Selectivity of major isoquinoline alkaloids from Chelidonium majus towards telomeric G-quadruplex: A study using a transition-FRET (t-FRET) assay

Background Natural bioproducts are invaluable resources in drug discovery. Isoquinoline alkaloids of Chelidonium majus constitute a structurally diverse family of natural products that are of great interest, one of them being their selectivity for human telomeric G-quadruplex structure and telomerase inhibition. Methods The study focuses on the mechanism of telomerase inhibition by stabilization of telomeric G-quadruplex structures by berberine, chelerythrine, chelidonine, sanguinarine and papaverine. Telomerase activity and mRNA levels of hTERT were estimated using quantitative telomere repeat amplification protocol (q-TRAP) and qPCR, in MCF-7 cells treated with different groups of alkaloids. The selectivity of the main isoquinoline alkaloids of Chelidonium majus towards telomeric G-quadruplex forming sequences were explored using a sensitive modified thermal FRET-melting measurement in the presence of the complementary oligonucleotide CT22. We assessed and monitored G-quadruplex topologies using circular dichroism (CD) methods, and compared spectra to previously well-characterized motifs, either alone or in the presence of the alkaloids. Molecular modeling was performed to rationalize ligand binding to the G-quadruplex structure. Results The results highlight strong inhibitory effects of chelerythrine, sanguinarine and berberine on telomerase activity, most likely through substrate sequestration. These isoquinoline alkaloids interacted strongly with telomeric sequence G-quadruplex. In comparison, chelidonine and papaverine had no significant interaction with the telomeric quadruplex, while they strongly inhibited telomerase at transcription level of hTERT. Altogether, all of the studied alkaloids showed various levels and mechanisms of telomerase inhibition. Conclusions We report on a comparative study of anti-telomerase activity of the isoquinoline alkaloids of Chelidonium majus. Chelerythrine was most effective in inhibiting telomerase activity by substrate sequesteration through G-quadruplex stabilization. General significance Understanding structural and molecular mechanisms of anti-cancer agents can help in developing new and more potent drugs with fewer side effects. Isoquinolines are the most biologically active agents from Chelidonium majus, which have shown to be telomeric G-quadruplex stabilizers and potent telomerase inhibitors

Studies on the Effects of Betamethasone, L-Carnitine, and Betamethasone-L-Carnitine Combinations on the Dipalmitoyl Phosphatidylcholine Content and Phosphatidylcholine Species Composition in Foetal Rat Lungs

Peer Reviewe

L-Carnitine-Betamethasone Combination Vs Betamethasone for Prevention of Respiratory-Distress Syndrome

In this prospective randomised study the effects of antenatal treatment with a low dose betamethasone (2 mg/1 day) - L-carnitine (4 g/5 days) combination were compared with those of a high dose betamethasone, given alone (8 mg/2 days) on the prevention of respiratory distress syndrome (RDS) and mortality in preterm infants. One-hundred women entering the trial gave birth to 109 liveborn infants, 55 in the betamethasone group (A), 54 in the betamethasone-L-carnitine combination group (B). Eight of the 55 (14.5%) infants in group A developed RDS, four of the 54 (7.3%) in group B, which was significantly more (p < 0.05), although in group B the betamethasone dose was dramatically reduced. The mortality also was significantly lower after treatment with a betamethasone-L-carnitine combination compared to betamethasone alone (4 of 55 infants or 7.3% in group A versus 1 of 54 infants or 1.8% in group B, p < 0.05). The present results demonstrate that in combination with L-carnitine, the betamethasone dose is markedly reducible with a concommitant significant reduction of the incidence of RDS and mortality of premature newborns