Promising Targets and Strategies to Control Neuroinflammation (Part II)

Neuroinflammation is the condition in which inflammation occurs in the central nervous system (CNS: brain and spinal cord), leading to the activation of microglia and astrocytes. Its role in several central pathologies is nowadays well-known, including neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) [1]. In fact, neuroinflammation has the role of restoring homeostasis in the CNS when an injury occurs. On the contrary, sustained inflammation is detrimental, and this typically occurs in and characterizes neurodegenerative diseases. The formation of protein aggregates distinctive to neurodegenerative diseases is one of the stimuli that exacerbate neuroinflammation [2]. Thus, searching for targets involved in the control of the neuroinflammatory condition in these still incurable diseases continuously attracts the scientific community's attention. In particular, several enzymes and receptors have been investigated for their role in neuroinflammation and neurodegeneration. In this thematic issue, promising targets and their ligands are discussed with strategies to develop entities able to control neuroinflammation. In particular, in this second part of the thematic issue, the discussed targets by eminent research groups are G protein-coupled receptors and the mitochondrial translocator protein TSPO. The first contribution, "A2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders” by Lambertucci et al., highlights the neuroprotective effects mediated by the A2A adenosine receptor antagonists summarizing most relevant and promising compounds along with their preclinical and clinical studies in neuroinflammation related diseases [3]. The second contribution, titled “Interplay Between Endocannabinoid System and Neurodegeneration: Focus on Polypharmacology,” by Seghetti et al. is focused on the most recent studies evaluating the role of cannabinoids in neurodegenerative diseases, especially on the potential for a multitarget strategy [4]. The third contribution, titled “Translocator Protein 18-kDa: A Promising Target to Treat Neuroinflammationrelated Degenerative Diseases,” by Tremolanti et al. reviews recent findings on the potential immunomodulatory effects of TSPO ligands against neuroinflammation, taking into consideration some pathologies of the nervous system in which inflammatory events are crucial for the onset and progression of the disease [5]. The last contribution, titled “Essential Principles and Recent Progress in the Development of TSPO PET Ligands for Neuroinflammation Imaging,” by Viviano et al. focuses on TSPO. This review discussed the design and development of TSPO PET ligands useful for assessing active gliosis associated with brain lesions following injury or disease [6]. We are grateful to all the eminent authors for their valuable contributions that have allowed us to make this thematic issue. We also thank the Italian Ministry of University and Research (MUR) for the financial support within the PRIN2017 (Grant no. 2017MT3993)

Promising Targets and Strategies to Control Neuroinflammation (Part I)

Neuroinflammation is a condition in which inflammation occurs in the central nervous system (CNS: brain and spinal cord), leading to the activation of microglia and astrocytes. Its role in several central pathologies is nowadays well-known, including neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) [1]. In fact, neuroinflammation has the role of restoring homeostasis in the CNS when an injury occurs. On the contrary, sustained inflammation is detrimental, and this typically occurs in and characterizes neurodegenerative diseases. The formation of protein aggregates distinctive to neurodegenerative diseases is one of the stimuli that exacerbate neuroinflammation [2]. Thus, searching for targets involved in the control of the neuroinflammatory condition in these still incurable diseases continuously attracts the scientific community's attention. In particular, several enzymes and receptors have been investigated for their role in neuroinflammation and neurodegeneration. In this thematic issue, promising targets and their ligands are discussed with strategies to develop entities able to control neuroinflammation. In particular, in this first part of the thematic issue, the discussed targets by eminent research groups are protein kinases. The first contribution, "Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases” by Gianferrara et al., describes GSK3β structure and its involvement in both neuroinflammation and neurodegeneration as well as GSK3β inhibitors with a special focus on that used in preclinical or clinical studies [3]. The second contribution, titled “Casein Kinase 1δ Inhibitors as Promising Therapeutic Agents for Neurodegenerative Disorders,” by Catarzi et al., highlights the development of CK1δ inhibitors, on their structure-activity relationships comprising computational studies which provide useful insight for the design of novel inhibitors [4]. The third contribution, titled “Role of Fyn Kinase Inhibitors in Switching Neuroinflammatory Pathways” by Marotta et al., reviews efforts to develop small molecules that inhibit Fyn, as an opportunity for therapeutic intervention in neurodegeneration [5]. The fourth and last contribution, titled “Computational Strategies to Identify New Drug Candidates against Neuroinflammation” by Pavan et al., aims to provide a general overview of the most common computational strategies that can be exploited to discover and design small molecules controlling neuroinflammation, reporting several case studies [6]. We are grateful to all the eminent authors for their valuable contributions that have allowed us to make this thematic issue. We also thank the Italian Ministry of University and Research (MUR) for the financial support within the PRIN2017 (Grant no. 2017MT3993)

Dust in and around galaxies: dust in cluster environments and its impact on gas cooling

Simulating the dust content of galaxies and their surrounding gas is challenging due to the wide range of physical processes affecting the dust evolution. Here we present cosmological hydrodynamical simulations of a cluster of galaxies, $M_\text{200,crit}=6 \times 10^{14}\,{\rm M_\odot}$, including a novel dust model for the moving mesh code {\sc Arepo}. This model includes dust production, growth, supernova-shock-driven destruction, ion-collision-driven thermal sputtering, and high temperature dust cooling through far infrared re-radiation of collisionally deposited electron energies. Adopting a rather low thermal sputtering rate, we find, consistent with observations, a present-day overall dust-to-gas ratio of $\sim 2\times 10^{-5}$, a total dust mass of $\sim 2\times 10^9\,{\rm M_\odot}$, and a dust mass fraction of $\sim 3\times 10^{-6}$. The typical thermal sputtering timescales within $\sim 100\,{\rm kpc}$ are around $\sim 10\,{\rm Myr}$, and increase towards the outer parts of the cluster to $\sim 10^3\,{\rm Myr}$ at a cluster-centric distance of $1\,{\rm Mpc}$. The condensation of gas phase metals into dust grains reduces high temperature metal-line cooling, but also leads to additional dust infrared cooling. The additional infrared cooling changes the overall cooling rate in the outer parts of the cluster, beyond $\sim 1\,{\rm Mpc}$, by factors of a few. This results in noticeable changes of the entropy, temperature, and density profiles of cluster gas once dust formation is included. The emitted dust infrared emission due to dust cooling is consistent with observational constraints.Comment: 14 pages, 10 figures. MNRAS accepte

Advances in Computational Techniques to Study GPCR-Ligand Recognition

G-protein-coupled receptors (GPCRs) are among the most intensely investigated drug targets. The recent revolutions in protein engineering and molecular modeling algorithms have overturned the research paradigm in the GPCR field. While the numerous ligand-bound X-ray structures determined have provided invaluable insights into GPCR structure and function, the development of algorithms exploiting graphics processing units (GPUs) has made the simulation of GPCRs in explicit lipid-water environments feasible within reasonable computation times. In this review we present a survey of the recent advances in structure-based drug design approaches with a particular emphasis on the elucidation of the ligand recognition process in class A GPCRs by means of membrane molecular dynamics (MD) simulations

Morphology Choice Affects the Evolution of Affordance Detection in Robots

A vital component of intelligent action is affordance detection: understanding what actions external objects afford the viewer. This requires the agent to understand the physical nature of the object being viewed, its own physical nature, and the potential relationships possible when they interact. Although robotics researchers have investigated affordance detection, the way in which the morphology of the robot facilitates, obstructs, or otherwise influences the robot’s ability to detect affordances has yet to be studied. We do so here and find that a robot with an appropriate morphology can evolve to predict whether it will fit through an aperture with just minimal tactile feedback. We also find that some robot morphologies facilitate the evolution of more accurate affordance detection, while others do not if all have the same evolutionary optimization budget. This work demonstrates that sensation, thought, and action are necessary but not sufficient for understanding how affordance detection may evolve in organisms or robots: morphology must also be taken into account. It also suggests that, in the future, we may optimize morphology along with control in order to facilitate affordance detection in robots, and thus improve their reliable and safe action in the world

The current status of pharmacotherapy for the treatment of Parkinson's disease: transition from single-target to multitarget therapy

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons. Motor features such as tremor, rigidity, bradykinesia and postural instability are common traits of PD. Current treatment options provide symptomatic relief to the condition but are unable to reverse disease progression. The conventional single-target therapeutic approach might not always induce the desired effect owing to the multifactorial nature of PD. Hence, multitarget strategies have been proposed to simultaneously target multiple proteins involved in the development of PD. Herein, we provide an overview of the pathogenesis of PD and the current pharmacotherapies. Furthermore, rationales and examples of multitarget approaches that have been tested in preclinical trials for the treatment of PD are also discussed

Targeting Protein Kinase CK1\u3b4 with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

Riluzole, approved by the US Food and Drug Administration (FDA) in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, whose mechanism of action is still obscure, mitigates progression of the illness, but unfortunately with only limited improvements. Herein we report the first demonstration, using a combination of computational and in vitro studies, that riluzole is an ATP-competitive inhibitor of the protein kinase CK1 isoform\u2005\u3b4, with an IC50 value of 16.1\u2005\u3bcm. This allows us to rewrite its possible molecular mechanism of action in the treatment of ALS. The inhibition of CK1\u3b4 catalytic activity indeed links the two main pathological hallmarks of ALS: transactive response DNA-binding protein of 43\u2005kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by the loss of expression of glial excitatory amino acid transporter-2 (EAAT2)

The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?

Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease

¿Qué actualizaciones existen a diciembre de 2021 acerca de la eficacia de dapagliflozina en el tratamiento de pacientes no diabéticos con IC con FEVI reducida?

Maite Inthamoussu: Facultad de Medicina, Universidad de la República. Montevideo, Uruguay -- Federico Garafoni: Facultad de Medicina, Universidad de la República. Montevideo, Uruguay -- Stephanie Viroga: Facultad de Medicina, Universidad de la República. Montevideo, Uruguay -- Noelia Speranza: Facultad de Medicina, Universidad de la República. Montevideo, Urugua