Abstract
Plants are an important source of pharmacologically active compounds. In the present work, we characterize the impact of black cumin (Nigella sativa L.) aqueous extracts on a yeast model of p53-dependent apoptosis. To this end, the Saccharomyces cerevisiae recombinant strain over-expressing p53 was used. The over-expression of p53 triggers the expression of apoptotic markers: the externalization of phosphatidylserine, mitochondrial defect associated with cytochrome-c release and the induction of DNA strand breaks. These different effects were attenuated by Nigella sativa L. aqueous extracts, whereas these extracts have no effect on the level of p53 expression. Thus, we focus on the anti-apoptotic molecules present in the aqueous extract of Nigella sativa L. These extracts were purified and characterized by complementary chromatographic methods. Specific fluorescent probes were used to determine the effect of the extracts on yeast apoptosis. Yeast cells over-expressing p53 decrease in relative size and have lower mitochondrial content. The decrease in cell size was proportional to the decrease in mitochondrial content and of mitochondrial membrane potential (ΔΨm). These effects were prevented by the purified aqueous fraction obtained by fractionation with different columns, named C4 fraction. Yeast cell death was also characterized by reactive oxygen species (ROS) overproduction. In the presence of the C4 fraction, ROS overproduction was strongly reduced. We also noted that the C4 fraction promotes the cell growth of control yeast cells, which do not express p53, supporting the fact that this purified extract acts on cellular mediators activating cell proliferation independently of p53. Altogether, our data obtained on yeast cells over-expressing p53 demonstrate that anti-apoptotic molecules targeting p53-induced apoptosis associated with mitochondrial dysfunction and ROS overproduction are present in the aqueous extracts of Nigella seeds and in the purified aqueous C4 fraction.
Highlights
Apoptosis is an evolutionarily conserved cell-death mechanism
We extend our investigation of apoptosis features due to p53 over-expression in the yeast system, and we study the activity of aqueous Nigella sativa L. extract in this model
Some molecules were shown to increase ∆ψm and the concentration of adenosine triphosphate (ATP), making them suitable to be applied as therapeutic tools in degenerative diseases. As it is currently well-admitted that reactive oxygen species (ROS) overproduction, which can result from a breakdown of RedOx homeostasis in various diseases and in the aging process, can favor cell senescence and cell death, there is a great interest to identify cytoprotective molecules in this context
Summary
Apoptosis is an evolutionarily conserved cell-death mechanism. One of its roles is to selectively eliminate damaged cells with irreparable DNA damage. Apoptosis is characterized by typical biochemical and morphological features, such as nuclear fragmentation and chromatin condensation, cell blebbing, the externalization of phosphatidyl-serine, and caspase cascade activation, leading to inter-nucleosomal DNA fragmentation [1]. Apoptosis misregulation can result in major human diseases, such as age-related diseases, including neurodegenerative, cardiovascular and eye diseases, viral infections, and cancers [2]. It is well admitted that wild-type p53 is a tumor suppressor gene, which is implicated in DNA repair, the cell-cycle process, aging and the death of cells that have been exposed to cellular stresses induced by physical, chemical or biological agents [3,4]. The ability of p53 to activate apoptosis through different pathways may define its tumor suppressor activity to prevent tumor development [5]
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