Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

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Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood–brain barrier transport
(Springer Nature, 2025-12-01) Gong, Qiyong; Tian, Xiaohe; Battaglia, Giuseppe; Chen, Junyang; Xiang, Pan; Duro-Castano, Aroa; Cai, Huawei; Guo, Bin; Liu, Xiqin; Yu, Yifan; Lui, Su; Luo, Kui; Ke, Bowen; Ruiz-Perez, Lorena
The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 traf cking toward transcytosis and thereby upregulating its expression to promote ef cient Aβ removal. In AD model mice, this intervention signi cantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA. Multiple imaging techniques con rmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited signi cant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive bene ts persisted for up to 6 months post-treatment. This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane traf cking level. Our ndings also reaf rm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions signi cantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.
The minimal chemotactic cell
(American Association for the Advancement of Science, 2025-07-25) Battaglia, Giuseppe; Borges Fernandes, Barbara; Apriceno, Azzurra; Arango-Restrepo, Andrés; Almadhi, Safa; Ghosh, Subhadip; Forth, Joe; López-Alonso, Jorge Pedro; Ubarretxena-Belandia, Iban; Rubi, José Miguel; Ruiz-Perez, Lorena; Williams, Ian
The movement of cells and microorganisms in response to chemical gradients (chemotaxis) has played an essential role in the evolution of many biological processes. Cellular navigation works via the holistic assembly of numerous components into machineries that transform chemical energy into locomotion. Herein we present and discuss the minimal elements required for cell-like vesicles to be chemotactic. We show that lipid vesicles can propel themselves in response to chemical gradients when only a transmembrane protein and an encapsulated enzyme are incorporated into the vesicle structure. The herein proposed model serves as a proof of concept to show that even the simplest cell-like structure can experience chemotactic navigation.
Thermoplasmonic Polymersome Membranes by In Situ Synthesis
(American Chemical Society, 2025-04-18) Barbieri, Valentino; González Colsa, Javier; Matias, Diana; Duro-Castano, Aroa; Thapa, Anshu; Ruiz-Perez, Lorena; Albella, Pablo; Volpe, Giorgio; Battaglia, Giuseppe
Thermoplasmonic nanoparticles, known for releasing heat upon illumination, find diverse applications in catalysis, optics, and biomedicine. Incorporating plasmonic metals within organic vesicle membranes can lead to the formation of nanoreactors capable of regulating temperature-sensitive microscopic processes. Yet, the controlled formation of stable hybrid vesicles displaying significant thermoplasmonic properties remains challenging. This work presents the in situ synthesis of highly efficient thermoplasmonic polymer vesicles, or hybrid polymersomes, by nucleating ∼2 nm gold nanoparticles within preformed polymersome membranes. This process preserves the vesicles’ morphology, stability, and overall functionality. Despite the small size of the embedded plasmonic nanoparticles, these hybrid polymersomes can efficiently convert laser light into a notable temperature increase on a larger scale through collective heating. We develop a theoretical framework that rationalizes the structure–property relations of hybrid polymersomes and accurately predicts their collective thermoplasmonic response. Finally, we demonstrate the biomedical potential of our polymersomes by employing their photothermal properties to induce the hyperthermal death of cancer cells in vitro, an effect amplified by their superior cellular uptake. We envision that these hybrid polymersomes will evolve into a versatile platform for precise control over nanoscale chemical and biological processes through plasmonic heating, unlocking numerous opportunities across various scientific and medical contexts.
Portable ion mobility spectrometry and partial least squared discriminant analysis for odour source discrimination in wastewater treatment plants
(Elsevier B.V., 2025-11-15) Villa, Veronica; Fernández Romero, Luis; Lotesoriere, Beatrice Julia; Alonso Valdesueiro, Javier; Gutiérrez Gálvez, Agustín; Capelli, Laura; Marco Colás, Santiago
Odour emissions from Wastewater Treatment Plants are a relevant issue concerning environmental and social impact, regulatory compliance, and plant management. Instrumental Odour Monitoring Systems are widely used for real-time odour emissions monitoring, but seasonal and plant variability limit their long-term reliability. Therefore, new sensing technologies and approaches are being studied to improve their reliability and the transferability of predictions between different plants and seasons. In this context, this work investigates the suitability of portable Ion Mobility Spectrometers to discriminate the main odour sources in Wastewater Treatment Plants. Two measurement campaigns were carried out in different seasons, considering different odour sources in two independent plants. Through a proper data analysis approach, based on the importance of ionic information, portable Ion Mobility Spectrometry proved effective in discriminating odour sources from the two main process lines: water and sludge treatment. In the first phase, conducted in the same plant and season, a balanced classification rate of 94 % (95 %CI: 82 %–100 %) was achieved. Subsequently, including seasonal and plant variability, a model trained on one plant was applied to the second. The direct transfer of the calibration achieved a balanced classification accuracy of 96 % (95 %CI: 86 %–100 %), confirming the relevance of the selected ions for odour assessment across different plants. These results suggest that portable Ion Mobility Spectrometry is a technology that deserves further attention for instrumental odour monitoring. The consistent classification rates obtained both within a single plant and when transferring the model demonstrate that Ion Mobility Spectrometry, combined with feature selection, can reliably identify ions specifically relevant for odour emission assessment.
The long 5′ UTR of nrdAB modulates mRNA levels, stability, and virulence in Pseudomonas aeruginosa PAO1
(Nature Publishing Group, 2025-12-01) Martínez Mateos, Ángela; Rubio Canalejas, Alba; Pedraz López, Lucas; Torrents Serra, Eduard
The class Ia ribonucleotide reductase (RNR), encoded by the nrdAB operon in Pseudomonas aeruginosa, has a long 5’ untranslated region (5’ UTR) whose regulatory role remains poorly understood. In this study, we investigated the functional significance of the nrdAB 5’ UTR using a comprehensive set of bioinformatic and experimental approaches, including gene expression profiling, relative protein levels, and in vivo infection assays in the Galleria mellonella animal model. Our results demonstrate that the 5’ UTR negatively regulates nrdA expression by reducing transcript levels, decreasing mRNA stability and limiting protein abundance. Truncation of this region led to increased expression, particularly during the stationary phase, suggesting that this region may contribute to modulating RNR activity during the stationary phase, when dNTP demand is reduced. In vivo, the Δ5’ UTR mutant exhibited reduced virulence compared to the wild-type strain, accompanied by elevated nrdA mRNA levels and a modest decrease in nrdJ expression. Although these changes may contribute to altered RNR regulation during infection, they are unlikely to fully explain the observed phenotype, indicating that additional factors may be involved. Although no specific regulatory elements within or acting upon the 5’ UTR were probed under the tested conditions, the possibility of such mechanisms cannot be excluded, and further studies will be needed to elucidate the underlying molecular mechanisms. Overall, our findings demonstrate that the 5’ UTR plays a regulatory role in modulating nrdAB operon expression and contributes to maintaining RNR system homeostasis in P. aeruginosa.
Myo-MOVES: a custom electrical stimulation system for functional studies of 3D bioengineered muscle
(The Royal Society of Chemistry, 2025-10-01) Ruiz Gutiérrez, Martín; Tejedera Villafranca, Ainoa; Pujol Pinto, Sergi; Ramón Azcón, Javier; Fernandez Costa, Juan M.
Electrical pulse stimulation (EPS) is used to replicate motor neuron activation in muscle tissues, enabling in vitro studies of muscle contraction. However, both custom-built and commercial existing EPS systems often suffer from significant limitations, including limited scalability, high cost, and lack of flexibility for experimental adaptation. This work presents the Myo-MOVES platform, a practical solution for stimulating 3D skeletal muscle tissues. The device has been designed as an intuitive EPS system consisting of two main components: a selector and a stimulator that adapts to commercial 24-well culture plates. The Myo-MOVES selector enables targeted stimulation of single or multiple wells, while the stimulator delivers electrical signals via graphite electrodes to the plate containing 3D skeletal muscle samples. The Myo-MOVES platform was technically validated and employed as a proof of concept to investigate sarcolemmal damage induced by muscle contraction in Duchenne muscular dystrophy (DMD) 3D skeletal muscle tissues. Taking advantage of the versatility of the device, we validated Myo-MOVES through the assessment of force generation in DMD engineered muscle tissues and the detection of contraction-induced sarcolemmal damage via Evans blue dye uptake and the release of creatine kinase (CK), the gold standard marker of muscle damage. These findings demonstrate the feasibility of using Myo-MOVES to induce and study functionally relevant disease phenotypes in DMD 3D skeletal muscle tissues. These results highlight the system's potential as a valuable tool for future applications in the field of 3D skeletal muscle tissue engineering, including drug screening and the study of DMD therapies and other muscular diseases.
Optimized alveolar epithelial cell model for chronic Pseudomonas aeruginosa and Staphylococcus aureus coinfections
(Elsevier, 2025-11-21) Admella, Joana; Alcàcer Almansa, Júlia; Julian, Esther; Torrents Serra, Eduard
Pseudomonas aeruginosa is a relevant pathogen in chronic respiratory infections, which are usually associated with biofilm formation, complicating in vitro modeling and effective treatment strategies. While P. aeruginosa can coexist with several microorganisms, its association with Staphylococcus aureus is widespread in cystic fibrosis (CF) patients and other bronchiectasis. Finding a reliable and straightforward in vitro model to study long-term P. aeruginosa infections is extremely hard due to the secretion of highly virulent toxins that compromise the model within less than 10 h. Several optimizations, including the use of bovine serum albumin (BSA) and extracellular matrix proteins, led to enhanced A549 cell viability up to 30 h post-infection. Within this time frame, we developed P. aeruginosa biofilms, explored host-pathogen interactions, and delved deeper into the relationship between P. aeruginosa and S. aureus. Additionally, ciprofloxacin treatment was evaluated, revealing changes and differences in antibiotic susceptibility and underlying significant differences between bacterial strains
CSRR chemical sensing in uncontrolled environments by PLS regression
(Institute of Electrical and Electronics Engineers (IEEE), 2025-09-18) Alonso Valdesueiro, Javier; Fernández Romero, Luis; Gutiérrez Gálvez, Agustín; Marco Colás, Santiago
Complementary Split Ring Resonators (CSRRs) have been widely researched as planar sensors, but their use in routine chemical analysis is limited due to dependence on high-end equipment, controlled conditions, and susceptibility to environmental and handling variations. This work introduces a novel approach combining a CSRR sensor with machine learning (ML) to enable reliable quantification of compounds. A low-cost benchtop CSRR system was tested for ethanol concentration prediction in water (10–96%), using 450 randomized measurements. PCA was applied for data exploration, and a PLS regression model with Leave-One-Group-Out cross-validation achieved a 3.7% RMSEP, six times better than univariate calibration (23.4%). The results show that ML can mitigate measurement uncertainties, making CSRR sensors viable for robust, low-cost concentration analysis under realistic laboratory conditions.
Ferrofluid-based bioink for 3d printed skeletal muscle tissues with enhanced force and magnetic response
(John Wiley & Sons, 2025-06-25) Fuentes Llanos, Judith; Guix Noguera, Maria; Cenev, Zoran M.; Bakenecker, Anna; Ruiz González, Noelia; Beaune, Grégory; Timonen, Jaakko V. I.; Sánchez Ordóñez, Samuel; Magdanz, Veronika
3D printing has emerged as a transformative technology in several manufacturing processes, being of particular interest in biomedical research for allowing the creation of 3D structures that mimic native tissues. The process of tissue 3D printing entails the construction of functional, 3D tissue structures. In this article, the integration of ferrofluid consisting of iron oxide nanoparticles into muscle cell-laden bioink is presented to obtain a 3D printed magnetically responsive muscle tissue, i.e., the ferromuscle. Using extrusion-based methods, the seamless integration of biocompatible ferrofluids are achieved to cell-laden hydrogels. The resulting ferromuscle tissue exhibits improved tissue differentiation demonstrated by the increased force output upon electrical stimulation compared to muscle tissue prepared without ferrofluid. Moreover, the magnetic component originating from the iron oxide nanoparticles allows magnetic guidance, as well as good cytocompatibility and biodegradability in cell culture. These findings offer a new versatile fabrication approach to integrate magnetic components into living constructs, with potential applications as bioactuators and for future integration in smart, functional muscle implants.
Antifouling surface-attached hydrogel nanocoatings redefined: green solvent-based, degradable, and high-performance protection against foulants
(John Wiley & Sons, 2025-05-28) Englert, Jenny; Palà Sánchez, Marc; Quandt, Jonas; Sieben, Hannah; Grottke, Oliver; Marx, Bernd; Lligadas, Gerard; Rodríguez Emmenegger, César
Antifouling coatings are vital to enhance the performance of medical devices, aiming to mitigate bodily reactions by shielding their surface. Despite significant advancements in antifouling coatings, like those based on zwitterionic monomers and hydroxyl-functionalized (meth)acrylamides, limitations like decreased antifouling properties after functionalization and complement system activation hinder their application in blood. Here, a novel class of ultrathin surface-attached hydrogels is presented, consisting of hydrophilic non-charged green solvent-based monomers and preventing protein adsorption while offering on-demand degradability. Unlike the best antifouling brushes, the coatings are easily applicable, unaffected by charges, and free of complement system-activating groups. The hydrogels are formed using copolymers of N,N-dimethyl lactamide acrylate (DMLA) and benzophenone acrylate (BPA). Moreover, 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) is incorporated to introduce hydrolyzable ester. The coating of state-of-the-art devices is demonstrated with X-ray photoelectron spectroscopy (XPS), analyze surface energy components, and confirm their antifouling properties with surface plasmon resonance (SPR). The coatings are non-cytotoxic toward MRC-5 fibroblasts, exhibit repellency against methicillin-resistant Staphylococcus aureus (MRSA), and effectively prevent thrombus formation on devices in blood. This work establishes a versatile platform for next-generation coatings in medical and industrial applications, matching the antifouling efficiency of the most advanced solutions and offering regeneration of substrates by erasing the coating.
Advanced antibacterial strategies for combatting biomaterial-associated infections: a comprehensive review
(John Wiley & Sons, 2024-12-09) Kasapgil, Esra; Garay Sarmiento, Manuela; Rodríguez Emmenegger, César
Biomaterial-associated infections (BAIs) pose significant challenges in modern medical technologies, being a major postoperative complication and leading cause of implant failure. These infections significantly risk patient health, resulting in prolonged hospitalization, increased morbidity and mortality rates, and elevated treatment expenses. This comprehensive review examines the mechanisms driving bacterial adhesion and biofilm formation on biomaterial surfaces, offering an in-depth analysis of current antimicrobial strategies for preventing BAIs. We explore antimicrobial-eluting biomaterials, contact-killing surfaces, and antifouling coatings, emphasizing the application of antifouling polymer brushes on medical devices. Recent advancements in multifunctional antimicrobial biomaterials, which integrate multiple mechanisms for superior protection against BAIs, are also discussed. By evaluating the advantages and limitations of these strategies, this review aims to guide the design and development of highly efficient and biocompatible antimicrobial biomaterials. We highlight potential design routes that facilitate the transition from laboratory research to clinical applications. Additionally, we provide insights into the potential of synthetic biology as a novel approach to combat antimicrobial resistance. This review aspires to inspire future research and innovation, ultimately improving patient outcomes and advancing medical device technology.
Extubating of a patient undergoing mechanical ventilation: What is the right time? A retrospective study assisted by artificial intelligence techniques
(International University of Sarajevo, 2024-12-25) Arismendi Pererira, Carlos Julio; Sandoval Rodríguez, Camilo Leonardo; Giraldo Giraldo, Beatriz F. (Beatriz Fabiola); Solano, E. H.
In the presence of acute respiratory failure, mechanical ventilation emerges as a temporary alternative to maintain adequate gas exchange in the body such as that which occurs in natural respiration. This technique is widely used in intensive care units. Our objective was to carry out an analysis and interpretation of cardiorespiratory signals in patients assisted by mechanical ventilation, using non-linear analysis techniques of dynamic systems, data mining and machine learning techniques to establish indices that allow determining the appropriate moment of disconnection. in patients during the weaning process. We use three categories: Failure, success and reintubated. We introduced a new variant of Moving Window with Variance Analysis, with which good results are obtained. We have found that by using all the time series available in the database, we have obtained an accuracy of 96% when using simple symbolic dynamics to differentiate between successful weaning and reintubated cases. and 86% when comparing success and failure, which contrasts with the results observed in the state of the art.
A new era in brain drug delivery: Integrating multivalency and computational optimisation for blood–brain barrier permeation
(Elsevier, 2025-06-14) Porro, Giulia Maria; Basile, Marco; Xie, Zhendong; Tuveri, Gianmarco; Battaglia, Giuseppe; Carvalho Ferreira Lopes, Cátia Daniela
Efficient drug delivery across the blood–brain barrier (BBB) remains a significant obstacle in treating central nervous system (CNS) disorders. This review provides an in-depth analysis of the structural and molecular mechanisms underlying BBB integrity and its functional properties. We detail the role of key cellular and molecular components that regulate selective molecular transport across the barrier, alongside a description of the current therapeutic approaches for brain drug delivery, including those leveraging receptor-mediated transcytosis. Emphasis is placed on multivalency-based strategies that enhance the specificity of nanoparticle targeting and improve transport efficacy across the BBB. Additionally, we discuss the added value of integrating mathematical and computational models with experimental validation for accelerating BBB-targeted delivery systems optimisation.
Enzyme controlled transient phospholipid vesicles for regulated cargo release
(Wiley-VCH, 2025-05-12) Venugopal, Akhil; Ghosh, Subhadip; Calò, Annalisa; Tuveri, Gian Marco; Battaglia, Giuseppe; Kumar, Mohit
Metabolism in biological systems involves the continuous formation and breakdown of chemical and structural components, driven by chemical energy. In specific, metabolic processes on cellular membranes result in in situ formation and degradation of the constituent phospholipid molecules, by consuming fuel, to dynamically regulate the properties. Synthetic analogs of such chemically fueled phospholipid vesicles have been challenging. Here we report a bio-inspired approach for the in situ formation of phospholipids, from water soluble precursors, and their fuel driven self-assembly into vesicles. We show that the kinetic competition between anabolic and catabolic-like reactions leads to the formation and enzymatic degradation of the double-tailed, vesicle-forming phospholipid. Spectroscopic and microscopic analysis demonstrate the formation of transient vesicles whose lifetime can be easily tuned from minutes to hours. Importantly, our design results in the formation of uniform sized (65 nm) vesicles simply by mixing the precursors, thus avoiding the traditional complex methods. Finally, our sub-100 nm vesicles are of the right size for application in drug delivery. We have demonstrated that the release kinetics of the incorporated cargo molecules can be dynamically regulated for potential applications in adaptive nanomedicine.
Bioengineering fascicle-like skeletal muscle bioactuators via pluronic-assisted co-axial 3D bioprinting (PACA-3D)
(Institute of Physics Pub., 2025-06-06) Fuentes Llanos, Judith; Mestre Castillo, Rafael; Guix Noguera, Maria; Esporrín Ubieto, David; Ghailan Tribak, Ibtissam; Ruiz González, Noelia; Patiño Padial, Tania; Sánchez Ordóñez, Samuel
Advances in 3D bioprinting have opened new possibilities for developing bioengineered muscle models that can mimic the architecture and function of native tissues. However, current bioengineering approaches do not fully recreate the complex fascicle-like hierarchical organization of the skeletal muscle tissue, impacting on the muscle maturation due to the lack of oxygen and nutrient supply in the scaffold inner regions. A key challenge is the production of precise and width-controlled independent filaments that do not fuse during the printing process when subsequently extruded, ensuring the formation of fascicle-like structures. This study addresses the limitation of filament fusion by utilizing a pluronic-assisted co-axial 3D bioprinting system (PACA-3D) creates a physical confinement of the bioink during the extrusion process, effectively obtaining thin and independent printed filaments with controlled shapes. The use of PACA-3D enabled the fabrication of skeletal muscle-based bioactuators with improved cell differentiation and significantly increased force output, obtaining 3 times stronger bioengineered muscle when compared to bioactuators fabricated using conventional 3D extrusion bioprinting techniques, where a single syringe containing the bioink is used. The versatility of our technology has been demonstrated using different biomaterials, demonstrating its potential to develop more complex biohybrid tissue-based architectures with improved functionality, as well as aiming for better scalability and printing flexibility.
Unlocking the full potential of human pluripotent stem cell–derived kidney organoids through bioengineering
(Elsevier, 2025-04-24) Goux Corredera, Iphigénie; Amato, Gaia; Moya Rull, Daniel; Garreta Bahima, Elena; Montserrat Pulido, Núria
Human pluripotent stem cells hold inherent properties, allowing researchers to recapitulate key morphogenetic processes. These characteristics, coupled with bioengineering techniques, have led to the definition of early procedures to derive organ-like cell cultures, the so-called organoids. With regard to kidney organoids, challenges stand ahead, such as the need to enhance cellular composition, maturation, and function to that found in the native organ. To this end, the kidney organoid field has begun to nourish from innovative engineering approaches aiming to gain control on the externally imposed biochemical and biophysical cues. In this review, we first introduce how previous research in kidney development and human pluripotent stem cells has informed the establishment of current kidney organoid procedures. We then discuss recent engineering approaches to guide kidney organoid self-organization, differentiation, and maturation. In addition, we present current strategies to engineer vascularization and promote in vivo–like physiological microenvironments as potential solutions to increase kidney organoid lifespan and functionality. We finally emphasize how working at the cusp of cell mechanics and computational biology will set the ground for successful translational applications of kidney organoids.
Tuning the matrix: recent advances in mechanobiology unveiled through polyacrylamide hydrogels
(Elsevier, 2025-06-13) Ciccone, Giuseppe; Salmeron-Sanchez, Manuel
Over the past 30 years, polyacrylamide (PAAm) hydrogels have become essential tools to mimic the mechanical properties, chemical composition, and dimensionality of the extracellular matrix (ECM) in in vitro mechanobiology studies. This brief review highlights recent developments that have transformed PAAm hydrogels from simple 2D static elastic hydrogels to complex ECM-mimicking systems involving protein micropatterning, mechanical patterning, stretching, DNA tension probes, viscoelasticity, and the microfabrication of 3D systems. We focus on novel mechanobiological questions that have been elucidated using these platforms and give a perspective on the future of PAAm hydrogels for mechanobiology research.
Novel selective strategies targeting the BCL-2 family to enhance clinical efficacy in ALK-rearranged non-small cell lung cancer
(Springer Science and Business Media LLC, 2025-03-20) Martín, Fernando; Alcon, Clara; Marín, Elba; Morales Sánchez, Paula; Manzano Muñoz, Albert; Diaz, Sherley; García López, Mireia; Samitier i Martí, Josep; Lu, Albert; Villanueva Garatachea, Alberto; Reguart, Noemí; Teixido Febrero, Cristina; Montero Boronat, Joan
ALK (anaplastic lymphoma kinase) rearrangements represent the third most predominant driver oncogene in non-small cell lung cancer (NSCLC). Although ALK inhibitors are the tyrosine kinase inhibitors (TKIs) with the longest survival rates in lung cancer, the complex systemic clinical evaluation and the apoptotic cell death evasion of drug-tolerant persister (DTP) cancer cells may limit their therapeutic response. We found that dynamic BH3 profiling (DBP) presents an excellent predictive capacity to ALK-TKIs, that would facilitate their use in a clinical setting and complementing the readout of standard diagnostic assays. In addition, we revealed novel acute adaptive mechanisms in response to ALK inhibitors in cell lines and patient-derived tumor cells. Consistently, all our cell models confirmed a rapid downregulation of the sensitizer protein NOXA, leading to dependence on the anti-apoptotic protein MCL-1 after treatment with ALK-TKIs. In some cases, the anti-apoptotic protein BCL-xL may contribute equally to this anti-apoptotic response. Importantly, these acute dependencies could be prevented with BH3 mimetics in vitro and in vivo, blocking tumor adaptation to treatment. Finally, we also demonstrated how dual reactivation of PI3K/AKT and MAPK signaling pathways can impair lorlatinib response, which could be overcome with specific inhibitors of both signaling pathways. In conclusion, our findings propose several therapeutic combinations that should be explored in future clinical trials to enhance ALK inhibitors efficacy and improve the clinical response in a broad NSCLC patient population.
Light-Activated Pharmacological Tools for Exploring the Cholinergic System
(Wiley, 2025-03-23) Colleoni, Alessio; Galli, Giulia; Dallanoce, Clelia; Amici, Marco de; Gorostiza Langa, Pablo Ignacio; Matera, Carlo
Cholinergic transmission plays a critical role in both the central and peripheral nervous systems, affecting processes such as learning, memory, and inflammation. Conventional cholinergic drugs generally suffer from poor selectivity and temporal precision, leading to undesired effects and limited therapeutic efficacy. Photopharmacology aims to overcome the limitations of traditional drugs using photocleavable or photoswitchable ligands and spatiotemporal patterns of illumination. Spanning from muscarinic and nicotinic modulators to cholinesterase inhibitors, this review explores the development and application of light-activated compounds as tools for unraveling the role of cholinergic signaling in both physiological and pathological contexts, while also paving the way for innovative phototherapeutic approaches.
Molecular Tools to Study and Control Dopaminergic Neurotransmission With Light
(Wiley, 2025-04-10) Malieieva, Galyna; Matera, Carlo; Roda, Silvia; Colleoni, Alessio; Amici, Marco de; Gorostiza Langa, Pablo Ignacio
Dopaminergic neurotransmission is involved in several important brain functions, such as motor control, learning, reward-motivated behavior, and emotions. Dysfunctions of dopaminergic system may lead to the development of various neurological and psychiatric disorders, like Parkinson's disease, schizophrenia, depression, and addictions. Despite years of sustained research, it is not fully established how dopaminergic neurotransmission governs these important functions through a relatively small number of neurons that release dopamine. Light-driven neurotechnologies, based on the use of small light-regulated molecules or overexpression of light-regulated proteins in neurons, have greatly contributed to the advancement of our understanding of dopaminergic circuits and our ability to control them selectively. Here, we overview the current state-of-the-art of light-driven control of dopaminergic neurotransmission. While we provide a concise guideline for the readers interested in pharmacological, pharmacogenetic, and optogenetic approaches to modulate dopaminergic neurotransmission, our primary focus is on the usage of photocaged and photo-switchable small dopaminergic molecules. We argue that photopharmacology, photoswitchable molecules of varied modalities, can be employed in a wide range of experimental paradigms, providing unprecedent insights into the principles of dopaminergic control, and represent the most promising light-based therapeutic approach for spatiotemporally precise correction of dopamine-related neural functions and pathologies.

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