Can red algae astaxanthin be anti-inflammatory?

 Red chlorella is rich in natural astaxanthin with levulin structure, which has been listed as a new resource food with nutritional and food safety in China. In the case of the new coronavirus pneumonia (COVID⁃19) outbreak, when there is no specific treatment drug yet, dietary supplementation with new biological products with clear structure, homologous medicinal and food sources, and obvious efficacy has positive significance in strengthening health, preventing the new coronavirus disease, alleviating its symptoms, and speeding up the recovery.

 

1 Basic properties of astaxanthin

Astaxanthin is an oxidized derivative of carotenoids (chemical name 3,3 ′ ⁃ dihydroxy ⁃ 4,4 ′ ⁃ diketo ⁃ β , β ′ ⁃ carotenoids), with the molecular formula C40H52O4 and molecular weight 596.86, belonging to tetraterpene organic compounds, and it contains a conjugated π-bond composed of 13 unsaturated bonds in the molecule [Fig. 1 (a)], which is also the compound with the most known conjugated double bond in the natural world. This is also the compound with the largest number of conjugated double bonds known in nature. The hydroxyl groups at both ends of the head give it hydrophilicity, and the hydrocarbon chains in the middle of the molecule give it hydrophobicity, so the whole astaxanthin molecule has both hydrophilic and hydrophobic characteristics. Astaxanthin is also known to be the only carotenoid organic molecule that can cross the three major barriers of the human blood brain, blood pancreas and blood testis. Astaxanthin has superb antioxidant properties, and its antioxidant capacity is usually 550~1000 times that of the traditional antioxidant vitamin E [Fig. 1(b)], and it is also the organic molecule with the strongest antioxidant capacity among edible substances known to mankind. Astaxanthin can cross the cell membrane and embedded in the cell membrane [Figure 1(c)] [1], can capture active free radicals from inside, outside and in the middle of the cell membrane, protect the cell membrane, enhance the biological function of the membrane, and protect the cell membrane from oxidative damage.

 

The optical isomer of astaxanthin from red algae is a left-spin structure, which is completely different from the right-spin structure of astaxanthin produced by fermentation of other fungi, and the composition of 1/4 left-spin isomer, 1/4 right-spin isomer, and 1/2 endocyclic isomer is significantly different from that of artificially synthesized astaxanthin, so the astaxanthin from red algae is natural and medicinal and food homologous and it combines nutritive function and various biological effects. Astaxanthin from red chlorella has been listed as a new resource food in China. The large-scale cultivation of red chlorella and astaxanthin production has been industrialized and gradually matured in China, and commercialization is also gradually emerging. As a powerful antioxidant, astaxanthin has been shown in a series of animal experiments to play an obvious role in reducing various types of inflammation and lung diseases, protecting important organs and regulating immunity.

 

2 Role of Astaxanthin in Reducing Inflammatory Hyperresponses

When tissues and organs are stimulated by injury, bleeding or pathogenic infection, local inflammation such as redness, swelling, fever and pain will typically occur; and when the inflammation is severe, it will be accompanied by systemic reactions and symptoms such as fever and leukocytosis. These are normal physiological reactions. The local redness and swelling is due to the increased blood flow, increased fluid and accelerated blood circulation, which can bring more white blood cells to flow from the blood vessels to the tissues to kill pathogens; at the same time, with the help of blood circulation, it can take away more metabolic wastes and remove foreign bodies and cell debris.

 

When the body's immune system senses an invasion, the immune cells secrete cytokines that promote the production and mobilization of immune proteins by the immune cells. Cytokines include pro-inflammatory cytokines (which activate a variety of immune cells to promote inflammation) and anti-inflammatory cytokines (which activate certain cells to regulate the inflammatory response). The balance between the two maintains homeostasis, while an imbalance between the two leads to disruption of the immune system, sepsis, shock, and even death.

 

2.1 Astaxanthin inhibits the inflammatory response in sepsis

In mice, astaxanthin pretreatment significantly reduces the mortality of septic mice, inhibits the inflammatory response to sepsis by inhibiting the release of inflammatory factors, reduces the functional damage of various tissues and organs, and protects the function of vital organs [2]. Astaxanthin reduces the inflammatory and oxidative responses in sepsis-induced mice, reduces organ damage, decreases the bacterial load in the abdominal cavity, and improves the survival rate of rats with cecal ligation and puncture (CLP)-induced sepsis [3].

 

2.2 Astaxanthin inhibits the release of pro-inflammatory factors in human serum

In humans (soccer players during winter training), astaxanthin can effectively inhibit the release of serum pro-inflammatory factors, increase the level of serum inflammatory inhibitory factors, and improve the inflammatory response [4]. In mice, astaxanthin can increase cardiac mitochondrial membrane potential (MMP), and reduce the level of plasma interleukin IL ⁃ 1α, tumor necrosis factor TNF ⁃ α and other inflammatory factors, so as to play a certain cardioprotective effect [5].

 

2.3 Astaxanthin has attenuating and inhibiting effects on various types of inflammatory responses

Different animal models have shown that astaxanthin has both attenuating and inhibiting effects on various types of inflammation (Table 1).

 

2.4 Astaxanthin reduces liver inflammation and liver damage by inhibiting inflammatory factors

In mice, astaxanthin reduces serum liver enzymes and pathological damage by inhibiting the release of inflammatory factors (e.g., TNF ⁃ α, IL ⁃ 6, IL ⁃ 1 β, and IFN ⁃ γ), and decreases the phosphorylation of the B lymphocytoma ⁃ 2 protein (Bcl ⁃ 2) by down-regulation of the TNF ⁃ α-mediated JNK/p ⁃ JNK pathway, thereby exerting an anti-apoptotic effect on autoimmune hepatitis induced by ConA [18]. ConA-induced autoimmune hepatitis [18]. In streptozotocin-induced diabetic rats, astaxanthin inhibited diabetes-induced hepatic impairment by preventing the formation of advanced glycosylation end products and by exerting anti-inflammatory effects [19]. Astaxanthin can regulate the expression of antioxidant enzyme mRNA in liver tissue, thereby alleviating LPS-induced oxidative stress in the liver, reducing acute liver injury, protecting the morphology of mouse hepatocytes, and increasing the level of antioxidant activity in the liver [20].

 

Astaxanthin has a significant protective effect on acetaminophen-induced liver injury in mice, and its mechanism of action may be that astaxanthin can inhibit the inflammatory response induced by high doses of acetaminophen, repair damaged cell membranes, reduce the permeability of hepatocyte membranes, and reduce the content of transaminases, and it can also inhibit the reaction of lipid peroxidation as well as increase the activity of enzymes in the body such as superoxide dichibutyrosinase (SOD), glutathione peroxidase (GSH ⁃Px) and other enzymes in the body, thereby protecting the liver [21-22]. In rats, astaxanthin reduces the levels of malondialdehyde (MDA) and glutathione sulfotransferase (GST), increases the levels of glutathione (GSH) and the activity of SOD, and improves the antioxidant capacity to alleviate carbon tetrachloride-induced chronic liver injury in rats [23]. In mice, astaxanthin significantly improves the internal environment of liver and intestinal tissues by regulating the expression of genes and proteins of a series of inflammation-related signaling pathways, affecting the balance of the structure and composition of the intestinal flora, and promoting the decrease of pro-inflammatory factors in the blood, which leads to a significant decrease of endotoxin content in the blood, a significant increase of lipocalin content, a significant decrease of the level of enzymes related to liver injury and fat accumulation, and a reduction of a series of changes such as the reduction of the phenomenon of fat accumulation in the liver tissue. A series of changes, such as the decrease of pro-inflammatory factors in the blood of mice, the significant decrease of endotoxin content in the blood, the significant increase of lipocalin content, the significant decrease of liver injury and fat accumulation related enzymes, the reduction of fat accumulation in liver tissues, confirmed that astaxanthin has an obvious protective effect on alcoholic liver injury [24].

 

2.5 Astaxanthin combination products can also inhibit a variety of other inflammatory responses.

In mice, astaxanthin shows the following functions: significantly reduce the swelling of mouse auricle, can inhibit the edema and tissue fluid exudation in the early stage of inflammation, and has certain anti-acute inflammation; significantly reduce the weight of rat granuloma, have the ability to inhibit the generation of granuloma in the late stage of inflammation, and play a certain inhibitory role in the proliferative stage of inflammation; have significant inhibitory effect on the acute pleurisy induced by carrageenan; have a significant preventive and therapeutic effect on the arthritis in the rat model of collagenous arthritis (CIA), and have obvious anti-inflammatory and swelling effects. It has significant preventive and therapeutic effects on the arthritis of collagenous arthritis rat (CIA) model, and has obvious anti-inflammatory and swelling effects, which can reduce or slow down the inflammatory reaction, and promote the absorption and dissipation of foot-plantar inflammation and swelling [25].

 

2.6 Human observation

Astaxanthin supplementation prior to exercise was found to enhance salivary immunoglobulin (IgA) response and reduce muscle damage in young soccer players, thereby avoiding inflammation caused by rigorous physical training; furthermore, astaxanthin exerted significant physiological modulation in individuals with mucosal immune damage [26]. In young women, astaxanthin reduces markers of DNA damage and acute-phase proteins, stimulates schizophrenin-induced lymphocyte proliferation, increases the cytotoxicity of natural killer cells, and increases the total number of T-cells and B-cell subpopulations, resulting in an improved immune response [27].

Astaxanthin has been studied in different mammalian organisms (mice, rats, humans) in different organ tissues (liver, intestines, nerves, heart, blood, ear, skin, etc.) as well as in different cell lines, and it has been found that astaxanthin reduces the production of pro-inflammatory factors, inhibits inflammation, or promotes the inhibition of the production of pro-inflammatory factors, and maintains the dynamic balance between pro-inflammatory factors and anti-inflammatory factors, avoiding the occurrence of inflammatory stimuli and damage. It can reduce the production of pro-inflammatory factors, inhibit inflammation, or promote the inhibition of the production of inflammatory factors, maintain the dynamic balance between pro-inflammatory factors and anti-inflammatory factors, and avoid the occurrence of inflammatory overreaction and injury. It can be predicted that dietary supplementation with astaxanthin from the new resource food Rhodococcus erythropolis can effectively reduce and minimize the inflammatory response caused by COVID⁃19.

 

3 Astaxanthin and Lung Disease (Reduction of Acute Lung Injury, Lung Fibrosis, Lung Cancer, etc.)

3.1 Astaxanthin improves acute lung injury

In mice, astaxanthin protects against LPS-induced acute lung injury by modulating the release of pro-inflammatory and anti-inflammatory factors and antagonizing oxidative stress. Astaxanthin reduced the LPS-induced increases in blood TNF⁃α, IL⁃8, MPO, MDA, and the wet weight/dry weight ratio of lung tissue, and inhibited the reduction of IL⁃10, blood SOD, and GSH⁃Px activity, and improved the distribution of lymphocyte subsets in the blood [28]. Astaxanthin significantly attenuated acute lung injury in mice caused by CLP, and its mechanism may be related to the inhibition of inflammation, oxidative/nitrative stress, and apoptosis of lung cells by astaxanthin [29].

 

3.2 Astaxanthin reduces pulmonary fibrosis

In mice, astaxanthin effectively attenuates radiogenic pulmonary fibrosis by increasing the antioxidant capacity of the body and down-regulating the expression of the pro-fibrotic factor TFF⁃β1 [30]. In rats, astaxanthin significantly inhibited bleomycin-induced pulmonary fibrosis by decreasing the level of transforming growth factor ⁃β1 (TGF ⁃β1) and down-regulating the Smads/ERK pathway [31-32]. Astaxanthin inhibits lung parenchymal deformation and collagen deposition, and prevents pulmonary fibrosis by promoting apoptosis of myofibroblasts, which is dependent on the mitochondrial kinetic protein Drp⁃1 to mediate mitochondrial division [33]. In vitro and in vivo, astaxanthin can significantly improve the alveolar structure in vivo, reduce collagen deposition, and alleviate or prevent pulmonary fibrosis by preventing the differentiation and transfer of activated cells, inhibiting proliferation, and promoting apoptosis [34].

 

3.3 Astaxanthin inhibits lung cancer cells

In nude mice, astaxanthin controls tumor cell proliferation, inhibits tumor cell metastasis, causes tumor cell apoptosis, and enhances the antitumor effect of the organism by mediating the expression of Bcl ⁃2, Bcl ⁃2-related X protein (Bax), and vascular endothelial growth factor-related protein (VEGF ⁃C). Medium and high doses of astaxanthin have therapeutic effects on human lung cancer A549 nude mice transplanted tumors, and the best therapeutic effect is achieved with high doses of astaxanthin [35]. In NSCLC (Non ⁃ small cell lung cancer) cells, astaxanthin enhances the cytotoxicity of Pemetrexed (an anticancer drug) in lung cancer cells by down-regulating the expression of MKK1/2 ⁃ ERK1/2-mediated thymidylate synthase [36]. Astaxanthin can enhance the cytotoxicity of mitomycin C (Mitomycin ⁃C) on human non ⁃small cell lung cancer cells by decreasing the activity of AKT kinase and down-regulating the expression of Rad51, a DNA double-strand break repair protein [37]. The feeding of astaxanthin to tumor-bearing mice confirmed the inhibitory effect of astaxanthin on the lung metastasis of melanoma cells and increased the survival rate of the model mice [38].

 

From the above studies, it is easy to find that astaxanthin from red algae has functional effects such as improving acute lung injury, reducing pulmonary fibrosis and inhibiting lung cancer. In the absence of effective therapeutic drugs for COVID⁃19, dietary supplementation of new biological products with clear structure, homology of medicine and food, and obvious efficacy is of great practical significance in enhancing health, preventing/postponing and mitigating COVID⁃19 diseases, and accelerating physical recovery.

 

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