Fernandez S

References (10)

Title : VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome - Lleo_2021_Alzheimers.Res.Ther_13_119
Author(s) : Lleo A , Carmona-Iragui M , Videla L , Fernandez S , Benejam B , Pegueroles J , Barroeta I , Altuna M , Valldeneu S , Xiao MF , Xu D , Nunez-Llaves R , Querol-Vilaseca M , Sirisi S , Bejanin A , Iulita MF , Clarimon J , Blesa R , Worley P , Alcolea D , Fortea J , Belbin O
Ref : Alzheimers Res Ther , 13 :119 , 2021
Abstract : BACKGROUND: There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. METHODS: We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Abeta(42:40) ratio, CSF Abeta(1-42), CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. RESULTS: In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Abeta(42:40) (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002). CONCLUSION: These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
ESTHER : Lleo_2021_Alzheimers.Res.Ther_13_119
PubMedSearch : Lleo_2021_Alzheimers.Res.Ther_13_119
PubMedID: 34183050

Title : 3-(Benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H-indazole: a PET radiotracer to measure acetylcholinesterase in brain - Fernandez_2017_Future.Med.Chem_9_983
Author(s) : Fernandez S , Giglio J , Reyes AL , Damian A , Perez C , Perez DI , Gonzalez M , Oliver P , Rey A , Engler H , Cerecetto H
Ref : Future Med Chem , 9 :983 , 2017
Abstract : AIM: Noninvasive studies of the acetylcholinesterase (AChE) level in Alzheimer's disease (AD) patients can contribute to a better understanding of the disease and its therapeutic. We propose 3-(benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H-indazole, [18F]-IND1, structurally related to the AChE-inhibitor CP126,998, as a new positron emission tomography-radiotracer. EXPERIMENTAL: Radiosynthesis, with 18F, stability, lipophilicity and protein binding of [18F]-IND1 were studied. In vivo behavior, in normal mice and on AD mice models, were also analyzed.
RESULTS: [18F]-IND1 was obtained in good radiochemical yield, was stable for at least 2 h in different conditions, and had adequate lipophilicity for blood-brain barrier penetration. Biodistribution studies, in normal mice, showed that [18F]-IND1 was retained in the brain after 1 h. In vivo tacrine-blocking experiments indicated this uptake could be specifically due to AChE interaction. Studies in transgenic AD mice showed differential, compared with normal mice, binding in many brain regions. CONCLUSION: [18F]-IND1 can be used to detect AChE changes in AD patients.
ESTHER : Fernandez_2017_Future.Med.Chem_9_983
PubMedSearch : Fernandez_2017_Future.Med.Chem_9_983
PubMedID: 28632402

Title : Regulation of adipocyte lipolysis - Fruhbeck_2014_Nutr.Res.Rev_27_63
Author(s) : Fruhbeck G , Mendez-Gimenez L , Fernandez-Formoso JA , Fernandez S , Rodriguez A
Ref : Nutr Res Rev , 27 :63 , 2014
Abstract : In adipocytes the hydrolysis of TAG to produce fatty acids and glycerol under fasting conditions or times of elevated energy demands is tightly regulated by neuroendocrine signals, resulting in the activation of lipolytic enzymes. Among the classic regulators of lipolysis, adrenergic stimulation and the insulin-mediated control of lipid mobilisation are the best known. Initially, hormone-sensitive lipase (HSL) was thought to be the rate-limiting enzyme of the first lipolytic step, while we now know that adipocyte TAG lipase is the key enzyme for lipolysis initiation. Pivotal, previously unsuspected components have also been identified at the protective interface of the lipid droplet surface and in the signalling pathways that control lipolysis. Perilipin, comparative gene identification-58 (CGI-58) and other proteins of the lipid droplet surface are currently known to be key regulators of the lipolytic machinery, protecting or exposing the TAG core of the droplet to lipases. The neuroendocrine control of lipolysis is prototypically exerted by catecholaminergic stimulation and insulin-induced suppression, both of which affect cyclic AMP levels and hence the protein kinase A-mediated phosphorylation of HSL and perilipin. Interestingly, in recent decades adipose tissue has been shown to secrete a large number of adipokines, which exert direct effects on lipolysis, while adipocytes reportedly express a wide range of receptors for signals involved in lipid mobilisation. Recently recognised mediators of lipolysis include some adipokines, structural membrane proteins, atrial natriuretic peptides, AMP-activated protein kinase and mitogen-activated protein kinase. Lipolysis needs to be reanalysed from the broader perspective of its specific physiological or pathological context since basal or stimulated lipolytic rates occur under diverse conditions and by different mechanisms.
ESTHER : Fruhbeck_2014_Nutr.Res.Rev_27_63
PubMedSearch : Fruhbeck_2014_Nutr.Res.Rev_27_63
PubMedID: 24872083

Title : In vitro digestion of the self-emulsifying lipid excipient Labrasol() by gastrointestinal lipases and influence of its colloidal structure on lipolysis rate - Fernandez_2013_Pharm.Res_30_3077
Author(s) : Fernandez S , Jannin V , Chevrier S , Chavant Y , Demarne F , Carriere F
Ref : Pharm Res , 30 :3077 , 2013
Abstract : PURPOSE: Labrasol((a)) is a self-emulsifying excipient used to improve the oral bioavailability of poorly water-soluble drugs. It is a mixture of acylglycerols and PEG esters, these compounds being substrates for digestive lipases. The characterization of Labrasol((a)) gastrointestinal lipolysis is essential for understanding its mode of action. METHODS: Labrasol((a)) lipolysis was investigated using either individual enzymes (gastric lipase, pancreatic lipase-related protein 2, pancreatic carboxyl ester hydrolase) or a combination of enzymes under in vitro conditions mimicking first the gastric phase of lipolysis and second the duodenal one. Specific methods for quantifying lipolysis products were established in order to determine which compounds in Labrasol((a)) were preferentially hydrolyzed. RESULTS: Gastric lipase showed a preference for di- and triacylglycerols and the main acylglycerols remaining after gastric lipolysis were monoacylglycerols. PEG-8 diesters were also hydrolyzed to a large extent by gastric lipase. Most of the compounds initially present in Labrasol((a)) were found to be totally hydrolyzed after the duodenal phase of lipolysis. The rate of Labrasol((a)) hydrolysis by individual lipases was found to vary significantly with the dilution of the excipient in water and the resulting colloidal structures (translucent dispersion; opaque emulsion; transparent microemulsion), each lipase displaying a distinct pattern depending on the particle size. CONCLUSIONS: The lipases with distinct substrate specificities used in this study were found to be sensitive probes of phase transitions occurring upon Labrasol((a)) dilution. In addition to their use for developing in vitro digestion models, these enzymes are interesting tools for the characterization of self-emulsifying lipid-based formulations.
ESTHER : Fernandez_2013_Pharm.Res_30_3077
PubMedSearch : Fernandez_2013_Pharm.Res_30_3077
PubMedID: 23636839
Gene_locus related to this paper: human-PNLIPRP2

Title : Preparation of nucleoside-carbohydrate phosphodiester prodrug analogues by chemoenzymatic procedure - Rodriguez-Perez_2008_Nucleic.Acids.Symp.Ser.(Oxf)__101
Author(s) : Rodriguez-Perez T , Fernandez S , Sanghvi YS , Gotor V , Ferrero M
Ref : Nucleic Acids Symp Ser (Oxf) , :101 , 2008
Abstract : An efficient synthesis protocol for the glucosyl-nucleoside phosphodiester derivatives has been developed. These mononucleotides were designed to act as pronucleotides with potential to deliver the parent compound as its monophosphate. Key step of the synthesis is the regioselective hydrolysis of peracetylated alpha-D-glucose catalyzed by Candida rugosa lipase.
ESTHER : Rodriguez-Perez_2008_Nucleic.Acids.Symp.Ser.(Oxf)__101
PubMedSearch : Rodriguez-Perez_2008_Nucleic.Acids.Symp.Ser.(Oxf)__101
PubMedID: 18776273

Title : Lipolysis of the semi-solid self-emulsifying excipient Gelucire 44\/14 by digestive lipases - Fernandez_2008_Biochim.Biophys.Acta_1781_367
Author(s) : Fernandez S , Rodier JD , Ritter N , Mahler B , Demarne F , Carriere F , Jannin V
Ref : Biochimica & Biophysica Acta , 1781 :367 , 2008
Abstract : Gelucire 44/14 is a semi-solid self-emulsifying excipient used for the oral delivery of poorly water-soluble drugs. It is composed of C8-C18 acylglycerols and PEG-32 esters, all of which are potential substrates for digestive lipases. Here we studied the lipolysis of Gelucire 44/14 by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases. Human pancreatic lipase (HPL), the main lipase involved in the digestion of triacylglycerols, did not show any significant activity on Gelucire 44/14 or on either of its individual compounds, C8-C18 acylglycerols and PEG-32 esters. Other pancreatic lipases such as human pancreatic lipase-related protein 2 (HPLRP2) showed low activity on Gelucire 44/14 although the highest activity of HPLRP2 was that observed on the C8-C18 acylglycerol fraction, which accounts for 20% (w/w) of Gelucire 44/14. In addition, HPLRP2 showed low activities on the PEG-32 esters, whether these were tested individually or mixed together. Carboxyl ester hydrolase (CEH) showed high activity on Gelucire 44/14, and the highest activities of CEH were those recorded on the total PEG-32 ester fraction and on each individual PEG-32 ester, except for PEG-32 monostearate. The highest activity of all the enzymes tested was that of dog gastric lipase (DGL) on Gelucire 44/14, although DGL showed low activity on the PEG-32 ester fraction and on each individual PEG-32 ester. We compared the lipolysis of Gelucire 44/14 with that of Labrasol, another self-emulsifying excipient, which is liquid at room temperature. Human pancreatic juice showed similar rates of activity on both Gelucire 44/14 and Labrasol. This finding means that these excipients are hydrolyzed in vivo during pancreatic digestion, mainly by CEH in the case of Gelucire 44/14 and by both HPLRP2 and CEH in that of Labrasol, whereas HPL showed very low activities on each of these two excipients. This is the first time the effects of PEG and acyl chain length on the lipolytic activity of digestive lipases on PEG esters have been investigated.
ESTHER : Fernandez_2008_Biochim.Biophys.Acta_1781_367
PubMedSearch : Fernandez_2008_Biochim.Biophys.Acta_1781_367
PubMedID: 18571509

Title : Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol, medium chain glycerides and PEG esters - Fernandez_2007_Biochim.Biophys.Acta_1771_633
Author(s) : Fernandez S , Jannin V , Rodier JD , Ritter N , Mahler B , Carriere F
Ref : Biochimica & Biophysica Acta , 1771 :633 , 2007
Abstract : Labrasol is a lipid-based self-emulsifying excipient used in the preparation of lipophilic drugs intended for oral delivery. It is mainly composed of PEG esters and glycerides with medium acyl chains, which are potential substrates for digestive lipases. The hydrolysis of Labrasol by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases was investigated in the present study. Classical human pancreatic lipase (HPL) and porcine pancreatic lipase, which are the main lipases involved in the digestion of dietary triglycerides, showed very low levels of activity on the entire Labrasol excipient as well as on separated fractions of glycerides and PEG esters. On the other hand, gastric lipase, pancreatic lipase-related protein 2 (PLRP2) and carboxyl ester hydrolase (CEH) showed high specific activities on Labrasol. These lipases were found to hydrolyze the main components of Labrasol (PEG esters and monoglycerides) used as individual substrates, whereas these esters were found to be poor substrates for HPL. The lipolytic activity of pancreatic extracts and human pancreatic juice on Labrasol(R) is therefore mainly due to the combined action of CEH and PLRP2. These two pancreatic enzymes, together with gastric lipase, are probably the main enzymes involved in the in vivo lipolysis of Labrasol taken orally.
ESTHER : Fernandez_2007_Biochim.Biophys.Acta_1771_633
PubMedSearch : Fernandez_2007_Biochim.Biophys.Acta_1771_633
PubMedID: 17418634

Title : Exploring the specific features of interfacial enzymology based on lipase studies - Aloulou_2006_Biochim.Biophys.Acta_1761_995
Author(s) : Aloulou A , Rodriguez JA , Fernandez S , van Oosterhout D , Puccinelli D , Carriere F
Ref : Biochimica & Biophysica Acta , 1761 :995 , 2006
Abstract : Many enzymes are active at interfaces in the living world (such as in the signaling processes at the surface of cell membranes, digestion of dietary lipids, starch and cellulose degradation, etc.), but fundamental enzymology remains largely focused on the interactions between enzymes and soluble substrates. The biochemical and kinetic characterization of lipolytic enzymes has opened up new paths of research in the field of interfacial enzymology. Lipases are water-soluble enzymes hydrolyzing insoluble triglyceride substrates, and studies on these enzymes have led to the development of specific interfacial kinetic models. Structure-function studies on lipases have thrown light on the interfacial recognition sites present in the molecular structure of these enzymes, the conformational changes occurring in the presence of lipids and amphiphiles, and the stability of the enzymes present at interfaces. The pH-dependent activity, substrate specificity and inhibition of these enzymes can all result from both "classical" interactions between a substrate or inhibitor and the active site, as well as from the adsorption of the enzymes at the surface of aggregated substrate particles such as oil drops, lipid bilayers or monomolecular lipid films. The adsorption step can provide an alternative target for improving substrate specificity and developing specific enzyme inhibitors. Several data obtained with gastric lipase, classical pancreatic lipase, pancreatic lipase-related protein 2 and phosphatidylserine-specific phospholipase A1 were chosen here to illustrate these specific features of interfacial enzymology.
ESTHER : Aloulou_2006_Biochim.Biophys.Acta_1761_995
PubMedSearch : Aloulou_2006_Biochim.Biophys.Acta_1761_995
PubMedID: 16931141

Title : Remote interactions explain the unusual regioselectivity of lipase from Pseudomonas cepacia toward the secondary hydroxyl of 2'-deoxynucleosides - Lavandera_2006_Chembiochem_7_693
Author(s) : Lavandera I , Fernandez S , Magdalena J , Ferrero M , Grewal H , Savile CK , Kazlauskas RJ , Gotor V
Ref : Chembiochem , 7 :693 , 2006
Abstract : Lipase from Pseudomonas cepacia (PCL) surprisingly favors acylation of the secondary hydroxyl at the 3'-position over the primary hydroxyl at the 5'-position in 2'-deoxynucleosides by up to >98:1. Catalytically productive tetrahedral intermediate analogues for both orientations were found by molecular modeling. However, acylation of the 3'-hydroxyl places the thymine base in the alternate hydrophobic pocket of PCL's substrate-binding site where it can hydrogen bond to the side-chain hydroxyls of Tyr23 and Tyr29 and the main chain carbonyl of Leu17. Conversely, acylation of the 5'-hydroxyl leaves the thymine base in the solvent where there is no favorable binding to the enzyme. We propose that these remote stabilizing interactions between the thymine base and PCL's substrate-binding site stabilize the 3'-acylation transition state and thus account for the unusual regioselectivity.
ESTHER : Lavandera_2006_Chembiochem_7_693
PubMedSearch : Lavandera_2006_Chembiochem_7_693
PubMedID: 16491501

Title : An inverse substrate orientation for the regioselective acylation of 3',5'-diaminonucleosides catalyzed by Candida antarctica lipase B? - Lavandera_2005_Chembiochem_6_1381
Author(s) : Lavandera I , Fernandez S , Magdalena J , Ferrero M , Kazlauskas RJ , Gotor V
Ref : Chembiochem , 6 :1381 , 2005
Abstract : Candida antarctica lipase B (CAL-B) catalyzes the regioselective acylation of natural thymidine with oxime esters and also the regioselective acylation of an analogue, 3',5'-diamino-3',5'-dideoxythymidine with nonactivated esters. In both cases, acylation favors the less hindered 5'-position over the 3'-position by upto 80-fold. Computer modeling of phosphonate transition-state analogues for the acylation of thymidine suggests that CAL-B favors acylation of the 5'-position because this orientation allows the thymine ring to bind in a hydrophobic pocket and forms stronger key hydrogen bonds than acylation of the 3'-position. On the other hand, computer modeling of phosphonamidate analogues of the transition states for acylation of either the 3'- or 5'-amino groups in 3',5'-diamino-3',5'-dideoxythymidine shows similar orientations and hydrogen bonds and, thus, does not explain the high regioselectivity. However, computer modeling of inverse structures, in which the acyl chain binds in the nucleophile pocket and vice versa, does rationalize the observed regioselectivity. The inverse structures fit the 5'-, but not the 3'-intermediate thymine ring, into the hydrophobic pocket, and form a weak new hydrogen bond between the O-2 carbonyl atom of the thymine and the nucleophile amine only for the 5'-intermediate. A water molecule might transfer a proton from the ammonium group to the active-site histidine. As a test of this inverse orientation, we compared the acylation of thymidine and 3',5'-diamino-3',5'-dideoxythymidine with butyryl acyl donors and with isosteric methoxyacetyl acyl donors. Both acyl donors reacted at equal rates with thymidine, but the methoxyacetyl acyl donor reacted four times faster than the butyryl acyl donor with 3',5'-diamino-3',5'-dideoxythymidine. This faster rate is consistent with an inverse orientation for 3',5'-diamino-3',5'-dideoxythymidine, in which the ether oxygen atom of the methoxyacetyl group can form a similar hydrogen bond to the nucleophilic amine. This combination of modeling and experiments suggests that such lipase-catalyzed reactions of apparently close substrate analogues like alcohols and amines might follow different pathways.
ESTHER : Lavandera_2005_Chembiochem_6_1381
PubMedSearch : Lavandera_2005_Chembiochem_6_1381
PubMedID: 15977272
Gene_locus related to this paper: canar-LipB