Cyanotherapeutics: an emerging field for future drug discovery

ABSTRACT

Cyanobacteria are ubiquitously distributed oxygenic photosynthetic prokaryotes, present even in extreme environments. Many cyanobacteria have been found to be excellent sources of proteins and bioactive compounds. Their cosmopolitan availability, abundant important bioactive compounds and their associated health benefits make cyanobacteria an ideal target for therapeutic applications. Cyanobacteria have a potential role in nutraceutics and are also important in drug development. Several studies have advocated the use of cyanobacteria and their active principles in the treatment of various diseases because cyanobacteria display anti-cancer, antibacterial, anti-immunosuppressive, anti-tumour, neuroprotective, and antiviral activities. Thus, in this review, we have summarized and updated the therapeutic applications of cyanobacteria in drug development, with the introduction of the new term “cyanotherapeutics”.

KEYWORDS:

• Anticancer
• cyanobacteria
• cyanotherapeutics
• drug development
• neurodegenerative diseases
• pharmacological properties

Introduction

Natural compounds derived from living organisms have traditionally been used as medicine. Our ancestors relied on natural products to fight several diseases. Examples of applications of plant extracts are those of Raulfia serpintina (Apocynaceae) against snakebite (Dey & De, 2012; Lobay, 2015; Upasani et al., 2017), Phyllanthus niruri against liver diseases (Al Zarzour et al., 2017; Amin et al., 2012; Hong et al., 2015) and Centella asiatica for memory improvement (Puttarak et al., 2017; Veerendra Kumar & Gupta, 2003). Following the emergence of molecular biology and combinatorial chemistry, the use of natural products declined due to the formulation of chemical compounds that mimicked their function. However, the application of ethnobotany in disease cures has continued in the background (Heinrich, 2003; Jima & Megersa, 2018). Over the past few decades, there has been an increasing interest in drug development from natural compounds and research into the effect of natural compounds on the human body in health and disease (Ji, Li, & Zhang, 2009; Singh et al., 2017). In recent years several pharmaceutical companies have been working on “nutraceuticals”, the term being a combination of the words “nutrition” and “pharmaceuticals” (Defelice, 1989) which can be defined as a food or food product that possesses health benefits and has medicinal properties in the prevention/treatment of disease (Dominguez, 2013; Kalra, 2003). Cyanobacteria are an important target due to their cosmopolitan availability and their bioactive compounds such as polyunsaturated fatty acids (PUFAs), phycobiliproteins (PBPs), carotenoids, several enzymes and vitamins, with a long history of use (Ciferri & Tiboni, 1985; Ghosh et al., 2016) due to their beneficial properties (Burja, Banaigs, Abou-Mansour, Burgess, & Wright, 2001; Nunnery, Mevers, & Gerwick, 2010; Singh, Kate, & Banerjee, 2005). Available evidence suggests that cyanobacteria have been used since 1500 BC to treat gout, fistula and forms of cancer (Abarzua, Jakubowski, Eckert, & Fuchs, 1999; Bhadury & Wright, 2004; Dahms, Ying, & Pfeiffer, 2006).

Cyanobacteria are Gram-negative, oxygenic photosynthetic bacteria, diversified in a wide range of habitats ranging from the ice caps of Antarctica to hot springs and rock surfaces (Kulasooriya, 2012; Whitton & Potts, 2000). They are thought to be one of the most ancient groups of organisms and the ancestor of higher plant plastids (Knoll, 2008; Komarek, Kastovsky, Mares, & Johansen, 2014; Ughy, Nagy, & Kós, 2015). The bioactive compounds available in cyanobacteria possess several health benefits (Table 1) and have some specific applications such as their use in the formation of medicinal drugs, fuels, cosmetics, food additives and plastics. Cyanobacteria have biochemical pathways that produce unique bioactive molecules with potential commercial and medical applications based on their antifungal, antibiotic, antimicrobial, immunosuppressant, anti-inflammatory, anticancer, antiviral, antibacterial, anticoagulant, antimalarial, antiprotozoal, antituberculosis, anti-HIV (human immunodeficiency virus) and antitumour activities (Fig 1) (Abed, Dobretsov, & Sudesh, 2009; Bhadury & Wright, 2004; Burja et al., 2001; Devillers et al., 2007; Jaspars & Lawton, 1998; Kajiyama, Kanzaki, Kawazu, & Kobayashi, 1998; Koehn, Lomgley, & Reed, 1992; Matthew, Salvador, Schupp, Paul, & Luesch, 2010; Shimizu, 2003). The anti-HIV activity was due to Cyanovirin-N, a carbohydrate binding protein from Nostocellipsosporum (Botos & Wlodawer, 2003; Boyd et al., 1997).

Table 1. Bioactive compounds obtained from cyanobacteria

Sr. no.	Bioactive compounds	Source	Biological action	References
1.	Borohycin	Nostocsp.	Cytotoxicity activity: Anti-tumour activity	(Banker, 1998; Gupta C, 2012)
2.	Apratoxin A	Nostocsp.	Cytotoxicity activity; Induce G1 phases cell cycle & apoptosis; Anti-tumour activity	(Grinberg et al., 2002)
3.	Cryptophycin	Nostocsp.	Prevent Cell division; Anti-cancer activity	(Back, 2005), (Medina et al., 2008)
4.	Stypoldione	Stypopodium znale	Affect Cell division	(Medina et al., 2008)
5.	Largazole	Symploca genus	Anti-cancer activity; Osteogenic activity	(Luesch et al., 2001)
6.	Dolastatin 10	Dolabella auricularia	Anti-proliferative agent	(Bhaskar et al., 2003; Natsume et al., 2003)
7.	Dolastatin 15	Dolabella auricularia	Anti-cancer activity	(Stevenson et al., 2002)
8.	Calothrixin A	Calothrix	Anti-cancer activity	(Cardellina et al., 1979)
9.	Lyngbyatoxin A	Lyngbya majuscula	Anti-HIV activity	(Carte, 1996)
10.	Microcolin A	L. majusculata	Immunosuppressive	(Feldman et al., 1999)
11.	Curacin A	L. majusculata	Anti-Brest cancer activity	(Xiong et al., 2006)
12.	Spirulan & Ca-spirulan	Spirulinasp.	Anti-HIV1, HIV2, Anti-influenza	(Sielaff et al., 2006)
13.	Cyanovirin-N	Nostoc ellipsosporum	Anti-HIV, Inhibits herps simplex virus-6 & measles	(Vijayakumar, 2015)
14.	Scytovirin	Scytonema varium	Anti-tumour activity, Anti-bacterial activity, Anti-viral activity, protease inhibition activity	(Shi et al., 1999)
15.	Dragonamide C & Dragonamide D	Lyngbyasp.	Anti-cancer activity	(Gunasekera et al., 2008)
16.	Almiramides A–C	Lyngbya majuscule	Antiparasitic activity against leishmania	(Sanchez et al., 2010)
17.	Norharmane	Nostoc insulare	Antibacterial	(Volk & Furkert, 2006)
18.	Malyngolide	Lyngbya majuscula	Antibacterial	(Burja et al., 2001)
19.	Kawaguchipeptin B	Microcystis aeruginosa	Antibacterial	(Dahms et al., 2006)
20.	Kalkitotoxin	Lyngbya majuscula	Neuroprotective Drug, Sodium channel blocker	(Shimizu, 2003)
21.	Scytonemin	Scytonema, Nostoc, Lyngbya	UV protection, Anti-inflammatory	(Stevenson et al., 2002)
22.	Mycosporin like Amino acids (MAAs)	Scytonema javanicum	UV protection, Cosmetics use	(Klisch and Hader, 2008; Oren and Gunde-Cimerman 2007; Singh et al., 2010)
23.	Phycobiliproteins	Cyanobacteria	Antimicrobial, anti-oxidant, anti-inflammatory, neuroprotective properties	(Romay et al., 2003; Dewi et al., 2018)
24.	Astaxanthin	Cyanobacteria	Anti-tumour activity	(Chen et al., 2003)
25.	Lycopene	Cyanobacteria	Anto-oxidant activity	(Klebanov et al., 1998)
26.	Carotenoids, β-Carotene, Lutein, Zeaxanthin, Cryptoxanthin, α-carotene, Lycopene	Nostoc muscorum, Phormidium foveolarum, and Spirulina platensis	Anti-oxidant, anticancer	(Cardozo et al., 2007; Kumar et al., 2017; Prasanna et al., 2010)

Figure 1. Cyanobacteria and their potential applications (Gerwick et al., 2001; Jha & Zi-Rong, 2004; Senthilkumar & John, 2008; Xiong et al., 2006)

Metabolites such as sulphated polysaccharides, which have antiviral activity, and which have also been reported to have anti-cancer properties (Raposo, de Morais, & Bernardo de Morais, 2013), are produced by Arthrospira sp. (Patterson, Larsen, & Moore, 1994). Arthrospira sp. also forms gamma-linolenic acid (GLA) that is useful in the control of cholesterol levels, lowering blood pressure and protecting the cardiovascular system (Białek & Rutkowska, 2015; Furmaniak et al., 2017). Apratoxins (Nostoc sp.), lynbyabellin (Lyngbya majuscula) and curacin (L. majuscula) were successfully used in drug discovery for different cancers (Vijayakumar, 2015). These properties result from the availability of carotenoids, chlorophylls, phycocyanins, various amino acids and minerals (Singh et al., 2005).

Cyanobacteria are an ideal model system for research on topics ranging from ecophysiology to molecular regulation of cellular events. Cyanobacteria have notable genetic plasticity and variability, making many strains easy to transform (Kühl et al., 2012a) (Kühl et al., 2012b). Many cyanobacterial genomes have been fully sequenced and are available in the databases (Cyano Clust, http://cyanoclust.c.u-tokyo.ac.jp/), Kazusa (http://www.kazusa.or.jp/), DOE Joint Genome Institute in the USA (http://www.jgi.doe.gov/), CyanoBase, CYORF (http://cyano. genome.jp/), Cyanosite (http://www-cyanosite.bio.purdue edu/). Thus, this review gathers together the information on the application of cyanobacteria for health benefits under the new term “cyanotherapeutics”.

Cyanobacteria as a source of food and nutraceuticals

Some cyanobacterial strains can be eaten directly without performing purification. Cyanobacteria contain 60% protein and are rich in beta-carotene, thiamine, riboflavin and Vitamin B12. Nostoc commune contains fibre and proteins and plays an important role in nutritionally rich human diets (Burja et al., 2001; Devillers et al., 2007; Jaspars & Lawton, 1998).

Cyanobacteria such as Spirulina, Anabaena and Nostoc are commonly used as a food source in countries such as Mexico, Chile, and the Philippines (Abed et al., 2009). Arthrospira platensis, commonly known as Spirulina, is one of the most popular cyanobacteria used as a health supplement in the form of powder, tablets or capsules. Spirulina is a rich source of proteins (60%), β-carotene and vitamin B₁₂ (Abed et al., 2009). NASA and the European Space Agency have remarked on the health value of Spirulina and stated that Spirulina can serve as a major source of food/food supplements and nutrition (Cornet & Dubertret, 1990; Mathur, 2018). Several other cyanobacterial species are also used as a food source and as nutraceuticals (Singh, Tiwari, Rai, & Mohapatra, 2011). Consumption of cyanobacteria results in several health benefits so they have traditionally been used as a “food for fitness”. Arthospira platensis is a rich source of β-carotene and several other biomolecules of nutraceutical value are popularly regarded as “food for the future” (Desai & Sivakami, 2004; Khan, Bhadouria, & Bisen, 2005; Mohan, Misra, Srivastav, Umapathy, & Kumar, 2014).

The pharmacological properties of cyanobacteria

As discussed above cyanobacteria are a source of several secondary metabolites/bioactive compounds (i.e., PUFAs, PBPs, carotenoids, and various enzymes and vitamins; Ghosh et al., 2016) and have great potential to be used as pharmacological agents in various disease conditions (Dunlap et al., 2007; Gademann & Portmann, 2008; Tan, 2007). Properties of bioactive compounds isolated from cyanobacteria include anti-cancer, anti-inflammatory, anti-malarial, anti-bacterial and neuroprotective activity (Abed et al., 2009; Bhadury & Wright, 2004; Burja et al., 2001; Devillers et al., 2007; Jaspars & Lawton, 1998; Kajiyama et al., 1998; Koehn et al., 1992; Matthew et al., 2010; Shimizu, 2003) suggesting a tremendous potential for the pharmacological industry in drug development. Some of these potential applications are discussed in the following sections.

Cyanobacteria as a neuroprotective agent

The photosynthetic accessory PBP pigments of cyanobacteria such as phycocyanin (PC), allophycocyanin (APC) and phycoerythrin (PE) have pharmacological properties such as antioxidant, anti-inflammatory, antitumour/cancer and neuroprotective activities (Bannu et al., 2019; Diyana, Plamen, Detelina, Rumen, & MIvanka, 2018; Jiang et al., 2017). Recently, Arthrospira platensis has been found to have immunostimulant, antiviral, hypocholesterolemic and hypoglycaemic activities and has high antioxidant activity due to c-phycocyanin (C-PC), GLA and phenolic compounds (Abdel-Daim, Abuzead, & Halawa, 2013; Kumar, Mella-Herrera, & Golden, 2010). C-PC is an active component of Spirulina which shows neuroprotective activity by inhibiting cyclooxygenase 2 (COX-2) and it has been suggested that the apoprotein associated with phycocyanin plays a key role in the inhibition of COX-2 (Reddy et al., 2000; Romay, Gonzalez, Ledon, Remirez, & Rimbau, 2003). Reactive Oxygen Species (ROS) play a vital role in the induction of neurodegeneration, and phycocyanin (C-PC) and phycocyanobilin show strong antioxidant activity, reduce ROS and help in protection from neurodegenerative conditions (Cervantes-Llanos et al., 2018; Pentón-Rol, Marín-Prida, & Falcón-Cama, 2018). Furthermore, it has been shown that dietary supplementation of Spirulina protects tyrosine hydroxylase positive neurons in an intra-striatal 6-OHDA lesion model of Parkinson’s disease (Chattopadhyaya et al., 2015; Stramberg, Gemma, Vila, & Bickford, 2005). The available report demonstrated that microglia play a key role in generating neurodegenerative diseases and supplementation of Spirulina shows a neuroprotective effect by down-regulating MHC II expression in microglia (Pabon et al., 2012). Bachstetter et al. (2010) found that Spirulina protected hippocampus neural progenitor cells against lipopolysaccharide (LPS) induced acute systemic inflammation. Patro, Sharma, Kariaya, and Patro (2011) have shown that Arthospira platensis suppressed glia activation and improved motor function in collagen-induced arthritic rats. Furthermore, Arthospira platensis reduces the accumulation of NF200 in the spinal cord neurons of arthritic rats, which inhibits neurodegeneration (Patro et al., 2011). Perez-Juarez, Chamorro, Alva-Sanchez, Paniagua-Castro, and Pacheco-Rosado (2016) have shown that administration of kainic acid induces neurodegeneration by causing neuronal damage in the CA3 hippocampal region which is reduced by supplementation of Spirulina. It was also demonstrated that supplementation of Spirulina reduces oxidative stress in the hippocampal region resulting in a neuroprotective effect (Hwang et al., 2011; Perez-Juarez et al., 2016).

Cyanobacterial LPSs present on the outer cell membrane of cyanobacteria possess immunostimulatory activity (Liu & Bing, 2011). Several studies have been conducted to evaluate the biological activity of cynobacterial LPSs (Durai, Batool, & Choi, 2015; Ianaro, Tersigni, & D’Acquisto, 2009; Liu & Bing, 2011; Moosová et al., 2019; Stewart, Webb, Schluter, & Shaw, 2006). The most characterized cyanobacterial LPS is “cyanobacterial product” (CyP) from Oscillatoria planktothrix FP1 which shows a neuroprotective effect by its antagonist activity to Toll-Like Receptor (TLR)-4 (Gemma, Molteni, & Rossetti, 2016; Molteni, Bosi, & Rossetti, 2018). A report from our group demonstrated that dietary supplementation by Spirulina improved locomotor activity and increased the lifespan in paraquat (herbicide) sensitive DJ-1β^Δ93flies (Parkinson’s disease model in Drosophila) (Kumar, Christian, Panchal, Guruprasad, & Tiwari, 2017). Down the line, other studies from our group have also shown the neuroprotective activity of Spirulina using Drosophila models of Alzheimer’s disease (Authors’ unpublished data).

In addition to various biologically active compounds cyanobacteria also produce many toxic compounds (“cyanotoxins”) such as microcystins (from Microcystis, Anabaena, Hapalosiphon, Nostoc, Oscillatoria, and Synechocystis), nodularin (Nodularia), saxitoxins (STXs) (Anabaena, Aphanizomenon, Lyngbya, Cylindrospermopsis), anatoxins-a (Anabaena, Planktothrix, Microcystis), cylindrospermopsin (Cylindrospermopsis) and aplysiatoxins and lyngbyatoxin-a (Lyngbya) (Burja et al., 2001; Dias, Paulino, & Pereira, 2015; Ferrão-Filho & Kozlowsky-Suzuki, 2011; Rastogi, Sonani, & Madamwar, 2015; Singh et al., 2005; van Apeldoorn, van Egmond, Speijers, & Bakker, 2007).

Anti-cancer activity of cyanobacteria

It has been demonstrated that cyanobacteria possess several bioactive derivatives that have the potential to kill cancer cells. Curacin A and cryptophycins isolated from cyanobacteria possess cytotoxic activity through an interaction with microtubule-binding proteins, which arrests cell division and induces apoptosis (Gerwick, Tan, & Sitachitta, 2001; Han, Kim, & Kim, 2008; Jordan & Wilson, 1998; Moore, Corbett, Patterson, & Valeriote, 1996). Oftedal et al., (2010) have shown that extracts from Anabaena sp. M27, M30 and M44 result in the induction of cell death in acute myeloid leukaemia (AML) in humans. Cryptophycin isolated from cyanobacteria, such as Nostoc sp. GSV224 (a Nostoc species discovered at the University of Hawaii to be a cryptophycin producer), possess anti-cancer activity against KB human nasopharyngeal cancer cells and LoVo human colorectal cancer cells (Patterson et al., 1991; Yasin et al., 2019). The cytotoxicity induced by cryptophycins was due to its interaction with microtubule-binding proteins disrupting tubulin dynamics and eventually causing death of tumour cells (Panda, Himes, Moore, Wilson, & Jordan, 1997). Cryptophycin acts as a tubulin-destabilizing agent and arrests tumour cells into the G-M phase of the cell cycle, resulting in hyper-phosphorylation of Bcl-2 and apoptotic signalling (Dias et al., 2015; Drew, Fine, Do, Douglas, & Petrylak, 2002; Smith, Zhang, Mooberry, Patterson, & Moore, 1994). However, the Phase II clinical trial of a synthetic analogue “crytophycin 52” failed the initial tests and showed severe toxicity, thus, it was abandoned for further anti-cancer drug development (Edelman et al., 2003).

Curacin and dolastatin have been shown to possess cytotoxic activity (Gerwick et al., 2001; Jordan & Wilson, 1998; Moore et al., 1996) and have potential for anti-cancer drug development (Chaganty, Golakoti, Heltzel, Moore, & Yoshida, 2004; Moore et al., 1996). Curacin-A was first isolated from Lyngbya majuscula (Gerwick, Roberts, Proteau, & Chen, 1994) and acts as an inhibitor of cell growth and mitosis activity by interacting with tubulin (Verdier-Pinard et al., 1998; Xiong, O’Keefe, Byrd, & McMahon, 2006; Yasin et al., 2019). Nostoc sp. has been shown to be more potent than currently available drugs for cancer such as taxol and vinblastine (Moore et al., 1996). Dolastatin-10, a metabolite isolated from cyanobacteria living in symbiosis with the sea hare Dolabella auricularia (Luesch, Moore, Paul, Mooberry, & Corbett, 2001) is a potent anti-proliferative agent, resulting from the presence of four amino acid residues, dolavaline, dolaisoleucine, dolaproline and dolaphenine, which bind with tubulin to arrest the cell into the G2/M phase, and also induce apoptosis (Maki et al., 1995). Dolastatin-10 failed the clinical trial (Phase II) due to its low yield but several dolastatin-10 synthetic derivatives have shown potential as an antiproliferative agent. Several studies have suggested that semisynthetic or synthetic derivatives of dolastatin, i.e., auristatin PE (TZT–1027, soblidotin) (Gradishar et al., 2012), synthadotin (ILX651; Rafiei & Haddadi, 2017) and cematodin (LU–103793; Ercolak, Sahin, Gunaldi, Duman, & Afsar, 2015)) possess better pharmacological and pharmacokinetic properties (Lichota, 2018; Mita et al., 2006; Watanabe, Minami, & Kobayashi, 2006). Several other cyanobacterial bioactive compounds have been tested in different human tumour cell lines for their cytotoxic activity. Apratoxin D, an analogue of apratoxin (apratoxin family of cytotoxins isolated from a Lyngbya sp.) from Lyngbya majascula is cytotoxic to human lung cancer cells (Gutierrez et al., 2008; Masuda et al., 2014; Thornburg et al., 2013) and symplocamide A from Symploca sp. possesses cytotoxic activity against lung cancer and neuroblastoma cells (Linington et al., 2008; Tan, 2010).

Bioactive compounds isolated from cyanobacteria have the ability to induce apoptosis and autophagy in the cancerous cell (Han et al., 2008; Kim et al., 2012). It was shown that HL-60 (a human leukaemia cell line) cells incubated with an extract from Synechocystis and Synechococcus sp. showed cell shrinkage and apoptosis (Martins et al., 2008). Biselyngbyaside (a macrolide glycoside) from Lyngbya sp. and an extract from marine benthic Anabaena sp. have been shown to induce cell death in mature osteoclasts (Teruya, Sasaki, Kitamura, Nakayama, & Suenaga, 2009; Yonezawa et al., 2012) and in an AML cell line (Oftedal et al., 2010).

There are other cyanobacterial bioactive compounds that have the potential to inhibit cancer by arresting the cell cycle, inducing mitochondrial fragmentation, oxidative damage, alteration of apoptotic signalling pathways, modulation of caspase signalling and via sodium channels (Fig 2). In a study by Gunasekera, Ross, Paul, Matthew, and Luesch (2008), dragonamide C and dragonamide D isolated from Lyngbya polychroa displayed anti-cancerous activity similar to that of dragonamides against leishmaniasis (Balunas et al., 2009; Jimenez & Scheuer, 2001; McPhail et al., 2007). Calothrixin A, an indolophenanthridine from Calothrix sp., induces cell cycle arrest in the G2/M phase in human cancer cell lines (Chen, Smith, & Waring, 2003). Dolastatins isolated from cyanobacterial strains can arrest cell cycles (Luesch et al., 2001). Hectochlorin and lyngbyabellins, lipopeptides isolated from the genus Lyngbya, can induce arrest in G2/M phase in a human Burkitt lymphoma cell line (Marquez et al., 2002).

Figure 2. Anti-cancer activity associated with cyanobacteria (Luesch et al., 2001; Xiong et al., 2006; Yonezawa et al., 2012; Marquez et al., 2002; Drew et al., 2002)

Aurilides A and B isolated from marine cyanobacteria can induce mitochondrial dysfunction (Sato et al., 2011). Since mitochondria play a key role in the generation of oxidative stress, mitochondrial fragmentation in cancerous cells will affect the oxidative stress level and may cause oxidative damage to the cancerous cells. There are several cyanobacterial compounds that can alter mitochondrial dynamics and increase oxidative damage to cancerous cells. Calothrixin A has been shown to increase intracellular ROS, which induces oxidative stress and DNA fragmentation in Jurkat human T cells (Chen et al., 2003). Cryptophycins 1 and 52 have also been shown to induce caspase-1 and caspase-3 dependent cell death and DNA fragmentation (Drew, Fine, Do, Douglas, & Petrylak, 2002; Mooberry, Busquets, & Tien, 1997). A study by the National Cancer Institute demonstrated that β-carotene is anticarcinogenic in nature with strong antioxidant properties. Spirulina was used for the treatment of radiation sickness after the Chernobyl disaster in Russia (Loseva & Dardynskaya, 1993).

Cyanobacteria and diabetes

Diabetes mellitus is a major threat to the global population, and one of the leading causes of human death after cancer and cardiovascular diseases (Senthilkumar & John, 2008). It is a metabolic disorder in which insulin deficiency occurs and blood glucose/blood sugar remains high for a prolonged time (Pandurangan & Kim, 2016), ultimately resulting in the onset of hypertension, nephropathy, retinopathy and cardiomyopathy (Senthilkumar & John, 2008). There are two types of diabetes, type 1 and type 2. In type 1 diabetes, insulin production is inhibited by the body, while in type 2 diabetes, body cells are not able to respond to insulin resulting in insulin resistance (Lauritano & Ianora, 2016; Pandurangan & Kim, 2016). The number of diabetic patients is increasing significantly across the globe, which is of immediate concern.

Due to several health-related problems caused by the prolonged use of allopathic medicines, researchers are interested in using traditional medicines to cure/improve diabetic conditions. Thus, several efforts have been taken to identify plants or plant-based components with anti-diabetic properties (Białek & Rutkowska, 2015; Kar, Maharana, Pattnaik, & Dash, 2006). The possible application of cyanobacteria for anti-diabetic activity has been investigated (Gerwick, Mrozek, Moghaddam, & Agarwal, 1989; Layam & Reddy, 2006; Pandurangan & Kim, 2016; Priatni et al., 2016). Some cyanobacterial such as Chroococcus minor, Synechocystis pavalakki, Phormidium corium, Arthrospira platensis, Oscillatoria chalybea, Spirulina labyrinthiformis, and Fischerella sp. show hypoglycaemic effects (Ahmed, Badawi, Mostafa, & Higazy, 2018; Senthilkumar & John, 2008). Arthrospira platensis, in particular, forms phytochemicals such as flavonoids, phytopigments, and sterols which have shown a strong hypoglycaemic effect, helping to reduce the blood glucose, Serum Glutamic Oxaloacetc Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT), Acid phosphatase (ACP) and Alkaline phosphatase (ALP) levels in alloxan-induced diabetic rats, and suggesting that Spirulina has antihyperglycaemic activities (Senthilkumar & John, 2008). Further, the supplementation of Spirulina helps in the prevention of complications of type 2 diabetes by lowering blood glucose levels during fasting and post-prandially (after a meal), i.e., haemoglobin A1 c (HbA1 c) level (Parikh, Mani, & Iyer, 2001). Additionally, Spirulina also helps in the regulation of lipid profiles in type 2 diabetes (Parikh et al., 2001). Pandurangan and Kim (2016) have shown that oral administration of the cyanobacterial extract to streptozotocin diabetic rats for up to 60 days showed reduced blood glucose levels and lipid peroxidation in diabetic rats. They showed that reduction in blood glucose level was due to increased plasma insulin, serum C-peptide and improved glycolytic enzymes resulting from cyanobacterial administration in diabetic rats. Layam and Reddy (2006) showed that supplementation with Spirulina increases weight gain in diabetic rats due to the improved function of plasma insulin, C-peptide and hexokinase activity. Thus, they proposed an antihyperglycaemic effect of Spirulina. Further, an in vitro study by Ghosh et al. (2016) demonstrated the antihyperglycaemic effect of cyanobacterial pigments such as C-phycoerytherin (C-PE), phycocyanin (C-PC), lycopene and myxoxanthophyll. Their study suggested that the antihyperglycaemic effect was due to the inhibition of α-glucosidase by said cyanobacterial pigments.

Cyanobacteria and anti-viral activity

Several studies have suggested that antiviral activity is associated with cyanobacteria (Luescher-Mattli, 2003; Nowotny, Mentel, Wegner, Mundt, & Lindequist, 1997). Nowotny et al. (1997) demonstrated that a crude extract from Microcystis aeruginosa has antiviral activity against Influenza A virus; bioactive compounds from Lyngbya lagerheimii and Phormidium tenue possess anti-HIV activity (Gustafson et al., 1989; Schaeffer & Krylov, 2000; Vijayakumar, 2015); extract from Spirulina has the potential to inhibit the replication of viruses (o measles and HIV-1; Cohen, Jorgensen, Revsbech, & Poplawski, 1986; Jha & Zi-Rong, 2004). Chen et al. (2016) have shown anti-viral properties associated with cold water extract of A. platensis. The group demonstrated that viral plaque formation in a broad range of influenza viruses, including oseltamivir-resistant strains, was inhibited by the A. platensis extract. Furthermore, they observed that Spirulina extracts increased the lifespan of influenza-infected mice. The mechanism identified was inhibition of the influenza haemagglutination at an early stage of infection that decreased the virus yields in cells. Patterson et al. (1994) demonstrated that Chroococcales commonly produce antiviral agents. Extracts from 694 strains representing 334 species of cyanobacteria were examined for anti-HIV-1 activity and 529 strains were examined for anti-HSV-2 and anti-RSV activity. Approximately 10% of extracts exhibited antiviral activity against HSV-2 or HIV-1, whereas ~2% showed activity against RSV. They observed that antiviral activity was more commonly associated with lipophilic extracts than with hydrophilic extracts (Patterson et al., 1994). A study by Hernandez-Corona, Nieves, Meckes, Chamorro, & Barron (2002) demonstrated the antiviral activity of hot water extract of Spirulina maxima against Herpes simplex virus type 2 (HSV-2). Several cyanobacterial species release acidic polysaccharides, such as calcium spirulan (Ca-SP) from Arthospira platensis, which act as potent inhibitors of herpes simplex virus-1 (Hayashi, Hayashi, & Kojima, 1996; Kanekiyo et al., 2005), and a fucoidan from the sporophyll of Undaria pinnatifida (Hayashi, 2008). Ichthyopeptins A and B, two cyclic depsipeptide compounds released from Microcystis ichthyoblabe, show antiviral activity against influenza A virus (Zainuddin et al., 2007). Calcium spirulan (Ca-Sp) prevents several viruses from replicating and exhibits antiviral activity against the human immunodeficiency virus type 1 (HIV-1), HSV-1, influenza virus, human cytomegalovirus (HVMV), mumps virus and measles virus (Barrón, Martín Torres-Valencia, Chamorro-Cevallos, & Zúñiga-Estrada, 2007; Hayashi, 2008; Ramakrishnan, 2013; Simpore et al., 2005).

El-Baz, El-Senousy, El-Sayed, and Kamel (2013) have demonstrated that 53.3%, 66.7%, 76.7%, 56.7% and 50% ethanol extract of Arthospira platensis reduces infectious units of adenovirus type 7, Coxsackievirus B4, astrovirus type 1, rotavirus Wa strainand adenovirus type 40, respectively, in vitro. Further, five freshwater cyanobacterial species, Anabaena sphaerica, Chroococcus turgidus, Oscillatoria limnetica, and Arthospira platensis exhibit antiviral activity against adenovirus type 40 (Abdo, Hetta, El-Senousy, Din, & Ali, 2012).

Cyanobacteria and immunomodulatory activity

Several studies have suggested immunomodulatory and anti-inflammatory activities associated with Spirulina (Abdel-Daim et al., 2013; Finamore, Palmery, Bensehaila, & Peluso, 2017; Ou, Lin, Yang, Pan, & Cheng, 2013; Wu et al., 2016). A study by Abdel-Daim et al. (2013) showed that supplementation of Arthospira platensis powder (500 and 1000 mg kg⁻¹) to mice decreases tumour necrosis factor-alpha (TNF-α) in serum and alters the expression of oxidative stress markers such as nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPX) in hepatic, renal and brain tissues (Abdel-Daim et al., 2013). Their work has shown the anti-inflammatory and immunomodulatory effect of Spirulina in acetic acid induced ulcerative colitis rats. Finamore et al. (2017) showed that supplementation of Spirulina affects the innate immune response and promotes the activity of natural killer cells thus having anti-hypersensitive, anti-inflammatory and immunostimulating effects (Ou et al., 2013). Further, a study by Wu et al. (2016) has suggested that the immunomodulatory and anti-inflammatory response are due to the active components of Spirulina such as phycocyanin and β-carotene and their regulatory effect on ERK1/2, JNK, p38 and IkB signalling pathway.

Bio-economic aspects of the use of cyanobacteria in medicines

There is a continuous increase in the world’s population which may reach nine billion by 2050 (Singh et al., 2017). The increase in population with limited natural resources will have major impacts on food and health. Moreover, dependency on agricultural crops in limited land space will be insufficient to meet the requirements of growing populations (Huisman et al., 2018; Zahra et al., 2020). It requires us to explore cost-effective alternative resources to meet the continuously increasing demand of a global population growing in terms of nutrition and healthcare. Cyanobacteria and algae can help to fulfil the growing demand of increasing populations (Mulkidjanian et al., 2006; Pisciotta et al., 2010). In this review, we have shown the potential application of Cyanobacteria for human welfare and in medicines. As is known very well, the use of allopathic medicines for most health issues has been of immense value for quick relief of health problems. However, being a symptomatic cure system, allopathic medicines have severe side effects on other cells and eventually on the human body as a whole. It has been reported that continuous and prolonged use of allopathic medicine may affect the immune system and give rise to the development of multidrug resistance (Aslam et al., 2018; Karam, Chastre, Wilcox, & Vincent, 2016). So, the total cost of the use of allopathic medicine to treat a particular health-related issue remains higher as compared to the involvement of natural therapy or ayurvedic treatment. It can be better explained by citing the prolonged use of Paracetamol to cure a fever that triggers a threat of liver damage (McCrae, Morrison, MacIntyre, Dear, & Webb, 2018). Similarly, use of chemotherapy for cancer patients culminates in problems such as excessive hair loss, weaker immune system, improper metabolism, dermatological disorders (Aslam et al., 2018; Biswal & Mehta, 2018). While the use of ayurvedic/herbal medicine has no known side effects, it takes relatively longer but has great potential to cure several health-related issues. In terms of the bio-economic use of allopathic vs. ayurvedic medicine, the latter is much cheaper in the long run. It is pertinent to mention that among all the medicinal plants currently used for therapeutic purposes, some of the unique characteristics of cyanobacteria such as being the store house of a wide variety of bioactive compounds with a wide range of applications in pharmaceuticals, not requiring much nutrition for their growth and can be grown with little/residual nutrient with high production in terms of lipids (60–65% of dry weight), proteins (33–p50%), carbohydrates, etc. as compared to the agricultural land-based crops with a high cost of cultivation. They have fast-growing potential with no requirement of agricultural land, for cultivation, only a tank containing water and nutrient is sufficient for their luxuriant growth, easy to harvest and transport along with harbouring medically important biomolecules. Also, cyanobacteria have a higher yield per area as compared to agricultural crops and the ability to grow on non-productive and non-arable lands and different water conditions (Zahra et al. 2020). These features make cyanobacteria bio-economically good potential candidates for further exploration towards therapeutics purposes.

Allopathic medicines can be good in the case of any medical emergency such as heart attack, brain haemorrhage and serious accidents. However, for the treatment of chronic cases, allopathic medicines may not be the best choice because use may increase the treatment cost many-fold and worsen the situation over time. Many drugs have been launched onto the market but after years of use, it was noticed that there were serious side effects so they were banned.

Being the factories for several bioactive compounds, cyanobacteria may be a potential target to treat several diseases. There have been many studies investigating the pharmacological properties associated with cyanobacteria and their bioactive components. However, to bring cyanobacteria and their active components into translational mode, detailed in vivo and in vitro studies using different animal models and clinical studies will be essential (El Semary & Fouda, 2015; Guihéneuf, Khan, & Tran, 2016; Malathi, Ramesh Babu, Mounika, & Digamber Rao, 2015; Mukund & Sivasubramanian, 2014; Volk & Furkert, 2006).

Acknowledgments

The financial assistance from Gujarat Council of Scientific and Technology (GUJCOST/MRP/2015-16/2680), India to AKT is duly acknowledged. The authors are thankful to the Puri Foundation for Education in India for Infrastructure support.

Disclosure statement

The authors declare that there are no conflicts of interest.