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by Keyword: d-1

Matera, Carlo, Calvé, Pablo, Casadó-Anguera, Verònica, Sortino, Rosalba, Gomila, Alexandre MJ., Moreno, Estefanía, Gener, Thomas, Delgado-Sallent, Cristina, Nebot, Pau, Costazza, Davide, Conde-Berriozabal, Sara, Masana, Mercè, Hernando, Jordi, Casadó, Vicent, Puig, MVictoria, Gorostiza, Pau, (2022). Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals International Journal Of Molecular Sciences 23, 10114

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.

JTD Keywords: behavior, brainwave, d-1, dopamine, gpcr, in vivo electrophysiology, inhibitors, optogenetics, optopharmacology, photochromism, photopharmacology, photoswitch, stimulation, zebrafish, Azobenzene, Receptors


Monteil, V, Eaton, B, Postnikova, E, Murphy, M, Braunsfeld, B, Crozier, I, Kricek, F, Niederhofer, J, Schwarzbock, A, Breid, H, Devignot, S, Klingstrom, J, Thalin, C, Kellner, MJ, Christ, W, Havervall, S, Mereiter, S, Knapp, S, Jimenez, AS, Bugajska-Schretter, A, Dohnal, A, Ruf, C, Gugenberger, R, Hagelkruys, A, Montserrat, N, Kozieradzki, I, Ali, OH, Stadlmann, J, Holbrook, MR, Schmaljohn, C, Oostenbrink, C, Shoemaker, RH, Mirazimi, A, Wirnsberger, G, Penninger, JM, (2022). Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants Embo Molecular Medicine 14, e15230

The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here, we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by all current VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

JTD Keywords: Clinical trial, Converting enzyme 2, Covid-19, Spike, Treatment, Vaccine


Rizzello, L, De Matteis, V, (2022). Identification of SARS-CoV-2 by Gold Nanoparticles Biocell 46, 2369-2380

The SARS-CoV-2 outbreaks highlighted the need for effective, reliable, fast, easy-to-do and cheap diagnostics procedures. We pragmatically experienced that an early positive-case detection, inevitably coupled with a mass vaccination campaign, is a milestone to control the COVID-19 pandemic. Gold nanoparticles (AuNPs) can indeed play a crucial role in this context, as their physicochemical, optics and electronics properties are being extensively used in photothermal therapy (PTT), radiation therapy (RT), drug delivery and diagnostic. AuNPs can be synthesized by several approaches to obtain different sizes and shapes that can be easily functionalized with many kinds of molecules such as antibodies, proteins, probes, and lipids. In addition, AuNPs showed high biocompatibility making them useful tool in medicine field. We thus reviewed here the most relevant evidence on AuNPs as effective way to detect the presence of SARS-CoV-2 antigens. We trust future diagnostic efforts must take this 'old-fashioned' nanotechnology tool into consideration for the development and commercialization of reliable and feasible detection kits.

JTD Keywords: Aggregation, Antibodies, Assay, Covid-19, Diagnosis, Enhanced raman-scattering, Gold nanoparticles, Immunoassay, Pandemic disease, Physicochemical properties, Rapid detection, Sars-cov-2, Sensors, Surface-plasmon resonance, Therapy


Garreta E, Prado P, Stanifer ML, Monteil V, Marco A, Ullate-Agote A, Moya-Rull D, Vilas-Zornoza A, Tarantino C, Romero JP, Jonsson G, Oria R, Leopoldi A, Hagelkruys A, Gallo M, González F, Domingo-Pedrol P, Gavaldà A, Del Pozo CH, Hasan Ali O, Ventura-Aguiar P, Campistol JM, Prosper F, Mirazimi A, Boulant S, Penninger JM, Montserrat N, (2022). A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells Cell Metabolism 34, 857-873

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

JTD Keywords: complications, coronavirus, cultured-cells, disease, distal tubule, mouse, protein, reveals, spike, Ace2, Angiotensin-converting enzyme 2, Angiotensin-converting enzyme-2, Covid-19, Diabetes 2, Human kidney organoids, Sars-cov-2


Gawish R, Starkl P, Pimenov L, Hladik A, Lakovits K, Oberndorfer F, Cronin SJF, Ohradanova-Repic A, Wirnsberger G, Agerer B, Endler L, Capraz T, Perthold JW, Cikes D, Koglgruber R, Hagelkruys A, Montserrat N, Mirazimi A, Boon L, Stockinger H, Bergthaler A, Oostenbrink C, Penninger JM, Knapp S, (2022). ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFNy-driven immunopathology Elife 11, e74623

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al.

JTD Keywords: covid-19 mouse model, covid-19 therapy, cytokine storm, mavie16, mouse, program, recombinant soluble ace2, tmprss2, Adaptive immunity, Angiotensin converting enzyme 2, Angiotensin-converting enzyme 2, Animal, Animal cell, Animal experiment, Animal model, Animal tissue, Animals, Apoptosis, Article, Bagg albino mouse, Breathing rate, Bronchoalveolar lavage fluid, C57bl mouse, Cell composition, Cell infiltration, Controlled study, Coronavirus disease 2019, Coronavirus spike glycoprotein, Covid-19, Cytokeratin 18, Cytokine production, Dipeptidyl carboxypeptidase, Disease model, Disease models, animal, Disease severity, Drosophila-melanogaster, Enzyme linked immunosorbent assay, Expression vector, Flow cytometry, Gamma interferon, Gene editing, Gene expression, Gene mutation, Genetic engineering, Genetics, Glycosylation, High mobility group b1 protein, Histology, Histopathology, Immune response, Immunocompetent cell, Immunology, Immunopathology, Interferon-gamma, Interleukin 2, Metabolism, Mice, inbred balb c, Mice, inbred c57bl, Mouse-adapted sars-cov-2, Myeloperoxidase, Neuropilin 1, Nonhuman, Nucleocapsid protein, Pathogenicity, Peptidyl-dipeptidase a, Pyroptosis, Renin angiotensin aldosterone system, Rna extraction, Rna isolation, Sars-cov-2, Severe acute respiratory syndrome coronavirus 2, Spike glycoprotein, coronavirus, T lymphocyte activation, Trabecular meshwork, Tumor necrosis factor, Virology, Virus load, Virus replication, Virus transmission, Virus virulence


Pérez-López B, Mir M, (2021). Commercialized diagnostic technologies to combat SARS-CoV2: Advantages and disadvantages Talanta 225,

© 2020 Elsevier B.V. The current situation of the Covid-19 pandemic is indicated by a huge number of infections, high lethality, and rapid spread. These circumstances have stopped the activity of almost the entire world, affecting severely the global economy. A rapid diagnosis of the Covid-19 and a generalized testing protocol is essential to fight against the pandemic and to maintain health control in the population. Principal biosensing and diagnostic technologies used to monitor the spread of the SARS-CoV-2 are based on specific genomic analysis and rapid immune tests, both with different technology platforms that include advantages and disadvantages. Most of the in vitro diagnosis companies are competing to be the first on validating under different regulations their technology for placing their platforms for Covid-19 detection as fast as possible in this big international market. A comprehensive analysis of the commercialized technologies for the genomic based sensing and the antibody/antigen detection methods devoted to Covid-19 diagnosis is described in this review, which have been detailed and listed under different countries regulations. The effectiveness of the described technologies throughout the different stages of the disease and a critical comparison of the emerging technologies in the market to counterattack this pandemic have been discussed.

JTD Keywords: covid-19, in vitro diagnosis (ivd), lateral flow immunoassay, point of care (poc), reverse transcriptase polymerase chain reaction (rt-pcr), sars-cov-2, Covid-19, In vitro diagnosis (ivd), Lateral flow immunoassay, Point of care (poc), Reverse transcriptase polymerase chain reaction (rt-pcr), Sars-cov-2


Monteil V, Dyczynski M, Lauschke VM, Kwon H, Wirnsberger G, Youhanna S, Zhang H, Slutsky AS, Hurtado del Pozo C, Horn M, Montserrat N, Penninger JM, Mirazimi A, (2021). Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection Embo Molecular Medicine 13,

© 2020 The Authors. Published under the terms of the CC BY 4.0 license There is a critical need for safe and effective drugs for COVID-19. Only remdesivir has received authorization for COVID-19 and has been shown to improve outcomes but not decrease mortality. However, the dose of remdesivir is limited by hepatic and kidney toxicity. ACE2 is the critical cell surface receptor for SARS-CoV-2. Here, we investigated additive effect of combination therapy using remdesivir with recombinant soluble ACE2 (high/low dose) on Vero E6 and kidney organoids, targeting two different modalities of SARS-CoV-2 life cycle: cell entry via its receptor ACE2 and intracellular viral RNA replication. This combination treatment markedly improved their therapeutic windows against SARS-CoV-2 in both models. By using single amino-acid resolution screening in haploid ES cells, we report a singular critical pathway required for remdesivir toxicity, namely, Adenylate Kinase 2. The data provided here demonstrate that combining two therapeutic modalities with different targets, common strategy in HIV treatment, exhibit strong additive effects at sub-toxic concentrations. Our data lay the groundwork for the study of combinatorial regimens in future COVID-19 clinical trials.

JTD Keywords: clinical trial, combination therapy, covid-19, Clinical trial, Combination therapy, Covid-19, Treatment


Monteil, Vanessa, Kwon, Hyesoo, Prado, Patricia, Hagelkrüys, Astrid, Wimmer, Reiner A., Stahl, Martin, Leopoldi, Alexandra, Garreta, Elena, Hurtado Del Pozo, Carmen, Prosper, Felipe, Romero, Juan Pablo, Wirnsberger, Gerald, Zhang, Haibo, Slutsky, Arthur S., Conder, Ryan, Montserrat, Nuria, Mirazimi, Ali, Penninger, Josef M., (2020). Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2 Cell 181, (4), 905-913.e7

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.

JTD Keywords: COVID-19, Angiotensin converting enzyme 2, Blood vessels, Human organoids, Kidney, Severe acute respiratory syndrome coronavirus, Spike glycoproteins, Treatment