Antiagregacijsko djelovanje flavonoida

doctoral thesis

• Title (english): Antiaggregatory effect of flavonoids
• Author: Ivana Babić
• Mentor: Mirza Bojić (mentor)
• Mentor: Renata Zadro (komentor)
• Committee member: Željan Maleš (predsjednik povjerenstva)
• Committee member: Renata Zadro (član povjerenstva)
• Committee member: Mila Lovrić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2020-02-10, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Flavonoidi su heterociklički spojevi iz prirode koje unosimo hranom. Antiagregacijska terapija u kardiovaskularnim oboljenjima ima ozbiljne nuspojave krvarenja u gastrointestinalni trakt. Flavonoidi pokazuju antiagregacijsko djelovanje, čiji mehanizam nije rasvijetljen. Njegovo razumijevanje omogućilo bi upotrebu flavonoida kao dostupne i neškodljive opcije u antiagregacijskoj terapiji. Određeni su kromatografski parametri lipofilnosti 21 flavonoida: parametri retencijski faktor RF i hidrofobni parametar RM. Vrijednosti RM uspoređene su s logaritmom koeficijenta razdijeljenja, logP, dobivenim putem programskih aplikacija. Impedancijskom agregometrijom, određene su minimalna antiagregacijska koncentracija, flavanona, te ispitano pojačano antiagregacijsko djelovanje inhibitora enzima fosfolipaze C, ciklooksigenaze i inhibitora Ca2+-kanala u prisutnosti flavanona, te antiagregacijsko djelovanje kombinacija flavanona, 6-hidroksiflavona i pinocembrin-7-metiletera. Protočnom citometrijom ispitano je smanjenje aktivacije trombocita nakon inkubacije s flavanonom, praćenjem ekspresije aktivnog oblika integrina αIIbβ3. Kromatografski parametri RM, bili su u rasponu od -0,5942 za luteolin do 0,5202 za tektokrizin i krizin-dimetileter. Snažna pozitivna korelaciju prisutna je za logP programskih aplikacija i RM (r 0,66-0,93 p <0.05). Flavanon postiže izuzetno niske minimalne antiagregacijske koncentracije, značajno pridonosi djelovanju inhibitora enzima fosfolipaze C, te nešto slabije inhibitoru Ca2+ kanala dok djelovanju inhibitora ciklooksigenaze ne pridonosi. U kombinacijama s drugim flavonoidima, flavanon ostvaruje značajno povećan antiagregacijski učinak. Djelovanjem flavanona smanjena je aktivacija integrina αIIbβ3. Lipofilnost i djelovanje na fosfolipazu C omogućuju sveobuhvatnost antiagregacijskog djelovanja flavonoida, a uz minimalne antiagregacijske koncentracije flavanona ostvarive prehranom kao i pojačano djelovanje kombinacije flavonoida predstavljaju osnovu njihove moguće primjene u antiagregacijskoj terapiji.

Abstract (english)

Flavonoids are heterocyclic compounds found in nature which we consume true everyday diet. Antiplatelet therapy has serious side-effects as bleeding in the gastrointestinal tract. Flavonoids exhibit antiaggregatory effect, with not fully enlightened mechanism. Understanding of this mechanism would allow the use of flavonoids as available and innocuous options in antiplatelet therapy. The chromatographic parameters, retention factor RF and the hydrophobic parameter RM were determined as the lipophilic parameters of flavonoids. The RM values were compared to the logarithm of log of coefficient of partition, obtained through program applications. Impedance aggregometry was used to determine the minimum antiaggregating concentration of flavanone and to investigate the enhanced activity of phospholipase C, cyclooxygenase and Ca2+ channel blockers in the presence of flavanones, and the antiaggregatory action of a combination of flavanone, 6-hydroxyphlavone and pinocembrin-7-methylether. Flow cytometry was used to monitor the expression of activated conformation of integrin αIIbβ3 after incubation of platelets with flavanone. The chromatographic parameters of RM ranged from -0.5942 for luteolin to 0.5202 for tectocrysine and chrysine-dimethylether. Strong positive correlation is present for logP derived thru program applications and RM (r 0.66-0.93 p <0.05). Flavanon achieves extremely low minimum antiaggregating concentrations, significantly contributes to the inhibition of phospholipase C enzyme and a slightly less to activity of Ca2+ channel blockers while it doesn’t contribute to the action of cyclooxygenase inhibitor. In combination with other flavonoids, flavanone achieves significant antiaggregating effect. Flavanone decreased the activation of integrin αIIbβ3. Lipophilicity and interaction with phospholipase C, enable the antiaggregatory action of flavonoids. They, as well as minimal antiaggregating concentrations achievable by diet and enhanced action of flavonoid combinations represent the basis for their possible use option in antiplatelet therapy.

• Keywords: flavonoidi; flavanon; logP; RM; lipofilnost; impedancijska agregometrija; PLC; COX-1; kalcijevi kanali; inhibitori; protočna citometrija; PAC-1
• Keywords (english): flavonoids; flavanone; logP; RM; lipophilicity; impedance aggregometry; PLC; COX-1; calcium channels; inhibitors; flow cytometry; PAC-1
• Language: croatian
• URN:NBN: urn:nbn:hr:163:084602
• Promotion: 2021
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-05-24 13:26:38