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The Enhancement of Astaxanthin Production Using Medium Cultures Components, Stressors, Nanoparticles, Elicitors, and Gene Engineering in Haematococcus pluvialis

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27 January 2023

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03 February 2023

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Abstract
Natural astaxanthin is a precious substance obtained from some organisms such as microalgae. This plant has many benefits for humans, so research into its cost-effective and economical production has recently increased. For this purpose, some methods such as the use of different culture media, gene engineering, different stresses, nanoparticles, bio acids, and phytohormones are important. Accordingly, this review study was conducted to demonstrate the effect of the factors mentioned above for the high production of astaxanthin in microalgae, especially Haematococcus pluvialis (H.p).
Keywords: 
Subject: Biology and Life Sciences  -   Biology and Biotechnology

Introduction

Green microalgae have more than 7,000 species that live in a variety of habitats. They produced beneficial components for humans, such as astaxanthin, carotenoids, canthaxins, and so on. Astaxanthin (3,3-dihydroxy-β, β-carotene-4, 4′-dione) is a precious keto carotenoid and a coloring agent in aquaculture (Borowitzka, 1992b, Borowitzka, 1992a, Kobayashi et al., 1993). Naturally, astaxanthin (AX) pigments are synthesized by several types of microalgae, plants, bacteria, and fungi. (Gao and Meng, 2012). The most important natural producer of astaxanthin is H. pluvialis (Chlorophyceae, Volvocales) with 80% dry weight of astaxanthin. (Garshasbi et al., 2020), H.p is a unicellular freshwater microalgae. The microalga has two life cycles, moving green and fixed red, the second cycle is called cyst, at which stage astaxanthin is produced (Xi et al., 2016). Various stresses and inducers on H.p stimulate astaxanthin production. Researchers are looking for economical approaches to maximizing this product. The use of different stresses, inducer materials, culture media, and gene engineering are the main methods. Stresses include excess light (Xi et al., 2016), salt (Johnson and An, 1991)and nitrogen deficiency (Boussiba, 2000). Inducers include biological acids, including salicylic(Raman and Ravi, 2011), linoleic, Jasmonic acids (Xi et al., 2016), and nanoparticles, such as TiO2, SiO2, Cd, etc. (Xia et al., 2015). Such research has been done on other organisms such as Chlorella sorokiniana (hassan jalili, 2016), Bifidobacterium animalis subsp. lactis Bb 12 (Jalili et al., 2010), and Chlorella vulgaris (Jafari et al., 2016). In this review, the outcomes of researchs firstly on the structure of astaxanthin, secondly the best medium cultures, effective genes and the effect of different stressors and inducers on microalgae, especially on H.pluvialis for AX production, were collected.

Astaxanthin structure

The main structure of AX consists of a lycopene structure with typically 40 carbon atoms, two polar ring ends, and dual hydrogen bonds. (Higuera-Ciapara et al., 2006a). Astaxanthin has different structures depending on the type of fatty acid used in it, these fatty acids include palmitic, oleic, stearic, linoleic, or none of them. Natural AX is esterified while artificial one is not. (Johnson and An, 1991). Astaxanthin (3,3′-dihydroxy-ß-carotene-4,4′-dione) is a member of the lutein, lycopene, and β-carotene family, synthesized by some microalgae, yeast, plants, bacteria, and could be found in some living creatures including salmon, trout, lobster, shrimp, and fish eggs (Higuera-Ciapara et al., 2006b), (Ambati et al., 2014). There are three forms of AX in crustaceans (Arango, 1996).AX is found in nature in two forms and three variable configurations (Yang et al., 2013),(Al-Bulishi et al., 2015). Astaxanthin is produced in microalgae for defense and cellular storage purposes and is synthesized from pyruvate and glyceraldehyde-3-phosphate via the carotenoid pathway. The antioxidant power of astaxanthin is 65, 54, and 10 times higher than that of vitamin C, beta-carotene, and zeaxanthin, respectively. (Miki, 1991), (Koller et al., 2014, Pérez-López et al., 2014), (Pérez-López et al., 2014).Today, more than 95% of the consumable Astaxanthin used in the world is produced industrially; while the natural one of H. pluvialis is about <1% (Koller et al., 2014). The synthetic Astaxanthin contains C10 -aldehyde and asta-C15 - triarylphosphonium salt that connect in a Wittig reaction (Krause et al., 1997), The natural antioxidant AX has 20 times the capacity compared to the industrial sample and is very useful for humans (Lorenz and Cysewski, 2000). The appropriate natural one is a preferred choice for human consumption, because of its benefits and antioxidant power (Li et al., 2011). This microalgae (H. pluvialis) has a complex life cycle that includes four different morphological stages (Micro, Macrospore, Palmela, and Apalanspur). The life cycle change of Haematococcus pluvialis depends on environmental conditions can affect the antioxidant power of astaxanthin, which means that if the microalgae cells in the aplanospore (red blood cell) stage are placed in a suitable culture medium without any stress, they re-enter the microspore (green cell) stage. (Boussiba, 2000), (Li et al., 2011).

The best medium cultures for Astaxanthin production

Depending on the purpose, there are many medium cultures for growing microalgae. For example, in the Phaffia rhodozyma mutant (NCHU-FS501), the addition of glucose to agar in malt yeast culture had a high positive effect on AX production. (Fang and Chiou, 1996). A new two-stage mix trophic culture system using NIES-C media (Park et al., 2014) and an attached cultivation system using the immobilized biofilm in BG-11 medium(Zhang et al., 2014) were invented for Astaxanthin production for H.pluvialis. In the autotrophic media for cell growth and Astaxanthin production, BBM, in the mixotrophic media also KM1, MM2 and KM2 were the best respectively, for carotenoid synthesis KM1in Agar was the most appropriate medium. KM2 with trace elements and B vitamins was excellent for the production of astaxanthin (Fang and Chiou, 1996). Optimal Astaxanthin production (0.8 g.l mg.l-1 or 3.8% of Dry wigth (DW) )was obtained in initial biomass densities (IBDs) with no nitrogen, and maximum Astaxanthin (16.0 mg. l-1 ) earned in 0.8 (g.l-1) (DW), with 4.4 mM nitrogen in medium culture (Wang et al., 2013a). No P and low N with Photosynthetically active radiation 240 μmol photons m−2 sec−1 (PAR) in BBM medium culture produced the best biomass containing 33% lipids that had more saturated fatty acids, and less unsaturated fatty acids (linoleic, oleic, and α/γ-linolenic) (Saha et al., 2013). Researchers displayed that the best compounds for optimal H .lacustris growth rate were 0.25 (g.l-1) potassium nitrate, 0.51 (g.l-1) sodium acetate, 0.63 (ml.l-1) the major element stock solution and 0.2 (ml.l-1) trace elements. In another study it was displayed that the special compounds for the most biomass production were1.64 (g.l-1) sodium acetate, 0.37 (g.l-1) potassium nitrate, 2.52 (ml.l-1) the major element stock solution and 0.03 (ml.l-1) the trace element stock.(Gong and Chen, 1997) .
H.pluvialis (strain vischer 1923/2) grows the best at high nitrate concentration (about 0.5– 1.0 g.l-1), phosphate concentration of (0.1.g.l-1 K2HPo4) and much amount of Fe2+. Nitrate Decreasing or phosphate increasing induces the exchange of green cells to reddish palmella cells. Acetate improves green and red cells that contain Astaxanthin. The maximum temperature and salinity for H.pluvialis are 28C° and approximately above1% NaCl (Li et al., 2011). H.pluvialis grows well in high nitrate concentration (about 0.5 to 1.0 g.l-1 KNO3), the average rate of phosphate (about 0.1 g.l-1 K2HPO4) and most of Fe. Low concentration of nitrate and high rate of phosphate initiate Astaxanthin production (Li et al., 2011). Addition of acetate and ferrous ion to the basal medium culture (BBM) of H.pluvialis exchange green cell to red cells containing Astaxanthin. For carotenoid and AX precursor formations, mevalonate and pyruvate are useful and pyruvate is very special (Kobayashi et al., 1991). H. pluvialis in rich medium culture with FeZ+ and acetate in high light produced the most amount of Astaxanthin. Continuous illumination was better than cyclic illumination. Also, the type of light is important for increasing astaxanthin. Red and blue lights are the best spectra for AX formation (Kakizono et al., 1992). Environmental factors on cell growth and astaxanthin production were studied in H.pluvialis. A group of researchers discovered that maximum growth rate of H.pluvialis earned in BBM medium culture in 28°C, continues white fluorescent illumination and, direct aeration, while maximum Astaxanthin production determined in BAR medium culture, continuous illumination and sodium acetate without aeration (Domínguez-Bocanegra and Torres-Muñoz, 2004). H.pluvialis can grow both heterotrophically and mixotrophically by acetate in the dark and light, respectively. There are two independent metabolic pathways for mixotrophic growth of H.pluvialis (Kobayashi et al., 1992). Acetate and especially acetate plus Fe2+ can change H.pluvialis green cells to red cyst cell. Acetate and Fe2+induce green and red cyst cells, respectively (Kobayashi et al., 1993). In a study, two microalgae (Tetraselmis sp and C. sorokiniana) were investigated for Astaxanthin production. It was produced in aerated and unaerated conditions.(Rasid et al., 2014) . Scientists have developed a new method for extracting astaxanthin using hydrochloric acid at specific time and temperature (Sarada et al., 2006). Distilled water with CO2 without N with illumination of 546 μmol photons (m-2 s-1) was the best medium culture for the production of astaxanthin from Haematococcus.(Imamoglu et al., 2009). Growth factors for H.pluvialis growth were measured in an experimental design. The best temperature for astaxanthin production was 25 ° C to 28 ° C and saturation radiation of 90 μmol quantum (m−2s−1) (Fan et al., 1994). An H.pluvialis medium culture optimization test was performed between 18 compounds in semi-continuous culture to determine the highest productivity. The best result was obtained in %20 OHM medium culture that contained 3.77 × 10 5 cells. Ml-1, it was three times as much activity compared with BBM medium culture, and higher cell density was obtained using three times nutrition (Fábregas et al., 2000). Scientists invented a two-stage culture system to produce astaxanthin from H. pluvialis. In this method, green cells were grown in semi-continuous cultures and then exposed to high light in batch cultures to produce astaxanthin. (Fábregas et al., 2000) In an experiment performed by a group of scientists, many factors were tested for the formation of astaxanthin. Nitrogen and phosphate deficiency, high levels of iron and radiation alone increase AX formation(Harker et al., 1996). The effect of some factors such as high light intensity and starvation of iron, sulfur and phosphate to produce more astaxanthin in medium culture was tested in an experiment, so especially sulfur starvation had the best results. (He et al., 2007) .In a comparison experiment between new photobioreactors for H.pluvialis culture, NIES-144 and 3-lC-ALPBR photobioreactors had the highest cell growth rate and 90-l FP -ALPBR had the highest economic efficiency (Issarapayup et al., 2009). The effects of surface response (RSM) NaNo3, Co2, light intensity and inoculation volume on the growth of Haematococcus pluvialis cells were studied. Good results were obtained in NaNo3 1.06 g .l-1, Co2 1.54, light intensity 2.42 Klux and inoculation volume 24.97 (Issarapayup et al., 2009). In one study, the effects of temperature and light / dark cycle on astaxanthin production were investigated. The results showed that increasing the night temperature reduces astaxanthin, while increasing the light temperature increases its content. (Wang et al., 2014). A new open pound system was tested to determine growth cells and produce astaxanthin (two-stage growth one-step process) in four strains of Haematococcus pluvialis, two strains were selected for mass culture, H. pluvialis 26 and H. pluvialis WZ which can produce 51.06 and 40.25 mg biomass per liter. (Zhang et al., 2009). The important factors for Astaxanthin production in a variety of microalgae, Haematococcus pluvialis UTEX 16, were identified.
Among high irradiation, nitrogen deficiency, addition of acetate and addition of iron ions with acetate, addition of iron ions to acetate had a negative effect on astaxanthin production. (Choi et al., 2002)In one study, important factors for biomass and astaxanthin production by RSM method in Haematococcus pluvialis (CCAP 7.34) were investigated. They were photon flux density (50–60 μmol.m-2 s-1 for biomass production, and ∼1600 μmol .m-2 s-1 for Astaxanthin accumulation), low amount of NaCl, and temperature between 14–15 °C, the most effective factor was irradiation (Harker et al., 1995). When green Haematococcus was starved for phosphate or nitrogen separately or together, the rate of Astaxanthin accumulation raised up to 4% cell dry weight. Also Nitrogen starvation accumulated Astaxanthin faster and more than phosphate starvation (Boussiba et al., 1999). The biomass of Haematococcus pluvialis in Chemostat culture with dilution rate of 0.9 per day, brightness level of 1.220 (μE/m2 · s) and different nitrate levels from 1.7 to 20.7 (mM), is related to nitrate level. NaNo3 0.15 (g.l-1) was the best factor for astaxanthin production and cell growth. The use of malonate in culture increased carotenoid synthesis by an average of 13 times (Orosa et al., 2005). Batch culture with three medium cultures containing medium cultures of BBM, BG11 and 3NBBM was studied. The best BBM culture medium was the best for growth. BBM medium with 3 times phosphate produced 86% growth and maximum cell density, also growth rate of H.pluvialis cells with inoculation size of 105 2 2 cells per liter in BBM medium with 0.046 (mM) iron or 0.185 (mM) boron Was greater than cell growth with two or half iron levels (Nahidian et al., 2018). A new system for cultivation of H.pluvialis microalgae designed. In this system, a photo bioreactors (PBR) fence for green cells in addition to a raceway pond for red cells was designed. The result was excellent(Panis and Carreon, 2016). It is determined that photorespiration did not affect dry Wight, chlorophyll and OJIP transients. Photosystem II (PSII) system performance and total photosynthetic O2 evolution capacity were clearly reduced by inhibition of light respiration. Therefore, astaxanthin content is positively correlated with light respiration, so it plays an important role in the AX production cycle (Zhang et al., 2016).
AX production was optimized by heterotrophic-photoautotrophic culture in H.pluvialis . The optimum situation for AX production was PH 8 and 25℃, different acetate concentrations were between 10 (mM.l-1) and 30 (mM.l-1) for cell growth. When growth environment was changed from heterotrophic to photoautotrophic, a decrease in a cell number was seen but AX accumulation was more significant. AX concentrations and productivity were 114 (mg.L-1) and 4.4(mg.L-1.day-1), respectively, which are high in current methods (Hata et al., 2001). Maximum AX production was determined in 12-14 hours of light in H.pluvialis (Praveenkumar et al., 2015). A new method for producing AX on an industrial scale was discovered. This method is based on Aquasearch Growth Module(AGM), the results of this method are: 1- Increasing biomass density 2- Increasing AX production (Olaizola, 2000). In a new study, a fed-batch medium culture was used to further grow H.pluvialis cells and produce AX, which contained 10 times more nutrients in addition to blue LEDs. In batch feeding culture, cell growth increased also AX production increased under the influence of blue LED. (Lababpour et al., 2005).
The effects of light, temperature and C/N ratio on cell growth and AX production were measured in H.pluvialis . Light increased cell growth and AX production 6-fold. The cell growth in multidirectional light (three-directional) was increased 4 times more than control. Biomass in the low temperature (25℃) was increased while in higher temperature (35℃) AX production increased. (Tripathi et al., 2002).Irradiation (170 μmol .m-2s-1), low phosphate and salt increasing (NaCl 0.8%) increased AX synthesis and decreased cell biomass in Haematococcus pluvialis. One result of this study was that AX synthesis increased when Haematococcus pluvialis cell division was inhibited. (Boussiba et al., 1999). A three-dimensional reconstruction experiment was performed to understand how AX accumulates in H.pluvialis cells. This study showed that the formation of AX in motile cells and cysts is directly related to the resizing of intracellular organs, some of which are chloroplasts, nuclei and mitochondria. The chloroplast has inverse proportion with AX in cyst cells, also starch grain, cell walls, Golgi apparatus, nucleus, and mitochondria in a cyst cell become smaller than those in movable stage cells. In the AX synthesis step, chloroplasts break down but are not completely removed in red cyst cells (Wayama et al., 2013). A new method was designed by combining two methods to increase commercial biomass and AX. This method uses two strategies: 1- maximum production in minimum time and 2- continuous cultivation under limited stress. The volume of biomass and AX was about 4% of dry biomass and AX 1.5 (mg .L-1), which can be increased at any stage and other stresses such as radiation can be used. (Aflalo et al., 2007). The effect of primary hematococcal biomass on astaxanthin accumulation in outdoor culture was measured that the optimal biomass was 0.8 (g .l-1) and the highest AX accumulation was 1.17 (mg . day-1). (Wang et al., 2013b). Inoculation density of 10 M and radiation intensity of 100 (μmol . m-2 s-1) with 1.8 (g . m-2) NaNO3 in BG-11 medium culture were the best conditions for H.pluvialis growth and AX production (Katsuda et al., 2006). BBM was the best medium culture for autotrophic growth, KM1 was the best medium culture for AX production. Its production in H.pluvialis was induced by adding trace element and vitamin B to MM1 and MM2 medium cultures (Fang and Chiou, 1996). In continuous cultures of Chemostat with N deficiency in Haematococcus lacustris (Gir.) Rostaf (UTEX 16), the highest AX accumulation was obtained with the lowest dilution rate. One study found that pigment production was positively correlated with surface radiation density. AX content was independent of culture elements (Lee and Soh, 1991). The percentage of Haematococcus pluvialis MUR 145 Aplanospore components was determined in an assay. It contained (3S, 3′S)-astaxanthin diester 34%, canthaxanthin (4%), echinenone (4%), β-carotene (5%), (3S, 3′S)-astaxanthin monoester (46%), lutein (6%) and (3S,3′S)-astaxanthin (1%) (Chen et al., 2015).

Astaxanthin producing Genes and engineering

Some scholars displayed that Astaxanthin synthesis is influenced by 8 genes in H.pluvialis, Astaxanthin synthesis is more controlled by carotenoid hydroxylase and less by isopentenyl isomerase، phytoene desaturase، phytoene synthase and carotenoid oxygenase, respectively (Shah et al., 2016). In a study of the metabolic pathway of astaxanthin in Haematococcus pluvialis and Chlorella zofingiensis, two different pathways and their genes were discovered. (Danxiang Han &Yantao Li 2013)The transcripts of 8 genes that Participated in Astaxanthin biosynthesis were investigated in H.pluvialis , it was exposed on 2, 4-epibrassinolide (EBR) then transcripts were tested by the qRT-PCR method. The results showed that 25 and 50 mg .l-1 EBR concentrations were the best for AX accumulation. Also 25(mg.l-1) EBR had more effect on the expression of ipi-1, ipi-2, crtR- B, lyc, and crtO relative to psy, pds, and bkt, also 50(mg.l-1) EBR more affected on some genes than other genes (Gao et al., 2013b). Using the β-end ketolase gene from Agrobacterium aurantiacum, the metabolic pathway of Zeaxanthin β-d-diglucoside, as well as the new substances astaxanthin β-d-diglucoside and adonixanthin β-d-diglucoside were synthesized (Danxiang Han &Yantao Li 2013). It determined that Biosynthetic processes of carotenoids were performed with several enzymes produced by carotenoid genes in H.pluvialis. (Huang et al., 2006). The biosynthetic pathway of Astaxanthin in H. pluvialis was demonstrated using the inhibitors and some of the related genes that were cloned. (Grünewald et al., 2000). For example, two genes in H. pluvialis that encode isopentyl pyrophosphate isomerase, ipi1 and ipi2, are upregulated at the transcriptional level to facilitate the synthesis of pyrophosphate from isopentyl (EONSEON et al., 2006). Phytoene synthase (psy) is the first step in the biosynthesis of carotenoids to form phytoene, which make up the entire carotenoid precursor (EONSEON et al., 2006). Two enzymes that are similar in structure and activity, phytoene desaturase (pds) and carotene desaturase (zds), combine to convert colorless python to red lycopene, but their isomer structure has not yet been determined. (EONSEON et al., 2006). Lycopene to β-carotene cycle contains lycopene beta catalysis enzymes (lyc) that are necessary for Carotene to Astaxanthin conversation under environmental stressors (EONSEON et al., 2006). In the conversion of beta-carotene to astaxanthin, the enzymes beta-carotene ketolase (bkt2) (Gao et al., 2012), beta-carotene oxygenase (crtO) and beta-hydroxylase (crtRB) perform the necessary oxygenation interaction. (Vidhyavathi et al., 2008). Gene Regulation can be seen in RNA, especially in response to environmental stressors. (EONSEON et al., 2006). For example, psy and crtR-B gene expression will be increased comprehensively when H. pluvialis exposed to light and salt, so Astaxanthin accumulation will be increased in the cell (Steinbrenner and Linden, 2001). The results show that Astaxanthin biosynthesis is associated with the regulation of gene expression (Vidhyavathi et al., 2008). A new biosynthetic metabolic pathway involving five genes for astaxanthin biosynthesis has been developed by scientists (Misawa et al., 1995). The new cDNA was obtained from H.pluvialis which can produce AX, and also contains the beta-carotene genes of the bacterium Erwinia uredovora (Kajiwara et al., 1995). A gene isolated from Xanthophyllomyces dendrorhous was cloned into the beta-carotene mutant gene to produce Astaxanthin. The results showed that this gene has two functions, the first is ketolase and the second is hydroxylase. (Ojima et al., 2006). Researchers found that the CrtS gene plays an important role in the conversion of β-carotene to xanthophyll 12. (Álvarez et al., 2006).Two genes, crtW38 and crtW148, were cloned from a cyanobacterium, Nostoc punctiforme PCC 73102, into Escherichia coli and expressed, both of which convert β-carotene to canthaxanthin, but only crtW148 was able to produce astaxanthin. (Steiger and Sandmann, 2004). In a gene engineering experiment, the gene that produces the enzyme carotenoid biosynthesis (phytoene desaturase) was extracted from Haematococcus pluvialis and mutated by site-induced mutagenesis. In a gene engineering experiment, a gene that produces the carotenoid biosynthesis enzyme and phytoene desaturase, was extracted from Haematococcus pluvialis and mutated by locally induced mutagenesis. In this mutation, the leucine codon in code 504 was changed to the arginine codon. The results showed that phytoene desaturase enzyme was active in the conversion of phytoene to ζ-carotene, and was 43 times more resistant about to herbicide norflurazon, also some transformed H.Pluvialis had higher Astaxanthin production than wild type in the high irradiation (Verwaal et al., 2007) .In one study, the light regulation of the beta-carotenoid gene and the synthesis of astaxanthin in H.pluvialis including four genes: lycopene cyclase, phytoene synthase, phytoene desaturase and carotenoid hydroxylase were studied. All four transcription genes showed higher synthesis of astaxanthin and carotenoids in high light than in normal light. Also, under blue and red light, transcription of carotenoid synthesis genes is increased and photosynthetic plastoquinone pool is used as a redox sensor to control carotenoid synthesis genes in microalgae. (Steinbrenner and Linden, 2003). AX gene expression was measured in three H.pluvialis strains under salinity stress for 10 days. Strains were New South Wales (NSW), South Australia (SA) and Queensland (QLD)). Transcription of seven carotenogenic genes (ipi-1, ipi-2, psy, lyc, crtR-B, bkt2 and crtO) increased differently between the three strains. In QLD and NSW strains, the expression of psy, lyc, bkt2, crtR-B and crtO was much higher, the level of gene expression was not exactly related to the AX content in the three strains. (Gao et al., 2015)AX metabolite pathway contains the main enzyme β-carotene ketolase (BKT) that exchange β-carotene to echinenone and canthaxanthin. In the gene engineering experiment, the BKT gene was isolated from H.pluvialis and cloned into pRT100 as a vector and then transferred to the pCAMBIA 1304 binary vector. The TDNA of this vector using of Agrobacterium was put in H.pluvialis . Transformed H.pluvialis , tested with Southern blotting and also by PCR analysis. 2-3 folds AX and β-carotene, 8–10 folds echinenone and canthaxanthin were seen in results, also other genes that intermediated in AX production like phytoene synthase (psy), phytoene desaturase (pds), lycopene cyclase (lcy), bkt, and β-carotene hydroxylase (bkh) showed higher expression than untransformed cells (Gao et al., 2015). One study showed that the synthesis of AX and fatty acids in H.pluvialis is not fully coordinated and that the relationship between them is coordinated through feedback in the metabolite pathway. AX esterification leads to the synthesis and accumulation of AX. Production and esterification of AX occurs in the endoplasmic reticulum, and the enzyme diacylglycerol acyltransferases is suggested to guide the diacylglycerol acyltransferases pathway. (Chen et al., 2015). In one experiment, a new blue phototropin receptor (PHOT) cDNA was fabricated, cloned, and bioinformatics analyzed. The algal phot gene was first discovered in H.pluvialis , which cooperates in the control of AX biosynthesis (Cui et al., 2017). The association between AX and fatty acid biosynthesis was demonstrated using a molecular model. Results showed that AX synthesis and esterification occurred in the endoplasmic reticulum, also a special diacylglycerol acyltransferases enzyme esterifies AX (Chen et al., 2015). Some researchers have shown that the expression of PDS and CHY genes in H.pluvialis increased by 86.89 with the addition of folic acid. (Zhao et al., 2015). Three beta-carotene ketolase (bkt) genes were identified in the metabolic pathway of AX biosynthesis. Bkt1, Bkt2, formerly called crtO, and newly discovered Bkt3, Bkt3 with Bkt2 share 95% of the DNA in the H.pluvialis nucleus. These genes are activated rapidly against stress (Huang et al., 2006). In order to rapidly determine the pathway of AX biosynthesis, H.pluvialis mutants that were sensitive to inhibition were generated by random mutation. The result of this assay was the production of a new strain with cell biomass and AX production up to 79% and 153% more than control under normal light irradiation, respectively. (Zhao et al., 2015). In another experiment, growing microalgae cells were exposed to mutagenic agents such as UV, EMS and NTG and then exposed to the herbicide Glufosinate. The mutants showed a 23 to 59 percent increase in carotenoid and AX production. The enzyme expression levels of phytoene desaturase, phytoene synthase, beta-carotene ketolase, lycopene cyclase and beta-carotene hydroxylase increased up to 22 times to the control (Kamath et al., 2008). By adding MJ and GA3 to H.pluvialis culture, the expression level of three beta-carotene ketolase (bkts) genes increased. Activated Cis elements MJ and GA3 were identified upstream of the 5́ BKT regions(Lu et al., 2010).

Effect of different stresses, Nanoparticles, Bio acids, and Phytohormones on microalgae growth and Astaxanthin enhancement.

1-Different stresses

A mutant in Phaffia rhodozyma (NCHU-FS501) showed that temperature and pH have very little effect on carotenoid production volume but play an important role in astaxanthin production and growth rate. (Wang et al., 2013a). Salt stress can effectively cause astaxanthin to accumulate in H. pluvialis ،(Steinbrenner and Linden, 2001, Sarada et al., 2002a)Salt stress (0.1% NaCl, MgCl2, KCl or CaCl2) increased astaxanthin production and cysts in Haematococcus pluvialis during 8 days of darkness. (Kobayashi et al., 1997b). Increasing Salt and light, nitrogen and phosphate deficiency increased Astaxanthin production in the microalgae (Harker et al., 1996). Microalgae cells exposed to high light (170 μmol . m-2s-1) and deficient in iron, sulfur and phosphate showed increased production of astaxanthin. (He et al., 2007). High light and nitrogen starvation increased oleic acid and AX in Haematococcus pluvialis(Zhekisheva et al., 2002).A study showed that high light and low nitrogen with a type cascade process such as increasing of D1 protein induce AX production and protects cellular PSII system with AX accumulation in the cell, but when the microalgae was covered from light, AX accumulated around Nucleolus(Wang et al., 2003). Results of a test displayed that flashing blue Light Emitting Diode (LED) with light intensity (2–12 μmol m−2 s−1), work cycle (17–67%) and regularity (25–200 Hz) was applied for maximum grow cell and AX accumulation in H. Pluvialis(H.pluvialis ). (Katsuda et al., 2006). The optimum situation for AX accumulation (>1.4%w/w) and AX syntheses in H.pluvialis (13 mg.l-1) was in addition of sodium acetate 31–50 mM and sodium chloride 0.55–0.63% w/v to medium culture, also culture age was more important than two above objects. (Sarada et al., 2002a). Also, the optimal growth of H. pluvialis was obtained in the concentration of (about 0.5 to 1.0 g .l-1 KNO3) nitrate, (about 0.1 g.l-1 K2HPO4) phosphate concentration in addition to the wide range of iron. If the nitrate concentration decreases or the phosphate exceeds the amount mentioned, it accelerates the conversion of green microalgae cells into palmella and aplanospore and begins to produce AX. (Li et al., 2011). The results of an experiment displayed that the best nitrate concentration for the microalgae growth and AX production in H.pluvialis was NaNO3 0.15 (g.l-1) (Li et al., 2011). Some scholars announced that the most effective factor in cell growth and AX production is light irradiation. Light intensity 75µE/m2s induced the best result for biomass production (2.7g.l-1) and light intensity of 160µE/m2/s had the most effect on AX production (6.5mg.l-1). The best result was obtained for the production of AX (30.07 mg . g-1) in Haematococcus pluvialis in distilled water with CO2 without any nitrogen at 546 (μmol photon . m-2 s-1) (Park and Lee, 2001). AX production was related to a high carbon/nitrogen ratio (Kakizono et al., 1992). In batch culture, low temperature at night and suitable food increased dry biomass, also using blue and white light with a ratio of 3: 1, green cells were changed to red cells (Sun et al., 2015). In a test Haematococcus pluvialis mutant( with60Co-γ irradiation) was exposed to 6% CO2 and high light so the amount of AX and biomass increased (Sun et al., 2015). The researchers showed that AX production in H.pluvialis increases with phototrophic conditions, nutritional deficiencies along with dilution and increased light radiation. (Ranjbar et al., 2008). Each picogram of astaxanthin in Haematococcus pluvialis was associated with 3-5 picograms of oleic, palmitic and linoleic acids with triacylglycerol under stress (Ranjbar et al., 2008). The highest accumulation of AX was obtained with high light irradiation and ٪15 Co2 in H.pluvialis . (Christian et al., 2018). Four forms of oxygen include singlet oxygen, superoxide anion radical, hydrogen peroxide, and peroxy radical were able to exchange with Fe2+ in carotenoid formation of H.pluvialis (Kobayashi et al., 1993). The results of an experiment showed that cell growth and AX production were good using three forms of iron containing FeC6H5O7, Fe(OH) x 32x and EDTA-Fe, and FeC6H5O7 was the best. Cell density and AX accumulation were 2 and 7 times higher than those restricted to iron (Cai et al., 2009). Excessive light exposure, nitrogen deficiency and acetate addition increase the AX content in the cell, Iron ions, along with acetate, also increase cellular AX in H.pluvialis . (Choi et al., 2002). The results of one experiment showed that the highest AX production was obtained at pH 7, salinity ٪ 25 and 10 ppm Ag (Tan, 2016). Researchers published that NaCl (>1.0% w/v) was toxic for H.pluvialis culture, also the age of culture was effective for AX production. Calcium nitrate and PH=7 increased AX production in H.pluvialis (Sarada et al., 2002b). Potassium acetate increased AX syntheses and productivity (Pan-utai et al., 2017). AX production in H.pluvialis medium culture was considered by two ionic shortage, N- and Mg2+, accompanied by low and high light irradiation, 40 and 230 μmol m2 s−1, respectively. The most AX production (49.5 μg.ml-1) was earned under N- shortage with high light irradiation. Mg2+ shortage produced lower AX than N- deficiency, 7 and 26 (μg.ml-1) of AX was earned for the least and highest light irradiation respectively. Without the two elements, AX was lower than N deficiency alone but greater than Mg2 + deficiency. N deficiency alone had a greater effect than high light intensity on AX production (Fábregas et al., 1998). The scientists claimed that a comparison between H.pluvialis and other green microalgae that were deficient in N in the medium culture showed that H.pluvialis produced the highest AX. The amount of AX in H.pluvialis was ( 22.7 mg/g biomass) while in Scenedesmus vacuolatus, Protosiphon botryoides, Scotiellopsis oocystiformis, Chlorella zofingiensis, and Neochloris wimmeri was 6.8, 2.7, 14.3, 10.9 and 19.2 mg AX /g biomass, respectively (Orosa et al., 2001). AX synthesis has been shown to be depressed by some inhibitors such as norflurazon and diphenylamine (DPA), but neutral lipid biosynthesis is not inhibited. Sethoxydim, a fat biosynthesis inhibitor, rapidly reduces fat concentration but gradually reduces AX production in H.pluvialis. The synthesis of TAG (oleic acid) with high irradiation is not exactly related to the production of AX. Rather, TAG is the most required substance for AX esterification in H.pluvialis (Zhekisheva et al., 2005). The researchers tested three H.pluvialis strains including New South Wales (NSW), South Australia (SA) and Queensland (QLD) to produce AX under 0.17 M NaCl for 10 days. AX content increased in all strains. SA, NSW, and QLD were up to 5.6, 16.2, and 17.7 mg.g-1 dry weight (DW), respectively. (Gao et al., 2015). The scientists measured the effect of CO2, temperature, pressure and ethanol on the extraction of AX from H.pluvialis . The results showed that at 2−4 ml/min CO2 motion, 313-353 K temperature, 20-55 MPa pressure and 67−7.5% (v/v) ethanol, the AX content in the extracted solvent was increased. When the rate of CO2 became higher than before, the amount of extracted solvent could be increased while AX content in the extract was stable, 12.3%, but the role of Ethanol as the receiver was enhancing of extracted AX (80.6%) along with average temperature and pressure (Machmudah et al., 2006). A new method was discovered to convert E-AX to Z and 13-AX using ethyl acetate (70 ° C) plus I-TiO2 as catalyst. A new method was discovered for changing of E-AX to Z and 13- AX using of ethyl acetate (70 °C) with I-TiO2 as a catalyst, Because 13-AX has the highest antioxidant activity (Yang et al., 2017).

2- Nanoparticles

Nanoparticles usually have a toxic effect on growth but have a positive stimulatory effect on AX biosynthesis in microalgae, here are some studies: Cd Nanoparticle in 10mg.l-1 enhanced AX accumulation in H. pluvialis (Hong, 2016). The results of several observations showed that nanoparticles of ZnO, TiO2, Ag and platinum in contact with the microalga p.subcapitata slow down its growth(Déniel et al., 2019). 50 μΜ.l-1 iron(II)NPs along with high temperature (23.4–33.5 ◦C ) enhances AX production up to 147% compared with that of low temperature (17.5–27.3 ◦C) (Hong et al., 2016). Cerium oxide NP in contact with microalga causes the accumulation and sedimentation of it. Also, silicon dioxide nanoparticles cause the microalga Chlorella kessleri to fade(Déniel et al., 2019). A group of scientists demonstrated that carbon, copper oxide and cobalt NPs by blocking light and shading to Platymonas subcordiforus, Chaetoceros curvisetus and Skeletonema costatum microalgae reduce their growth, respectively.(Déniel et al., 2019). Amino clay-conjugated TiO2 NPs increased AX, KR-1 and fatty acid in Chlorella sp and H.pluvialis (Lee et al., 2014). Cerium oxide NP covered with polystyrene (80 nm; 0,01g.l-1) ruins the microalgae photosystem II (PS II) and destroy chlorophyll in C. reinhardtii (Déniel et al., 2019). Ag (2.83 ± 0.70 mg.l-1) and Cd (4.98 ± 0.09 mg.l-1) nanoparticles increased AX and cell density in H.pluvialis (Cheng et al., 2018). Fe and Zn nanoparticles enhanced the production of AX, chlorophyll and biomass in H.pluvialis (Rastar et al.).The highest accumulation of astaxanthin (0.008 ± 0.458 mg .l-1) was obtained under 10mg.l-1 Ag nanoparticles after 14 days in H.pluvialis . Lead nanoparticles have a negative effect on AX production and cell density in H.pluvialis (Rasheed, 2018). Copper nanoparticles at high concentrations have no effect on AX production in H.pluvialis . (Thinakren, 2018). The researchers used gold nanoparticles to slightly damage the H.pluvialis cell wall, which increased AX production in the recovery process. (Praveenkumar et al., 2015). The effect of silver nanoparticles on green microalgae Pithophora oedogonia and Chara Vulgaris was investigated. The results showed that Ag nanoparticles reduced chlorophyll, chromosomes, mitotic chromosome distribution and cell growth(Dash et al., 2012). Some scientists have shown that polystyrene nanoparticles can increase the response of microalga (Chlamydomonas reinhardtii) to certain environmental stresses, such as nitrogen deprivation (Déniel et al., 2020). AuNPs (5 nm) were able to increase carotenoid synthesis by 42.7% compared to untreated microalgae (Chlorella zofingiensis). (Li et al., 2020). Liquid fluorescent carbon nanotubes (C-paints) can increase the efficiency and production of astaxanthin in H.pluvialis (Choi et al., 2020). The toxic effect of ZnO NPs from 10-200 μg . ml-1 in 24 h for 96 h on the production of astaxanthin in H.pluvialis was demonstrated. (Djearamane et al., 2019). 10 ppm for both Ag (0.83 mg .l-1) and Cd (4.98 mg .l-1) nanoparticles increased the concentration of astaxanthin in H.pluvialis (Cheng et al., 2018). Silver nanoparticles when applied simultaneously with silver salt on C. reinhardtii microalga produced oxygen free radicals which reduced the growth of microalga. (Déniel et al., 2019) CU NPs diminished growth and astaxanthin content in H.pluvialis (Wong et al.). Scientists have shown that Dunaliella salina, when exposed to salicylic acid, treatment with AgNPs cannot affect its astaxanthin (Bahador et al., 2019). Some researchers have shown that magnesium aminoclay (MgAC) NPs at a concentration of 1.0 g.l-1 increase the amount of astaxanthin 13.7 times compared to the control treatment in H.pluvialis (Kim et al., 2020a). It was shown that 2.49 mg.l-1 Fe NPs plus 4.41 mg.l-1 Zn NPs enhances astaxanthin, fatty acid, and chlorophyll to the highest concentration which is 7.29 mg.l-1 for astaxanthin (Kim et al., 2020a). The scientists showed that Ag NPs with 10 mg.l-1could increase the concentration of astaxanthin to 0.458 ± 0.002 mg.l-1, but at higher concentrations of 100 and 200 mg.L-1, the AX content decreased. (Hu et al., 2020). Magnesium aminoclay (MgAC) nanoparticles in 10 mg.l-1 treatment could enhance astaxanthin, fatty acid content and the cell size in Haematococcus pluvialis compared to the control treatment (Kim et al., 2020b). Addition of ZnO NPs at the rate of 200-72 μg.ml-1 to H.pluvialis culture was associated with reduced astaxanthin, biomass, bioavailability, intracellular and extracellular damage. (Djearamane et al., 2019). Al203 nanoparticles increased the growth of Chlorella sp at a concentration of 1000 mgl-1 by 18.9% after 4 days.(Ji et al., 2011). A group of scientists showed that when copper oxide nanoparticles are placed in the culture medium of Chlamydomonas reinhardtii, it increases growth at low concentrations (0.1 mg L -1) and decreases its growth at high concentrations (1000 mg L -1). A similar result was obtained in the study on C. reinhardtii when exposed to Cr203 nanoparticles at concentrations of 0.1 and 1 g .l-1. (da Costa et al., 2016). A group of scientists showed that 2.49 mg L -1 Fe NPs and 4.41 mg L -1 Zn NPs had the greatest effect on the growth and production of chlorophyll and astaxanthin in Hematococcus polyvialis microalgae compared to other forms and concentrations of these two elements(Rastar et al., 2018). One scientific study determined that CU NPs in different concentrations from 10 to 200 mg L -1 has negative effects on biomass and astaxanthin production in H.pluvialis.

3- Bioacids, Phytohormones, etc

Some materials such as biocides, hormones, in different concentrations enhance either biomass and AX synthesis or one of them in different microalgae. There are many studies in this case, such as the following: In low irradiation (30 µmol. M-2 s-1), methyl jasmonate (10µM) had little effect on AX enhancement while Salicylic acid (100 µM) enhanced AX production to 6.8 times compared to the control (Sarada et al., 2002a). Some scientists have reported that ethanol and linoleic acid increased astaxanthin production by 142% and 282% in H.lacustris, respectively. (Liu et al., 2020) . A scientific study showed that linoleic acid and methyl jasmonate have the ability to increase astaxanthin alone and with the help of salt several times more than the control in C. sorokiniana and S. acutus microalgae(Khalili et al., 2019). The group also displayed that the addition of 32 μM LA to the culture medium of Chlorella sorokiniana with and without light stress increases the content of astaxanthin and biomass in microalgae(Khalili et al., 2020). A scientific study showed that Jasmonic acid increases biomass in Chlorella vulgaris.(Jusoh et al., 2015). Some researchers have reported that fulvic acid (FA) increases both lipid and astaxanthin levels in high light and nitrogen deficiency in H.pluvialis. (Zhao et al., 2019).Production and accumulation of AX in H.pluvialis were increased using jasmonic acid (JA) treatment (50 mg.L-1) (Gao et al., 2012). Malonate has a positive effect on the production of carotenoids up to 13 times in H.pluvialis . Malonate has a positive effect on carotenoid production until 13 times in H.pluvialis (Li et al., 2011). Butyl hydroxyanisd enhanced AX accumulation and biomass culture in H.pluvialis (Shang et al., 2016). The highest amount of AX (31.32mg.g-1) or 2.36 times the control treatment was obtained after treatment with 10μM.L-1 melatonin. (Ding et al., 2018). Abscisic acid (ABA) can convert green cells into cyst cells but does not stimulate AX production in H.pluvialis (Kobayashi et al., 1997a). The results showed that Arachidonic acid (AA) at moderate concentrations (62.5 mg.L-1) increased H.pluvialis cell growth but at low concentrations (0.1-12.5 mg.L-1) and high concentrations (312.5-1562.5 mg.l-1) reduced it, but AA in high concentrations(312.5 -1562.5 mg.L-1) increased AX production by 48.8% compared to control(Wang et al., 2010). Fulvic acid increased AX accumulation in H.pluvialis LUGU by 86.89% and 9.78% at 5 and 10 mg.L-1, respectively (Zhao et al., 2015). The effect of methyl jasmonate (MJ) and gibberellin A3 (GA3) on the AX biosynthesis pathway were measured. H.pluvialis cells exposed to MJ and GA3 showed some increase in AX production (Lu et al., 2010). A group of academics found that increasing both light and salicylic acid together increased the production of astaxanthin and fat, and that there was a link between the gene network of them. (Hu et al., 2021). Some scholars showed that addition of 100 μM gibrelin acid to the medium culture of the marine Chrysophyte Monodopsis subterranean increased biomass and total fatty acid up to 3.3 and 3.9 folds respectively, also the addition of 1 μM methyl jasmonate to it increased it’s biomass up to 2.7 folds. (Arora and Mishra, 2021).

Auxins

In a study it was displayed that addition of an auxin-producing symbiotic bacterium (Achromobacter sp) to Haematococcus pluvialis increased growth (biomass) and extended exponential growth phase(Lee et al., 2019). A group of scientists in a scientific study stated that a concentration of 10 μM IAA produced the highest production of biomass (431 mg l − 1), protein and carotenoids among the other two auxins, including 1-naphthalene acetic acid (NAA) and 2,4-dichlorophenoxyacetic acetic acid (2,4-D) in the green microalga Ankistrodesmus falcatus CMSACR1001. (Vijay et al., 2020). The results of one scientific study showed that auxins such as Indole Propionic acid and Indole Acetic acid promote astaxanthin and lipid content in the microalga Chromochloris zofingiensis(Chen et al., 2020). In general, the effect of auxins in microalgae and plants is similar.(Garshasbi et al., 2009, Garshasbi et al., 2012)

Cytokinins

Cytokines have a stimulating effect on the growth and carotenoids of microalgae, much like those of plants. Preliminary research has shown that the use of two types of cytokines increases cell division and dry weight of C. vulgaris microalgae(Burkiewicz, 1987). The results of a scientific study showed that increasing kinetin (a type of cytokinin) in the medium culture of C. pyrenoidosa increases cell division by up to 16% compared to the control treatment(Vance, 1987). The results of one study showed that cytokines (CKs) increase cellular growth and defense in microalgae. (Romanenko et al., 2016). Scientists showed that cytokine(zeatin) has not any effect on Astaxanthin accumulation in H.pluvialis.(Yu et al., 2015). Some scientists showed that cytokines in forty-five (45) microalgal species increased cell division, growth processes, and photosynthetic activity, also they had a cellular protective role. (Romanenko et al., 2016). In two separate studies on two microalgae varieties of Chlorella including C.pyrenoidosa and C.vulgaris, the effect of 7 different types of cytokines was measured on them and it was found that adding N-6-benzylaminopurine (BAP), N-6-furfurylaminopurine (kinetin, Kin), and allantoin/5-ureidohydantoin (AT) to C. pyrenoidosa increases chlorophyll a, b, water-soluble proteins, and aldohexoses (Czerpak et al., 1999), also showed the greatest stimulant effect of N,N0 diphenylurea (DPU), kinetin (Kin), and trans-zeatin (Z) hormones in concentrations of 10-6 to 10-8 M on the microalga, C.vulgaris, While the order of the effect of cytokines on its growth and stimulation was as follows; DPU>Z> Kin>BA.(Piotrowska and Czerpak, 2009).

Gibberellins

The effect of gibberellin on the growth and development of algae is same as on plants, which means that up to a certain concentration increases growth in them(Brian, 1959).Some scholars stated that Gibberellins in microalgae lag phase decrease and increase cellular growth and division, respectively. Also increase biomass, carotenoids and proteins, but reduce the effects of heavy metals.(Romanenko et al., 2016). The results of a group of researchers showed that the addition of two compounds, methyl jasmonate and gibberellin A3 with an effect on the beta-carotene ketolase (bkt) gene caused more astaxanthin production in the microalga, H. pluvialis. (Lu et al., 2010). Some researchers have reported that gibberellin GA3 at concentrations of 20 and 40 mg .l-1increases the expression of some genes of the astaxanthin production pathway, such as bk2, ipi-2, psy, compared to other genes in this pathway in H.pluvialis. (Gao et al., 2013a). The results of a scientific study showed that the adding of 100 M gibberellin(GA3) to Scenedesmus obliquus medium culture increased fresh weight by up to 30% and fatty acids by up to 42.6% of the control treatment.(Mansouri and Ebrahim Nezhad, 2020) . The results of a scientific study showed that H. pluvialis under stress with GA3 5.0 mg L-1 produced earlier and more astaxanthin (6-46%) than GA3 20 mg L-1 and control. (MENG and GAO, 2007).

Absic acids(ABA)

Abscisic acid often decreases growth, astaxanthin, and other growth parameters in microalgae such as plants. Results of one study revealed that ABA changes vegetative green cells to red cyst cells but not has any effect on astaxanthin formation in H.pluvialis.(Kobayashi et al., 1997a).
ABA decreased growth, astaxanthin, and lipids in the green microalga, Chromochloris zofingiensis (Chen et al., 2020). It showed that between some plant growth regulators (PGRs) such as 1-naphthaleneacetic acid (NAA); salicylic acid (SA); 2,4-epibrassinolide (EBR); 6-benzylaminopurine (6-BA); gibberellin (GA3); ethephon (ETH); abscisic acid (ABA); and spermidine (SPD), ABA increased Lipid but decreased carotenoid content in Chlorella vulgaris (Lin et al., 2018). Indole-3-acetic acid, salicylic acid, abscisic acid, and methyl jasmonate were tested on BR2 gene expression of the carotenoid metabolic pathway in Chlorella sp. Results showed that only Indole-3-acetic acid induced carotenoid synthesis and ABA and other phytohormones decreased it (Alsenani et al., 2019).

Conclusion

In this review, many types of research and results about AX structure, different medium cultures, genes, and engineering also effects of different material, environmental stresses, nanoparticles, bio acids, and hormones on different microalgae especially H. pluvialis were studied. It was shown that there are many medium cultures for different microalgae to produce AX. There are generally 8 genes in the pathway of astaxanthin synthesis in Haematococcus. Most substances, bioacids and stresses increase the production of Astaxanthin to a special level in different microalgae. The effect of nanoparticles is not general. Some increase astaxanthin production, but most of them are toxic and reduce it and a few are ineffective. Often Auxins, Cytokinins and Gibberellins increase but Absic acids(ABA) decrease AX production in different microalgae. It is hoped that studies on AX and H. pluvialis will become easier every day, and find more efficient ways to produce natural AX because it has many benefits for humans.

Acknowledgments

We thank everyone who helped us complete this article, especially the professors of the University of Tehran.

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