General features and history: The botanical name is Amaranthus cruentus (AC) and it belongs to the Amaranthaceae family of the Amaranthus genus and fits in the category of self-flowering species. It is a somewhat drought-tolerant annual vegetable plant. The English name is Red Amaranth [1]. In Bengali, it is popularly named as Lal Shak (লাল শাক্). The plant also produces nutritious grain, used as a staple, Amaranth grain. In Hindi, it is called Ramdana or Rajgira. The grain is gluten-free. So, those having gluten allergy can enjoy foods made of Amaranth grain flour. AC is also often cultivated as an ornamental plant in many places owing to its feather-like flowering plumes. It is an annual herb that grows ~ 6 ft in height and blooms from summer to autumn. Its other variety Amaranthus hybridus has almost identical morphology except for the green color. It seems to grow slightly taller ~ 11 ft and occasionally holds a touch of pink or red color on leaves. This herb/vegetable green of either variety is cultivated all over India since it prefers tropical climates, but the plant is considered native to Peru. However, history further indicates that this plant was first cultivated in Central and South America around 4000 – 6000 BC during pre-Columbian civilizations like the Aztecs. The grain collected from matured plants was consumed as a staple food by the Aztecs, Mayans, and Incas. The plant was also ritually used in religious ceremonies. The ancient Aztecs used to eat the red leaves using honey. Aztecs also extracted red dye from the leaves and colored the icons or statues of their gods prepared from grains and honey. At the end of ritual performances, they used to break them apart and eat. After the invasion of Spanish conquistadors and the defeat of the Aztecs, Christianity was forced on the pagan natives. In that course, the Spanish outlawed the use of Amaranth grain. The fields were burnt and destroyed. The farmers were killed. Luckily, they could not eradicate the seeds. In remote areas, people used to cultivate it for consumption. It is the way Red Amaranth survived [2, https://www.ancientgrains.com/amaranth/amaranth-history-and-origin]. After 300 years of obscurity, Red Amaranth and its grain appeared in the USA around the 1970s as specified by the George Mateljan Foundation [https://www.truehealthinitiative.org/council_member/geoerge-mateljan/]. They elaborated on the history of disappearing and reintroducing grain and leaves as a nutritious diet. Currently, it is no longer counted to be a staple food in the US or South and Central America. On the other hand, the grain is sold as a healthy food. It is also often eaten as a cereal. They are grounded in flour to prepare bread. The grain can be popped like popcorn or made porridge to consume with sugar or honey. It is also provided for subsistence during famine in parts of Africa due to its nutritious quality [3]. In many states of India like West Bengal, Maharashtra, and Chhattisgarh, the leaves of Red Amaranth (লাল শাক্) are frequently used for cooking many dishes like curry adding Hyacinth bean (Lablab bean/শিম) or to make Bhaji, a stir-fried vegetable dish, particularly consumed during monsoon season. In Himachal Pradesh of northern India, the grain is powdered to prepare Kheer, an Indian dessert. The flour prepared from grains is customarily used to prepare deep-fried chapatis. The native American Pueblo people residing once near the Zuni River valley of New Mexico used the red feathery part of the plant to make fine meals for coloring their ceremonial bread. The crushed leaves and blossoms are used as cosmetics like rouge to color the cheeks [4].
Chemical components and nutritional aspects: Extracts of AC whether leaves, stems, or grains provide plenty of medicinal benefits therefore interests are created to identify the phyto-components of therapeutic activities. Factually, both leaves and grains are promising food that grows all year around in tropical climates. The leafy vegetables and their grains are fortified with proteins (13 – 22% by dry weight) enriched with lysine, glutamic, and aspartic amino acids. They also provide high levels of minerals, dietary fibers (~ 13%), bioactive pigments, and other important phytocomponents like betacyanin, carotenoids, betaxanthins, chlorophylls, ascorbic acids, beta-carotene, polyphenolics, and flavonoids which have free radical scavenging effects, protecting or maintaining normal health [5]. For a long period, most of the Amaranth species have been used as folk medicine for their antimicrobial, anticancer, antidiabetic, and antimalarial effects even using occasionally as a snake antidote [6,7]. Natural phytopigments of AC are frequently used worldwide in the commercial food industry for coloring food and drinks. The elemental analysis of grains shows that it is heavily loaded with necessary minerals eg (per 100 g), Calcium – ~ 1000 mg, Magnesium ~ 50 – 97 mg, Potassium ~ 270 – 475 mg, and Zinc ~ 0.5 – 1.2 mg. In leaves, the mineral contents are also quite high eg, Iron ~ 15 – 32 mg, Zinc ~ 1.0 – 3.5 mg, Calcium ~ 1320 – 1677 mg, Potassium ~ 384 mg, and Magnesium ~ 513.9 mg [8]. Aside from the essential minerals, the leaves also contain Vitamin C (955.2 mg/100 g), β- carotene (1043 mg), Betalains (66.4µg), β-xanthine (33.1µg), and β-cyanins (33.3µg) [9]. The complete chemical analysis has identified versatile active components eg, alkaloids, flavonoids, glycosides, phenolic acids, steroids, saponins, amino acids, vitamins, minerals, terpenoids, lipids, betaine, catechuic tannins, and carotenoids [10]. Alkaloids, glycosides, terpenes, and sugars are the basic components in roots [11]. Studies have shown that AC is potentially a good dietary source of provitamin A or carotenoids like β-carotene. The carotenoid content is highest in leaves followed by stems, and roots. The major carotenoid identified in leaves is canthaxanthin which is an excellent antitumor agent followed by β-carotene, and lutein. Lutein is considered a retardant to age-related eye diseases. The β-carotene content in AC is more than seven times that of tomatoes. It is often used to treat anemia in African countries [12].
Major Phyto-components of Amaranth Plant and Grains [12].
Amaranth grain known in India as Rajgira or Rama’s grain / Ramdana is a nutritious food and a large source of anthocyanins and polyphenolics [13]. Grain is protein enriched with a balanced amino acid profile of eight essential amino acids with high lysine content. It is also rich in starch, oil, fiber, vitamins (A, K, C, E, and B) and minerals. Interestingly, it has no gluten [14]. Due to its high protein content along with plenty of unsaturated fatty acids, the AC grain is an excellent food supplement. Further, it is a good source of squalene, and triterpene, a powerful antioxidant and a cardio-protectant having anticancer properties [15,16]. It has been reported that it also has a Lunasin-like peptide isolated from protein fraction (11.1 µg / g of extracted protein). The mature grains contain 60 % of Soyabean Lunasin peptide which has significant anticancer and anti-inflammatory actions [17,18]. The nutritional significance of AC grains is mainly due to their fatty acids and protein content. Among the unsaturated fatty acids, the most abundant are linoleic (~ 62%), oleic (~20%), linolenic (~ 1%), and arachidonic acids. The saturated fatty acids are palmitic (~13%), stearic (~2.6%), myristic (~0.1%), and arachidic (~0.7%). Concerning the lipid or oil fraction of AC, the major components are tocopherols, tocotrienols, and sterols. Besides the fatty acids, amaranth oil also contains squalene, betanidine, α-, β-, γ-, δ – tocopherol and α-, β-, γ-, δ- tocotrienols [19].
Pharmacological activities: AC shows hordes of health benefits. Its astringent property originates from several phytocomponents like saponins, betacyans, and protoalkaloids [20]. As indicated in PDR, AC has been used to treat ulcers, diarrhea, and pharyngitis. Reports further indicate that AC or other Amaranth species provide a beneficial role in the case of heavy menstruation, acne, eczema, and mouth sores if used as mouthwash. Saponins, betacyanin, proto alkaloids, and other phytochemicals are likely to be liable for those effects [20]. Literature further indicates that AC and other similar species can exert favorable actions on cardiovascular and CNS health. It has antioxidant, antimicrobial, and antidiabetic activities. In the medicinal industry, they are processed to make products against atherosclerosis, stomach ulcers, tuberculosis, fungi, sepsis, and inflammatory conditions [21]. According to Ayurvedic Pharmacopoeia of India, the seed oil exhibits hypolipemic, anti-atherosclerotic, hypotensive, and antioxidant properties [22]. It is used in Unani Medicine as a spermatogenetic drug and is also prescribed in cases of dysentery, cough, and hemorrhages [23].
Beneficial Actions of AC [19]
Anticancer effect – The aqueous extract of AC shows a potent antiproliferation effect on human peripheral lymphocytes. So, it can be used as a therapeutic measure against cancers. The extract by methanol, hexane, and ethylacetate also has produced similar antiproliferative and anticancer actions on the human colon adenocarcinoma cell line, COLO-320-DM [24]. Besides AC, other Amaranth species also exert similar antitumor/anticancer activities [12]. The chemoprevention and antiproliferation effects are owing to its numerous phytocomponents like polyphenols, flavonoids, anthocyanins, betacyanins, various carotenoids, tocopherols and tocotrienols. In addition, the chemopreventive action is further identified due to the synthesis of a soyaben-lunasin-like peptide that exhibits significant anti-neoplastic effects both in vivo and in vitro. The extract of AC or its grain inhibits NIH-3T3 cell lines (mouse fibroblast) transformation to cancerous foci and histone acetylation H5 and H4 by 70 – 77% [25]. Moreover, the stem extract causes ~ 45 % growth inhibition of EAC cells (Ehrlich ascites carcinoma) subsequent upregulation of p53, Bax, and Caspase-3, and subsequent downregulation of Bcl-2 mRNA in treated mice showing mitochondria-mediated apoptosis of EAC cells compared to its control. Amaranth extracts can be counted to be a potential target for the study of cancer [26].
Antioxidant effects – About twenty five different phenolic components have been identified in AC plant extract which are considered to be majorly responsible for antioxidant activities. Among them, Betaxanthins and Betalains are seen as more potent regarding free radical scavenging activities [23]. In addition to those, two acidic polysaccharides AHP-H-1 and AHP-H-2 which are isolated from Amaranth species are also noticed to have strong antioxidant activity [27].
Hepatoprotective activity – Experiments on hepatoprotective actions are studied by using whole plant ethanolic extract dose-dependently (6,7,8,9, and 10 mg/ml concentration) on CCl4-induced freshly isolated rat hepatocytes and HepG2 cells [28]. The hepatoprotective effect has been further verified by using aqueous plant extract on paracetamol (Tylenol) overdose-induced hepatoxicity in albino Wister rat livers. The histological, biochemical, physical, and functional changes caused by paracetamol / Tylenol have been significantly prevented by the plant extract proving the protective role [29]. Several authors also indicated that the protective effect is also caused by plant oil since oil can modulate the physicochemical properties of the cell hepatocyte membrane by stabilizing them thus acting as a protective agent [22]. It is also known that squalene exhibits strong antioxidant as well as hepatoprotective roles in controlling cholesterol levels. Due to the high squalene content in Amaranth oil, it is logical to presume that it could be a part of hepatoprotective action [21].
Neuroprotective and antidepressant effects – It has been established that advanced glycation end-products (AGEs) are largely detrimental to the neurons inducing cytotoxicity and causing oxidative stress. In experiments using the human neuroblastoma cell line (SH-SY5Y), it has been proven that Amaranth plant extract can protect it from AGE-induced cytotoxicity [30]. It is also examined that the extract reduces oxidative stress by suppressing the gene expression of HMOX-1, RAGE, and ReIA. In addition to those effects, other antioxidants in Amaranth also exert an associative role in protecting the neurons [31,32]. The methanol extract of the plant shows potent antidepressant activity in experimental rats although the mechanism of action is not fully understood [32].
Antihyperglycemic and hypolipidemic activity – It has been noticed that the methanolic extract of Amaranth leaves showed significant antidiabetic and anticholesterolemic actions in Streptozotocin-induced diabetic rats [33]. Experiments have further proven that oral administration of aqueous leaf extracts considerably reduced serum glucose, triglycerides, total cholesterol, LDL, and VLDL subsequently enhancing HDL levels in alloxan-treated diabetic rats [34]. Extraction by petroleum ether, chloroform, methanol, and water also inhibits hemoglobin glycosylation [35]. The oral administration of aqueous stem extract is also seen effective in decreasing plasma glucose levels, and hepatic glucose-6-phosphatase activity while increasing hepatic glycogen content along with hexokinase actions in both type 1 and type 2 diabetic rats [36]. Further studies have convincingly established that Amaranth is a promising natural source for managing diabetes and its associated complexities.
Cardioprotective effect – Generally, a diet enriched with polyphenols reduces the incidence of coronary heart disease and the formation of atherosclerotic plaque. Amaranth flour or protein concentrate prepared from AC seeds tends to bind bile acids therefore enabling to lower the cholesterol levels in the blood [37]. In the case of isoproterenol-induced myocardial-infracted rats, the oral administration of dried whole plant altered the levels of C-reactive proteins, total proteins, albumin, globin, ceruloplasmin, and glycoprotein levels in serum and heart [38]. It also lowers the levels of several serum enzymes (AST, ALT, LDH, CPK), cardiac troponin, GSSG, and LPO of the membrane [39]. The antiatherosclerosis studies using numerous Amaranth seeds or grains have successfully established that it can significantly decrease the levels of cholesterol, LDL-C, total cholesterol, triglycerides, and apoprotein levels in animals fed with high-fat diet. But besides polyphenols, three novel peptides isolated from the grains of AC can significantly inhibit the enzyme HMG-CoA reductase, an important enzyme needed to biosynthesize cholesterol [40]. In a way, AC and other Amaranth species are considerably active in preventing atherosclerosis providing cardioprotective effects.
Anti-inflammatory and anti-nociceptive effects – A multitude of experiments were conducted to establish the effects of Amaranth. Extraction of leaves by any solvents including aqueous media shows anti-inflammatory, antinociceptive, and antipyretic effects but in different degrees. It has been noticed that ethyl acetate extract can inhibit the systemic anaphylactic shock generated in mice by using compound 48/80 induced secretagogue. The extract stabilizes the mast cell lipid membrane thus preventing the perturbation of the membrane layer blocking the mast cell degranulation and simultaneously foiling the histamine release from rat peritoneal mast cells during in vitro experiments. In a way, it could act as a precaution to control anaphylactic shock [41]. The antipyretic effects of leaf extracts are tested in animal models by using yeast-induced body temperature elevation in rats. The effect is comparable to the antipyretic drug, Tylenol/Paracetamol [42,43]. The aqueous alcoholic leaf extract exhibits anti-nociceptive activity in the acetic acid-induced writhing model. The anti-inflammatory and anti-nociceptive actions are also noticed against carrageenan-induced rat paw edema and cotton pellet-induced granuloma in rats [44]. Similarly, methanol extract from leaves and roots also shows significant central and peripheral anti-nociceptive and anti-inflammatory effects in mouse models [45].
Anti-depression effect – The antidepressant effect of methanol extract has been tested on animals subjected to Forced Swimming Test and Tail Suspension Test models while using Imipramine and Escitalopram, the tricyclic anti-depressants/selective serotonin inhibitors (SSRIs) as reference controls. At higher concentrations, the extract showed significant effects that are comparable to the SSRIs as controls [46].
Miscellaneous effects: The extract of AC shows a few other effects: 1) Anti-microbial, 2) Anti-malarial, 3) Gastroprotective, 4) Laxative, 4) Spasmolytic, 5) Bronchodilator, and 6) Contraction of the urinary bladder via nicotinic, muscarinic, and histaminic receptor stimulation [12].
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