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Yang J, Shin Y, Kim HJ, Kim HE, Chun JS. Prokineticin 2 is a catabolic regulator of osteoarthritic cartilage destruction in mouse. Arthritis Res Ther 2023; 25:236. [PMID: 38057865 PMCID: PMC10699050 DOI: 10.1186/s13075-023-03206-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Our preliminary study indicates that the multi-functional protein, prokineticin 2 (Prok2), is upregulated in osteoarthritic (OA) chondrocytes as a target of the hypoxia-inducible factor (HIF)-2α. This study aims to elucidate the potential roles of Prok2 in OA. METHODS Prok2 expression was assessed through microarray analysis in chondrocytes and confirmed via immunostaining in OA cartilage. Experimental OA was induced through destabilization of the medial meniscus (DMM). Functions of Prok2 were assessed by adenoviral overexpression, intra-articular (IA) injection of recombinant Prok2 (rProk2), and knockdown of Prok2 in joint tissues. We also explored the potential utility of Prok2 as an OA biomarker using enzyme-linked immunosorbent assay (ELISA). RESULTS HIF-2α upregulated Prok2, one of the prokineticin signaling components, in OA chondrocytes of mice and humans. Adenoviral overexpression of Prok2 in chondrocytes and cartilage explants, as well as the application of rProk2, led to an upregulation of matrix metalloproteinase (MMP)3 and MMP13. Consistently, the overexpression of Prok2 in joint tissues or IA injection of rProk2 exacerbated cartilage destruction and hindpaw mechanical allodynia induced by DMM. However, the knockdown of Prok2 in joint tissues did not significantly affect DMM-induced cartilage destruction. Additionally, despite being a secreted protein, the serum levels of Prok2 in OA mice and human OA patients were found to be below the range detected by ELISA. CONCLUSION The upregulation of Prok2 exacerbates OA cartilage destruction and hindpaw mechanical allodynia. However, its knockdown is not sufficient to inhibit experimental OA and Prok2 is not a potential candidate serum biomarker of OA.
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Affiliation(s)
- Jiye Yang
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Youngnim Shin
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Hwee-Jin Kim
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Hyo-Eun Kim
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Jang-Soo Chun
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
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Amodeo G, Franchi S, Galimberti G, Riboldi B, Sacerdote P. The Prokineticin System in Inflammatory Bowel Diseases: A Clinical and Preclinical Overview. Biomedicines 2023; 11:2985. [PMID: 38001985 PMCID: PMC10669895 DOI: 10.3390/biomedicines11112985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/23/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC), which are characterized by chronic inflammation of the gastrointestinal (GI) tract. IBDs clinical manifestations are heterogeneous and characterized by a chronic relapsing-remitting course. Typical gastrointestinal signs and symptoms include diarrhea, GI bleeding, weight loss, and abdominal pain. Moreover, the presence of pain often manifests in the remitting disease phase. As a result, patients report a further reduction in life quality. Despite the scientific advances implemented in the last two decades and the therapies aimed at inducing or maintaining IBDs in a remissive condition, to date, their pathophysiology still remains unknown. In this scenario, the importance of identifying a common and effective therapeutic target for both digestive symptoms and pain remains a priority. Recent clinical and preclinical studies have reported the prokineticin system (PKS) as an emerging therapeutic target for IBDs. PKS alterations are likely to play a role in IBDs at multiple levels, such as in intestinal motility, local inflammation, ulceration processes, localized abdominal and visceral pain, as well as central nervous system sensitization, leading to the development of chronic and widespread pain. This narrative review summarized the evidence about the involvement of the PKS in IBD and discussed its potential as a druggable target.
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Affiliation(s)
- Giada Amodeo
- Dipartimento di Scienze Farmacologiche e Biomolecolari “Rodolfo Paoletti”, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy; (S.F.); (G.G.); (B.R.); (P.S.)
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Vincenzi M, Kremić A, Jouve A, Lattanzi R, Miele R, Benharouga M, Alfaidy N, Migrenne-Li S, Kanthasamy AG, Porcionatto M, Ferrara N, Tetko IV, Désaubry L, Nebigil CG. Therapeutic Potential of Targeting Prokineticin Receptors in Diseases. Pharmacol Rev 2023; 75:1167-1199. [PMID: 37684054 PMCID: PMC10595023 DOI: 10.1124/pharmrev.122.000801] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 09/10/2023] Open
Abstract
The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research. SIGNIFICANCE STATEMENT: This review provides an in-depth view of the prokineticin family and PK receptors that can be active without their endogenous ligand and exhibits "constitutive" activity in diseases. Their non- peptide ligands display promising effects in several preclinical disease models. PKs can be the diagnostic biomarker of several diseases. A thorough understanding of the role of prokineticin family and their receptor types in health and diseases is critical to develop novel therapeutic strategies with safety concerns.
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Affiliation(s)
- Martina Vincenzi
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Amin Kremić
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Appoline Jouve
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Roberta Lattanzi
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Rossella Miele
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Mohamed Benharouga
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Nadia Alfaidy
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Stephanie Migrenne-Li
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Anumantha G Kanthasamy
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Marimelia Porcionatto
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Napoleone Ferrara
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Igor V Tetko
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Laurent Désaubry
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
| | - Canan G Nebigil
- Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, Center of Research in Biomedicine of Strasbourg, Strasbourg, France (M.V., A.K., A.J., L.D., C.G.N.); Department of Physiology and Pharmacology (M.V., R.L.), and Department of Biochemical Sciences "Alessandro Rossi Fanelli" (R.M.), Sapienza University of Rome, Rome, Italy; University Grenoble Alpes, INSERM, CEA, Grenoble, France (M.B., N.A.); Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France (S.M.); Department of Physiology and Pharamacology, Center for Neurologic Disease Research, University of Georgia, Athens, Georgia (A.G.K.); Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil (M.A.P.); Moores Cancer Center, University of California, San Diego, La Jolla, California (N.F.); and Institute of Structural Biology, Helmholtz Munich - German Research Center for Environmental Health (GmbH), Neuherberg, Germany (I.V.T.); and BIGCHEM GmbH, Valerystr. 49, Unterschleissheim, Germany (I.V.T.)
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Giada A, Giulia G, Paola S, Silvia F. Characterization of prokineticin system in Crohn's disease pathophysiology and pain, and its modulation by alcohol abuse: A preclinical study. Biochim Biophys Acta Mol Basis Dis 2023:166791. [PMID: 37336367 DOI: 10.1016/j.bbadis.2023.166791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/21/2023] [Accepted: 06/14/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND Crohn's disease-(CD) pathogenesis is still unknown and chronic pain is a frequent symptom in CD-patients. Identifying novel therapeutic targets and predisposing factors is a primary goal. In this regard, prokineticin system-(PKS) appears a promising target. AIMS AND METHODS TNBS-model was used. DAI, abdominal and visceral pain, and muscle strength were monitored. CD-mice were sacrificed at two times (day 7 and 14 after TNBS) in order to identify PKS involvement in CD pathophysiology and pain. PKS characterization was performed in mesenteric lymph nodes-(MLN), colon, myenteric plexus-(MP), dorsal root ganglia-(DRGs) and spinal cord-(SC). Inflammation/neuroinflammation was also assessed in the same tissues. In order to evaluate alcohol abuse as a possible trigger for CD and its effect on PKS activation, naïve mice were administered (oral-gavage) with ethanol for 10 consecutive days. PKS as well as inflammation/neuroinflammation were evaluated in MLN, colon and MP. RESULTS TNBS treated-mice showed a rapid increase in DAI, abdominal/visceral hypersensitivity and a progressive strength loss. In all tissue analysed of CD-mice, a quick and significant increase of mRNA of PKs and PKRs was observed, associated with an increase of pro-inflammatory cytokines (IL-1β, IL-6 and TNFα) and macrophage/glia markers (iba1, CD11b and GFAP) levels. In alcohol abuse model, ethanol induced in colon and MP a significant PKS activation accompanied by inflammation/neuroinflammation. CONCLUSIONS We can assume that PKS may be involved in CD development and pain. Furthermore, alcohol appears to activate PKS and may be a trigger factor for CD.
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Affiliation(s)
- Amodeo Giada
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy.
| | - Galimberti Giulia
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy
| | - Sacerdote Paola
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy
| | - Franchi Silvia
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", University of Milan, Milan, Via Vanvitelli 32, 20129 Milano, Italy
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Impellizzeri D, Maftei D, Severini C, Miele R, Balboni G, Siracusa R, Cordaro M, Di Paola R, Cuzzocrea S, Lattanzi R. Blocking prokineticin receptors attenuates synovitis and joint destruction in collagen-induced arthritis. J Mol Med (Berl) 2023; 101:569-580. [PMID: 36988653 DOI: 10.1007/s00109-023-02307-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 02/09/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated by an interdependent network of proinflammatory molecules such as chemokines. Prokineticin 2 (PK2) is a chemokine-like peptide that modulates nociceptive threshold and immuno-inflammatory processes via two G-protein-linked receptors, prokineticin receptor 1 and 2 (PKR1 and PKR2). In the present study, we investigated the effects of the prokineticin receptor antagonist PC1 on arthritic pain and the inflammatory response in type II collagen-induced arthritis (CIA) in mice. We demonstrated that PC1, administered subcutaneously from day 25 to day 35 after CIA, improved clinical signs of arthritis such as paw edema, pain, and impaired locomotor activity. In CIA mice, PC1 was also able to lower plasma malondialdehyde (MDA) levels, suggesting a role in reducing oxidative damage, as well as joint expression levels of PK2, PKRs, TNFα, IL-1β, CD4, CD8, and NF-kB. These results suggest that blocking PKRs may be a successful strategy to control arthritic pain and pathology development. KEY MESSAGES: PK2/PKRs expression levels strongly increase in the synovium of RA mice. PC1 treatment shows anti-arthritic activity and reduces arthritis-induced pain. PC1 treatment significantly lowers synovial PK2/PKRs levels. PC1 treatment lowers plasma MDA levels and synovial levels of TNFα and IL -1β PC1 treatment is a viable therapeutic option for RA.
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Affiliation(s)
- Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy
| | - Daniela Maftei
- Department of Physiology and Pharmacology, Vittorio Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Cinzia Severini
- Department of Biochemistry and Cell Biology, National Research Council of Italy, Rome, Italy
| | - Rossella Miele
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Gianfranco Balboni
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy
| | - Marika Cordaro
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166, Messina, Italy
| | - Roberta Lattanzi
- Department of Physiology and Pharmacology, Vittorio Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
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6
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Chen ZA, Ma HH, Wang Y, Tian H, Mi JW, Yao DM, Yang CJ. Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn's disease based on three machine learning methods. Sci Rep 2023; 13:2694. [PMID: 36792688 PMCID: PMC9931764 DOI: 10.1038/s41598-022-26345-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/13/2022] [Indexed: 02/17/2023] Open
Abstract
Crohn's disease (CD) is a complex autoimmune disorder presumed to be driven by complex interactions of genetic, immune, microbial and even environmental factors. Intrinsic molecular mechanisms in CD, however, remain poorly understood. The identification of novel biomarkers in CD cases based on larger samples through machine learning approaches may inform the diagnosis and treatment of diseases. A comprehensive analysis was conducted on all CD datasets of Gene Expression Omnibus (GEO); our team then used the robust rank aggregation (RRA) method to identify differentially expressed genes (DEGs) between controls and CD patients. PPI (protein‒protein interaction) network and functional enrichment analyses were performed to investigate the potential functions of the DEGs, with molecular complex detection (MCODE) identifying some important functional modules from the PPI network. Three machine learning algorithms, support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and least absolute shrinkage and selection operator (LASSO), were applied to determine characteristic genes, which were verified by ROC curve analysis and immunohistochemistry (IHC) using clinical samples. Univariable and multivariable logistic regression were used to establish a machine learning score for diagnosis. Single-sample GSEA (ssGSEA) was performed to examine the correlation between immune infiltration and biomarkers. In total, 5 datasets met the inclusion criteria: GSE75214, GSE95095, GSE126124, GSE179285, and GSE186582. Based on RRA integrated analysis, 203 significant DEGs were identified (120 upregulated genes and 83 downregulated genes), and MCODE revealed some important functional modules in the PPI network. Machine learning identified LCN2, REG1A, AQP9, CCL2, GIP, PROK2, DEFA5, CXCL9, and NAMPT; AQP9, PROK2, LCN2, and NAMPT were further verified by ROC curves and IHC in the external cohort. The final machine learning score was defined as [Expression level of AQP9 × (2.644)] + [Expression level of LCN2 × (0.958)] + [Expression level of NAMPT × (1.115)]. ssGSEA showed markedly elevated levels of dendritic cells and innate immune cells, such as macrophages and NK cells, in CD, consistent with the gene enrichment results that the DEGs are mainly involved in the IL-17 signaling pathway and humoral immune response. The selected biomarkers analyzed by the RRA method and machine learning are highly reliable. These findings improve our understanding of the molecular mechanisms of CD pathogenesis.
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Affiliation(s)
- Zi-An Chen
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Hui-hui Ma
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Yan Wang
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Hui Tian
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Jian-wei Mi
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Dong-Mei Yao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. .,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000, Hebei, China.
| | - Chuan-Jie Yang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. .,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000, Hebei, China.
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7
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Zhang D, Li Y, Liang M, Liang Y, Tian J, He Q, Yang B, Jin J, Zhu W. LC-MS/MS based metabolomics and proteomics reveal candidate biomarkers and molecular mechanism of early IgA nephropathy. Clin Proteomics 2022; 19:51. [PMID: 36572849 PMCID: PMC9793667 DOI: 10.1186/s12014-022-09387-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/07/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN), a globally common primary chronic glomerulopathy, is one of the leading causes of end-stage renal disease. However, the underlying mechanisms of IgAN have yet to be demonstrated. There were no adequate and reliable plasma biomarkers for clinical diagnosis, especially at the early stage. In the present study, integrative proteomics and metabolomics were aimed at exploring the mechanism of IgAN and identifying potential biomarkers. METHODS Plasma from IgAN and healthy individuals were collected and analyzed in a randomized controlled manner. Data-independent acquisition quantification proteomics and mass spectrometry based untargeted metabolomics techniques were used to profile the differentially expressed proteins (DEPs) and differentially abundant metabolites (DAMs) between two groups and identify potential biomarkers for IgAN from health at the early stage. Disease-related pathways were screened out by clustering and function enrichment analyses of DEPs and DAMs. And the potential biomarkers for IgAN were identified through the machine learning approach. Additionally, an independent cohort was used to validate the priority candidates by enzyme-linked immunosorbent assay (ELISA). RESULTS Proteomic and metabolomic analyses of IgAN plasma showed that the complement and the immune system were activated, while the energy and amino acid metabolism were disordered in the IgAN patients. PRKAR2A, IL6ST, SOS1, and palmitoleic acid have been identified as potential biomarkers. Based on the AUC value for the training and test sets, the classification performance was 0.994 and 0.977, respectively. The AUC of the external validation of the four biomarkers was 0.91. CONCLUSION In this study, we combined proteomics and metabolomics techniques to analyze the plasma of IgAN patients and healthy individuals, constructing a biomarker panel, which could provide new insights and provide potential novel molecular diagnoses for IgAN.
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Affiliation(s)
- Di Zhang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Yaohan Li
- grid.13402.340000 0004 1759 700XCollege of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310027 Zhejiang China ,grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
| | - Mingzhu Liang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Yan Liang
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Jingkui Tian
- grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
| | - Qiang He
- grid.417400.60000 0004 1799 0055Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, 310000 Zhejiang China
| | - Bingxian Yang
- grid.413273.00000 0001 0574 8737College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018 China
| | - Juan Jin
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
| | - Wei Zhu
- grid.410726.60000 0004 1797 8419The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310002 Zhejiang China
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8
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Lattanzi R, Miele R. Non-Peptide Agonists and Antagonists of the Prokineticin Receptors. Curr Issues Mol Biol 2022; 44:6323-6332. [PMID: 36547092 PMCID: PMC9776816 DOI: 10.3390/cimb44120431] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
The prokineticin family comprises a group of secreted peptides that can be classified as chemokines based on their structural features and chemotactic and immunomodulatory functions. Prokineticins (PKs) bind with high affinity to two G protein-coupled receptors (GPCRs). Prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) are involved in a variety of physiological functions such as angiogenesis and neurogenesis, hematopoiesis, the control of hypothalamic hormone secretion, the regulation of circadian rhythm and the modulation of complex behaviors such as feeding and drinking. Dysregulation of the system leads to an inflammatory process that is the substrate for many pathological conditions such as cancer, pain, neuroinflammation and neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The use of PKR's antagonists reduces PK2/PKRs upregulation triggered by various inflammatory processes, suggesting that a pharmacological blockade of PKRs may be a successful strategy to treat inflammatory/neuroinflammatory diseases, at least in rodents. Under certain circumstances, the PK system exhibits protective/neuroprotective effects, so PKR agonists have also been developed to modulate the prokineticin system.
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Affiliation(s)
- Roberta Lattanzi
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Rossella Miele
- Department of Biochemical Sciences “A. Rossi Fanelli”, CNR-Institute of Molecular Biology and Pathology, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
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9
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Yu X, Chen J, Tang H, Tu Q, Li Y, Yuan X, Zhang X, Cao J, Molloy DP, Yin Y, Chen D, Song Z, Xu P. Identifying Prokineticin2 as a Novel Immunomodulatory Factor in Diagnosis and Treatment of Sepsis. Crit Care Med 2022; 50:674-684. [PMID: 34582411 PMCID: PMC8923365 DOI: 10.1097/ccm.0000000000005335] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Sepsis remains a highly lethal disease, whereas the precise reasons for death remain poorly understood. Prokineticin2 is a secreted protein that regulates diverse biological processes. Whether prokineticin2 is beneficial or deleterious to sepsis and the underlying mechanisms remain unknown. DESIGN Prospective randomized animal investigation and in vitro studies. SETTING Research laboratory at a medical university hospital. SUBJECTS Prokineticin2 deficiency and wild-type C57BL/6 mice were used for in vivo studies; sepsis patients by Sepsis-3 definitions, patient controls, and healthy controls were used to obtain blood for in vitro studies. INTERVENTIONS Prokineticin2 concentrations were measured and analyzed in human septic patients, patient controls, and healthy individuals. The effects of prokineticin2 on sepsis-related survival, bacterial burden, organ injury, and inflammation were assessed in an animal model of cecal ligation and puncture-induced polymicrobial sepsis. In vitro cell models were also used to study the role of prokineticin2 on antibacterial response of macrophages. MEASUREMENTS AND MAIN RESULTS Prokineticin2 concentration is dramatically decreased in the patients with sepsis and septic shock compared with those of patient controls and healthy controls. Furthermore, the prokineticin2 concentration in these patients died of sepsis or septic shock is significantly lower than those survival patients with sepsis or septic shock, indicating the potential value of prokineticin2 in the diagnosis of sepsis and septic shock, as well as the potential value in predicting mortality in adult patients with sepsis and septic shock. In animal model, recombinant prokineticin2 administration protected against sepsis-related deaths in both heterozygous prokineticin2 deficient mice and wild-type mice and alleviated sepsis-induced multiple organ damage. In in vitro cell models, prokineticin2 enhanced the phagocytic and bactericidal functions of macrophage through signal transducers and activators of transcription 3 pathway which could be abolished by signal transducers and activators of transcription 3 inhibitors S3I-201. Depletion of macrophages reversed prokineticin2-mediated protection against polymicrobial sepsis. CONCLUSIONS This study elucidated a previously unrecognized role of prokineticin2 in clinical diagnosis and treatment of sepsis. The proof-of-concept study determined a central role of prokineticin2 in alleviating sepsis-induced death by regulation of macrophage function, which presents a new strategy for sepsis immunotherapy.
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Affiliation(s)
- Xiaoyan Yu
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
| | - Jingyi Chen
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
| | - Hong Tang
- Department of Critical Care Medicine, Department of Surgical Intensive Care Unit, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qianqian Tu
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
| | - Yue Li
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Xi Yuan
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
| | - Xuemei Zhang
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing, China
| | - Ju Cao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - David Paul Molloy
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, ChongQing Medical University, Chongqing, China
| | - Yibing Yin
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing, China
| | - Dapeng Chen
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
| | - Zhixin Song
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
| | - Pingyong Xu
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
- Key Laboratory of RNA Biology, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
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10
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Lattanzi R, Maftei D, Vincenzi M, Fullone MR, Miele R. Identification and Characterization of a New Splicing Variant of Prokineticin 2. Life (Basel) 2022; 12:248. [PMID: 35207535 PMCID: PMC8876856 DOI: 10.3390/life12020248] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 11/17/2022] Open
Abstract
Prokineticin 2 (PROK2) is a secreted bioactive peptide that regulates a variety of biological responses via two GPCRs, the prokineticin receptors (PROKRs). The aim of this study was to characterize a new alternatively spliced product of the prok2 gene consisting of four exons. The 40-amino acid peptide, designated PROK2C, is encoded by exon 1 and exon 4, and its expression was detected in the hippocampus and spinal cord of mice. PROK2C was expressed in a heterologous system, Pichia pastoris, and its binding specificity to the amino-terminal regions of PROKR1 and PROKR2 was investigated by GST pull-down experiments. In addition, the introduction of the unnatural amino acid p-benzoyl-L-phenylalanine using amber codon suppression technology demonstrated the role of tryptophan at position 212 of PROKR2 for PROK2C binding by photoactivatable cross-linking. The functional significance of this new isoform was determined in vivo by nociceptive experiments, which showed that PROK2C elicits strong sensitization of peripheral nociceptors to painful stimuli. In order to analyze the induction of PROK2C signal transduction, STAT3 and ERK phosphorylation levels were determined in mammalian CHO cells expressing PROKR1 and PROKR2. Our data show by in vivo and in vitro experiments that PROK2C can bind and activate both prokineticin receptors.
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Affiliation(s)
- Roberta Lattanzi
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (D.M.); (M.V.)
| | - Daniela Maftei
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (D.M.); (M.V.)
| | - Martina Vincenzi
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (D.M.); (M.V.)
| | - Maria Rosaria Fullone
- Department of Biochemical Sciences “Alessandro Rossi Fanelli”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Rossella Miele
- Department of Biochemical Sciences “Alessandro Rossi Fanelli”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;
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11
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Lattanzi R, Miele R. Prokineticin-Receptor Network: Mechanisms of Regulation. Life (Basel) 2022; 12:172. [PMID: 35207461 PMCID: PMC8877203 DOI: 10.3390/life12020172] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 12/17/2022] Open
Abstract
Prokineticins are a new class of chemokine-like peptides that bind their G protein-coupled receptors, PKR1 and PKR2, and promote chemotaxis and the production of pro-inflammatory cytokines following tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms of prokineticins pathway regulation that, like other chemokines, include: genetic polymorphisms; mRNA splice modulation; expression regulation at transcriptional and post-transcriptional levels; prokineticins interactions with cell-surface glycosaminoglycans; PKRs degradation, localization, post-translational modifications and oligomerization; alternative signaling responses; binding to pharmacological inhibitors. Understanding these mechanisms, which together exert substantial biochemical control and greatly enhance the complexity of the prokineticin-receptor network, leads to novel opportunities for therapeutic intervention. In this way, besides targeting prokineticins or their receptors directly, it could be possible to indirectly influence their activity by modulating their expression and localization or blocking the downstream signaling pathways.
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Affiliation(s)
- Roberta Lattanzi
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Rossella Miele
- Department of Biochemical Sciences “A. Rossi Fanelli”, CNR-Institute of Molecular Biology and Pathology, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
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12
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Fiore M, Tarani L, Radicioni A, Spaziani M, Ferraguti G, Putotto C, Gabanella F, Maftei D, Lattanzi R, Minni A, Greco A, Tarani F, Petrella C. Serum Prokineticin-2 in Prepubertal and Adult Klinefelter Individuals. Can J Physiol Pharmacol 2021; 100:151-157. [PMID: 34614364 DOI: 10.1139/cjpp-2021-0457] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The prokineticin-2 (PROK2) is a small peptide belonging to the prokineticin family. In humans and rodents this chemokine is primarily involved in the control of central and peripheral reproductive processes. Klinefelter's syndrome (KS) is the first cause of male genetic infertility, due to an extra X chromosome, which may occur with a classical karyotype (47, XXY) or mosaic forms (46, XY/47, XXY). In affected subjects, pubertal maturation usually begins at an adequate chronological age, but when development is almost complete, they display a primary gonadal failure, with early spermatogenesis damage, and later onset of testosterone insufficiency. Thus, the main aim of the present study was to investigate the serum levels of PROK2 in prepubertal and adult KS patients, comparing them with healthy subjects. We showed for the first time the presence of PROK2 in the children serum but with significant changes in KS individuals. Indeed, compared to healthy subjects characterized by PROK2 serum elevation during the growth, KS individuals showed constant serum levels during the sexual maturation phase (higher during the prepubertal phase but lower during the adult age). In conclusion, these data indicate that in KS individuals PROK2 may be considered a biomarker for investigating the SK infertility process.
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Affiliation(s)
- Marco Fiore
- IBCN-CNR, Institute of Cell Biology and Neurobiology, Roma, Italy;
| | - Luigi Tarani
- "Sapienza" University of Rome, Department of Pediatrics, Rome, Italy;
| | - Antonio Radicioni
- Sapienza University of Rome, Department of Experimental Medicine, Rome, Italy;
| | - Matteo Spaziani
- Sapienza University of Rome, Department of Experimental Medicine, Rome, Italy;
| | - Giampiero Ferraguti
- Sapienza University of Rome, Department of Cellular Biotechnologies and Hematology, Rome, Italy;
| | - Carolina Putotto
- "Sapienza" University of Rome, Department of Pediatrics, rome, Italy;
| | - Francesca Gabanella
- IBBC-CNR), Rome, Italy.,Institute of Molecular Biology and Pathology (IBPM-CNR), Rome, Italy;
| | - Daniela Maftei
- Sapienza University of Rome, Department of Physiology and Pharmacology "Vittorio Erspamer", Rome, Italy;
| | - Roberta Lattanzi
- Sapienza University of Rome, Department of Physiology and Pharmacology "Vittorio Erspamer", Rome, Italy;
| | - Antonio Minni
- Sapienza University of Rome, Department of Sense Organs, Rome, Italy;
| | - Antonio Greco
- University of Rome La Sapienza, 9311, Rome, Lazio, Italy;
| | - Francesca Tarani
- "Sapienza" University of Rome, Department of Pediatrics, rome, Italy;
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13
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Noda K, Dufner B, Ito H, Yoshida K, Balboni G, Straub RH. Differential inflammation-mediated function of prokineticin 2 in the synovial fibroblasts of patients with rheumatoid arthritis compared with osteoarthritis. Sci Rep 2021; 11:18399. [PMID: 34526577 PMCID: PMC8443611 DOI: 10.1038/s41598-021-97809-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023] Open
Abstract
Prokineticin 2 (PK2) is a secreted protein involved in several pathological and physiological processes, including the regulation of inflammation, sickness behaviors, and circadian rhythms. Recently, it was reported that PK2 is associated with the pathogenesis of collagen-induced arthritis in mice. However, the role of PK2 in the pathogenesis of rheumatoid arthritis (RA) or osteoarthritis (OA) remains unknown. In this study, we collected synovial tissue, plasma, synovial fluid, and synovial fibroblasts (SF) from RA and OA patients to analyze the function of PK2 using immunohistochemistry, enzyme-linked immunosorbent assays, and tissue superfusion studies. PK2 and its receptors prokineticin receptor (PKR) 1 and 2 were expressed in RA and OA synovial tissues. PKR1 expression was downregulated in RA synovial tissue compared with OA synovial tissue. The PK2 concentration was higher in RA synovial fluid than in OA synovial fluid but similar between RA and OA plasma. PK2 suppressed the production of IL-6 from TNFα-prestimulated OA-SF, and this effect was attenuated in TNFα-prestimulated RA-SF. This phenomenon was accompanied by the upregulation of PKR1 in OA-SF. This study provides a new model to explain some aspects underlying the chronicity of inflammation in RA.
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Affiliation(s)
- Kentaro Noda
- grid.411941.80000 0000 9194 7179Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Biopark I, Am Biopark 9, 93053 Regensburg, Germany ,grid.411898.d0000 0001 0661 2073Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Bianca Dufner
- grid.411941.80000 0000 9194 7179Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Biopark I, Am Biopark 9, 93053 Regensburg, Germany
| | - Haruyasu Ito
- grid.411898.d0000 0001 0661 2073Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ken Yoshida
- grid.411898.d0000 0001 0661 2073Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Gianfranco Balboni
- grid.7763.50000 0004 1755 3242Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Rainer H. Straub
- grid.411941.80000 0000 9194 7179Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Biopark I, Am Biopark 9, 93053 Regensburg, Germany
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14
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Li Y, Zhou T, Su YF, Hu ZY, Wei JJ, Wang W, Liu CY, Zhao K, Zhang HP. Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats. Asian J Androl 2021; 22:500-506. [PMID: 31744994 PMCID: PMC7523614 DOI: 10.4103/aja.aja_109_19] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Varicocele is one of the most important causes of male infertility, as this condition leads to a decline in sperm quality. It is generally believed that the presence of varicocele induces an increase in reactive oxygen species levels, leading to oxidative stress and sperm apoptosis; however, the specific pathogenic mechanisms affecting spermatogenesis remain elusive. Prokineticin 2 (PK2), a secretory protein, is associated with multiple biological processes, including cell migration, proliferation, and apoptosis. In the testis, PK2 is expressed in spermatocytes under normal physiological conditions. To investigate the role of PK2 in varicocele, a rat varicocele model was established to locate and quantify the expression of PK2 and its receptor, prokineticin receptor 1 (PKR1), by immunohistochemistry and quantitative real-time PCR assays (qPCR). Moreover, H2O2 was applied to mimic the oxidative stress state of varicocele through coculturing with a spermatocyte-derived cell line (GC-2) in vitro, and the apoptosis rate was detected by flow cytometry. Here, we illustrated that the expression levels of PK2 and PKR1 were upregulated in the spermatocytes of the rat model. Administration of H2O2 stimulated the overexpression of PK2 in GC-2. Transfection of recombinant pCMV-HA-PK2 into GC-2 cells promoted apoptosis by upregulating cleaved-caspase-3, caspase-8, and B cell lymphoma 2-associated X; downregulating B cell lymphoma 2; and promoting the accumulation of intracellular calcium. Overall, we revealed that the varicocele-induced oxidative stress stimulated the overexpression of PK2, leading to apoptosis of spermatocytes. Our study provides new insight into the mechanisms underlying oxidative stress-associated male infertility and suggests a novel therapeutic target for male infertility.
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Affiliation(s)
- Ying Li
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ting Zhou
- Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430030, China
| | - Yu-Fang Su
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhi-Yong Hu
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jia-Jing Wei
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Wang
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chun-Yan Liu
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kai Zhao
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hui-Ping Zhang
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Magnan C, Migrenne-Li S. Pleiotropic effects of prokineticin 2 in the control of energy metabolism. Biochimie 2021; 186:73-81. [PMID: 33932486 DOI: 10.1016/j.biochi.2021.04.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/09/2021] [Accepted: 04/24/2021] [Indexed: 11/19/2022]
Abstract
Prokineticins are family of small proteins involved in many important biological processes including food intake and control of energy balance. The prokineticin 2 (PROK2) is expressed in several peripheral tissues and areas in the central nervous system. PROK2 activates G protein-coupled receptors, namely, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Preclinical models exhibiting disturbances of the PROK2 pathway (at the level of PROK2 or its receptors) are characterized by changes in food intake, feeding behavior and insulin sensitivity related to a dysfunction of the energy balance control. In Humans, mutations of PROK2 and PROKR2 genes are associated to the Kallmann syndrome (KS) that affects both the hormonal reproductive axis and the sense of smell and may also lead to obesity. Moreover, plasma PROK2 concentration has been correlated with various cardiometabolic risk factors and type 2 diabetes (T2D). The present review summarizes knowledge on PROK2 structure, signaling and function focusing on its role in control of food intake and energy homeostasis.
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Wang H, Jia Y, Yu X, Peng L, Mou C, Song Z, Chen D, Li X. Circulating Prokineticin 2 Levels Are Increased in Children with Obesity and Correlated with Insulin Resistance. Int J Endocrinol 2021; 2021:6630102. [PMID: 33883996 PMCID: PMC8041561 DOI: 10.1155/2021/6630102] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 03/15/2021] [Accepted: 03/24/2021] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE Prokineticin 2 (PK2) has been shown to regulate food intake, fat production, and the inflammation process, which play vital roles in the pathogenesis of obesity. The first aim of this study was to investigate serum PK2 levels in children with obesity and normal-weight children. The second aim was to compare the levels of PK2 between children with obesity, with and without nonalcoholic fatty liver disease (NAFLD). METHODS Seventy normal-weight children and 91 children with obesity (22 with NAFLD) were recruited. Circulating PK2, IL-6, and TNF-α were measured by enzyme-linked immunosorbent assays. Anthropometric and biochemical measurements related to adiposity, lipid profile, and insulin resistance were examined for all participants. RESULTS Serum PK2 was significantly higher in children with obesity than in the normal-weight controls. Circulating PK2 levels were not different between the patients with and without NAFLD. Circulating PK2 was positively correlated with BMI, BMI z-score, insulin, glucose, HOMA-IR, total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and gamma-glutamyl transpeptidase. Binary logistic regression revealed that the odds ratios for obesity were significantly elevated with increasing PK2. CONCLUSIONS PK2 was strongly associated with obesity, and it may also be related to metabolic disorders and insulin resistance. This trial is registered with ChiCTR2000038838.
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Affiliation(s)
- Han Wang
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China
| | - Yanjun Jia
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Xiaoyan Yu
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China
| | - Li Peng
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China
| | - Chunfeng Mou
- Department of Nuclear Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Zhixin Song
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China
| | - Dapeng Chen
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China
| | - Xiaoqiang Li
- Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China
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Casella I, Ambrosio C. Prokineticin receptors interact unselectively with several G protein subtypes but bind selectively to β-arrestin 2. Cell Signal 2021; 83:110000. [PMID: 33811988 DOI: 10.1016/j.cellsig.2021.110000] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 11/19/2022]
Abstract
Prokineticin 1 (pk1) and prokineticin 2 (pk2) interact with two structurally related G-protein coupled receptors, prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). Cellular signalling studies show that the activated receptors can evoke Ca2+-mobilization, pertussis toxin-sensitive ERK phosphorylation, and intracellular cAMP accumulation, which suggests the partecipation of several G protein subtypes, such as Gq/11, Gi/o and Gs. However, direct interactions with these transduction proteins have not been studied yet. Here we measured by bioluminescence resonance energy transfer (BRET) the association of PKR1 and PKR2 with different heterotrimeric Gα proteins in response to pk1 and pk2 activation. Using host-cell lines carrying gene deletions of Gαq/11 or Gαs, and pertussis toxin treatment to abolish the receptor interactions with Gαi/o, we determined that both receptors could couple with comparable efficiency to Gq/11 and Gi/o, but far less efficiently to Gs or other pertussis toxin-insensitive G proteins. We also used BRET methodology to assess the association of prokineticin receptors with β-arrestin isoforms. Fluorescent versions of the isoforms were transfected both in HEK293 cells and in double KO β-arrestin 1/2 mouse fibroblasts, to study receptor interaction with the reconstituted individual β-arrestins without background expression of the endogenous genes. Both receptors formed stable BRET-emitting complexes with β-arrestin 2 but not with β-arrestin 1, indicating strong selectivity for the former. In all the studied transducer interactions and in both receptors, pk2 was more potent than pk1 in promoting receptor binding to transduction proteins.
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Affiliation(s)
- Ida Casella
- Istituto Superiore di Sanità, National Center for Drug Reserch and Evaluation, Viale Regina Elena, 299, 00161 Rome, Italy.
| | - Caterina Ambrosio
- Istituto Superiore di Sanità, National Center for Drug Reserch and Evaluation, Viale Regina Elena, 299, 00161 Rome, Italy
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Ye T, Zhang G, Liu H, Shi J, Qiu H, Liu Y, Han F, Hou N. Relationships Between Perivascular Adipose Tissue and Abdominal Aortic Aneurysms. Front Endocrinol (Lausanne) 2021; 12:704845. [PMID: 34194399 PMCID: PMC8236981 DOI: 10.3389/fendo.2021.704845] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 05/25/2021] [Indexed: 02/05/2023] Open
Abstract
Abdominal aortic aneurysms (AAAs) are typically asymptomatic, and there is a high mortality rate associated with aneurysm rupture. AAA pathogenesis involves extracellular matrix degradation, vascular smooth muscle cell phenotype switching, inflammation, and oxidative stress. There is increasing evidence of excessive adipocyte accumulation in ruptured AAA walls. These excessive numbers of adipocytes in the vascular wall have been closely linked with AAA progression. Perivascular adipose tissue (PVAT), a unique type of adipose tissue, can be involved in adipocyte accumulation in the AAA wall. PVAT produces various chemokines and adipocytokines around vessels to maintain vascular homeostasis through paracrine and autocrine mechanisms in normal physiological conditions. Nevertheless, PVAT loses its normal function and promotes the progression of vascular diseases in pathological conditions. There is evidence of significantly reduced AAA diameter in vessel walls of removed PVAT. There is a need to highlight the critical roles of cytokines, cells, and microRNA derived from PVAT in the regulation of AAA development. PVAT may constitute an important therapeutic target for the prevention and treatment of AAAs. In this review, we discuss the relationship between PVAT and AAA development; we also highlight the potential for PVAT-derived factors to serve as a therapeutic target in the treatment of AAAs.
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Affiliation(s)
- Tongtong Ye
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Guangdong Zhang
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hangyu Liu
- Department of Ophthalmology, Weifang Eye Hospital, Weifang, China
| | - Junfeng Shi
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hongyan Qiu
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yongping Liu
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
- *Correspondence: Ningning Hou, ; Fang Han,
| | - Ningning Hou
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- *Correspondence: Ningning Hou, ; Fang Han,
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Chen S, Yang D, Liu B, Chen Y, Ye W, Chen M, Zheng Y. Identification of crucial genes mediating abdominal aortic aneurysm pathogenesis based on gene expression profiling of perivascular adipose tissue by WGCNA. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:52. [PMID: 33553345 PMCID: PMC7859787 DOI: 10.21037/atm-20-3758] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background With a mortality rate of 65–85%, a ruptured abdominal aortic aneurysm (AAA) can have catastrophic consequences for patients. However, few effective pharmaceutical treatments are available to treat this condition. Therefore, elucidating the pathogenesis of AAA and finding the potential molecular targets for medical therapies are vital lines of research. Methods An mRNA microarray dataset of perivascular adipose tissue (PVAT) in AAA patients was downloaded and differentially expressed gene (DEG) screening was performed. Weighted gene co-expression networks for dilated and non-dilated PVAT samples were constructed via weighted correlation network analysis (WGCNA) and used to detect gene modules. Functional annotation analysis was performed for the DEGs and gene modules. We identified the hub genes of the modules and created a DEG co-expression network. We then mined crucial genes based on this network using Molecular Complex Detection (MCODE) in Cytoscape. Crucial genes with top-6 degree in the crucial gene cluster were visualized, and their potential clinical significance was determined. Results Of the 173 DEGs screened, 99 were upregulated and 74 were downregulated. Co-expression networks were built and we detected 6 and 5 modules for dilated and non-dilated PVAT samples, respectively. The turquoise and black modules for dilated PVAT samples were related to inflammation and immune response. MAP4K1 and PROK2 were the hub genes of these 2 modules, respectively. Then a DEG co-expression network with 112 nodes and 953 edges was created. PLAU was the crucial gene with the highest connectivity and showed potential clinical significance. Conclusions Using WGCNA, gene modules were detected and hub genes and crucial genes were identified. These crucial genes might be potential targets for pharmaceutic therapies and have potential clinical significance. Future in vitro and in vivo experiments are required to more comprehensively explore the biological mechanisms by which these genes affect AAA pathogenesis
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Affiliation(s)
- Siliang Chen
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dan Yang
- Department of Computational Biology and Bioinformatics, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bao Liu
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuexin Chen
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - We Ye
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengyin Chen
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuehong Zheng
- Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Goto T, Sapio MR, Maric D, Robinson JM, Saligan LN, Mannes AJ, Iadarola MJ. Longitudinal Transcriptomic Profiling in Carrageenan-Induced Rat Hind Paw Peripheral Inflammation and Hyperalgesia Reveals Progressive Recruitment of Innate Immune System Components. THE JOURNAL OF PAIN 2020; 22:322-343. [PMID: 33227508 DOI: 10.1016/j.jpain.2020.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/16/2020] [Accepted: 11/02/2020] [Indexed: 12/28/2022]
Abstract
Pain is a common but potentially debilitating symptom, often requiring complex management strategies. To understand the molecular dynamics of peripheral inflammation and nociceptive pain, we investigated longitudinal changes in behavior, tissue structure, and transcriptomic profiles in the rat carrageenan-induced peripheral inflammation model. Sequential changes in the number of differentially expressed genes are consistent with temporal recruitment of key leukocyte populations, mainly neutrophils and macrophages with each wave being preceded by upregulation of the cell-specific chemoattractants, Cxcl1 and Cxcl2, and Ccl2 and Ccl7, respectively. We defined 12 temporal gene clusters based on expression pattern. Within the patterns we extracted genes comprising the inflammatory secretome and others related to nociceptive tissue remodeling and to sensory perception of pain. Structural tissue changes, involving upregulation of multiple collagens occurred as soon as 1-hour postinjection, consistent with inflammatory tissue remodeling. Inflammatory expression profiling revealed a broad-spectrum, temporally orchestrated molecular and cellular recruitment process. The results provide numerous potential targets for modulation of pain and inflammation. PERSPECTIVE: This study investigates the highly orchestrated biological response during tissue inflammation with precise assessment of molecular dynamics at the transcriptional level. The results identify transcriptional changes that define an evolving inflammatory state in rats. This study provides foundational data for identifying markers of, and potential treatments for, inflammation and pain in patients.
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Affiliation(s)
- Taichi Goto
- National Institutes of Health, National Institute of Nursing Research, Symptom Biology Unit, Bethesda, Maryland
| | - Matthew R Sapio
- National Institutes of Health, Clinical Center, Department of Perioperative Medicine, Bethesda, Maryland
| | - Dragan Maric
- National Institutes of Health, National Institute of Neurological Disorders and Stroke, Flow and Imaging Cytometry Core Facility, Bethesda, Maryland
| | - Jeffrey M Robinson
- University of Maryland, Baltimore County, Translational Life Science Technology Program, Baltimore, Maryland
| | - Leorey N Saligan
- National Institutes of Health, National Institute of Nursing Research, Symptom Biology Unit, Bethesda, Maryland
| | - Andrew J Mannes
- National Institutes of Health, Clinical Center, Department of Perioperative Medicine, Bethesda, Maryland
| | - Michael J Iadarola
- National Institutes of Health, Clinical Center, Department of Perioperative Medicine, Bethesda, Maryland.
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Moschetti G, Kalpachidou T, Amodeo G, Lattanzi R, Sacerdote P, Kress M, Franchi S. Prokineticin Receptor Inhibition With PC1 Protects Mouse Primary Sensory Neurons From Neurotoxic Effects of Chemotherapeutic Drugs in vitro. Front Immunol 2020; 11:2119. [PMID: 33072073 PMCID: PMC7541916 DOI: 10.3389/fimmu.2020.02119] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022] Open
Abstract
Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.
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Affiliation(s)
- Giorgia Moschetti
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Theodora Kalpachidou
- Department of Physiology and Biomedical Physics, Medical University of Innsbruck, Innsbruck, Austria
| | - Giada Amodeo
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Roberta Lattanzi
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Paola Sacerdote
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Michaela Kress
- Department of Physiology and Biomedical Physics, Medical University of Innsbruck, Innsbruck, Austria
| | - Silvia Franchi
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
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Su G, Sun G, Liu H, Shu L, Zhang W, Liang Z. Prokineticin 2 relieves hypoxia/reoxygenation-induced injury through activation of Akt/mTOR pathway in H9c2 cardiomyocytes. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 48:345-352. [PMID: 31899964 DOI: 10.1080/21691401.2019.1709850] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Prokineticin 2 (PK2) was reported to be decreased in the hearts of end-state heart failure patients. Our study aimed to explore the effects of PK2 on hypoxia/reoxygenation (H/R) injury and the underlying mechanism. H9c2 cardiomyocytes were treated with 5 nM PK2 in the presence or absence of 5 mM dual phosphatidylinositol 3-kinase (PI3K)/the mammalian target of rapamycin (mTOR) inhibitor (BEZ235) for 24 h and then subjected to H/R treatment. Cell viability and lactate dehydrogenase (LDH) release were evaluated by CCK-8 and LDH release assays, respectively. Apoptosis was determined by flow cytometry analysis. Oxidative stress was assessed by measuring superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) content. Results showed that H/R treatment decreased PK2 expression and inactivated the Akt/mTOR pathway in H9c2 cardiomyocytes. PK2 treatment activated the Akt/mTOR pathway in H/R-exposed H9c2 cardiomyocytes. H/R stimulation suppressed cell viability, increased LDH release, induced apoptosis and oxidative stress in H9c2 cardiomyocytes, while these effects were neutralised by treatment with PK2. However, the inhibitory effects of PK2 on H/R-induced injury in H9c2 cardiomyocytes were abolished by the addition of BEZ235. In conclusion, PK2 relieved H/R-induced injury in H9c2 cardiomyocytes by activation of the Akt/mTOR pathway.
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Affiliation(s)
- Gang Su
- Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangli Sun
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hai Liu
- Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liliang Shu
- Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weiwei Zhang
- Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenxing Liang
- Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Maftei D, Vellani V, Artico M, Giacomoni C, Severini C, Lattanzi R. Abnormal Pain Sensation in Mice Lacking the Prokineticin Receptor PKR2: Interaction of PKR2 with Transient Receptor Potential TRPV1 and TRPA1. Neuroscience 2020; 427:16-28. [DOI: 10.1016/j.neuroscience.2019.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 12/24/2022]
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Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5681701. [PMID: 31871550 PMCID: PMC6906848 DOI: 10.1155/2019/5681701] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/18/2019] [Accepted: 10/25/2019] [Indexed: 12/17/2022]
Abstract
Approximately 90% of male diabetes mellitus patients have varying degrees of testicular dysfunction. The molecular mechanism underlying diabetes-induced testicular damage has not been thoroughly elucidated. In this research, we sought to determine the influence of metformin (Met) on diabetes-induced testicular injury and the mechanism involved with a focus on testicular dysfunction, apoptosis, autophagy, and prokineticin 2 (PK2) signalling. In our study, C57BL/6J mice were randomly divided into the normal control group, the diabetes group, and the Met-treated group. Streptozotocin (50 mg·kg−1·d−1) was injected intraperitoneally into the mice for 5 days in a row to induce type 1 diabetes, which was diagnosed by a blood glucose level ≥ 16.7 mmol/L after 7 days. The experimental animals were orally administered Met (250 mg·kg−1·d−1) for 16 weeks. Properties of testicular function, including sperm motility and the total concentration of epididymal sperm, were assessed. Changes in testicular structure, such as the blood-testis barrier, histological pathology, and organelles, were observed. The levels of apoptosis and expression of related proteins, such as Bax and Bcl-2, were measured. Moreover, autophagy-related proteins, including Beclin-1, p62, and LC3B, as well as the PK2/PKR pathway, which consists of PK2, PKR1, PKR2, AKT, and GSK3β, were analysed. Upon the induction of diabetes, reproductive capacity was significantly impaired and a disordered arrangement of testicular seminiferous tubules and destroyed organelles in spermatogenic cells was observed. Met administration preserved testicular function and structure. In addition, in mice with diabetes, the levels of PK2, PKR2, p-Akt, and p-GSK3β were significantly decreased at different times, while that of PKR1 was markedly increased, and these changes were normalized by Met. Furthermore, diabetic mice showed increased apoptosis and decreased autophagy in the testes, the effects of which were nullified by Met. These results suggest that Met rescues diabetes-induced testicular damage by attenuating apoptosis and inducing autophagy. This effect is likely mediated by the PK2/PKR/AKT/GSK3β signalling pathway.
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Maftei D, Ratano P, Fusco I, Marconi V, Squillace S, Negri L, Severini C, Balboni G, Steardo L, Bronzuoli MR, Scuderi C, Campolongo P, Lattanzi R. The prokineticin receptor antagonist PC1 rescues memory impairment induced by β amyloid administration through the modulation of prokineticin system. Neuropharmacology 2019; 158:107739. [DOI: 10.1016/j.neuropharm.2019.107739] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 07/26/2019] [Accepted: 08/09/2019] [Indexed: 12/18/2022]
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Moschetti G, Amodeo G, Paladini MS, Molteni R, Balboni G, Panerai A, Sacerdote P, Franchi S. Prokineticin 2 promotes and sustains neuroinflammation in vincristine treated mice: Focus on pain and emotional like behavior. Brain Behav Immun 2019; 82:422-431. [PMID: 31525509 DOI: 10.1016/j.bbi.2019.09.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 09/10/2019] [Accepted: 09/12/2019] [Indexed: 12/16/2022] Open
Abstract
Vincristine (VCR) treatment is often associated to painful neuropathy. Its development is independent from antitumoral mechanism and involves neuroinflammation. We investigated the role of the chemokine prokineticin (PK)2 in a mouse model of VCR induced neuropathy using a PK-receptors (PK-R) antagonist to counteract its development. We also evaluated emotional like deficits in VCR mice. VCR (0,1 mg/kg) was i.p. injected in C57BL/6J male mice once a day for 14 consecutive days. Pain, anxiety and depressive like behaviors were assessed in animals. PK2, PK-Rs, cytokines, neuroinflammatory markers (CD68, CD11b, GFAP, TLR4) and ATF3 were evaluated in DRG, spinal cord, prefrontal cortex and hippocampus. The PK-Rs antagonist PC1, was s.c. injected (150 μg/kg) twice a day from day 7 (hypersensitivity state) until day 14. Its effect on pain and neuroinflammation was evaluated. VCR mice developed neuropathic pain but not mood alterations. After 7 days of VCR treatment we observed a neuroinflammatory condition in DRG with high levels of PK-Rs, TLR4, CD68, ATF3 and IL-1β without relevant alterations in spinal cord. At day 14, an upregulation of PK system and a marked neuroinflammation was evident also in spinal cord. Moreover, at the same time, we observed initial alterations in supraspinal brain areas. PC1 treatment significantly counteracted neuropathic pain and blunted neuroinflammation.
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Affiliation(s)
- Giorgia Moschetti
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Giada Amodeo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Maria Serena Paladini
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy
| | - Raffaella Molteni
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy
| | - Gianfranco Balboni
- Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy
| | - Alberto Panerai
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paola Sacerdote
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Silvia Franchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
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Li Y, Su Y, Zhou T, Hu Z, Wei J, Wang W, Liu C, Zhang H, Zhao K. Activation of the NLRP3 Inflammasome Pathway by Prokineticin 2 in Testicular Macrophages of Uropathogenic Escherichia coli- Induced Orchitis. Front Immunol 2019; 10:1872. [PMID: 31474981 PMCID: PMC6702272 DOI: 10.3389/fimmu.2019.01872] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 07/24/2019] [Indexed: 12/16/2022] Open
Abstract
Infections of the reproductive tract are known to contribute to testicular inflammatory impairment, leading to an increase of pro-inflammatory cytokines such as IL-1β, and a decline in sperm quality. Prokineticin 2 (PK2), a secretory protein, is closely associated with the secretion of pro-inflammatory cytokines in inflamed tissue. It was reported that increased PK2 is related to the upregulation of IL-1β, but the underlying mechanism remains elusive. Here, we illustrated that PK2 was upregulated in testicular macrophages (TM) in a rat model of uropathogenic Escherichia coli (UPEC) infection, which induced the activation of the NLRP3 inflammasome pathway to boost IL-1β secretion. Administration of PK2 inhibitor alleviated the inflammatory damage and suppressed IL-1β secretion. Moreover, PK2 promoted NLRP3 expression and the release of cleaved IL-1β from TM to the supernatants after the challenge with UPEC in vitro. IL-1β in the supernatants affected Leydig cells by suppressing the expression of genes encoding for the enzymes P450scc and P450c17, which are involved in testosterone production. Overall, we revealed that increased PK2 levels in TM in UPEC-induced orchitis may impair testosterone synthesis via the activation of the NLRP3 pathway. Our study provides a new insight into the mechanisms underlying inflammation-associated male infertility and suggests an anti-inflammatory therapeutic target for male infertility.
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Affiliation(s)
- Ying Li
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Prenatal Diagnostic Center, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yufang Su
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Zhou
- Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan, China
| | - Zhiyong Hu
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajing Wei
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Liu
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiping Zhang
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Family Planning Research Institute/Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Moschetti G, Amodeo G, Maftei D, Lattanzi R, Procacci P, Sartori P, Balboni G, Onnis V, Conte V, Panerai A, Sacerdote P, Franchi S. Targeting prokineticin system counteracts hypersensitivity, neuroinflammation, and tissue damage in a mouse model of bortezomib-induced peripheral neuropathy. J Neuroinflammation 2019; 16:89. [PMID: 30995914 PMCID: PMC6471808 DOI: 10.1186/s12974-019-1461-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 03/25/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Neuropathy is a dose-limiting side effect of many chemotherapeutics, including bortezomib. The mechanisms underlying this condition are not fully elucidated even if a contribution of neuroinflammation was suggested. Here, we investigated the role of a chemokine family, the prokineticins (PKs), in the development of bortezomib-induced peripheral neuropathy (BIPN), and we used a PK receptor antagonist to counteract the development and progression of the pathology. METHODS Neuropathy was induced in male C57BL/6J mice by using a protocol capable to induce a detectable neuropathic phenotype limiting systemic side effects. The presence of allodynia (both mechanical and thermal) and thermal hyperalgesia was monitored over time. Mice were sacrificed at two different time points: 14 and 28 days after the first bortezomib (BTZ) injection. At these times, PK system activation (PK2 and PK-Rs), macrophage and glial activation markers, and cytokine production were evaluated in the main station involved in pain transmission (sciatic nerve, DRG, and spinal cord), and the effect of a PK receptors antagonist (PC1) on the same behavioral and biochemical parameters was assessed. Structural damage of DRG during BTZ treatment and an eventual protective effect of PC1 were also evaluated. RESULTS BTZ induces in mice a dose-related allodynia and hyperalgesia and a progressive structural damage to the DRG. We observed a precocious increase of macrophage activation markers and unbalance of pro- and anti-inflammatory cytokines in sciatic nerve and DRG together with an upregulation of GFAP in the spinal cord. At higher BTZ cumulative dose PK2 and PK receptors are upregulated in the PNS and in the spinal cord. The therapeutic treatment with the PK-R antagonist PC1 counteracts the development of allodynia and hyperalgesia, ameliorates the structural damage in the PNS, decreases the levels of activated macrophage markers, and prevents full neuroimmune activation in the spinal cord. CONCLUSIONS PK system may be a strategical pharmacological target to counteract BTZ-induced peripheral neuropathy. Blocking PK2 activity reduces progressive BTZ toxicity in the DRG, reducing neuroinflammation and structural damage to DRG, and it may prevent spinal cord sensitization.
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Affiliation(s)
- Giorgia Moschetti
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Vanvitelli, 32, 20129, Milan, Italy
| | - Giada Amodeo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Vanvitelli, 32, 20129, Milan, Italy
| | - Daniela Maftei
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Rome, Italy
| | - Roberta Lattanzi
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Patrizia Procacci
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Patrizia Sartori
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Gianfranco Balboni
- Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy
| | - Valentina Onnis
- Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy
| | - Vincenzo Conte
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Alberto Panerai
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Vanvitelli, 32, 20129, Milan, Italy
| | - Paola Sacerdote
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Vanvitelli, 32, 20129, Milan, Italy
| | - Silvia Franchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Vanvitelli, 32, 20129, Milan, Italy.
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Mundim MV, Zamproni LN, Pinto AAS, Galindo LT, Xavier AM, Glezer I, Porcionatto M. A new function for Prokineticin 2: Recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury. Mol Cell Neurosci 2018; 94:1-10. [PMID: 30391355 DOI: 10.1016/j.mcn.2018.10.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/13/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
Traumatic brain injury is an important cause of global morbidity and mortality. After an initial injury, there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim to both counteract these mechanisms and replenish the lost cell population in order to improve recovery. The adult mammal brain has at least two neurogenic regions that maintain physiological functions: the subgranular zone of the dentate gyrus in the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) adjacent to the lateral ventricles, which produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that cells migrate from the SVZ and RMS to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis, expressed exclusively by cortical microglia in the cortex as early as 24 h after injury. We then show that administration of a PROK2 receptor antagonist decreases the number of SVZ cells that reach the injured cortex, while injection of recombinant PROK2 into the cortex of uninjured mice attracts SVZ cells. We also demonstrate that cells expressing PROK2 in vitro directionally attract SVZ cells. These data suggest that PROK2 could be utilized in regeneration efforts for the acutely injured mammalian cortex.
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Affiliation(s)
- Mayara Vieira Mundim
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - Laura Nicoleti Zamproni
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - Agnes Araújo Sardinha Pinto
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - Layla Testa Galindo
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil
| | - André Machado Xavier
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua 3 de Maio, 100 - 4o andar, São Paulo, SP 04044-020, Brazil
| | - Isaias Glezer
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua 3 de Maio, 100 - 4o andar, São Paulo, SP 04044-020, Brazil
| | - Marimélia Porcionatto
- Department of Biochemistry, Laboratory of Neurobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 3o andar, São Paulo, SP 04039-032, Brazil.
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30
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Negri L, Ferrara N. The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis. Physiol Rev 2018. [PMID: 29537336 DOI: 10.1152/physrev.00012.2017] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The mammalian prokineticins family comprises two conserved proteins, EG-VEGF/PROK1 and Bv8/PROK2, and their two highly related G protein-coupled receptors, PKR1 and PKR2. This signaling system has been linked to several important biological functions, including gastrointestinal tract motility, regulation of circadian rhythms, neurogenesis, angiogenesis and cancer progression, hematopoiesis, and nociception. Mutations in PKR2 or Bv8/PROK2 have been associated with Kallmann syndrome, a developmental disorder characterized by defective olfactory bulb neurogenesis, impaired development of gonadotropin-releasing hormone neurons, and infertility. Also, Bv8/PROK2 is strongly upregulated in neutrophils and other inflammatory cells in response to granulocyte-colony stimulating factor or other myeloid growth factors and functions as a pronociceptive mediator in inflamed tissues as well as a regulator of myeloid cell-dependent tumor angiogenesis. Bv8/PROK2 has been also implicated in neuropathic pain. Anti-Bv8/PROK2 antibodies or small molecule PKR inhibitors ameliorate pain arising from tissue injury and inhibit angiogenesis and inflammation associated with tumors or some autoimmune disorders.
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Affiliation(s)
- Lucia Negri
- Sapienza University of Rome, Rome, Italy ; and University of California, San Diego, La Jolla, California
| | - Napoleone Ferrara
- Sapienza University of Rome, Rome, Italy ; and University of California, San Diego, La Jolla, California
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31
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Burroughs S, Schwindinger WF, Venditti JJ, Trautwein T, Dalsania A, Klingerman CM. Prokineticin-2 and ghrelin robustly influence the sexual and ingestive behaviors of female Syrian hamsters. Horm Behav 2018; 106:135-143. [PMID: 30189212 DOI: 10.1016/j.yhbeh.2018.08.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/20/2018] [Accepted: 08/31/2018] [Indexed: 12/20/2022]
Abstract
Prokineticins are involved in many physiological processes including circadian rhythms, neurogenesis, angiogenesis, and cancer. Recently, they have been found to play a role in regulating food intake. Historically, proteins that increase feeding behavior in mammals decrease reproductive behavior to prevent pregnancy and lactation when food is scarce. In the current study, prokineticin-2 (PK2) had pronounced effects on reproductive and ingestive behaviors when given to female Syrian hamsters. Administration of PK2 prevented ingestive behaviors induced by food restriction, such as the amount of time spent with food and eating. Hamsters given PK2 preferred to engage in reproductive behaviors, including spending time with a male and lordosis. Furthermore, analysis of blood plasma revealed that changes to behavior persisted despite similar levels of des-acyl ghrelin (DAG) and reduced glucose concentrations in the blood. Additionally, administering 10 mg/kg of acyl ghrelin (AG) to a different cohort of animals significantly decreased the amount of time females spent with a potential mating partner, increased the amount of time females spent with food, decreased the duration of lordosis, and increased the duration of eating. Results from the current study support the need for further research investigating the reproductive and ingestive roles of PK2 and ghrelin.
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Affiliation(s)
- S Burroughs
- Department of Biological and Allied Health Sciences, Bloomsburg University of Pennsylvania, 400 E. Second St. Bloomsburg, PA 17815, United States of America
| | - W F Schwindinger
- Department of Biological and Allied Health Sciences, Bloomsburg University of Pennsylvania, 400 E. Second St. Bloomsburg, PA 17815, United States of America
| | - J J Venditti
- Department of Biological and Allied Health Sciences, Bloomsburg University of Pennsylvania, 400 E. Second St. Bloomsburg, PA 17815, United States of America
| | - T Trautwein
- Department of Biological and Allied Health Sciences, Bloomsburg University of Pennsylvania, 400 E. Second St. Bloomsburg, PA 17815, United States of America
| | - A Dalsania
- Department of Biological and Allied Health Sciences, Bloomsburg University of Pennsylvania, 400 E. Second St. Bloomsburg, PA 17815, United States of America
| | - C M Klingerman
- Department of Biological and Allied Health Sciences, Bloomsburg University of Pennsylvania, 400 E. Second St. Bloomsburg, PA 17815, United States of America.
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32
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Zhao Y, Wu J, Wang X, Jia H, Chen DN, Li JD. Prokineticins and their G protein-coupled receptors in health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 161:149-179. [PMID: 30711026 DOI: 10.1016/bs.pmbts.2018.09.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Prokineticins are two conserved small proteins (~8kDa), prokineticin 1 (PROK1; also called EG-VEGF) and prokineticin 2 (PROK2; also called Bv8), with an N-terminal AVITGA sequence and 10 cysteines forming 5 disulfide bridges. PROK1 and PROK2 bind to two highly related G protein-coupled receptors (GPCRs), prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Prokineticins and their receptors are widely expressed. PROK1 is predominantly expressed in peripheral tissues, especially steroidogenic organs, whereas PROK2 is mainly expressed in the central nervous system and nonsteroidogenic cells of the testes. Prokineticins signaling has been implicated in several important physiological functions, including gastrointestinal smooth muscle contraction, circadian rhythm regulation, neurogenesis, angiogenesis, pain perception, mood regulation, and reproduction. Dysregulation of prokineticins signaling has been observed in a variety of diseases, such as cancer, ischemia, and neurodegeneration, in which prokineticins signaling seems to be a promising therapeutic target. Based on the phenotypes of knockout mice, PROKR2 and PROK2 have recently been identified as causative genes for idiopathic hypogonadotropic hypogonadism, a developmental disorder characterized by impaired development of gonadotropin-releasing hormone neurons and infertility. In vitro functional studies with these disease-associated PROKR2 mutations uncovered some novel features for this receptor, such as biased signaling, which may be used to understand GPCR signaling regulation in general.
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Affiliation(s)
- Yaguang Zhao
- School of Life Sciences, Central South University, Changsha, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Jiayu Wu
- School of Life Sciences, Central South University, Changsha, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Xinying Wang
- School of Life Sciences, Central South University, Changsha, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Hong Jia
- School of Life Sciences, Central South University, Changsha, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Dan-Na Chen
- Department of Basic Medical Sciences, Changsha Medical University, Changsha, China.
| | - Jia-Da Li
- School of Life Sciences, Central South University, Changsha, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China.
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Lattanzi R, Maftei D, Negri L, Fusco I, Miele R. PK2β ligand, a splice variant of prokineticin 2, is able to modulate and drive signaling through PKR1 receptor. Neuropeptides 2018; 71:32-42. [PMID: 30253862 DOI: 10.1016/j.npep.2018.06.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 06/27/2018] [Accepted: 06/27/2018] [Indexed: 11/15/2022]
Abstract
Prokineticin-2 (PK2) is a secreted bioactive peptide that signals through two GPCRs, the prokineticin receptors (PKRs), and regulates a variety of biological processes including angiogenesis, immunity and nociception. The PK2 primary transcript has two alternative splice variants, PK2 and PK2L (a Long form) which is cleaved in an active peptide, named PK2β that preferentially binds to PKR1 receptor. The aim of this study was to characterize the PK2β. Using different Saccharomyces cerevisiae strains, we examined the specificity of PKR1 and PKR2 G-protein coupling following PK2β binding. Data obtained in yeast confirmed that PK2 binds both receptors, inducing a comparable response throughout a promiscuous coupling of G protein subtypes. Conversely, we demonstrated, for the first time, that PK2β preferentially binding to PKR1, activates a signaling cascade that not depends on Gαi/o coupling. The binding specificity of PK2β for PKR1 was evaluated by the analysis of PKR mutant in yeast and GST pull-down experiments, suggesting an important role of PKR1 amino-terminal region. We also evaluated the ability of PK2β to differentially activate PKR1 and/or PKR2 by in vivo nociceptive experiments and we showed that PK2β induces intense sensitization of peripheral nociceptors to painful stimuli through the activation of PKR1. To analyze PK2β-induced signal transduction, we demonstrated the inability of PK2β to induce STAT3 protein phosphorylation in organotypic primary explants from mice Dorsal Root Ganglion (DRG), an important pain station. The control of the concentration ratio between PK2β and PK2 could be one of the keys to allow the specificity of the cell response of prokineticin signaling pathway.
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Affiliation(s)
- Roberta Lattanzi
- Dipartimento di Fisiologia e Farmacologia "Vittorio Erspamer", Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Daniela Maftei
- Dipartimento di Fisiologia e Farmacologia "Vittorio Erspamer", Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Lucia Negri
- Dipartimento di Fisiologia e Farmacologia "Vittorio Erspamer", Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Ilaria Fusco
- Dipartimento di Fisiologia e Farmacologia "Vittorio Erspamer", Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy
| | - Rossella Miele
- Dipartimento di Scienze Biochimiche A. Rossi Fanelli, CNR Istituto di Biologia e Patologia Molecolare, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
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34
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Li Y, Wang J, Yu L, Zhao K, Chen B, Li C, Yang F, Yuan H, Zhang H. Effects of prokineticin 2 on testicular inflammation in rats. Am J Reprod Immunol 2018. [PMID: 29516577 DOI: 10.1111/aji.12843] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
PROBLEM Prokineticin 2 (PK2), a pro-inflammatory peptide, is highly expressed in primary spermatocytes. However, systematic research on PK2 and testicular inflammation is lacking to date. METHOD OF STUDY An experimental autoimmune orchitis (EAO) model was established to detect the expression of PK2 and its receptor (prokineticin receptor 1, PKR1) 50 and 80 days after immunization. PK2 siRNA sequence was injected into the rat rete testis to downregulate the expression of PK2. PK2 was over-expressed in the testis by injecting PK2 protein through the rat rete testis at different concentrations. Testicular morphology and expression of inducible nitric oxide synthase (iNOS) were detected after the intervention. RESULTS Results showed that PK2 and PKR1 were upregulated in EAO at 50 days and downregulated at 80 days. PK2 over-expression contributed to the apoptosis of spermatogenic epithelial cells and increased infiltration of the inflammatory cells, whereas PK2 under-expression showed no change. Furthermore, iNOS expression was increased significantly when PK2 was over-expressed. CONCLUSION This finding demonstrated that the PK2/PKR1 signals may have an essential role in the regulation of testicular inflammation through iNOS. PK2 interference may represent a novel and promising therapeutic strategy for the clinical management of orchitis.
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Affiliation(s)
- Ying Li
- Institute of Family Planning Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaojiao Wang
- Haidian Maternal & Child Health Hospital, Beijing, China
| | - Lili Yu
- Guangxi Maternal & Child Health Hospital, Nanning, China
| | - Kai Zhao
- Institute of Family Planning Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Biao Chen
- Department of Gynecology and Obstetrics, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan, China
| | - Cuiling Li
- Department of Medical Ultrasound, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fan Yang
- German Cancer Research Center, Heidelberg, Germany
| | - Hongfang Yuan
- Institute of Family Planning Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiping Zhang
- Institute of Family Planning Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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35
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Franchi S, Sacerdote P, Panerai A. The prokineticin system: an interface between neural inflammation and pain. Neurol Sci 2018; 38:27-30. [PMID: 28527062 DOI: 10.1007/s10072-017-2875-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Prokineticins (PK) 1 and 2 belong to a new family of chemokines capable to interact with two different G coupled receptors: Prokineticin receptor (PKR)1 and 2. Both prokineticins and their receptors are widely distributed in different tissues and regulate several biological functions. In particular, a role of the PK system in inflammation and nociception has been established. PKRs are expressed in regions of the nervous system associated with pain and in primary sensitive neurons they colocalize with transient potential receptor vanilloid-TRPV1 providing an anatomical interaction in nociceptor sensitization. Moreover, PKs are strongly upregulated in immune and glial cells and sustain a proinflammatory loop in inflamed tissues. Recent evidences indicate that the block of the PK system represents a promising strategy to contrast inflammation and pain.
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Affiliation(s)
- Silvia Franchi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi Milano, Milan, Italy
| | - Paola Sacerdote
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi Milano, Milan, Italy
| | - Alberto Panerai
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi Milano, Milan, Italy.
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Caioli S, Severini C, Ciotti T, Florenzano F, Pimpinella D, Petrocchi Passeri P, Balboni G, Polisca P, Lattanzi R, Nisticò R, Negri L, Zona C. Prokineticin system modulation as a new target to counteract the amyloid beta toxicity induced by glutamatergic alterations in an in vitro model of Alzheimer's disease. Neuropharmacology 2017; 116:82-97. [DOI: 10.1016/j.neuropharm.2016.12.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 11/29/2016] [Accepted: 12/14/2016] [Indexed: 12/28/2022]
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Zinni M, Zuena AR, Marconi V, Petrella C, Fusco I, Giuli C, Canu N, Severini C, Broccardo M, Theodorou V, Lattanzi R, Casolini P. Maternal exposure to low levels of corticosterone during lactation protects adult rat progeny against TNBS-induced colitis: A study on GR-mediated anti-inflammatory effect and prokineticin system. PLoS One 2017; 12:e0173484. [PMID: 28267767 PMCID: PMC5340375 DOI: 10.1371/journal.pone.0173484] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 02/22/2017] [Indexed: 01/01/2023] Open
Abstract
The early phase of life represents a critical period for the development of an organism. Interestingly, early life experiences are able to influence the development of the gastrointestinal tract and the reactivity to colonic inflammatory stress. We recently demonstrated that adult male rats exposed to low doses of corticosterone during lactation (CORT-nursed rats) are protected against experimental colitis induced by the intracolonic infusion of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Based on these interesting results, we wanted to better investigate which cellular actors could be involved in the protection of CORT-nursed rats from TNBS-induced experimental colitis. Therefore, in the present work, we focused our attention on different factors implicated in GR-mediated anti-inflammatory effect. To address this issue, colonic tissues, collected from control and CORT-nursed healthy animals and from control and CORT-nursed colitic rats, were processed and the following inflammatory factors were evaluated: the expression of (i) glucocorticoid receptors (GR), (ii) glucocorticoid-induced leucine zipper (GILZ), (iii) phospho-p65NF-κB, (iv) the pro-inflammatory cytokines IL-1β and TNF-α, (v) the prokineticins PK2 and PK2L and (vi) their receptors PKR1 and PKR2. We found that adult CORT-nursed rats, in comparison to controls, showed increased expression of colonic GR and reduced expression of pro-inflammatory molecules (IL-1β, TNF-α, PK2 and PK2L) in response to inflammatory colitis. The observed changes were associated with an increase in GILZ colonic expression and with a reduction in phospo-p65NF-κB colonic expression.
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Affiliation(s)
- Manuela Zinni
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Anna Rita Zuena
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Veronica Marconi
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Carla Petrella
- Institute of Cell Biology and Neurobiology, CNR, Rome, Italy
| | - Ilaria Fusco
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Chiara Giuli
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Nadia Canu
- Institute of Cell Biology and Neurobiology, CNR, Rome, Italy
- Department of System Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Cinzia Severini
- Institute of Cell Biology and Neurobiology, CNR, Rome, Italy
| | - Maria Broccardo
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Vassilia Theodorou
- INRA, EI-Purpan, UMR 1331 TOXALIM Neuro-Gastroenterology and Nutrition Team, Toulouse, France
| | - Roberta Lattanzi
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
| | - Paola Casolini
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
- * E-mail:
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Özdemir FT, Demiralp EE, Aydın SZ, Atagündüz P, Ergun T, Direskeneli H. Immune and inflammatory gene expressions are different in Behçet's disease compared to those in Familial Mediterranean Fever. Eur J Rheumatol 2017; 3:146-152. [PMID: 28149656 DOI: 10.5152/eurjrheum.2016.15099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 07/15/2016] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE The immune classification of Behçet's disease (BD) is still controversial. In this study, we aimed to compare the immune/inflammatory gene expressions in BD with those in familial Mediterranean fever (FMF), an autoinflammatory disorder with innate immune activation. MATERIAL AND METHODS CD4+ T cells and CD14+ monocytes were isolated from the peripheral blood mononuclear cells of Behçet's disease patients (n=10), FMF (n=6) patients, and healthy controls (n=4) with microbeads, and then, the mRNA was isolated. The expressions of 440 genes associated with immune and inflammatory responses were studied with a focused DNA microarray using a chemiluminescent tagging system. Changes above 1.5-fold and below 0.8-fold were accepted to be significant. RESULTS In BD patients, in the CD4+ T-lymphocyte subset, interleukin 18 receptor accessory protein (1.7-fold), IL-7 receptor (1.9-fold), and prokineticin 2 (2.5-fold) were all increased compared to those in FMF patients, whereas chemokine (C-X3-C motif ) receptor-1 (CX3CR1) (0.7-fold) and endothelial cell growth factor-1 (0.6-fold) were decreased. In the CD14+ monocyte population, the V-fos FBJ murine osteosarcoma viral oncogene homolog (1.5-fold), Interleukin-8 (IL-8) (2.1-fold), and Tumor Necrosis Factor alpha (TNF-α) (1.8-fold) were all increased, whereas the chemokine (C-C motif ) ligand 5 (CCL5) (0.6-fold), C-C chemokine receptor type 7 (0.6-fold), and CX3CR1 (0.7-fold) were decreased, again when compared to those in FMF. Compared to healthy controls in the CD4+ T-lymphocyte population, in both BD and FMF patients, pro-platelet basic protein and CD27 had elevated expression. In BD and FMF patients, 24 and 19 genes, respectively, were downregulated, with 15 overlapping genes between both disorders. In the CD14+ monocytes population, chemokine (C-C motif ) receptor-1 (CCR1) was upregulated both in BD and FMF patients compared to that in the controls, whereas CCL5 was downregulated. CONCLUSION Immune and inflammatory gene expressions seem to be variable in both the innate (CD14+) and adaptive (CD4+) immune responses in BD and FMF patients compared to those in controls, suggesting differences in immune regulation between the two disorders.
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Affiliation(s)
- Filiz Türe Özdemir
- Department of Immunology, Marmara University School of Medicine, İstanbul, Turkey
| | - Emel Ekşioğlu Demiralp
- Department of Immunology, Marmara University School of Medicine, İstanbul, Turkey; Department of Immunology, Memorial Şişli Hospital, İstanbul, Turkey
| | - Sibel Z Aydın
- Department of Rheumatology, Marmara University School of Medicine, İstanbul, Turkey; Department of Rheumatology, Ottawa University School of Medicine, Ottawa, Canada
| | - Pamir Atagündüz
- Department of Rheumatology, Marmara University School of Medicine, İstanbul, Turkey
| | - Tülin Ergun
- Department of Dermatology, Marmara University School of Medicine, İstanbul, Turkey
| | - Haner Direskeneli
- Department of Rheumatology, Marmara University School of Medicine, İstanbul, Turkey
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Chen B, Yu L, Wang J, Li C, Zhao K, Zhang H. Involvement of Prokineticin 2 and Prokineticin Receptor 1 in Lipopolysaccharide-Induced Testitis in Rats. Inflammation 2017; 39:534-42. [PMID: 26490969 DOI: 10.1007/s10753-015-0277-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Prokineticin 2, a newly discovered proinflammatory peptide, has been amply evidenced to be involved in the occurrence and progress of local and systematical inflammation. Although the presence of Prokineticn 2 in mammal testis has been documented clearly, research targeting the involvement of prokineticin 2 in testicular pathology, especially testitis, is rather scarce. Employing a lipopolysaccharide-induced testitis rat model, we for the first time demonstrated the expression and upregulation of prokineticin 2 in orchitis at several levels. Our effort also addressed the differential expression patterns of prokineticin 2 and interleukin-1β, a key inflammation indicator, during testitis suggesting Prokineticn 2 serves more than a proinflammatory factor in the context of testitis. Given one of the cognate receptors of prokineticin 2, prokineticin receptor 1 (PKR1) was also significantly upregulated in orchitis as discussed in the current study, it is very likely that PK2/PKR1 signaling contribute to the development of inflammation-related testicular diseases.
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Affiliation(s)
- Biao Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lili Yu
- Department of obstetrics, The Maternal & Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Jiaojiao Wang
- Institute of Family Planning Research, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cuiling Li
- Institute of Family Planning Research, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kai Zhao
- Institute of Family Planning Research, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huiping Zhang
- Institute of Family Planning Research, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. .,Institute of Family Planning Research, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, China, , 430030.
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40
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Landucci E, Lattanzi R, Gerace E, Scartabelli T, Balboni G, Negri L, Pellegrini-Giampietro DE. Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro. Neuropharmacology 2016; 108:39-48. [PMID: 27140692 DOI: 10.1016/j.neuropharm.2016.04.043] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 04/27/2016] [Accepted: 04/28/2016] [Indexed: 11/24/2022]
Abstract
Bv8/prokineticin 2 (PK2) is a member of a bioactive family of peptides that regulate multiple functions in the CNS including hyperalgesia, neurogenesis, neuronal survival and inflammation. Recent studies have associated PK2 and prokineticin receptors (PKR) with human diseases, but because their role in neuropathology is still debated we examined whether prokineticins exert a protective or deleterious role in models of cerebral ischemia and ischemic tolerance in vitro. In order to mimic cerebral ischemia, we exposed primary murine cortical cell cultures or rat organotypic hippocampal slices to appropriate periods of oxygen-glucose deprivation (OGD), which leads to neuronal damage 24 h later. Ischemic tolerance was induced by exposing hippocampal slices to a preconditioning subtoxic pharmacological stimulus (3 μM NMDA for 1 h) 24 h before the exposure to OGD. Bv8 (10-100 nM) attenuated OGD injury in cortical cultures and hippocampal slices, and the effect was prevented by the PKR antagonist PC7. The development of OGD tolerance was associated with an increase in the expression of PK2, PKR1 and PKR2 mRNA and proteins and was prevented by addition of the antagonist PC7 into the medium during preconditioning. Both Bv8 at protective concentrations and the NMDA preconditioning stimulus promoted the phosphorylation of ERK1/2 and Akt. These findings indicate that the prokineticin system can be up-regulated by a defensive preconditioning subtoxic NMDA stimulus and that PK2 may act as an endogenous neuroprotective factor through the activation of the ERK1/2 and Akt transduction pathways.
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Affiliation(s)
- Elisa Landucci
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
| | - Roberta Lattanzi
- Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Rome "La Sapienza", Piazza A. Moro 5, 00185 Rome, Italy
| | - Elisabetta Gerace
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
| | - Tania Scartabelli
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
| | - Gianfranco Balboni
- Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
| | - Lucia Negri
- Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Rome "La Sapienza", Piazza A. Moro 5, 00185 Rome, Italy
| | - Domenico E Pellegrini-Giampietro
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
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Castelli M, Amodeo G, Negri L, Lattanzi R, Maftei D, Gotti C, Pistillo F, Onnis V, Congu C, Panerai AE, Sacerdote P, Franchi S. Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes. PLoS One 2016; 11:e0146259. [PMID: 26730729 PMCID: PMC4701417 DOI: 10.1371/journal.pone.0146259] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 12/15/2015] [Indexed: 11/19/2022] Open
Abstract
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.
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MESH Headings
- Animals
- Blotting, Western
- Cytokines/genetics
- Cytokines/metabolism
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Disease Models, Animal
- Gastrointestinal Hormones/genetics
- Gastrointestinal Hormones/metabolism
- Gene Expression
- Hyperalgesia/genetics
- Hyperalgesia/metabolism
- Hyperalgesia/prevention & control
- Inflammation/genetics
- Inflammation/metabolism
- Inflammation/prevention & control
- Male
- Mice, Inbred C57BL
- Neuralgia/genetics
- Neuralgia/metabolism
- Neuralgia/prevention & control
- Neuropeptides/genetics
- Neuropeptides/metabolism
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
- Receptors, N-Methyl-D-Aspartate/genetics
- Receptors, N-Methyl-D-Aspartate/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sciatic Nerve/metabolism
- Spinal Cord/metabolism
- Triazines/pharmacology
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Affiliation(s)
- Mara Castelli
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Giada Amodeo
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Lucia Negri
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University of Rome, Roma, Italy
| | - Roberta Lattanzi
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University of Rome, Roma, Italy
| | - Daniela Maftei
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University of Rome, Roma, Italy
| | - Cecilia Gotti
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Milano, Italy
| | - Francesco Pistillo
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Milano, Italy
| | - Valentina Onnis
- Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy
| | - Cenzo Congu
- Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy
| | - Alberto E. Panerai
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Paola Sacerdote
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
- * E-mail:
| | - Silvia Franchi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
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Wang Y, Guo X, Ma H, Lu L, Zhang R. Prokineticin-2 is associated with metabolic syndrome in a middle-aged and elderly Chinese population. Lipids Health Dis 2016; 15:1. [PMID: 26728949 PMCID: PMC4700697 DOI: 10.1186/s12944-015-0172-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 12/29/2015] [Indexed: 12/13/2022] Open
Abstract
Background Prokineticin-2 is confirmed to be involved in the inflammatory process. Inflammation plays an important role in the pathogenesis of metabolic syndrome (MS). However, whether prokineticin-2 is associated with MS or not remains unknown. Thus, we present this study to explore the association between prokineticin-2 and MS in a Chinese population. Methods This study included 162 middle-aged and elderly Chinese patients with cardiovascular risk factors. The relationship between serum prokineticin-2 levels and various cardiometabolic risk factors, and MS were evaluated. Results The participants with serum prokineticin-2 levels >6.32 ng/ml had increased waist circumference, body mass index (BMI), plasma triglyceride, diastolic blood pressure (DBP), blood glucose, and serum uric acid, but decreased age, plasma high-density lipoprotein cholesterol (HDL-C), and HDL-C/total cholesterol (TC) (all P < 0.05). A higher percentage of them had history of lipid disorders (19.3 vs 2.5 %, P = 0.001) and MS (77.1 vs 48.1 %, P < 0.001). Prokineticin-2 was positively correlated with TC (partial correlation coefficient: 0.233, P = 0.011), triglyceride (partial correlation coefficient: 0.504, P < 0.001), fasting plasma glucose (partial correlation coefficient: 0.336, P < 0.001), HbA1c (partial correlation coefficient: 0.285, P = 0.002), and uric acid (partial correlation coefficient: 0.234, P = 0.011) respectively, but was negatively correlated with HDL-C/TC (partial correlation coefficient: −0.269, P = 0.003) with adjustment for age, man, and BMI. Prokineticin-2 was significantly elevated in participants with MS (7.72 ± 3.34 vs 5.56 ± 2.39 ng/ml, P < 0.001). Furthermore, prokineticin-2 was significantly elevated in participants with increased numbers of MS components (5.17 ± 2.29 vs 5.94 ± 2.47 vs 7.13 ± 3.33 vs 8.32 ± 2.81 vs 9.82 ± 4.37 ng/ml, P for trend <0.001). Multiple logistic regression analysis indicated that prokineticin-2 was independently associated with MS (OR: 1.307, 95 % confidence interval: 1.127–1.515, P < 0.001) with adjustment for other potential confounders. If serum prokineticin-2 value can be considered as an indicator to discriminate MS, receiver operating characteristic curve analysis exhibited the area under the curve as 0.701. Conclusions Prokineticin-2 is correlated with various cardiometabolic risk factors including blood lipid, blood glucose, blood pressure, BMI, and uric acid. And furthermore, the increased prokineticin-2 is independently associated with MS.
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Affiliation(s)
- Yong Wang
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China.,Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Xiaoyan Guo
- Department of Gastroenterology, Gongli Hospital of Pudong New District, The Second Military Medical University, Shanghai, 200135, China
| | - Heng Ma
- Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, 264000, China
| | - Lin Lu
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China.,Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ruiyan Zhang
- Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China. .,Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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PK2/PKR1 Signaling Regulates Bladder Function and Sensation in Rats with Cyclophosphamide-Induced Cystitis. Mediators Inflamm 2015; 2015:289519. [PMID: 26798205 PMCID: PMC4700194 DOI: 10.1155/2015/289519] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 10/30/2015] [Accepted: 11/16/2015] [Indexed: 12/15/2022] Open
Abstract
Prokineticin 2 (PK2) is a novel chemokine-like peptide with multiple proinflammatory and nociception-related activities. This study aimed to explore the potential role of PK2 in modulating bladder activity and sensation in rats with cyclophosphamide- (CYP-) induced cystitis. Changes of PK2 and prokineticin receptors (PKRs) in normal and inflamed urinary bladders were determined at several time points (4 h, 48 h, and 8 d) after CYP treatment. Combining a nonselective antagonist of prokineticin receptors (PKRA), we further evaluated the regulatory role of PK2 in modulating bladder function and visceral pain sensation via conscious cystometry and pain behavioral scoring. PK2 and prokineticin receptor 1 (PKR1), but not prokineticin receptor 2, were detected in normal and upregulated in CYP-treated rat bladders at several levels. Immunohistochemistry staining localized PKR1 primarily in the urothelium. Blocking PKRs with PKRA showed no effect on micturition reflex activity and bladder sensation in control rats while it increased the voiding volume, prolonged voiding interval, and ameliorated visceral hyperalgesia in rats suffering from CYP-induced cystitis. In conclusion, PK2/PKR1 signaling pathway contributes to the modulation of inflammation-mediated voiding dysfunction and spontaneous visceral pain. Local blockade of PKRs may represent a novel and promising therapeutic strategy for the clinical management of inflammation-related bladder diseases.
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Bv8/prokineticin 2 is involved in Aβ-induced neurotoxicity. Sci Rep 2015; 5:15301. [PMID: 26477583 PMCID: PMC4610025 DOI: 10.1038/srep15301] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 08/26/2015] [Indexed: 11/08/2022] Open
Abstract
Bv8/Prokineticin 2 (PROK2) is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Among multiple biological roles demonstrated for PROK2, it was recently established that PROK2 is an insult-inducible endangering mediator for cerebral damage. Aim of the present study was to evaluate the PROK2 and its receptors' potential involvement in amyloid beta (Aβ) neurotoxicity, a hallmark of Alzheimer's disease (AD) and various forms of traumatic brain injury (TBI). Analyzing primary cortical cultures (CNs) and cortex and hippocampus from Aβ treated rats, we found that PROK2 and its receptors PKR1 and PKR2 mRNA are up-regulated by Aβ, suggesting their potential involvement in AD. Hence we evaluated if impairing the prokineticin system activation might have protective effect against neuronal death induced by Aβ. We found that a PKR antagonist concentration-dependently protects CNs against Aβ(1-42)-induced neurotoxicity, by reducing the Aβ-induced PROK2 neuronal up-regulation. Moreover, the antagonist completely rescued LTP impairment in hippocampal slices from 6 month-old Tg2576 AD mice without affecting basal synaptic transmission and paired pulse-facilitation paradigms. These results indicate that PROK2 plays a role in cerebral amyloidosis and that PROK2 antagonists may represent a new approach for ameliorating the defining pathology of AD.
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45
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Prokineticin 2 facilitates mechanical allodynia induced by α,β-methylene ATP in rats. Eur J Pharmacol 2015; 767:24-9. [PMID: 26435025 DOI: 10.1016/j.ejphar.2015.09.047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 09/25/2015] [Accepted: 09/29/2015] [Indexed: 01/19/2023]
Abstract
Prokineticin 2 (PK2), a new chemokine, causes mechanical hypersensitivity in the rat hind paw, but little is known about the molecular mechanism. Here, we have found that ionotropic P2X receptor is essential to mechanical allodynia induced by PK2. First, intraplantar injection of high dose (3 or 10 pmol) of PK2 significantly increased paw withdrawal response frequency (%) to innocuous mechanical stimuli (mechanical allodynia). And the mechanical allodynia induced by PK2 was prevented by co-administration of TNP-ATP, a selective P2X receptor antagonist. Second, although low dose (0.3 or 1 pmol) of PK2 itself did not produce an allodynic response, it significantly facilitated the mechanical allodynia evoked by intraplantar injection of α,β-methylene ATP (α,β-meATP). Third, PK2 concentration-dependently potentiated α,β-meATP-activated currents in rat dorsal root ganglion (DRG) neurons. Finally, PK2 receptors and intracellular signal transduction were involved in PK2 potentiation of α,β-meATP-induced mechanical allodynia and α,β-meATP-activated currents, since the potentiation were blocked by PK2 receptor antagonist PKRA and selective PKC inhibitor GF 109203X. These results suggested that PK2 facilitated mechanical allodynia induced by α,β-meATP through a mechanism involved in sensitization of cutaneous P2X receptors expressed by nociceptive nerve endings.
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Abstract
PURPOSE OF REVIEW Because of its increasing prevalence and morbi-mortality, obesity is a major health problem. Obesity etiology includes a combination of excess dietary calories and decreased physical activity, coupled with either predisposing genetic factors or metabolic disorders such as insulin resistance. Adipose tissue secretes several metabolically important proteins known as 'adipokines' that play a major role in obesity and insulin resistance. High levels of a newly identified group of adipokines, called prokineticins, have been found in obese adipose tissues. Prokineticins are peptide hormones released principally from macrophages and reproductive organs. They act on the G protein-coupled receptors PKR1 and PKR2. This review aims to provide an overview of current knowledge of the role of prokineticins and their receptors in the development of obesity and insulin resistance. RECENT FINDINGS The principal biological effect of prokineticins in the central nervous system is the control of food intake. Nevertheless, peripheral biological effects of prokineticin are associated with increasing insulin sensitivity and suppressing the adipose tissue expansion. SUMMARY We outline the biological significance of the central and peripheral effects of prokineticins, and the potential of their receptors as targets for the treatment of obesity and insulin resistance.
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Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel. Pharmacol Res 2015; 99:362-9. [DOI: 10.1016/j.phrs.2015.07.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 07/10/2015] [Accepted: 07/10/2015] [Indexed: 11/22/2022]
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Luo J, Feng J, Liu S, Walters ET, Hu H. Molecular and cellular mechanisms that initiate pain and itch. Cell Mol Life Sci 2015; 72:3201-23. [PMID: 25894692 PMCID: PMC4534341 DOI: 10.1007/s00018-015-1904-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 03/20/2015] [Accepted: 04/07/2015] [Indexed: 12/17/2022]
Abstract
Somatosensory neurons mediate our sense of touch. They are critically involved in transducing pain and itch sensations under physiological and pathological conditions, along with other skin-resident cells. Tissue damage and inflammation can produce a localized or systemic sensitization of our senses of pain and itch, which can facilitate our detection of threats in the environment. Although acute pain and itch protect us from further damage, persistent pain and itch are debilitating. Recent exciting discoveries have significantly advanced our knowledge of the roles of membrane-bound G protein-coupled receptors and ion channels in the encoding of information leading to pain and itch sensations. This review focuses on molecular and cellular events that are important in early stages of the biological processing that culminates in our senses of pain and itch.
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Affiliation(s)
- Jialie Luo
- Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA
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Abou-Hamdan M, Costanza M, Fontana E, Di Dario M, Musio S, Congiu C, Onnis V, Lattanzi R, Radaelli M, Martinelli V, Salvadori S, Negri L, Poliani PL, Farina C, Balboni G, Steinman L, Pedotti R. Critical role for prokineticin 2 in CNS autoimmunity. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2015; 2:e95. [PMID: 25884014 PMCID: PMC4396530 DOI: 10.1212/nxi.0000000000000095] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 02/02/2015] [Indexed: 12/14/2022]
Abstract
Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-γ and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-γ and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen. Conclusion: These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy.
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Affiliation(s)
- Mhamad Abou-Hamdan
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Massimo Costanza
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Elena Fontana
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Marco Di Dario
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Silvia Musio
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Cenzo Congiu
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Valentina Onnis
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Roberta Lattanzi
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Marta Radaelli
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Vittorio Martinelli
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Severo Salvadori
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Lucia Negri
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Pietro Luigi Poliani
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Cinthia Farina
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Gianfranco Balboni
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Lawrence Steinman
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
| | - Rosetta Pedotti
- Neuroimmunology and Neuromuscular Disorder Unit (M.A.-H., M.C., S.M., R.P.), Neurological Institute Foundation IRCCS Carlo Besta, Milan, Italy; Department of Molecular and Translational Medicine (E.F., P.L.P.), Pathology Unit, University of Brescia, Italy; Institute of Experimental Neurology (M.D.D., M.R., V.M., C.F.), San Raffaele Scientific Institute, Milan, Italy; Department of Life and Environmental Sciences (C.C., V.O., G.B.), Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, Italy; Department of Physiology and Pharmacology Vittorio Erspamer (R.L., L.N.), Sapienza University of Rome, Italy; Department of Chemical and Pharmaceutical Sciences (S.S.), University of Ferrara, Italy; and Department of Neurology (L.S., R.P.), Stanford University School of Medicine, Stanford, CA
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Zhao C, Qi L, Wu L, Yi T, Wu H, Guo X, Zhou C, Liu H, Wang X. Suspended moxibustion at Tianshu (ST25) inhibits prokineticin 1 and prokineticin receptor 1 expression in the spinal cord of rats with chronic visceral hypersensitivity. Neural Regen Res 2015; 7:1145-50. [PMID: 25722707 PMCID: PMC4340031 DOI: 10.3969/j.issn.1673-5374.2012.15.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 02/24/2012] [Indexed: 12/12/2022] Open
Abstract
Suspended moxibustion can decrease the expression of prokineticin 1 and its receptor in colonic tissue from rats modeling chronic visceral hyperalgesia. This study aimed to verify if rat spinal cord prokineticin 1 and its receptor contribute to the analgesic effect of suspended moxibustion in a rat model of irritable bowel syndrome where rats display chronic visceral hypersensitivity. Results showed that suspended moxibustion at Tianshu (ST25) point significantly decreased visceral sensitivity to colorectal distention in a chronic visceral hyperalgesia rat model; also protein and mRNA expression of prokineticin 1 and prokineticin receptor 1 in the spinal cord of rats was significantly decreased. Experimental findings indicate that prokineticin 1 and prokineticin receptor 1 are involved in the analgesia using suspended moxibustion in rats with chronic visceral hyperalgesia.
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Affiliation(s)
- Chen Zhao
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Qi
- Key Unit of Acupuncture-Moxibustion and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Luyi Wu
- Qigong Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Tao Yi
- Key Unit of Acupuncture-Moxibustion and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Huangan Wu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xinxin Guo
- Key Unit of Acupuncture-Moxibustion and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Cili Zhou
- Key Unit of Acupuncture-Moxibustion and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Huirong Liu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaomei Wang
- Key Unit of Acupuncture-Moxibustion and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
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