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Red Cabbage Anthocyanins As Inhibitors of Lipopolysaccharide

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Red Cabbage Anthocyanins As Inhibitors of Lipopolysaccharide International Journal of Biological Macromolecules 80 (2015) 702–709 Contents lists available at ScienceDirect International Journal of Biological Macromolecules j ournal homepage: www.elsevier.com/locate/ijbiomac Red cabbage anthocyanins as inhibitors of lipopolysaccharide-induced oxidative stress in blood platelets a,b a,∗ c a Joanna Saluk , Michal Bijak , Malgorzata M. Posmyk , Halina M. Zbikowska a Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland b Department of Toxicology, Faculty of Pharmacy with Division of Medical Analytics, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland c Department of Ecophysiology and Plant Development, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland a r a t i c l e i n f o b s t r a c t Article history: LPS is a Gram-negative bacteria endotoxin, which is an important pro-inflammatory agent. Blood platelets Received 12 May 2015 take part both in inflammatory processes and in pathogenesis of septic shock following accumulation Received in revised form 6 July 2015 of LPS. As a platelet agonist LPS causes the intraplatelet overproduction of ROS/RNS that are responsible Accepted 18 July 2015 for adverse modifications in the structure of platelet compounds being associated with a development Available online 21 July 2015 of platelet-dependent diseases. Existing evidence suggests that anthocyanins (ATH) are able to protect the circulatory system. The Keywords: antioxidative properties of ATH are believed to be mainly responsible for their positive health effects. Lipopolysaccharide The main goal of the present in vitro study was to investigate the potential protective properties of red Red cabbage Platelets cabbage ATH against oxidative damage induced by LPS in blood platelets. Exposure of platelets to LPS •− resulted in carbonyl group increase, 3-nitrotyrosine formation, lipid peroxidation and O2 generation. We have shown that ATH extract effectively decreased oxidative stress induced by LPSs. The in silico analysis demonstrated that both cyanin and LPS were located at the same region of human TLR4-MD-2 complex. Our findings suggest that there could be two-way ATH platelet protection mechanism, by their antiox- idant properties and directly by binding with TLRs. © 2015 Elsevier B.V. All rights reserved. 1. Introduction response. It is also a mediator of endotoxic shock causing the high morbidity and mortality [3]. Cytokines are produced to support In the last decade increasing body of knowledge has accumu- the biological defence system. However, their excessive production lated on pathogenesis and treatment of sepsis. However, it still may evoke organ failure and/or immunosuppression. The cytokine remains a significant problem in modern therapy. Lipopolysac- production can be induced by activation of Toll-like receptors charide (LPS, endotoxin) is a major structural component of the (TLR) for LPS, expressed on the surface of immunity cells. Differ- outer membrane of Gram-negative bacteria. It is responsible for ent human leucocyte populations selectively express the special the organization and stability of the membrane and serves as a type of TLR [4]. Macrophages and neutrophils express TLR and also physical barrier providing the bacteria a protection from the envi- CD14 that recognizes the complex of LPS with lipopolysaccharide ronment. LPS is recognized by the host immune system in response binding protein (LPB). It initiates signalling pathway leading to acti- to bacterial pathogen invasion [1]. Humans are very sensitive to vation of nuclear factor-kappaB (NF-kappaB) and transcription of LPS activity; in patients with sepsis symptoms the estimated con- genes responsible for production of pro-inflammatory mediators centrations of endotoxin in blood ranged 5–500 pg/ml, while in [5]. Inflammation involves the release of variety of mediators to asymptomatic group the concentration of 2.4 ± 1 pg/ml was found combat pathogens but much elevated level of these substances is [2]. LPS is a strong activator of immune system, inducing produc- dangerous and may lead to organ failure. High production of ROS tion of cytokines, e.g. TNF-␣, IL-1, IL-6, or reactive oxygen species and reactive nitrogen species (RNS) is also involved in sepsis [6]. (ROS) that is responsible for the development of inflammatory In physiological state there is equilibrium between ROS generation and their efficient removal by antioxidant defence systems, but this balance is disturbed under oxidative stress conditions associated ∗ with exposure of cells to LPS. A strong stimulation of immune cells Corresponding author. E-mail address: [email protected] (M. Bijak). with endotoxin resulted in oxidative burst (massive ROS and nitric http://dx.doi.org/10.1016/j.ijbiomac.2015.07.039 0141-8130/© 2015 Elsevier B.V. All rights reserved. J. Saluk et al. / International Journal of Biological Macromolecules 80 (2015) 702–709 703 −• oxide (NO) generation) [6]. ROS, including superoxide anion (O2 ), v/v/w) and centrifuged [15,16]. The supernatant (crude red cab- • hydroxyl radical (HO ) and hydrogen peroxide (H2O2), are highly bage extract) was dried in a vacuum rotary evaporator in a water ◦ toxic and they contribute to damage of cells and apoptosis. bath at 40 C. The condensed solution (30 mg/ml) was prepared Searching for new drugs with antioxidant properties that with methanol/H2O/HCl (10/90/1, v/v/w) and then purified on a possess the ability to neutralize LPS toxicity seems to be a proper high load C18 SPE mini-column (Alltech Assoc.) previously acti- direction to combat sepsis. Treatment of sepsis with antibiotics vated with methanol. The samples (1.5 ml) were desalted with that kill pathogens but are not able to inactivate endotoxin can 0.01% aqueous HCl before removal of small phenolics by rinsing be insufficient. It has been suggested that antibiotics can increase with ethyl acetate. Afterward the column was eluted with acidified the release of endotoxin from bacteria cell wall which in extreme methanol gradients in the following order: 10, 20, 50 and 80%. The cases may lead to endotoxic shock [7,8]. Consequently, the systemic volume of solvent applied was always 5 ml per column (3× sam- inflammation can occur as a response of organism to the endo- ple volume). Colourful fractions in 50% methanol were collected toxin damaging effects. Oxidative stress causes peroxidation of cell and analyzed by high-performance liquid chromatography (HPLC). membrane lipids, modification of protein structure and function. This fraction was once again dried in a vacuum rotary evaporator in ◦ Patients with inflammatory diseases often exhibit the modified a water bath at 40 C, and then the condensed aqueous solution of platelet function [9]. Platelets play a key role in haemostasis and 130 mM ATH extract (84% of ATH) was prepared. ATH concentration alterations of their function can lead to cardiovascular diseases in the extracts was determined and verified spectrophotometri- including thrombosis. cally, with the use of cyanidin 3,5-diglucoside as a standard, and −1 −1 ε × We have previously proved that LPS could act as a platelet ago- calculated using absorption coefficient 525 nm = 30 mM cm nist inducing various steps of platelet activation [10–12]. Moreover, [18]. the LPS-induced hyperactivity of platelets has led to overproduc- tion of ROS, the molecules responsible for the formation of highly 2.3. HPLC analysis reactive oxidation products that could be involved in the pathogen- esis of blood platelet-dependent diseases [13,14]. Our preliminary HPLC Knauer system equipped with a UV–Vis detector and 100 18 study [15] has also demonstrated that anthocyanins (ATH) from red a Eurospher- C– column (25 cm × 4.6 mm; 5 ml) was used to cabbage showed antioxidant properties and partly protected both determine the phenolic profiles of red cabbage extract. blood platelets and plasma proteins and lipids against oxidative The binary mobile phase, according to method described by − damage induced by H2O2 or ONOO [16]. Dyrby et al. [19], consisted of water/formic acid (90:10, v/v) (solvent The present study was designed to investigate whether the A) and water/acetonitrile/formic acid (40:50:10, v/v/v) (solvent B). ATH extract isolated from red cabbage leaves can protect human The total run time was 50 min with flow rate 1 ml/min. The gradient blood platelets against oxidative damage caused by LPS (from programme consisted of the following series: 0 min: 88% A + 12% Escherichia coli and from Pseudomonas aeruginosa). We measured B; 26 min: 70% A + 30% B; 40–43 min: 0% A + 100% B; 48–50 min: the commonly used oxidative stress markers, such as the con- 88% A + 12% B. Phenolics were classified in four subclasses and centration of thiobarbituric acid reactive substances (TBARS), quantified by the maximum UV–vis absorption of each of them. generation of superoxide anion, the carbonyl group formation and The hydroxybenzoic acid derivatives were quantified at 280 nm tyrosine residue nitration. The aim of the study was also to explain and expressed as gallic acid equivalents; hydroxycinnamic acid the mechanisms of platelet protection by the ATH extract using derivatives at 320 nm as chlorogenic acid equivalents; flavonols at bioinformatics ligand docking methods. 360 nm as rutin equivalents; and anthocyanins at 520 nm as cyani- din 3,5-diglucoside equivalents [20]. HPLC analysis of the extracts from red cabbage leaves showed the following polyphenol groups: 2. Materials and methods hydroxycinnamic acids (16%) and anthocyanins (84%). Seven ATH- derivatives were clearly detected when the detector was set at 2.1. Materials 520 nm (peaks with the retention times of 9.05; 12.47; 25.02; 28.77; 29.6; 32.72 and 33.73). LPS from E. coli and from P. aeruginosa, rabbit antibody anti-DNP, thrombin, cytochrome c, thiobarbituric acid (TBA), o- 2.4.
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