LPS PMA=Phorbol
6. Natural products as source for therapeutic intervention
6.2. Pharmacological modulation of neutrophil functions
Many plant extracts and compounds are able to induce phagocytosis such as selenium and vitamin E (Mukherjee, 2008). The aqueous extract of roots of Baliospermum montanum can significantly increase the ingestion of Candida albicans by neutrophils (Patil et al., 2009). Another example is the hydroalcoholic extract of Ziziphus jujuba leaves, which has been shown to increase neutrophil phagocytosis (Ganachari et al., 2004). Treatment of neutrophils with plant Santolina chamaecyparissus leaf extracts inhibits the release of elastase, thus inhibits degranulation function (Boudoukha et al., 2016).
Cranberry juice-derived proanthocyanidins (PACs) has anti-adherence properties against Candida albicans through iron chelating from the environment, this leads to decreased proinflammatory cytokines by oral epithelial cells infected with C. albicans (Rane et al., 2014).
Many substances have been found to modulate antimicrobial functions such as cytokine release by neutrophils such as Green tea extract. This attenuates the release of pro-inflammatory cytokines and the inflammatory features of neutrophils from obese rats (Albuquerque et al., 2016). Another example for modulating antimicrobial functions is wariſteine, alkaloid purified from root and leaves of Cissampelos sympodialis. This alkaloid inhibits the antimicrobial events such as production of NETs. Warifteine has been used as a potential treatment for inflammatory diseases associated with NETs production (Lima et al., 2014). The ethanolic extracts from leaves and fruits of Schinus molle var. areira are useful in the treatment of lipid pathologies, they identified a significant increase in the percentage of neutrophils (Bras et al., 2010) The data are summarized in (Table. 3).
23
Table 3: Some natural products and their modulatory effect Plant extracts Action Compoumnd
concentration
oral exposure (Bras et al., 2010)
Selenium and
(IUs) means International units 1 IU of the natural form is equivalent to 0.67 mg of alpha-tocopherol.
24 7. The aim of the work
Staphylococcus aureus is a serious human pathogen and can cause life-threatening disease, which are difficult to treat due to the emergence of multiple antibiotic resistances. The first-line of natural defense against S. aureus is the innate immune system including phagocytes. Traditional herbal medicine provides a lot of therapies to support the body's resistance to sickness through effects on the innate immune system. The overall goal of this study was to characterize the immune-boosting capacity of natural plant extracts against S. aureus infections. To study the effects of natural plant extracts on the human neutrophils, human neutrophils were needed in this study. Since it is difficult and time-consuming to harvest primary human neutrophils form blood of healthy donors, the first aim of this study was to find an alternative model to human neutrophils. The human leukemia cell line HL-60 cells are considered an alternative cell culture model to study neutrophil differentiation.
1. The first aim was to characterize the antimicrobial activity of dimethylsulfoxid (DMSO) and retinoic acid-differentiated HL-60 cells against the pathogen S.
aureus in comparison to primary human blood-derived neutrophils, with special emphasis on the formation of neutrophil extracellular traps (NETs) (Yaseen et al., 2017) (Chapter 2).
2. In an initial study, the acetone bark extract from Guarea kunthiana (GUKUBA) was used to examine its capability to boost host defence in human and bovine neutrophils against S. aureus (Jerjomiceva et al., 2016) (Chapter 3).
3. The third aim was the screening of novel natural products that have antimicrobial activity and that can boost immune cells against bacterial infections. Twenty-three plant extracts from Costa Rica were screened; three of the tested products significantly reduced the growth number of S. aureus in the presence of human blood without direct antibacterial effects: Byrsonima crassifolia acetone bark extract, Mandevilla veraguasensis acetone extract and Verbesina oersteiana aceton bark extract (VEOEBA) (Yaseen et al., 2017) (Chapter 4).
4. The fourth aim was to study the mechanistical effects of the identified immunomodulatimg plant extracts. The effects of the extracts on the
25
following antibacterial functions were studied: phagocytosis, NETs release and degranulation. Furthermore, vitexin as one active compound was characterized for its ability to boost the antimicrobial effect of neutrophils (Chapter 5).
26
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