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  1. Article ; Online: The multifaceted role of EGLN family prolyl hydroxylases in cancer: going beyond HIF regulation.

    Strocchi, Silvia / Reggiani, Francesca / Gobbi, Giulia / Ciarrocchi, Alessia / Sancisi, Valentina

    Oncogene

    2022  Volume 41, Issue 29, Page(s) 3665–3679

    Abstract: EGLN1, EGLN2 and EGLN3 are proline hydroxylase whose main function is the regulation of the HIF factors. They work as oxygen sensors and are the main responsible of HIFα subunits degradation in normoxia. Being their activity strictly oxygen-dependent, ... ...

    Abstract EGLN1, EGLN2 and EGLN3 are proline hydroxylase whose main function is the regulation of the HIF factors. They work as oxygen sensors and are the main responsible of HIFα subunits degradation in normoxia. Being their activity strictly oxygen-dependent, when oxygen tension lowers, their control on HIFα is released, leading to activation of systemic and cellular response to hypoxia. However, EGLN family members activity is not limited to HIF modulation, but it includes the regulation of essential mechanisms for cell survival, cell cycle metabolism, proliferation and transcription. This is due to their reported hydroxylase activity on a number of non-HIF targets and sometimes to hydroxylase-independent functions. For these reasons, EGLN enzymes appear fundamental for development and progression of different cancer types, playing either a tumor-suppressive or a tumor-promoting role, according to EGLN isoform and to tumor context. Notably, EGLN1, the most studied isoform, has been shown to have also a central role in tumor micro-environment modulation, mediating CAF activation and impairing HIF1α -related angiogenesis, thus covering an important function in cancer metastasis promotion. Considering the recent knowledge acquired on EGLNs, the possibility to target these enzymes for cancer treatment is emerging. However, due to their multifaceted and controversial roles in different cancer types, the use of EGLN inhibitors as anti-cancer drugs should be carefully evaluated in each context.
    MeSH term(s) Humans ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; Hypoxia-Inducible Factor-Proline Dioxygenases ; Neoplasms/drug therapy ; Neoplasms/genetics ; Oxygen/metabolism ; Procollagen-Proline Dioxygenase/metabolism ; Prolyl Hydroxylases ; Tumor Microenvironment
    Chemical Substances Hypoxia-Inducible Factor 1, alpha Subunit ; Prolyl Hydroxylases (EC 1.14.11.-) ; Procollagen-Proline Dioxygenase (EC 1.14.11.2) ; EGLN2 protein, human (EC 1.14.11.29) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2022-06-15
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-022-02378-8
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2218: Show issues Location:
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  2. Article ; Online: The long non-coding RNA TAZ-AS202 promotes lung cancer progression via regulation of the E2F1 transcription factor and activation of Ephrin signaling.

    Gobbi, Giulia / Grieco, Alessandra / Torricelli, Federica / Sauta, Elisabetta / Santandrea, Giacomo / Zanetti, Eleonora / Fantini, Valentina / Reggiani, Francesca / Strocchi, Silvia / Paci, Massimiliano / Vohra, Manik / Saladi, Srinivas Vinod / Ambrosetti, Davide Carlo / Ciarrocchi, Alessia / Sancisi, Valentina

    Cell death & disease

    2023  Volume 14, Issue 11, Page(s) 752

    Abstract: Long non-coding RNAs (lncRNAs) are transcripts without coding potential that are pervasively expressed from the genome and have been increasingly reported to play crucial roles in all aspects of cell biology. They have been also heavily implicated in ... ...

    Abstract Long non-coding RNAs (lncRNAs) are transcripts without coding potential that are pervasively expressed from the genome and have been increasingly reported to play crucial roles in all aspects of cell biology. They have been also heavily implicated in cancer development and progression, with both oncogenic and tumor suppressor functions. In this work, we identified and characterized a novel lncRNA, TAZ-AS202, expressed from the TAZ genomic locus and exerting pro-oncogenic functions in non-small cell lung cancer. TAZ-AS202 expression is under the control of YAP/TAZ-containing transcriptional complexes. We demonstrated that TAZ-AS202 is overexpressed in lung cancer tissue, compared with surrounding lung epithelium. In lung cancer cell lines TAZ-AS202 promotes cell migration and cell invasion. TAZ-AS202 regulates the expression of a set of genes belonging to cancer-associated pathways, including WNT and EPH-Ephrin signaling. The molecular mechanism underlying TAZ-AS202 function does not involve change of TAZ expression or activity, but increases the protein level of the transcription factor E2F1, which in turn regulates the expression of a large set of target genes, including the EPHB2 receptor. Notably, the silencing of both E2F1 and EPHB2 recapitulates TAZ-AS202 silencing cellular phenotype, indicating that they are essential mediators of its activity. Overall, this work unveiled a new regulatory mechanism that, by increasing E2F1 protein, modifies the non-small cell lung cancer cells transcriptional program, leading to enhanced aggressiveness features. The TAZ-AS202/E2F1/EPHB2 axis may be the target for new therapeutic strategies.
    MeSH term(s) Humans ; Lung Neoplasms/pathology ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Carcinoma, Non-Small-Cell Lung/genetics ; E2F1 Transcription Factor/genetics ; E2F1 Transcription Factor/metabolism ; Ephrins/genetics ; Ephrins/metabolism ; Cell Line, Tumor ; Lung/metabolism ; Gene Expression Regulation, Neoplastic/genetics
    Chemical Substances RNA, Long Noncoding ; E2F1 Transcription Factor ; Ephrins ; E2F1 protein, human
    Language English
    Publishing date 2023-11-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-06277-y
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  3. Article ; Online: iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death.

    Messelodi, Daria / Bertuccio, Salvatore Nicola / Indio, Valentina / Strocchi, Silvia / Taddia, Alberto / Serravalle, Salvatore / Bandini, Jessica / Astolfi, Annalisa / Pession, Andrea

    Cells

    2021  Volume 10, Issue 11

    Abstract: Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of ... ...

    Abstract Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are still unclear. To investigate biological mechanisms underlying the macrophage activation in GD, we derived iPSCs from a healthy donor and a GD patient line and differentiated them into hematopoietic progenitors. While GD iPSCs are able to efficiently give rise to CD33+/CD45+ myeloid progenitors, the maturation towards the CD14+/CD163+ monocyte/macrophages fate resulted enhanced in the GD lines, that in addition displayed a decreased growth potential compared to control cells either in semisolid or in liquid culture. The GD lines growth impairment was associated with a significant upregulation of RIPK3 and MLKL, two key effectors of necroptosis, the inflammation related cell death pathway. The activation of necroptosis, which has already been linked to neuronopathic GD, may play a role in the disease proinflammatory condition and in the identified cell growth defects. Understanding the GD macrophage role in the alteration of mechanisms linked to cellular metabolism imbalance, cell death and inflammation are crucial in identifying new ways to approach the disease.
    MeSH term(s) Cell Death ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Gaucher Disease/pathology ; Humans ; Induced Pluripotent Stem Cells/pathology ; Inflammation/pathology ; Macrophage Activation ; Macrophages/pathology ; Monocytes/pathology ; Necroptosis ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
    Chemical Substances MLKL protein, human (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2021-10-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10112822
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  4. 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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    Zs.MO 81: Show issues

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  5. Article ; Online: Exploring MYC relevance to cancer biology from the perspective of cell competition.

    Paglia, Simona / Sollazzo, Manuela / Di Giacomo, Simone / Strocchi, Silvia / Grifoni, Daniela

    Seminars in cancer biology

    2019  Volume 63, Page(s) 49–59

    Abstract: Cancer has long been regarded and treated as a foreign body appearing by mistake inside a living organism. However, now we know that cancer cells communicate with neighbours, thereby creating modified environments able to support their unusual need for ... ...

    Abstract Cancer has long been regarded and treated as a foreign body appearing by mistake inside a living organism. However, now we know that cancer cells communicate with neighbours, thereby creating modified environments able to support their unusual need for nutrients and space. Understanding the molecular basis of these bi-directional interactions is thus mandatory to approach the complex nature of cancer. Since their discovery, MYC proteins have been showing to regulate a steadily increasing number of processes impacting cell fitness, and are consistently found upregulated in almost all human tumours. Of interest, MYC takes part in cell competition, an evolutionarily conserved fitness comparison strategy aimed at detecting weakened cells, which are then committed to death, removed from the tissue and replaced by fitter neighbours. During physiological development, MYC-mediated cell competition is engaged to eliminate cells with suboptimal MYC levels, so as to guarantee selective growth of the fittest and proper homeostasis, while transformed cells expressing high levels of MYC coopt cell competition to subvert tissue constraints, ultimately disrupting homeostasis. Therefore, the interplay between cells with different MYC levels may result in opposite functional outcomes, depending on the nature of the players. In the present review, we describe the most recent findings on the role of MYC-mediated cell competition in different contexts, with a special emphasis on its impact on cancer initiation and progression. We also discuss the relevance of competition-associated cell death to cancer disease.
    MeSH term(s) Animals ; Cell Communication/physiology ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasms/etiology ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism
    Chemical Substances Proto-Oncogene Proteins c-myc
    Language English
    Publishing date 2019-05-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2019.05.009
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2922: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation.

    Messelodi, Daria / Strocchi, Silvia / Bertuccio, Salvatore Nicola / Baden, Pascale / Indio, Valentina / Giorgi, Federico M / Taddia, Alberto / Serravalle, Salvatore / Valente, Sabrina / di Fonzo, Alessio / Frattini, Emanuele / Bernardoni, Roberto / Pession, Annalisa / Grifoni, Daniela / Deleidi, Michela / Astolfi, Annalisa / Pession, Andrea

    Communications biology

    2023  Volume 6, Issue 1, Page(s) 431

    Abstract: Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic ...

    Abstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.
    MeSH term(s) Humans ; Gaucher Disease/genetics ; Gaucher Disease/metabolism ; Gaucher Disease/therapy ; Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Hippo Signaling Pathway ; Neurons/metabolism ; Cell Proliferation
    Chemical Substances Glucosylceramidase (EC 3.2.1.45)
    Language English
    Publishing date 2023-04-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-023-04813-2
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  7. Article ; Online: Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a

    Gandini, Annachiara / Gonçalves, Ana Elisa / Strocchi, Silvia / Albertini, Claudia / Janočková, Jana / Tramarin, Anna / Grifoni, Daniela / Poeta, Eleonora / Soukup, Ondrej / Muñoz-Torrero, Diego / Monti, Barbara / Sabaté, Raimon / Bartolini, Manuela / Legname, Giuseppe / Bolognesi, Maria Laura

    ACS chemical neuroscience

    2022  Volume 13, Issue 23, Page(s) 3314–3329

    Abstract: Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating ... ...

    Abstract Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aβ clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact
    MeSH term(s) Animals ; Alzheimer Disease/drug therapy ; Drosophila ; tau Proteins ; Drosophila melanogaster
    Chemical Substances tau Proteins
    Language English
    Publishing date 2022-11-29
    Publishing country United States
    Document type Journal Article
    ISSN 1948-7193
    ISSN (online) 1948-7193
    DOI 10.1021/acschemneuro.2c00357
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  8. Article ; Online: Pterostilbene Promotes Mean Lifespan in Both Male and Female

    Beghelli, Daniela / Zallocco, Lorenzo / Barbalace, Maria Cristina / Paglia, Simona / Strocchi, Silvia / Cirilli, Ilenia / Marzano, Valeria / Putignani, Lorenza / Lupidi, Giulio / Hrelia, Silvana / Giusti, Laura / Angeloni, Cristina

    Oxidative medicine and cellular longevity

    2022  Volume 2022, Page(s) 1744408

    Abstract: Aging is a multifactorial phenomenon characterized by degenerative processes closely connected to oxidative damage and chronic inflammation. Recently, many studies have shown that natural bioactive compounds are useful in delaying the aging process. In ... ...

    Abstract Aging is a multifactorial phenomenon characterized by degenerative processes closely connected to oxidative damage and chronic inflammation. Recently, many studies have shown that natural bioactive compounds are useful in delaying the aging process. In this work, we studied the effects of an
    MeSH term(s) Animals ; Anti-Inflammatory Agents/metabolism ; Antioxidants/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Female ; Longevity/drug effects ; Longevity/genetics ; Male ; Oxidative Stress/drug effects ; Proteome/drug effects ; Proteome/metabolism ; Sex Factors ; Stilbenes/pharmacology
    Chemical Substances Anti-Inflammatory Agents ; Antioxidants ; Drosophila Proteins ; Proteome ; Stilbenes ; pterostilbene (26R60S6A5I)
    Language English
    Publishing date 2022-02-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2455981-7
    ISSN 1942-0994 ; 1942-0994
    ISSN (online) 1942-0994
    ISSN 1942-0994
    DOI 10.1155/2022/1744408
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  9. Article: CSNK1A1, KDM2A, and LTB4R2 Are New Druggable Vulnerabilities in Lung Cancer.

    Sauta, Elisabetta / Reggiani, Francesca / Torricelli, Federica / Zanetti, Eleonora / Tagliavini, Elena / Santandrea, Giacomo / Gobbi, Giulia / Strocchi, Silvia / Paci, Massimiliano / Damia, Giovanna / Bellazzi, Riccardo / Ambrosetti, Davide / Ciarrocchi, Alessia / Sancisi, Valentina

    Cancers

    2021  Volume 13, Issue 14

    Abstract: Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell ... ...

    Abstract Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD) subtypes. Despite the introduction of innovative therapeutics, mainly designed to specifically treat AD patients, the prognosis of lung cancer remains poor. In particular, available treatments for SCLC and SCC patients are currently limited to platinum-based chemotherapy and immune checkpoint inhibitors. In this work, we used an integrative approach to identify novel vulnerabilities in lung cancer. First, we compared the data from a CRISPR/Cas9 dependency screening performed in our laboratory with Cancer Dependency Map Project data, essentiality comprising information on 73 lung cancer cell lines. Next, to identify relevant therapeutic targets, we integrated dependency data with pharmacological data and TCGA gene expression information. Through this analysis, we identified CSNK1A1, KDM2A, and LTB4R2 as relevant druggable essentiality genes in lung cancer. We validated the antiproliferative effect of genetic or pharmacological inhibition of these genes in two lung cancer cell lines. Overall, our results identified new vulnerabilities associated with different lung cancer histotypes, laying the basis for the development of new therapeutic strategies.
    Language English
    Publishing date 2021-07-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13143477
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