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Article ; Online: Increased Expression of Transferrin Receptor 1 in the Brain Cortex of 5xFAD Mouse Model of Alzheimer's Disease Is Associated with Activation of HIF-1 Signaling Pathway.

Petralla, Sabrina / Saveleva, Liudmila / Kanninen, Katja M / Oster, Julia S / Panayotova, Maria / Fricker, Gert / Puris, Elena

Molecular neurobiology

2024

Abstract: Alzheimer's disease (AD) is the most common cause of dementia. Despite intensive research efforts, there are currently no effective treatments to cure and prevent AD. There is growing evidence that dysregulation of iron homeostasis may contribute to the ... ...

Abstract	Alzheimer's disease (AD) is the most common cause of dementia. Despite intensive research efforts, there are currently no effective treatments to cure and prevent AD. There is growing evidence that dysregulation of iron homeostasis may contribute to the pathogenesis of AD. Given the important role of the transferrin receptor 1 (TfR1) in regulating iron distribution in the brain, as well as in the drug delivery, we investigated its expression in the brain cortex and isolated brain microvessels from female 8-month-old 5xFAD mice mimicking advanced stage of AD. Moreover, we explored the association between the TfR1 expression and the activation of the HIF-1 signaling pathway, as well as oxidative stress and inflammation in 5xFAD mice. Finally, we studied the impact of Aβ
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-024-03990-3
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Article ; Online: Monoacylglycerol Lipase Inhibitor JJKK048 Ameliorates ABCG2 Transporter-Mediated Regorafenib Resistance Induced by Hypoxia in Triple Negative Breast Cancer Cells.

Puris, Elena / Petralla, Sabrina / Auriola, Seppo / Kidron, Heidi / Fricker, Gert / Gynther, Mikko

Journal of pharmaceutical sciences

2023 Volume 112, Issue 9, Page(s) 2581–2590

Abstract: Triple negative breast cancer (TNBC) is among the most aggressive and deadly cancer subtypes. Intra-tumoral hypoxia is associated with aggressiveness and drug resistance in TNBC. One of the underlying mechanisms of hypoxia-induced drug resistance is the ... ...

Abstract	Triple negative breast cancer (TNBC) is among the most aggressive and deadly cancer subtypes. Intra-tumoral hypoxia is associated with aggressiveness and drug resistance in TNBC. One of the underlying mechanisms of hypoxia-induced drug resistance is the elevated expression of efflux transporters such as breast cancer resistant protein (ABCG2). In the present study, we investigated the possibility of ameliorating ABCG2-mediated drug resistance in hypoxic TNBC cells by monoacylglycerol lipase (MAGL) inhibition and the consequent downregulation of ABCG2 expression. The effect of MAGL inhibition on ABCG2 expression, function, and efficacy of regorafenib, an ABCG2 substrate was investigated in cobalt dichloride (CoCl
MeSH term(s)	Humans ; Triple Negative Breast Neoplasms/drug therapy ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Monoacylglycerol Lipases/metabolism ; Monoacylglycerol Lipases/pharmacology ; Cell Line, Tumor ; Hypoxia ; Drug Resistance, Neoplasm ; Neoplasm Proteins/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily G, Member 2 ; regorafenib (24T2A1DOYB) ; Monoacylglycerol Lipases (EC 3.1.1.23) ; ABCG2 protein, human ; Neoplasm Proteins
Language	English
Publishing date	2023-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2023.05.012
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Article ; Online: Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Albertini, Claudia / Petralla, Sabrina / Massenzio, Francesca / Monti, Barbara / Rizzardi, Nicola / Bergamini, Christian / Uliassi, Elisa / Borges, Fernanda / Chavarria, Daniel / Fricker, Gert / Goettert, Marcia / Kronenberger, Thales / Gehringer, Matthias / Laufer, Stefan / Bolognesi, Maria L

Archiv der Pharmazie

2024 , Page(s) e2300525

Abstract: Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine ...

Abstract	Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38α-MAPK inhibitory activity (IC
Language	English
Publishing date	2024-02-27
Publishing country	Germany
Document type	Journal Article
ZDB-ID	6381-2
ISSN	1521-4184 ; 0365-6233 ; 1437-1014
ISSN (online)	1521-4184
ISSN	0365-6233 ; 1437-1014
DOI	10.1002/ardp.202300525
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Article ; Online: Altered protein expression of membrane transporters in isolated cerebral microvessels and brain cortex of a rat Alzheimer's disease model.

Puris, Elena / Auriola, Seppo / Petralla, Sabrina / Hartman, Robin / Gynther, Mikko / de Lange, Elizabeth C M / Fricker, Gert

Neurobiology of disease

2022 Volume 169, Page(s) 105741

Abstract: There is growing evidence that membrane transporters expressed at the blood-brain barrier (BBB) and brain parenchymal cells play an important role in Alzheimer's disease (AD) development and progression. However, quantitative information about changes in ...

Abstract	There is growing evidence that membrane transporters expressed at the blood-brain barrier (BBB) and brain parenchymal cells play an important role in Alzheimer's disease (AD) development and progression. However, quantitative information about changes in transporter protein expression at neurovascular unit cells in AD is limited. Here, we studied the changes in the absolute protein expression of five ATP-binding cassette (ABC) and thirteen solute carrier (SLC) transporters in the isolated brain microvessels and brain cortical tissue of TgF344-AD rats compared to age-matched wild-type (WT) animals using liquid chromatography tandem mass spectrometry based quantitative targeted absolute proteomic analysis. Moreover, sex-specific alterations in transporter expression in the brain cortical tissue of this model were examined. Protein expressions of Abcg2, Abcc1 and FATP1 (encoded by Slc27a1) in the isolated brain microvessels of TgF344-AD rats were 3.1-, 2.0-, 4.3-fold higher compared to WT controls, respectively (p < 0.05). Abcc1 and 4F2hc (encoded by Slc3a2) protein expression was significantly up-regulated in the brain cortical tissue of male TgF344-AD rats compared to male WT rats (p < 0.05). The study provides novel information for the elucidation of molecular mechanisms underlying AD and valuable knowledge about the optimal use of the TgF344-AD rat model in AD drug development and drug delivery research.
MeSH term(s)	Alzheimer Disease/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Female ; Male ; Membrane Transport Proteins ; Microvessels/metabolism ; Proteomics/methods ; Rats
Chemical Substances	Membrane Transport Proteins
Language	English
Publishing date	2022-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2022.105741
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Article ; Online: Epigenetics and Communication Mechanisms in Microglia Activation with a View on Technological Approaches.

Petralla, Sabrina / De Chirico, Francesca / Miti, Andrea / Tartagni, Ottavia / Massenzio, Francesca / Poeta, Eleonora / Virgili, Marco / Zuccheri, Giampaolo / Monti, Barbara

Biomolecules

2021 Volume 11, Issue 2

Abstract: Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain ... ...

Abstract	Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain parenchyma, in pathological conditions, microglia can show different activated phenotypes: In the early phases, microglia acquire the M2 phenotype, increasing phagocytosis and releasing neurotrophic and neuroprotective factors. In advanced phases, they acquire the M1 phenotype, becoming neurotoxic and contributing to neurodegeneration. Underlying this phenotypic change, there is a switch in the expression of specific microglial genes, in turn modulated by epigenetic changes, such as DNA methylation, histones post-translational modifications and activity of miRNAs. New roles are attributed to microglial cells, including specific communication with neurons, both through direct cell-cell contact and by release of many different molecules, either directly or indirectly, through extracellular vesicles. In this review, recent findings on the bidirectional interaction between neurons and microglia, in both physiological and pathological conditions, are highlighted, with a focus on the complex field of microglia immunomodulation through epigenetic mechanisms and/or released factors. In addition, advanced technologies used to study these mechanisms, such as microfluidic, 3D culture and in vivo imaging, are presented.
MeSH term(s)	Animals ; DNA Methylation/genetics ; Epigenesis, Genetic/genetics ; Exosomes/genetics ; Humans ; MicroRNAs/genetics ; Microfluidics ; Microglia/metabolism ; Protein Processing, Post-Translational/genetics
Chemical Substances	MicroRNAs
Language	English
Publishing date	2021-02-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11020306
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Article ; Online: From Combinations to Single-Molecule Polypharmacology-Cromolyn-Ibuprofen Conjugates for Alzheimer's Disease.

Albertini, Claudia / Naldi, Marina / Petralla, Sabrina / Strocchi, Silvia / Grifoni, Daniela / Monti, Barbara / Bartolini, Manuela / Bolognesi, Maria Laura

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 4

Abstract: Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective ... ...

Abstract	Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn-ibuprofen drug combination into single-molecule "codrugs." Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn-ibuprofen conjugates (
MeSH term(s)	Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/toxicity ; Animals ; Behavior, Animal/drug effects ; Cell Survival/drug effects ; Cromolyn Sodium/chemical synthesis ; Cromolyn Sodium/chemistry ; Cromolyn Sodium/pharmacology ; Cromolyn Sodium/therapeutic use ; Drosophila/drug effects ; Drug Design ; Endocytosis/drug effects ; Ibuprofen/chemical synthesis ; Ibuprofen/chemistry ; Ibuprofen/pharmacology ; Ibuprofen/therapeutic use ; Immunomodulation/drug effects ; Mice ; Microglia/drug effects ; Microglia/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Neuroprotective Agents/pharmacology ; Neurotoxins/toxicity ; Polypharmacology ; Protein Aggregates/drug effects ; Rats, Wistar ; Rats
Chemical Substances	Amyloid beta-Peptides ; Neuroprotective Agents ; Neurotoxins ; Protein Aggregates ; Cromolyn Sodium (Q2WXR1I0PK) ; Ibuprofen (WK2XYI10QM)
Language	English
Publishing date	2021-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26041112
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Article ; Online: Chronic treatment with hormonal contraceptives alters hippocampal BDNF and histone H3 post-translational modifications but not learning and memory in female rats.

Boi, Laura / Petralla, Sabrina / Monti, Barbara / Talani, Giuseppe / Sanna, Enrico / Pisu, Maria Giuseppina / Calderisi, Giulia / Maciocco, Elisabetta / Serra, Mariangela / Concas, Alessandra / Porcu, Patrizia

Hormones and behavior

2022 Volume 144, Page(s) 105218

Abstract: Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, ... ...

Abstract	Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health.
MeSH term(s)	Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Contraceptive Agents/metabolism ; Contraceptive Agents/pharmacology ; Female ; Hippocampus ; Histones/metabolism ; Humans ; Neuronal Plasticity ; Protein Processing, Post-Translational ; Rats
Chemical Substances	Brain-Derived Neurotrophic Factor ; Contraceptive Agents ; Histones
Language	English
Publishing date	2022-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	214409-8
ISSN	1095-6867 ; 0018-506X
ISSN (online)	1095-6867
ISSN	0018-506X
DOI	10.1016/j.yhbeh.2022.105218
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Article ; Online: Dietary Protein Source Influences Brain Inflammation and Memory in a Male Senescence-Accelerated Mouse Model of Dementia.

Petralla, Sabrina / Parenti, Cristina / Ravaioli, Valentina / Fancello, Irene / Massenzio, Francesca / Virgili, Marco / Monti, Barbara / Pena-Altamira, Emiliano

Molecular neurobiology

2020 Volume 58, Issue 4, Page(s) 1312–1329

Abstract: Dementia is a pathological condition characterized by a decline in memory, as well as in other cognitive and social functions. The cellular and molecular mechanisms of brain damage in dementia are not completely understood; however, neuroinflammation is ... ...

Abstract	Dementia is a pathological condition characterized by a decline in memory, as well as in other cognitive and social functions. The cellular and molecular mechanisms of brain damage in dementia are not completely understood; however, neuroinflammation is involved. Evidence suggests that chronic inflammation may impair cognitive performance and that dietary protein source may differentially influence this process. Dietary protein source has previously been shown to modify systemic inflammation in mouse models. Thus, we aimed to investigate the effect of chronic dietary protein source substitution in an ageing and dementia male mouse model, the senescence-accelerated mouse-prone 8 (SAMP8) model. We observed that dietary protein source differentially modified memory as shown by inhibitory avoidance testing at 4 months of age. Also, dietary protein source differentially modified neuroinflammation and gliosis in male SAMP8 mice. Our results suggest that chronic dietary protein source substitution may influence brain ageing and memory-related mechanisms in male SAMP8 mice. Moreover, the choice of dietary protein source in mouse diets for experimental purposes may need to be carefully considered when interpreting results.
MeSH term(s)	Aging/pathology ; Animals ; Astrocytes/pathology ; Autophagy ; Biomarkers/metabolism ; Body Weight ; Cognition ; Dementia/complications ; Dementia/pathology ; Dementia/physiopathology ; Dietary Proteins/adverse effects ; Disease Models, Animal ; Encephalitis/complications ; Encephalitis/pathology ; Encephalitis/physiopathology ; Feeding Behavior ; Gliosis/complications ; Gliosis/pathology ; Gliosis/physiopathology ; Male ; Memory ; Microglia/pathology ; Nerve Growth Factor/metabolism ; Neurogenesis ; Oligodendroglia/pathology
Chemical Substances	Biomarkers ; Dietary Proteins ; Nerve Growth Factor (9061-61-4)
Language	English
Publishing date	2020-11-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-020-02191-y
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Article: Histone Acetylation Defects in Brain Precursor Cells: A Potential Pathogenic Mechanism Causing Proliferation and Differentiation Dysfunctions in Mitochondrial Aspartate-Glutamate Carrier Isoform 1 Deficiency.

Poeta, Eleonora / Petralla, Sabrina / Babini, Giorgia / Renzi, Brunaldo / Celauro, Luigi / Magnifico, Maria Chiara / Barile, Simona Nicole / Masotti, Martina / De Chirico, Francesca / Massenzio, Francesca / Viggiano, Luigi / Palmieri, Luigi / Virgili, Marco / Lasorsa, Francesco Massimo / Monti, Barbara

Frontiers in cellular neuroscience

2022 Volume 15, Page(s) 773709

Abstract: Mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) deficiency is an ultra-rare genetic disease characterized by global hypomyelination and brain atrophy, caused by mutations in ... ...

Abstract	Mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) deficiency is an ultra-rare genetic disease characterized by global hypomyelination and brain atrophy, caused by mutations in the
Language	English
Publishing date	2022-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2021.773709
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Article: Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer's Disease.

Peña-Altamira, Emiliano / Petralla, Sabrina / Massenzio, Francesca / Virgili, Marco / Bolognesi, Maria L / Monti, Barbara

Frontiers in aging neuroscience

2017 Volume 9, Page(s) 175

Abstract: The study of microglia, the immune cells of the brain, has experienced a renaissance after the discovery of microglia polarization. In fact, the concept that activated microglia can shift into the M1 pro-inflammatory or M2 neuroprotective phenotypes, ... ...

Abstract	The study of microglia, the immune cells of the brain, has experienced a renaissance after the discovery of microglia polarization. In fact, the concept that activated microglia can shift into the M1 pro-inflammatory or M2 neuroprotective phenotypes, depending on brain microenvironment, has completely changed the understanding of microglia in brain aging and neurodegenerative diseases. Microglia polarization is particularly important in aging since an increased inflammatory status of body compartments, including the brain, has been reported in elderly people. In addition, inflammatory markers, mainly derived from activated microglia, are widely present in neurodegenerative diseases. Microglial inflammatory dysfunction, also linked to microglial senescence, has been extensively demonstrated and associated with cognitive impairment in neuropathological conditions related to aging. In fact, microglia polarization is known to influence cognitive function and has therefore become a main player in neurodegenerative diseases leading to dementia. As the life span of human beings increases, so does the prevalence of cognitive dysfunction. Thus, therapeutic strategies aimed to modify microglia polarization are currently being developed. Pharmacological approaches able to shift microglia from M1 pro-inflammatory to M2 neuroprotective phenotype are actually being studied, by acting on many different molecular targets, such as glycogen synthase kinase-3 (GSK3) β, AMP-activated protein kinase (AMPK), histone deacetylases (HDACs), etc. Furthermore, nutritional approaches can also modify microglia polarization and, consequently, impact cognitive function. Several bioactive compounds normally present in foods, such as polyphenols, can have anti-inflammatory effects on microglia. Both pharmacological and nutritional approaches seem to be promising, but still need further development. Here we review recent data on these approaches and propose that their combination could have a synergistic effect to counteract cognitive aging impairment and Alzheimer's disease (AD) through immunomodulation of microglia polarization, i.e., by driving the shift of activated microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype.
Language	English
Publishing date	2017-06-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2017.00175
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