Publication: Antioksidan aktiviteye sahip sarı kantaron (hypericum perforatum) flavonoidlerinin anti-enflamatuar ve anti-depresan etkilerinin in vitro ve in siliko incelenmesi
Abstract
Tıbbi bitkiler, ulaşılabilirliği ve minimum yan etkileri sebebiyle günümüzde hala popüler bir tedavi yöntemidir. Sarı kantaron (Hypericum Perforatum L., HPL), yüzyıllardır bir çok hastalığın tedavisinde tıbbi bitki olarak kullanılmaktadır. Biyolojik makromolekül hasarına ve metabolik işlev bozukluklarına yol açan oksidatif stresle mücadele ederek antioksidan aktivite gösterdiği bilinmektedir. Monoamin oksidaz (MAO) enziminin inhibisyonu yoluyla anksiyete ve hafif-orta şiddette depresyonu tedavi etmesinin yanı sıra anti-enflamatuar ve yara iyileştirici özellikleri için de tercih edilir. Sarı kantaron ekstrelerinin Siklooksijenaz (COX) ve Lipoksijenazı (LOX) inhibe ettiği bilinmektedir. Siklooksijenazın iki izoformu vardır; yapısal olarak ifade edilen siklooksijenaz-1 (COX-1) ve çeşitli uyaranlarla yukarı regüle edilen siklooksijenaz-2 (COX-2). COX-1 inhibitörleri gastrointestinal (GI) yan etkilerle ilişkilendirilirken, COX-2 inhibitörleri nispeten daha az GI yan etkisine sahiptir, ancak daha yüksek kardiyovasküler toksisite gösterir.COX ile benzer şekilde enflamasyona etki eden bir diğer enzim grubu LOX’lardır ancak seçici LOX/ COX çalışmaları iyi sonuçlar vermemiştir. Bu nedenle, minimum yan etkileri olan yeni anti-enflamatuar ilaçların keşfi zorunlu hale gelmiştir. Her iki enzimin eşzamanlı inhibisyonuna odaklanmak, daha geniş spektrumlu, azaltılmış yan etkiler ve daha düşük dozajlara sahip yeni antienflamatuar ilaçların keşfi için umut vericidir. Bu tez çalışmasında, sarı kantaron çiçek ve yaprakları etanol ile ekstre edilmiştir metanol ile fraksiyonlanmıştır. Alkol ekstraktının ve fraksiyonların antioksidanaktiviteleri belirlenmiş ve alkol ekstraktından izole edilen bileşikler tanımlanmış, izolatların ve bitki-alkol ekstresinin antioksidan aktiviteleri belirlenmiştir. Bitkiekstresinin sentetik antioksidanlara benzer bir antioksidan aktiviteye sahip olduğu görülmüştür. Aynı zamanda, bitkinin aktif bileşenleri literatürden seçilerek MAO, COX ve LOX'a bağlanma afiniteleri doking yöntemi ile hesaplanmıştır. Bu bileşiklerin, COX-1 ile karşılaştırıldığında tercihen COX-2'yi inhibe ettiği görülmüştür. Kuersetin seçici MAO-A aktivitesi gösterirken, hiperisin seçici MAO-B aktivitesi göstermiştir. Hiperisin ve kemferol, etkili ve umut verici çift etkili COX-2/ 5-LOX inhibitörler olarak gelecekteki çalışmalar için önerilmektedir.
Medicinal plants today are still popular for treatment of many diseases due to their availability, efficacy and minimal side effects.St. John's Wort (Hypericum Perforatum L., HPL) has been used as a medicinal plant for the treatment of many disorders for centuries. It is known to show antioxidant activity by combating oxidative stress leading to biological macromolecule damage and metabolic dysfunctions. It isindicated for the treatment of anxiety and mild to moderately severe depression through the inhibition of the monoamine oxidase (MAO) enzyme and is also preferred for its wound-healing properties due to its anti-inflamatory effect. St. John's Wort extracts have been shown to inhibit Cyclooxygenases (COXs) and Lipooxygenases (LOXs). There are two forms of cyclooxygenases; cyclooxygenase-1 (COX-1), which is constitutively expressed, and cyclooxygenase-2 (COX-2), which is upregulated by diverse stimuli. COX-1 inhibitors have been associated with gastrointestinal (GI) side effects, while COX-2 inhibitors have relatively few GI side effects, but have a higher incidence of cardiovascular toxicity. LOXs are also another group of enzymes that affect inflammation similar to COXs but the selective LOX/ COX inhibition studies have not yielded satisfactory results. Hence, the discovery of new anti-inflammatory drugs with minimum side effects is mandatory. Focusing on the simultaneous inhibition of both enzymes is promising for the discovery of new anti-inflammatory drugs with wider spectrum, reduced side effects and lower dosages.In this thesis study St. John's Wort patels and leaves were extracted by ethanol and further fractionated by methanol. Antioxidant activities of the total extract and the fractions have been determined and the compounds which wereisolated from alcoholicextract were identified. The plant extracts havedisplayed antioxidant activity similar to synthetic antioxidants.At the same time the binding affinities towards MAO, COX and LOX of the active compounds,which were selected from previous reports, were calculated by the docking method. Those compounds preferentially inhibited COX-2 when compared to COX-1. Quercetin displayed selective MAO-A activity while hypericin showed selective MAO-B activity. Hypericin and kaemferol are suggested for future studies as effective and promising dual inhibitors for COX-2/ 5-LOX enzymes.
Medicinal plants today are still popular for treatment of many diseases due to their availability, efficacy and minimal side effects.St. John's Wort (Hypericum Perforatum L., HPL) has been used as a medicinal plant for the treatment of many disorders for centuries. It is known to show antioxidant activity by combating oxidative stress leading to biological macromolecule damage and metabolic dysfunctions. It isindicated for the treatment of anxiety and mild to moderately severe depression through the inhibition of the monoamine oxidase (MAO) enzyme and is also preferred for its wound-healing properties due to its anti-inflamatory effect. St. John's Wort extracts have been shown to inhibit Cyclooxygenases (COXs) and Lipooxygenases (LOXs). There are two forms of cyclooxygenases; cyclooxygenase-1 (COX-1), which is constitutively expressed, and cyclooxygenase-2 (COX-2), which is upregulated by diverse stimuli. COX-1 inhibitors have been associated with gastrointestinal (GI) side effects, while COX-2 inhibitors have relatively few GI side effects, but have a higher incidence of cardiovascular toxicity. LOXs are also another group of enzymes that affect inflammation similar to COXs but the selective LOX/ COX inhibition studies have not yielded satisfactory results. Hence, the discovery of new anti-inflammatory drugs with minimum side effects is mandatory. Focusing on the simultaneous inhibition of both enzymes is promising for the discovery of new anti-inflammatory drugs with wider spectrum, reduced side effects and lower dosages.In this thesis study St. John's Wort patels and leaves were extracted by ethanol and further fractionated by methanol. Antioxidant activities of the total extract and the fractions have been determined and the compounds which wereisolated from alcoholicextract were identified. The plant extracts havedisplayed antioxidant activity similar to synthetic antioxidants.At the same time the binding affinities towards MAO, COX and LOX of the active compounds,which were selected from previous reports, were calculated by the docking method. Those compounds preferentially inhibited COX-2 when compared to COX-1. Quercetin displayed selective MAO-A activity while hypericin showed selective MAO-B activity. Hypericin and kaemferol are suggested for future studies as effective and promising dual inhibitors for COX-2/ 5-LOX enzymes.