo (FRIAT), ISCIII Red de Investigacion Renal (REDinREN) RD016/009, Salary support: ISCIII Miguel Servet to MDSN, Universidad Autónoma deMadrid to LC

Análisis de hábitos de la Comunidad Universitaria. Consumo de drogas (alcohol, síntesis, y plantas) Detección y Prevención. Relación con el rendimiento académico y laboral.

Estudio descriptivo y análisis de hábitos de la Comunidad Universitaria. Consumo de drogas (alcohol, síntesis, y plantas) Detección y Prevención. Relación con el rendimiento académico y laboral. Estudio realizado en la Facultad de Farmacia, UCM, durante el curso académico 2016-2017 a los alumnos de todos los cursos mediante la aplicación de del cuestionario ASSITS v3.0 y una encuesta de resultados académicos. En el trabajo se exponen los resultados de 877 encuestas (37 % del total de alumnos).Depto. de Farmacia Galénica y Tecnología AlimentariaDepto. de Farmacología, Farmacognosia y BotánicaFac. de FarmaciaFALSEsubmitte

Phosphate, microbiota and ckd

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventu-ally, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 860329, FIS/Fondos FEDER (PI18/01366, PI20/00744, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-C

Fosl1 es un factor de transcripción nefroprotector en la respuesta adaptativa durante el daño renal

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de Lectura: 22-07-2022Esta tesis tiene embargado el acceso al texto completo hasta el 22-01-2024El fracaso renal agudo (FRA) es un síndrome clínico caracterizado por una disminución repentina de la función renal. Los pacientes con FRA presentan un mayor riesgo de desarrollar enfermedad renal crónica (ERC), que es una de las causas de muerte que más rápido aumenta en el mundo. La ERC, a su vez, predispone al FRA. No existe tratamiento para el FRA, más allá de reemplazar la función renal con diálisis. Fosl1 es un factor de transcripción que regula eventos moleculares involucrados en el FRA y la ERC. Sin embargo, se desconoce su papel en las células tubulares en las enfermedades renales. Mediante biología de sistemas hemos identificado a la familia AP-1 como activada en la enfermedad renal. Entre los componentes canónicos de AP-1, Fosl1 aumentó en dos estudios transcriptómicos de FRA murino nefrotóxico y en células tubulares proximales expuestas a TWEAK, una citoquina mediadora del FRA. El aumento de proteína de Fosl1 se localizó en los núcleos de células tubulares proximales en el FRA experimental y humano. Además, en el FRA humano, FOSL1 estaba presente en las células tubulares proximales en la orina y el ARNm de FOSL1 aumentó también en la orina. La deficiencia de Fosl1 en las células tubulares proximales aumentó la gravedad del FRA nefrotóxico, causando una mayor pérdida de función renal y Klotho y una inflamación renal más grave. La regulación negativa de Klotho precedió a la pérdida de función renal. Además, el promotor de Klotho estaba enriquecido en los sitios de unión de Fosl1, a los que se unió directamente Fosl1 en el FRA-cisplatino. En células tubulares proximales cultivadas, el silenciamiento de Fosl1 aumentó la respuesta proinflamatoria y disminuyó Klotho. Además, hemos identificado las vías de activación de Fosl1 en células tubulares proximales cultivadas expuestas a TWEAK. Por tanto, el aumento de Fosl1 durante el FRA conserva Klotho, amortigua la respuesta inflamatoria, la gravedad de la lesión de las células tubulares y el FRA. La expresión de Fosl1 aumenta también en la ERC experimental y la deficiencia selectiva de Fosl1 en células tubulares proximales predispone o acelera la fibrosis al regular la expresión de mediadores profibrogénicos e inflamatorios en las primeras etapas de la ERC. Además, la deficiencia de Fosl1 aumenta la pérdida de masa renal. En resumen, la expresión de Fosl1 durante la enfermedad renal es una respuesta adaptativa que limita eventos moleculares como la inflamación y la fibrosi

Synthesis and Neuroprotective Properties of N‑Substituted C‑Dialkoxyphosphorylated Nitrones

Herein, we report the synthesis and neuroprotective power of some N-substituted C-(dialkoxy)phosphorylated nitrones 4a−g, by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified (Z)-N-tert-butyl-1- (diethoxyphosphoryl)methanimine oxide (4e) as the most potent, nontoxic, and neuroprotective agent, with a high activity against neuronal necrotic cell death, a result that correlates very well with its great capacity for the inhibition of the superoxide production (72%), as well as with the inhibition of lipid peroxidation (62%), and the 5-lipoxygenase activity (45%) at 100 μM concentrations. Thus, nitrone 4e could be a convenient promising compound for further investigationThe synthetic part of the project was supported by the National Science Centre (grant UMO-2015/17/B/ST5/ 00076). D.H.-L. gratefully acknowledges Dr A. Leo and Biobyte Corp., 201 West 4th Street, Suite 204, Claremont, CA 91711, for free access to the C-QSAR program. J.M.-C. and M.J.O.-G. thank MINECO (Government of Spain) (SAF2015- 65586-R) and Universidad Camilo José Cela (NitroStroke project, 2015-12) for suppor

TWEAK increases CD74 expression and sensitizes to DDT proinflammatory actions in tubular cells.

CD74 is a multifunctional protein and a receptor for Macrophage Migration Inhibitory Factor (MIF) and MIF-2 / D-dopachrome tautomerase (DDT) cytokines, upregulated in diabetic kidney disease. However, the drivers of CD74 expression and DDT function in kidney cells are poorly characterized. TWEAK is a proinflammatory cytokine that promotes kidney injury. We have now identified CD74 gene expression as upregulated in the kidneys in response to systemic TWEAK administration in mice, and have characterized the in vivo CD74 expression and the functional consequences in cultured cells. TWEAK administration to mice resulted in a progressive time-dependent (up to 24h) upregulation of kidney CD74 mRNA (RT-PCR) and protein (Western blot). Furthermore, the CD74 ligands MIF and DDT were also upregulated at the protein level 24h after TWEAK administration. Immunohistochemistry localized the increased CD74, MIF and DDT expression to tubular cells. In cultured tubular cells, TWEAK increased CD74 mRNA and protein expression dose-dependently, with a temporal pattern similar to in vivo. TWEAK-induced CD74 localized to the cell membrane, where it can function as a cytokine receptor. For the first time, we explored the actions of DDT in tubular cells and found that DDT amplified the increase in MCP-1 and RANTES expression in response to TWEAK. By contrast, DDT did not significantly modify TWEAK-induced Klotho downregulation. In conclusion, TWEAK upregulates CD74 and its ligands MIF and DDT in renal tubular cells. This may have functional consequences for kidney injury since DDT amplified the inflammatory response to TWEAK

The transcription factor Fosl1 preserves Klotho expression and protects from acute kidney injury.

Increased expression of AP-1 transcription factor components has been reported in acute kidney injury (AKI). However, the role of specific components, such as Fosl1, in tubular cells or AKI is unknown. Upstream regulator analysis of murine nephrotoxic AKI transcriptomics identified AP-1 as highly upregulated. Among AP-1 canonical components, Fosl1 was found to be upregulated in two transcriptomics datasets from nephrotoxic murine AKI induced by folic acid or cisplatin and from proximal tubular cells exposed to TWEAK, a cytokine mediator of AKI. Fosl1 was minimally expressed in the kidneys of control uninjured mice. Increased Fosl1 protein was localized to proximal tubular cell nuclei in AKI. In human AKI, FOSL1 was found present in proximal tubular cells in kidney sections and in urine along with increased urinary FOSL1 mRNA. Selective Fosl1 deficiency in proximal tubular cells (Fosl1Δtub) increased the severity of murine cisplatin- or folate-induced AKI as characterized by lower kidney function, more severe kidney inflammation and Klotho downregulation. Indeed, elevated AP-1 activity was observed after cisplatin-induced AKI in Fosl1Δtub mice compared to wild-type mice. More severe Klotho downregulation preceded more severe kidney dysfunction. The Klotho promoter was enriched in Fosl1 binding sites and Fosl1 bound to the Klotho promoter in cisplatin-AKI. In cultured proximal tubular cells, Fosl1 targeting increased the proinflammatory response and downregulated Klotho. In vivo, recombinant Klotho administration protected Fosl1Δtub mice from cisplatin-AKI. Thus, increased proximal tubular Fosl1 expression during AKI is an adaptive response, preserves Klotho, and limits the severity of tubular cell injury and AKI.This research was funded by Instituto de Salud Carlos III (ISCIII)–Fondo de Investigacion Sanitaria (FIS)–Fondo Europeo de Desarrollo Regional (FEDER) grants PI18/01366 and PI21/00251 and ISCIII-RETIC REDinREN RD16/0009. We acknowledge Comunidad de Madrid en Biomedicina grant B2017/BMD-3686 CIFRA2-CM and ISCIII FIS/FEDER grants PI19/00588, PI19/00815, European Research Area-PerMedJTC2018 KIDNEY ATTACK AC18/00064, and ISCIII Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS) program to RICORS2040 (RD21/0005/0001). MDS-N was supported by Spain’s Ministry of Science and Innovation (MICINN) Ramon y Cajal program RYC2018-024461-I. LC was supported by grant FPI-UAM 2018.S