GSK-3βren inhibizio bidezko TDP-43aren lokalizazioaren eta kopuruaren azterketa C2C12 zeluletan, muskulu distrofietan izan dezakeen eragina finkatzeko

[EUS] Lan honen bidez lortu nahi den helburu nagusia LiCl bidezko tratamenduak TDP-43 proteinaren kontzentrazioa zein lokalizazio zelularra aldatzen duen finkatzea da. Halaber, ikerketa honen bidez lortu nahi diren gainerako helburuak ondokoak dira: • Litioa bezala, GSK3βren inhibitzaileak diren Tideglusib eta VPO.7 bidezko tratamenduek TDP43aren lokalizazio zelularrean eraginik duten behatzea. • Erabilitako farmakoek, Wnt bidezidorraren bidez β-kateninarengan eragiten dutenez, TPD-43rekiko efektua β-kateninarekiko menpekoa ote den azaltzea. Azkenik, litio, Tideglusib eta VP0.7 farmakoek muskulu distrofietan agertzen den TDP-43 miogranulu zitoplasmatikoen kontzentrazio patologikoaren murrizketa lortuko balute, farmako hauek distrofia muskularren tratamendurako proposatuak izango lirateke.[ES] El objetivo principal que se persigue con este trabajo es determinar qué localización celular de la proteína TDP-43 es debida al tratamiento con LiCl. Asimismo, el resto de objetivos que se persiguen con esta investigación son: • Observar si, al igual que el litio, los tratamientos mediante Tideglusib y VPO.7, inhibidores del GSK3ß, afectan a la localización celular del TDP43. • Explicar si el efecto sobre el TPD-43, al incidir los fármacos utilizados en la senda Wnt sobre la ßkatenina, depende de la misma. Por último, si los fármacos Litio, Tidegclub y VP0.7 obtuvieran una reducción de la concentración patológica de los miogránulos citoplasmáticos TDP-43 presentes en las distrofias musculares, éstos serían propuestos para el tratamiento de las distrofias musculares

Alternative p38MAPKs as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

Trabajo presentado en el 44º Congreso Nacional de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Málaga (España) del 06 al 09 de septiembre de 2022.Chronic inflammation in inflammatory bowel disease (IBD) is a risk factor for Colorectal cancer (CRC) development, but our understanding of this interplay at a molecular level is still limited. p38γ and p38δ, are central in the development of mouse colitis-associated CRC (CAC) by modulating the inflammatory immune response. However, their implication in human CRC and IBD is not well defined. In this study we perform an integrative analysis of p38γ and p38δ mRNA and protein expression and activation in human patients; using human CRC derived organoids and plasma samples, as well as data from different human CRC and IBD mRNA databases. We found that, p38δ levels were decreased, whereas p38γ expression and phosphorylation were significantly increased in CRC compared to normal colon samples. This increase correlated with the expression of genes implicated in inflammation. Examine of p38γ/p38δ in IBD patients showed that p38γ mRNA and protein levels were increased in Crohn’s disease and ulcerative colitis patients. Contrary, p38δ mRNA was significantly decreased. We also investigated the expression of miRNAs, miR-128-2, miR133a and miR-155, implicated in inflammation and cancer development. In mouse model of colitis and CAC, miR128-2 level was regulated by p38γ/p38δ. In the plasma of IBD and CRC patients, miR128-2 was increased compared to healthy donors, and this correlated with p38γ and p38δ levels. Our results show an opposite regulation of p38γ and p38δ in both CRC and IBD; and suggest that p38γ acts as a link between colitis and CRC by favouring an inflammatory environment that promotes tumour development. We provided evidence that p38γ/p38δ, together with miR-128-2, can be useful as biomarkers, and as potential treatment targets, for colitis and early-stage CRC

p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

descripción no proporcionada por scopusThis research was funded by the MCIN/AEI/10.13039/501100011033 (PID2019-108349RB100 and SAF2016-79792R) to AC and JJSE; Villum Foundation, grant no. 13152 to KA; by Agencia Estatal de Investigación (PID2019-104867RBI00/AEI/10.13039/501100011033) and the Instituto de Salud Carlos III- Fondo Europeo de Desarrollo Regional (CIBERONC/CB16/12/00273 and ICI20/00057) to AM and AB. PF received MCIN FPI fellowship (BES-2017-080139)

Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates

Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well as in other disorders including endocrine syndromes, diabetes, and ageing, being their primary cause unknown. Nowadays, there is no cure for TA. Intriguingly, both hypoxia and calcium dyshomeostasis prompt TA formation, pointing to a possible role for mitochondria in their setting. However, a functional link between mitochondrial dysfunctions and TA remains unknown. Herein, we investigate the alteration in muscle-proteome of TAM patients, the molecular mechanism of TA onset and a potential therapy in a preclinical mouse model of the disease. We show that in vivo chronic inhibition of the mitochondrial ATP synthase in muscle causes TA. Upon long-term restrained oxidative phosphorylation (OXPHOS), oxidative soleus experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA result from the overresponse of the fission controller DRP1, that upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. Remarkably, the muscle proteome of TAM patients displays similar alterations in mitochondrial dynamics and in ATP synthase contents. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorder