What are natural astaxanthin used for?

 So far, at least 600 kinds of natural carotenoids have been discovered by human beings. Based on the presence or absence of oxygen in their chemical structures, carotenoids can be divided into two groups: oxygen-containing carotenoids - lutein, including lutein, astaxanthin, etc.; and non-oxygen containing carotenoids - carotene, including β-carotene, lycopene, etc. [1]. --Carotenoids, including β-carotene, lycopene, etc.[1] . Astaxanthin (astaxanthin) is widely found in nature, but it cannot be synthesized by higher organisms and is generally obtained through ingestion. Natural astaxanthin is mainly biosynthesized by microalgae or phytoplankton, and subsequently accumulates in zooplankton and crustaceans, and then appears in higher organisms, such as fish and birds, through predation. Astaxanthin is also synthesized by some enzymes and bacteria, although structural differences exist in the synthesized astaxanthin, as shown in Table 1.

 

Different structures of astaxanthin show significant differences in physiological function, with all-trans astaxanthin being the most stable form and cis-levo-astaxanthin having superior biological activity compared to other structures of astaxanthin [2]. Currently, 95% of the astaxanthin on the market is synthesized using petrochemicals, however, there are no known human safety studies on synthetic astaxanthin and it has never been shown to have any health benefits in human clinical trials, so synthetic astaxanthin is not approved by the FDA as a dietary supplement for humans [3]. Natural astaxanthin extracted from red algae, which is chemically structured mainly in the all-trans levulose form, is currently the main source of astaxanthin as a human dietary supplement[4] . Astaxanthin has been shown to be an optimal preventive and therapeutic agent for a variety of diseases in several clinical studies. This paper reviews the bioavailability and physiological functions of astaxanthin, including antioxidant, anti-inflammatory, cognitive improvement, and DNA damage repair, and attempts to identify knowledge gaps in astaxanthin bioactivities in the current research to provide theoretical guidance for functional studies of astaxanthin.

 

1 Bioavailability of astaxanthin

Because astaxanthin is hydrophobic, its intestinal absorption mechanism is similar to that of dietary lipids. Astaxanthin is separated from its protein conjugates by the action of digestive enzymes in the gastrointestinal tract of animals and is emulsified with other lipids in the duodenum by bile to form chyme particles, which automatically diffuse to the surface of the intestinal wall and are then absorbed by the intestinal mucosal cells and subsequently released into the lymphatic system. Once the lipoprotein lipase in the liver digests the chyme, astaxanthin assimilates with lipoproteins, particularly LDL, and is further distributed to other tissues[5] . The absorption of astaxanthin is influenced by its chemical nature and by dietary and non-dietary related parameters[1] . As shown in Table 2, the form in which it is present and whether it is bound to other compounds (e.g., proteins, fats) is a direct factor affecting the extent of astaxanthin absorption; indirectly, it is affected by the fact that heat or compression can result in the disruption of the cell wall and thus facilitate the release of astaxanthin; and any disease associated with abnormal absorption of fats from the digestive tract significantly affects astaxanthin absorption as the body ages[6].

 

After being absorbed and metabolized by intestinal epithelial cells, astaxanthin is found in different states in the plasma. It has been reported that after astaxanthin intake, the cis-isomer of astaxanthin is significantly higher than the all-trans-isomer of astaxanthin in the blood[7] , but the reason for this was not analyzed. According to the latest research results, the cis-isomers of astaxanthin in human plasma are mainly the 13-cis-isomer and the 9-cis-isomer. The higher plasma levels of cis-isomers are due to the fact that after ingestion of all-trans-astaxanthin-based foods, all-trans-astaxanthin isomerizes into cis-isomers due to a variety of factors in the process of digestion and absorption in the body. The cis-isomers are beneficial for their use as cis-isomers, since cis-astaxanthin has a high bioavailability and high cellular secretion rate, which can be beneficial for their use in the blood. The cis-type astaxanthin has a high bioavailability and a high cellular secretion rate, which is favorable for its absorption in the human body [8]. The geometric isomerization of astaxanthin in humans has been demonstrated, but there are few reports on the stereoisomerization of astaxanthin in humans, and the question of whether astaxanthin exists in the levorotatory or dextrorotatory form has not yet been identified, which is of interest.

 

2 Physiological functions of astaxanthin

2.1 Antioxidant activity

Astaxanthin neutralizes free radicals or other oxidants by accepting or supplying electrons and is not destroyed or becomes a pro-oxidant in the process. Its linear, polar-non-polar molecular layout allows it to insert itself precisely into membranes and span their entire width without disrupting the cell membranes[9] , and these properties of astaxanthin provide the basis for its in vivo antioxidant effects. Free radicals, most of which are oxygen radicals, are generated during human life movement, and the seizure of electrons from cells in the body is a key factor in the triggering of various diseases, and the presence of antioxidants is essential for eliminating excessive free radicals in the human body [10]. Table 3 shows a comparison of the free radical scavenging ability of natural antioxidants. Based on the current study, astaxanthin is the most suitable scavenger for scavenging mono-linear oxygen radicals and superoxide anion radicals in comparison to other natural antioxidants. During unilinear oxygen quenching, energy is transferred from unilinear oxygen to astaxanthin molecules, and the energy-rich astaxanthin molecules return to the ground state by converting energy into heat, leaving the astaxanthin molecule intact and ready for the next unilinear oxygen quenching [17]. B. Capelli et al. [14], in an assay to determine scavenging of superoxide anionic radicals by natural antioxidants, showed that the ability of natural antioxidants to scavenge superoxide anionic radicals is more important than that of vitamins C, E, and E, and that they are better at doing so. B. Capelli et al. [14] showed that astaxanthin was not only 14-16 times more active in scavenging free radicals than vitamin C, vitamin E, β-carotene, and Angelica dahurica, but was also about 20 times more active in scavenging free radicals than synthetic astaxanthin. However, a recent study contradicts the findings of B. Capelli et al. and Janina Dose et al. [18], who showed that synthetic astaxanthin was not able to scavenge superoxide anion radicals. This discrepancy may be due to differences in experimental methods or conditions, or to the fact that synthetic astaxanthin does not have an antioxidant capacity. Whether the antioxidant capacity is related to the purity of the antioxidant has not been shown in the literature.

 

2.2 Anti-inflammatory activity

Inflammation is a key part of healthy immune function, but chronic inflammation is often considered the root cause of a variety of health problems, including atherosclerosis, skin damage, neurodegeneration, tumors, and immune dysregulation, etc. Astaxanthin's ability to travel throughout the body allows it to target many areas of high stress inflammation, such as the heart, brain, eyes, and skin, and thus exert its anti-inflammatory effects. Table 4 shows experimental studies on the anti-inflammatory activity of astaxanthin.

 

Atherosclerosis (AS) is a major cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. Recent studies of AS have focused on inflammation, providing new insights into the mechanisms of the disease. It has been suggested that AS is a disease characterized by chronic inflammatory changes, and that many inflammatory signaling pathways are involved in the early onset of AS, progression of lesions, and ultimately acute complications [27]. Astaxanthin's ability to attenuate excessive hepatic lipid accumulation and peroxidation and activate stellate cells to ameliorate hepatic inflammation and fibrosis[19] may make it a novel and promising therapeutic agent for atherosclerosis. Sustained oxidative stress is a key mechanism for chronic inflammation. Ultraviolet (UV)-induced skin inflammation is mainly due to the production of intracellular reactive nitrogen/oxygen species and keratinocyte apoptosis. Astaxanthin causes a significant decrease in the levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and reduces the release of prostaglandin E2 from keratinocytes after UV irradiation, which inhibits apoptosis of keratinocytes [20]. The inhibitory effect of astaxanthin on iNOS is important for the development of skin anti-inflammatory drugs in inflammatory diseases. Increased concentrations of pro-inflammatory factors and decreased production of anti-inflammatory mediators characterize the aging brain, and are also a pathological feature of many neurodegenerative diseases. Microglia are resident macrophages in the brain and are closely involved in the CNS immune response [28]. With age, the CNS response becomes dysregulated and is characterized by an elevated basal output of proinflammatory factors in the absence of immune stimulation and an insensitivity to regulatory signals that terminate microglia activation, resulting in neural tissue damage [27]. Astaxanthin can specifically regulate microglia function, and Balietti et al. [22] observed that astaxanthin reduced IL-1β in the hippocampus and cerebellum of aged female rats and increased IL-10 in the cerebellum of females and the hippocampus of males by feeding astaxanthin to aged rats, suggesting that supplementation with astaxanthin can differentially alter cytokine activity in the sexes for the treatment of neurological disorders. This suggests that astaxanthin supplementation can alter cytokine activity differently in different sexes, thus achieving the goal of treating neurological diseases.

 

Chronic inflammation is also one of the hallmarks of cancer. The inflammatory response is usually associated with a microbiological response, and there are numerous bacterial strains in the gut that usually coexist harmoniously with the host, but any substantial change in the bacterial community can have a considerable impact on the inflammatory response and promote tumor development [29]. Recently, it has been shown that astaxanthin (100 mg/kg) can inhibit tumor growth by suppressing the growth of Lactobacillus species in prostate cancer patients and benign prostatic hyperplasia, whereas the number of specific strains of Lactobacillus species is similar, with significant differences between groups [24]. Immune cells are particularly sensitive to oxidative stress because they contain a high percentage of polyunsaturated fatty acids in their plasma membrane, which normally produces more oxidized products.  Excessive production of reactive oxygen and nitrogen species can lead to an imbalance in the balance of oxidants and antioxidants in the body, resulting in the destruction of cell membranes, proteins and DNA [30]. Astaxanthin can significantly affect the immune function. In a high-temperature stress test, dietary astaxanthin supplementation (80-320 mg/kg) significantly increased the expression of SOD, CAT, and HSP70 genes in pufferfish, inhibited high-temperature-induced ROS production, and improved the growth performance of the pufferfish, as well as enhanced its non-specific immunity [25]. In addition, the immunomodulatory effect of astaxanthin can also be applied to specific immunity. Liu Yingfen et al. [26] demonstrated that astaxanthin from the red algae Rhodococcus aureus was able to enhance the proliferation of lymphocytes and other specific immune responses in a test to investigate the immunity of astaxanthin in mice.

 

2.3 Improvement of cognitive abilities

Doxorubicin (DOX) is one of the most effective and essential antitumor drugs approved by the FDA for the treatment of many cancers [31]. Despite its outstanding clinical effects, DOX is associated with strong neurotoxicity in the form of memory deficits, slowed reflexes, poor concentration, and speech difficulties. It has been demonstrated that treatment with astaxanthin (25 mg/kg) can prevent DOX-induced cognitive disorders by stopping DOX-induced oxidative and inflammatory damage, preventing the release of inflammatory mediators, inhibiting the activation of neuroglial cells, and inhibiting the overactive AChE enzyme, while preserving the integrity of mitochondria [32]. The mechanism is shown in Figure 1. Traumatic brain injury (TBI) is a disease that seriously jeopardizes human health, and its pathogenesis is based on a cascade of direct physical trauma or secondary injury that induces neuronal cell death and activates chronic inflammation, ultimately leading to neurodegeneration, which has a serious impact on the body's motor, cognitive, and intellectual functions [33]. It has been found that oral administration of AST to TBI models reduces lesion size and neuronal loss in the cortex, restores the levels of brain-derived neurotrophic factors, synaptophysin and synapsin in the cerebral cortex, and improves neuronal survival and plasticity, thereby promoting the recovery of cognitive functions [34].

 

2.4 Repair of DNA damage

Human cells produce a large number of different types of DNA damage on a daily basis in response to exogenous and endogenous DNA damage factors, and there are comprehensive DNA repair mechanisms within the human cell to respond to these damages and to restore DNA integrity and fidelity to maintain genetic stability.The DNA damage response is a cornerstone of the cell's ability to maintain genome stability, and defects in this response lead to the development and progression of many diseases, including cancer. The DNA damage response is the cornerstone of the cell's genomic stability, and its defects can lead to the development of many diseases, including cancer. Cyclophosphamide is a widely used alkylating agent in cancer therapy. However, it exhibits severe cytotoxicity to normal cells in humans and experimental animals, and its toxic effects are associated with genomic instability and DNA damage. Astaxanthin has been shown to protect against cyclophosphamide-induced oxidative stress and DNA damage by activating the Nrf2 signaling pathway and regulating the gene expression of NQO-1 and HO-1 [35]. Protein kinase B plays an important role in the regulation of DNA damage response and genome stability, and studies have shown that inhibition of protein kinase B activity affects the repair of DNA double-strand breaks, whereas astaxanthin regulates the protein kinase B signaling pathway, which helps to maintain genome stability and counteract DNA damage [3].

 

3 Conclusion

Natural astaxanthin has been shown to be a safe and bioavailable compound in toxicological tests. Astaxanthin products are widely consumed as dietary supplements in Europe, Japan, and the United States, and the FDA recommends an optimal intake of 4-6 mg of astaxanthin per day, with a maximum intake of 12 mg[3] . Meanwhile, astaxanthin has a good market in many fields such as cosmetics (creams, lip balms, etc.), the feed industry (feed additives), the pharmaceutical industry (Cyanotech (USA) has introduced astaxanthin medicines to alleviate exercise fatigue), and the food industry (coloring).

Based on the above references and experimental data (which are not comprehensive), the following experimental shortcomings and salient issues may exist in astaxanthin research, and exploring different solutions to address these shortcomings could help make astaxanthin a valuable option for the prevention and treatment of various acute and chronic diseases.

(1) Experimental data are needed to identify the state in which astaxanthin is produced, including cis-trans isomers of astaxanthin and degradation or oxidation products of astaxanthin.

(2) Optimal prophylactic/therapeutic doses of astaxanthin for in vivo testing require experimental support.

(3) Fewer studies have been conducted on the combined effects of astaxanthin and drugs.

(4) Do different sources of astaxanthin have different effects when used in the same experiment?

(5) Lack of studies on excretion of astaxanthin after astaxanthin interventions in the body.

(6) What happens to astaxanthin when the astaxanthin intervention in the body is terminated?

(7) In what state (solid, semi-solid, liquid) does astaxanthin enter the body when taken?

 

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