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The growing demand for natural alternatives to synthetic compounds has propelled the large-scale production of microalgae and their bioactive constituents. Among these, phycocyanin, a prominent pigment abundant in blue-green algae, has emerged as a subject of intense research interest due to its multifaceted biological activities, which include antioxidative, anti-inflammatory, anticancer, and neuroprotective properties. Its versatility has led to widespread use across various industries, from food and cosmetics to pharmaceuticals, underscoring its economic significance. As a result, efforts have been intensified to refine production processes, enhance purity, and ensure stability to increase its market value. Furthermore, the exploration of secondary metabolites derived from microalgae production holds promise for cross-industry applications, fostering industrial symbiosis and a circular economy. This chapter aims to elucidate the antioxidant capacity of phycocyanin derived from microalgae and delve into its potential for therapeutic approaches.
Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Inov4Agro, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Portugal
Raquel Fernandes
Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Inov4Agro, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Portugal
Ana Novo Barros*
Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Inov4Agro, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Portugal
*Address all correspondence to: abarros@utad.pt
1. Introduction
Over the years, there has been an increase in demand for natural compounds as alternatives to chemical and synthetic molecules. This new era brings forth promising opportunities, including the exploration of emerging novel targets and the utilization of cutting-edge technologies tailored for drug discovery from natural sources [1]. These natural compounds have demonstrated the potential to provide reduced side effects and lower toxicity when compared to certain synthetic molecules used in cancer chemotherapy drugs [2, 3]. While synthesized compounds serve as valuable resources in current drug discovery programs, natural products remain significant due to their unique chemical structures and biological activities [4]. Furthermore, the progression of a natural compound from a “screening hit” to a “drug lead” and eventually to a “marketed drug” requires larger quantities of the compound, often surpassing what can be obtained through re-isolation from plant sources [5]. Natural products have also played a pivotal role as lead compounds in health promotion and in the discovery and development of new drugs [6].
Marine resources, particularly microalgae, have gained global recognition for their remarkable nutritional profile and their potential as alternative sources of essential biomolecules, including proteins, carbohydrates, and lipids. These bioactive compounds derived from microalgae exhibit significant biological functions and find applications across diverse industries [7, 8, 9]. Notably, microalgae have emerged as promising candidates for producing metabolites with pharmaceutical applications, offering natural alternatives for the development of analog compounds to therapeutic drugs [10]. As a result, there is a rising demand for algae products, underscoring the increasing recognition of the significant contributions that microalgae can make across several industrial sectors [7, 8, 9].
Over the years, extensive research has been conducted on highly valuable proteins produced by certain species of microalgae, namely phycocyanin, which has been reported to be associated with relevant and beneficial properties for human health [11]. Phycocyanin is highly recognized for its pharmacological properties, including cardiovascular protection, anti-inflammatory effects, anticancer, and anti-neurodegenerative properties, most of them related to its antioxidant activity. This therapeutic potential underscore phycocyanin’s significance as a molecule of great interest in biomedical research [11, 12].
Hence, the aim of this chapter is to review the antioxidative activity of phycocyanin derived from several microalgae species and explore its potential for the treatment of different diseases.
Phycocyanin (Figure 1) is a water-soluble, non-toxic, blue pigment, and biologically active compound that exists in various species of microalgae [12, 13].
Figure 1.
Phycocyanin structure. Adapted from Fernandes et al. [11].
Based on their spectral properties, phycocyanin can be classified into three main groups: allophycocyanin, which is obtained from both red and blue-green algae, cyano-phycocyanin (C-PC), which is derived from blue-green algae, and R-phycocyanin (R-PC), which is formed from red algae [12, 13]. The protein consists of an α polypeptide (10–19 kDa) and a β polypeptide (14–21 kDa) forming a monomer, which contributes to its stability [11]. While the structure and function of phycocyanin are largely similar across different microalgae species, differences in the composition and properties of the molecule may exist. Some possible distinctions between phycocyanin molecules from different microalgae species include the amino acid sequence composition, which may affect its physical and chemical properties; the absorption spectra, which can impact its light-harvesting efficiency and coloration; the stability of phycocyanin, which can be influenced by factors such as pH, temperature, and salt concentration; oligomeric structure; and its localization within the cell, such as the thylakoid membrane or the cytoplasm [13, 14].
Over the years, several microalgae species, mostly cyanobacteria, have been reported to be natural producers of phycocyanin (Table 1), namely Arthrospira platensis, Arthrospira fusiformis, Arthrospira maxima, Arthronema africanum, Anabaena sp., Aphanizomenon flos-aquae, Calothrix sp., Cyanidioschyzon merolae, Cyanidium caldarium, Cyanothece sp., Galdieria sulphuraria, Geitlerinema sp., Limnothrix sp., Lyngbya sp., Microcystis aeruginosa, Nostoc commune, Oscillatoria minima, Oscillatoria quadripunctulata, Phormidium sp., Plectonema sp., Pseudanabaena sp., Synechocystis sp., Synechococcus sp., Synechococcus vulcanus, and Thermosynechcoccus vulcanus. Interestingly, red macroalgae were also reported as producers of phycocyanin, Gracilaria chilensis, and Polysiphonia urceolata (Table 1) [13, 15, 16, 17, 18, 19, 20, 21, 22].
Nevertheless, A. platensis, commonly known as Spirulina, stands out as the principal natural source of phycocyanin (14–25%) and is the most used among various microalgae species [11, 15, 23]. In fact, one of the reasons for the current large-scale cultivation of Spirulina is the increasing demand for natural compounds, particularly for the production of high-value proteins such as phycocyanin. Depending on its purity, phycocyanin finds applications in several industries, including food, cosmetics, and pharmaceuticals [11].
The purity of phycocyanin is assessed using the A620/A280 ratio, where A620 represents the absorbance of phycocyanin at 620 nm and A280 corresponds to the absorbance of other proteins at 280 nm. This purity index will determine its market value and, consequently, its applicability. Phycocyanin is considered food, cosmetic, reagent, or analytic grade when A620/A280 is, respectively, greater than 0.7, 1.5, 3.9, or 4.0 [11]. Furthermore, enhancing methods or processes of extraction (e.g., freeze/thaw, mixing/homogenization, bead milling, ultrasonication, electric field, high-pressure homogenization, and enzymatic extraction) and purification (e.g., ammonium sulfate precipitation, membrane filtration, chromatography), as well as developing more stable formulations (e.g., light, temperature, pH, preservatives, biomass/solvent ratio), can significantly increase the commercial value of phycocyanin [11, 15, 24]. In fact, it is estimated that the market of phycocyanin will grow at a Compound Annual Growth Rate (CAGR) of 28.1% from 2023 to 2030, reaching $279.6 million. Also, the global phycocyanin market is anticipated to reach 3587.2 tonnes by 2030, expanding at a CAGR of 33.8% between 2023 and 2030 [15].
Nevertheless, several factors will determine phycocyanin production, including environmental conditions, cultivation methods, and the genetic diversity among strains or populations of the same microalgae species [11, 13, 16]. The phycocyanin molecular structure, composition, and purity will establish its potential biological functions including antioxidant, anti-cancer, anti-inflammatory, and neuroprotective activities [11, 12].
Phycocyanin derived from different microalgae species has demonstrated the capacity to mitigate damage induced by reactive oxygen species (ROS) and free radicals, thus endowing it with antioxidant properties [25]. This antioxidative potential of phycocyanin has received significant interest in biomedical research due to its potential therapeutic applications. Moreover, studies suggest that phycocyanin can modulate antioxidant enzymes, enhancing cellular defenses against oxidative stress. Additionally, phycocyanin has been shown to reduce lipid peroxidation and prevent DNA damage induced by oxidative stress.
3.1 Free radical scavenging
Free radicals are highly reactive molecules characterized by unpaired electrons, rendering them unstable and capable of damaging cells, proteins, and DNA through oxidative stress. Elevated levels of free radicals are implicated in the onset of various diseases, such as cancer, cardiovascular, metabolic, and neurodegenerative diseases [26]. The mechanism through which these reactive molecules are neutralized and eliminated is known as free radical scavenging. Antioxidant compounds play a pivotal role in this process by facilitating the donation of electrons or hydrogen groups, thereby neutralizing free radicals and avoiding their propagation within cells [26]. In phycocyanin, its chromophore named phycocyanobilin has a special structure that allows it to directly neutralize free radicals by donating an electron, thus preventing cell damage [27].
Phycocyanin (200 μg/mL) extracted from the cyanobacteria Geitlerinema sp. revealed a scavenging activity of 78.75% and a hydrogen-peroxide-radical-scavenging activity of 95.27%, suggesting it as a promising pharmaceutical and nutraceutical compound [28]. Another study on 150 μg/mL phycocyanin extracted from this species demonstrated a reducing power efficiency of 85.15%, recognizing the correlation between the reducing power and antioxidant activity of phycocyanin [29].
Purified phycocyanin from Synechococcus sp. displayed 89% antioxidant activity of 2,2-diphenyl-1-picryhydrazyl (DPPH) and 11% of superoxide free radical scavenging activity [30]. Another study demonstrated its proton-donating ability and a 70% scavenging capacity at a dose of 80 μg [31].
Phycocyanin obtained from Pseudanabaena sp. and Limnothrix sp. cyanobacteria revealed antioxidant properties assessed by the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method using concentrations ranging from 0.25 to 1.00 mg/mL [32].
The antioxidant activity of phycocyanin isolated from three cyanobacterial species Lyngbya, Phormidium, and Spirulina was also studied in vitro. The results demonstrated that phycocyanin from Lyngbya, Phormidium, and Spirulina were able to scavenge peroxyl radicals with a relative rate constant ratios of, respectively, 3.13, 1.89, and 1.80. Interestingly, phycocyanin extracted from Lyngbya was found to be a more effective inhibitor of peroxyl radicals (IC50 6.63 μM), compared to Spirulina (IC50 12.15 μM) and Phormidium (IC50 12.74 μM) phycocyanin. In this study, the electron spin resonance spectra of phycocyanin indicated the presence of free radical active sites, which may play an important role in its radical scavenging property [33].
Moreover, phycocyanin at 1 mg/mL isolated from Oscillatoria minima showed 44% of DPPH radical scavenging activity and 95% of ABTS radical scavenging activity [34].
Purified phycocyanin at 0.15 mg/mL isolated from Limnothrix sp. revealed 100% antioxidant activity measured by DPPH [35].
A study using phycocyanin extract (10–150 nM) obtained from Aphanizomenon flos-aquae demonstrated a protective role against oxidative damage induced by a pro-oxidant agent in human erythrocytes [20]. In this study, the authors demonstrated a decreased production of free radicals after phycocyanin extract treatment [20].
Interestingly, a study has shown that the antioxidant activity of phycocyanobilin from Spirulina is comparable to that of phycocyanin when adjusting the concentrations of phycocyanobilin yield. This finding suggests that phycocyanobilin likely accounts for the majority of the antioxidant activity associated with phycocyanin [36]. Other studies demonstrated the higher capacity of allophycocyanin and phycocyanin to scavenge, respectively, peroxyl and hydroxyl radicals [37].
3.2 Boosting antioxidant enzymes
Antioxidant enzymes play a pivotal in shielding cells against oxidative harm by counteracting detrimental free radicals and ROS. Superoxide dismutase (SOD) catalyzes the conversion of superoxide radicals (O2−) into hydrogen peroxide (H2O2) and molecular oxygen (O2), preventing oxidative damage to cells and tissues [38]. Similarly, catalase facilitates the breakdown of H2O2 into water (H2O) and O2, thereby diminishing the accumulation of H2O2 [39]. Hydrogen peroxide, a reactive oxygen species, can induce oxidative stress and harm cellular components. Catalase aids in neutralizing hydrogen peroxide, safeguarding cells from oxidative injury. Glutathione peroxidase (GPx) reduces H2O2 to H2O, limiting its harmful effects, while also mediating growth factor-mediated signal transduction and mitochondrial function, and preserving normal thiol redox-balance [40]. Glutathione reductase (GR) generates reduced glutathione (GSH), an antioxidant molecule protecting cells from oxidative damage, from its oxidized form (GSSG) [41].
A study demonstrated that a 5 mg/mL phycocyanin dosage from A. platensis mitigated cisplatin-induced mortality and inflammation by increasing GPx, γ-glutamyl transferase, and glutathione levels in the liver, along with catalase and SOD levels in the kidney in mice [42]. Supplementation of fish diet with phycocyanin from A. platensis also exhibited an increase of SOD, catalase, and GPx [43]. Moreover, the administration of 0.45 g of phycocyanin from A. platensis per day resulted in an increase in the liver’s reduced-to-oxidized glutathione ratio and a decrease in liver gene expression of SOD and GPx in male mice born from supplemented mothers in a model of atherosclerosis [44].
Phycocyanin from A. maxima at doses of 250 μg/mL in vitro and 400 mg/kg in in vivo models, prevented SOD and GPx activity, indicating a protective role against free radical-induced damage caused by carbon tetrachloride-induced hepatocyte damage [45].
Furthermore, a study on Microcystis aeruginosa exhibited a positive correlation between phycocyanin, GSH content, and SOD enzymes, underscoring its antioxidant potential and the regulation of redox-sensitive signaling [19].
3.3 Protecting cells from lipid peroxidation
Lipid peroxidation is a process where ROS attack lipids, particularly polyunsaturated fatty acids (PUFAs), within cell membranes, leading to the formation of lipid peroxides and other toxic compounds [46].
Phycocyanobilin from A. platensis, ranging from 100 to 1000 μM, effectively inhibited the peroxidation of methyl linoleate and the oxidation of phosphatidylcholine liposomes [36]. Additionally, phycocyanin administered at doses between 25 and 50 mg/kg prevented ethanol-induced lipid peroxidation, thereby reducing oxidative stress, ethanol-induced anxiety, and ethanol-induced testicular damage in rats [47, 48].
Moreover, a daily dosage of 50 mg/kg of phycocyanin from A. maxima resulted in a 57% reduction in lipid peroxidation, thus preventing oxidative stress induced by acute myocardial infarction in rats [49].
Phycocyanin extracted from Geitlerinema sp. at 200 μg/mL revealed an anti-lipid peroxidation activity of 53.65% [28].
Treatment of rats with phycocyanin from Plectonema species, ranging from 100 to 200 mg/kg, protected against type 2 diabetes mellitus by maintaining the redox state through the reduction of lipid peroxidation [18].
A phycocyanin extract (10–100 nM) from A. flos-aquae inhibited the extent of lipid peroxidation induced by cupric chloride in human plasma samples [20].
Finally, individual and released phycocyanobilin from phycocyanin in vivo demonstrated its potential to scavenge reactive oxygen and nitrogen species by counteracting lipid peroxidation and inhibiting oxidase enzymes [50].
3.4 DNA damage control
Free radicals can induce DNA damage through oxidative stress. When free radicals interact with DNA molecules, they can trigger chemical modifications to the DNA bases, such as oxidation, thereby interfering with the accurate replication and transcription of DNA [51]. Antioxidants play a crucial role in protecting DNA from damage by neutralizing free radicals and reducing oxidative stress, maintaining genomic integrity.
Pretreatment and treatment of mice subjected to irradiation with 200 mg/kg phycocyanin from Spirulina via oral gavage for 7 days attenuated the expression of H2AX, an indicator of DMA damage in mice [52]. Another study showcased the protective effect of phycocyanin and phycocyanobilin in scavenging peroxynitrite, a molecule known to mediate oxidative damage to DNA [53]. Furthermore, Niu et al. [54] demonstrated the protective effect of phycocyanin on DNA damage and blastocyst autophagy in porcine embryo development. In a colon cancer rat model, a combination of 200 mg/kg of phycocyanin from Spirulina and piroxicam prevented genomic DNA instability and fragmentation [55].
Elevated levels of free radicals, oxidative stress, and dysfunctional immunity are involved in many human diseases. Consequently, the therapeutic potential of phycocyanin, mainly extracted from Spirulina, owing to its potent antioxidant activity, has been extensively explored in biomedical research including inflammatory diseases, cancer, cardiovascular, and neurodegenerative conditions [56]. Spirulina exhibits remarkable adaptability to extreme climatic conditions, guaranteeing reliable and consistent production of phycocyanin. Additionally, these microalgae yield larger quantities of phycocyanin compared to other microalgae species, further enhancing its potential as a research model for exploring the therapeutic potential of phycocyanin’s antioxidant activity [11].
Several studies have reported the effect of phycocyanin on inflammation, resulting in a reduction in the production of tumor necrosis factor-α (TNF-α) and subsequently attenuating neutrophil infiltration [57, 58]. Moreover, phycocyanin has been shown to inhibit the activation of nuclear factor-kappa B (NF-κB) and decrease the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines [58]. Research has demonstrated the protective role of phycocyanin in various inflammatory conditions, including acute myocardial infarction, atherosclerosis, liver, and lung injury [11]. Additionally, studies have reported the activity of phycocyanin in attenuating cardiovascular disease. Administration of 50 mg/kg of phycocyanin in rats with acute myocardial infarction reduced levels of ROS, Bax expression, and caspase-9 release [49].
The role of phycocyanin in cancer was demonstrated in liver cancer [59], breast cancer [60], colon cancer [61], leukemia [62], and lung cancer [63]. The potential mechanisms underlying phycocyanin’s anticancer activity against cancer cells include suppressing the cell cycle at specific phases, modifying the redox state of cells, and promoting the expression of various genes and receptors responsible for necrosis and apoptosis [12]. Phycocyanin initiates the activation of genes such as caspase-9 and -3, responsible for DNA fragmentation and cell shrinkage, indicating its significant role in apoptotic pathways. Additionally, it induces cleavage of poly [ADP-ribose] polymerase 1 (PARP-1) and alters the ratio of Bcl-2/Bax [64].
Phycocyanin has also been implicated in neurodegenerative disorders, including multiple sclerosis, acting as a scavenger of peroxynitrite species, an inhibitor of lipid peroxidation and DNA damage, and a promoter of remyelination of damaged brain tissue [65, 66]. Additionally, phycocyanin attenuates the production of enzymes involved in Alzheimer’s disease, such as Aβ production [67]. Further studies demonstrated that phycocyanin binds to the Aβ40/42 peptide, disrupting a key mechanism of Alzheimer’s disease [68]. Other reports showed that daily intraperitoneal injection of phycocyanin attenuated the production of pro-apoptotic (Bax, Bcl-2, caspase-9) and pro-inflammatory mediators (TNF-α, NF-κB, interleukin (IL)-6, IL-1β) [69, 70]. The potential of phycocyanin as a drug for neurodegenerative disorders is an area of interest for future development and utilization.
Phycocyanin, a highly valuable protein, is widely used in the food, cosmetic, and pharmaceutical industries due to its biological activities, particularly antioxidative. Advances in microalgae cultivation techniques hold promise for enhancing phycocyanin production, while the development of efficient extraction and purification methods is crucial for obtaining high-quality products. Furthermore, strategies to stabilize phycocyanin during processing and storage are essential to maintain its antioxidant properties over time. Different studies highlight phycocyanin’s antioxidant activity as a valuable natural resource with diverse applications in biomedicine. However, further research efforts are needed to delve deeper into its antioxidative mechanisms and therapeutic potential against various diseases. In fact, phycocyanin holds significant promise as a therapeutic agent for conditions such as cancer, inflammation, neurodegenerative disorders, and metabolic syndromes. However, additional preclinical and clinical studies are necessary to thoroughly assess its efficacy and safety profiles. In summary, the antioxidant activity of phycocyanin represents a valuable asset with broad applications in biomedicine, emphasizing the importance of ongoing research efforts and technological advancements to fully explore its potential for enhancing human health and well-being.
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Written By
Joana Campos, Raquel Fernandes and Ana Novo Barros
Submitted: 08 April 2024Reviewed: 20 May 2024Published: 05 June 2024
Open access peer-reviewed chapter - ONLINE FIRST
