Trilobolide (TB), a sesquiterpene lactone isolated from Laser trilobum is an inhibitor of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). We have found that upon the in vitro exposure to TB, rodent peritoneal cells and human peripheral blood mononuclear cells secrete high amounts of IFN-γ. The effect is associated with the stimulation of high output NO biosynthesis in rat cells. The stimulatory potential of TB depends on the activation of MAP kinases p38 and ERK1/2, and transcription factor NF-κB. BAPTA-AM, a chelator of the intracellular calcium, remained without any effect on the secretion of IFN-γ triggered by TB. These results demonstrate that TB is a potent immunostimulatory agent.

• MeSH
• butyráty chemie   farmakologie   MeSH
• EGTA analogy a deriváty   farmakologie   MeSH
• furany chemie   farmakologie   MeSH
• interferon gama metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neutrofily účinky léků   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• peritoneum cytologie   MeSH
• potkani inbrední LEW MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester MeSH Prohlížeč
• butyráty MeSH
• EGTA MeSH
• furany MeSH
• interferon gama MeSH
• oxid dusnatý MeSH
• trilobolide MeSH Prohlížeč

Our previous research on immunostimulatory properties of trilobolide and its structurally related natural analogues isolated from Laser trilobum (L.) Borkh., encouraged us to investigate structurally related guaianolides belonging to a specific group of sesquiterpene lactones with characteristic glycol moiety attached to the lactone ring. Ever increasing attention has been paid to certain guaianolides such as thapsigargin and trilobolide for their promising anti-inflammatory, anticancer, anti-infectious and SERCA inhibitory activities. However, due to their alkylation capabilities, they might be cytotoxic. Search for compounds with preserved immunobiological properties and decreased cytotoxicity led us to transform some of their structural features, particularly those related to their side chain functionality. For this reason, we prepared a series of over 20 various deacylated, acyl modified, or relactonized derivatives of trilobolide. The immunobiological effects were screened in vitro using the rat peritoneal cells primed with lipopolysaccharide. Secretion of interferon-γ (IFN-γ), interleukins (IL) IL-1β, IL-6 and tumour necrosis factor-α (TNF-α) were determined by ELISA, and nitric oxide (NO) production by Griess reagent. Relation between the molecular structure and immunobiological activity was investigated. Acetylation at 7-OH and 11-OH positions of the lactone ring, or acyl modification of the guaianolide functionalities (including relactonization) of trilobolide, led to inability to stimulate secretion of cytokines and production of NO. Interestingly, minor structural changes achieved by catalytic hydrogenation or hydrogenolysis retained the original immunoactivity of trilobolide. It can be concluded that several new chemically transformed sesquiterpene lactones resembling the immunobiological properties of trilobolide or thapsigargin were prepared and identified. The implication of the lactone vicinal diol (glycol) moiety, combined with other structure functionality, was confirmed as essential for immune properties of the trilobolide or thapsigargin type of guaianolides.

• Klíčová slova
• Cytokines, Guaianolides, Immunoactivity, Nitric oxide, Sesquiterpene lactones, Trilobolide derivatives,
• MeSH
• Apiaceae chemie   MeSH
• butyráty chemie   MeSH
• cytokiny metabolismus   MeSH
• furany chemie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• laktony chemie   farmakologie   MeSH
• molekulární struktura MeSH
• oxid dusnatý metabolismus   MeSH
• peritoneální makrofágy účinky léků   MeSH
• potkani Wistar MeSH
• seskviterpeny chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• butyráty MeSH
• cytokiny MeSH
• furany MeSH
• laktony MeSH
• oxid dusnatý MeSH
• seskviterpeny MeSH
• trilobolide MeSH Prohlížeč