CIENCIAS EXPERIMENTALES

Permanent URI for this collectionhttps://hdl.handle.net/10641/1423

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Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life.
(Pediatric Research, 2024) Monedero Cobeta, Ignacio; Gómez Bris, Raquel; Rodríguez-Rodríguez, Pilar; Sáez Somolinos, Ángela; Quintana-Villamandos, Begoña; Gonzalez Granado, Jose María; Magdalena Arribas, Silvia
Background Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases. Methods We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0–1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR. Results Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males. Conclusions Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming.
Effects of motor imagery-based neurofeedback training after bilateral repetitive transcranial magnetic stimulation on post-stroke upper limb motor function: an exploratory crossover clinical trial.
(Journal of Rehabilitation Medicine, 2024) Sánchez Cuesta, Francisco José; González Zamorano, Yeray; Moreno Verdú, Marcos; Vourvopoulos, Athanasios; Serrano, Ignacio J.; Del Castillo-Sobrino, Maria Dolores; Figueiredo, Patrícia; Romero Muñoz, Juan Pablo
Objective: To examine the clinical effects of combining motor imagery-based neurofeedback training with bilateral repetitive transcranial magnetic stimulation for upper limb motor function in subacute and chronic stroke. Design: Clinical trial following an AB/BA crossover design with counterbalanced assignment. Subjects: Twenty individuals with subacute (n = 4) or chronic stroke (n = 16). Methods: Ten consecutive sessions of bilateral repetitive transcranial magnetic stimulation alone (therapy A) were compared vs a combination of10 consecutive sessions of bilateral repetitive transcranial magnetic stimulation with 12 non-consecutive sessions of motor imagery-based neurofeedback training (therapy B). Patients received both therapies (1-month washout period), in sequence AB or BA. Participants were assessed before and after each therapy and at 15-days follow-up, using the Fugl-Meyer Assessment-upper limb, hand-grip strength, and the Nottingham Sensory Assessment as primary outcome measures. Results: Both therapies resulted in improved functionality and sensory function. Therapy B consistently exhibited superior effects compared with therapy A, according to Fugl-Meyer Assessment and tactile and kinaesthetic sensory function across multiple time-points, irrespective of treatment sequence. No statistically significant differences between therapies were found for hand-grip strength. Conclusion: Following subacute and chronic stroke, integrating bilateral repetitive transcranial magnetic stimulation and motor imagery-based neurofeedback training has the potential to enhance functional performance compared with using bilateral repetitive transcranial magnetic stimulation alone in upper limb recovery.
TDCS for parkinson‘s disease disease-related pain: A randomized trial.
(Clinical Neurophysiology, 2024) González-Zamorano, Yeray; Sánchez Cuesta, Francisco José; Moreno Verdú, Marcos; Arroyo Ferrer, Aida; Fernández Carnero, Josué; Ray Chaudhuri, K.; Fieldwalker, Anna; Romero Muñoz, Juan Pablo
Objective To evaluate the effects of transcranial direct current stimulation (tDCS) on Parkinson’s disease (PD)-related pain. Methods This triple-blind randomized controlled trial included twenty-two patients (age range 38–85, 10 male) with PD-related pain. Eleven subjects received ten sessions of 20 minutes tDCS over the primary motor cortex contralateral to pain at 2 mA intensity. Eleven subjects received sham stimulation. Outcome measures included changes in the Kinǵs Parkinsońs Pain Scale (KPPS), Brief Pain Inventory (BPI), widespread mechanical hyperalgesia (WMH), temporal summation of pain (TS), and conditioned pain modulation (CPM). Results Significant differences were found in KPPS between groups favoring the active-tDCS group compared to the sham-tDCS group at 15-days follow-up (p = 0.014) but not at 2 days post-intervention (p = 0.059). The active-group showed significant improvements over the sham-group after 15 days (p = 0.017). Significant changes were found in CPM between groups in favor of active-tDCS group at 2 days post-intervention (p = 0.002) and at 15 days (p = 0.017). No meaningful differences were observed in BPI or TS. Conclusions tDCS of the primary motor cortex alleviates perceived PD-related pain, reduces pain sensitization, and enhances descending pain inhibition. Significance This is the first study to test and demonstrate the use of tDCS for improving PD-related pain.
Robotic exoskeleton embodiment in post‑stroke hemiparetic patients: an experimental study about the integration of the assistance provided by the REFLEX knee exoskeleto.
(Scientific Reports, 2023) Lora Millán, Julio Salvador; Sánchez-Cuesta, Francisco José; Romero Muñoz, Juan Pablo; Moreno, Juan C.; Rocon, Eduardo
Hemiparetic gait is the most common motor-disorder after stroke and, in spite of rehabilitation efforts, it is persistent in 50% of community dwelling stroke-survivors. Robotic exoskeletons have been proposed as assistive devices to support impaired joints. An example of these devices is the REFLEX knee exoskeleton, which assists the gait of hemiparetic subjects and whose action seems to be properly embodied by stroke survivors, who were able to adapt the motion of their non-assisted limbs and, therefore, reduce their compensation mechanisms. This paper presents an experimental validation carried out to deepen into the effects of REFLEX’s assistance in hemiparetic subjects. Special attention was paid to the effect produced in the muscular activity as a metric to evaluate the embodiment of this technology. Significant differences were obtained at the subject level due to the assistance; however, the high dispersion of the measured outcomes avoided extracting global effects at the group level. These results highlight the need of individually tailoring the action of the robot to the individual needs of each patient to maximize the beneficial outcomes. Extra research effort should be done to elucidate the neural mechanisms involved in the embodiment of external devices by stroke survivors.
Repetitive transcranial magnetic stimulation of primary motor cortex for stroke upper limb motor sequelae rehabilitation: A systematic review.
(NeuroRehabilitation, 2023) Sánchez-Cuesta, Francisco José; González-Zamorano, Yeray; Arroyo Ferrer, Aída; Moreno-Verdú, Marcos; Romero Muñoz, Juan Pablo
BACKGROUND:Repetitive Transcranial Magnetic Stimulation (rTMS) over the primary motor cortex (M1) has been used to treat stroke motor sequelae regulating cortical excitability. Early interventions are widely recommended, but there is also evidence showing interventions in subacute or chronic phases are still useful. OBJECTIVE:To synthetize the evidence of rTMS protocols to improve upper limb motor function in people with subacute and/or chronic stroke. METHODS:Four databases were searched in July 2022. Clinical trials investigating the effectiveness of different rTMS protocols on upper limb motor function in subacute or chronic phases post-stroke were included. PRISMA guidelines and PEDro scale were used. RESULTS:Thirty-two studies representing 1137 participants were included. Positive effects of all types of rTMS protocols on upper limb motor function were found. These effects were heterogeneous and not always clinically relevant or related to neurophysiological changes but produced evident changes if evaluated with functional tests. CONCLUSION:rTMS interventions over M1 are effective for improving upper limb motor function in people with subacute and chronic stroke. When rTMS protocols were priming physical rehabilitation better effects were achieved. Studies considering minimal clinical differences and different dosing will help to generalize the use of these protocols in clinical practice.
Editorial Special Issue Neuroscience “Tauopathies”.
(Neuroscience, 2023) Ávila, Jesús; Santa-María, Ismael; Sotiropulos, Ioannis
Mechanisms linking cerebrovascular dysfunction and tauopathy: Adding a layer of epiregulatory complexity.
(British Journal of Pharmacology, 2023) Kim, Yoon A.; Mellen Rodriguez, Marian; Kizil, Caghan; Santa-María, Ismael
Intracellular accumulation of hyperphosphorylated misfolded tau proteins are found in many neurodegenerative tauopathies, including Alzheimer's disease (AD). Tau pathology can impact cerebrovascular physiology and function through multiple mechanisms. In vitro and in vivo studies have shown that alterations in the blood–brain barrier (BBB) integrity and function can result in synaptic abnormalities and neuronal damage. In the present review, we will summarize how tau proteostasis dysregulation contributes to vascular dysfunction and, conversely, we will examine the factors and pathways leading to tau pathological alterations triggered by cerebrovascular dysfunction. Finally, we will highlight the role epigenetic and epitranscriptomic factors play in regulating the integrity of the cerebrovascular system and the progression of tauopathy including a few observartions on potential therapeutic interventions.
Case-control study assessing the impact of COVID19 in advanced kidney cancer patients treated with antiangiogenics or immunotherapy. The COVID-REN study.
(Clinical and Translational Oncology, 2023) García-Donas, Jesús; De Velasco, Guillermo; Madurga Lacalle, Rodrigo; Rodríguez-Moreno, Juan Francisco
Background: Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e: antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management. Methods: We designed a retrospective case-control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender and treatment. Results: 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C) Patients with COVID required more dose interruptions (25 vs six) and hospitalizations (10 vs none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19. Conclusions: Kidney cancer patients that developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy
Highly efficient carbon catalysts for the green synthesis of 1,5-benzodiazepines: Experimental and theoretical study.
(Catalysis Today, 2024) Godino Ojer, Marina; Ripoll Morales, Vanessa; Pastrana-Martínez, Luisa M.; Morales-Torres, Sergio; Maldonado-Hódar, Francisco J.; Pérez-Mayoral, Elena
A family of sustainable carbon catalysts with different chemical surface, active and selective for the synthesis of benzodiazepine 1 (BDZ), from o-phenylendiamine (OPD) 2 and acetone 3, under mild conditions, is reported. Catalysts were prepared by acids treatments with H2SO4 or H3PO4 of an activated carbon doped with ZnO at 3% wt (N3Zn) and, subsequently, submitted to additional thermal treatment in air. Simultaneously to the ZnO leaching, surface C-SO3 groups were generated by treatment of N3Zn with H2SO4 (N3Zn-S) whereas treatment with H3PO4 led to C-PO3 functions (N3Zn-P sample). The thermal treatment partially removes the C-SO3 groups (N3Zn-S-C sample) while C-PO3 functions were partially oxidized to C-OPO3 groups (N3Zn-P-C). Our results suggest that these chemical surface modifications of the catalysts are key on catalytic performance, pointed out the importance of the nature and distribution of acid sites at the surface. Remarkably, investigated carbon catalysts (N3Zn-S samples) were more active than the NS catalyst obtained by direct treatment of AC with H2SO4, this last mainly functionalized with C-OSO3 groups. Although the catalysts resulting of the H3PO4 treatment showed both a similar activity, some differences on selectivity to BDZ 1 were observed, attributed to certain specificity of P-functions at the surface depending on the acid strength of active sites and the reaction conditions. These results were supported by DFT calculations.
Layer-by-layer assembly: A versatile approach for tailored biomedical films and drug delivery.
(Journal of Drug Delivery Science and Technology, 2024) L.S. dos Santos, Victoria; C. Araújo, Rayssa; S. Lisboa, Erika; M. Lopes, André; L. de Albuquerque-Júnior, Ricardo; C. Cardoso, Juliana; Blanco Llamero, Cristina; A. Deshpande, Tanvi; O.W. Anderson, Henning; Priefer, Ronny; B. Souto, Eliana; Severino, Patrícia
Layer-by-layer (LbL) assembly has revolutionized the field of biomedical engineering by enabling the precise design and fabrication of thin multilayer films with diverse functionalities. This article provides a comprehensive review of the applications of LbL assembly in drug delivery, antimicrobial action, wound healing, and tissue engineering. The LbL technique involves the sequential adsorption of oppositely charged materials onto a substrate, facilitating the incorporation of different chemical species through electrostatic interactions and other driving forces. This approach offers remarkable control over film properties such as porosity, mass, and thickness, and provides the flexibility to incorporate multiple components within the film structure. In drug delivery applications, LbL-produced films have demonstrated exceptional potential for controlled and sustained release of therapeutic agents, minimizing dosing frequency and improving patient compliance. Studies successfully report incorporated antimicrobials, anticancer agents and growth factors into LbL assemblies, demonstrating their effectiveness in targeted drug delivery and combating microbial infections. In addition, LBL assembly has emerged as a promising approach for wound healing strategies. By incorporating bioactive molecules and growth factors, these films promote tissue regeneration, angiogenesis and accelerated wound closure, thereby improving the overall wound healing process. In the field of tissue engineering, LbL-produced films provide a versatile platform for constructing bioactive structures that mimic the extracellular matrix and support cell attachment, proliferation, and differentiation. This versatile approach has significant implications for the development of tissue substitutes and regenerative therapies. This review also emphasizes the influence of LbL assembly methods on film properties, including thickness and porosity, and highlights the effect of various parameters such as pH, solvent, ionic strength, and temperature on film formation.
Transcranial Direct Current Stimulation (tDCS) Effects on Quantitative Sensory Testing (QST) and Nociceptive Processing in Healthy Subjects: A Systematic Review and Meta-Analysis.
(Brain Sciences, 2024) Gurdiel-Álvarez, Francisco; González-Zamorano, Yeray; Lerma-Lara, Sergio; Gómez-Soriano, Julio; Sánchez-González, Juan Luis; Fernández-Carnero, Josué; Navarro-López, Víctor
Background: The aim of this study is to determine the effect that different tDCS protocols have on pain processing in healthy people, assessed using quantitative sensory tests (QST) and evoked pain intensity. Methods: We systematically searched in EMBASE, CINAHL, PubMed, PEDro, PsycInfo, and Web of Science. Articles on tDCS on a healthy population and regarding QST, such as pressure pain thresholds (PPT), heat pain thresholds (HPT), cold pain threshold (CPT), or evoked pain intensity were selected. Quality was analyzed using the Cochrane Risk of Bias Tool and PEDro scale. Results: Twenty-six RCTs were included in the qualitative analysis and sixteen in the meta-analysis. There were no significant differences in PPTs between tDCS and sham, but differences were observed when applying tDCS over S1 in PPTs compared to sham. Significant differences in CPTs were observed between tDCS and sham over DLPFC and differences in pain intensity were observed between tDCS and sham over M1. Non-significant effects were found for the effects of tDCS on HPTs. Conclusion: tDCS anodic over S1 stimulation increases PPTs, while a-tDCS over DLPFC affects CPTs. The HPTs with tDCS are worse. Finally, M1 a-tDCS seems to reduce evoked pain intensity in healthy subjects.
Azithromycin preserves adult hippocampal neurogenesis and behavior in a mouse model of sepsis.
(Brain, Behavior, and Immunity, 2024) Rodríguez-Moreno, Carla B.; Cañeque-Rufo, Héctor; Flor-García, Miguel; Terreros-Roncal, Julia; Moreno-Jiménez, Elena P.; Pallas-Bazarra, Noemí; Bressa, Carlo; Larrosa, Mar; Cafini, Fabio; Llorens-Martín, María
The mammalian hippocampus can generate new neurons throughout life. Known as adult hippocampal neurogenesis (AHN), this process participates in learning, memory, mood regulation, and forgetting. The continuous incorporation of new neurons enhances the plasticity of the hippocampus and contributes to the cognitive reserve in aged individuals. However, the integrity of AHN is targeted by numerous pathological conditions, including neurodegenerative diseases and sustained inflammation. In this regard, the latter causes cognitive decline, mood alterations, and multiple AHN impairments. In fact, the systemic administration of Lipopolysaccharide (LPS) from E. coli to mice (a model of sepsis) triggers depression-like behavior, impairs pattern separation, and decreases the survival, maturation, and synaptic integration of adult-born hippocampal dentate granule cells. Here we tested the capacity of the macrolide antibiotic azithromycin to neutralize the deleterious consequences of LPS administration in female C57BL6J mice. This antibiotic exerted potent neuroprotective effects. It reversed the increased immobility time during the Porsolt test, hippocampal secretion of pro-inflammatory cytokines, and AHN impairments. Moreover, azithromycin promoted the synaptic integration of adult-born neurons and functionally remodeled the gut microbiome. Therefore, our data point to azithromycin as a clinically relevant drug with the putative capacity to ameliorate the negative consequences of chronic inflammation by modulating AHN and hippocampal-related behaviors.
Amino-grafted basic mesoporous silicas: a type of highly performant catalysts for the green synthesis of 2-amino-4H-chromenes.
(Catalysis Today, 2024) González Rodal, Daniel; Godino Ojer, Marina; Palomino-Cabello, Carlos; Turnes-Palomino, Gemma; López-Peinado, Antonio J.; Pérez-Mayoral, Elena
Novel series of amino-grafted mesoporous silica materials applied to the green and efficient synthesis of 2-amino-4H-chromenes, from salicylaldehydes and ethyl cyanoacetate, under mild and free-solvent conditions, is herein reported for the first time. These catalysts are easily prepared by using the post-synthetic method, by functionalizing the SBA-15 silica with the corresponding amino silanes. The observed catalytic performance is mainly controlled by the type and concentration of basic sites. The methodology herein reported could be considered as an environmentally friendly alternative for the selective chromene synthesis, which allows to achieve high yields in short reaction times using notably small amounts of the catalysts. The experimental results are also supported with theoretical calculations, which suggest that the amine groups at the silica surface are behind the observed catalytic performance with the assistance of the silica matrix.
Microemulsion of essential oil of Citrus aurantium var. dulcis for control of Aleurocanthus woglumi and evaluation of selectivity against Aschersonia aleyrodis and Ceraeochrysa cornuta.
(Crop Protection, 2024) Oliveira, Joseane de Jesus; Dos Passos, Eliana M.; Alves, Suely M.; Sarmento, Victor H.V.; Bjerk, Thiago R.; Cardoso, Juliana C.; Blanco Llamero, Cristina; Souto, Eliana B.; Severino, Patrícia; Da Costa Mendonça, Marcelo
The aim of this study was to develop a microemulsion from the essential oil of Citrus aurantium var. dulcis (EOCA) as an alternative to synthetic pesticides, and to evaluate its efficacy against Aleurocanthus woglumi and selectivity towards the natural enemies Aschersonia aleyrodis and Ceraeochrysa cornuta. Chemical composition of the essential oil determined by gas chromatography coupled with mass spectrometry revealed limonene, myrcene, linalool and α-pinene as major components. The microemulsion was prepared using a ternary diagram illustrating the composition of water, essential oil, surfactant (procetyl AWS) and co-surfactant (ethanol). Selected microemulsions were characterized by polarized light microscopy, revealing to be isotropic with a Newtonian behaviour when measuring the shear stress against shear rate. The mean droplet size of microemulsions ranged from 53.69 nm to 2.22 μm. The insecticidal activity was evaluated by assessing three application routes, namely, contact, systemic and translaminar. Selectivity of microemulsions was determined by the percentage of growth inhibition (PGI) of fungi on A. aleyrodis and by contact on eggs and larvae of C. cornuta. The oil (LC50 = 36.07 mg/mL) in its pure form had a lower insecticidal effect on A. woglumi than the microemulsions (LC50 = 18.65 mg/mL). The microemulsions showed systemic insecticidal activity with approximately 90% mortality at 72 h (LC90 = 55.50 mg/mL). On A. aleyrodis, the microemulsion interfered with biomass production, which was concentration dependent. At a concentration of 15.68 mg/mL, a 91% inhibition of biomass production were observed. In the selectivity experiments against C. cornuta, the microemulsions were selective for eggs and larvae, and did not interfere with its predatory capacity.
Key Parameters for Detectivity Improvement of Low Noise Anisotropic Magnetoresistive Sensors Made of La2/3Sr1/3MnO3 Single Layers on Vicinal Substrates.
(ACS Applied Electronic Materials, 2023) Enger, Luiz; Flament, Stéphane; Bhatti, Imtiaz; Martínez, Isidoro; Méchin, Laurence
The current trend in magnetoresistive sensors development is to increase the sensitivity of single sensing elements by using multilayer structures and to design them into arrays. Such arrays are designed to compensate the excess low frequency noise of individual elements, which limits their magnetic resolution. Here, we report the modeling, design, and fabrication of single layer anisotropic magnetoresistive (AMR) sensors using low noise epitaxial La2/3Sr1/3MnO3 (LSMO) oxide thin films deposited on vicinal SrTiO3 substrates. The fabrication process is simple, and the operation of the sensor is based on a step-induced uniaxial magnetic anisotropy, described using the Stoner–Wohlfarth model. A coherent magnetization reversal process is observed by magneto-optical Kerr effect imaging. A good agreement between experimental data and the expected sensor response confirms the correct operation of the device. Three main fabrication parameters, namely the vicinal angle of the substrate, the deposition temperature, the thin film thickness, and their effects on film anisotropy field and device detectivity have been studied. Detectivity levels as low as 1.4 nT Hz–1/2 at 1 Hz and 240 pT Hz–1/2 in the white noise region are achieved with a single Wheatstone bridge element operating at 310 K. Compared to GMR and AMR sensors, these results are promising for further development and for their use as single layer LSMO low field AMR sensors, including applications as implantable biomedical devices.
Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies
(Frontiers in Neuroendocrinology, 2023) Ten Blanco, Marc; Flores, África; Cristino, Luigia; Pereda Pérez, Inmaculada; Berrendero, Fernando
Orexins (also known as hypocretins) are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system and bind two different G protein-coupled receptors (OX1R and OX2R). Since its discovery in 1998, the orexin system has gained the interest of the scientific community as a potential therapeutic target for the treatment of different pathological conditions. Considering previous basic science research, a dual orexin receptor antagonist, suvorexant, was the first orexin agent to be approved by the US Food and Drug Administration to treat insomnia. In this review, we discuss and update the main preclinical and human studies involving the orexin system with several psychiatric and neurodegenerative diseases. This system constitutes a nice example of how basic scientific research driven by curiosity can be the best route to the generation of new and powerful pharmacological treatments.
Polydopamine surface functionalized submicron ZnO for broadening the processing window of 3D printable PLA composites.
(Journal of Polymer Research, 2023) Yang, Xiao‑Mei; Yin, Guang-Zhong; Zafra Amorós, Olga; Arroyo-Hernández, María; De la Vega, Jimena; Torralba, José Manuel
The “catalytic degradation” of metal oxides limits the wide application of PLA when PLA needs to be modified by adding metal oxides to achieve desired properties. Zinc oxide (ZnO) is a common and widely used agent as it can be used for many properties, such as antioxidant, antibacterial, etc. However, detrimental effects often exist on the properties of polymers after introducing the ZnO, due to the catalytic degradation. In this study, we used polydopamine (PDA) to construct ZnO@PDA core-shell submicron particles via the self-polymerization of dopamine (DA) in alkaline solution, aimed to produce a surface functionalization that would be used to control the rate of degradation of PLA by ZnO during thermal processing, and promote the preservation of mechanical properties. PLA with different contents of ZnO and ZnO@PDA were prepared by a simple melt extrusion method. The degradation behavior, mechanical properties and antibacterial activity of ZnO/PLA and ZnO@PDA/PLA were investigated. It was found that the incorporation of ZnO@PDA in PLA at different contents exhibits a dramatic control over the degradation rate when compared to that of the ZnO/PLA with the same filler content. Notably, the T5% and T50% of 3%-ZnO@PDA/PLA increased by 36.4 oC and 31.9 oC. GPC results showed the molecular weight of 3%-ZnO@PDA/PLA was only reduced by 15.8% after thermal processing. In addition, 3%-ZnO@PDA/PLA can be 3D-printed smoothly. That is to say, the introduction of ZnO@PDA can increase the processing window of PLA/ZnO composites, providing the possibility for materials that need to be included in civil application. Accordingly, ZnO@PDA/PLA samples showed higher tensile strength and elongation at break than that of corresponding ZnO/PLA samples. Regarding the antibacterial behavior, the ZnO@PDA/PLA have more bacterial growth disability effect against Gram(+) bacteria than that of pure PLA.
Randomized phase II clinical trial of ruxolitinib plus simvastatin in COVID19 clinical outcome and cytokine evolution.
(Frontiers in Immunology, 2023) García-Donas, Jesús; Martínez-Urbistondo, Diego; Velázquez Kennedy, Kyra; Madurga Lacalle, Rodrigo
Background: Managing the inflammatory response to SARS-Cov-2 could prevent respiratory insufficiency. Cytokine profiles could identify cases at risk of severe disease. Methods: We designed a randomized phase II clinical trial to determine whether the combination of ruxolitinib (5 mg twice a day for 7 days followed by 10 mg BID for 7 days) plus simvastatin (40 mg once a day for 14 days), could reduce the incidence of respiratory insufficiency in COVID-19. 48 cytokines were correlated with clinical outcome. Participants: Patients admitted due to COVID-19 infection with mild disease. Results: Up to 92 were included. Mean age was 64 ± 17, and 28 (30%) were female. 11 (22%) patients in the control arm and 6 (12%) in the experimental arm reached an OSCI grade of 5 or higher (p = 0.29). Unsupervised analysis of cytokines detected two clusters (CL-1 and CL-2). CL-1 presented a higher risk of clinical deterioration vs CL-2 (13 [33%] vs 2 [6%] cases, p = 0.009) and death (5 [11%] vs 0 cases, p = 0.059). Supervised Machine Learning (ML) analysis led to a model that predicted patient deterioration 48h before occurrence with a 85% accuracy. Conclusions: Ruxolitinib plus simvastatin did not impact the outcome of COVID-19. Cytokine profiling identified patients at risk of severe COVID-19 and predicted clinical deterioration.
Target Therapy in Malignant Pleural Mesothelioma: Hope or Mirage?.
(International Journal of Molecular Sciences, 2023) Borea, Federica; Franczak, Marika A.; García, María; Perrino, Matteo; Cordua, Nadia; Smolenski, Ryszard T.; Peters, Godefridus J.; Dziadziuszko, Rafal; Santoro, Armando; Zucali, Paolo A.; Giovannetti, Elisa
Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring systemic treatment. Chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care for approximately 20 years, without any relevant therapeutic advance until the introduction of immune checkpoint inhibitors. Nevertheless, the prognosis remains poor, with an average survival of only 18 months. Thanks to a better understanding of the molecular mechanisms underlying tumor biology, targeted therapy has become an essential therapeutic option in several solid malignancies. Unfortunately, most of the clinical trials evaluating potentially targeted drugs for MPM have failed. This review aims to present the main findings of the most promising targeted therapies in MPM, and to explore possible reasons leading to treatments failures. The ultimate goal is to determine whether there is still a place for continued preclinical/clinical research in this area.
Nerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer’s disease.
(Regenerative Medicine, 2023) Siddiqui, Tohid; Ilyas Cosacak, Mehmet; Popova, Stanislava; Santa-María, Ismael; Kizil, Caghan
Neurogenesis, crucial for brain resilience, is reduced in Alzheimer’s disease (AD) that induces astroglial reactivity at the expense of the pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology. However, the molecular mechanisms promoting pro-neurogenic astroglial fate despite AD pathology are unknown. In this study, we used APP/PS1dE9 mouse model and induced Nerve growth factor receptor (Ngfr) expression in the hippocampus. Ngfr, which promotes neurogenic fate of astroglia during the amyloid pathology-induced neuroregeneration in zebrafish brain, stimulated proliferative and neurogenic outcomes. Histological analyses of the changes in proliferation and neurogenesis, single-cell transcriptomics, spatial proteomics, and functional knockdown studies showed that the induced expression of Ngfr reduced the reactive astrocyte marker Lipocalin-2 (Lcn2), which we found was sufficient to reduce neurogenesis in astroglia. Anti-neurogenic effects of Lcn2 was mediated by Slc22a17, blockage of which recapitulated the pro-neurogenicity by Ngfr. Long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Postmortem human AD hippocampi and 3D human astroglial cultures showed elevated LCN2 levels correlate with reactive gliosis and reduced neurogenesis. Comparing transcriptional changes in mouse, zebrafish, and human AD brains for cell intrinsic differential gene expression and weighted gene co-expression networks revealed common altered downstream effectors of NGFR signaling, such as PFKP, which can enhance proliferation and neurogenesis in vitro when blocked. Our study suggests that the reactive non-neurogenic astroglia in AD can be coaxed to a pro-neurogenic fate and AD pathology can be alleviated with Ngfr. We suggest that enhancing pro-neurogenic astroglial fate may have therapeutic ramifications in AD.

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