Marine Polyhydroxynaphthoquinone, Echinochrome A: Prevention of Atherosclerotic Inflammation and Probable Molecular Targets

Aleksandr A Artyukov, Elena A Zelepuga, Larisa N Bogdanovich, Natalia M Lupach, Vyacheslav L Novikov, Tatyana A Rutckova, Emma P Kozlovskaya, Aleksandr A Artyukov, Elena A Zelepuga, Larisa N Bogdanovich, Natalia M Lupach, Vyacheslav L Novikov, Tatyana A Rutckova, Emma P Kozlovskaya

Abstract

The effect of low doses of echinochrome A (EchA), a natural polyhydroxy-1,4-naphthoquinone pigment from the sea urchin Scaphechinus mirabilis, has been studied in clinical trials, when it was used as an active substance of the drug Histochrome® and biologically active supplement Thymarin. Several parameters of lipid metabolism, antioxidant status, and the state of the immune system were analyzed in patients with cardiovascular diseases (CVD), including contaminating atherosclerosis. It has been shown that EchA effectively normalizes lipid metabolism, recovers antioxidant status and reduces atherosclerotic inflammation, regardless of the method of these preparations' administrations. Treatment of EchA has led to the stabilization of patients, improved function of the intracellular matrix and decreased epithelial dysfunction. The increased expression of surface human leukocyte antigen DR isotype (HLA-DR) receptors reflects the intensification of intercellular cooperation of immune cells, as well as an increase in the efficiency of processing and presentation of antigens, while the regulation of CD95 + expression levels suggests the stimulation of cell renewal processes. The immune system goes to a different level of functioning. Computer simulations suggest that EchA, with its aromatic structure of the naphthoquinone nucleus, may be a suitable ligand of the cytosolic aryl cell receptor, which affects the response of the immune system and causes the rapid expression of detoxification enzymes such as CYP and DT diaphorase, which play a protective role with CVD. Therefore, EchA possesses not only an antiradical effect and antioxidant activity, but is also a SOD3 mimetic, producing hydrogen peroxide and controlling the expression of cell enzymes through hypoxia-inducible factors (HIF), peroxisome proliferator-activated receptors (PPARs) and aryl hydrocarbon receptor (AhR).

Keywords: Histochrome; Thymarin; atherosclerosis; cardiovascular diseases (CVD); echinochrome A (EchA); mechanism of action; oxidative stress; polyhydroxy-1,4-naphthoquinones.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Structure of echinochrome A (EchA), K2 and C vitamins.
Figure 2
Figure 2
Indicators of lipid metabolism in patients of the control-volunteers and the main groups (before and after treatment with Histochrome, m ± SD-Standard Deviation). Abbreviations: Cholesterol: cholesterol, mmol/L; TAG: triglycerides, mmol/l; VLDL: cholesterol of very-low-density lipoproteins, mmol/L; LDL: cholesterol of low-density lipoproteins, mmol/L; HDL: cholesterol of high-density lipoproteins, mol/L; APOA1: apolipoprotein A1, g/L; AIP: (total cholesterol − HDL)/HDL. * differences with the control group were reliable at p < 0.05; ** differences before and after treatment were reliable at p < 0.05.
Figure 3
Figure 3
Relative content of lymphocytes expressing the activation and the differentiation markers in the blood in patients of the control-volunteers and experimental groups (before and after treatment with Histochrome, m ± SD). * differences with the control group were reliable at p < 0.05; ** differences before and after treatment were reliable at p < 0.05.
Figure 4
Figure 4
Spatial structural model of EchA complex with the ligand binding domain of human aryl hydrocarbon receptor (huAhR LBD). (A) Ribbon diagram of a structural model of EchA complex with huAhR LBD; EchA molecule is represented as ball and stick, colored according to elements; the hydrophobic cavity surface around the EchA is colored by aromaticity; residues involved in EchA binding represented as sticks and colored by elements. (B) A scheme of EchA intermolecular non-covalent interactions in complex with huAhR LBD; intermolecular non-covalent interactions are shown as dashed lines, and direct hydrogen bonds are colored in green; water-mediated hydrogen bonds in blue; π- alkyl, π-π stacked, and π-π T-shaped interactions in magenta.

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