Person:
Izquierdo García, José Luis

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José Luis
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Izquierdo García
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https://hdl.handle.net/20.500.14352/77717
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Universidad Complutense de Madrid
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Farmacia
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Author: Rodríguez Ramírez De Arellano, Ignacio ×

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    Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model
    (Front. Pharmacol, 2023) Morales-Cano, Daniel; Barreira, Bianca; Pandolfi, Rachele; Villa-Valverde, Palmira; Izquierdo García, José Luis; Esquivel Ruiz, Sergio Antonio; Callejo Arranz, María; Rodríguez Ramírez De Arellano, Ignacio; Cogolludo Torralba, Ángel Luis; Ruiz-Cabello Osuna, Jesús; Pérez Vizcaíno, Francisco; Moreno Gutiérrez, Laura
    Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit. Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods. Results: In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA. Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.
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    Comparison of Algorithms to Compute Relaxation Time Maps in Magnetic Resonance Imaging
    (Applied Sciences, 2023) Rodríguez Ramírez De Arellano, Ignacio; Izquierdo García, José Luis; Yazdanparast, Ehsan; Castejón, David; Ruiz-Cabello Osuna, Jesús
    Magnetic resonance imaging (MRI) is a valuable diagnostic tool that provides detailed information about the structure and function of tissues in the human body. In particular, measuring relaxation times, such as T1 and T2, can provide important insights into the composition and properties of different tissues. Accurate relaxation time mapping is therefore critical for clinical diagnosis and treatment planning, as it can help to identify and characterize pathological conditions, monitor disease progression, and guide interventions. However, the computation of relaxation time maps in MRI is a complex and challenging task that requires sophisticated mathematical algorithms. Thus, there is a need for robust and accurate algorithms that can reliably extract the desired information from MRI data. This article compares the performance of the Reduced Dimension Nonlinear Least Squares (RD-NLS) algorithm versus several widely used algorithms to compute relaxation times in MRI, such as Levenberg-Marquardt and Nelder-Mead. RD-NLS simplifies the search space for the optimum fit by leveraging the partial linear relationship between signal intensity and model parameters. The comparison was performed on several datasets and signal models, resulting in T1 and T2 maps. The algorithms were evaluated based on their fit error, with the RD-NLS algorithm showing a lower error than other fit-ting algorithms. The improvement was particularly notable in T1 maps, with less of a difference in T2 maps. Additionally, the average T1 values computed with different algorithms differed by up to 14 ms, indicating the importance of algorithm selection. These results suggest that the RD-NLS algorithm outperforms other commonly used algorithms for computing relaxation times in MRI.