Phycocyanobilin Synthesis Essay

1. NADPH Oxidase, Uncoupled eNOS, and Decreased NO Bioactivity Mediate Diabetic Complications

Oxidative stress, and the disruption of nitric oxide production and bioactivity which this entails, are believed to be key mediators of the complications of diabetes. Although increased mitochondrial superoxide production in glucose-permeable tissues can contribute to this oxidative stress, up-regulation of NADPH oxidase activity and uncoupled nitric oxide synthase are major culprits in this regard [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. The hyperglycemia and, in type 2 diabetics, excessive free fatty acid levels characteristic of diabetes can stimulate NADPH oxidase activity via increased diacylglycerol synthesis and subsequent activation of protein kinase C [1]. In adipocytes, activation of toll-like receptor 4 by saturated fatty acid/fetuin-A complexes stimulates NADPH oxidase activity, contributing to adipocyte insulin resistance and aberrant production of adipokines typical of type 2 diabetes [16,17,18]. Moreover, interaction of advanced glycation end products (AGEs) with the receptor for AGEs (RAGE) receptor triggers activation of NADPH oxidase; there is strong reason to suspect that the resulting oxidative stress is a key mediator of the diabetic complications driven by AGE exposure [2].

The ways in which oxidative stress and the associated decline in NO bioactivity promote diabetic complications are complex, and still being unraveled. In regard to glomerular damage in diabetic nephropathy, modulation of podocyte and mesangial cell function plays a key role. Podocytes express high activities of eNOS and soluble guanylate cyclase [19]. Exposure of these cells to hyperglycemia triggers activation of protein kinase C, which in turn induces expression of Nox4 [20]. The resulting oxidative stress lowers cGMP levels and protein kinase G (PKG) activity, and, as a result, podocytes produce and secrete less of the basement membrane proteins nephrin and podocin required for prevention of albuminuria [21]. This oxidative stress, if severe, can also trigger podocyte apoptosis. Hyperglycemia acts on mesangial cells to boost synthesis of latent TGF-beta. Activation of TGF-beta requires interaction with thrombospondin-1 (TSP1), and, under hyperglycemic conditions, PKG activity suppresses transcription of the TSP1 gene [22]. Hence, the loss of PKG activity in the diabetic glomerulus boosts TSP1 activity, which in turn promotes activation of latent TGF-beta; this hormone then induces glomerulosclerosis by stimulating mesangial cell production of fibronectin and collagen.

With respect to diabetic retinopathy, increased contraction of retinal microvascular pericytes contributes to the lessening of retinal perfusion that in turn evokes pathologenic neovascularization [23]. Pericytes express eNOS, soluble guanylate cyclase, and PKG, and NO/cGMP suppress the contraction of pericytes, as they do in vascular smooth muscle [23,24]. Hyperglycemia and advanced glycation end products (AGEs), via stimulation of NAPDH oxidase in pericytes, impair NO bioactivity and hence trigger pericyte contraction [25,26,27,28]. Moreover, this oxidative stress can also trigger pericyte apoptosis [26]. NADPH oxidase activation may play a more general role in AGE-mediated micro- and macrovascular complications of diabetes [2]. Defective repair of the retinal microvasculature also contributes to the genesis of diabetic retinopathy. CD34+ endothelial precursor cells (EPCs), originating in the bone marrow, migrate to sites of endothelial damage to promote repair. However, this protective mechanism is dysfunctional in diabetics [29]. EPCs express eNOS activity, and cGMP-mediated activation of PKG is essential for regulated migration of these cells [29,30]. Hyperglycemia triggers NADPH oxidase activity in EPCs, and this in turn uncouples eNOS and impairs PKG activity, inhibiting the migration of EPCs and thus impeding repair of damaged retinal capillaries [14,31,32]. This dysfunction of EPCs may also play a role in impaired wound healing characteristic of diabetes [33].

Dysfunction and apoptotic death of Schwann cells is believed to play a role in diabetic neuropathy [34]. Healthy Schwann cells aid survival of neighboring neurons by producing the trophic hormones nerve growth factor (NGF) and neurotrophin-3 (NT3). This protection is contingent on neuronal production of NO (via nNOS), which in turn promotes production of cGMP and activation of PKG in Schwann cells [35]. Hyperglycemia promotes oxidative stress in Schwann cells and neurons, which in turn could be expected to impede NO bioactivity; in addition, hyperglycemia boosts PDE5 activity in Schwann cells, which likewise lowers cGMP levels [36,37,38]. Oxidative stress and NO bioactivity might also influence diabetic neural function by modulating endoneurial blood flow, a decline of which plays a role in diabetic neuropathy. Hyperglycemic activation of NADPH oxidase in endothelial cells can impair endoneurial perfusion by impeding NO-mediated dilation of vascular smooth muscle [39].

The increased risk or macrovascular disease in diabetics likewise may reflect, in part, endothelial dysfunction stemming from NAPDH oxidase activation, eNOS uncoupling, and loss of NO bioactivity [9,40]. Loss of such bioactivity also appears to contribute to diabetic cardiomyopathy and platelet hyperaggregabilty [41,42].

Activation of NADPH oxidase in adipose tissue and pancreatic beta cells plays a mediating role in the insulin resistance and beta cell dysfunction characteristic of type 2 diabetes. Activation of NADPH oxidase in adipocytes and resident macrophages contributes to the inflammation that compromises adipocyte insulin sensitivity, which in turn leads to the excess flux of free fatty acids that promotes systemic insulin resistance and hyperlipidemia [1,18,43]. Furthermore, chronic excessive activation of NADPH oxidase in beta cells is a mediator of the failure of glucose-stimulated insulin secretion and of the beta cell apoptosis that collaborate with systemic insulin resistance to usher in overt diabetes [1,44,45,46,47,48,49,50].

Recent prospective epidemiology points to concurrent statin use as possibly protective with respect to diabetic retinopathy and neuropathy [51]. These findings are intriguing in light of the fact that potent doses of lipophilic statins have the potential to down-regulate the activity of certain NADPH oxidase complexes by inhibiting isoprenylation of Rac1 [52].

2. Phycocyanobilin: A Nutraceutical Inhibitor of NADPH Oxidase

There is good reason to suspect that phycocyanobilin (PhyCB), a light-harvesting chromophore of cyanobacteria (such as spirulina) that is a metabolite and homolog of biliverdin, can inhibit certain isoforms of NADPH oxidase in a manner analogous to bilirubin [53,54,55,56,57,58]. It is notable that diabetics with Gilbert syndrome—in which plasma levels of free bilirubin are chronically elevated—are only about a third as likely as other diabetics to develop nephropathy, retinopathy, or coronary disease [59]. Other epidemiology likewise links increased plasma bilirubin with reduced risk for these complications, as well as peripheral atherosclerosis and diabetic neuropathy [60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]. Oral administration of either PhyCB or biliverdin has been shown to inhibit glomerular sclerosis and oxidative stress in diabetic mice [58,81]. Additionally, oral administration of either whole spirulina or of phycocyanin (the protein which contains PhyCB as a covalently-linked chromophore) has shown anti-atherosclerotic effects in rodent models of this disorder [82,83,84,85,86]. These findings correlate well with epidemiology correlating increased plasma bilirubin with decreased risk for atherogenesis [87,88,89,90].

With respect to the role of NADPH oxidase activation in the genesis of metabolic syndrome and type 2 diabetes, studies with rodent models of these syndromes report favorable effects of oral phycocyanin or whole spirulina on glycemic control, serum lipid profile, blood pressure, and steatohepatitis [91,92,93,94,95,96]. Also, two clinical trials, in which spirulina was administered (likely in suboptimal doses) to type 2 diabetics, likewise found modest improvements in these parameters [97,98]. Furthermore, epidemiological studies, some of them prospective, have found that increased serum bilirubin is associated with decreased risk for metabolic syndrome or type 2 diabetes [69,99,100,101,102,103,104,105,106]. Moreover, among patients who are already diabetic, serum bilirubin is reported to correlate inversely with HbA1c and duration of diabetes, and directly with C-peptide levels [107,108,109]. Oral administration of biliverdin, the bilirubin precursor, prevents or postpones beta cell failure in diabetes-prone db/db mice [110].

Concentrated preparations of PhyCB per se for nutraceutical use are not yet available. Doses of up to 1 g phycocyanin daily have achieved “generally recognized as safe” status from the U.S. Food and Drug Administration [111]. Spirulina has been a traditional food in some cultures, and rodents can ingest 30% of their calories from spirulina for 13 weeks without clear harm; much lower intakes exert a wide range of protective effects in rodent models of disease, and provide protection from many toxins [112,113,114]. Whereas it is certainly conceivable that a sufficiently high intake of concentrated PhyCB could notably compromise immune defenses, much lower intakes can be expected to have valuable clinical potential if humans assimilate and metabolize this compound like rodents do.

3. High-Dose Folate Combats eNOS Uncoupling

Oxidative stress impairs effective NO activity in several ways: oxidizing tetrahydrobiopterin; inhibiting dimethylarginine dimethylaminohydrolase (DDAH), and thereby boosting intracellular levels of the eNOS inhibitor/uncoupler asymmetric dimethylarginine (ADMA) [115,116,117,118,119]; and direct quenching of NO by superoxide, leading to production of the potent oxidant peroxynitrite. Peroxynitrite is a mediator of the oxidation of tetrahydrobiopterin; and it can also inhibit a key target of NO bioactivity, soluble guanylate cyclase (sGC), by oxidizing the ferrous iron in its attached heme group [120,121,122,123]. Oxidized sGC is not only unresponsive to NO, but it also is prone to lose its heme group, leading to its proteasomal degradation.

Tetrahydrobiopterin is a cofactor for endothelial nitric oxide synthase (eNOS). Dihydrobiopterin, its oxidation product, is a competitive inhibitor of tetrahydrobiopterin’s binding to eNOS, and a low ratio of tetrahydrobiopterin to dihydrobiopterin promotes eNOS uncoupling, such that eNOS becomes a source of superoxide [124,125]. High-dose folate can be expected to promote recoupling of this enzyme by increasing the ratio of tetrahydrobiopterin to dihydrobiopterin. When administered in supraphysiological doses, elevated levels of reduced metabolites of folate accumulate within vascular endothelium and other tissues [126]. These reduced metabolites have versatile oxidant scavenging activity—in particular, they scavenge products of peroxynitrite which oxidize tetrahydrobiopterin to dihydrobiopterin [126,127,128]. Moreover, these folate metabolites promote induction of the enzyme dihydrofolate reductase, an enzyme which participates not only in folate metabolism, but also reduces dihydrobiopterin to the tetrahydro form [126,129,130,131]. Hence, high-dose folate has potential for suppressing eNOS uncoupling both by slowing the rate of oxidation of tetrahydrobiopterin, and by promoting the reconversion of dihydrobiopterin to tetrahydrobiopterin. Favorable effects of high-dose folate (5 mg, three times daily) on oxidative stress in diabetics have been reported that may reflect improved function of eNOS, as well as the scavenging activities of reduced folates [132,133]. Intravenous administration of 5-methyltetrahydrofolate has been reported to achieve acute improvement of endothelium-dependent vasodilation in diabetics, likewise likely stemming from recoupling of eNOS [134,135,136]. Oral folate has improved diabetic endothelial function in some studies but not others; the negative studies employed doses no higher than 5 mg daily [135,136,137]. Kurt Oster, who pioneered the clinical use of high-dose folate for vascular health, employed and recommended a daily dose of 40–80 mg [138,139]. He reported that administration of high-dose folate was associated with rapid healing of a diabetic ulcer that previously had been refractory, likely reflecting a key role for NO in wound healing [140,141,142,143]. No evident adverse effects were seen with this regimen.

4. Citrulline Can Counter the Adverse Impact of ADMA and Arginase on eNOS Activity

eNOS can also generate superoxide when it fails to bind its substrate L-arginine [144,145,146]. Although intracellular concentrations of arginine are usually far higher than its binding constant to eNOS, cells generate an arginine metabolite, asymmetric dimethylarginine (ADMA), which has very high affinity for eNOS and acts as a competitive inhibitor of arginine’s binding [147]. This agent is actively transported into endothelial cells, which markedly amplifies its capacity to act as a competitive antagonist for arginine [148]. ADMA originates when arginine groups in intact proteins are methylated on their guanidino head groups by a group of enzymes known as “protein arginine N-methyltransferases” (PRMTs); “asymmetric” refers to the fact that, in ADMA, one of the two nitrogens in this head group is dimethylated, whereas the other remains unmethylated [149

Department of Chemistry, Ahmadu Bello University, P.M.B. 1069, Zaria, Kaduna, Nigeria

Copyright © 2013 Abdulmumin A. Nuhu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cyanobacteria are aquatic and photosynthetic organisms known for their rich pigments. They are extensively employed as food supplements due to their rich contents of proteins. While many species, such as Anabaena sp., produce hepatotoxins (e.g., microcystins and nodularins) and neurotoxins (such as anatoxin a), Spirulina (Arthrospira) displays anticancer and antimicrobial (antibacterial, antifungal, and antiviral) activities via the production of phycocyanin, phycocyanobilin, allophycocyanin, and other valuable products. This paper is an effort to collect these nutritional and medicinal applications of Arthrospira in an easily accessible essay from the vast literature on cyanobacteria.

1. Introduction

Cyanobacteria are ancient photosynthetic organisms that are found in various aquatic environments [1–3]. Their photosynthetic pigments confer different colors on them, but they are generally regarded as blue-green. Calling them algae is, however, a misnomer since they are truly prokaryotes that share most of the characteristics of eubacteria. Some of these organisms have nitrogen-fixing potential which makes them important in rice paddy waters [4].

Cyanobacteria form colonies [5] or live as individual cells [6]. They also form coccoid [7] or filamentous structures [8]. The filamentous colonies show the ability to differentiate into three different cell types [9]. Vegetative cells, the normal photosynthetic cells formed under favorable growth conditions; climate-resistant spores in harsh environmental conditions and a thick-walled heterocyst containing the enzyme nitrogenase for nitrogen fixation.

In the last 3.5 billion years, cyanobacterial morphology has been largely maintained as they are very resistant to contamination. Sigler et al. [10] have shown that cyanobacteria form monophyletic taxon. Culture-based morphological characteristics of endolithic cyanobacteria have been extensively described by Al-Thukair and Golubic [11]. Since characterization of microorganisms based on morphology is highly subjective and sometimes very speculative, the shift by genome-based characterization is now gaining momentum. Koksharova and Wolk [12] have presented a good review on the available genetic tools for cyanobacteria studies.

Cyanobacteria are very resistant as they produce protective compounds which shield them against harsh environmental conditions [13]. Some of these compounds also have strong insecticidal activities [14]. Toxic species, including Anabaena species, produce toxins such as microcystins and nodularins which are hepatotoxic, and neurotoxins such as anatoxin a [15, 16].

The Darling River cyanobacterial bloom of 1991 is a clear representation of the environmental hazard that such species pose [17]. However, some species of cyanobacteria possess the ability to produce substances with therapeutic activities such as anticancer and antimicrobial applications [18–22].

Among the myriads of cyanobacteria, Arthrospira platensis is a blue-green cyanobacterium that thrives in elevated alkaline pH [23]. A. platensis is recognized by its peculiar shape of cylindrical trichomes that are arranged in a left-handed helix throughout the filament [24]. The correct taxonomic definitions of Arthrospira have been revealed through the study of the ultrastructural details of its trichomes and 16S rRNA gene sequences [25]. An important ligation detection reaction, in combination with universal array, capable of identifying various cyanobacteria, including Arthrospira, in environmental samples, has been developed [26]. Good understanding of the ecology of this alkaliphilic organism is a catalyst to its mass production and commercial viability as food supplement. By the end of year 2009, its total annual production in Ordos Plateau of Mongolia was in excess of 700 t [27]. With retrospect, the Mexicans [28] and Kanenbu tribe of Chad [29] have been exploiting the protein potentials of S. platensis in their diets for long time now, and about 3000 metric tons of S. platensis is currently produced for commercial purposes [30]. A fed-batch process has been employed in the cultivation of Arthrospira [31], and different solid-liquid separation techniques give various degrees of recovery. Which technique is ultimately selected will depend on the cyanobacterial species, intended concentration of the finished product, and product quality [32]. Cultivation of A. platensis under different trophic modes was shown to affect the product yield [33]. High-value compounds from this organism have been put to assorted uses as cosmaceuticals, nutraceuticals, and as functional foods [34]. Phycocyanin and allophycocyanin, two of such important compounds, have been determined in Spirulina supplements and raw materials by a 2-wavelength spectrophotometric method [35]. Bioactivity and health functions of Arthrospira food supplements have been reviewed [36–38]. Specific functions that have been tested for compounds extracted from this organism are grouped under the following subheadings.

2. Nutritional Functions

Arthrospira (Spirulina) is among the richest sources of proteins. Its protein content is about 60–70% [39]. In a study that attempted using Spirulina as a protein supplement, it was observed that it can replace up to 40% of protein content in tilapia diets [40]. Rabelo et al. [41] have explained the development of cassava doughnuts enriched with S. platensis biomass.

Unlike many other cyanobacteria that have proven toxicity, no such property has been attributed to Spirulina. While testing for mutagenicity, acute, subchronic, and chronic toxicities and teratogenicity in animal experimentations, Chamorro et al. [42] have shown that Spirulina did not exhibit any potential for organ or system toxicity even though the doses given were elevated above those for expected human consumption. Rather, Spirulina was shown to protect fish from sublethal levels of some chemicals [43]. Likewise, dietary supplementation of Spirulina has helped in alleviating the incidence of anemia experienced during pregnancy and lactation. In the study conducted by Kapoor and Mehta [44], dietary supplementation of S. platensis was found to increase the iron storage of rats, better than achieved from the combination of casein and wheat gluten diets, during the first half of pregnancy and lactation. A review that treats the influence of different compounds from Spirulina on the immune system has been written [45].

3. Antioxidant Functions

Apart from its importance as a food additive for supplementary dietary proteins, there are also a lot of potentials for medical and therapeutic applications [46]. For example, A. platensis plays a hepatoprotective role [47]. This role, which has to do with the antioxidant activity of Spirulina, has been previously asserted by various researchers. The antioxidant activity of Spirulina is ascribed to the presence of two phycobiliproteins: phycocyanin and allophycocyanin, as determined by its action against OH radical generated from ascorbate/iron/H2O2 system. The activity was found to be proportional to the concentration of the phycobiliproteins and was mainly due to the phycocyanin content [48]. As an antioxidant effect, oxygen stress was inhibited by phycocyanin and phycocyanobilin from Spirulina leading to protection against diabetic nephropathy [49]. In an earlier experiment to determine the radical scavenging activity of C-phycocyanin isolate of S. platensis, an intraperitoneally administered C-phycocyanin was found to reduce the peroxide values of CCl4-induced lipid peroxidation in rat liver microsomes [50]. Following a study conducted on 60 patients presenting with chronic diffuse disorders in the liver and on 70 experimental animals, Gorban’ et al. [51] have found that Spirulina administration prevented the transformation of chronic hepatitis into hepatic cirrhosis. Recently, Paniagua-Castro et al. [52] have demonstrated the protective efficacy of Arthrospira against cadmium-induced teratogenicity in mice.

There are indications that these therapeutic potentials are not the exclusive rights of S. platensis. Spirulina fusiformis also has shown some free radical scavenging activities. In rats, Kuhad et al. [53] have found that radical scavenging activity of S. fusiformis did protect against nephrotoxicity resulting from oxidative and nitrosative stress of the aminoglycoside, gentamicin, an antibiotic commonly used for the treatment of Gram-negative bacterial infections. Pretreatment of mice with Arthrospira maxima effectively led to the reduction in liver total lipids, liver triacylglycerols, and serum triacylglycerols, thus protecting against Simvastatin-induced hyperlipidemia [54]. The hexane extract of Spirulina achieved an impressive 89.7% removal of arsenic from rat liver tissue, which is a better result than obtained with either alcohol or dichloromethane extract [55]. In a more recent finding, aqueous extract of S. platensis showed suppressive potency, through free radical scavenging activity, against cyclophosphamide-induced lipid peroxidation in goat liver homogenates [56].

As a nephroprotective activity, S. platensis extract counteracted the hyperoxaluria experimentally induced by the administration of sodium-oxalate to rats, through stabilization of antioxidant enzymes and glutathione metabolizing enzymes [57]. Protections against mercuric chloride-(HgCl2-) induced renal damage and oxidative stress were attributed to the administration of A. maxima to experimental mice [58]. Administration of A. platensis to rats also rendered protection against HgCl2-induced testis injury and sperm quality deteriorations [59].

S. platensis biomass preparations have shown some corrective influences on atherosclerotic processes in 68 patients with ischemic heart disease (IHD) and atherogenic dyslipidemia. The patients’ immunological states were altered, in addition to changes in lipid spectra [60]. Pretreatment of experimental animals with Spirulina has proved its cardioprotective function, this time against doxorubicin-induced toxicity, as evident from lower mortality, lower degree of lipid peroxidation, decreased ascites, and normalization of antioxidant enzymes, without compromising the antitumor activity of the drug, doxorubicin [61]. The contribution of reactive oxygen species (ROS) to brain injury in neurodegenerative conditions, such as Parkinson’s disease, is hampered with proper administration of A. maxima supplement. Following a 40-day pretreatment with 700 mg/kg/day of this supplement, various indicators of toxicity in rat injected with a single dose of 6-hydroxydopamine, 6-OHDA (16 μg/2 μL), were decreased [62]. This is an indication of the neuroprotective effect of this supplement against the harmful effect of free radicals. Arthrospira supplement has also a radioprotective effect. This is demonstrated by its free radical scavenging function against gamma-irradiation-induced oxidative stress and tissue damage in rats [63]. Cell death through apoptosis is prevented or delayed by using a cold water extract of S. platensis [64]. Hence, it is suggested that the inclusion of cyanobacterial supplement in beverages and food products should be strongly considered.

4. Antitumor Functions

Strong evidences have shown that S. platensis is also imbued with antitumor and anticancer functions. In this regard, it was discovered that significant to full tumor regression was obtained with intravenous injection of Radachlorin, a new chlorine photosensitizer that was derived from S. platensis [65]. It was shown that hot-water extract of S. platensis facilitated enhanced antitumor activity of natural killer (NK) cells in rats [66]. Recently, complex polysaccharides from Spirulina have brought about suppression of glioma cell growth by downregulating angiogenesis via partial regulation of interleukin-17 production [67]. High production of tumor necrosis factor-α (TNF-α), in macrophages, was recorded in the presence of acidic polysaccharides from A. platensis [68]. Li et al. [69] have shown that with increased phycocyanin concentration, expression of CD59 proteins in HeLa cells was promoted while Fas protein that induces apoptosis was increased with an attendant decline in the multiplication of HeLa cells. These findings are an evidence for the multidimensional applications of phycocyanin content of S. platensis.

5. Antiviral Functions

Many compounds with antimicrobial activities have been isolated from different marine organisms, and a number of evidences are put forward for the antiviral activity of Spirulina [70, 71]. This antiviral activity, in a large part, is attributable to the richness of S. platensis in vital proteins, fatty acids, minerals, and other important constituents [72].

Previously, calcium spirulan (Ca-SP), a novel sulfated polysaccharide that was isolated from hot water extract of S. platensis, has shown antiviral activities against different enveloped viruses such as Herpes simplex virus type-I, measles virus, HIV-I and influenza virus. This high sought for antiviral activity has been suggested to be due to the effect that chelation of calcium ions to sulfate groups has on molecular conformation [73]. Both extracellular and intracellular spirulan-like molecules from the polysaccharide fractions of A. platensis displayed significant antiviral activities against wide range of viruses, including human cytomegalovirus and HIV-I [74]. About 50% and 23% reductions in viral load were recorded for methanolic and aqueous extracts of S. platensis, respectively [75]. Reduction in viral load was attributed to inhibition of HIV-I replication in human T cells, langerhans cells, and peripheral blood mononuclear cells (PBMCs), with up to 50% reduction accorded to PBMCs [76]. Antiviral and immunostimulatory properties of S. platensis preparations were elicited through increased mobilization of macrophages, cytokine production, antibodies generation, accumulation of NK cells, and mobilization of B and T cells [77]. A recent study on the antiviral activity of Spirulina has resulted in the isolation of Cyanovirin-N (CV-N), a novel cyanobacterial carbohydrate-binding protein that inhibits HIV-I and other enveloped viral particles [78]. The Kanenbu tribe of Chad and most people in Korea and Japan, who consume Spirulina diet daily, have been shown to display lower cases of HIV/AIDS than their surrounding neighbors who do not take such diet. Therefore, it is expected that consistent intake of diets containing Spirulina can help in reducing the prevalence of HIV/AIDS [79]. Antiherpetic activities were noted for the crude extracts of S. fusiformis [80]. While Hernández-Corona et al. [81] have reported antiviral activity of S. maxima against HSV-2, Shalaby et al. reported similar activity for S. platensis against HSV-I [82].

6. Antibacterial Functions

Spirulina is not without antibacterial activity. In 3-week-old chicks injected with either Escherichia coli or Staphylococcus aureus suspensions, 0.1% Spirulina was found to enhance their bacterial clearance abilities, as shown by the improvement in the activities of different phagocytotic cells, including heterophils, thrombocytes, macrophages, and monocytes in the chickens [83]. Microalgal cultures of A. platensis have displayed significant antibacterial activity against six Vibrio strains: Vibrio parahaemolyticus, Vibrio anguillarum, Vibrio splendidus, Vibrio scophthalmi, Vibrio alginolyticus, and Vibrio lentus [84]. Antibacterial activity against Streptococcus pyogenes and/or S. aureus was proven for the phycobiliproteins isolated from A. fusiformis [85]. Purified C-phycocyanin from S. platensis markedly inhibited the growth of some drug resistant bacteria: E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and S. aureus [86]. This shows the potentials of compounds isolated from these cyanobacterial species in the fight against drug resistance.

7. Antifungal Functions

Recently, Spirulina has also exhibited antifungal activities [87]. Activity of 13 mm was recorded against Candida glabrata in the butanol extract of Spirulina sp. [88]. The immunostimulatory effect of S. platensis extract was tested in Balb/C mice infected with candidiasis [89]. In this experiment, pretreatment of the mice with 800 mg/kg of the extract for 4 days before intravenous inoculation with C. albicans resulted in increased production of cytokines TNF-α and interferon-gamma (IFN-γ), leading to increased survival time and better fungal clearance than in control groups. Glucosamine production was reduced by about 56% when the antifungal activity of the methanolic extract of S. platensis was tested against Aspergillus flavus [90]. Contrary to these findings, S. platensis grown in Zarrouk media, DB1 media and papaya skin extract media did not show any antifungal activity [91]. In some instances, extracts from S. platensis may display a stimulatory effect toward cultured microorganisms. It was found by Gorobets et al. [92] that different doses of S. platensis, when added to culture fluid, displayed important stimulatory and inhibitory effects on the cultured microorganisms due to the presence of complex metabolites that were active in the prepared nutrient agar. Similarly, S. platensis biomass was used to maintain the counts of starter organisms in acidophilus-bifidus-thermophilus (ABT) milks at satisfactory levels during whole duration of storage. This is a novel opportunity for the production and maintenance of functional dairy foods [93].

8. Miscellaneous Functions

Many compounds produced from marine organisms, including cyanobacteria, have important protective functions against various allergic responses such as asthma, atopic dermatitis, and allergic rhinitis [94].

Powders of S. platensis have inhibited anaphylactic reaction resulting from antidinitrophenol IgE-induced histamine release or from TNF-α of rats [95]. Spirulina was also found effective against allergic rhinitis [96]. In an earlier human feeding study conducted in this regard, Spirulina-based dietary supplement was found effective in suppressing the level of interleukin- (IL-) 4 [23]. Zymosan-induced upsurge in the level of beta-glucuronidase of experimental mice was significantly reduced following the administration of phycocyanin [97]. This antiarthritic action may be due to the combination of various mechanisms such as free radical scavenging, inhibition of arachidonic acid metabolism as well as inhibition of TNF-α within the mice.

S. platensis has also neuroprotective ability. Its neuroprotective effect was demonstrated in adult Sprague-Dawley rats through a significant reduction in the volume of cerebral cortex infarction and increased poststroke locomotor activity. Hence, it is suggested that chronic treatment with Spirulina can reduce ischemic brain damage [98]. A report has shown that lead-induced increase in mast cells in rat ovary, during estrous cycle, is curtailed by using Spirulina at 300 mg/kg [99].

Another important compound synthesized by Spirulina, which equally has a lot of vital applications, is polyhydroxyalkanoates. These are polyesters produced by bacterial fermentation of sugars or lipids. According to Campbell et al. [100], S. platensis stores about 6% of its total dry weight and this value decreases during stationary phase of its growth profile. However, Jau et al. [101] have posited that this value can be increased to 10% when the organisms are grown under nitrogen-deficient, mixotrophic culture medium. The use of recombinant E. coli, due to its fast rate of growth and minimal nutrient requirements, to overproduce polyhydroxyalkanoates, has the potential of increasing the number of polyhydroxyalkanoates inclusions per cell [102]. Polyhydroxyalkanoates hold an assuring promise in therapeutic applications as drug carriers that display a release pattern similar to those of monolithic devices; an early rapid release followed by a prolonged, but slower release pattern. This type of drug-release behavior is normally required for depositing adequate concentration of drug of interest at the site of infection [103]. Among the polyhydroxyalkanoates, 4-hydroxybutyrate has long been advocated for the treatment of alcohol withdrawal syndrome in alcohol-dependent subjects [104].

9. Conclusions

In the foregoing essay, various nutritional and medicinal potencies have been attributed to metabolites from the cyanobacteria, Spirulina (Arthrospira) sp. In the present clamor for alternative medicine, these organisms serve as very viable potential sources of bioactive products with commercial imports. Therefore, more should be done in the study, culture, isolation, and purification of these organisms to enable beneficial harvest of their important inclusions.

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