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Article: The role of prolyl oligopeptidase, understanding the puzzle.

García-Horsman, J Arturo

2020 Volume 8, Issue 16, Page(s) 983

Language	English
Publishing date	2020-09-13
Publishing country	China
Document type	Editorial ; Comment
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm-20-3412
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Article: Mechanism of Action of Prolyl Oligopeptidase (PREP) in Degenerative Brain Diseases: Has Peptidase Activity Only a Modulatory Role on the Interactions of PREP with Proteins?

Männistö, Pekka T / García-Horsman, J Arturo

Frontiers in aging neuroscience

2017 Volume 9, Page(s) 27

Abstract: In the aging brain, the correct balance of neural transmission and its regulation is of particular significance, and neuropeptides have a significant role. Prolyl oligopeptidase (PREP) is a protein highly expressed in brain, and evidence indicates that ... ...

Abstract	In the aging brain, the correct balance of neural transmission and its regulation is of particular significance, and neuropeptides have a significant role. Prolyl oligopeptidase (PREP) is a protein highly expressed in brain, and evidence indicates that it is related to aging and in neurodegenration. Although PREP is regarded as a peptidase, the physiological substrates in the brain have not been defined, and after intense research, the molecular mechanisms where this protein is involved have not been defined. We propose that PREP functions as a regulator of other proteins though peptide gated direct interaction. We speculate that, at least in some processes where PREP has shown to be relevant, the peptidase activity is only a consequence of the interactions, and not the main physiological activity.
Language	English
Publishing date	2017-02-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2017.00027
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Article ; Online: Prolyl oligopeptidase in brain function and dysfunction.

García-Horsman, J Arturo

CNS & neurological disorders drug targets

2010 Volume 10, Issue 3, Page(s) 296

MeSH term(s)	Brain/physiology ; Brain/physiopathology ; Cognition Disorders/drug therapy ; Cognition Disorders/physiopathology ; Humans ; Molecular Targeted Therapy ; Neuropeptides/metabolism ; Serine Endopeptidases/physiology
Chemical Substances	Neuropeptides ; Serine Endopeptidases (EC 3.4.21.-) ; prolyl oligopeptidase (EC 3.4.21.26)
Language	English
Publishing date	2010-12-20
Publishing country	United Arab Emirates
Document type	Editorial
ZDB-ID	2228394-8
ISSN	1996-3181 ; 1871-5273
ISSN (online)	1996-3181
ISSN	1871-5273
DOI	10.2174/187152711794653788
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Article ; Online: Labelling, molecular modelling and biological evaluation of vardenafil: a potential agent for diagnostic evaluation of erectile dysfunction.

El-Kawy, O A / García-Horsman, J A / Tuominen, R K

Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine

2016 Volume 118, Page(s) 258–265

Abstract: ... ...

Abstract	99m
Language	English
Publishing date	2016-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1142596-9
ISSN	1872-9800 ; 0883-2889 ; 0969-8043
ISSN (online)	1872-9800
ISSN	0883-2889 ; 0969-8043
DOI	10.1016/j.apradiso.2016.09.023
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Article ; Online: Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

Wilson, Clive G / Aarons, Leon / Augustijns, Patrick / Brouwers, Joachim / Darwich, Adam S / De Waal, Tom / Garbacz, Grzegorz / Hansmann, Simone / Hoc, Dagmara / Ivanova, Anela / Koziolek, Mirko / Reppas, Christos / Schick, Philipp / Vertzoni, Maria / García-Horsman, J Arturo

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2021 Volume 172, Page(s) 106100

Abstract: This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of ... ...

Abstract	This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.
MeSH term(s)	Administration, Oral ; COVID-19 ; Computer Simulation ; Gastrointestinal Absorption/physiology ; Gastrointestinal Tract/metabolism ; Humans ; Intestinal Absorption ; Male ; Models, Biological ; Pharmaceutical Preparations/metabolism ; Solubility
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2021-12-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2021.106100
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Article ; Online: Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.

Serfozo, Peter / Wysocki, Jan / Gulua, Gvantca / Schulze, Arndt / Ye, Minghao / Liu, Pan / Jin, Jing / Bader, Michael / Myöhänen, Timo / García-Horsman, J Arturo / Batlle, Daniel

Hypertension (Dallas, Tex. : 1979)

2019 Volume 75, Issue 1, Page(s) 173–182

Abstract: The Ang II (Angiotensin II)-Angiotensin-(1-7) axis of the Renin Angiotensin System encompasses 3 enzymes that form Angiotensin-(1-7) [Ang-(1-7)] directly from Ang II: ACE2 (angiotensin-converting enzyme 2), PRCP (prolylcarboxypeptidase), and POP ( ... ...

Abstract	The Ang II (Angiotensin II)-Angiotensin-(1-7) axis of the Renin Angiotensin System encompasses 3 enzymes that form Angiotensin-(1-7) [Ang-(1-7)] directly from Ang II: ACE2 (angiotensin-converting enzyme 2), PRCP (prolylcarboxypeptidase), and POP (prolyloligopeptidase). We investigated their relative contribution to Ang-(1-7) formation in vivo and also ex vivo in serum, lungs, and kidneys using models of genetic ablation coupled with pharmacological inhibitors. In wild-type (WT) mice, infusion of Ang II resulted in a rapid increase of plasma Ang-(1-7). In
MeSH term(s)	Angiotensin I/blood ; Angiotensin II/pharmacology ; Angiotensin-Converting Enzyme 2 ; Animals ; Blood Pressure/drug effects ; Blood Pressure/physiology ; Carboxypeptidases/genetics ; Carboxypeptidases/metabolism ; Male ; Mice ; Mice, Knockout ; Peptide Fragments/blood ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Prolyl Oligopeptidases ; Renin-Angiotensin System/drug effects ; Renin-Angiotensin System/physiology ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism
Chemical Substances	Peptide Fragments ; Angiotensin II (11128-99-7) ; Angiotensin I (9041-90-1) ; Carboxypeptidases (EC 3.4.-) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; lysosomal Pro-X carboxypeptidase (EC 3.4.16.2) ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; Prolyl Oligopeptidases (EC 3.4.21.26) ; angiotensin I (1-7) (IJ3FUK8MOF)
Language	English
Publishing date	2019-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.119.14071
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Article ; Online: Hormonal and testing conditions for the induction of conditioned place preference by paced mating.

Camacho, Francisco J / García-Horsman, Patricia / Paredes, Raúl G

Hormones and behavior

2009 Volume 56, Issue 4, Page(s) 410–415

Abstract: The ability to control or pace the sexual interaction has important physiological and behavioral consequences for the female rat. Paced mating favors reproduction and induces a positive affective state as revealed by conditioned place preference (CPP). ... ...

Abstract	The ability to control or pace the sexual interaction has important physiological and behavioral consequences for the female rat. Paced mating favors reproduction and induces a positive affective state as revealed by conditioned place preference (CPP). In the present experiment we evaluated: 1) If paced mating induces CPP in naturally cycling females; 2) If females developed a positive affective state if they paced the sexual interaction through a 1- or a 3-hole pacing chamber; 3) If females that mate with the same male without pacing the sexual interaction develop CPP. In the first experiment intact females were divided in 4 different groups; 2 paced the sexual interaction until receiving 1 or 3 ejaculations; the other 2 groups mated, without pacing the sexual interaction, until receiving 1 or 3 ejaculations. Only the group that paced the sexual interaction until receiving 3 ejaculations developed a positive affective state. In experiments 2 and 3 hormonally treated ovariectomized females were used. In experiment 2 females were allowed to pace the sexual interaction through a 1- or a 3-hole pacing chamber: A clear positive affective state was induced in both testing conditions. Finally, in experiment 3 females did not develop CPP for non-paced sex despite the fact that they mated with the same male in the conditioning sessions. These results demonstrate that the pattern of vaginocervical stimulation that the females received by engaging in approach and avoidance behaviors to pace the sexual interaction can induce a positive affective state in naturally cycling females. They also confirm the existence of a threshold of vaginocervical stimulation for paced mating to induce CPP in female rats.
MeSH term(s)	Affect/physiology ; Analysis of Variance ; Animals ; Conditioning, Classical/physiology ; Female ; Hormones/metabolism ; Male ; Menstrual Cycle ; Ovariectomy ; Random Allocation ; Rats ; Rats, Wistar ; Sexual Behavior, Animal/physiology ; Space Perception/physiology ; Time Factors
Chemical Substances	Hormones
Language	English
Publishing date	2009-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	214409-8
ISSN	1095-6867 ; 0018-506X
ISSN (online)	1095-6867
ISSN	0018-506X
DOI	10.1016/j.yhbeh.2009.07.007
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Article ; Online: The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients.

Tenorio-Laranga, Jofre / Montoliu, Carmina / Urios, Amparo / Hernandez-Rabaza, Vicente / Ahabrach, Hanan / García-Horsman, J Arturo / Felipo, Vicente

Journal of neuroinflammation

2015 Volume 12, Page(s) 183

Abstract: Background: Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain ... ...

Abstract	Background: Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. Methods: PREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro-inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation. Results: In PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE. Conclusions: These results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response.
MeSH term(s)	Adult ; Aged ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Brain/enzymology ; Cyclic GMP/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Fibrosis/complications ; Hepatic Encephalopathy/drug therapy ; Hepatic Encephalopathy/etiology ; Humans ; Ibuprofen/therapeutic use ; Liver Failure/etiology ; Liver Failure/metabolism ; Lymphocytes/metabolism ; Male ; Middle Aged ; Nitric Oxide/metabolism ; Portacaval Shunt, Surgical/adverse effects ; Rats ; Rats, Wistar ; Serine Endopeptidases/metabolism ; Systemic Inflammatory Response Syndrome/drug therapy ; Systemic Inflammatory Response Syndrome/etiology
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Cytokines ; Nitric Oxide (31C4KY9ESH) ; Serine Endopeptidases (EC 3.4.21.-) ; prolyl oligopeptidase (EC 3.4.21.26) ; Cyclic GMP (H2D2X058MU) ; Ibuprofen (WK2XYI10QM)
Language	English
Publishing date	2015-09-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/s12974-015-0404-7
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Article ; Online: Hunting for peptide substrates of prolyl oligopeptidase: classical versus non-classical bioactive peptides.

Tenorio-Laranga, Jofre / Männistö, Pekka T / García-Horsman, J Arturo

CNS & neurological disorders drug targets

2010 Volume 10, Issue 3, Page(s) 319–326

Abstract: Prolyl oligopeptidase (POP) is a serine protease that cleaves peptides shorter than 30-mer at the carboxyl side of an internal proline. POP has been proposed to be involved in some pathologies including mood disorders and neurodegenerative diseases. ... ...

Abstract	Prolyl oligopeptidase (POP) is a serine protease that cleaves peptides shorter than 30-mer at the carboxyl side of an internal proline. POP has been proposed to be involved in some pathologies including mood disorders and neurodegenerative diseases. However, the physiological role of POP remains unknown. To validate POP as a drug target, it is essential to obtain a thorough understanding of its function in vivo. Identification of physiological substrates and products of POP is an important step towards this goal. Recent peptidomic studies have revealed some biological substrates of POP and have given information about the in vivo consequences of POP inhibition. The aim of this review is to evaluate new advances in this research area and to critically confront these data with initial conclusions and proposals. It seems that substantial activity of POP occurs intracellularly in contrast to the previously proposed role of this peptidase on the direct degradation of extracellular neuropeptides.
MeSH term(s)	Brain/enzymology ; Brain/metabolism ; Drug Discovery/methods ; Humans ; Molecular Targeted Therapy ; Neuropeptides/physiology ; Serine Endopeptidases/physiology ; Substrate Specificity/physiology
Chemical Substances	Neuropeptides ; Serine Endopeptidases (EC 3.4.21.-) ; prolyl oligopeptidase (EC 3.4.21.26)
Language	English
Publishing date	2010-12-20
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2228394-8
ISSN	1996-3181 ; 1871-5273
ISSN (online)	1996-3181
ISSN	1871-5273
DOI	10.2174/187152711794653841
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Article ; Online: Different doses of estradiol benzoate induce conditioned place preference after paced mating.

Corona, Rebeca / Camacho, Francisco J / García-Horsman, Patricia / Guerrero, Alfonso / Ogando, Annette / Paredes, Raúl G

Hormones and behavior

2011 Volume 60, Issue 3, Page(s) 264–268

Abstract: The ovarian hormones estrogen and progesterone are required for the complete display of sexual behavior in female rats. Paced mating produces a reward state in intact cycling and ovariectomized (OVX), hormonally primed females as evaluated by the ... ...

Abstract	The ovarian hormones estrogen and progesterone are required for the complete display of sexual behavior in female rats. Paced mating produces a reward state in intact cycling and ovariectomized (OVX), hormonally primed females as evaluated by the conditioned place preference (CPP) paradigm. Most of the studies that have evaluated CPP induced by paced mating in OVX females have used relatively high doses of estradiol benzoate (EB). In the present study we determined if different doses of EB, combined with progesterone (P), could induce CPP after paced mating. For this purpose OVX female rats were divided in five groups that received one of different doses of estradiol benzoate (5, 2.5, 1.25 or 0.625 μg estradiol+0.5mg of progesterone) before being allowed to pace the sexual interaction and conditioned in a CPP paradigm. We found that the lowest dose of EB used (0.625 μg) significantly reduced the lordosis quotient and the lordosis coefficient. Even though these females paced the sexual interaction, they didn't change its original preference, suggesting that sexual interaction did not induce a positive affective, reward state. Females allowed to pace the sexual interaction with higher doses of EB developed CPP after paced mating. These results indicate that a threshold of estradiol is required for paced mating to induce CPP.
MeSH term(s)	Animals ; Conditioning (Psychology)/drug effects ; Estradiol/administration & dosage ; Estradiol/analogs & derivatives ; Female ; Male ; Mating Preference, Animal/drug effects ; Posture ; Progesterone/administration & dosage ; Rats ; Rats, Wistar
Chemical Substances	estradiol 3-benzoate (1S4CJB5ZGN) ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2011-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	214409-8
ISSN	1095-6867 ; 0018-506X
ISSN (online)	1095-6867
ISSN	0018-506X
DOI	10.1016/j.yhbeh.2011.05.013
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