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Daphnetin: A Novel Anti- Helicobacter pylori Agent

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Daphnetin: A Novel Anti- Helicobacter pylori Agent

Genzhu Wang et al. Int J Mol Sci.

Abstract

Background: Antibiotic-resistant H. pylori was increasingly found in infected individuals, which resulted in treatment failure and required alternative therapeutic strategies. Daphnetin, a coumarin-derivative compound, has multiple pharmacological activities.

Methods: The mechanism of daphnetin on H. pylori was investigated focusing on its effect on cell morphologies, transcription of genes related to virulence, adhesion, and cytotoxicity to human gastric epithelial (GES-1) cell line.

Results: Daphnetin showed good activities against multidrug resistant (MDR) H. pylori clinical isolates, with minimal inhibitory concentration (MIC) values ranging from 25 to 100 μg/mL. In addition, daphnetin exposure resulted in H. pylori morphological changes. Moreover, daphnetin caused increased translocation of phosphatidylserine (PS), DNA damage, and recA expression, and RecA protein production vs. control group. Of great importance, daphnetin significantly decreased H. pylori adhesion to GES-1 cell line vs. control group, which may be related to the reduced expression of colonization related genes (e.g., babA and ureI).

Conclusions: These results suggested that daphnetin has good activity against MDR H. pylori. The mechanism(s) of daphnetin against H. pylori were related to change of membrane structure, increase of DNA damage and PS translocation, and decrease of H. pylori attachment to GES-1 cells.

Keywords: Helicobacter pylori; colonization; daphnetin; mechanism of action.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Structure of daphnetin (Molecular Weight 178.143 g/mol).
Figure 2
Figure 2
The morphology of H. pylori cells with/without daphnetin exposure observed by SEM. Control (A,D); H. pylori were treated with 6.25 μg/mL (B,E) or 12.5 μg/mL of daphnetin (C,F). Magnification: A–C = 4000; D–F = 40000.
Figure 3
Figure 3
The morphology of H. pylori cells with/without daphnetin exposure observed by TEM. Control (AC); H. pylori treated with 12.5 μg/mL daphnetin (DF). Magnification: A and D = 3000; B and E = 5000; and C and F = 8000.
Figure 4
Figure 4
Detection of DNA damage and recA expression in H. pylori. DNA damage detected using TUNEL by flow cytometry (A) and confocal (B). (C) The expression of recA in H. pylori with/without daphnetin exposure. (** p < 0.001 vs. control). The expression of the study genes without daphnetin exposure was normalized as 1.
Figure 5
Figure 5
The transcription of babA (A) and ureI (B) in H. pylori with/without daphnetin exposure. The expression of the study genes without daphnetin exposure was normalized as 1. Inhibitory effect of daphnetin on adhesion of H. pylori to GES-1 cells (C). The level of adherence of H. pylori was detected by confocal (magnification: 600). All the data were presented as mean and standard deviations (SD). * p < 0.05, ** p < 0.01 vs. control.
Figure 6
Figure 6
Hypothesized model of the mechanism(s) of daphnetin against H. pylori. Daphnetin exposure caused DNA damage and subsequently induced recA expression. In addition, recA negatively regulated babA transcription. To our best knowledge, no study indicated a direct interaction between recA and urel. Lower babA and urel transcription, and their respective protein production could reduce H. pylori adherence to GES-1 cells. Moreover, daphnetin exhibited effect on membrane changes (e.g., outer membrane structural change and increased PS exposure). In the current study, no significant impact of daphnetin on membrane permeability and depolarization was observed (dotted line indicates no statistical significance between control and daphnetin exposure groups).

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