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Canan G Nebigil - One of the best experts on this subject based on the ideXlab platform.
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Prokineticin signaling in heart-brain developmental axis: Therapeutic options for heart and brain injuries
Pharmacological Research, 2020Co-Authors: Laurent Désaubry, Anumantha Kanthasamy, Canan G NebigilAbstract:Heart and brain development occur simultaneously during the embryogenesis, and both organ development and injuries are interconnected. Early neuronal and cardiac injuries share mutual cellular events, such as angiogenesis and plasticity that could either delay disease progression or, in the long run, result in detrimental health effects. For this reason, the common mechanisms provide a new and previously undervalued window of opportunity for intervention. Because angiogenesis, cardiogenesis and neurogenesis are essential for the development and regeneration of the heart and brain, we discuss therein the role of Prokineticin as an angiogenic neuropeptide in heart-brain development and injuries. We focus on the role of Prokineticin signaling and the effect of drugs targeting Prokineticin receptors in neuroprotection and cardioprotection, with a special emphasis on heart failure, neurodegenerativParkinson's disease and ischemic heart and brain injuries. Indeed, Prokineticin triggers common pro-survival signaling pathway in heart and brain. Our review aims at stimulating researchers and clinicians in neurocardiology to focus on the role of Prokineticin signaling in the reciprocal interaction between heart and brain. We hope to facilitate the discovery of new treatment strategies, acting in both heart and brain degenerative diseases.
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Prokineticin is a new linker between obesity and cardiovascular diseases
Frontiers in Cardiovascular Medicine, 2017Co-Authors: Canan G NebigilAbstract:Obesity is a fast growing epidemic event worldwide. Fatness is associated with a number of comorbidities, including cardiovascular diseases (CVD). Although obesity can be heredity in 30% to 70% cases, the environmental contributions also play an important role in the increasing prevalence of obesity. The relationship between development of obesity and CVD are poorly characterized. Obesity and CVD can also be resulted from a common mechanism such as metabolic, inflammatory, and neurohormonal changes. Prokineticins are defined as cytokines (immunoregulatory proteins), adipokines (adipocyte-secreted hormone), angiogenic (increasing vessel formation) or aneroxic (lowering food intake) hormones. Prokineticin-mediated signaling plays a key role in the development of obesity and CVD. Two forms of Prokineticins exist in circulation and in various tissues including the brain, heart, kidney, and adipose. Prokineticins act on the two G protein-coupled receptors (GPCRs) namely, PKR1 and PKR2. Prokineticin-2 via PKR1 receptor controls food intake and prevents adipose tissue expansion. The anti-adipocyte effect of PKR1 signaling is due to suppression of preadipocyte proliferation and differentiation capacity into adipocytes. Prokineticin-2/PKR1 signaling promotes transcapillary passages of insulin and increases insulin sensitivity. It also plays an important role in the heart and kidney development and functions. Here we discuss Prokineticin-2 as a new adipocytokine in the association between obesity and CVD. We also highlight targeting PKR1 can be a new approach to treat obesity and CVD.
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Genetic inactivation of Prokineticin receptor-1 leads to heart and kidney
2016Co-Authors: Mounia Boulberdaa, Kyoji Urayama, Nadia Messaddeq, Gulen Turkeri, Mojdeh Dormishian, Luc Zimmer, Virginie Laugel, Canan G NebigilAbstract:Objective—Prokineticins are potent angiogenic hormones that use 2 receptors, Prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. Methods and Results—We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin progenitor cell proliferation and differentiation. Conclusion—Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs. (Arterioscler Thromb Vasc Biol. 2011;31:842-850.) Key Words: angiogenesis cardiomyopathies kidney pharmacology receptor
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Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity
PLOS ONE, 2013Co-Authors: Cecilia Szatkowski, Nadia Messaddeq, Mounia Boulberdaa, Mojdeh Dormishian, Judith Vallet, Phillippe Valet, Daniel Metzger, Pierre Chambon, Canan G NebigilAbstract:Background Adipocyte renewal from preadipocytes occurs throughout the lifetime and contributes to obesity. To date, little is known about the mechanisms that control preadipocyte proliferation and differentiation. Prokineticin-2 is an angiogenic and anorexigenic hormone that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. Prokineticin-2 regulates food intake and energy metabolism via central mechanisms (PKR2). The peripheral effect of Prokineticin-2 on adipocytes/preadipocytes has not been studied yet.
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The FASEB Journal • Research Communication The Prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis
2013Co-Authors: Kyoji Urayama, Célia Guilini, Nadia Messaddeq, Marja Steenman, Hitoshi Kurose, Georg Ert, Canan G NebigilAbstract:ABSTRACT Prokineticins are potent angiogenic factors that bind to two G protein-coupled receptors to initiate their biological effects. We hypothesize that Prokineticin receptor-1 (PKR1/GPR73) signaling may contribute to cardiomyocyte survival or repair in myocardial infarction. Since we showed that Prokineticin-2 and PKR1 are expressed in adult mouse heart and cardiac cells, we investigated the role of Prokineticin-2 on capillary endothelial cell and cardiomyocyte function. In cultured cardiac endothelial cells, Prokineticin-2 or overexpression of PKR1 induces vessel-like formation without increasing VEGF levels. In cardiomyocytes and H9c2 cells, Prokineticin-2 or overexpressing PKR1 activates Akt to protect cardiomyocytes against oxidative stress. The survival and angiogenesis promotin
Roberta Lattanzi - One of the best experts on this subject based on the ideXlab platform.
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serum Prokineticin 2 in prepubertal and adult klinefelter individuals
Canadian Journal of Physiology and Pharmacology, 2021Co-Authors: Marco Fiore, Roberta Lattanzi, Daniela Maftei, Luigi Tarani, A Radicioni, Matteo Spaziani, Giampiero Ferraguti, Carolina Putotto, Francesca Gabanella, Antonio MinniAbstract: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 ...
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analysis of role of aromatic residues in extracellular loop 2 of Prokineticin receptor 2 in ligand binding probed with genetically encoded photo crosslinkers
Biochimica et Biophysica Acta, 2021Co-Authors: Maria Rosaria Fullone, Roberta Lattanzi, Daniela Maftei, Maria Carmela Bonaccorsi, Rossella MieleAbstract:Prokineticin 2 (PK2) and Prokineticin 2 beta (PK2β), products of alternative splicing of pk2 gene, are chemokine-like proteins. While PK2 mediates its biological activities by signaling with the same efficiency through two homologous G protein coupled receptors, Prokineticin receptor 1 (PKR1) and Prokineticin receptor 2 (PKR2), PK2β is able to bind specifically PKR1. Extracellular loop 2 (ECL2) of chemokine receptors is a part of a transmembrane (TM) ligand binding site. In the ECL2 of PKR2 is present, as well as in all chemokine receptors, an aromatic residue cluster, involving tryptophan 212 localized four residues after an ECL2 conserved cysteine, and Phenylalanine 198 located in the top of TM 4. In this work, the photoactivatable unnatural amino acid p-benzoyl-L-phenylalanine is incorporated by amber codon suppression technology into PKR2 in position 212. Experiments of photoactivatable cross-linking demonstrated the role of tryptophan in position 212 for binding the ligand contacting Tryptophan in position 24. We also analyzed the role of Phenylalanine 198 in the specificity of PKRs binding. The comparison of TM-bundle binding sites between PKR1 and PKR2 revealed that they are completely conserved except for one residue: valine 207 in human PKR1, which is phenylalanine 198 in human PKR2. The F198V mutation in PKR2 permits to obtain a receptor able to bind more efficiently PK2β, a ligand highly specific for PKR1.
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trypanosoma cruzi trans sialidase induces stat3 and erk activation by Prokineticin receptor 2 binding
Cell Biochemistry and Function, 2021Co-Authors: Roberta Lattanzi, Daniela Maftei, Maria Rosaria Fullone, Rossella MieleAbstract:Tc85, as other members of trans-sialidase family, is involved in Trypanosoma cruzi parasite adhesion to mammalian cells. Particularly, Tc85 acts through specific interactions with Prokineticin receptor 2, a G-protein coupled receptor involved in diverse physiological and pathological processes. In this manuscript, through biochemical analyses, we demonstrated that LamG, a Tc85 domain, physically interacts with the Prokineticin receptor 2. Moreover, expressing Prokineticin receptor 1 and 2 we demonstrated that LamG specifically activates Prokineticin receptor 2 through a strong coupling with Gαi or Gαq proteins in yeast strains and inducing ERK and NFAT phosphorylation in CHO mammalian cells. To demonstrate a Tc85 physiological role in T. cruzi infection of the nervous system, we evidenced a strong STAT3 and ERK activation by LamG in mice Dorsal Root Ganglia. L173R is the most common Prokineticin receptor 2 mutation reported in Kallmann syndrome and it is a founder mutation. Our results demonstrated that in cells co-expressing Prokineticin receptor 2 mutant (L173R) and wild-type, LamG is unable to induce signal transduction. The L173R mutation in heterozygosity may allow for a selective advantage due to increased protection from T. cruzi infection. SIGNIFICANCE OF THE STUDY: The Chagas' disease affecting millions of people worldwide is caused by an eukaryotic microorganism called T. cruzi. Pharmacological treatment for patients with Chagas' disease is still limited. Indeed, the small number of drugs available shows important side effects that can be debilitating for patient health. In order to replicate and produce new parasites T. cruzi uses a complex of different proteins produced by both the parasite and the human host cells. So, understanding the molecular details used by T. cruzi to be internalised by different types of human cells is an important step towards the development of new drugs for this disease. Prokineticin receptors are relevant for host-parasite interaction. To characterise the signal transduction cascade induced by their activation may help to understand the molecular details of cell infection, leading to novel therapeutic alternative for this debilitating disease.
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the role of Prokineticin 2 in oxidative stress and in neuropathological processes
Frontiers in Pharmacology, 2021Co-Authors: Roberta Lattanzi, Daniela Maftei, Cinzia Severini, Luciano Saso, Aldo BadianiAbstract:The Prokineticin (PK) family, Prokineticin 1 and Bv8/Prokineticin 2 (PROK2), initially discovered as regulators of gastrointestinal motility, interacts with two G protein-coupled receptors, PKR1 and PKR2, regulating important biological functions such as circadian rhythms, metabolism, angiogenesis, neurogenesis, muscle contractility, hematopoiesis, immune response, reproduction and pain perception. PROK2 and PK receptors, in particular PKR2, are widespread distributed in the central nervous system, in both neurons and glial cells. The PROK2 expression levels can be increased by a series of pathological insults, such as hypoxia, reactive oxygen species, beta amyloid and excitotoxic glutamate. This suggests that the PK system, participating in different cellular processes that cause neuronal death, can be a key mediator in neurological/neurodegenerative diseases. While many PROK2/PKRs effects in physiological processes have been documented, their role in neuropathological conditions is not fully clarified, since PROK2 can have a double function in the mechanisms underlying to neurodegeneration or neuroprotection. Here, we briefly outline the latest findings on the modulation of PROK2 and its cognate receptors following different pathological insults, providing information about their opposite neurotoxic and neuroprotective role in different pathological conditions.
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the balance of concentration between Prokineticin 2β and Prokineticin 2 modulates the food intake by stat3 signaling
BBA Advances, 2021Co-Authors: Daniela Maftei, Roberta Lattanzi, Maria Rosaria Fullone, Martina Vincenzi, Silvia Squillace, Rossella MieleAbstract:Abstract The secreted bioactive peptide Prokineticin 2 (PK2) is a potent adipokine and its central and peripheral administration reduces food intake in rodents. The pk2 gene has two splice variants, PK2 and PK2L (PK2 long form), which is cleaved into an active peptide, PK2β, that preferentially binds Prokineticin receptor 1 (PKR1). We investigated the role of PK2β in the regulation of food intake. We demonstrated that intraperitoneal injection of PK2β, in contrast to PK2, did not reduce food intake in mice. Exposure of hypotalamic explants to PK2, but not PK2β, induced phosphorylation of STAT3 and ERK. We also evidenced that in adipocytes from PKR1 knock-out mice, a model of obesity, there were higher PK2β levels than PK2 inducing a decreased activation of STAT3 and ERK. Our results suggest that variations in PK2 and PK2β levels, due to modulation of pk2 gene splicing processes, affect food intake in mice.
Kyoji Urayama - One of the best experts on this subject based on the ideXlab platform.
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Genetic inactivation of Prokineticin receptor-1 leads to heart and kidney
2016Co-Authors: Mounia Boulberdaa, Kyoji Urayama, Nadia Messaddeq, Gulen Turkeri, Mojdeh Dormishian, Luc Zimmer, Virginie Laugel, Canan G NebigilAbstract:Objective—Prokineticins are potent angiogenic hormones that use 2 receptors, Prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. Methods and Results—We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin progenitor cell proliferation and differentiation. Conclusion—Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs. (Arterioscler Thromb Vasc Biol. 2011;31:842-850.) Key Words: angiogenesis cardiomyopathies kidney pharmacology receptor
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The FASEB Journal • Research Communication The Prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis
2013Co-Authors: Kyoji Urayama, Célia Guilini, Nadia Messaddeq, Marja Steenman, Hitoshi Kurose, Georg Ert, Canan G NebigilAbstract:ABSTRACT Prokineticins are potent angiogenic factors that bind to two G protein-coupled receptors to initiate their biological effects. We hypothesize that Prokineticin receptor-1 (PKR1/GPR73) signaling may contribute to cardiomyocyte survival or repair in myocardial infarction. Since we showed that Prokineticin-2 and PKR1 are expressed in adult mouse heart and cardiac cells, we investigated the role of Prokineticin-2 on capillary endothelial cell and cardiomyocyte function. In cultured cardiac endothelial cells, Prokineticin-2 or overexpression of PKR1 induces vessel-like formation without increasing VEGF levels. In cardiomyocytes and H9c2 cells, Prokineticin-2 or overexpressing PKR1 activates Akt to protect cardiomyocytes against oxidative stress. The survival and angiogenesis promotin
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genetic inactivation of Prokineticin receptor 1 leads to heart and kidney disorders
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Mounia Boulberdaa, Kyoji Urayama, Nadia Messaddeq, Gulen Turkeri, Mojdeh Dormishian, Cecilia Szatkowski, Luc Zimmer, Virginie Laugel, Pascal Dolle, Canan G NebigilAbstract:Objective— Prokineticins are potent angiogenic hormones that use 2 receptors, Prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. Methods and Results— We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin+ progenitor cell proliferation and differentiation. Conclusion— Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs.
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divergent roles of Prokineticin receptors in the endothelial cells angiogenesis and fenestration
American Journal of Physiology-heart and Circulatory Physiology, 2010Co-Authors: Célia Guilini, Kyoji Urayama, Deniz Dedeoglu, Nadia Messaddeq, Hitoshi Kurose, Gulen Turkeri, Canan G NebigilAbstract:Prokineticins are secreted peptides that activate two G protein-coupled receptors: PKR1 and PKR2. Prokineticins induce angiogenesis and fenestration, but the cognate receptors involved in these fun...
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Transgenic myocardial overexpression of Prokineticin receptor-2 (GPR73b) induces hypertrophy and capillary vessel leakage.
Cardiovascular Research, 2009Co-Authors: Kyoji Urayama, Deniz Dedeoglu, Célia Guilini, Stefan Frantz, Georg Ertl, Nadia Messaddeq, Canan G NebigilAbstract:AIMS: Prokineticins are small secreted bioactive molecules. They exert their biological activity by binding to two G protein-coupled receptors. Previously, we have shown that the overexpression of Prokineticin receptor-1 (PKR1) in transgenic (TG) mouse hearts induced neovascularization. Since PKR1 and PKR2 are 85% identical and expressed in cardiovascular tissues, we hypothesized that PKR2 may also contribute to cardiomyocyte growth and vascularization. METHODS AND RESULTS: We have generated TG mice overexpressing PKR2 in cardiomyocytes. TG mice exhibit increased hypertrophic gene expression and heart-to-body weight ratio accompanied by an increased length of cardiomyocytes at the age of 12 weeks. Increased left ventricular end-systolic and diastolic diameters without cardiac dysfunction at the age of 24 weeks indicate that TG mice have an eccentric hypertrophy with compensated cardiac function. Quantitative morphological analysis showed that TG hearts have a normal microvessel density and number of branch points. However, they exhibit increased abnormal endothelial cell shape and ultrastructure, changed cellular distribution of a tight junction protein zona occludens-1 (ZO-1), and vascular leakage in heart without a rise of angiogenic factor levels at early and late age. The application of media conditioned by H9c2 cardioblast cells overexpressing PKR2 significantly induced impaired ZO-1 localization in H5V endothelial cells, mimicking the TG model. CONCLUSION: These findings provide the first genetic evidence that cardiomyocyte PKR2 signalling leads to eccentric hypertrophy in an autocrine regulation and impaired endothelial integrity in a paracrine regulation without inducing angiogenesis. These TG mice may provide a new genetic model for heart diseases.
Nadia Messaddeq - One of the best experts on this subject based on the ideXlab platform.
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Genetic inactivation of Prokineticin receptor-1 leads to heart and kidney
2016Co-Authors: Mounia Boulberdaa, Kyoji Urayama, Nadia Messaddeq, Gulen Turkeri, Mojdeh Dormishian, Luc Zimmer, Virginie Laugel, Canan G NebigilAbstract:Objective—Prokineticins are potent angiogenic hormones that use 2 receptors, Prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. Methods and Results—We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin progenitor cell proliferation and differentiation. Conclusion—Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs. (Arterioscler Thromb Vasc Biol. 2011;31:842-850.) Key Words: angiogenesis cardiomyopathies kidney pharmacology receptor
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Prokineticin Receptor 1 as a Novel Suppressor of Preadipocyte Proliferation and Differentiation to Control
2016Co-Authors: Judith Vallet, Nadia Messaddeq, Mojdeh Dormishian, Mounia Boulberdaa Daniel MetzgerAbstract:Background: Adipocyte renewal from preadipocytes occurs throughout the lifetime and contributes to obesity. To date, little is known about the mechanisms that control preadipocyte proliferation and differentiation. Prokineticin-2 is an angiogenic and anorexigenic hormone that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. Prokineticin-2 regulates food intake and energy metabolism via central mechanisms (PKR2). The peripheral effect of Prokineticin-2 on adipocytes/preadipocytes has not been studied yet. Methodology/Principal Findings: Since adipocytes and preadipocytes express mainly Prokineticin receptor-1 (PKR1), here, we explored the role of PKR1 in adipose tissue expansion, generating PKR1-null (PKR12/2) and adipocyte-specific (PKR1ad2/ 2) mutant mice, and using murine and human preadipocyte cell lines. Both PKR12/2 and PKR1ad2/2 had excessive abdominal adipose tissue, but only PKR12/2 mice showed severe obesity and diabetes-like syndrome. PKR1ad2/2) mice had increased proliferating preadipocytes and newly formed adipocyte levels, leading to expansion of adipose tissue. Using PKR1-knockdown in 3T3-L1 preadipocytes, we show that PKR1 directly inhibits preadipocyte proliferation and differentiation. These PKR1 cell autonomous actions appear targeted at preadipocyte cell cycle regulatory pathways, through reducing cyclin D, E, cdk2, c-Myc levels. Conclusions/Significance: These results suggest PKR1 to be a crucial player in the preadipocyte proliferation an
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Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity
PLOS ONE, 2013Co-Authors: Cecilia Szatkowski, Nadia Messaddeq, Mounia Boulberdaa, Mojdeh Dormishian, Judith Vallet, Phillippe Valet, Daniel Metzger, Pierre Chambon, Canan G NebigilAbstract:Background Adipocyte renewal from preadipocytes occurs throughout the lifetime and contributes to obesity. To date, little is known about the mechanisms that control preadipocyte proliferation and differentiation. Prokineticin-2 is an angiogenic and anorexigenic hormone that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. Prokineticin-2 regulates food intake and energy metabolism via central mechanisms (PKR2). The peripheral effect of Prokineticin-2 on adipocytes/preadipocytes has not been studied yet.
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The FASEB Journal • Research Communication The Prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis
2013Co-Authors: Kyoji Urayama, Célia Guilini, Nadia Messaddeq, Marja Steenman, Hitoshi Kurose, Georg Ert, Canan G NebigilAbstract:ABSTRACT Prokineticins are potent angiogenic factors that bind to two G protein-coupled receptors to initiate their biological effects. We hypothesize that Prokineticin receptor-1 (PKR1/GPR73) signaling may contribute to cardiomyocyte survival or repair in myocardial infarction. Since we showed that Prokineticin-2 and PKR1 are expressed in adult mouse heart and cardiac cells, we investigated the role of Prokineticin-2 on capillary endothelial cell and cardiomyocyte function. In cultured cardiac endothelial cells, Prokineticin-2 or overexpression of PKR1 induces vessel-like formation without increasing VEGF levels. In cardiomyocytes and H9c2 cells, Prokineticin-2 or overexpressing PKR1 activates Akt to protect cardiomyocytes against oxidative stress. The survival and angiogenesis promotin
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Prokineticin Receptor 1 as a Novel Suppressor of Preadipocyte Proliferation and Differentiation to Control Obesity
2013Co-Authors: Cecilia Szatkowski, Nadia Messaddeq, Mounia Boulberdaa, Mojdeh Dormishian, Judith Vallet, Phillippe Valet, Daniel Metzger, Pierre Chambon, Canan G NebigilAbstract:BackgroundAdipocyte renewal from preadipocytes occurs throughout the lifetime and contributes to obesity. To date, little is known about the mechanisms that control preadipocyte proliferation and differentiation. Prokineticin-2 is an angiogenic and anorexigenic hormone that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. Prokineticin-2 regulates food intake and energy metabolism via central mechanisms (PKR2). The peripheral effect of Prokineticin-2 on adipocytes/preadipocytes has not been studied yet.Methodology/Principal FindingsSince adipocytes and preadipocytes express mainly Prokineticin receptor-1 (PKR1), here, we explored the role of PKR1 in adipose tissue expansion, generating PKR1-null (PKR1−/−) and adipocyte-specific (PKR1ad−/−) mutant mice, and using murine and human preadipocyte cell lines. Both PKR1−/− and PKR1ad−/− had excessive abdominal adipose tissue, but only PKR1−/− mice showed severe obesity and diabetes-like syndrome. PKR1ad−/−) mice had increased proliferating preadipocytes and newly formed adipocyte levels, leading to expansion of adipose tissue. Using PKR1-knockdown in 3T3-L1 preadipocytes, we show that PKR1 directly inhibits preadipocyte proliferation and differentiation. These PKR1 cell autonomous actions appear targeted at preadipocyte cell cycle regulatory pathways, through reducing cyclin D, E, cdk2, c-Myc levels.Conclusions/SignificanceThese results suggest PKR1 to be a crucial player in the preadipocyte proliferation and differentiation. Our data should facilitate studies of both the pathogenesis and therapy of obesity in humans.
L. Negri - One of the best experts on this subject based on the ideXlab platform.
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pk2β ligand a splice variant of Prokineticin 2 is able to modulate and drive signaling through pkr1 receptor
Neuropeptides, 2018Co-Authors: Roberta Lattanzi, Daniela Maftei, L. Negri, Ilaria Fusco, Rossella MieleAbstract: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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RESEARCH ARTICLE Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes
2016Co-Authors: M. Castelli, Roberta Lattanzi, Daniela Maftei, G. Amodeo, L. Negri, C. Gotti, F. Pistillo, V. Onnis, C. Congu, Alberto E. PaneraiAbstract: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 exper-imental 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 corre-lated 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 produc-tion. 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 pre
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Antagonism of the Prokineticin system prevents and reverses allodynia and inflammation in a mouse model of diabetes
'Public Library of Science (PLoS)', 2016Co-Authors: M. Castelli, G. Amodeo, L. Negri, R. Lattanzi, D. Maftei, C. Gotti, F. Pistillo, V. Onnis, C. Congu, A. PaneraiAbstract: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.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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a new convenient synthetic method and preliminary pharmacological characterization of triazinediones as Prokineticin receptor antagonists
ChemInform, 2014Co-Authors: Cenzo Congiu, Roberta Lattanzi, Daniela Maftei, L. Negri, V. Onnis, Severo Salvadori, Alessandro Deplano, Veronica Marconi, Gianfranco BalboniAbstract:A new improved synthetic methodology to form triazinediones as potential antagonists for Prokineticin receptors is described.
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bv8 pk2 and Prokineticin receptors a druggable pronociceptive system
Current Opinion in Pharmacology, 2012Co-Authors: L. Negri, Roberta LattanziAbstract:Mammalian Bv8 (also called Prokineticin 2) is a secreted protein that regulates diverse biological processes including pain perception. It belongs to a new family of chemokines, which activate two G-protein linked receptors (Prokineticin receptor 1 and 2, PKR1 and PKR2) expressed in regions of the nervous system associated with pain and in cells participating to immuno-inflammatory responses. Primary sensitive neurons co-express PKRs and the transient potential receptor vanilloid 1, cooperating in nociceptor sensitization. Bv8, strongly upregulated in neutrophils and other inflammatory cells, is a main pronociceptive mediator in inflamed tissues, where it sensitizes peripheral nociceptors, stimulates neutrophil chemotaxis and modulates the release of inflammatory and pronociceptive cytokines. Availability of a nonpeptide PKR antagonist, leading to blockade of the Bv8/PKR system, ameliorates pain arising from tissue injury and reduces the time required for recovery from injury.
