MARTINA VINCENZI

PhD Graduate

PhD program:: XXXVI



Thesis title: Multifaceted roles of prokineticins and prokineticin receptors

More than two decades of research on the prokineticin system show that prokineticins (PKs) are involved in several physiological processes such as angiogenesis, neurogenesis, nociception, regulation of the circadian cycle, and reproduction by acting as angiogenic, anorectic and proinflammatory cytokines, hormones, and neuropeptides. Therefore, mutations, dysfunctions or dysregulations of PKs and their cognate receptors (PKRs) may be involved in various pathologies and trigger disease progression or promote their cure, depending on the pathological insults. After reviewing the current knowledge on the functions of the PK system in health and disease and evidencing the promising effects of PKR non-peptide ligands in various preclinical models, in the present thesis I have highlighted the multifaceted roles of PK2 and PKRs in diseases with a strong neuroinflammatory component as Parkinson’s disease (PD) and post-COVID-19 olfactory dysfunction (OD) as well as in acquired chemoresistance in cancer suggesting the potential of PK2 and PKRs as biomarkers and/or novel therapeutic targets in humans. We investigated the dynamics of PK2 pathway, at both the mRNA and protein levels, in olfactory neurons of PD patients at different disease stages and determined the relationship between PK2 upregulation and clinicopathological features of PD. In particular, the increase in PK2 levels in early disease stages and in accordance with the severity of motor symptoms and the accumulation of α-synuclein suggests that PK2 serves as both disease biomarker and novel therapeutic target for PD. Furthermore, overexpression of PK2 was also found in olfactory neurons from patients with post-COVID-19 OD compared to healthy controls. We hypothesised that PK2 is neuroprotective in PD, especially at the beginning of the disease course, and that it seems to support recovery of the sense of smell following post-COVID-19 OD. These data highlight for the first time the promising role of PKR agonists as a disease-modifying therapy in both PD and post-COVID-19 OD. In addition, we also examined the expression profile of Substance P (SP), a neurotransmitter whose role in PD and olfaction has been extensively described by previous studies, in olfactory neurons of PD and post-COVID-19 OD patients. We found a correlation between olfactory neuronal SP and gastrointestinal dysfunction in PD, confirming the reliability of olfactory neurons as a model to study PD progression. In post-COVID-19 OD, persistent activation of SP appears to maintain inflammation and contribute to olfactory impairment, counteracting the functions of PK2. Finally, we developed heterocellular spheroid models of human breast and lung cancer that resemble the in vivo tumour response to treatment, to investigate pathways of acquired resistance to Doxorubicin (Dox). We demonstrated that hypoxia-induced HIF-1α plays a role in mediating resistance. This occurs through the increase of CD73, an enzyme responsible for ATP hydrolysis into adenosine. Moreover, hypoxia-induced HIF-1α and the subsequently activation of CD73 promotes the release of PK2, which may be a biomarker for the development of resistance associated with Dox therapy. Despite the promising results here reported, a more detailed characterization of PK2 pathway dynamics in humans is needed to validate its clinical value.

Research products

11573/1716076 - 2024 - MRAP2a Binds and Modulates Activity and Localisation of Prokineticin Receptor 1 in Zebrafish
Fullone, Maria Rosaria; Maftei, Daniela; Vincenzi, Martina; Lattanzi, Roberta; Miele, Rossella - 01a Articolo in rivista
paper: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 7816-7829 - issn: 1422-0067 - wos: WOS:001277588400001 (0) - scopus: 2-s2.0-85199753937 (0)

11573/1716068 - 2024 - MRAP2 inhibits β-arrestin-2 recruitment to the Prokineticin 2 receptor 2
Lattanzi, R.; Casella, I.; Fullone, M. R.; Maftei, D.; Vincenzi, M.; Miele, R. - 01a Articolo in rivista
paper: CURRENT ISSUES IN MOLECULAR BIOLOGY (-Horizon Scientific Press-Caister Academic Press. -Wymondham: Caister Academic.) pp. 1-13 - issn: 1467-3037 - wos: WOS:001175101900001 (2) - scopus: (0)

11573/1716072 - 2024 - Mapping the interaction site for β-arrestin-2 in the prokineticin 2 receptor
Lattanzi, R.; Casella, I.; Fullone, M. R.; Vincenzi, M.; Maftei, D.; Miele, R. - 01a Articolo in rivista
paper: CELLULAR SIGNALLING (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 111175-111183 - issn: 0898-6568 - wos: WOS:001231058200001 (0) - scopus: 2-s2.0-85190328726 (0)

11573/1717238 - 2024 - Biochemical characterization of Prokineticin 2 binding to Prokineticin receptor 1 in zebrafish
Lattanzi, Roberta; Fullone, Maria Rosaria; De Biase, Alessio; Maftei, Daniela; Vincenzi, Martina; Miele, Rossella - 01a Articolo in rivista
paper: NEUROPEPTIDES (Harcourt Publishers Limited:Foots Cray High Street, Sidcup Kent DA14 5HP United Kingdom:011 44 20 83085700, EMAIL: journals@harcourt.com, INTERNET: http://www.harcourt-international.com, Fax: 011 44 20 83085876) pp. 1-11 - issn: 0143-4179 - wos: WOS:001286022500001 (0) - scopus: 2-s2.0-85199764808 (1)

11573/1718046 - 2024 - N-palmitoyl-D-glucosamine limits mucosal damage and VEGFmediated angiogenesis by PPARα-dependent suppression of pAkt/mTOR/HIF1α pathway and increase in PEA levels in AOM/DSS colorectal carcinoma in mice
Palenca, Irene; Basili Franzin, Silvia; Zilli, Aurora; Seguella, Luisa; Troiani, Anna; Pepi, Federico; Vincenzi, Martina; Giugliano, Giuseppe; Catapano, Viviana; Di Filippo, Italia; Sarnelli, Giovanni; Esposito, Giuseppe - 01a Articolo in rivista
paper: PHYTOTHERAPY RESEARCH (New York : J. Wiley) pp. - - issn: 1099-1573 - wos: (0) - scopus: (0)

11573/1669994 - 2023 - Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction
Schirinzi, Tommaso; Lattanzi, Roberta; Maftei, Daniela; Grillo, Piergiorgio; Zenuni, Henri; Boffa, Laura; Albanese, Maria; Simonetta, Clara; Bovenzi, Roberta; Maurizi, Riccardo; Loccisano, Laura; Vincenzi, Martina; Greco, Antonio; Di Girolamo, Stefano; Mercuri, Nicola B; Passali, Francesco M; Severini, Cinzia - 01a Articolo in rivista
paper: BRAIN BEHAVIOR AND IMMUNITY (Academic Press Incorporated:6277 Sea Harbor Drive:Orlando, FL 32887:(800)543-9534, (407)345-4100, EMAIL: ap@acad.com, INTERNET: http://www.idealibrary.com, Fax: (407)352-3445) pp. 302-308 - issn: 0889-1591 - wos: WOS:000908927600001 (12) - scopus: 2-s2.0-85144482971 (13)

11573/1679667 - 2023 - Olfactory neuron substance P is overexpressed in Parkinson's disease reflecting gut dysfunction
Schirinzi, Tommaso; Maftei, Daniela; Grillo, Piergiorgio; Bovenzi, Roberta; Bissacco, Jacopo; Simonetta, Clara; Mascioli, Davide; Zenuni, Henri; Cerroni, Rocco; Vincenzi, Martina; Maurizi, Riccardo; Passali, Francesco M; Di Girolamo, Stefano; Ralli, Massimo; Magliulo, Giuseppe; Tirassa, Paola; Stefani, Alessandro; Mercuri, Nicola B; Lattanzi, Roberta; Severini, Cinzia - 01f Lettera, Nota
paper: MOVEMENT DISORDERS (-WILEY-LISS, DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, USA, NJ, 07030 -Lippincott, Williams & Wilkins:530 Walnut Street:Philadelphia, PA 19106:(800)638-3030, (301)223-2300, EMAIL: orders@lww.com, INTERNET: http://www.lww.com, Fax: (301)223-2320, (301)223-2320) pp. - - issn: 0885-3185 - wos: WOS:000984574700001 (8) - scopus: 2-s2.0-85158162279 (8)

11573/1662802 - 2023 - Olfactory neuron prokineticin-2 as a potential target in Parkinson's disease
Schirinzi, Tommaso; Maftei, Daniela; Passali, Francesco M; Grillo, Piergiorgio; Zenuni, Henri; Mascioli, Davide; Maurizi, Riccardo; Loccisano, Laura; Vincenzi, Martina; Rinaldi, Anna Maria; Ralli, Massimo; Di Girolamo, Stefano; Stefani, Alessandro; Lattanzi, Roberta; Severini, Cinzia; Mercuri, Nicola B - 01a Articolo in rivista
paper: ANNALS OF NEUROLOGY (-attuale: WILEY-LISS, DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, USA, NJ, 07030 -Lippincott, Williams & Wilkins:530 Walnut Street:Philadelphia, PA 19106:(800)638-3030, (301)223-2300, EMAIL: orders@lww.com, INTERNET: http://www.lww.com, Fax: (301)223-2320, (301)223-2320) pp. 196-204 - issn: 0364-5134 - wos: WOS:000871938600001 (14) - scopus: 2-s2.0-85140481586 (14)

11573/1689470 - 2023 - Therapeutic Potential of Targeting Prokineticin Receptors in Diseases
Vincenzi, Martina; Kremic, Amin; Jouve, Appoline; Lattanzi, Roberta; Miele, Rossella; Benharouga, Mohamed; Alfaidy-Benharouga, Nadia; Migrenne-Li, Stephanie; Kanthasamy, Anumantha G; Porcionatto, Marimelia; Ferrara, Napoleone; Tetko, Igor V; Désaubry, Laurent; Nebigil, Canan G - 01g Articolo di rassegna (Review)
paper: PHARMACOLOGICAL REVIEWS (American Society for Pharmacology and Experimental Therapeutics:9650 Rockville Pike:Bethesda, MD 20814:(301)530-7024, EMAIL: pstoute@aspet.org, INTERNET: http://www.aspet.org, Fax: (301)634-7099) pp. 1167-1199 - issn: 0031-6997 - wos: WOS:001098885600004 (5) - scopus: 2-s2.0-85174750998 (6)

11573/1662801 - 2022 - Arginine 125 is an essential residue for the function of MRAP2
Fullone, M. R.; Maftei, D.; Vincenzi, M.; Lattanzi, R.; Miele, R. - 01a Articolo in rivista
paper: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 9853- - issn: 1422-0067 - wos: WOS:000851170800001 (7) - scopus: 2-s2.0-85137570586 (7)

11573/1628889 - 2022 - Identification of regions involved in the physical interaction between melanocortin receptor accessory protein 2 and prokineticin receptor 2
Fullone, Maria Rosaria; Maftei, Daniela; Vincenzi, Martina; Lattanzi, Roberta; Miele, Rossella - 01a Articolo in rivista
paper: BIOMOLECULES (Basel: MDPI) pp. 474-478 - issn: 2218-273X - wos: WOS:000775906200001 (11) - scopus: 2-s2.0-85126726814 (12)

11573/1615609 - 2022 - Identification and characterization of a new splicing variant of prokineticin 2
Lattanzi, R.; Maftei, D.; Vincenzi, M.; Fullone, M. R.; Miele, R. - 01a Articolo in rivista
paper: LIFE (Basel: MDPI) pp. 248- - issn: 2075-1729 - wos: WOS:000764561200001 (9) - scopus: 2-s2.0-85124425064 (11)

11573/1621109 - 2022 - Targeting chemokines and chemokine GPCRs to enhance strong opioid efficacy in neuropathic pain
Vincenzi, Martina; Milella, Michele Stanislaw; D'ottavio, Ginevra; Caprioli, Daniele; Reverte, Ingrid; Maftei, Daniela - 01g Articolo di rassegna (Review)
paper: LIFE (Basel: MDPI) pp. 1-22 - issn: 2075-1729 - wos: WOS:000775133800001 (7) - scopus: 2-s2.0-85126534951 (7)

11573/1545987 - 2021 - A palmitoylethanolamide producing lactobacillus paracasei improves clostridium difficile toxin a-induced colitis
Esposito, Giuseppe; Corpetti, Chiara; Pesce3, Marcella; Seguella, Luisa; Annunziata, Giuseppe; Del Re, Alessandro; Vincenzi, Martina; Lattanzi, Roberta; Lu, Jie; Sanseverino, Walter; Sarnelli, Giovanni - 01a Articolo in rivista
paper: FRONTIERS IN PHARMACOLOGY (Lausanne: Frontiers Media S.A., 2010-) pp. 1-13 - issn: 1663-9812 - wos: WOS:000648986000001 (5) - scopus: 2-s2.0-85105612462 (6)

11573/1586257 - 2021 - Role of Enteric Glia as Bridging Element between Gut Inflammation and Visceral Pain Consolidation during Acute Colitis in Rats
Lucarini, Elena; Seguella, Luisa; Vincenzi, Martina; Parisio, Carmen; Micheli, Laura; Toti, Alessandra; Corpetti, Chiara; Del Re, Alessandro; Squillace, Silvia; Maftei, Daniela; Lattanzi, Roberta; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Esposito, Giuseppe - 01a Articolo in rivista
paper: BIOMEDICINES (Basel: MDPI) pp. 1-15 - issn: 2227-9059 - wos: WOS:000726682500001 (13) - scopus: 2-s2.0-85119678308 (16)

11573/1604635 - 2021 - The balance of concentration between Prokineticin 2β and Prokineticin 2 modulates the food intake by STAT3 signaling
Maftei, Daniela; Lattanzi, Roberta; Vincenzi, Martina; Squillace, Silvia; Fullone, Maria Rosaria; Miele, Rossella - 01a Articolo in rivista
paper: BBA ADVANCES () pp. 100028- - issn: 2667-1603 - wos: WOS:001223634700006 (14) - scopus: 2-s2.0-85119583395 (14)

11573/1438201 - 2021 - Lathyrus sativus diamine oxidase reduces clostridium difficile toxin a-induced toxicity in caco-2 cells by rescuing rhoa-gtpase and inhibiting pp38-mapKknf-κb/hif-1α activation
Pietrangeli, Paola; Corpetti, Chiara; Seguella, Luisa; Del Re, Alessandro; Pesce, Marcella; Vincenzi, Martina; Lori, Chiara; Annunziata, Giuseppe; A Mateescu, Mircea; Sarnelli, Giovanni; Esposito, Giuseppe; Marcocci, Lucia - 01a Articolo in rivista
paper: PHYTOTHERAPY RESEARCH (New York : J. Wiley) pp. 415-423 - issn: 1099-1573 - wos: WOS:000567717700001 (3) - scopus: 2-s2.0-85090792133 (5)

11573/1548098 - 2021 - High-fat diet impairs duodenal barrier function and elicits glia-dependent changes along the gut-brain axis that are required for anxiogenic and depressive-like behaviors
Seguella, Luisa; Pesce, Mirella; Capuano, Riccardo; Casano, Fabrizio; Pesce, Marcella; Corpetti, Chiara; Vincenzi, Martina; Maftei, Daniela; Lattanzi, Roberta; Del Re, Alessandro; Sarnelli, Giovanni; Gulbransen, Brian D.; Esposito, Giuseppe - 01a Articolo in rivista
paper: JOURNAL OF NEUROINFLAMMATION (London : BioMed Central.) pp. 1-17 - issn: 1742-2094 - wos: WOS:000656975100001 (24) - scopus: 2-s2.0-85105796293 (30)

11573/1466526 - 2020 - Phytotherapics in COVID19: why palmitoylethanolamide?
Pesce, M.; Seguella, L.; Cassarano, S.; Aurino, L.; Sanseverino, W.; Lu, J.; Corpetti, C.; Del Re, A.; Vincenzi, M.; Sarnelli, G.; Esposito, G. - 01g Articolo di rassegna (Review)
paper: PHYTOTHERAPY RESEARCH (John Wiley & Sons Limited:1 Oldlands Way, Bognor Regis, P022 9SA United Kingdom:011 44 1243 779777, EMAIL: cs-journals@wiley.co.uk, INTERNET: http://www.wiley.co.uk, Fax: 011 44 1243 843232) pp. - - issn: 0951-418X - wos: WOS:000596645100001 (13) - scopus: 2-s2.0-85097307819 (14)

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