Flavonoidid, immuunsus ja vähk: katseklaasist kliiniliste uuringuteni

Flavonoidid on taimede sünteesitud ained, mille arvukad eksperimentaalsed uuringud on näidanud erinevaid soodsaid toimeid inimese tervisele. Need polüfenoolsed ühendid avaldavad pidurdavat mõju kasvaja tekkele ja arengule, toimides mitmete erinevate molekulaarsete mehhanismide kaudu, seejuures reguleerides ka immuunsüsteemi tööd ja alandades põletikuvastust. Artiklis on antud ülevaade flavonoidide olemusest, mitmekesisusest ja peamistest immunomodulatoorsetest mehhanismidest ning toodud esile kitsaskohad katseklaasi- ja loommudelite tulemuste ülekandmisel inimorganismile. On tõenäoline, et üldsuse kasvav huvi flavonoidide ja flavonoidirikaste toiduproduktide kasutamise vastu koos teadlaskonna jätkuvate jõupingutustega suurendada nende taimsete metaboliitide toimetõhusust võivad tulevikus pakkuda uusi võimalusi vähi ennetamiseks ja laiendada olemasolevat ravimiarsenali vähivastaseks võitluseks.Eesti Arst 2017; 96(5):252–25

Taimsete produktide roll keemiaravi arengus

Vaatamata jõudsatele edasiminekutele vähiravis on pahaloomulised kasvajad endiselt üheks olulisemaks surmapõhjuseks kogu maailmas. WHO prognoositud haigestumise jätkuv kiire kasv lähiaastakümneil nõuab ka kemopreventiivsete ja kemoterapeutiliste meetmete uurimise intensiivistamist. Üle poole tänapäeval kliinilises kasutuses olevatest keemiaraviühenditest on oma olemuselt looduslikku päritolu, olles eraldatud looduslikust allikast või omades looduslikul produktil põhinevat struktuuri. Oluliseks lähtematerjaliks on seejuures osutunud taimsed ekstraktid. Artiklis on antud ülevaade nelja taimedest tuletatud keemiaravirühma (vinka-alkaloidid, podofüllotoksiinid, taksaanid ja kamptotetsiini analoogid) saamisloost, kasvajavastasest aktiivsusest ja molekulaarsetest toimemehhanismidest. Toetudes taimsete produktide keemiliste struktuuride ja bioaktiivsete omaduste mitmekesisusele, võib lähiaastail eeldada uute ravimikandidaatide jätkuvat avastamist.Eesti Arst 2016; 95(11):728–73

Tetrasoolium- (MTT) metoodika võimaldab uurida potentsiaalselt aktiivsete ühendite kemosensitiivsust ja -resistentsust

3-(4,5-dimetüültiasool-2-üül)-2,5-difenüültetrasooliumbromiidi (MTT) kolorimeetriline analüüs on viimase paari aastakümne jooksul leidnud laialdast rakendust nii sünteetiliste kui ka looduslike ainete ja ekstraktide vähivastaste omaduste skriinimisel, et hinnata uuritavate ühendite võimalikku antiproliferatiivset ja tsütotoksilist toimet. Lühiülevaates on välja toodud metoodika põhiprintsiibid, analüüsitud selle eeliseid ja piiranguid ning kirjeldatud ka potentsiaalseid rakendusvõimalusi.Eesti Arst 2015; 94(8):472–47

Antioxidant phytoconstituents from Onosma bracteata Wall. (Boraginaceae) ameliorate the CCl4 induced hepatic damage: in vivo study in male wistar rats

Onosma bracteata Wall. (Boraginaceae) is a highly valuable medicinal herb that is used for the treatment of fever, bronchitis, asthma, rheumatism, stomach irritation, and other inflammatory disorders. The present study aims to explore the hepatoprotective potential of ethanolic extract (Obeth) from O. bracteata aerial parts against carbon tetrachloride (CCl4) which causes hepatic damage in the male Wistar rats. Obeth showed effective radical quenching activity with an EC50 of 115.14 and 199.33 µg/mL in superoxide radical scavenging and lipid peroxidation analyses respectively along with plasmid DNA protective potential in plasmid nicking assay. The Obeth modulated mutagenicity of 2 Aminofluorine (2AF) in the pre-incubation mode of investigation (EC50 10.48 µg/0.1 mL/plate) in TA100 strain of Salmonella typhimurium. In in vivo studies, pretreatment of Obeth (50, 100, and 200 mg/kg) had the potential to normalize the biochemical markers aggravated by CCl4 (1mL/kg b.wt.) including liver antioxidative enzymes. Histopathological analysis also revealed the restoration of CCl4-induced liver histopathological alterations. Immunohistochemical studies showed that the treatment of Obeth downregulated the expression levels of p53 and cyclin D in hepatocytes. and downregulation in the Western blotting analysis revealed the downregulation of p-NF-kB, COX-2, and p53. HPLC data analysis showed the supremacy of major compounds namely, catechin, kaempferol, epicatechin, and Onosmin A in Obeth. The present investigation establishes the hepatoprotective and chemopreventive potential of O. bracteata against CCl4-induced hepatotoxicity via antioxidant defense system and modulation of the expression of proteins associated with the process of carcinogenesis in hepatic cells

Autophagy induction by Scutellaria flavones in cancer: recent advances

In parallel with a steady rise in cancer incidence worldwide, the scientific community is increasingly focused on finding novel, safer and more efficient modalities for managing this disease. Over the past decades, natural products have been described as a significant source of new structural leads for novel drug candidates. Scutellaria root is one of the most studied natural products because of its anticancer potential. Besides just describing the cytotoxic properties of plant constituents, their molecular mechanisms of action in different cancer types are equally important. Therefore, this review article focuses on the role of the Scutellaria flavones wogonin, baicalein, baicalin, scutellarein and scutellarin in regulating the autophagic machinery in diverse cancer models, highlighting these molecules as potential lead compounds for the fight against malignant neoplasms. The knowledge that autophagy can function as a dual-edged sword, acting in both a pro- and antitumorigenic manner, further complicates the issue, revealing an amazing property of flavonoids that behave either as anti- or proautophagic agents

The Role of Flavonoids as Potential Plant Fungicides in Preventing Human Carcinogenesis: A Short Communication

In the context of the steadily increasing prevalence of malignant disorders all over the world, identification of any novel possibilities for suppressing carcinogenesis is crucial leading to saving human lives. One of the important sources of exposure to potential carcinogens is food products which can be contaminated with different types of mycotoxins. These structurally diverse chemicals are produced by certain fungi, whereas many of them may be associated with the development of malignant neoplasms in distinct organ systems. In this perspective article, the ability of specific plant secondary metabolites from the class of flavonoids to suppress the release of carcinogenic mycotoxins from certain fungi, mostly the members of Aspergillus and Penicillium genera, is highlighted. This finding might support the development of novel flavonoid-based plant fungicides in the future, to lower the contamination of food products with mycotoxins and thereby also reduce the cancer prevalence in humans. In addition, the application of flavonoids as natural products instead of synthetic chemicals in plant cultivation is probably also more acceptable for final consumers, representing an actual step toward a greener future

Anticancer effects of flavonoids on melanoma cells: are murine cells more sensitive compared to humans?

In the past few decades, research in new drugs for treatment of oncological disorders has refocused on naturally occurring products. Among various plant-derived compounds flavonoids are considered as promising chemopreventive and chemotherapeutic agents exerting specific antiproliferative and cytotoxic activities towards various cancer cell lines. Such tumoricidal action can depend on the structure of flavonoids and their concentrations, but also on the cellular milieu and cancer type. Analysing the anticancer effects of various flavonoids on different human and murine melanoma cell lines, one further aspect influencing the antineoplastic action of flavonoids is pointed out in this article, i.e. the species origin of malignant cells. It is shown that murine melanoma cells tend to exert somewhat lower resistance to different flavonoids compared to human melanoma cells, emphasising that anticancer effects exhibited by natural polyphenolic agents in mouse cells can not be directly extrapolated to humans

A supposed mechanism of synergistic action of catechol-containing natural polyphenols

Over the past decades, accumulated evidences have been published about different synergistic biological activities between natural dietary polyphenols. Although these effects could be physiologically important in chemoprevention, cardioprotection and neuroprotection, but probably also in treatment of serious chronic diseases, such as cancer, the exact mechanisms behind this potentiation have still remained largely unknown. In this article, supposition about the involvement of phase II metabolic enzyme, catechol-O-methyltransferase (COMT), in the synergistic action of catechol-containing polyphenols is proposed. Serving as substrates, these compounds can also behave as COMT inhibitors suppressing the O-methylation of the other catechol-containing component in the combined mixture. At that, negative feedback by the increased amount of S-adenosyl-L-homocysteine generated from the methyl-group donor S-adenosyl-L-methionine during the enzymatic conversion can play an important role. Presuming that O-methylated conjugates are in general biologically less active than their unmetabolised counterparts, cotreatment of cells with combination of two catecholic natural agents can lead to a superior effect as compared to the administration of either compound alone. This mechanism can provide an explanation to the beneficial synergistic effects described for green tea extracts in chemoprevention or red wine consumption in protection of cardiovascular system in comparison with their single components tested separately. However, as currently only little is known about the possible biological activities of O-methylated conjugates of dietary polyphenolic phytochemicals, their nature and effects definitely need to be further studied. These results could prove (or disprove) the hypothesis raised in this article but also contribute to the development of physiologically or even clinically useful mixtures of polyphenols with catechol structure in the future

A supposed mechanism of synergistic action of catechol-containing natural polyphenols

Over the past decades, accumulated evidences have been published about different synergistic biological activities between natural dietary polyphenols. Although these effects could be physiologically important in chemoprevention, cardioprotection and neuroprotection, but probably also in treatment of serious chronic diseases, such as cancer, the exact mechanisms behind this potentiation have still remained largely unknown. In this article, supposition about the involvement of phase II metabolic enzyme, catechol-O-methyltransferase (COMT), in the synergistic action of catechol-containing polyphenols is proposed. Serving as substrates, these compounds can also behave as COMT inhibitors suppressing the O-methylation of the other catechol-containing component in the combined mixture. At that, negative feedback by the increased amount of S-adenosyl-L-homocysteine generated from the methyl-group donor S-adenosyl-L-methionine during the enzymatic conversion can play an important role. Presuming that O-methylated conjugates are in general biologically less active than their unmetabolised counterparts, cotreatment of cells with combination of two catecholic natural agents can lead to a superior effect as compared to the administration of either compound alone. This mechanism can provide an explanation to the beneficial synergistic effects described for green tea extracts in chemoprevention or red wine consumption in protection of cardiovascular system in comparison with their single components tested separately. However, as currently only little is known about the possible biological activities of O-methylated conjugates of dietary polyphenolic phytochemicals, their nature and effects definitely need to be further studied. These results could prove (or disprove) the hypothesis raised in this article but also contribute to the development of physiologically or even clinically useful mixtures of polyphenols with catechol structure in the future

Use of murine L1210 and P388 lymphocytic leukemia cells in cytotoxic studies of flavonoids

In studies of antileukemic properties of flavonoids two murine cellular systems (L1210 and P388) are widely used beside the various established human leukemia lines. Differently from conventional clinically used chemotherapeutics, P388 cells reveal somewhat lower susceptibility towards plant polyphenolic agents than L1210 cells. Moreover, based on the cytotoxic analysis of different flavonoids, we provide some novel evidence of Burkitt`s lymphoma as a human equivalent of L1210 mouse model, enabling thus the use of L1210 murine model in development of novel antilymphoma drugs proceeding from natural polyphenols. At that, structurally different flavones can be considered as potential lead compounds; however, the most potent flavonoid described so far in B-cell lymphoma cells is the rotenoid deguelin, certainly requiring further in vitro and in vivo investigation