Parkinson’s disease (PD) is a progressive disease and the second most common neurodegenerative disorder. Pathologically, PD is characterized by the loss of dopaminergic neurons of the substantia nigra and α-synuclein aggregation which lead to motor and cognitive dysfunction. Is believed that other pathways may also be involved such as oxidative stress and neuroinflammation and can also affect other neuronal connections. Currently, there are no therapeutic alternatives able to cure PD. Pharmacological therapy options are focused on symptoms relief and management. Therefore, exploring molecules that can act in the prevention or treatment of PD is necessary. Resveratrol has attracted attention for its anti-inflammatory and antioxidant activities, but its therapeutic effectiveness is limited due its low solubility in aqueous system and low bioavailability. Molecule glycosylation via synthetic induction of structural optimization reactions using enzymes appears as an alternative, guaranteeing specify and regioselectivity.
First, we aim to synthesize and controlled functionalize the resveratrol molecule through enzymatic pathways. This part of the work will be done in US2B, Nantes Université, France. The implementation of such a process will increase the solubility and bioavailability of these functionalized compounds, being able to potentiate their biological responses, allowing specific therapeutic applications. We also purpose to predict the pharmacokinetic parameters of resveratrol and its glycosylated forms, as well as its molecular interactions with PD targets using in silico approaches. Furthermore, we will evaluate the toxicity and effects of resveratrol glycosylation in a zebrafish (Danio rerio) in vivo experimental model of PD at the Universidade Federal do Rio Grande, Brazil.
Publications
2023
Demonceaux, Marie; Goux, Marine; Schimith, Lucia Emanueli; Santos, Michele Goulart Dos; Hendrickx, Johann; Offmann, Bernard; André-Miral, Corinne
Enzymatic synthesis, characterization and molecular docking of a new functionalized polyphenol: Resveratrol-3, 4’-⍺-diglucoside Article de journal
Dans: Results in Chemistry, p. 100956, 2023.
@article{demonceaux2023enzymatic,
title = {Enzymatic synthesis, characterization and molecular docking of a new functionalized polyphenol: Resveratrol-3, 4’-⍺-diglucoside},
author = {Marie Demonceaux and Marine Goux and Lucia Emanueli Schimith and Michele Goulart Dos Santos and Johann Hendrickx and Bernard Offmann and Corinne André-Miral},
url = {https://www.sciencedirect.com/science/article/pii/S2211715623001959},
doi = {10.1016/j.rechem.2023.100956},
year = {2023},
date = {2023-05-16},
urldate = {2023-05-16},
journal = {Results in Chemistry},
pages = {100956},
publisher = {Elsevier},
abstract = {Transglucosylation of resveratrol by the Q345F variant of sucrose phosphorylase from Bifidobacterium adolescentis (BaSP) was extensively studied during the last decade. Indeed, Q345F is able to catalyze the synthesis of resveratrol-3-O-⍺-D-glucoside (RES-3) with yield up to 97% using a cost-effective glucosyl donor, sucrose (Kraus et al., Chemical Communications, 53(90), 12182–12184 (2017)). Despite the fact that two further products were detectable in low amounts after glucoside synthesis, they were never identified. Here, we isolated and fully characterized one of those two minor products: resveratrol-3,4′-O-⍺-D-diglucoside (RES-3,4′). This original compound had never been described before. Using bioinformatics models, we successfully explained the formation of this diglucosylated product. Indeed, with RES-3 as acceptor substrate, Q345F is able to transfer a glucosyl moiety in position 4′-OH, what had been reported as impossible in the literature. The low yield observed is due to the steric hindrance into the catalytic site between RES-3 and residues Tyr132 and Tyr344. Nevertheless, the substrate orientation in the active site is favored by stabilizing interactions. Ring A of RES-3 bearing the diol moiety is stabilized by hydrogen bonds with residues Asp50, Arg135, Asn347 and Arg399. Hydroxyl group OH-4′ shares hydrogen bonds with the catalytic residues Asp192 and Glu232. Multiple hydrophobic contacts complete the stabilization of the substrate to favor the glucosylation at position 4′. Understanding of the mechanisms allowing the glucosylation at position 4′ of resveratrol will help the development of enzymatic tools to target and control the enzymatic synthesis of original ⍺-glucosylated polyphenols with high added value and better biodisponibility.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Transglucosylation of resveratrol by the Q345F variant of sucrose phosphorylase from Bifidobacterium adolescentis (BaSP) was extensively studied during the last decade. Indeed, Q345F is able to catalyze the synthesis of resveratrol-3-O-⍺-D-glucoside (RES-3) with yield up to 97% using a cost-effective glucosyl donor, sucrose (Kraus et al., Chemical Communications, 53(90), 12182–12184 (2017)). Despite the fact that two further products were detectable in low amounts after glucoside synthesis, they were never identified. Here, we isolated and fully characterized one of those two minor products: resveratrol-3,4′-O-⍺-D-diglucoside (RES-3,4′). This original compound had never been described before. Using bioinformatics models, we successfully explained the formation of this diglucosylated product. Indeed, with RES-3 as acceptor substrate, Q345F is able to transfer a glucosyl moiety in position 4′-OH, what had been reported as impossible in the literature. The low yield observed is due to the steric hindrance into the catalytic site between RES-3 and residues Tyr132 and Tyr344. Nevertheless, the substrate orientation in the active site is favored by stabilizing interactions. Ring A of RES-3 bearing the diol moiety is stabilized by hydrogen bonds with residues Asp50, Arg135, Asn347 and Arg399. Hydroxyl group OH-4′ shares hydrogen bonds with the catalytic residues Asp192 and Glu232. Multiple hydrophobic contacts complete the stabilization of the substrate to favor the glucosylation at position 4′. Understanding of the mechanisms allowing the glucosylation at position 4′ of resveratrol will help the development of enzymatic tools to target and control the enzymatic synthesis of original ⍺-glucosylated polyphenols with high added value and better biodisponibility.
2022
Schimith, Lucia E; Santos, Michele G Dos; Arbo, Bruno D; André-Miral, Corinne; Muccillo-Baisch, Ana L; Hort, Mariana A
Polydatin as a therapeutic alternative for central nervous system disorders: A systematic review of animal studies Article de journal
Dans: Phytotherapy Research, vol. 36, no. 7, p. 2852–2877, 2022.
@article{schimith2022polydatin,
title = {Polydatin as a therapeutic alternative for central nervous system disorders: A systematic review of animal studies},
author = {Lucia E Schimith and Michele G Dos Santos and Bruno D Arbo and Corinne André-Miral and Ana L Muccillo-Baisch and Mariana A Hort},
url = {https://onlinelibrary.wiley.com/doi/10.1002/ptr.7497},
doi = {10.1002/ptr.7497},
year = {2022},
date = {2022-05-25},
urldate = {2022-05-25},
journal = {Phytotherapy Research},
volume = {36},
number = {7},
pages = {2852--2877},
publisher = {Wiley Online Library},
abstract = {Polydatin, or piceid, is a natural stilbene found in grapes, peanuts, and wines. Polydatin presents pharmacological activities, including neuroprotective properties, exerting preventive and/or therapeutic effects in central nervous system (CNS) disorders. In the present study, we summarize and discuss the neuroprotective effects of polydatin in CNS disorders and related pathological conditions in preclinical animal studies. A systematic review was performed by searching online databases, returning a total of 110 records, where 27 articles were selected and discussed here. The included studies showed neuroprotective effects of polydatin in experimental models of neurological disorders, including cerebrovascular disorders, Parkinson's disease, traumatic brain injuries, diabetic neuropathy, glioblastoma, and neurotoxicity induced by chemical agents. Most studies were focused on stroke (22.2%) and conducted in male rodents. The intervention protocol with polydatin was mainly acute (66.7%), with postdamage induction treatment being the most commonly used regimen (55.2%). Overall, polydatin ameliorated behavioral dysfunctions and/or promoted neurological function by virtue of its antioxidant and antiinflammatory properties. In summary, this review offers important scientific evidence for the neuroprotective effects and distinct pharmacological mechanisms of polydatin that not only enhances the present understanding but is also useful for the development of future preclinical and clinical investigations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Polydatin, or piceid, is a natural stilbene found in grapes, peanuts, and wines. Polydatin presents pharmacological activities, including neuroprotective properties, exerting preventive and/or therapeutic effects in central nervous system (CNS) disorders. In the present study, we summarize and discuss the neuroprotective effects of polydatin in CNS disorders and related pathological conditions in preclinical animal studies. A systematic review was performed by searching online databases, returning a total of 110 records, where 27 articles were selected and discussed here. The included studies showed neuroprotective effects of polydatin in experimental models of neurological disorders, including cerebrovascular disorders, Parkinson's disease, traumatic brain injuries, diabetic neuropathy, glioblastoma, and neurotoxicity induced by chemical agents. Most studies were focused on stroke (22.2%) and conducted in male rodents. The intervention protocol with polydatin was mainly acute (66.7%), with postdamage induction treatment being the most commonly used regimen (55.2%). Overall, polydatin ameliorated behavioral dysfunctions and/or promoted neurological function by virtue of its antioxidant and antiinflammatory properties. In summary, this review offers important scientific evidence for the neuroprotective effects and distinct pharmacological mechanisms of polydatin that not only enhances the present understanding but is also useful for the development of future preclinical and clinical investigations.
Santos, Michele Goulart Dos; Schimith, Lucia Emanueli; André-Miral, Corinne; Muccillo-Baisch, Ana Luiza; Arbo, Bruno Dutra; Hort, Mariana Appel
Neuroprotective effects of resveratrol in in vivo and in vitro experimental models of Parkinson’s disease: A systematic review Article de journal
Dans: Neurotoxicity Research, p. 1–27, 2022.
@article{dos2022neuroprotective,
title = {Neuroprotective effects of resveratrol in in vivo and in vitro experimental models of Parkinson’s disease: A systematic review},
author = {Michele Goulart Dos Santos and Lucia Emanueli Schimith and Corinne André-Miral and Ana Luiza Muccillo-Baisch and Bruno Dutra Arbo and Mariana Appel Hort},
editor = {Springer},
doi = {10.1007/s12640-021-00450-x},
year = {2022},
date = {2022-01-12},
urldate = {2022-01-12},
journal = {Neurotoxicity Research},
pages = {1--27},
publisher = {Springer},
abstract = {Parkinson’s disease (PD) is currently the second most common neurodegenerative disease, being characterized by motor and non-motor symptoms. The therapeutic options available for its treatment are limited, do not slow the progression of the disease, and have serious side effects. For this reason, many studies have sought to find compounds with neuroprotective properties that bring additional benefits to current therapy. In this context, resveratrol is a phenolic compound, found in many plant species, capable of crossing the blood–brain barrier and having multiple biological properties. Experimental studies in vitro and in vivo have shown that it can prevent or slow the progression of a variety of diseases, including PD. In this systematic review, we summarize the effects of resveratrol in experimental in vivo and in vitro models of PD and discuss the molecular mechanisms involved in its action. The bibliographic search was performed in the databases of PubMed, Web of Science, SciELO, and Google Scholar, and based on the inclusion criteria, 41 articles were selected and discussed. Most of the included studies have demonstrated neuroprotective effects of resveratrol. In general, resveratrol prevented behavioral and/or neurological disorders, improved antioxidant defenses, reduced neuroinflammatory processes, and inhibited apoptosis. In summary, this systematic review offers important scientific evidence of neuroprotective effects of resveratrol in PD and also provide valuable information about its mechanism of action that can support future clinical studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Parkinson’s disease (PD) is currently the second most common neurodegenerative disease, being characterized by motor and non-motor symptoms. The therapeutic options available for its treatment are limited, do not slow the progression of the disease, and have serious side effects. For this reason, many studies have sought to find compounds with neuroprotective properties that bring additional benefits to current therapy. In this context, resveratrol is a phenolic compound, found in many plant species, capable of crossing the blood–brain barrier and having multiple biological properties. Experimental studies in vitro and in vivo have shown that it can prevent or slow the progression of a variety of diseases, including PD. In this systematic review, we summarize the effects of resveratrol in experimental in vivo and in vitro models of PD and discuss the molecular mechanisms involved in its action. The bibliographic search was performed in the databases of PubMed, Web of Science, SciELO, and Google Scholar, and based on the inclusion criteria, 41 articles were selected and discussed. Most of the included studies have demonstrated neuroprotective effects of resveratrol. In general, resveratrol prevented behavioral and/or neurological disorders, improved antioxidant defenses, reduced neuroinflammatory processes, and inhibited apoptosis. In summary, this systematic review offers important scientific evidence of neuroprotective effects of resveratrol in PD and also provide valuable information about its mechanism of action that can support future clinical studies.
2020
Arbo, Bruno Dutra; André-Miral, Corinne; Nasre-Nasser, Raif Gregorio; Schimith, Lúcia Emanueli; Santos, Michele Goulart; Costa-Silva, Dennis; Muccillo-Baisch, Ana Luiza; Hort, Mariana Appel
Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease Article de journal
Dans: Frontiers in Aging Neuroscience, vol. 12, p. 103, 2020, ISSN: 1663-4365.
@article{10.3389/fnagi.2020.00103,
title = {Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease},
author = {Bruno Dutra Arbo and Corinne André-Miral and Raif Gregorio Nasre-Nasser and Lúcia Emanueli Schimith and Michele Goulart Santos and Dennis Costa-Silva and Ana Luiza Muccillo-Baisch and Mariana Appel Hort},
url = {https://www.frontiersin.org/article/10.3389/fnagi.2020.00103},
doi = {10.3389/fnagi.2020.00103},
issn = {1663-4365},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {Frontiers in Aging Neuroscience},
volume = {12},
pages = {103},
abstract = {Neurodegenerative diseases are characterized by the progressive loss of neurons in different regions of the nervous system. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases, and the symptoms associated with these pathologies are closely related to the regions that are most affected by the process of neurodegeneration. Despite their high prevalence, currently, there is no cure or disease-modifying drugs for the treatment of these conditions. In the last decades, due to the need for the development of new treatments for neurodegenerative diseases, several authors have investigated the neuroprotective actions of naturally occurring molecules, such as resveratrol. Resveratrol is a stilbene found in several plants, including grapes, blueberries, raspberries, and peanuts. Studies have shown that resveratrol presents neuroprotective actions in experimental models of AD and PD, however, its clinical application is limited due to its rapid metabolism and low bioavailability. In this context, studies have proposed that structural changes in the resveratrol molecule, including glycosylation, alkylation, halogenation, hydroxylation, methylation, and prenylation could lead to the development of derivatives with enhanced bioavailability and pharmacological activity. Therefore, this review article aims to discuss how resveratrol derivatives could represent viable molecules in the search for new drugs for the treatment of AD and PD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Neurodegenerative diseases are characterized by the progressive loss of neurons in different regions of the nervous system. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases, and the symptoms associated with these pathologies are closely related to the regions that are most affected by the process of neurodegeneration. Despite their high prevalence, currently, there is no cure or disease-modifying drugs for the treatment of these conditions. In the last decades, due to the need for the development of new treatments for neurodegenerative diseases, several authors have investigated the neuroprotective actions of naturally occurring molecules, such as resveratrol. Resveratrol is a stilbene found in several plants, including grapes, blueberries, raspberries, and peanuts. Studies have shown that resveratrol presents neuroprotective actions in experimental models of AD and PD, however, its clinical application is limited due to its rapid metabolism and low bioavailability. In this context, studies have proposed that structural changes in the resveratrol molecule, including glycosylation, alkylation, halogenation, hydroxylation, methylation, and prenylation could lead to the development of derivatives with enhanced bioavailability and pharmacological activity. Therefore, this review article aims to discuss how resveratrol derivatives could represent viable molecules in the search for new drugs for the treatment of AD and PD.
Lien
