Trilobolide and its analogues belong to the guaianolide type of sesquiterpene lactones, which are characteristic and widely distributed within the families Asteraceae and Apiaceae. Certain guaianolides are receiving continuously increasing attention for their promising sarco-endoplasmic reticulum Ca2+-ATPase (SERCA)-inhibitory activity. However, because of their alkylation capabilities, they are generally toxic. Therefore, the search for compounds with significant immunobiological properties but with decreased cytotoxicities suitable for use in immune-based pharmacotherapy is ongoing. Therefore, we extended our previous investigation of the immunobiological effects of trilobolide to a series of structurally related guaianolides and germacranolides. To evaluate the relationship, we tested a series of selected derivatives containing α-methyl lactone or exomethylene lactone ring. For a wider comparison, we also included some of their glycosidic derivatives. We assessed the in vitro immunobiological effects of the tested compounds on nitric oxide (NO) production, cytokine secretion, and prostaglandin E2 (PGE2) release by mouse peritoneal cells, activated primarily by lipopolysaccharide (LPS), and evaluated their viability. The inhibitory effects of the apparently most active substance, 8-deoxylactucin, seem to be the most promising.

• Klíčová slova
• 8-deoxylactucin, 8-epiisoamberboin, germacranolides, guaianolides, immune-modulatory effects,
• MeSH
• butyráty MeSH
• cytokiny metabolismus   MeSH
• dinoproston metabolismus   biosyntéza   MeSH
• furany MeSH
• laktony * farmakologie   chemie   MeSH
• lipopolysacharidy farmakologie   MeSH
• myši MeSH
• oxid dusnatý * metabolismus   MeSH
• peritoneální makrofágy účinky léků   metabolismus   MeSH
• seskviterpeny germakranové * farmakologie   chemie   MeSH
• seskviterpeny guajanové * farmakologie   chemie   MeSH
• seskviterpeny farmakologie   chemie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• butyráty MeSH
• cytokiny MeSH
• dinoproston MeSH
• furany MeSH
• germacranolide MeSH Prohlížeč
• laktony * MeSH
• lipopolysacharidy MeSH
• oxid dusnatý * MeSH
• seskviterpeny germakranové * MeSH
• seskviterpeny guajanové * MeSH
• seskviterpeny MeSH
• trilobolide MeSH Prohlížeč

Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide-alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

• Klíčová slova
• anti-inflammatory properties, archangelolide, dansyl fluorescent conjugate, sarco/endoplasmic reticulum calcium ATPase, sesquiterpene lactone, trilobolide analogue,
• Publikační typ
• časopisecké články MeSH

Like thapsigargin, which is undergoing clinical trials, trilobolide is a natural product with promising anticancer and anti-inflammatory properties. Similar to thapsigargin, it has limited aqueous solubility that strongly reduces its potential medicinal applications. The targeted delivery of hydrophobic drugs can be achieved using liposome-based carriers. Therefore, we designed a traceable liposomal drug delivery system for trilobolide. The fluorescent green-emitting dye BODIPY, cholesterol and trilobolide were used to create construct 6. The liposomes were composed of dipalmitoyl-3-trimethylammoniumpropane and phosphatidylethanolamine. The whole system was characterized by atomic force microscopy, the average size of the liposomes was 150 nm in width and 30 nm in height. We evaluated the biological activity of construct 6 and its liposomal formulation, both of which showed immunomodulatory properties in primary rat macrophages. The uptake and intracellular distribution of construct 6 and its liposomal formulation was monitored by means of live-cell fluorescence microscopy in two cancer cell lines. The encapsulation of construct 6 into the liposomes improved the drug distribution in cancer cells and was followed by cell death. This new liposomal trilobolide derivative not only retains the biological properties of pure trilobolide, but also enhances the bioavailability, and thus has potential for the use in theranostic applications.

• Klíčová slova
• BODIPY conjugates, cancer targeting, drug delivery, liposomes, natural compounds, sesquiterpene lactone trilobolide,
• Publikační typ
• časopisecké články MeSH

The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions.

• MeSH
• cytokiny antagonisté a inhibitory   biosyntéza   genetika   imunologie   MeSH
• farmakokinetika MeSH
• farmakologie MeSH
• imunoterapie MeSH
• léková rezistence MeSH
• lidé MeSH
• lymfocyty účinky léků   imunologie   metabolismus   MeSH
• makrofágy účinky léků   imunologie   metabolismus   MeSH
• objevování léků MeSH
• receptory cytokinové antagonisté a inhibitory   biosyntéza   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• toll-like receptory agonisté   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH
• receptory cytokinové MeSH
• systém (enzymů) cytochromů P-450 MeSH
• toll-like receptory MeSH