Abstract
Kinetin (N6-furfuryladenine) belongs to a group of plant growth hormones involved in cell division, differentiation and other physiological processes. One of the possible ways to obtain biologically active compounds is to complex biologically relevant natural compounds to suitable metal atoms. In this work, two structural groups of Zn(II) complexes [Zn(Ln)2Cl2]·Solv (1–5) and [Zn(HLn)Cl3]·xLn (6–7); n = 1–5, Solv = CH3OH for 1 and 2H2O for 2; x = 1 for 6 and 2 for 7; involving a phytohormone kinetin and its derivatives (Ln) were evaluated for their ability to modulate secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and matrix metalloproteinase (MMP)-2 in a lipopolysaccharide (LPS)-activated macrophage-like THP-1 cell model. The penetration of the complexes to cells was also detected. The mechanism of interactions of the zinc(II) complexes with a fluorescent sensor N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ) and sulfur-containing biomolecules (l-cysteine and reduced glutathione) was studied by electrospray-ionization mass spectrometry and flow-injection analysis with fluorescence detection. The present study showed that the tested complexes exhibited a low cytotoxic effect on the THP-1 cell line (IC50>40 µM), apart from complex 4, with an IC50 = 10.9±1.1 µM. Regarding the inflammation-related processes, the Zn(II) complexes significantly decreased IL-1β production by a factor of 1.47–2.22 compared with the control (DMSO), but did not affect TNF-α and MMP-2 secretions. However, application of the Zn(II) complexes noticeably changed the pro-MMP-2/MMP-2 ratio towards a higher amount of maturated MMP-2, when they induced a 4-times higher production of maturated MMP-2 in comparison with the vehicle-treated cells under LPS stimulation. These results indicated that the complexes are able to modulate an inflammatory response by influencing secretion and activity of several inflammation-related cytokines and enzymes.
Highlights
Cytokinins form a group of plant hormones, which take part in regulation of all stages of plant growth represented by different cellular processes, including cell division, control of leaf senescence, control of nutrient allocation, root nodule development, stem cell maintenance, and regulation of auxin action [1]
In contrast to the studies on topically applied kinetin, this study provides evidence that several antioxidant enzymes were inhibited by the kinetin exposure leading to the presumption that this condition could facilitate the process of inflammation
One of the possible ways to obtain biologically active compounds with unique pharmacological properties is complexing of biologically relevant natural compounds, very often of plant origin, to suitable metal atoms. This approach can lead to substances which can exert a different mode of interaction with the organism in connection with the possible synergistic effect of the metal ion and organic molecule, as we demonstrated in the case of anti-inflammatory effects of gold(I) complexes with derivatives of cytokinin N6-benzylaminopurine [17]
Summary
Cytokinins form a group of plant hormones, which take part in regulation of all stages of plant growth represented by different cellular processes, including cell division, control of leaf senescence, control of nutrient allocation, root nodule development, stem cell maintenance, and regulation of auxin action [1]. Kinetin (N6-furfuryladenine) is classified among naturally occurring cytokinins [2] and since its isolation and identification, kinetin has been widely used in various aspects of plant research, including applications in biotechnology and cell biology mainly due to its stimulation on plant growth, retardation of leaf senescence and modulation of response of plants to various environmental stresses. In addition to the regulatory functions in plants, kinetin has showed strong anti-ageing activity on different animal targets, such as fruit flies [3], or human dermal cells [4,5]. These positive effects led to the commercial application of kinetin in rejuvenating medicinal cosmetics [6,7]. The substantial antiproliferative effects of some cytokinins were established and the studies performed so far indicate, that this direction in research could lead to identification of potent bioactive compounds with relevant anti-cancer activity
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