Studies on the effect of thymoquinone on oxidative stress and cell wall integrity of Candida glabrata
Notice bibliographique
Résumé
Thymoquinone is a major active ingredient of black seeds which are produced by the plant, Nigella sativa. Thymoquinone exhibits various chemotherapeutic and chemo-preventative activities including immunostimulation, antimicrobial, anticancer and chemoprotection activities (reviewed by Darakhshan et al., 2015). Despite available data on thymoquinone’s anticancer mechanism of action, there is no description of its antifungal mode of action. This thesis presents data on thymoquinone’s effect on the redox status of C. glabrata and reveals a binding site of TQ on the surface of these cells. The data presented in chapter 2 demonstrates for the first time the growth inhibitory effect of TQ on the species C. krusei and C. glabrata beside other Candida species. This chapter also shows that in C. glabrata, thymoquinone exhibited concentration-dependent fungicidal activity on planktonic cells and caused necrotic death. In addition, the antifungal effect of thymoquinone against C. glabrata biofilms was examined. The biofilms were stabilised using a poly propylene biofilm reactor designed to mimic Calgary biofilm device (Almshawit et al., 2014b). The advantages of this novel reactor are described. Thymoquinone may act as anti-oxidant or pro-oxidant depending on the milieu (Mansour et al., 2002). Chapter 3 demonstrated that thymoquinone causes oxidative stress in C. glabrata as a result of increased reactive oxygen species generation. This chapter also reports depletion of reduced glutathione levels and reduced mitochondrial membrane potential. In addition, this chapter provides experimental characterisation of the ALO1 gene and evidence of production of D-erythroascorbic acid by C. glabrata. Chapter 4 shows that activation of CWI-MAPK in C. glabrata results following treatment with thymoquinone, hydrogen peroxide, doxycycline or hypo-osmotic treatment. However, CWI-MAPK mutants were neither sensitive nor resistant to thymoquinone. In contrast the downstream kinase mutant (C. glabrata Δslt2) was sensitive to H2O2 (Chapter 5). Activation of CWI-MAPK by hypo-osmolarity was exploited to develop a hypothesis that this mechanism could be used to screen potential CWI-MAPK inhibitors. Survival of cells in water was used as a model to screen such inhibitor. The results give insights into important facts that should be considered when using water suspensions of C. glabrata cells. Finally chapter 5 describes for the first time an interaction between thymoquinone and the fungal cell wall. This study demonstrates that thymoquinone induced stress promotes chitin synthesis after induction of CWI-MAPK. Chitin was shown to bind thymoquinone and facilitate its transport through the cell wall inside the cell. This was supported by the observation that inhibition of chitin synthesis led to a decrease in thymoquinone antifungal efficacy. This finding is important in a reconsideration of the use of TQ together with other cell wall active antifungal compounds such as nikkomycin Z.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».