BINMEI, global leader in blue spirulina

Abstract: in the past 40 years, the important role of oxidative stress in the occurrence and deterioration of many diseases has been widely concerned. The oxidative stress caused by harmful stimulation is related to the occurrence of many diseases such as atherosclerosis, hepatitis, pneumonia, Alzheimer’s disease, cataract, and so on. As a natural product extracted from algae, phycocyanin is often used as a health product and food additive. Studies have found that phycocyanin can eliminate free radicals and reduce oxidative stress. In this paper, the therapeutic or preventive effect of phycocyanin on oxidative stress-related diseases is reviewed, and its application prospect is prospected to provide reference for the application of the active protein.

Keywords: oxidative stress; phycocyanin; mechanism

More and more studies have shown that oxidative stress and the occurrence and development of many diseases. The accelerated pace of life, increased stress, serious environmental pollution, increased harmful substances in the living environment, exposure to ultraviolet radiation, and inflammation of the body can lead to excessive reactive oxygen species and oxidative stress-induced diseases. oxidative stress (os) refers to the excessive production of reactive oxygen free radicals (ros), which are highly active in the body after being subjected to harmful stimuli, and the imbalance of oxidation and oxidation in the body and the tendency to oxidize, which can cause DNA oxidative damage, neutrophil inflammatory infiltration, abnormal expression of the protein, and thus cause a variety of diseases. Finding a drug or functional food that can reduce oxidative stress to prevent and cure diseases becomes an urgent question. phycocyanin (pc) is a multifunctional natural product with antioxidant, anti-inflammatory, anti-tumor, and other effects (2). many studies have shown that phycocyanin can reduce the occurrence of disease and slow the deterioration of disease to some extent by reducing oxidative stress. Compared with many chemical drugs, phycocyanin is a non-toxic and harmless natural product called a better choice for the prevention and treatment of oxidative stress-related diseases. In this paper, the possible diseases caused by oxidative stress, and the effect and mechanism of phycocyanin on its prevention and treatment are summarized.

1 Oxidative stress and disease

In normal physiological conditions, the cell’s normal redox process produces a certain amount of reactive oxygen species, as well as a series of Antioxidants such as superoxide dismutase (SOD), catalase, glutathione reductase, and glutathione peroxidase, which eliminate harmful substances produced by organisms during metabolism, and non-enzymatic antioxidants such as excessive metalloproteins, pan-enzyme reducing substances, and vitamins, can remove ROS to achieve the leveling of the oxidation system and antioxidant systems. oxidative stress is the imbalance of the body’s oxidation and antioxidant capacity, which causes the oxygen free radicals in the body’s tissues or cells to increase or cause a large accumulation of ros in tissues or cells due to the reduction of scavenging ability. the excessive accumulation of ros can cause a series of oxidative damage leading to multiple diseases (figure 1). after oxidative stress occurs in the body, it will produce a variety of toxic metabolites, such as malondialdehyde (MDA), the end product of lipid peroxidation reaction, is a toxic end product, which can cause crosslinking polymerization of life macromolecules such as proteins and nucleic acids to produce cytotoxicity. its content directly reflects the intensity and rate of lipid peroxidation in the body, and indirectly reflects the ability of the body to scavenge free radicals. A large number of studies have shown that in cancer, cardiovascular and cerebrovascular diseases, type II diabetes, cataracts, Alzheimer’s disease and other diseases of the pathogenesis of a large number of diseases are significant ros response was enhanced, while the level of oxidative stress injury index (e.g., mda in serum) was significantly increased (3). therefore, the use of highly active, multifunctional antioxidants to remove ros and alleviate oxidative stress response has become a new idea for the treatment of multiple diseases ^[1].

2Overview of phycocyanin and its relation to reducing oxidative stress

The phycocyanin is a kind of light-harvesting  protein ——, which is widely found in cyanobacteria and red algae. Spirulina blue protein usually consists of two subunits, and the molecular weight of the subunits is about 15 kD.the four-adjacent structure of the algal blue egg white-haired chromophore is similar to that of the animal erythrocyte heme structure. the peptide chain covalently binds an open chain of four-paragons cyclocross, the four-paradox compounds of the open chain, and the deadnexin through the sulfur bond junction. Spirulina blue protein soluble in white water, blue in the solution, with a special absorption peak at 620 nm, can be used A₂₆₀/A₂₈₀ indicating its purity. phycocyanin in addition to antioxidant, anti-inflammatory, anti-tumor properties, song life, etc^.[7] the long-term toxicity of natural phycocyanin to rats was tested. the experimental results proved that phycocyanin was not toxic. Wang Xueqing et al.^[4] proved that phycocyanin peptides were non-toxic to normal cells.

For the first time, Romay et al.^[8] made a comprehensive evaluation of the potential of phycocyanin as an antioxidant in vivo and in vitro in 1998. In 1999, Romay et al reported that phycocyanin could act on phagocyte respiratory burst by reducing free radicals (OH, H2O2, RO) and too many peroxides to inhibit luminous antioxidative of Luminol under alkaline conditions. In the following 20 years of studies on the physiological activity of phycocyanin, the antioxidative activity of phycocyanin was also studied. these mechanisms are linked to the imbalance between the oxidative system and the antioxidant system caused by oxidative stress, so phycocyanin has the potential to treat a variety of diseases caused by oxidative stress (Figure 2).

3Effect of phycocyanin on oxidative stress-related diseases

3.1 Effect and mechanism of phycocyanin on oxidative stress-induced atherosclerosis

The occurrence and development of Atherosclerosis (As) involved in oxidative stress is a complex process, as one of the causes of atherosclerosis, ROS and other pathogenic factors through synergistic action, resulting in micro-injury of blood vessels, but also toxic to vascular wall cells, the determination shows that when the free radicals and lipid peroxidation products in the blood of model animals or patients are increased, the LDL in the blood is easily attacked and modified by ROS, and the modified components have a stronger effect on pulse actuation sclerosis. Researchers detected modified components at the blood and focus of patients and model animals, demonstrating that ROS may be one of the causes of atherosclerosis^[11].

ROS associated with atherosclerosis has multiple sources, such as nicotinamide gland verbose nucleic acid oxidase, endothelial nitric oxide synthase, xanthate oxidase, myeloperoxidase, in which the main body that generates ros in the blood vessels is nicotinamide glandular silencing nucleic acid oxidase ^[13]. Algae proteins may have a therapeutic effect on atherosclerosis by weakening oxidative stress, according to Riss et al.^[13]. Oral administration of Spirulina blue protein may increase the antioxidant capacity of plasma by increasing the level of antioxidant enzymes in the body and inhibiting the free radicals of reactive oxygen species, but also reduce the expression of nicotinamide adenosine dinuclear oxidase, reducing the production of ROS and reducing atherosclerosis caused by oxidative stress. Heme oxygenase-1 can metabolize heme, produce potent antioxidative bilirubin, Strasky and so on can be experimentally found that mouse oral phycocyanin can activate heme oxygenase-1, increase the expression of heme oxygenase-1 in apolipoprotein E gene-deficient mouse atherosclerosis, reduce lesions, and phycocyanin can also regulate oxidative stress and endothelial cell dysfunction of marker proteins, such as endothelial nitric oxide synthase and nicotinic acid oxidase, which provide new ideas for reducing atherosclerosis in phycocyanin.

3.2Effect and mechanism of phycocyanin on liver disease induced by oxidative stress

oxidative stress can lead to membrane lipid peroxidation, thereby altering biofilm activity, disrupting enzyme activity, and causing liver damage under the combined action of cytokines tnf-a and nf-kb. Therefore, oxidative stress plays an important role in the pathogenesis and development of liver diseases such as fatty liver, viral hepatitis, and liver fibrosis .” accumulation of fat in hepatocytes caused by insular resistance and imbalance of fat metabolism; the second blow is that environmental stressors and metabolic stressors damage hepatocyte mitochondria to produce oxidative stress and cause steatohepatitis under the action of multiple cytokines, and may trigger further steatohepatitis and steatohepatitis. Although the pathogenesis of the liver disease is complex and not fully explained, oxidative stress plays an important role in it. Studies have shown that excessive ROS can destroy the oxidative system in the liver, and ROS can initiate growth transforming factor β (transforming growth factor β), TGF [3], NK-kB, interleukin-8(interleukin-8, IL-8). Increased ROS can also cause intracellular ATP failure and impaired mitochondrial oxidation capacity, which will affect the oxidation of acetaldehyde. causing acetaldehyde to accumulate continuously in the liver, causing damage to the liver. Therefore, oxidative stress is closely related to a variety of liver diseases, reducing oxidative stress, can reduce liver injury.

Pak et al the ros and inflammatory factors were significantly increased in the rat liver mitochondria of the nonalcoholic fatty liver model group, whereas the ros of the phycocyanin treatment group showed no significant changes compared with the blank control group, suggesting that phycocyanin could inhibit the development of the nonalcoholic fatty liver disease by reducing oxidative stress and inflammation. Studies on the protective effect of phycocyanin on the alcoholic fatty liver by Xia et al.^[18] showed that administration of phycocyanin in mice could inhibit the activity of serum alanine aminotransferase (alt), aspartate、 aminotransferase (AST), triglyceride (TG) and total cholesterol, chol), low-density lipoprotein (low-density lipoprotein, LDL), and can increase SOD in the liver and decrease malondialdehyde (malondialdehyde, MDA), thereby reducing oxidative stress. ou et al. proved in vivo and in vitro experiments that phycocyanin (gavage) can also alleviate liver injury caused by cc by scavenging ros and enhancing the activity of sod and glutathione peroxidase (gsh-px).

3.3Effect and mechanism of phycocyanin on oxidative stress-induced cataract

Cataract (Cataract) is one of the most common eye diseases, and patients have blurred vision loss due to lens protein degeneration and turbidity, which can seriously lead to blindness.^[20]. The pathogenesis of cataract is complex and is closely related to the age, family heredity, physical and chemical injury, and immune-inflammatory response. Among them, the change of oxidation index in cataract patients has attracted the attention of scholars, the imbalance of oxidation and antioxidant system in patients produces oxidative stress response, which may be caused by lens protein degeneration. One of the causes of cataracts, so reducing levels of oxidative stress is also an effective way to treat cataracts^[22].

phycocyanin as an antioxidant has also played a certain role in improving cataracts. kothadia et al. si found that phycocyanin can alleviate galactose-induced cataracts by increasing gsh expression and eliminating free radicals.Kumari et al. can use sodium selenite to induce cataract in rats, followed by the treatment of phycocyanin in rats. the results show that phycocyanin can regulate antioxidant enzyme expression, increase antioxidant enzyme activity, reduce oxidative stress response, and reduce the deterioration degree of cataract induced by sodium selenite.

3.4Effect of phycocyanin on neuropathy caused by oxidative stress and its mechanism

In the event of oxidative stress, excessive ROS causes lipid peroxidation in the neuronal cell membrane, while increasing the permeability of the cell membrane, the possibility of toxic edema in neuronal cells increases, resulting in damage to neurons ^[25]. Studies have shown that in animal models of aging, Parkinson’s, depression, oxidative stress index SOD content decreased, MDA content increased, and oxidative stress increased in animals, indicating that oxidative stress may be a common basis for three diseases. In addition, studies have shown that oxidative stress plays an important role in neurological diseases such as cerebral ischemia and reperfusion injury, Alzheimer’s disease SI and epilepsy 3-28. Therefore, the anti-oxidation intervention for patients with neurological diseases can also achieve a better therapeutic effect.

Min et al.^[29] Experiments have shown that the administration of mouse phycocyanin through the nasal cavity protects the brain from oxidative damage.Birnbaum et al. Studies have shown that oral phycocyanin can reduce epilepsy by eliminating free radicals. red alginate can produce a large number of reactive oxygen free radicals, resulting in epilepsy in rats, Rimbaud et al.^[30] using red alginate to induce epilepsy in rats, and using phycocyanin to intervene, found that phycocyanin can eliminate free radicals, protect neurons, and alleviate epilepsy. Bermejo-Besc6s et al.^[31] reported that phycocyanin can protect SH-SY5Y nerve cells under oxidative stress, and iron can cause an oxidative stress response in SH-SY5Y nerve cells, and the addition of phycocyanin can activate antioxidant-related enzymes, such as SOD, CAT, GSH-Px and so on, to alleviate oxidative stress response, thereby protecting SH-SY5Y cells. The results of Bermejo-Bescos’s experiments also predict that phycocyanin may protect against nerve damage caused by free radicals and play a good role in Alzheimer’s disease and Parkinson’s disease.

3.5Effect and mechanism of phycocyanin on oxidative stress-induced kidney disease

oxidative stress can also trigger the occurrence of renal disease, the increase of ros, the increase of oxidative stress level, the increase of glomerular permeability, the easier precipitation of plasma protein in the basement membrane, and the hardening of kidney vessels; in addition, ros can also be deposited in the extracellular matrix, resulting in mesangial expansion and damage to the kidney. diabetic nephropathy is one of the complications of diabetes, and the oxidative stress response also plays a certain role in diabetic nephropathy. in the hyperglycemic environment, hyperglycemia can inhibit the expression of antioxidase (sod, cat, gsh-px) in the kidney, resulting in increased levels of oxidative stress in kidney tissues, excessive ros accumulation and damage to the kidney.

The results of experiments showed that the expression of NADPH oxidase (oxidative stress marker) in the kidney of H-type diabetic mice after oral administration of phycocyanin for 10 weeks while reducing proteinuria and reducing the condition of renal mesangial expansion, suggested that phycocyanin could prevent the occurrence of diabetic nephropathy by reducing the oxidative stress response.the results of the shukkur^l experiment showed that phycocyanin protects against mitochondrial permeability. in canine kidney cells, phycocyanin reduces oxalate-induced reactive oxygen species (ros) and lipid peroxidation (LPO) responses, thereby preventing cellular damage caused by oxalic acid-triggered intracellular oxidative stress responses.

3.6Effect and mechanism of phycocyanin on lung diseases caused by oxidative stress

There are two main factors causing oxidative stress response to lung diseases, one is exogenous factors, such as smoke, environmental pollutants, chemicals and so on, which contain a large number of free radicals themselves, which can directly stimulate the respiratory tract and lung, and cause cell and organ damage; the other factor is the endogenous factor, mainly the activation of neutrophils in lung microcirculation, the release of a large amount of ROS, which can also upregulate or activate NK-kB, aggravate the inflammatory reaction, and directly stimulate the proliferation of fibroblasts with TNF-a, ET-1 and other factors, causing pulmonary fibrosis 3. Intraperitoneal injection of phycocyanin can reduce lung injury in rats caused by paraquat by increasing the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue and plasma. The results of pathological sectioning and immunohistochemical analysis showed that cyan protein could reduce the progression of lung fibrosis induced by reducing the level of the oxidation reaction. the peroxide in the lung tissues of rats with sepsis acute lung injury model was significantly increased, whereas phycocyanin could significantly reduce the amount of peroxide, promote the phosphorylation of protein kinase b (akt), induce the transcription factor e2 related factor 2(nrf2) and upregulate heme oxygenase (ho-1). ho-1 could reduce the content of superoxide in lung tissues through multiple pathways and play a protective role in rats with acute sepsis lunar injury.

3.7Effect and mechanism of phycocyanin on radiation-induced oxidative stress damage

In addition to the above oxidative stress-related diseases, it may also be applied to radiation protection. When a cell or tissue is irradiated by radiation, the cell or tissue undergoes oxidative stress by producing a large number of free radicals, causing damage to the cell or tissue DM0Zhang et al.^[41] found that radiation-induced lung damage can be reduced by regulating levels of oxidative stress. Zhang Chengwu et al. ^[42] received a lethal dose in mice60We found that compared with the simple radiation group, the survival rate of the mice in the phycocyanin intervention group increased significantly for 30 days, and it could promote the recovery of hematopoietic function in the mice after irradiation. Ivanova et al.^[43] found in vitro experiments showed that both catalase and glutamate transferase were elevated when irradiated and incubated with phycocyanin, compared to only irradiated lymphocytes. There are many studies that can alleviate the tissue damage caused by radiation by regulating and reducing the oxidative stress response. At present, there are few studies on the mechanism of tissue damage protection and protection of phycocyanin after irradiation.

4. Summary and outlook

To sum up, oxidative stress is related to many diseases, which may be the common pathogenesis of diseases such as cardiovascular system, digestive system, respiratory system, nervous system and so on^[44], and phycocyanin can be used as an antioxidant to regulate the imbalance between antioxidant system and oxidation system in vivo, and down-regulate the level of oxidative stress to achieve the effect of treating diseases. In addition, the antioxidative activity of recombinant phycocyanin was studied in our group. The results showed that different recombinant glycoproteins had different scavenging abilities to different types of free radicals. However, the application of recombinant phycocyanin in oxidative stress-related diseases was few. Compared with natural phycocyanin, researchers gave more properties of recombinant phycocyanin, such as higher stability.

Nowadays, there are many types of research on the pharmacological action of phycocyanin, but there are little researches on its pharmacokinetics. In addition, phycocyanin, as a macromolecular substance, maybe hydrolyzed by different digestive enzymes after entering the body by the way of gavage. As the technology of separation and purification becomes more mature ^[46], the higher

purity phycocyanin has been applied to the research of health products or candidate drugs. At the same time, phycocyanin has the characteristics of non-toxic and multi-function, and its application prospect will be very broad.