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- Garcia, Catarina, et al.
(författare)
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Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in Plectranthus spp. The cytotoxic diterpene 6,7-dehydroroyleanone (1) is the main component of the P. madagascariensis (Pers.) Benth. essential oil, while 7α-acetoxy-6β-hydroxyroyleanone (2) can be isolated from acetonic extracts of P. grandidentatus Gürke. The reactivity of the natural royleanones 1 and 2 was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-O-tert-butyl-carbonate-royleanone (20), 6,7-dehydro-12-O-methylroyleanone (21), 6,7-dehydro-12-O-benzoylroyleanone (22), and 7α-acetoxy-6β-hydroxy-12-O-benzoylroyleanone (23) were obtained as pure with overall modest to excellent yields (21–97%). P-gp inhibition potential of the derivatives 20–23 was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6β-benzoyloxy-12-O-(4-chloro)benzoylroyleanone (4), has also been tested. The P-gp inhibiting effects of compounds 1–4 were also assessed through a Rhodamine 123 accumulation assay. Derivatives 4 and 23 have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound 4 presented higher anti-P-gp potential than the natural diterpenes 1, 2, and 3, with comparable inhibitory potential to Dexverapamil. Moreover, derivative 4 showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin.
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- Duarte, Ana I., et al.
(författare)
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Dual Therapy with Liraglutide and Ghrelin Promotes Brain and Peripheral Energy Metabolism in the R6/2 Mouse Model of Huntington's Disease
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal loss alongside altered energy metabolism, are key features of Huntington's disease (HD) pathology. The orexigenic gut-peptide hormone ghrelin is known to stimulate appetite and affect whole body energy metabolism. Liraglutide is an efficient anti-type 2 diabetes incretin drug, with neuroprotective effects alongside anorectic properties. Combining liraglutide with the orexigenic peptide ghrelin may potentially promote brain/cognitive function in HD. The R6/2 mouse model of HD exhibits progressive central pathology, weight loss, deranged glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using a co-administration of liraglutide and ghrelin. We investigated their effect on brain cortical hormone-mediated intracellular signalling pathways, metabolic and apoptotic markers, and the impact on motor function in HD. We here demonstrate that liraglutide, alone or together with ghrelin (subcutaneous daily injections of 150 μg/kg (ghrelin) and 0.2 mg/kg (liraglutide), for 2 weeks), normalized glucose homeostatic features in the R6/2 mouse, without substantially affecting body weight or body composition. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels in R6/2 mice, alongside higher ADP levels. Liraglutide plus ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice. Taken together, our findings encourage further studies targeting energy metabolism in HD.
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- Guerreiro, Duarte N., et al.
(författare)
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Mild Stress Conditions during Laboratory Culture Promote the Proliferation of Mutations That Negatively Affect Sigma B Activity in Listeria monocytogenes
- 2020
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Ingår i: Journal of Bacteriology. - : American Society for Microbiology. - 0021-9193 .- 1098-5530. ; 202:9
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Tidskriftsartikel (refereegranskat)abstract
- In Listeria monocytogenes, the full details of how stress signals are integrated into the σB regulatory pathway are not yet available. To help shed light on this question, we investigated a collection of transposon mutants that were predicted to have compromised activity of the alternative sigma factor B (σB). These mutants were tested for acid tolerance, a trait that is known to be under σB regulation, and they were found to display increased acid sensitivity, similar to a mutant lacking σB (ΔsigB). The transposon insertions were confirmed by whole-genome sequencing, but in each case, the strains were also found to carry a frameshift mutation in the sigB operon. The changes were predicted to result in premature stop codons, with negative consequences for σB activation, independently of the transposon location. Reduced σB activation in these mutants was confirmed. Growth measurements under conditions similar to those used during the construction of the transposon library revealed that the frameshifted sigB operon alleles conferred a growth advantage at higher temperatures, during late exponential phase. Mixed-culture experiments at 42°C demonstrated that the loss of σB activity allowed mutants to take over a population of parental bacteria. Together, our results suggest that mutations affecting σB activity can arise during laboratory culture because of the growth advantage conferred by these mutations under mild stress conditions. The data highlight the significant cost of stress protection in this foodborne pathogen and emphasize the need for whole-genome sequence analysis of newly constructed strains to confirm the expected genotype.IMPORTANCE: In the present study, we investigated a collection of Listeria monocytogenes strains that all carried sigB operon mutations. The mutants all had reduced σB activity and were found to have a growth advantage under conditions of mild heat stress (42°C). In mixed cultures, these mutants outcompeted the wild type when mild heat stress was present but not at an optimal growth temperature. An analysis of 22,340 published L. monocytogenes genome sequences found a high rate of premature stop codons present in genes positively regulating σB activity. Together, these findings suggest that the occurrence of mutations that attenuate σB activity can be favored under conditions of mild stress, probably highlighting the burden on cellular resources that stems from deploying the general stress response.
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