358 results on '"Molteni, R"'
Search Results
102. Oxygen Delivery to the Brain Before and After Birth
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Jones, M. D., primary, Rosenberg, A. A., additional, Simmons, M. A., additional, Molteni, R. A., additional, Koehler, R. C., additional, and Traystman, R. J., additional
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- 1982
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103. Luminescence of ZnIn2Se4 crystals
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Grilli, E., primary, Guzzi, M., additional, and Molteni, R., additional
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- 1976
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104. Response of cerebral blood flow to changes in PCO2 in fetal, newborn, and adult sheep
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Rosenberg, A. A., primary, Jones, M. D., additional, Traystman, R. J., additional, Simmons, M. A., additional, and Molteni, R. A., additional
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- 1982
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- View/download PDF
105. Oxygen Delivery to the Brain Before and After Birth
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JONES, M. D., primary, ROSENBERG, A. A., additional, SIMMONS, M. A., additional, MOLTENI, R. A., additional, KOEHLER, R. C., additional, TRAYSTMAN, R. J., additional, and Marx, Gertie F., additional
- Published
- 1983
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106. Regulation of FGF-1 and FGF-2 gene expression in primary culture of rat astrocytes following beta adrenergic receptor activation
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Molteni, R., Fumagalli, F., Lovati, E., and Racagni, G.
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- 1995
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107. Regulatory mechanisms of neurotrophic factor gene expression in the central nervous system
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Riva, M. A., Molteni, R., Lovati, E., and Fumagalli, F.
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- 1995
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108. Regulation of NMDA receptor subunit gene expression in rat cerebellar granule cells
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Tascedda, F., Blom, J. M. C., Molteni, R., and Racagni, G.
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- 1995
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109. Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production
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Eleonora Cantoni, Ivan Merelli, Davide Stefanoni, Alessandro Tomelleri, Corrado Campochiaro, Vito Giordano, Maddalena Panigada, Elena M Baldissera, Laura Merlo Pich, Valentina Natoli, Athanasios Ziogas, Jorge Domínguez-Andrés, Giacomo De Luca, Davide Mazza, Samuel Zambrano, Daniela Gnani, Marina Ferrarini, Elisabetta Ferrero, Alessandra Agresti, Barbara Vergani, Biagio Eugenio Leone, Simone Cenci, Angelo Ravelli, Marco Matucci-Cerinic, Angelo D’Alessandro, Leo A B Joosten, Lorenzo Dagna, Mihai G Netea, Raffaella Molteni, Giulio Cavalli, Cantoni, E, Merelli, I, Stefanoni, D, Tomelleri, A, Campochiaro, C, Giordano, V, Panigada, M, Baldissera, E, Merlo Pich, L, Natoli, V, Ziogas, A, Domínguez-Andrés, J, De Luca, G, Mazza, D, Zambrano, S, Gnani, D, Ferrarini, M, Ferrero, E, Agresti, A, Vergani, B, Leone, B, Cenci, S, Ravelli, A, Matucci-Cerinic, M, D'Alessandro, A, Joosten, L, Dagna, L, Netea, M, Molteni, R, and Cavalli, G
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IL-6 ,trained immunity ,Rheumatology ,immunometabolism ,Pharmacology (medical) ,monocyte/macrophage ,epigenetic - Abstract
ObjectiveTrained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production.MethodsMonocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes.ResultsGCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production.ConclusionsMyelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.
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- 2023
110. Immunometabolic activation of macrophages leads to cytokine production in the pathogenesis of KRAS-mutated histiocytosis
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Elisabetta Ferrero, Antonello Villa, Davide Stefanoni, Travis Nemkov, Angelo D’Alessandro, Isak Tengesdal, Daniela Belloni, Raffaella Molteni, Barbara Vergani, Giacomo De Luca, Greta Grassini, Maria Giulia Cangi, Lorenzo Dagna, Claudio Doglioni, Giulio Cavalli, Marina Ferrarini, Ferrero, Elisabetta, Villa, Antonello, Stefanoni, Davide, Nemkov, Travi, D'Alessandro, Angelo, Tengesdal, Isak, Belloni, Daniela, Molteni, Raffaella, Vergani, Barbara, De Luca, Giacomo, Grassini, Greta, Cangi, Maria Giulia, Dagna, Lorenzo, Doglioni, Claudio, Cavalli, Giulio, Ferrarini, Marina, Ferrero, E, Villa, A, Stefanoni, D, Nemkov, T, D'Alessandro, A, Tengesdal, I, Belloni, D, Molteni, R, Vergani, B, De Luca, G, Grassini, G, Giulia Cangi, M, Dagna, L, Doglioni, C, Cavalli, G, and Ferrarini, M
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Proto-Oncogene Proteins p21(ras) ,Rheumatology ,3D culture, histiocytosis tissue, KRAS, immunometabolism, macrophage activation ,Macrophages ,Mutation ,MED/06 - ONCOLOGIA MEDICA ,Cytokines ,Gene Expression ,Humans ,Pharmacology (medical) ,Histiocytosis - Published
- 2021
111. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity
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Davide Stefanoni, Silvia Giugliano, Eleonora Cantoni, Giulio Cavalli, Elan Z. Eisenmensser, Isak W. Tengesdal, Kiki Schraa, Lorenzo Dagna, Mihai G. Netea, Laura Cassina, Angelo D'Alessandro, Travis Nemkov, Leo A. B. Joosten, Eric M. Pietras, Jorge Domínguez-Andrés, Mark S. Gresnigt, Rob J.W. Arts, Taylor S. Mills, Raffaella Molteni, Alessandra Boletta, Charles A. Dinarello, Cavalli, Giulio, Tengesdal, I W, Gresnigt, M, Nemkov, T, Arts, R J W, Dominguez-Andres, J, Molteni, R, Stefanoni, D, Cantoni, E, Cassina, L, Giugliano, S, Schraa, K, Mills, T, Pietras, E M, Eisenmensser, E Z, Dagna, L, Boletta, A, D'Alessandro, A, Joosten, L A B, Netea, M G, and Dinarello, C A
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0301 basic medicine ,Male ,Neutrophils ,medicine.medical_treatment ,immunometabolism ,Anti-Inflammatory Agents ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Epigenesis, Genetic ,trained immunity ,0302 clinical medicine ,Medicine ,lcsh:QH301-705.5 ,innate immunity ,biology ,cell energy metabolism ,Candidiasis ,Interleukin ,3. Good health ,Histone ,Cytokine ,regulatory cytokine ,Host-Pathogen Interactions ,medicine.symptom ,Glycolysis ,medicine.drug_class ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Anti-inflammatory ,IL-1 family ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Immunity ,Animals ,Humans ,Epigenetics ,Innate immune system ,epigenetics ,business.industry ,cytokines ,infection ,Immunity, Innate ,Mice, Inbred C57BL ,030104 developmental biology ,lcsh:Biology (General) ,inflammation ,Immunology ,biology.protein ,business ,030217 neurology & neurosurgery ,Interleukin-1 - Abstract
Summary Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.
- Published
- 2021
112. PQM130, a novel feruloyl-donepezil hybrid compound, effectively ameliorates the cognitive impairments and pathology in a mouse model of Alzheimer's disease
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Claudio Viegas, Giulia Sita, Andrea Tarozzi, Letizia Pruccoli, Ariele Faria dos Santos, Agnese Graziosi, Maria Serena Paladini, Gloria Ravegnini, Fabiana Morroni, Raffaella Molteni, Patrizia Hrelia, Kris Simone Tranches Dias, Ihosvany Camps, Morroni F., Sita G., Graziosi A., Ravegnini G., Molteni R., Paladini M.S., Dias K.S.T., Dos Santos A.F., Viegas C., Camps I., Pruccoli L., Tarozzi A., and Hrelia P.
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0301 basic medicine ,Feruloyl-donepezil hybrid ,medicine.drug_class ,Pharmacology ,medicine.disease_cause ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,GSK-3 ,medicine ,Pharmacology (medical) ,Donepezil ,Multitarget ligand ,Neuroinflammation ,Original Research ,Amyloid-β oligomer ,business.industry ,Drug discovery ,Neurodegeneration ,lcsh:RM1-950 ,Neurotoxicity ,apoptosis ,Apoptosi ,Alzheimer's disease ,medicine.disease ,amyloid-β oligomers ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,Acetylcholinesterase inhibitor ,Oxidative stress ,030220 oncology & carcinogenesis ,business ,Alzheimer’s disease ,medicine.drug - Abstract
Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl–donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ1-42 oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5–1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal–regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development.
- Published
- 2019
113. Evaluation of effects exercised on the antibody response by a glucan extracted from C. Albicans, administered by parenteral route
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De Bernardi, M., Feletti, F., Contos, S., Germogli, R., Mattaboni, P., and Molteni, R.
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- 1992
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114. International union of basic and clinical pharmacology CIV: The neurobiology of treatment-resistant depression: From antidepressant classifications to novel pharmacological targets
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Francesca Calabrese, Marco A. Riva, Giorgio Racagni, Markus Dold, Julien Mendlewicz, Filippo Drago, Filippo Caraci, Raffaella Molteni, Chiara Fabbri, Siegfried Kasper, Gian Marco Leggio, Lucie Bartova, Caraci F., Calabrese F., Molteni R., Bartova L., Dold M., Leggio G.M., Fabbri C., Mendlewicz J., Racagni G., Kasper S., Riva M.A., and Drago F.
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neurotrophins ,law.invention ,Depressive Disorder, Treatment-Resistant ,03 medical and health sciences ,0302 clinical medicine ,law ,Drug Discovery ,Animals ,Humans ,Medicine ,antidepressant drugs ,depression, antidepressant drugs, treatment-resistance, neurotrophins, classification ,Pharmacology ,treatment-resistance ,Clinical pharmacology ,Animal ,business.industry ,Drug discovery ,Cognition ,medicine.disease ,Antidepressive Agents ,030227 psychiatry ,Phenotype ,Drug development ,Targeted drug delivery ,classification ,depression ,Antidepressive Agent ,Molecular Medicine ,Antidepressant ,Major depressive disorder ,business ,Neuroscience ,Treatment-resistant depression ,030217 neurology & neurosurgery ,Human - Abstract
Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.
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- 2018
115. A Microfluidic Human Model of Blood–Brain Barrier Employing Primary Human Astrocytes
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Lorenzo Bello, Marco Rasile, Davide Pozzi, Eliana Lauranzano, Ruggero Pardi, Lorena Passoni, Michela Matteoli, Raffaella Molteni, Marco Pizzocri, Elena Campo, Ana Ruiz‐Moreno, Lauranzano, E., Campo, E., Rasile, M., Molteni, R., Pizzocri, M., Passoni, L., Bello, L., Pozzi, D., Pardi, R., Matteoli, M., and Ruiz-Moreno, A.
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Primary Cell Culture ,Models, Neurological ,Central nervous system ,microfluidics ,T cells ,Models, Cardiovascular ,Biomedical Engineering ,Microfluidic Analytical Techniques ,Biology ,blood–brain barrier ,Blood–brain barrier ,cytokines ,General Biochemistry, Genetics and Molecular Biology ,Biomaterials ,medicine.anatomical_structure ,Drug development ,Blood-Brain Barrier ,Astrocytes ,Parenchyma ,medicine ,Humans ,Neuroscience ,Homeostasis - Abstract
The neurovascular unit (NVU) is the most important biological barrier between vascular districts and central nervous system (CNS) parenchyma, which maintains brain homeostasis, protects the CNS from pathogens penetration, and mediates neuroimmune communication. T lymphocytes migration across the blood-brain barrier is heavily affected in different brain diseases, representing a major target for novel drug development. In vitro models of NVU could represent a primary tool to investigate the molecular events occurring at this interface. To move toward the establishment of personalized therapies, a patient-related NVU-model is set, incorporating human primary astrocytes integrated into a microfluidic platform. The model is morphologically and functionally characterized, proving to be an advantageous tool to investigate human T lymphocytes transmigration and thus the efficacy of potential novel drugs affecting this process.
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- 2019
116. Microfluidics for in vitro biomimetic shear stress-dependent leukocyte adhesion assays
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Raffaella Molteni, Gabriele Dubini, Elena Bianchi, Ruggero Pardi, Bianchi, E, Molteni, R, Pardi, Ruggero, and Dubini, G.
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Microfluidics ,Integrin ,Biomedical Engineering ,Biophysics ,High-throughput ,Cell Communication ,Mechanotransduction, Cellular ,Models, Biological ,Shear-stress dependent cellular in vitro assay ,Chemokine receptor ,Stress, Physiological ,In vivo ,Leukocyte adhesion and transmigration ,Parallel-plate flow chambers ,Cell Adhesion ,Leukocytes ,Shear stress ,Animals ,Humans ,Leukocyte Rolling ,Orthopedics and Sports Medicine ,Mechanotransduction ,biology ,Chemistry ,Rehabilitation ,Endothelial Cells ,Adhesion ,Microfluidic Analytical Techniques ,Leukocyte extravasation ,Cell biology ,Selectins ,biology.protein ,Shear Strength ,Shear flow - Abstract
Recruitment of leukocytes from blood to tissues is a multi-step process playing a major role in the activation of inflammatory responses. Tethering and rolling of leukocytes along the vessel wall, followed by arrest and transmigration through the endothelium result from chemoattractant-dependent signals, inducing adhesive and migratory events. Shear forces exerted by the blood flow on leukocytes induce rolling via selectin-mediated interactions with endothelial cells and increase the probability of leukocytes to engage their chemokine receptors, facilitating integrin activation and consequent arrest. Flow-derived shear forces generate mechanical stimuli concurring with biochemical signals in the modulation of leukocyte-endothelial cell interactions. In the last few years, a host of in vitro studies have clarified the biochemical adhesion cascade and the role of shear stress in leukocyte extravasation. The limitation of the static environment in Boyden devices has been overcome both by the use of parallel-plate flow chambers and by custom models mimicking the in vivo conditions, along with widespread microfluidic approaches to in vitro modeling. These devices create an in vitro biomimetic environment where the multi-step transmigration process can be imaged and quantified under mechanical and biochemical controlled conditions, including fluid dynamic settings, channel design, materials and surface coatings. This paper reviews the technological solutions recently proposed to model, observe and quantify leukocyte adhesion behavior under shear flow, with a final survey of high-throughput solutions featuring multiple parallel assays as well as thorough and time-saving statistical interpretation of the experimental results. (c) 2012 Elsevier Ltd. All rights reserved.
- Published
- 2013
117. Mode of action of agomelatine: Synergy between melatonergic and 5-HT2C receptors
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G. Racagni, D. Tardito, M.A. Riva, R. Molteni, A. Mallei, L. Musazzi, F. Calabrese, M. Popoli, Racagni, G, Tardito, D, Riva, M, Molteni, R, Mallei, A, Musazzi, L, Calabrese, F, and Popoli, M
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agomelatine - Published
- 2012
118. Mode of action of agomelatine: Synergy between melatonergic and 5-HT(2C) receptors
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Giorgio Racagni, Laura Musazzi, Marco A. Riva, Raffaella Molteni, Francesca Calabrese, Maurizio Popoli, Daniela Tardito, Racagni, G, Riva, M, Molteni, R, Musazzi, L, Calabrese, F, Popoli, M, and Tardito, D
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Receptors, Melatonin ,Melatonergic receptor ,Pharmacology ,Acetamides ,Receptor, Serotonin, 5-HT2C ,Animals ,Humans ,Medicine ,Agomelatine ,Serotonergic receptor ,Circadian rhythm ,Receptor ,Mode of action ,Biological Psychiatry ,business.industry ,Depression ,Antidepressive Agents ,Melatonergic ,Psychiatry and Mental health ,Serotonin 5-HT2 Receptor Antagonists ,Serotonin ,business ,Neuroscience ,medicine.drug - Abstract
Objectives. The association between depression and circadian rhythm disturbances is well established and successful treatment of depressed patients is accompanied by restoration of circadian rhythms. The new antidepressant agomelatine is an agonist of melatonergic MT(1)/MT(2) receptors as well as an antagonist of serotonergic 5-HT(2C) receptors. Animal studies showed that agomelatine resynchronizes disturbed circadian rhythms and reduces depression-like behaviour. Methods. This review analyzes results from different experimental studies. Results. Recent data on the effects of agomelatine on cellular processes involved in antidepressant mechanisms have shown that the drug is able to increase the expression of brain-derived neurotrophic factor in prefrontal cortex and hippocampus, as well as the expression of activity-regulated cytoskeleton associated protein (Arc) in the prefrontal cortex. In line with this, prolonged treatment with agomelatine increases neurogenesis within the hippocampus, particularly via enhancement of neuronal cell survival. Agomelatine attenuates stress-induced glutamate release in the prefrontal/frontal cortex. Treatment with 5-HT(2C) antagonists or melatonin alone failed to reproduce these effects. Conclusions. The unique mode of action of agomelatine may improve the management of major depression by counteracting the pathogenesis of depression at cellular level, thereby relieving the symptoms of depression. These effects are suggested to be due to a synergistic action on MT(1)/MT(2) and 5-HT(2C) receptors.
- Published
- 2011
119. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses
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Maria Gabriela Nielsen, Caterina Giovannini, Mariacarla Ventriglia, Marco A. Riva, Luciana Rillosi, Roberta Zanardini, Massimo Gennarelli, Anna Placentino, Luisella Bocchio-Chiavetto, Raffaella Molteni, Vincenzo Bagnardi, Bocchio Chiavetto, L, Bagnardi, V, Zanardini, R, Molteni, R, Gabriela Nielsen, M, Placentino, A, Giovannini, C, Rillosi, L, Ventriglia, M, Riva, M, and Gennarelli, M
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Adult ,Male ,medicine.medical_specialty ,Young Adult ,MBDNF ,Internal medicine ,medicine ,Major depression ,Humans ,Meta-analysi ,Young adult ,Sex Distribution ,Biological Psychiatry ,Depression (differential diagnoses) ,Aged ,Brain-derived neurotrophic factor ,Depressive Disorder, Major ,biology ,Brain-Derived Neurotrophic Factor ,Significant difference ,Gender ,Plasma levels ,Middle Aged ,Psychiatry and Mental health ,Endocrinology ,BDNF ,nervous system ,biology.protein ,Female ,Psychology ,Neurotrophin - Abstract
Objectives. Alterations of BDNF signalling in major depression (MD) are supported by studies demonstrating decreased levels of the neurotrophin serum and plasma content in MD patients. We conducted a replication study and we performed two meta-analyses on studies analysing serum and plasma BDNF levels in MD patients. Methods. The samples were composed by 489 patients/483 controls for the meta-analysis on serum and by 161 patients/211 controls for that on plasma levels. We performed also subgroup analyses to examine whether the decrease in BDNF levels in MD was influenced by gender. Results. In the replication study we found decreased serum BDNF levels in MD patients (P
- Published
- 2010
120. Beta-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation
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Monica Fabbri, Carolina Lage Crespo, Raffaella Molteni, Ruggero Pardi, Fritz Krombach, Carlo Laudanna, Ronen Alon, Valentin Grabovsky, Sara W. Feigelson, Christian Moser, Molteni, R, Crespo, Cl, Feigelson, S, Moser, C, Fabbri, M, Grabovsky, V, Krombach, F, Laudanna, C, Alon, R, and Pardi, Ruggero
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Keratinocytes ,Male ,DNA, Complementary ,Arrestins ,Recombinant Fusion Proteins ,Immunology ,Integrin ,Vascular Cell Adhesion Molecule-1 ,Signal transduction ,Biology ,Integrin alpha4beta1 ,Biochemistry ,Receptors, Interleukin-8B ,Chemokine receptor ,Mice ,Venules ,Cell Line, Tumor ,Cell Adhesion ,Leukocytes ,Animals ,Leukocyte Rolling ,Myeloid Cells ,RNA, Small Interfering ,Cell adhesion ,beta-Arrestins ,Mice, Knockout ,Beta-Arrestins ,Cell adhesion molecule ,Cell Biology ,Hematology ,Adhesion ,Leukocyte extravasation ,beta-Arrestin 2 ,Extravasation ,Cell biology ,Rats ,adhesion ,Leukemia, Basophilic, Acute ,biology.protein ,Shear Strength ,leukocytes - Abstract
Leukocyte extravasation involves interdependent signaling pathways underlying the complex dynamics of firm adhesion, crawling, and diapedesis. While signal transduction by agonist-bound chemokine receptors plays a central role in the above responses, it is unclear how it contributes to the sustained and concurrent nature of such responses, given the rapid kinetics of chemokine-induced trimeric G protein coupling and homologous desensitization. Our findings unveil a novel role of beta-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in beta-arrestin knockout mice with in vitro studies in engineered cellular models, we show that membrane-recruited beta-arrestin 2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both beta(1) and beta(2) integrins. While both beta-arrestin isoforms are required for rapid keratinocyte-derived chemokine (KC)-induced arrest onto limiting amounts of vascular cell adhesion molecule-1 (VCAM-1), adhesion strengthening under shear is selectively dependent on beta-arrestin 2. The latter synergizes with phospholipase C in promoting activation of Rap1A and B, both of which co-operatively control subsecond adhesion as well as postarrest adhesion stabilization. Thus, receptor-induced Galpha(i) and beta-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation.
- Published
- 2009
121. Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions
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Raffaella Molteni, Giorgio Racagni, Fabio Fumagalli, Enrico Tongiorgi, Francesca Calabrese, Marco A. Riva, Francesco Bedogni, Molteni, R, Calabrese, F, Bedogni, F, Tongiorgi, Enrico, Fumagalli, F, Racagni, G, and Riva, M. A.
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Male ,Cytoplasm ,Dopamine ,Hippocampus ,Substantia nigra ,Striatum ,Nucleus accumbens ,Rats, Sprague-Dawley ,Fluoxetine ,Neuroplasticity ,medicine ,Animals ,Pharmacology (medical) ,RNA, Messenger ,Pharmacology ,biology ,Brain-Derived Neurotrophic Factor ,Dopaminergic ,Brain ,Rats ,Up-Regulation ,Ventral tegmental area ,Psychiatry and Mental health ,medicine.anatomical_structure ,nervous system ,Gene Expression Regulation ,biology.protein ,Psychology ,Neuroscience ,Neurotrophin - Abstract
During the last few years several studies have highlighted the possibility that major depression can be characterized by a general reduction in brain plasticity and an increased vulnerability under challenging situations. Such dysfunction may be the consequence of reduced expression and function of proteins important for neuroplasticity such as brain-derived neurotrophic factor (BDNF). On this basis, by using a sensitive non-radioactive in-situ hybridization, we evaluated the effects of a chronic treatment with fluoxetine on BDNF expression within rat dopaminergic regions. In fact, besides the well-established role of the hippocampus, increasing evidence indicates that other brain regions may be involved in the pathophysiology of depression and consequently be relevant for the therapeutic action of antidepressant drugs. Our results indicate that 3 wk of fluoxetine administration up-regulates BDNF mRNA levels selectively within structures belonging to the meso-cortico-limbic pathway. The expression of the neurotrophin is significantly increased in the ventral tegmental area, prefrontal cortex, and shell region of the nucleus accumbens, whereas no changes were detected in the substantia nigra and striatum. Moreover, in agreement with previous studies, fluoxetine increased BDNF mRNA levels in the hippocampus, an effect that was limited to the cell bodies without any change in its dendritic targeting. These data show that chronic treatment with fluoxetine increases BDNF gene expression not only in limbic areas but also in dopaminergic regions, suggesting that such an effect may contribute to improve the function of the dopaminergic system in depressed subjects.
- Published
- 2005
122. Activity-based anorexia (ABA) model: Effects on brain neuroinflammation, redox balance and neuroplasticity during the acute phase.
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Spero V, Scherma M, D'Amelio S, Collu R, Dedoni S, Camoglio C, Siddi C, Fratta W, Molteni R, and Fadda P
- Abstract
Several evidences suggest that immuno-inflammatory responses are involved in the pathogenesis of anorexia nervosa (AN). Herein we investigate the possible alteration of key mediators of inflammation, redox balance, and neuroplasticity in the brain of rats showing an anorexic-like phenotype. We modeled AN in adolescent female rats using the activity-based anorexia (ABA) paradigm and measured gene expression levels of targets of interest in the prefrontal cortex (PFC) and dorsal hippocampus (DH). We observed reduced mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α, the inflammasome NLRP3, and the microglial marker CD11b in both PFC and DH of ABA animals. Conversely, the mRNA of IL-6, which acts as both a pro-inflammatory and anti-inflammatory cytokine, was increased. Moreover, we observed an overall upregulation of different antioxidant enzymes in PFC, while their profile was not affected or opposite in the DH, with the exception of MT1α. Interestingly, ABA animals showed elevated levels of the neuroplasticity marker BDNF in both PFC and DH. Our data indicate that ABA induction is associated with anatomical-specific cerebral alteration of mediators of neuroinflammation, oxidative balance and neuroplasticity. Although more research should be conducted, these results add important information about the role of these systems in the complex AN etiopathogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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123. Shadows of quantum machine learning.
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Jerbi S, Gyurik C, Marshall SC, Molteni R, and Dunjko V
- Abstract
Quantum machine learning is often highlighted as one of the most promising practical applications for which quantum computers could provide a computational advantage. However, a major obstacle to the widespread use of quantum machine learning models in practice is that these models, even once trained, still require access to a quantum computer in order to be evaluated on new data. To solve this issue, we introduce a class of quantum models where quantum resources are only required during training, while the deployment of the trained model is classical. Specifically, the training phase of our models ends with the generation of a 'shadow model' from which the classical deployment becomes possible. We prove that: (i) this class of models is universal for classically-deployed quantum machine learning; (ii) it does have restricted learning capacities compared to 'fully quantum' models, but nonetheless (iii) it achieves a provable learning advantage over fully classical learners, contingent on widely believed assumptions in complexity theory. These results provide compelling evidence that quantum machine learning can confer learning advantages across a substantially broader range of scenarios, where quantum computers are exclusively employed during the training phase. By enabling classical deployment, our approach facilitates the implementation of quantum machine learning models in various practical contexts., (© 2024. The Author(s).)
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- 2024
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124. TENT5C/FAM46C modulation in vivo reveals a trade-off between antibody secretion and tumor growth in multiple myeloma.
- Author
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Resnati M, Pennacchio S, Viviani L, Perini T, Materozzi M, Orfanelli U, Bordini J, Molteni R, Nuvolone M, Da Vià M, Lazzaroni F, Bolli N, Cenci S, and Milan E
- Subjects
- Humans, Animals, Mice, Multiple Myeloma pathology, Multiple Myeloma immunology, Multiple Myeloma metabolism
- Published
- 2024
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125. A novel chemically defined medium for the biotechnological and biomedical exploitation of the cell factory Leishmania tarentolae.
- Author
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Cattaneo GM, Varotto-Boccazzi I, Molteni R, Ronchetti F, Gabrieli P, Mendoza-Roldan JA, Otranto D, Montomoli E, Bandi C, and Epis S
- Subjects
- Biotechnology methods, Cell Culture Techniques methods, Animals, Leishmania genetics, Leishmania metabolism, Recombinant Proteins genetics, Recombinant Proteins metabolism, Culture Media chemistry
- Abstract
The development of media for cell culture is a major issue in the biopharmaceutical industry, for the production of therapeutics, immune-modulating molecules and protein antigens. Chemically defined media offer several advantages, as they are free of animal-derived components and guarantee high purity and a consistency in their composition. Microorganisms of the genus Leishmania represent a promising cellular platform for production of recombinant proteins, but their maintenance requires supplements of animal origin, such as hemin and fetal bovine serum. In the present study, three chemically defined media were assayed for culturing Leishmania tarentolae, using both a wild-type strain and a strain engineered to produce a viral antigen. Among the three media, Schneider's Drosophila Medium supplemented with Horseradish Peroxidase proved to be effective for the maintenance of L. tarentolae promastigotes, also allowing the heterologous protein production by the engineered strain. Finally, the engineered strain was maintained in culture up to the 12th week without antibiotic, revealing its capability to produce the recombinant protein in the absence of selective pressure., (© 2024. The Author(s).)
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- 2024
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126. New Findings on the Crystal Polymorphism of Imepitoin.
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Bruni G, Capsoni D, Pellegrini A, Altomare A, Coduri M, Ferrara C, Galinetto P, and Molteni R
- Abstract
Scientific and industrial reasons dictate the study of the solid state of imepitoin, a highly safe and tolerable anticonvulsant drug used in the therapy of epileptic dogs that was approved in the Europe Union in 2013. Our investigations allowed us to discover the existence of a new polymorph of imepitoin, which finds itself in a monotropic relationship with the crystalline form (polymorph I) already known and present on the market. This form (polymorph II), obtained by crystallization from xylene, remains metastable under ambient conditions for at least 1 year. Both solid forms were characterized by thermal (DSC and TGA), spectroscopic (FT-IR and Raman), microscopic (SEM and HSM), and diffractometric techniques. The thermodynamic relationship between the two polymorphs (monotropic) is such that it is not possible to study the melting of polymorph II, not even by adopting appropriate experimental strategies. Our measurements highlighted that the melting peak of imepitoin actually also includes an onset of melt decomposition. The ab initio structure solution, obtained from synchrotron X-ray powder diffraction data collected at room temperature, allowed us to determine the crystal structure of the new polymorph (II). It crystallizes in the monoclinic crystal structure, P2
1 / c space group (#14), with a = 14.8687(6) Å, b = 7.2434(2) Å, c = 12.5592(4) Å, β = 107.5586(8)°, V = 1289.61(8) Å3, and Z = 4.- Published
- 2024
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127. The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models.
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Bright Y, Maas DA, Verheij MMM, Paladini MS, Amatdjais-Groenen HIV, Molteni R, Riva MA, Martens GJM, and Homberg JR
- Subjects
- Rats, Mice, Animals, Apomorphine pharmacology, Apomorphine therapeutic use, Hydroxybenzoate Ethers therapeutic use, Disease Models, Animal, Cognition, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Schizophrenia chemically induced, Schizophrenia drug therapy
- Abstract
The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2024
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128. Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production.
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Cantoni E, Merelli I, Stefanoni D, Tomelleri A, Campochiaro C, Giordano V, Panigada M, Baldissera EM, Merlo Pich L, Natoli V, Ziogas A, Domínguez-Andrés J, De Luca G, Mazza D, Zambrano S, Gnani D, Ferrarini M, Ferrero E, Agresti A, Vergani B, Leone BE, Cenci S, Ravelli A, Matucci-Cerinic M, D'Alessandro A, Joosten LAB, Dagna L, Netea MG, Molteni R, and Cavalli G
- Subjects
- Humans, Monocytes metabolism, Trained Immunity, Inflammation, Cytokines, Giant Cell Arteritis pathology
- Abstract
Objective: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production., Methods: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes., Results: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production., Conclusions: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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129. Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression.
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Rossetti AC, Paladini MS, Brüning CA, Spero V, Cattaneo MG, Racagni G, Papp M, Riva MA, and Molteni R
- Subjects
- Animals, Rats, Male, Depression drug therapy, Depression etiology, Depression metabolism, Rats, Wistar, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Signal Transduction, Inflammation Mediators metabolism, Suppressor of Cytokine Signaling Proteins metabolism, Sucrose, Interleukin-6 genetics, Interleukin-6 metabolism, Depressive Disorder, Major drug therapy
- Abstract
Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine's therapeutic effects.
- Published
- 2022
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130. Altered responsiveness of the antioxidant system in chronically stressed animals: modulation by chronic lurasidone treatment.
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Spero V, Paladini MS, Brivio P, Riva MA, Calabrese F, and Molteni R
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- Animals, Antioxidants pharmacology, Brain metabolism, Brain-Derived Neurotrophic Factor metabolism, Humans, Male, Rats, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Lurasidone Hydrochloride pharmacology
- Abstract
Rationale: Although the occurrence of stressful events is very common during life, their impact may be different depending on the experience severity and duration. Specifically, acute challenges may trigger adaptive responses and even improve the individual's performance. However, such a physiological positive coping can only take place if the underlying molecular mechanisms are properly functioning. Indeed, if these systems are compromised by genetic factors or previous adverse conditions, the response set in motion by an acute challenge may be maladaptive and even cause the insurgence or the relapse of stress-related psychiatric disorders., Objectives: On these bases, we evaluated in the rat brain the role of the antioxidant component of the redox machinery on the acute stress responsiveness and its modulation by potential detrimental or beneficial events., Methods: The expression of several antioxidant enzymes was assessed in different brain areas of adult male rats exposed to acute stress 3 weeks after a chronic immobilization paradigm with or without a concomitant treatment with the antipsychotic lurasidone., Results: The acute challenge was able to trigger a marked antioxidant response that, despite the washout period, was impaired by the previous adverse experience and restored by lurasidone in an anatomical-specific manner., Conclusions: We found that a working antioxidant machinery takes part in acute stress response and may be differentially affected by other experiences. Given the essential role of stress responsiveness in almost every life process, the identification of the underlying mechanisms and their potential pharmacological modulation add further translational value to our data., (© 2022. The Author(s).)
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- 2022
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131. Prenatal Stress Impairs Spinal Cord Oligodendrocyte Maturation via BDNF Signaling in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.
- Author
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Paladini MS, Marangon D, Rossetti AC, Guidi A, Coppolino GT, Negri C, Spero V, Abbracchio MP, Lecca D, and Molteni R
- Subjects
- Animals, Brain-Derived Neurotrophic Factor metabolism, Female, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins metabolism, Oligodendroglia metabolism, Receptors, G-Protein-Coupled metabolism, Spinal Cord metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism, Multiple Sclerosis metabolism
- Abstract
One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring's brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis., (© 2020. The Author(s).)
- Published
- 2022
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132. Immunometabolic activation of macrophages leads to cytokine production in the pathogenesis of KRAS-mutated histiocytosis.
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Ferrero E, Villa A, Stefanoni D, Nemkov T, D'Alessandro A, Tengesdal I, Belloni D, Molteni R, Vergani B, De Luca G, Grassini G, Cangi MG, Dagna L, Doglioni C, Cavalli G, and Ferrarini M
- Subjects
- Cytokines metabolism, Gene Expression, Humans, Macrophages metabolism, Mutation, Histiocytosis genetics, Histiocytosis pathology, Proto-Oncogene Proteins p21(ras) genetics
- Published
- 2022
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133. Spatial ecology of crested porcupine in a metropolitan landscape.
- Author
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Mori E, Molteni R, Ancillotto L, Ficetola GF, and Falaschi M
- Abstract
Human settlements, including cities, may provide wildlife with new ecological niches, in terms of habitat types and food availability, thus requiring plasticity for adaptation. The crested porcupine Hystrix cristata is a habitat-generalist, large-sized rodent, also recorded in some suburban areas, but no information is available on its habitat use in metropolitan landscapes. Here, we assessed the land-use factors influencing the presence of crested porcupines in a metropolitan area of Central Italy. We collected data on the occurrence of crested porcupines from the metropolitan area of Rome, following an observer-oriented approach to record occurrences and retreive pseudo-absences. We then related the presence/absence of H. cristata to landscape composition. Occupancy models showed that cultivations and scrubland were positively related to porcupine presence, most likely as they provide food resources and shelter sites, respectively. Although the crested porcupine has been confirmed as a "generalist" species in terms of habitat selection, a strong preference for areas limiting the risk of being killed and providing enough food and shelter was observed. We therefore suggest that the crested porcupine may adapt to deeply modified landscapes such as large cities by selecting specific favourable land-use types., Competing Interests: Competing interestsAuthors declare that they have no competing interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)
- Published
- 2022
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134. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.
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Molteni R, Biavasco R, Stefanoni D, Nemkov T, Domínguez-Andrés J, Arts RJ, Merelli I, Mazza D, Zambrano S, Panigada M, Cantoni E, Tengesdal IW, Maksud P, Piras F, Cesana D, Cassina L, Distefano G, Loffreda A, Gnani D, De Luca G, Tomelleri A, Campochiaro C, Joosten LAB, Dinarello CA, Kajaste-Rudnitski A, Haroche J, Cardaci S, Cenci S, Dagna L, Doglioni C, Ferrarini M, Ferrero E, Boletta A, D'Alessandro A, Montini E, Netea MG, and Cavalli G
- Subjects
- Cells, Cultured, Epigenesis, Genetic, Erdheim-Chester Disease immunology, Erdheim-Chester Disease pathology, Humans, Immunity, Inflammation immunology, Inflammation pathology, Macrophages immunology, Macrophages metabolism, Macrophages pathology, Oncogenes, Point Mutation, Proto-Oncogene Proteins B-raf immunology, Erdheim-Chester Disease genetics, Inflammation genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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135. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity.
- Author
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Cavalli G, Tengesdal IW, Gresnigt M, Nemkov T, Arts RJW, Domínguez-Andrés J, Molteni R, Stefanoni D, Cantoni E, Cassina L, Giugliano S, Schraa K, Mills TS, Pietras EM, Eisenmensser EZ, Dagna L, Boletta A, D'Alessandro A, Joosten LAB, Netea MG, and Dinarello CA
- Subjects
- Animals, Candidiasis genetics, Candidiasis immunology, Candidiasis microbiology, Epigenesis, Genetic drug effects, Glycolysis drug effects, Glycolysis genetics, Host-Pathogen Interactions drug effects, Host-Pathogen Interactions immunology, Humans, Male, Mice, Inbred C57BL, Neutrophils drug effects, Neutrophils metabolism, Mice, Anti-Inflammatory Agents pharmacology, Immunity, Innate drug effects, Interleukin-1 pharmacology
- Abstract
Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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136. The way we were (and how we got here): fifty years of technology changes in dental and maxillofacial radiology.
- Author
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Molteni R
- Subjects
- Cone-Beam Computed Tomography, Radiography, Technology, Radiography, Dental, Digital, Radiology
- Abstract
The history of the last 50 years (1970-2020) of technological changes and progresses for equipment and procedures in dental and maxillofacial radiology is related from the insider perspective of an industrial physicist and technologist who has been instrumental at innovating and developing medical equipment in different parts of the world. The onset and improvement of all major categories of dental and maxillofacial radiographic equipment is presented, from the standpoint of their practical acceptance and impact among common dentists and maxillofacial radiologists: X-ray sources and detectors for intraoral radiography, and panoramic systems, both film-based and digital (including photo-stimulated phosphor plates); and cone beam CT.
- Published
- 2021
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137. Behavioral and molecular effects of the antipsychotic drug blonanserin in the chronic mild stress model.
- Author
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Paladini MS, Spero V, Begni V, Marchisella F, Guidi A, Gruca P, Lason M, Litwa E, Papp M, Riva MA, and Molteni R
- Subjects
- Animals, Antipsychotic Agents pharmacology, Behavior, Animal drug effects, Brain drug effects, Brain metabolism, Cytoskeletal Proteins genetics, Disease Models, Animal, Male, Maze Learning drug effects, Nerve Tissue Proteins genetics, Oxidoreductases genetics, Piperazines pharmacology, Piperidines pharmacology, Rats, Wistar, Stress, Psychological genetics, Rats, Antipsychotic Agents therapeutic use, Piperazines therapeutic use, Piperidines therapeutic use, Stress, Psychological drug therapy
- Abstract
Psychiatric disorders represent a critical challenge to our society, given their high global prevalence, complex symptomatology, elusive etiology and the variable effectiveness of pharmacological therapies. Recently, there has been a shift in investigating and redefining these diseases by integrating behavioral observations and multilevel neurobiological measures. Accordingly, endophenotype-oriented studies are needed to develop new therapeutic strategies, with the idea of targeting shared symptoms instead of one defined disease. With these premises, here we investigated the therapeutic properties of chronic treatment with the second-generation antipsychotic blonanserin in counteracting the alterations caused by 7 weeks of Chronic Mild Stress (CMS) in the rat. CMS is a well-established preclinical model able to induce depressive and anxiety-like alterations, which are shared by different psychiatric disorders. Our results demonstrated that the antipsychotic treatment normalizes the CMS-induced emotionality deficits, an effect that may be due to its ability in modulating, within the prefrontal cortex, redox mechanisms, a molecular dysfunction associated with several psychiatric disorders. These evidences provide new insights into the therapeutic properties and potential use of blonanserin as well as in its mechanisms of action and provide further support for the role of oxidative stress in the pathophysiology of psychiatric disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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138. Autophagy in the Regulation of Tissue Differentiation and Homeostasis.
- Author
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Perrotta C, Cattaneo MG, Molteni R, and De Palma C
- Abstract
Autophagy is a constitutive pathway that allows the lysosomal degradation of damaged components. This conserved process is essential for metabolic plasticity and tissue homeostasis and is crucial for mammalian post-mitotic cells. Autophagy also controls stem cell fate and defective autophagy is involved in many pathophysiological processes. In this review, we focus on established and recent breakthroughs aimed at elucidating the impact of autophagy in differentiation and homeostasis maintenance of endothelium, muscle, immune system, and brain providing a suitable framework of the emerging results and highlighting the pivotal role of autophagic response in tissue functions, stem cell dynamics and differentiation rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Perrotta, Cattaneo, Molteni and De Palma.)
- Published
- 2020
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139. Study of the different evaluation areas in the pesticide risk assessment process.
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Molteni R and Alonso-Prados JL
- Abstract
Approval of active substances and authorisation of plant protection products in the EU is made based on a strict risk assessment of the agronomic use of the plant protection products. Regulation 1107/2009 regulates the procedure in the EU with complex procedures involving many actors. 'The Farm to Fork strategy' and 'The Biodiversity for 2030 strategy', that are the heart of the 'European Green Deal', aiming to make food systems fair, healthy, environmentally friendly and put Europe's biodiversity on the path to recovery by 2030, for the benefit of people, climate and the planet. Therefore, 'The Farm to Fork strategy' and 'The Biodiversity for 2030 strategy' represents a challenge for the evaluation and authorisation of plant protection products in which the risk management will constitute a key element on the approval of active substances and authorisation of plant protection products. The aim of the work was to get knowledge of the large body of EU legislation and guidelines in the plant production products, identifying the most critical points of the pesticide evaluation in each of its areas, analysing the complexity and the interaction between these different areas. This study allowed to have a global and clearer vision of these procedures, with the focus on highlighting inconsistency and to propose speed up alternatives. Finally, this work will also facilitate not only the risk assessment but also the decision-making on the approval of active substances and the authorisation of plant protection products., (© 2020 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.)
- Published
- 2020
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140. Chronic Restraint Stress Inhibits the Response to a Second Hit in Adult Male Rats: A Role for BDNF Signaling.
- Author
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Brivio P, Sbrini G, Corsini G, Paladini MS, Racagni G, Molteni R, and Calabrese F
- Subjects
- Animals, Brain-Derived Neurotrophic Factor metabolism, Disease Models, Animal, Male, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Rats, Rats, Sprague-Dawley, Receptor, trkB genetics, Receptor, trkB metabolism, Signal Transduction, Stress, Psychological etiology, Stress, Psychological genetics, Brain-Derived Neurotrophic Factor genetics, Corticosterone metabolism, Prefrontal Cortex metabolism, Restraint, Physical psychology, Stress, Psychological metabolism
- Abstract
Depression is a recurrent disorder, with about 50% of patients experiencing relapse. Exposure to stressful events may have an adverse impact on the long-term course of the disorder and may alter the response to a subsequent stressor. Indeed, not all the systems impaired by stress may normalize during symptoms remission, facilitating the relapse to the pathology. Hence, we investigated the long-lasting effects of chronic restraint stress (CRS) and its influence on the modifications induced by the exposure to a second hit on brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC). We exposed adult male Sprague Dawley rats to 4 weeks of CRS, we left them undisturbed for the subsequent 3 weeks, and then we exposed animals to one hour of acute restraint stress (ARS). We found that CRS influenced the release of corticosterone induced by ARS and inhibited the ability of ARS to activate mature BDNF, its receptor Tropomyosin receptor kinase B (TRKB), and their associated intracellular cascades: the TRKB-PI3K-AKT), the MEK-MAPK/ERK, and the Phospholipase C γ (PLCγ) pathways, positively modulated by ARS in non-stressed animals. These results suggest that CRS induces protracted and detrimental consequences that interfere with the ability of PFC to cope with a challenging situation.
- Published
- 2020
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141. Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System.
- Author
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Hrelia P, Sita G, Ziche M, Ristori E, Marino A, Cordaro M, Molteni R, Spero V, Malaguti M, Morroni F, and Hrelia S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Humans, Middle Aged, Oxidation-Reduction, Risk Factors, Young Adult, Neurodegenerative Diseases therapy
- Abstract
Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Patrizia Hrelia et al.)
- Published
- 2020
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142. Oxidation-reduction mechanisms in psychiatric disorders: A novel target for pharmacological intervention.
- Author
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Rossetti AC, Paladini MS, Riva MA, and Molteni R
- Subjects
- Animals, Central Nervous System metabolism, Central Nervous System physiopathology, Humans, Mental Disorders metabolism, Mental Disorders physiopathology, Mental Disorders psychology, Oxidation-Reduction, Antioxidants therapeutic use, Central Nervous System drug effects, Central Nervous System Agents therapeutic use, Mental Disorders drug therapy, Oxidative Stress drug effects
- Abstract
While neurotransmitter dysfunction represents a key component in mental illnesses, there is now a wide agreement for a central pathophysiological hub that includes hormones, neuroinflammation, redox mechanisms as well as oxidative stress. With respect to oxidation-reduction (redox) mechanisms, preclinical and clinical evidence suggests that an imbalance in the pro/anti-oxidative homeostasis toward the increased production of substances with oxidizing potential may contribute to the etiology and manifestation of different psychiatric disorders. The substantial and continous demand for energy renders the brain highly susceptible to disturbances in its energy supply, especially following exposure to stressful events, which may lead to overproduction of reactive oxygen and nitrogen species under conditions of perturbed antioxidant defenses. This will eventually induce different molecular alterations, including extensive protein and lipid peroxidation, increased blood-brain barrier permeability and neuroinflammation, which may contribute to the changes in brain function and morphology observed in mental illnesses. This view may also reconcile different key concepts for psychiatric disorders, such as the neurodevelopmental origin of these diseases, as well as the vulnerability of selective cellular populations that are critical for specific functional abnormalities. The possibility to pharmacologically modulate the redox system is receiving increasing interest as a novel therapeutic strategy to counteract the detrimental effects of the unbalance in brain oxidative mechanisms. This review will describe the main mechanisms and mediators of the redox system and will examine the alterations of oxidative stress found in animal models of psychiatric disorders as well as in patients suffering from mental illnesses, such as schizophrenia and major depressive disorder. In addition, it will discuss studies that examined the effects of psychotropic drugs, including antipsychotics and antidepressants, on the oxidative balance as well as studies that investigated the effectiveness of a direct modulation of oxidative mechanisms in counteracting the behavioral and functional alterations associated with psychiatric disorders, which supports the promising role of the redox system as a novel therapeutic target for the improved treatment of brain disorders., Competing Interests: Declaration of Competing Interest M.A.R. has received compensation as speaker/consultant from Angelini, Lundbeck, Recordati, Sumitomo Dainippon Pharma and Sunovion, and he has received research grants from Sumitomo Dainippon Pharma and Sunovion. The other authors declare no financial interest or potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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143. Chronic treatment with the antipsychotic drug blonanserin modulates the responsiveness to acute stress with anatomical selectivity.
- Author
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Marchisella F, Paladini MS, Guidi A, Begni V, Brivio P, Spero V, Calabrese F, Molteni R, and Riva MA
- Subjects
- Animals, Brain physiology, Drug Administration Schedule, Genes, Immediate-Early physiology, Male, Rats, Rats, Sprague-Dawley, Receptors, Dopamine metabolism, Schizophrenia drug therapy, Schizophrenia genetics, Stress, Psychological genetics, Stress, Psychological psychology, Antipsychotic Agents administration & dosage, Brain drug effects, Genes, Immediate-Early drug effects, Piperazines administration & dosage, Piperidines administration & dosage, Stress, Psychological drug therapy
- Abstract
Rationale: Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive., Objective: Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia., Methods: We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4., Results: Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus., Conclusions: Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.
- Published
- 2020
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144. Prokineticin 2 promotes and sustains neuroinflammation in vincristine treated mice: Focus on pain and emotional like behavior.
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Moschetti G, Amodeo G, Paladini MS, Molteni R, Balboni G, Panerai A, Sacerdote P, and Franchi S
- Subjects
- Animals, Anxiety chemically induced, Anxiety metabolism, Behavior, Animal drug effects, Cytokines metabolism, Depression chemically induced, Depression metabolism, Disease Models, Animal, Hyperalgesia chemically induced, Hyperalgesia metabolism, Male, Mice, Mice, Inbred C57BL, Neuroimmunomodulation drug effects, Random Allocation, Sciatic Nerve drug effects, Sciatic Nerve metabolism, Spinal Cord drug effects, Spinal Cord metabolism, Gastrointestinal Hormones metabolism, Neuralgia chemically induced, Neuralgia metabolism, Neuropeptides metabolism, Vincristine toxicity
- Abstract
Vincristine (VCR) treatment is often associated to painful neuropathy. Its development is independent from antitumoral mechanism and involves neuroinflammation. We investigated the role of the chemokine prokineticin (PK)2 in a mouse model of VCR induced neuropathy using a PK-receptors (PK-R) antagonist to counteract its development. We also evaluated emotional like deficits in VCR mice. VCR (0,1 mg/kg) was i.p. injected in C57BL/6J male mice once a day for 14 consecutive days. Pain, anxiety and depressive like behaviors were assessed in animals. PK2, PK-Rs, cytokines, neuroinflammatory markers (CD68, CD11b, GFAP, TLR4) and ATF3 were evaluated in DRG, spinal cord, prefrontal cortex and hippocampus. The PK-Rs antagonist PC1, was s.c. injected (150 μg/kg) twice a day from day 7 (hypersensitivity state) until day 14. Its effect on pain and neuroinflammation was evaluated. VCR mice developed neuropathic pain but not mood alterations. After 7 days of VCR treatment we observed a neuroinflammatory condition in DRG with high levels of PK-Rs, TLR4, CD68, ATF3 and IL-1β without relevant alterations in spinal cord. At day 14, an upregulation of PK system and a marked neuroinflammation was evident also in spinal cord. Moreover, at the same time, we observed initial alterations in supraspinal brain areas. PC1 treatment significantly counteracted neuropathic pain and blunted neuroinflammation., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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145. Differential Neuroinflammatory Response in Male and Female Mice: A Role for BDNF.
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Rossetti AC, Paladini MS, Trepci A, Mallien A, Riva MA, Gass P, and Molteni R
- Abstract
A growing body of evidence supports the close relationship between major depressive disorder (MDD), a severe psychiatric disease more common among women than men, and alterations of the immune/inflammatory system. However, despite the large number of studies aimed at understanding the molecular bases of this association, a lack of information exists on the potential cross-talk between systems known to be involved in depression and components of the inflammatory response, especially with respect to sex differences. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a well-established role in MDD etiopathology: it is altered in depressed patients as well as in animal models of the disease and its changes are restored by antidepressant drugs. Interestingly, this neurotrophin is also involved in the inflammatory response. Indeed, it can be secreted by microglia, the primary innate immune cells in the central nervous system whose functions may be in turn regulated by BDNF. With these premises, in this study, we investigated the reciprocal impact of BDNF and the immune system by evaluating the neuroinflammatory response in male and female BDNF-heterozygous mutant mice acutely treated with the cytokine-inducer lipopolysaccharide (LPS). Specifically, we assessed the potential onset of an LPS-induced sickness behavior as well as changes of inflammatory mediators in the mouse hippocampus and frontal cortex, with respect to both genotype and sex. We found that the increased inflammatory response induced by LPS in the brain of male mice was independent of the genotype, whereas in the female, it was restricted to the heterozygous mice with no changes in the wild-type group, suggestive of a role for BDNF in the sex-dependent effect of the inflammatory challenge. Considering the involvement of both BDNF and neuroinflammation in several psychiatric diseases and the diverse incidence of such pathologies in males and females, a deeper investigation of the mechanisms underlying their interaction may have a critical translational relevance.
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- 2019
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146. A Microfluidic Human Model of Blood-Brain Barrier Employing Primary Human Astrocytes.
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Lauranzano E, Campo E, Rasile M, Molteni R, Pizzocri M, Passoni L, Bello L, Pozzi D, Pardi R, Matteoli M, and Ruiz-Moreno A
- Subjects
- Astrocytes cytology, Blood-Brain Barrier cytology, Humans, Primary Cell Culture, Astrocytes metabolism, Blood-Brain Barrier metabolism, Microfluidic Analytical Techniques, Models, Cardiovascular, Models, Neurological
- Abstract
The neurovascular unit (NVU) is the most important biological barrier between vascular districts and central nervous system (CNS) parenchyma, which maintains brain homeostasis, protects the CNS from pathogens penetration, and mediates neuroimmune communication. T lymphocytes migration across the blood-brain barrier is heavily affected in different brain diseases, representing a major target for novel drug development. In vitro models of NVU could represent a primary tool to investigate the molecular events occurring at this interface. To move toward the establishment of personalized therapies, a patient-related NVU-model is set, incorporating human primary astrocytes integrated into a microfluidic platform. The model is morphologically and functionally characterized, proving to be an advantageous tool to investigate human T lymphocytes transmigration and thus the efficacy of potential novel drugs affecting this process., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2019
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147. PQM130, a Novel Feruloyl-Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer's Disease.
- Author
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Morroni F, Sita G, Graziosi A, Ravegnini G, Molteni R, Paladini MS, Dias KST, Dos Santos AF, Viegas C Jr, Camps I, Pruccoli L, Tarozzi A, and Hrelia P
- Abstract
Alzheimer's disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl-donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ
1-42 oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5-1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development.- Published
- 2019
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148. From Healthy Aging to Frailty: In Search of the Underlying Mechanisms.
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Brivio P, Paladini MS, Racagni G, Riva MA, Calabrese F, and Molteni R
- Subjects
- Humans, Aging physiology, Frailty physiopathology, Healthy Aging
- Abstract
Population aging is accelerating rapidly worldwide, from 461 million people older than 65 years in 2004 to an estimated 2 billion people by 2050, leading to critical implications for the planning and delivery of health and social care. The most problematic expression of population aging is the clinical condition of frailty, which is a state of increased vulnerability that develops as a consequence of the accumulation of microscopic damages in many physiological systems that lead to a striking and disproportionate change in health state, even after an apparently small insult. Since little is known about the biology of frailty, an important perspective to understand this phenomenon is to establish how the alterations that physiologically occur during a condition of healthy aging may instead promote cumulative decline with subsequent depletion of homoeostatic reserve and increase the vulnerability also after minor stressor events. In this context, the present review aims to provide a description of the molecular mechanisms that, by having a critical impact on behavior and neuronal function in aging, might be relevant for the development of frailty. Moreover, since these biological systems are also involved in the coping strategies set in motion to respond to environmental challenges, we propose a role for lifestyle stress as an important player to drive frailty in aging., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2019
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149. Radiation dose in non-dental cone beam CT applications: a systematic review.
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Nardi C, Salerno S, Molteni R, Occhipinti M, Grazzini G, Norberti N, Cordopatri C, and Colagrande S
- Subjects
- Head diagnostic imaging, Humans, Neck diagnostic imaging, Cone-Beam Computed Tomography methods, Radiation Dosage
- Abstract
Background: Radiation-induced health risks are broadly questioned in the literature. As cone beam computed tomography (CBCT) is increasingly used in non-dental examinations, its effective dose needs to be known. This study aimed to review the published evidence on effective dose of non-dental CBCT for diagnostic use by focusing on dosimetry system used to estimate dose., Materials and Methods: A systematic review of the literature was performed on 12 November 2017. All the literature up to this date was included. The PubMed and web of science databases were searched. Studies were screened for inclusion based on defined inclusion and exclusion criteria according to the preferred reporting items for systematic reviews., Results: Fifteen studies met the inclusion criteria and were included in our review. Thirteen and two of them examined one and two anatomical areas, respectively. The anatomical areas were: ear (6), paranasal sinuses (4), ankle (3), wrist (2), knee (1), and cervical spine (1). Effective dose was estimated by different methods: (i) RANDO phantom associated with thermoluminescent dosimeters (6), metal oxide semiconductor field-effect transistor dosimeters (3), and optically stimulated luminescent dosimeters (1). (ii) Scanner outputs, namely computed tomography dose index (1) and dose area product (2). (iii) Monte Carlo simulations (2)., Conclusion: CBCT of extremities, cervical spine, ears and paranasal sinuses was found to be a low-dose volumetric imaging technique. Effective doses varied significantly because of different exposure settings of CBCT-units and different dosimetry systems used to estimate dose.
- Published
- 2018
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150. Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone.
- Author
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Rossetti AC, Paladini MS, Colombo M, Gruca P, Lason-Tyburkiewicz M, Tota-Glowczyk K, Papp M, Riva MA, and Molteni R
- Subjects
- Animals, Chronic Disease, Disease Models, Animal, GABAergic Neurons drug effects, GABAergic Neurons metabolism, Gene Expression drug effects, Hippocampus drug effects, Interneurons drug effects, Interneurons metabolism, Kelch-Like ECH-Associated Protein 1 metabolism, Male, NADPH Oxidase 2 metabolism, NF-E2-Related Factor 2 metabolism, Oxidation-Reduction, RNA, Messenger metabolism, Rats, Wistar, Stress, Psychological drug therapy, Antipsychotic Agents pharmacology, Hippocampus metabolism, Lurasidone Hydrochloride pharmacology, Parvalbumins metabolism, Stress, Psychological metabolism
- Abstract
Background: Psychiatric disorders are associated with altered function of inhibitory neurotransmission within the limbic system, which may be due to the vulnerability of selective neuronal subtypes to challenging environmental conditions, such as stress. In this context, parvalbumin-positive GABAergic interneurons, which are critically involved in processing complex cognitive tasks, are particularly vulnerable to stress exposure, an effect that may be the consequence of dysregulated redox mechanisms., Methods: Adult Male Wistar rats were subjected to the chronic mild stress procedure for 7 weeks. After 2 weeks, both control and stress groups were further divided into matched subgroups to receive chronic administration of vehicle or lurasidone (3 mg/kg/d) for the subsequent 5 weeks. Using real-time RT-PCR and western blot, we investigated the expression of GABAergic interneuron markers and the levels of key mediators of the oxidative balance in the dorsal and ventral hippocampus., Results: Chronic mild stress induced a specific decrease of parvalbumin expression in the dorsal hippocampus, an effect normalized by lurasidone treatment. Interestingly, the regulation of parvalbumin levels was correlated to the modulation of the antioxidant master regulator NRF2 and its chaperon protein KEAP1, which were also modulated by pharmacological intervention., Conclusions: Our findings suggest that the susceptibility of parvalbumin neurons to stress may represent a key mechanism contributing to functional and structural impairments in specific brain regions relevant for psychiatric disorders. Moreover, we provide new insights on the mechanism of action of lurasidone, demonstrating that its chronic treatment normalizes chronic mild stress-induced parvalbumin alterations, possibly by potentiating antioxidant mechanisms, which may ameliorate specific functions that are deteriorated in psychiatric patients.
- Published
- 2018
- Full Text
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