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Complex systems are inherently multilevel and multiscale systems. The infectious disease system is considered a complex system resulting from the interaction between three sub-systems (host, pathogen, and environment) organized into a hierarchical structure, ranging from the cellular to the macro-ecosystem level, with multiscales. Therefore, to describe infectious disease phenomena that change through time and space and at different scales, we built a model framework where infectious disease must be considered the set of biological responses of human hosts to pathogens, with biological pathways shared with other pathologies in an ecological interaction context. In this paper, we aimed to design a framework for building a disease model for COVID-19 based on current literature evidence. The model was set up by identifying the molecular pathophysiology related to the COVID-19 phenotypes, collecting the mechanistic knowledge scattered across scientific literature and bioinformatic databases, and integrating it using a logical/conceptual model systems biology. The model framework building process began from the results of a domain-based literature review regarding a multiomics approach to COVID-19. This evidence allowed us to define a framework of COVID-19 conceptual model and to report all concepts in a multilevel and multiscale structure. The same interdisciplinary working groups that carried out the scoping review were involved. The conclusive result is a conceptual method to design multiscale models of infectious diseases. The methodology, applied in this paper, is a set of partially ordered research and development activities that result in a COVID-19 multiscale model.
Francesco Messina; Chiara Montaldo; Isabella Abbate; Manuela Antonioli; Veronica Bordoni; Giulia Matusali; Alessandra Sacchi; Emanuela Giombini; Gian Fimia; Mauro Piacentini; Maria Capobianchi; Francesco Lauria; Giuseppe Ippolito; on behalf of COVID-19 Scoping Review Working Group. Rationale and Criteria for a COVID-19 Model Framework. Viruses 2021, 13, 1309 .
AMA StyleFrancesco Messina, Chiara Montaldo, Isabella Abbate, Manuela Antonioli, Veronica Bordoni, Giulia Matusali, Alessandra Sacchi, Emanuela Giombini, Gian Fimia, Mauro Piacentini, Maria Capobianchi, Francesco Lauria, Giuseppe Ippolito, on behalf of COVID-19 Scoping Review Working Group. Rationale and Criteria for a COVID-19 Model Framework. Viruses. 2021; 13 (7):1309.
Chicago/Turabian StyleFrancesco Messina; Chiara Montaldo; Isabella Abbate; Manuela Antonioli; Veronica Bordoni; Giulia Matusali; Alessandra Sacchi; Emanuela Giombini; Gian Fimia; Mauro Piacentini; Maria Capobianchi; Francesco Lauria; Giuseppe Ippolito; on behalf of COVID-19 Scoping Review Working Group. 2021. "Rationale and Criteria for a COVID-19 Model Framework." Viruses 13, no. 7: 1309.
Autophagy is a lysosomal-dependent degradative mechanism essential in maintaining cellular homeostasis, but it is also considered an ancient form of innate eukaryotic fighting against invading microorganisms. Mounting evidence has shown that HIV-1 is a critical target of autophagy that plays a role in HIV-1 replication and disease progression. In a special subset of HIV-1-infected patients that spontaneously and durably maintain extremely low viral replication, namely, long-term nonprogressors (LTNP), the resistance to HIV-1-induced pathogenesis is accompanied, in vivo, by a significant increase in the autophagic activity in peripheral blood mononuclear cells. Recently, a new player in the battle of autophagy against HIV-1 has been identified, namely, tripartite motif protein 5α (TRIM5α). In vitro data demonstrated that TRIM5α directly recognizes HIV-1 and targets it for autophagic destruction, thus protecting cells against HIV-1 infection. In this paper, we analyzed the involvement of this factor in the control of HIV-1 infection through autophagy, in vivo, in LTNP. The results obtained showed significantly higher levels of TRIM5α expression in cells from LTNP with respect to HIV-1-infected normal progressor patients. Interestingly, the colocalization of TRIM5α and HIV-1 proteins in autophagic vacuoles in LTNP cells suggested the participation of TRIM5α in the autophagy containment of HIV-1 in LTNP. Altogether, our results point to a protective role of TRIM5α in the successful control of the chronic viral infection in HIV-1-controllers through the autophagy mechanism. In our opinion, these findings could be relevant in fighting against HIV-1 disease, because autophagy inducers might be employed in combination with antiretroviral drugs.
Fabiola Ciccosanti; Marco Corazzari; Rita Casetti; Alessandra Amendola; Diletta Collalto; Giulia Refolo; Alessandra Vergori; Chiara Taibi; Gianpiero D’Offizi; Andrea Antinori; Chiara Agrati; Gian Fimia; Giuseppe Ippolito; Mauro Piacentini; Roberta Nardacci. High Levels of TRIM5α Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors. Cells 2021, 10, 1207 .
AMA StyleFabiola Ciccosanti, Marco Corazzari, Rita Casetti, Alessandra Amendola, Diletta Collalto, Giulia Refolo, Alessandra Vergori, Chiara Taibi, Gianpiero D’Offizi, Andrea Antinori, Chiara Agrati, Gian Fimia, Giuseppe Ippolito, Mauro Piacentini, Roberta Nardacci. High Levels of TRIM5α Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors. Cells. 2021; 10 (5):1207.
Chicago/Turabian StyleFabiola Ciccosanti; Marco Corazzari; Rita Casetti; Alessandra Amendola; Diletta Collalto; Giulia Refolo; Alessandra Vergori; Chiara Taibi; Gianpiero D’Offizi; Andrea Antinori; Chiara Agrati; Gian Fimia; Giuseppe Ippolito; Mauro Piacentini; Roberta Nardacci. 2021. "High Levels of TRIM5α Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors." Cells 10, no. 5: 1207.
The family of coronaviruses (CoVs) uses the autophagy machinery of host cells to promote their growth and replication; thus, this process stands out as a potential target to combat COVID-19. Considering the different roles of autophagy during viral infection, including SARS-CoV-2 infection, in this review, we discuss several clinically used drugs that have effects at different stages of autophagy. Among them, we mention (1) lysosomotropic agents, which can prevent CoVs infection by alkalinizing the acid pH in the endolysosomal system, such as chloroquine and hydroxychloroquine, azithromycin, artemisinins, two-pore channel modulators and imatinib; (2) protease inhibitors that can inhibit the proteolytic cleavage of the spike CoVs protein, which is necessary for viral entry into host cells, such as camostat mesylate, lopinavir, umifenovir and teicoplanin and (3) modulators of PI3K/AKT/mTOR signaling pathways, such as rapamycin, heparin, glucocorticoids, angiotensin-converting enzyme inhibitors (IECAs) and cannabidiol. Thus, this review aims to highlight and discuss autophagy-related drugs for COVID-19, from in vitro to in vivo studies. We identified specific compounds that may modulate autophagy and exhibit antiviral properties. We hope that research initiatives and efforts will identify novel or “off-label” drugs that can be used to effectively treat patients infected with SARS-CoV-2, reducing the risk of mortality.
Gustavo Pereira; Anderson Leão; Adolfo Erustes; Ingrid Morais; Talita Vrechi; Lucas Zamarioli; Cássia Pereira; Laís Marchioro; Letícia Sperandio; Ísis Lins; Mauro Piacentini; Gian Fimia; Patrícia Reckziegel; Soraya Smaili; Claudia Bincoletto. Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19. International Journal of Molecular Sciences 2021, 22, 4067 .
AMA StyleGustavo Pereira, Anderson Leão, Adolfo Erustes, Ingrid Morais, Talita Vrechi, Lucas Zamarioli, Cássia Pereira, Laís Marchioro, Letícia Sperandio, Ísis Lins, Mauro Piacentini, Gian Fimia, Patrícia Reckziegel, Soraya Smaili, Claudia Bincoletto. Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19. International Journal of Molecular Sciences. 2021; 22 (8):4067.
Chicago/Turabian StyleGustavo Pereira; Anderson Leão; Adolfo Erustes; Ingrid Morais; Talita Vrechi; Lucas Zamarioli; Cássia Pereira; Laís Marchioro; Letícia Sperandio; Ísis Lins; Mauro Piacentini; Gian Fimia; Patrícia Reckziegel; Soraya Smaili; Claudia Bincoletto. 2021. "Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19." International Journal of Molecular Sciences 22, no. 8: 4067.
COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular proteins hijacked by viruses for their life cycle and develop host-oriented antiviral therapeutics. Here we report the proteomic characterization of host proteins interacting with SARS-CoV-2 Nucleoprotein in infected Vero E6 cells. We identified 24 high-confidence proteins mainly playing a role in RNA metabolism and translation, including RNA helicases and scaffold proteins involved in the formation of stress granules, cytoplasmic aggregates of messenger ribonucleoproteins that accumulate as a result of stress-induced translation arrest. Analysis of stress granules upon SARS-CoV-2 infection showed that these structures are not induced in infected cells, neither eIF2α phosphorylation, an upstream event leading to stress-induced translation inhibition. Notably, we found that G3BP1, a stress granule component that associates with the Nucleoprotein, is required for efficient SARS-CoV-2 replication. Moreover, we showed that the Nucleoprotein-interacting RNA helicase DDX3X colocalizes with viral RNA foci and its inhibition by small molecules or small interfering RNAs significantly reduces viral replication. Altogether, these results indicate that SARS-CoV-2 subverts the stress granule machinery and exploits G3BP1 and DDX3X for its replication cycle, offering groundwork for future development of host-directed therapies.
Fabiola Ciccosanti; Martina Di Rienzo; Alessandra Romagnoli; Francesca Colavita; Giulia Refolo; Concetta Castilletti; Chiara Agrati; Annalaura Brai; Fabrizio Manetti; Lorenzo Botta; Maria Rosaria Capobianchi; Giuseppe Ippolito; Mauro Piacentini; Gian Maria Fimia. Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection. Antiviral Research 2021, 190, 105064 -105064.
AMA StyleFabiola Ciccosanti, Martina Di Rienzo, Alessandra Romagnoli, Francesca Colavita, Giulia Refolo, Concetta Castilletti, Chiara Agrati, Annalaura Brai, Fabrizio Manetti, Lorenzo Botta, Maria Rosaria Capobianchi, Giuseppe Ippolito, Mauro Piacentini, Gian Maria Fimia. Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection. Antiviral Research. 2021; 190 ():105064-105064.
Chicago/Turabian StyleFabiola Ciccosanti; Martina Di Rienzo; Alessandra Romagnoli; Francesca Colavita; Giulia Refolo; Concetta Castilletti; Chiara Agrati; Annalaura Brai; Fabrizio Manetti; Lorenzo Botta; Maria Rosaria Capobianchi; Giuseppe Ippolito; Mauro Piacentini; Gian Maria Fimia. 2021. "Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection." Antiviral Research 190, no. : 105064-105064.
TG2 is a multifunctional enzyme involved in several cellular processes and has emerging as a potential regulator of gene expression. In this regard, we have recently shown that TG2 is able to activate HSF1, the master transcriptional regulator of the stress‐responsive genes; however, its effect on the overall gene expression remains unclear. To address this point, we analyzed, by RNA-seq, the effect of TG2 on the overall transcriptome as well as we characterized the TG2 interactome in the nucleus. The data obtained from these omics approaches reveal that TG2 markedly influences the overall cellular transcriptome profile and specifically the Wnt and HSF1 pathways. In particular, its ablation leads to a drastic downregulation of many key members of these pathways. Interestingly, we found that key components of the Wnt/β-catenin pathway are also downregulated in cells lacking HSF1, thus confirming that TG2 regulates the HSF1 and this axis controls the Wnt signaling. Mechanistic studies revealed that TG2 can regulate the Wnt pathway by physically interacts with β-catenin and its nuclear interactome includes several proteins known to be involved in the regulation of the Wnt signaling. In order to verify whether this effect is playing a role in vivo, we ablated TG2 in Danio rerio. Our data show that the zebrafish lacking TG2 cannot complete the development and their death is associated with an evident downregulation of the Wnt pathway and a defective heat-shock response. Our findings show for the first time that TG2 is essential for the correct embryonal development of lower vertebrates, and its action is mediated by the Wnt/HSF1 axis.
Federica Rossin; Roberto Costa; Matteo Bordi; Manuela D’Eletto; Luca Occhigrossi; Maria Grazia Farrace; Nickolai Barlev; Fabiola Ciccosanti; Silvia Muccioli; Leonardo Chieregato; Ildiko Szabo; Gian Maria Fimia; Mauro Piacentini; Luigi Leanza. Transglutaminase Type 2 regulates the Wnt/β-catenin pathway in vertebrates. Cell Death & Disease 2021, 12, 1 -13.
AMA StyleFederica Rossin, Roberto Costa, Matteo Bordi, Manuela D’Eletto, Luca Occhigrossi, Maria Grazia Farrace, Nickolai Barlev, Fabiola Ciccosanti, Silvia Muccioli, Leonardo Chieregato, Ildiko Szabo, Gian Maria Fimia, Mauro Piacentini, Luigi Leanza. Transglutaminase Type 2 regulates the Wnt/β-catenin pathway in vertebrates. Cell Death & Disease. 2021; 12 (3):1-13.
Chicago/Turabian StyleFederica Rossin; Roberto Costa; Matteo Bordi; Manuela D’Eletto; Luca Occhigrossi; Maria Grazia Farrace; Nickolai Barlev; Fabiola Ciccosanti; Silvia Muccioli; Leonardo Chieregato; Ildiko Szabo; Gian Maria Fimia; Mauro Piacentini; Luigi Leanza. 2021. "Transglutaminase Type 2 regulates the Wnt/β-catenin pathway in vertebrates." Cell Death & Disease 12, no. 3: 1-13.
Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favourable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC.
Manuela Antonioli; Benedetta Pagni; Tiziana Vescovo; Rob Ellis; Benjamin Cosway; Francesca Rollo; Veronica Bordoni; Chiara Agrati; Marie Labus; Renato Covello; Maria Benevolo; Giuseppe Ippolito; Max Robinson; Mauro Piacentini; Penny Lovat; Gian Maria Fimia. HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1. Autophagy 2020, 1 -14.
AMA StyleManuela Antonioli, Benedetta Pagni, Tiziana Vescovo, Rob Ellis, Benjamin Cosway, Francesca Rollo, Veronica Bordoni, Chiara Agrati, Marie Labus, Renato Covello, Maria Benevolo, Giuseppe Ippolito, Max Robinson, Mauro Piacentini, Penny Lovat, Gian Maria Fimia. HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1. Autophagy. 2020; ():1-14.
Chicago/Turabian StyleManuela Antonioli; Benedetta Pagni; Tiziana Vescovo; Rob Ellis; Benjamin Cosway; Francesca Rollo; Veronica Bordoni; Chiara Agrati; Marie Labus; Renato Covello; Maria Benevolo; Giuseppe Ippolito; Max Robinson; Mauro Piacentini; Penny Lovat; Gian Maria Fimia. 2020. "HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1." Autophagy , no. : 1-14.
Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regulates autophagy by interacting with raft-like components. ERLIN1 is an endoplasmic reticulum lipid raft protein of the prohibitin family. However, little is known about its association with the MAM interface and its involvement in autophagic initiation. In this study, we investigated ERLIN1 association with MAM raft-like microdomains and its interaction with AMBRA1 in the regulation of the autophagic process. We show that ERLIN1 interacts with AMBRA1 at MAM raft-like microdomains, which represents an essential condition for autophagosome formation upon nutrient starvation, as demonstrated by knocking down ERLIN1 gene expression. Moreover, this interaction depends on the "integrity" of key molecules, such as ganglioside GD3 and MFN2. Indeed, knocking down ST8SIA1/GD3-synthase or MFN2 expression impairs AMBRA1-ERLIN1 interaction at the MAM level and hinders autophagy. In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes. Abbreviations: ACSL4/ACS4: acyl-CoA synthetase long chain family member 4; ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATG14: autophagy related 14; BECN1: beclin 1; CANX: calnexin; Cy5: cyanine 5; ECL: enhanced chemiluminescence; ER: endoplasmic reticulum; ERLIN1/KE04: ER lipid raft associated 1; FB1: fumonisin B1; FE: FRET efficiency; FRET: Förster/fluorescence resonance energy transfer; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD3: aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)ceramide; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; LMNB1: lamin B1; mAb: monoclonal antibody; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MYC/cMyc: proto-oncogene, bHLH transcription factor; P4HB: prolyl 4-hydroxylase subunit beta; pAb: polyclonal antibody; PE: phycoerythrin; SCAP/SREBP: SREBF chaperone; SD: standard deviation; ST8SIA1: ST8 alpha-N-acetyl-neuraminide alpha-2,8 sialyltransferase 1; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBB/beta-tubulin: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; VDAC1/porin: voltage dependent anion channel 1.
Valeria Manganelli; Paola Matarrese; Manuela Antonioli; Lucrezia Gambardella; Tiziana Vescovo; Christine Gretzmeier; Agostina Longo; Antonella Capozzi; Serena Recalchi; Gloria Riitano; Roberta Misasi; Joern Dengjel; Walter Malorni; Gian Maria Fimia; Maurizio Sorice; Tina Garofalo. Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs. Autophagy 2020, 1 -21.
AMA StyleValeria Manganelli, Paola Matarrese, Manuela Antonioli, Lucrezia Gambardella, Tiziana Vescovo, Christine Gretzmeier, Agostina Longo, Antonella Capozzi, Serena Recalchi, Gloria Riitano, Roberta Misasi, Joern Dengjel, Walter Malorni, Gian Maria Fimia, Maurizio Sorice, Tina Garofalo. Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs. Autophagy. 2020; ():1-21.
Chicago/Turabian StyleValeria Manganelli; Paola Matarrese; Manuela Antonioli; Lucrezia Gambardella; Tiziana Vescovo; Christine Gretzmeier; Agostina Longo; Antonella Capozzi; Serena Recalchi; Gloria Riitano; Roberta Misasi; Joern Dengjel; Walter Malorni; Gian Maria Fimia; Maurizio Sorice; Tina Garofalo. 2020. "Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs." Autophagy , no. : 1-21.
The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their ‘official’ pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.
Allan Sauvat; Fabiola Ciccosanti; Francesca Colavita; Martina Di Rienzo; Concetta Castilletti; Maria Rosaria Capobianchi; Oliver Kepp; Laurence Zitvogel; Gian Maria Fimia; Mauro Piacentini; Guido Kroemer. On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2. Cell Death & Disease 2020, 11, 1 -11.
AMA StyleAllan Sauvat, Fabiola Ciccosanti, Francesca Colavita, Martina Di Rienzo, Concetta Castilletti, Maria Rosaria Capobianchi, Oliver Kepp, Laurence Zitvogel, Gian Maria Fimia, Mauro Piacentini, Guido Kroemer. On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2. Cell Death & Disease. 2020; 11 (8):1-11.
Chicago/Turabian StyleAllan Sauvat; Fabiola Ciccosanti; Francesca Colavita; Martina Di Rienzo; Concetta Castilletti; Maria Rosaria Capobianchi; Oliver Kepp; Laurence Zitvogel; Gian Maria Fimia; Mauro Piacentini; Guido Kroemer. 2020. "On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2." Cell Death & Disease 11, no. 8: 1-11.
SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.
Chiara Agrati; Alessandra Sacchi; Veronica Bordoni; Eleonora Cimini; Stefania Notari; Germana Grassi; Rita Casetti; Eleonora Tartaglia; Eleonora Lalle; Alessandra D'Abramo; Concetta Castilletti; Luisa Marchioni; Yufang Shi; Andrea Mariano; Jin-Wen Song; Ji-Yuan Zhang; Fu-Sheng Wang; Chao Zhang; Gian Maria Fimia; Maria R. Capobianchi; Mauro Piacentini; Andrea Antinori; Emanuele Nicastri; Markus Maeurer; Professor Sir Alimuddin Zumla; Giuseppe Ippolito. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death & Differentiation 2020, 27, 3196 -3207.
AMA StyleChiara Agrati, Alessandra Sacchi, Veronica Bordoni, Eleonora Cimini, Stefania Notari, Germana Grassi, Rita Casetti, Eleonora Tartaglia, Eleonora Lalle, Alessandra D'Abramo, Concetta Castilletti, Luisa Marchioni, Yufang Shi, Andrea Mariano, Jin-Wen Song, Ji-Yuan Zhang, Fu-Sheng Wang, Chao Zhang, Gian Maria Fimia, Maria R. Capobianchi, Mauro Piacentini, Andrea Antinori, Emanuele Nicastri, Markus Maeurer, Professor Sir Alimuddin Zumla, Giuseppe Ippolito. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death & Differentiation. 2020; 27 (11):3196-3207.
Chicago/Turabian StyleChiara Agrati; Alessandra Sacchi; Veronica Bordoni; Eleonora Cimini; Stefania Notari; Germana Grassi; Rita Casetti; Eleonora Tartaglia; Eleonora Lalle; Alessandra D'Abramo; Concetta Castilletti; Luisa Marchioni; Yufang Shi; Andrea Mariano; Jin-Wen Song; Ji-Yuan Zhang; Fu-Sheng Wang; Chao Zhang; Gian Maria Fimia; Maria R. Capobianchi; Mauro Piacentini; Andrea Antinori; Emanuele Nicastri; Markus Maeurer; Professor Sir Alimuddin Zumla; Giuseppe Ippolito. 2020. "Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)." Cell Death & Differentiation 27, no. 11: 3196-3207.
Skin melanoma is one of the most aggressive and difficult-to-treat human malignancies, characterized by poor survival rates, thus requiring urgent novel therapeutic approaches. Although metabolic reprogramming has represented so far, a cancer hallmark, accumulating data indicate a high plasticity of cancer cells in modulating cellular metabolism to adapt to a heterogeneous and continuously changing microenvironment, suggesting a novel therapeutic approach for dietary manipulation in cancer therapy. To this aim, we exposed melanoma cells to combined nutrient-restriction/sorafenib. Results indicate that cell death was efficiently induced, with apoptosis representing the prominent feature. In contrast, autophagy was blocked in the final stage by this treatment, similarly to chloroquine, which also enhanced melanoma cell sensitization to combined treatment. Energy stress was evidenced by associated treatment with mitochondrial dysfunction and glycolysis impairment, suggesting metabolic stress determining melanoma cell death. A reduction of tumor growth after cycles of intermittent fasting together with sorafenib treatment was also observed in vivo, reinforcing that the nutrient shortage can potentiate anti-melanoma therapy. Our findings showed that the restriction of nutrients by intermittent fasting potentiates the effects of sorafenib due to the modulation of cellular metabolism, suggesting that it is possible to harness the energy of cancer cells for the treatment of melanoma.
Fernanda Antunes; Gustavo J. S. Pereira; Renata F. Saito; Marcus V. Buri; Mara Gagliardi; Claudia Bincoletto; Roger Chammas; Gian Maria Fimia; Mauro Piacentini; Marco Corazzari; Soraya Soubhi Smaili. Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress. Cells 2020, 9, 640 .
AMA StyleFernanda Antunes, Gustavo J. S. Pereira, Renata F. Saito, Marcus V. Buri, Mara Gagliardi, Claudia Bincoletto, Roger Chammas, Gian Maria Fimia, Mauro Piacentini, Marco Corazzari, Soraya Soubhi Smaili. Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress. Cells. 2020; 9 (3):640.
Chicago/Turabian StyleFernanda Antunes; Gustavo J. S. Pereira; Renata F. Saito; Marcus V. Buri; Mara Gagliardi; Claudia Bincoletto; Roger Chammas; Gian Maria Fimia; Mauro Piacentini; Marco Corazzari; Soraya Soubhi Smaili. 2020. "Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress." Cells 9, no. 3: 640.
About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.
Tiziana Vescovo; Benedetta Pagni; Mauro Piacentini; Gian Maria Fimia; Manuela Antonioli. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Frontiers in Cell and Developmental Biology 2020, 8, 47 .
AMA StyleTiziana Vescovo, Benedetta Pagni, Mauro Piacentini, Gian Maria Fimia, Manuela Antonioli. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Frontiers in Cell and Developmental Biology. 2020; 8 ():47.
Chicago/Turabian StyleTiziana Vescovo; Benedetta Pagni; Mauro Piacentini; Gian Maria Fimia; Manuela Antonioli. 2020. "Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development." Frontiers in Cell and Developmental Biology 8, no. : 47.
In the last years, proteomics has represented a valuable approach to elucidate key aspects in the regulation of type I/III interferons (IFNs) and autophagy, two main processes involved in the response to viral infection, to unveil the molecular strategies that viruses have evolved to counteract these processes. Besides their main metabolic roles, mitochondria are well recognized as pivotal organelles in controlling signaling pathways essential to restrain viral infections. In particular, a major role in antiviral defense is played by mitochondrial antiviral signaling (MAVS) protein, an adaptor protein that coordinates the activation of IFN inducing pathways and autophagy at the mitochondrial level. Here, we provide an overview of how mass spectrometry-based studies of protein–protein interactions and post-translational modifications (PTMs) have fostered our understanding of the molecular mechanisms that control the mitochondria-mediated antiviral immunity.
Giulia Refolo; Tiziana Vescovo; Mauro Piacentini; Gian Maria Fimia; Fabiola Ciccosanti. Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways. Frontiers in Cell and Developmental Biology 2020, 8, 1 .
AMA StyleGiulia Refolo, Tiziana Vescovo, Mauro Piacentini, Gian Maria Fimia, Fabiola Ciccosanti. Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways. Frontiers in Cell and Developmental Biology. 2020; 8 ():1.
Chicago/Turabian StyleGiulia Refolo; Tiziana Vescovo; Mauro Piacentini; Gian Maria Fimia; Fabiola Ciccosanti. 2020. "Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways." Frontiers in Cell and Developmental Biology 8, no. : 1.
Autophagy, a main intracellular catabolic process, is induced in response to a variety of cellular stresses to promptly degrade harmful agents and to coordinate the activity of prosurvival and prodeath processes in order to determine the fate of the injured cells. While the main components of the autophagy machinery are well characterized, the molecular mechanisms that confer selectivity to this process both in terms of stress detection and cargo engulfment have only been partly elucidated. Here, we discuss the emerging role played by the E3 ubiquitin ligases of the TRIM family in regulating autophagy in physiological and pathological conditions, such as inflammation, infection, tumorigenesis, and muscle atrophy. TRIM proteins employ different strategies to regulate the activity of the core autophagy machinery, acting either as scaffold proteins or via ubiquitin-mediated mechanisms. Moreover, they confer high selectivity to the autophagy-mediated degradation as described for the innate immune response, where TRIM proteins mediate both the engulfment of pathogens within autophagosomes and modulate the immune response by controlling the stability of signaling regulators. Importantly, the elucidation of the molecular mechanisms underlying the regulation of autophagy by TRIMs is providing important insights into how selective types of autophagy are altered under pathological conditions, as recently shown in cancer and muscular dystrophy.
Martina Di Rienzo; Alessandra Romagnoli; Manuela Antonioli; Mauro Piacentini; Gian Maria Fimia. TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses. Cell Death & Differentiation 2020, 27, 887 -902.
AMA StyleMartina Di Rienzo, Alessandra Romagnoli, Manuela Antonioli, Mauro Piacentini, Gian Maria Fimia. TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses. Cell Death & Differentiation. 2020; 27 (3):887-902.
Chicago/Turabian StyleMartina Di Rienzo; Alessandra Romagnoli; Manuela Antonioli; Mauro Piacentini; Gian Maria Fimia. 2020. "TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses." Cell Death & Differentiation 27, no. 3: 887-902.
The Ser/Thr protein kinase ULK1 is an upstream macroautophagy/autophagy regulator that is rapidly activated to ensure a proper adaptive response to stress conditions. Signaling pathways modulating ULK1 activity have been extensively characterized in response to nutrient/energy shortage, which mainly act by mediating ULK1 post-translational modifications, such as phosphorylation, acetylation and ubiquitination. Less characterized is how tissue-specific stress signals are able to activate ULK1 to induce autophagy. Our recent study has uncovered the E3 ubiquitin ligase TRIM32 as a novel ULK1 activator that regulates autophagy in muscle cells upon atrophy induction. TRIM32 is conveyed to ULK1 by the autophagy cofactor AMBRA1 to stimulate its kinase activity through unanchored K63-linked polyubiquitin chains. Notably, mutations in TRIM32 responsible for limb-girdle muscular dystrophy 2H disrupt its ability to bind ULK1 and to induce autophagy in muscle cells, resulting in a dysregulated activation of the atrophic process. In conclusion, we have identified a novel molecular mechanism by which autophagy is regulated in muscles, whose alteration is associated with the development of muscular dystrophy.
Martina Di Rienzo; Mauro Piacentini; Gian Maria Fimia. A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells. Autophagy 2019, 15, 1674 -1676.
AMA StyleMartina Di Rienzo, Mauro Piacentini, Gian Maria Fimia. A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells. Autophagy. 2019; 15 (9):1674-1676.
Chicago/Turabian StyleMartina Di Rienzo; Mauro Piacentini; Gian Maria Fimia. 2019. "A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells." Autophagy 15, no. 9: 1674-1676.
Statins efficiently inhibit cholesterol synthesis by blocking 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the mevalonate pathway. However, the effect of statins on intracellular cholesterol is partially counterbalanced by a consequent increased uptake of extracellular lipid sources. Hepatitis C virus (HCV) infection induces intracellular accumulation of cholesterol by promoting both new synthesis and uptake of circulating lipoproteins, which is required for HCV replication and release. Hepatocytes respond to the increase in intracellular cholesterol levels by inducing lipophagy, a selective type of autophagy mediating the degradation of lipid deposits within lysosomes. In a cellular system of HCV replication based on HuH7 hepatoma cells, statin treatment was shown to be sufficient to decrease intracellular cholesterol, which is accompanied by reduced HCV replication and decreased lipophagy, and has no apparent impact on endocytosis-mediated cholesterol uptake. To understand whether these results were influenced by an altered response of cholesterol influx in hepatoma cells, we analyzed the effect of statins in non-transformed murine hepatocytes (MMHD3) harboring subgenomic HCV replicons. Notably, we found that total amount of cholesterol is increased in MMHD3 cells upon mevastatin treatment, which is associated with increased HCV replication and lipophagy. Conversely, mevastatin is able to reduce cholesterol amounts only when cells are grown in the presence of delipidated serum to prevent extracellular lipid uptake. Under this condition, HCV replication is reduced and autophagy flux is severely impaired. Altogether, these results indicate that both de novo synthesis and extracellular uptake have to be targeted in non-transformed hepatocytes in order to decrease intracellular cholesterol levels and consequently limit HCV replication.
Tiziana Vescovo; Giulia Refolo; Matteo Ciancio Manuelli; Giuseppe Tisone; Mauro Piacentini; Gian Maria Fimia. The Impact of Mevastatin on HCV Replication and Autophagy of Non-Transformed HCV Replicon Hepatocytes Is Influenced by the Extracellular Lipid Uptake. Frontiers in Pharmacology 2019, 10, 718 .
AMA StyleTiziana Vescovo, Giulia Refolo, Matteo Ciancio Manuelli, Giuseppe Tisone, Mauro Piacentini, Gian Maria Fimia. The Impact of Mevastatin on HCV Replication and Autophagy of Non-Transformed HCV Replicon Hepatocytes Is Influenced by the Extracellular Lipid Uptake. Frontiers in Pharmacology. 2019; 10 ():718.
Chicago/Turabian StyleTiziana Vescovo; Giulia Refolo; Matteo Ciancio Manuelli; Giuseppe Tisone; Mauro Piacentini; Gian Maria Fimia. 2019. "The Impact of Mevastatin on HCV Replication and Autophagy of Non-Transformed HCV Replicon Hepatocytes Is Influenced by the Extracellular Lipid Uptake." Frontiers in Pharmacology 10, no. : 718.
Interferon-γ inducible protein 10 (IP-10), is a potent chemoattractant that promotes migration of monocytes and activated T-cells to inflammation foci. IP-10 is elevated in serum of patients with chronic hepatitis C virus (HCV) and tuberculosis (TB) infections, although it remains to be determined the contribution of IP-10 in restricting Mycobacterium tuberculosis (Mtb) replication. Here, we investigated the impact of IP-10 on mycobacteria replication using the ex vivo model of human whole-blood (WB) assay. In particular, we compared the levels of IP-10 upon infection with different Mtb clinical strains and species of non-tuberculous mycobacteria (NTM) and evaluated how IP-10 may contain bacterial replication. Interestingly, we observed that the inhibition of the host enzyme dipeptidyl peptidase IV (DPP-IV), which inactivates IP-10 through cleavage of two amino acids at the chemokine N-terminus, restricted mycobacterial persistence in WB, supporting the critical role of full length IP-10 in mediating an anti-Mtb response. Addition of recombinant IP-10 expressed in eukaryotic cells enhanced the anti-mycobacterial activity in WB, although no differences were observed when IP-10 containing different proportions of cleaved and non-cleaved forms of the chemokine were added. Moreover, recombinant IP-10 did not exert a direct anti-mycobacterial effect. Our results underscore the clinical relevance of IP-10 in mycobacteria pathogenesis and support the potential outcomes that may derive by targeting the IP-10/CXCR3 pathway as host directed therapies for the treatment of Mtb or NTM infections.
Ivana Palucci; Basem Battah; Alessandro Salustri; Flavio De Maio; Linda Petrone; Fabiola Ciccosanti; Michela Sali; Vincent Bondet; Darragh Duffy; Gian Maria Fimia; Delia Goletti; Giovanni Delogu. IP-10 contributes to the inhibition of mycobacterial growth in an ex vivo whole blood assay. International Journal of Medical Microbiology 2019, 309, 299 -306.
AMA StyleIvana Palucci, Basem Battah, Alessandro Salustri, Flavio De Maio, Linda Petrone, Fabiola Ciccosanti, Michela Sali, Vincent Bondet, Darragh Duffy, Gian Maria Fimia, Delia Goletti, Giovanni Delogu. IP-10 contributes to the inhibition of mycobacterial growth in an ex vivo whole blood assay. International Journal of Medical Microbiology. 2019; 309 (5):299-306.
Chicago/Turabian StyleIvana Palucci; Basem Battah; Alessandro Salustri; Flavio De Maio; Linda Petrone; Fabiola Ciccosanti; Michela Sali; Vincent Bondet; Darragh Duffy; Gian Maria Fimia; Delia Goletti; Giovanni Delogu. 2019. "IP-10 contributes to the inhibition of mycobacterial growth in an ex vivo whole blood assay." International Journal of Medical Microbiology 309, no. 5: 299-306.
Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32’s ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.
M. Di Rienzo; M. Antonioli; C. Fusco; Y. Liu; M. Mari; I. Orhon; G. Refolo; F. Germani; M. Corazzari; A. Romagnoli; F. Ciccosanti; B. Mandriani; M. T. Pellico; R. De La Torre; H. Ding; M. Dentice; M. Neri; A. Ferlini; F. Reggiori; M. Kulesz-Martin; M. Piacentini; G. Merla; G. M. Fimia. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Science Advances 2019, 5, eaau8857 .
AMA StyleM. Di Rienzo, M. Antonioli, C. Fusco, Y. Liu, M. Mari, I. Orhon, G. Refolo, F. Germani, M. Corazzari, A. Romagnoli, F. Ciccosanti, B. Mandriani, M. T. Pellico, R. De La Torre, H. Ding, M. Dentice, M. Neri, A. Ferlini, F. Reggiori, M. Kulesz-Martin, M. Piacentini, G. Merla, G. M. Fimia. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains. Science Advances. 2019; 5 (5):eaau8857.
Chicago/Turabian StyleM. Di Rienzo; M. Antonioli; C. Fusco; Y. Liu; M. Mari; I. Orhon; G. Refolo; F. Germani; M. Corazzari; A. Romagnoli; F. Ciccosanti; B. Mandriani; M. T. Pellico; R. De La Torre; H. Ding; M. Dentice; M. Neri; A. Ferlini; F. Reggiori; M. Kulesz-Martin; M. Piacentini; G. Merla; G. M. Fimia. 2019. "Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains." Science Advances 5, no. 5: eaau8857.
The limited availability of rapid and reliable flow cytometry-based assays for ex vivo quantification of autophagy has hampered their clinical applications for studies of diseases pathogenesis or for the implementation of autophagy-targeting therapies. To this aim, we modified and improved the protocol of a commercial kit developed for quantifying the microtubule-associated protein 1A/1B light chain 3B (LC3), the most reliable marker for autophagosomes currently available. The protocol modifications were set up measuring the autophagic flux in neoplastic (THP-1 cells) and primary cells (peripheral blood mononuclear cells; PBMC) of healthy donors. Moreover, PBMC of active tuberculosis (TB) patients were stimulated with the Mycobacterium tuberculosis purified protein derivatives or infected with live Mycobacterium bovis bacillus Calmette-Guerin (BCG). We found that the baseline median fluorescent intensity (MFI) of THP-1 cells changed depending on the time of sample acquisition to the flow cytometer. To solve this problem, a fixation step was introduced in different stages of the assay's protocol, obtaining more reproducible and sensitive results when a post-LC3 staining fixation was performed, in either THP1 or PBMC. Furthermore, since we found that results are influenced by the type and the dose of the lysosome inhibitor used, the best dose of Chloroquine for LC3 accumulation were set up in either THP-1 cells or PBMC. Finally, applying these experimental settings, we measured the autophagic flux in CD14+ cells from active TB patients' PBMC upon BCG infection. In conclusion, our data indicate that the protocol modifications here described in this work improve the stability and accuracy of a flow cytometry-based assay for the evaluation of autophagy, thus assuring more standardised cell analyses.
Tonino Alonzi; Elisa Petruccioli; Valentina Vanini; Gian Maria Fimia; Delia Goletti. Optimization of the autophagy measurement in a human cell line and primary cells by flow cytometry. European Journal of Histochemistry 2019, 63, 1 .
AMA StyleTonino Alonzi, Elisa Petruccioli, Valentina Vanini, Gian Maria Fimia, Delia Goletti. Optimization of the autophagy measurement in a human cell line and primary cells by flow cytometry. European Journal of Histochemistry. 2019; 63 (2):1.
Chicago/Turabian StyleTonino Alonzi; Elisa Petruccioli; Valentina Vanini; Gian Maria Fimia; Delia Goletti. 2019. "Optimization of the autophagy measurement in a human cell line and primary cells by flow cytometry." European Journal of Histochemistry 63, no. 2: 1.
Morphogenetic events that occur during development and regeneration are energy demanding processes requiring profound rearrangements in cell architecture, which need to be coordinated in timely fashion with other cellular activities, such as proliferation, migration and differentiation. In the last 15 years, it has become evident that autophagy, an evolutionarily-conserved catabolic process that mediates the lysosomal turnover of organelles and macromolecules, is an essential “tool” to ensure remodelling events that occur at cellular and tissue levels. Indeed, studies in several model organisms have shown that the inactivation of autophagy genes has a significant impact on embryogenesis and tissue regeneration, leading to extensive cell death and persistence of unnecessary cell components. Interestingly, the increased understanding of the mechanisms that confers selectivity to the autophagic process has also contributed to identifying development-specific targets of autophagy across species. Moreover, alternative ways to deliver materials to the lysosome, such as microautophagy, are also emerging as key actors in these contexts, providing a more complete view of how the cell component repertoire is renovated. In this review, we discuss the role of different types of autophagy in development and regeneration of invertebrates and vertebrates, focusing in particular on its contribution in cnidarians, platyhelminthes, nematodes, insects, zebrafish and mammals.
G. Tettamanti; E. Carata; Aurora Montali; L. Dini; G. M. Fimia. Autophagy in development and regeneration: role in tissue remodelling and cell survival. The European Zoological Journal 2019, 86, 113 -131.
AMA StyleG. Tettamanti, E. Carata, Aurora Montali, L. Dini, G. M. Fimia. Autophagy in development and regeneration: role in tissue remodelling and cell survival. The European Zoological Journal. 2019; 86 (1):113-131.
Chicago/Turabian StyleG. Tettamanti; E. Carata; Aurora Montali; L. Dini; G. M. Fimia. 2019. "Autophagy in development and regeneration: role in tissue remodelling and cell survival." The European Zoological Journal 86, no. 1: 113-131.
Linda Petrone; Vincent Bondet; Valentina Vanini; Gilda Cuzzi; Fabrizio Palmieri; Ivana Palucci; Giovanni Delogu; Fabiola Ciccosanti; Gian Maria Fimia; Thomas Blauenfeldt; Morten Ruhwald; Darragh Duffy; Delia Goletti. First description of agonist and antagonist IP-10 in urine of patients with active TB. International Journal of Infectious Diseases 2019, 78, 15 -21.
AMA StyleLinda Petrone, Vincent Bondet, Valentina Vanini, Gilda Cuzzi, Fabrizio Palmieri, Ivana Palucci, Giovanni Delogu, Fabiola Ciccosanti, Gian Maria Fimia, Thomas Blauenfeldt, Morten Ruhwald, Darragh Duffy, Delia Goletti. First description of agonist and antagonist IP-10 in urine of patients with active TB. International Journal of Infectious Diseases. 2019; 78 ():15-21.
Chicago/Turabian StyleLinda Petrone; Vincent Bondet; Valentina Vanini; Gilda Cuzzi; Fabrizio Palmieri; Ivana Palucci; Giovanni Delogu; Fabiola Ciccosanti; Gian Maria Fimia; Thomas Blauenfeldt; Morten Ruhwald; Darragh Duffy; Delia Goletti. 2019. "First description of agonist and antagonist IP-10 in urine of patients with active TB." International Journal of Infectious Diseases 78, no. : 15-21.