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In silico vrednotenje endokrinih učinkov izbranih naravnih polifenolov
Toporiš, Janja (Author), Jakopin, Žiga (Mentor) More about this mentor... This link opens in a new window

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Abstract
Polifenoli so najbolj zastopani antioksidanti v naš prehrani, predvsem gre za spojine prisotne v sadju, zelenjavi, žitih, stročnicah, čokoladi ter različnih pijačah, kot so kava, čaj in vino. Kot antioksidanti varujejo celične komponente pred oksidativnim stresom ter tako zmanjšajo nevarnost tveganja za nastanek različnih degenerativnih bolezni. Eksperimentalne študije dokazujejo tudi kardioprotektivno in antikancerogeno delovanje polifenolov. Med drugim delujejo preventivno tudi pri osteoporozi, sladkorni bolezni ter nevrodegenerativnih boleznih. Po drugi strani pa lahko vplivajo na encime, ki sodelujejo pri biosintezi hormonov ali se vežejo na same hormonske receptorje ter tako delujejo kot potencialni endokrini motilci. Kljub njihovi široki uporabi so zanimanje nutricionistov vzbudili šele v zadnjih nekaj letih. Glavni razlog njihovega poznega raziskovanja je prav kompleksnost njihove kemijske strukture. Polifenoli v prehrani se namreč nahajajo v kompleksnih oblikah, zato so podvrženi obsežnemu metabolizmu. Prav to je vzrok raznoliki biološki uporabnosti teh spojin. Pogosto je prav metabolit izhodnega polifenola tisti, ki je biološko aktiven. Izbrane polifenole in njihove metabolite smo preučevali s programom Endocrine Disruptome ter napovedali in ovrednotili endokrine učinke izbranih polifenolov. Pri delu smo se osredotočili predvsem na izoflavonoida genistein in daidzein. Slednjima smo namreč izpostavljeni v največji meri preko hrane. Ker sta strukturno zelo podobna endogenemu estradiolu, lahko delujeta tako na estrogenske kot tudi na androgenske receptorje. Pri preučevanju endokrine toksičnosti smo na podlagi objavljenih in vitro ter in vivo raziskav predpostavili, da se na estrogenski receptor z največjo afiniteto vežejo mikoestrogeni, sledijo kumestrani, nato flavonoidi in halkonoidi. Poleg tega smo napovedali tudi selektivno vezavo genisteina na estrogenski receptor β, s čimer lahko utemeljimo različno manifestiranje delovanja izoflavonoidov. Pri vezavi genisteina in daidzeina na androgenski receptor pa smo napovedali največje verjetnosti vezave tako na agonistično kot tudi na antagonistično konformacijo jedrnega receptorja. S pomočjo programa Endocrine Disruptome smo torej napovedali vezavno afiniteto polifenolov na jedrne receptorje. Dobljeni rezultati so bili precej podobni rezultatom in vitro študij. V manjši meri pa so se skladali z rezultati in vivo raziskav, saj pri tem nismo upoštevali biološke uporabnosti, zaradi katere se rezultati in vitro/in silico rezultatov razlikujejo od tistih in vivo. Z našimi rezultati smo potrdili, da obstaja potencialna nevarnost endokrinega delovanja polifenolov, in sicer je posredovana predvsem preko estrogenskih receptorjev.

Language:Slovenian
Keywords:endokrini motilci, polifenoli, in silico metode, endokrina toksičnost
Work type:Master's thesis/paper (mb22)
Tipology:2.09 - Master's Thesis
Organization:FFA - Faculty of Pharmacy
Year:2017
Publisher:[J. Toporiš]
Number of pages:72 f.
UDC:547.56+616.4(043.3)
COBISS.SI-ID:4392817 This link opens in a new window
Views:133
Downloads:49
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Secondary language

Language:English
Title:In silico evaluation of endocrine effects of selected natural polyphenols
Abstract:
Polyphenols are the most abundant antioxidative compounds in our diet that can be found in many types of fruit, vegetable, cereals, legumes, chocolate and in different beverages, such as coffee, tea and wine. The health effects of polyphenols depend on the amount consumed and on their bioavailability. Certain studies have subsequently confirmed health benefits of phytoestrogen intake, including a lowered risk of osteoporosis, heart disease and breast cancer. On the other hand, phytoestrogens are frequently considered as endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. They are able to bind to estrogen receptors and, in turn, exert estrogenic or antiestrogenic effects. In spite of their frequent use, they have only just recently received considerable attention due to their complex chemical structure. Namely, phytoestrogens are ingested predominantly as glycosides, which immediately undergo hydrolysis, further metabolism and/or absorption. Therefore, bioavailability differs considerably between the various polyphenols, and the most abundant polyphenols in our diet are not necessarily those that have the best bioavailability profile. Often phytoestrogens metabolites possess greater biological activity than that of their precursor molecule. In the scope of this thesis Endocrine Disruptome software was employed to predict the binding affinities of selected polyphenols, as well as those of their metabolites to a number of nuclear receptors. The main focus was on isoflavonoids genistein and daidzein, to which we are predominantly exposed to through food consumption. Due to the structural similarity of isoflavones with estradiol they possess weak estrogenic or androgenic effects. Based on thorough examination of previously published in vitro and in vivo studies we established that mycoestrogens have the highest affinity for estrogen receptors, followed by coumestrans, flavonoids and chalcones, that have the lowest binding affinity for nuclear receptor. In addition, there has been receptor selectivity for genistein predicted for estrogen receptor β, which might explain the differences in exerting effects of phytoestrogens. We have also predicted the highest binding affinity for genistein and daidzein of all examined polyphenols for agonistic and antagonistic conformation of estrogen receptor. Predictions for binding affinities of selected polyphenols and metabolites to nuclear receptors made by Endocrine Disruptome were quite similar to those, previously obtained in in vitro studies. Nevertheless, our results were not completely in agreement with those obtained in in vivo studies. This is due to poor bioavailability of phytoestrogens, which is reflected in differences between in vivo and in vitro/in silico results. We can also confirm the existence of potential for endocrine toxicity, which is predominantly caused by estrogen and androgen receptors. Despite a remarkable contribution of in silico methods as a practical tool for the prediction of the endocrine disrupting potential, further development of software is still needed to be able to produce reliable and accurate results.


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