Phytochemical competence and pharmacological perspectives of an endangered boon—Costus speciosus (Koen.) Sm.: a comprehensive review

Costus speciosus (Koen) Sm. popularly known as crepe ginger or spiral ginger and insulin plant is a perennial rhizomatous herb contain variable number of medicinally important bioactive phytochemicals having intensive pharmacological effects due to antioxidant, antimicrobial, insecticidal, anticancerous, and antidiabetic properties. This plant is widely distributed throughout India and has tremendous ethnobotanical uses. This review article is the coalescence of the distribution, morphology, phytochemistry, pharmacology, effect, and mode of action of pharmacologically active principles of Costus speciosus. The therapeutic potential possessed by the plant is mainly the attribution of the bioactive compounds such as phenolics, steroids, alkaloids, flavonoids, saponins, terpenoids, and tannins, which are found to be present in different parts of the plant. Bioactive constituents like diosgenin, gracillin, dioscin, prosapogenins A and B of dioscin, eremanthin, costunolide, β-sitosterol, β-D-glucoside, β-carotene, α-tocopherol quinine, dihydrophytylplastoquinone, 5α-stigmast-9(11) en3β-ol, tetracosanyl octadecanoate, methyl hexadecanoate, methyl octadecanoate, cycloartenol, cycloartanol, and cycloalaudenol are specifically found in C. speciosus. This review also focuses on the possible mechanisms followed by these bioactive compounds while exhibiting various pharmacological properties. Because of the presence of diosgenin, this plant is given the name “insulin plant.” Diosgenin along with an important sesquiterpene, costunolide, performs significantly high antioxidant, anticancer, and antidiabetic activities. Besides these properties, insecticidal, antifungal, antibacterial, and anthelminthic properties have also been discussed. This plant needs to be given more emphasis as it is exploited at the commercial level by the pharmaceutical industries, conservation status is getting poorer, and it is already in a near-threatened state. Therefore, more systematic and intensive research should be done in a sustainable manner. Spiral ginger plant shows diverse pharmacological effects due to presence of variety of bioactive phytochemicals, but the compounds like diosgenins, costunolides, eremanthin, and arbusculin are highly specific that exhibit effective antidiabetic, anticancerous, and antioxidative properties through different mechanism. Thus, C. speciosus can be exploited as an economically sustainable source of effective drugs against deadly diseases like diabetes and cancers with less or no side effects, and further research is needed to explore the intricacy of its pharmacological actions with human trials.

Page 2 of 27 Sohrab et al. Bulletin of the National Research Centre (2021) 45:209 Background There have been phenomenal developments in the field of synthetic drugs, their huge production, and easy availability, but despite these facts, these drugs have failed to provide adequate and proper medical relief to the common man. It is mainly because of their exorbitant prices and complicated side effects. Therefore, there is dire need to investigate for more potent, reversible, and less toxic drugs that could be achieved from the natural compounds of plants (Lewis 2001). The attributions of plants to humankind are far beyond just providing the source for food and shelter but is also to serve as the storehouse of remedies against different diseases, which can be substantiated by the report of WHO that about 80% of the world's population, to meet their medicinal needs, is dependent on medicinal plants or herbs, as shown in Fig. 1. Medicinal plants contain rich bioactive compounds which contribute significantly in the pharmacopoeial as well as modern synthetic drugs, and their demand is expanding throughout the world which compels the need for firm regulation on the use of vegetal herbs. Good agricultural and collection practices have been initiated by WHO which provide guidelines for the quality assurance, safety and effectiveness of the medicinal plants and the herbal products derived from them, which would help in maintaining the sustainable consumption of herbal drugs (WHO Guidelines on Good Agricultural and Collection Practices (GACP) for Medicinal Plants 2012). The use of herbal remedies is expanding in India also; for example, the reports of All India Trade Survey of Prioritized Medicinal Plants 2019 have highlighted the increase of 50% in the demand of medicinal plants; however, decline of 26% in the availability of these plants was also reported. Moreover, despite being one of the 17 mega-biodiversity countries and with the abundance of more than 8000 medicinal plant species (Botanical Survey of India 2019), the assessment of Indian and total world herbal market in 2019 revealed that the contributive share of India in the world export has been quite low (India hold US$ 56.6 million share, while world herbal trade was US$ 120 billion) which may be due to less advanced agricultural practices and lack of Studies have shown that these food additives, used by the food processing industries to prevent lipid peroxidation and also have applications in cosmetics, have been reported to possess possible toxic and carcinogenic effects on health (IARC, 1986). In view of this, urge for extracting natural antioxidants and other pharmacologically significant compounds from plant sources have been showing interest among researchers in recent years; therefore, these phytoconstituents with reduced cytotoxicity and side effects could be employed in pharmaceutical industries as well as in food sectors (as food additives for having better shelf life). There is also an increase in the number of microorganisms that are resistant toward traditional antibiotics being currently used and has become a grave concern worldwide (Gyawali and Ibrahim 2014). Therefore, the study of antimicrobial and antioxidant compounds derived from plants that have the potential to replace traditional synthetic antimicrobial agents must be done imperatively (Gyawali and Ibrahim 2014;Sharifi-Rad et al., 2017).
An important source of new chemical substances with potential therapeutic effects is the natural aromatic and medicinal plants (Kaushik and Jalalpure 2011), as these plants are reported to contain a broad range of bioactive compounds that are usually produced as secondary metabolites such as phenolic acids, flavonoids, coumarins, tannins, stilbenes, and lignans; nitrogen compounds like amines, alkaloids and betalains, vitamins, carotenoids, and other metabolites of endogenous nature which possess extensive biological activities such as antioxidant, anti-inflammatory, antiaging, antibacterial, antitumor, and other pharmacological potentiality (Karimi et al. 2013). Much of these bioactive compounds have been reported to be present extensively in the members of family Zingiberaceae (Habsah et al. 2000;Mau et al. 2003). The ginger family contains plants of vital importance that include shell gingers (Alpinia), ginger (Zingiber officinale), summer tulip (Curcuma alismatifolia), black zedoary or black turmeric (C. caesia), turmeric (C. longa), ginger lily (Hedychium), torch ginger (Etlingera elatior), and cardamom (Amomum elettaria) (Jiang et al. 2000).
Among these, the exclusive medicinal plant, Costus Speciosus, popularly known as spiral ginger, has been recognized for its ethnomedicinal uses due to its high pharmacognostic potentials. In the present review article, efforts have been made to delve deep into a wide range of pharmacological potential of the medicinal plant, C. speciosus, serving as a healthier and safer multipotential source for the replacement of harmful synthetic drugs, artificial preservatives, and food additives and also pave the way to find some valuable chemical compounds that might prove helpful in the eradication of various diseases. Also, bring to the notice of conservationists, ecologists, researchers, and stakeholders to strategize its conservation, monitor its ecosystem, and develop programs for the restoration of this medicinally important species (Maji et al. 2020).
The distribution of C. speciosus has been reported in different continents including Africa, Asia, North America, and Oceania, but it is basically the native of Southeast Asia and Malaysia. It is native to Asian countries like Bangladesh, Bhutan, Indonesia, China, India, Hong Kong, Malaysia, Nepal, Philippines, Singapore, Sri Lanka, Taiwan, Thailand, Vietnam, and Myanmar. However, in North America and Oceania this species occurs as introduced species. In North American countries like Cuba, the USA, Hawaii, and in many parts of Oceania, this plant is invasive in origin.
In India, the plant has a wide range of spread from Northern regions (through Himalayan hills) and Himachal Pradesh to Assam, West Bengal, and Central India (Vindhya Satpura hills); Southern regions include Andhra Pradesh (Eastern Ghats), Maharashtra (Western Ghats), Karnataka, Tamil Nadu, and Kerala (Pawar and Pawar 2014) with the exclusion of some states like Gujarat, Haryana, Punjab, and peninsular India as these states have arid and semi-arid geographical conditions (Anonymous 2007), which is not suitable for the growth of this plant. C. speciosus is called by different vernacular names (Table 1) in different parts of the country (Srivastava et al. 2011;Swati and Agarwal 2015;Mazumdar and Hussain 2021).

Taxonomy of Costus speciosus
Spiral ginger or Crepe ginger belongs to the family Zingiberaceae of order Zingiberales. This plant shows similarities with other Zingiberaceae members in their floral characters and inflorescences (Specht and Page 4 of 27 Sohrab et al. Bulletin of the National Research Centre (2021) 45:209 Stevenson 2006). However, it can be distinguished from other members of the family Zingiberaceae because of the presence of remarkable spiral stems and spiral phyllotaxy (Kirchoff and Rutishauser 1990). Because of this reason, the genus Costus was placed in a separate family, Costaceae, which is known to include approximately 175 species (Ariharan et al. 2012). The taxonomic position of C. speciosus is given in Table 2.

Morphology
Costus speciosus (Koen) Sm. (Zingiberaceae) is an ornamental erect, rhizomatous, perennial succulent herb, up to 2.7 m high, with tuberous rootstock (Gupta 2010). The rhizome of the plant has nodes, and internodes and the lower parts of the rhizome are sheathed, while going upward, it is leafy. The stem arising from the horizontal rhizome is sub-woody at the base. Leaves are broad sessile, thick, elliptic to oblong or oblanceolate-oblong, acute or acuminate, often cuspidate and arranged spirally on the stem. The dorsal side of the leaves is glabrous, while the ventral surface is silky and pubescent (Maji et al. 2020). The inflorescence of the plant is terminal, ellipsoid or ovoid, bracteate, and bracteolate with bright red bracts and pale red bracteoles. The shape of the bract is found to be ovate with a sharply pointed apex having leathery and pubescent texture. The flowers are large and white and present in thick cone-like terminal spikes. The calyx is reddish black, tri-lobed, rigid, deltoidovate, and cuspidate with sericeous apex. Tube-like corolla (approximately 1 cm) has oblong-elliptic lobes (approximately 5 cm) with white or red apex. White, trumpet-shaped labellum (6.5-9 cm) is present whose apex is crisped and toothed, with overlapping edges. Stamen (approximately 4.5 × 1.3 cm) is petaloid, white in color with an orange-yellow base, urn-shaped, and covered with short soft hairs (pubescent). The fruit is capsular (approximately 1.5-2 cm), red in color, globose trigonous, and a bit woody. They produce black and glossy seeds (5 in number) with white and fleshy aril (Srivastava et al., 2011;Mazumdar and Hussain 2021). In India, during mid of April-May, rhizomes start to sprout their buds and the growth of the plant is at peace when there is the rainy season, usually in July, and grows vegetatively till the month of September and October and then flowering continues till the end of October. After this stage is finished, fruits get ripened and all the leaves have fallen and the plant finally dies. But the underlying rhizome remains in the dormant stage from December to March, and again new sprouts come during the month of April of the subsequent years (Maji et al. 2020). Detailed description of the plant is depicted in Table 3 and Figs. 2 and 3.

Propagation, cultivation, and conservation
The propagation of the plant is done vegetatively by rhizomes and also by seeds as they are dispersed by rodents and birds when they feed on fruits (Englberger 2009). Division of culms and stem cuttings have also been used for propagation purposes (Pawar and Pawar 2014). It has been studied that when provided with the ideal growing conditions, shoots will grow and become a clump as wide as 3ft in the second year. According to the studies done by Merina Benny (2004), the seed germination percentage is above fifty percent under natural conditions (Benny 2004). But still, there is a need to develop a standard practice of cultivation of this plant as any such standardization of cultivation methods has not yet been done.  (Srivastava et al. 2011;Swati and Agarwal 2015;Mazumdar and Hussain 2021) A report by the World Health Organization has estimated that by the end of 2010, there were around 3.2 crores of diabetic patients in India and it was mentioned that India has the fastest-growing population of this disease. C. speciosus has become the great demand of the day as it provides an excellent alternative source of diosgenin and other synthetic and viable drugs against diabetes. But this imposes the threat of extinction as there is indiscriminate collection of this plant for its rhizome from the wild due to which it has been noticed that the Costus plant is disappearing very rapidly from its natural habitat. This has urged the researchers to study about the suitable tissue culture and micropropagation methods for conservation and large-scale production of C. speciosus as the rate of regeneration of this threatened species is quite slow. It is imperative to go in for augmentative research such that it can be provided to pharmaceutical industries, nurseries, and farmers at affordable prices (Rani et al. 2012). For this, various biotechnological approaches are being developed so that successful propagation or rather a micropropagation can be done from pseudostem without causing significant damage to the main mother plant (Philip Robinson et al. 2009). Shoot tip proliferation, multiplication at the clonal level, and in vitro production of rhizome have been done in this direction, and an extremely high percentage of regeneration of shoot was reported when triacontanol was used, which is illustrated in Fig. 4.

Ethnomedicinal uses
Medicinal plants have played a great role as an alternative and complementary medicinal source of most of the synthetic drugs in modern use. For this reason, many countries like India, Sri Lanka, West Indies, China, America,  and Africa have recognized C. speciosus for its ethnicmedico-botanical uses (Maji et al. 2020). India witnesses the use of this plant as one of the traditional medicines, and its medicinal values' ascription has been defined in Ayurveda also (Thambi and Shafi 2015). This plant has been used as food as well as medicine by the tribal people of hills of Southern regions of India (Pawar and Pawar 2014). Except for the regions of the northeastern and southern parts of India, C. speciosus is still recognized as an underexplored species. Studies show that the leaves, stem, and most notably the rhizome of C. speciosus are attributed with various medicinal properties. For instance, the roots and rhizomes of the plant have been reported to be used against disorders like rheumatism, anemia, bronchitis, skin diseases, constipation, jaundice, flatulence, asthma, helminthiasis, leprosy, pneumonia, dropsy, inflammation, hiccough, fever, and some urinary diseases in which urination is accompanied by the sensation of burning (Nair et al. 2014;Maji et al. 2020). Various other properties of the rhizomes show that they are strongly laxative in effect (purgative), astringent, depurative, anthelmintic, tonic, acrid, febrifuge, expectorant and are also believed to improve digestion (Nadkarni 2009;Gupta, 2010). The juice made up of the rhizomes of C. speciosus is used to cure leprosy and also for abortion (Anonymous 2007), and it is known to provide a cooling effect and thus used in headaches (Gupta 2010). Besides, the traditional use of the rhizomes, leaves, and stem too has been used for their medicinal properties; for example, the infusion of leaves and stem decoction has a sudorific effect and thus is utilized to treat high fever patients; sometimes, they are used in the bruised form and applied to the affected person suffering from the fever (Anonymous 2007;Malabadi 2005). In addition, the sap of young leaves and stems is used in eye and ear infections (Srivastava et al. 2011), catarrhal fever, cold and cough, and also against snake bites (Anonymous 2007;Nadkarni 2009).
Despite its significance as an ethnomedicinal drug for ages and the presence of diverse types of pharmacologically active phytochemical constituents, very limited authentic and verified information is available on marketed formulation and a patent on C. speciosus due to the lack of an appropriate number of human trials. However, certain Indian ayurvedic and natural health-product companies are now coming forward in this regard; for instance, Dabur India Limited, one of the leading ayurvedic companies, has developed an ayurvedic formulation based on Costus speciosus which is traded as Ketaki (crepe ginger/kemuka) powder, used for the treatment of hyperlipidemia, obesity, and management of diabetes and menstrual irregularities. In addition, C. speciosus extract, along with other herbs, has been used in the patented process for anti-inflammatory and analgesic preparation by Khamar (2002) with patent number WO-02/085394 by World Intellectual Property Organization under Patent Cooperation Treaty. However, for the betterment of the public health and promotion of natural and safer remedies for ailments more such formulations and developments should be encouraged (Fig. 5).

Phytochemical composition
Costus speciosus is reported to contain an abundance of phytochemicals of diverse nature such as phenolics, steroids, alkaloids, flavonoids, saponins, terpenoids, and tannins, which are found to be present in different parts of the plant. For instance, studies have shown that the leaves of the plant of C. speciosus contain α-amyrinsterate, lupeol, palmitates, and β-amyrin (Srivastava et al. 2011;Rani et al. 2012). Other phytochemicals like triterpenes, aliphatic hydroxy ketones, fatty acid, oxa-acid, abscisic acid, starch mucilage, corticosteroids, and tigogenin were reported from the rhizome of the plant (Pawar and Pawar 2014). Some other bioactive constituents that are specifically found in C. speciosus are diosgenin, gracillin, dioscin, prosapogenins A and B of dioscin, eremanthin, costusosides, β-sitosterol, β-D-glucoside, β-carotene, α-tocopherol quinine, dihydrophytylplastoquinone, 5α-stigmast-9(11)en3β-ol, tetracosanyl octadecanoate, methyl hexadecanoate, methyl octadecanoate, cycloartenol, cycloartanol, and cycloalaudenol (Eliza et al. 2009;Nehete et al. 2010;Singh et al. 2014;Pawar and Pawar 2014). Apart from the leaves and rhizomes, seeds have also been shown to conserve α-tocopherol, dihydrophytylplastoquinone, and its 6-methyl derivatives (Rani et al. 2012). Seeds of the plant produce oil which shows the prevalence of some saturated fatty acids, for example, myristic acid, stearic acid, behenic acid, palmitic acid, and monounsaturated fatty acid like oleic acid (monounsaturated omega-9 fatty acid), gadoleic acid, and polyunsaturated fatty acid include linoleic acid (polyunsaturated omega-6 fatty acid) (Rani et al. 2012;Rastogi and Mehrotra 2004a, b) (Fig. 6). To determine the chemical components of the complete seed after testing it for its oil content, seeds of the C. speciosus have been defatted, which revealed the existence of bioactive phytoconstituents such as glucose, rhamnose, galactose, and diosgenin (Malabadi et al., 2016). Recent researches done by Kumar et al. (2018a, b) using techniques such as GC/MS, ESI-MS/UPLC/MS, and NMR confirmed the presence of a diverse range of metabolites like terpenoids, phenolic compounds, sterols, fatty acids, and amino acids from the rhizomes and leaves of C. speciosus. Dehydrocostus lactone, arbusculin A, santamarine (douglanin), and reynosin are some of the sesquiterpenes isolated and identified from the rhizomes of the plant (Al-Attas et al. 2015). Srivastava et al. (2011) have reported the presence of diosgenin in different parts of the plant, which is shown in Fig. 7. Another most important sesquiterpene, Costunolide, which has tremendous pharmacological properties, has also been reported from C. speciosus (Duraipandiyan et al. 2012  Structures of some of the bioactive chemical ingredients found in Costus speciosus are shown in Fig. 8. From the analytical studies done by Abirami et al. (2014), the concentration of different phytoconstituents varies in different parts of the plant; for instance, the compounds of phenolic nature were reported to be most abundant in the leaves (119.02 mg/100 g); however, in rhizome 69.49 mg/100 g phenolic components were found which was still more than the concentration present in the stem and roots (65.24 mg/100 g and 30.88 mg/100 g, respectively). Similarly, the flavonoid-rich part of the plant was a leaf with a concentration of 96.18 mg/100 g, while 50.18 and 56.49 mg/100 g were reported from roots and stem, respectively. Another quantitative analysis to determine the percentage of concentration of crude bioactive compounds or chemical constituents in C. speciosus was done using UV-Visible spectrophotometry which evidently revealed the gratification of the plant with phenolic compounds (25.4 ± 0.4 mg/g of dry material) followed by tannin (20.3 ± 0.62 mg/g of dry material), saponin (18.3 ± 0.66 mg/g of dry material), flavonoid (13 ± 0.79 mg/g of dry material), terpenoid (11.2 ± 0.5 mg/g of dry material), alkaloid (6.4 ± 0.45 mg/g of dry material), steroid (1.03 ± 0.15 mg/g of dry material) (Raveendran 2015).
In addition, the appreciable quantity of antioxidant phytoconstituents like ascorbic acid (216 ± 2.51 mg), α-tocopherols (25 ± 0.81 mg), β-carotene (184 ± 6.8 µg), and glutathione (407 ± 2.58) (all the mentioned values were expressed based on per 100 g of dry material of the plant) has been reported by Devi and Urooj (2010). Besides these bioactive chemical compounds, C. speciosus is reported to contain certain trace elements, which are also required for the growth of the plant in a proper manner; however, they are needed in very small quantities. The rhizomes of the plant show the presence of N, K, Na, P, Ca, and Mg and the amount in which they are found are represented in Fig. 5. Different phytochemicals present in different parts of the plant are categorized in Table 4.

Physicochemical properties
Physicochemical properties of the phytoconstituents are one of the main aspects to be evaluated, while their interactions with other biomolecules are studied as the potential of the chemical compounds to possess various pharmacological and therapeutic effects is associated with and influenced by these properties. Considering the implications of physicochemical properties of different parts of C. speciosus and extractive values for the same, using different solvents has been done in previous studies. Evaluation of physicochemical parameters such as moisture content, water-soluble content, alcohol soluble content, acid insoluble ash, water-soluble ash, total ash, and sulfated ash has been done using different solvents like methanol, petroleum ether, ethyl acetate, chloroform, and water by several workers (Shrivastava et al. 2011;Singh et al. 2014;Kala et al. 2016;Borkataky et al. 2014;Maji et al. 2020) as shown in Fig. 9. It has to be noted that variations occur in the values of the ash content as the physicochemical properties get affected by the variations in the geographical locations of the plant. In addition to this, various other parameters like saponification values (179.84 mg KOH/g), refractive index (1.4672), acid value (23.54 mg KOH/g), and specific gravity (0.9125) of the oil content have been studied by Shrivastava et al. (2011).

Antioxidant activity
Antioxidants are the molecules that can inhibit the process of oxidation of other molecules by breaking the chain reactions of free radicals and also inducing the antioxidant enzymes of cells (Daisy et al. 2008). The antioxidants feed free radicals with electrons of their own, and in this process, they themselves do not become the free radicals. Investigative studies on free radicals have revealed that as the number of free radicals increases in the human body, it induces early aging in human beings (Halliwell 1991). Several factors decide the toxicity of free radicals like the kind of free radical, concentration, localization of production, and elimination kinetics (Nordgren and Fransen 2014). Superoxide anion, hydroxyl radical, singlet oxygen, peroxyl radical, alkoxy radical, and various other reactive nitrogen species damage the cell organelles and cellular activities and bring the body of plants and animals under oxidative stress, which is the condition when the antioxidant defenses are outnumbered by the free radicals. The most common free radicals that all aerobic organisms produce are reactive oxygen species (ROS). Biological molecules like DNA, proteins, lipids, and lipoproteins are vulnerable targets for them as ROS can react very easily with them. If the DNA repair system fails to reverse the damages to DNA, this leads to harmful mutations and more likely develop into cancer (Beckman et al. 1994). Similarly, when the target molecules of these harmful oxidants are proteins, they inhibit the enzymes, denature, and degrade the proteins. Oxidative injury is caused by the peroxidation of lipids and causes pathophysiological disorders like diabetes, cirrhosis, atherosclerosis, arthritis, cancer, inflammation, diabetes, and genotoxicity (Halliwell 1991;Nehete et al. 2010;Sunitha, 2016). Another study shows that the length of the telomere of chromosomes gets shortened due to oxidative stress (Gupta 2015). A brief description of different types of free radicals and damages caused by them is given in Table 5.
Antioxidants derived by the plants are the most efficient solution to the pathologies driven by free radical attacks (Girgis et al. 2015). For this, plants show effective counteraction mechanisms. One of the ways to deal with oxidative stress is scavenger enzymes that include glutathione S-transferases (EC 2.5.1.18), superoxide dismutase (EC 1.15.1.1), glutathione peroxidase (EC 1.11.1.9), and catalase (EC 1.11.1.6) (Gottfredsen et al. 2013). These enzymatic antioxidant defense systems prevent toxic hydroxyl ion formation (HO•) mainly by metabolizing superoxides, lipid peroxides, and hydrogen peroxides (Pietta 2000). For instance, superoxide dismutases, one of the chief cellular antioxidants, constituting a group of metalloenzymes, helps in the protection of the cell from the damaging and excessive concentration of free radical of superoxide anion O2− by decreasing them through the dismutation reaction in which the free radical (O2−) is converted into hydrogen peroxide  and molecular oxygen and shows therapeutic potential against cancer, aging, various inflammatory and neurodegenerative diseases (Younus 2018). Another scavenger enzyme, catalase, which, like superoxide dismutase, shows first-line defense against oxidative stress, causes decomposition of the hydrogen peroxide, and nullifies its harmful effects by forming molecules of innocuous nature, i.e., water and oxygen. Similarly, glutathione peroxidase, an intracellular enzyme, protects from oxidative damage by reducing hydrogen peroxide and lipid hydroperoxides to water and corresponding alcohols, respectively (Nandi et al. 2019). The scavenger enzymes mentioned above provide a first-line defense system against oxidative stress. However, it is to be noted that if reactive oxygen species even in small amounts escape this first-line defense, it can lead to the formation of highly toxic and reactive products by triggering lipid peroxidation. Thus, another path is required to combat with this problem by providing a second line of defense which involves the enzymeglutathione S transferase that can reduce the phospholipid hydroperoxide and fatty acid hydroperoxide and ultimately terminate the cascade of lipid peroxidation (Sharma et al. 2004).
Another mode of defense against ROS is exhibited by the molecules that are non-enzymes and are basically of low molecular weight, for example, Vitamin C (ascorbic acid), Vitamin E (α-tocopherol), β-carotene, glutathione, proline, phenolic acids, flavonoids, etc., while high molecular weight compounds are the secondary metabolites such as tannins and it is illustrated in Fig. 10. The low molecular weight non-enzyme antioxidant compounds play a great role in the growth and development of the plants as they can modulate not only the processes like cell division and cell elongation but also the senescence and death as they can interact with numerous components of the cell by functioning as redox-buffer (Foyer and Noctor 2005).
Medicinal plants contain flavonoids and phenolics that possess property to protect living organisms against the hazardous effect of ROS as they have strong freeradical scavenging potential and metal ions chelation properties (Govindarajan et al. 2005). C. speciosus is a very rich source of major antioxidant compounds such as phenolic acids, xanthones, tannins, lignans, flavones, ascorbic acid, β-carotene, α-tocopherol, glutathione, and flavonoids (Devi and Urooj 2010). Studies show that these compounds not only defend against ROS but also provide protection from the breaking of DNA strands (Jha et al. 2010;Pai Kotebagilu et al. 2014). To date, various in vitro studies have been conducted on different parts of C. speciosus like roots, stems, and leaves that have evidently established the tremendous antioxidant potential. The relative solubilities of different phytochemicals are different and follow the basic motive behind the extraction, i.e., extraction done on the basis; whether the plant matrices contain polar, nonpolar compounds or have intermediate polarity, many different extracts like methanol, ethanol, petroleum ether, n-hexane, benzene, pure acetone, and acetone-water mixture have been used to isolate a diverse variety of active secondary metabolites from C. speciosus. Based on evaluative studies done using antioxidant analysis methods like total antioxidant scavenging activity, 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide scavenging activity, thiobarbituric acid, and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid, it was reported that the antioxidant activity is mainly due to the phenolic contents present in different parts of the plant (Maji et al. 2020). In addition, the analysis of methanolic extracts of the rhizomes of C. speciosus showed the presence of various phytochemicals like steroids, glycosides, gracillin, methylprotogracillin, protogracillin, dioscin, methyl protodioscin, prosapogenin B of dioscin, diosgenin 3-O-β-D′ Glucopyranosyl, (1 → 3)-β-glucopyranoside, and (Shrivastava et al. 2011). Furthermore, when assayed with DPPH and nitric oxide scavenging methods, methanolic extracts of C. speciosus showed much powerful nitric oxide and free radical scavenging activities as compared to the ascorbic acid (Jha et al. 2010). One of the reasons behind the antioxidative potential of the methanolic extract as suggested by the researchers is the presence of flavonoids, triterpenoids, glycosides, steroids, and tannins in C. speciosus (El-Far et al. 2018). Apart from the abovementioned solvents being used, chloroform extract of C. speciosus has also shown significant potency against free radical scavenging (Chakraborty 2009). Another study says that using the benzene extract of C. speciosus gives the best results, which is used against chronic diseases like heart disorders and cancers (Nehete et al. 2010). This might be due to the great dissolving ability of benzene for a diverse range of organic components because benzene in its ring structure contains the pi-clouds that allow them to interact with the pi-clouds of various solutes. Nowadays, more focus is on using the mixture of different solvents in appropriate ratios, which paves the way for the exploration of various unexplored phytochemicals to study their phytochemical and pharmacognostic potency. Work has been done in this direction which showed that when the extract of acetone water and acetic acid in the appropriate ratio was used against starch hydrolases (a member of glucoside hydrolase family, which needs to be inhibited in Type 2 diabetes), it exhibited a strong antioxidant property and inhibitory effect on the concerned enzyme (Lee et al. 2015). Antioxidant activity shown by different extracts of Costus speciosus is mentioned in Table 6. Plant antioxidants when supplemented to animals have to go through many physiological and pharmacological changes, while getting absorbed, distributed, metabolized, stored, and then excreted out by the animal's body and also have to deal with several other factors such as their bioavailability, presence or absence of different transition metals, and co-antioxidant compounds. Therefore, parallel to the in vitro investigations, in vivo studies must also be undertaken, while they establish the therapeutic values of the bioactive components of the plants. Taking this into consideration, two pharmacologically significant chemical constituents, costunolide and eremanthin, of C. speciosus were orally administered in rats (streptozotocin-diabetic rats) through the in vivo method by an intragastric tube for two months. It was observed that there was a decline in the otherwise elevated level of thiobarbituric acid. However, in the brain, heart, kidney, pancreas, and liver, there was significant increment or elevation in the activities of superoxide dismutase, glutathione peroxidase, catalase, and in reduced glutathione content as shown in Fig. 11 (Eliza et al. 2010). Similarly, for the evaluation of antioxidative potential of C. speciosus, rhizomes of the plant were used as diet supplementation of Egyptian buffalo heifers for one month. Two groups were made in this study: One was that of control (no treatment was given, only basal diet), while the other was the group which was provided with the supplementation of C. speciosus rhizome. Comparative observations of both the scenarios revealed that the latter group of buffaloes showed up with the higher antioxidant potential of erythrocytes as was evinced by the total antioxidant capacity improvement's significant decline in malondialdehyde (El-Far and Abou-Ghanema 2013). Though phytochemical analysis has been done on a significant level for this plant, there is a need to focus on the genetic and proteomics level as very little research has been done in this context.

Hepatoprotective activity
Among various deadly diseases, one of the common diseases that cause morbidity and mortality worldwide (around 2 million deaths every year) is liver disease (Asrani et al. 2019). Chemotherapeutic substances, various synthetic drugs, and toxic chemical compound like carbon tetrachloride (CCl 4 ) create toxic effects on the liver (Maheswari et al. 2008). To assess the hepatotoxic activities, there are certain serum biomarkers used, such as acid phosphatase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and fluctuations in the level of these enzymatic biomarkers, which can be detected in the bloodstream as they get leaked out of the liver cells (Contreras-Zentella and Hernández-Muñoz 2016). Serum hepatic biomarkers helping in the detection of hepatotoxicity are shown in Fig. 12. The extract of the plant C. speciosus shows great potential for hepatoprotection as it contains phenolic compounds such as saponins, steroids, and glycosides Devi and Urooj 2010). It has been evidently analyzed by using the extract of C. speciosus against hepatotoxicity caused by carbon tetrachloride in Swiss Albino mice. It was observed that the serum level of total protein, bilirubin, and hepatic biomarkers, which was increased due to the CCl4 intoxication, came back to their normal levels when the mice were given the methanolic extract of the rhizome of C. speciosus. These observations were compared with the reference standard drug silymarin, which is a hepatoprotective drug, and it was found that the potential of the extract had better effects in hepatoprotection activity (Bhuyan and Zaman 2008). Acetone-water-acetic acid extract high oxygen radical capacity High oxygen radical absorbance capacity and free radical scavenging activity Lee et al. (2015) Benzene extract High total phenolic content and antioxidant activity Nehete et al. (2010) Fig . 11 Diagrammatic representation of the effect of antioxidant activity of costunolide and Eremanthin from Costus speciosus in Streptozotocin-diabetic rat (Eliza et al. 2010) Page 15 of 27 Sohrab et al. Bulletin of the National Research Centre (2021) 45:209 A similar study was conducted using the ethanolic extract of C. speciosus on Wister albino rats, and the results showed the potency of the plant against liver toxicity and their role as hepatoprotective agents ). In the same context, a study was conducted on normal mice using very common, widely available, and accessible antipyretic and analgesic drugs, Paracetamol, which is otherwise safe but when overdosed can result in severe disorders like hepatotoxicity and nephrotoxicity (Hazai et al. 2001;Heard 2008). Damages caused to the liver by this drug are mainly driven by the depletion of the glutathione (a natural antioxidant found in the liver) by N-acetyl-p-benzoquinoneimine (one of the metabolites of PA-liver damage) and lead to hepatocyte damage following the complete failure of the organ (Kulkarni 2013). Again, the increment in the serum levels of hepatic biomarkers (ALT, ALP, AST, and TNF α) was used as indicators to assess the toxicity caused by the paracetamol in the liver, and it was found that the methanolic extract of C. speciosus successfully decreased the levels back to normal, which evidences its hepatoprotective potential (Kang 2013). It has been proved that alcoholic rhizome extracts of the plant contain hepatoprotective components having an antioxidant activity that helps in the reduction of ROS in the liver (Bhuyan and Zaman 2008;Devi and Urooj 2010;Eliza et al. 2010). An illustration of the brief mechanism of CCl4 and paracetamol toxicity in the liver is shown in Fig. 13 and Table 7. Still, there is a need to investigate and do more comparative evaluations of C. speciosus extracts on various other chemicals and drugs like vinyl chloride, aflatoxins, isoniazid, and arsenic that can cause injuries to the liver and to establish the use of the plant as a source of a potent drug, extensive studies must be done on humans to confirm their hepatoprotective activity on them.

Anticholinesterase action
Anticholinesterase activity or cholinesterase inhibitory activity is shown by the chemicals that can prevent the neurotransmitter breakdown and thus lead to their accumulation in the synaptic cleft. The activity of these neurotransmitter compounds plays an important role against various neurological disorders such as Alzheimer and myasthenia gravis. In the recent arena of research, more focus is now being given to the plant sources that show similar or higher potential regarding the anticholinesterase action. In this regard, work done by Bhattacharya et al. (1972) gives evidence that the alkaloids isolated from the plant C. speciosus show considerable anticholinesterase activity when tested on the blood pressure of a dog and frog's rectal muscle (Maji et al., 2020). The alkaloids present confer the plant with anticholinesterase activity that also contributes as a depurative agent and in the treatment of eye diseases (Mishra et al. 2009). However, to specifically identify the individual alkaloids behind this activity, a lot more research work is needed to be done in the areas of selective screening and study of mechanisms involved.

Diuretic activity
The diuretic potential of C. speciosus has been reported to be used traditionally, but to explore its scientifically driven proofs, experiments have been done on Wistar albino rats using different extracts of the plant such as leaves and rhizomes. The activity of the aqueous and ethanolic extracts of the plant was compared by the activity of Furosemide diuretic drugs used commercially to treat various disorders like serious kidney problems, edema, and high blood pressure (Consumer Medicine Information-News Medical Life Sciences 2019), and it was found that the volume of the urine and diuretic index significantly increased. One more interesting observation was that the saluretic action of the plant extract was weaker than the Furosemide loop drug as there were lesser electrolyte secretions. However, there is a requirement to study the effects of diuretic responses of higher doses of the extracts to establish the exact mechanism of the action (Dubey et al. 2010;Prabhu et al. 2014).

Estrogenic activity
To study the activity of the plant of C. specious concerning its estrogenic action, the extract of the rhizome was given to rats and it was found that there was a stimulatory effect on the uterus (Lijuan et al. 2011). Another study was done on adult female mice using the methanolic extract, which revealed that the weight of the uterus increased; however, there was a decline in the weight of ovaries (Choudhury et al. 2012). There was also an increment in the concentration of glycogen and production of proliferative changes in the tested rats' uterus. It was explained that this activity is the attribution of the saponin content present in the plant (Rastogi and Mehrotra 2004a, b). This portion still requires a lot of studies to be done by using different extracts of the plant to explore various other changes in the uterine activities due to the estrogenic actions of the plant.

Antispasmodic activity
The antispasmodic or spasmolytic activity of any compound refers to its ability of the prevention of spasm or provides relief against the spasm caused particularly in involuntary muscles. A different extract of C. speciosus has been tested on the ileum of a guinea pig by Banerji et al. (1982). The results obtained proved that the plant has moderate levels of spasmolytic activity. When the activity of the C. speciosus extract and conventionally used antispasmodic drug papaverine was compared, it was found that the former showed weaker antispasmodic properties (Srivastava et al. 2011).

AlSaadi et al. (2018)
Page 18 of 27 Sohrab et al. Bulletin of the National Research Centre (2021) 45:209 Antifungal activity To study the antifungal activity of C. speciosus studies, a technique like a column chromatography has been used, which reveals that the antifungal property was due to the presence of sapogenins and saponins (Bandara et al. 1989). Various antifungal compounds such as saponin (B and C) and tigogenin have been investigated against fungi Botrytis cinerea, Curvularia sp., Alternaria sp., Sclerotinia sclerotiorum, and Fusarium lini. These compounds were found to be effective against the germination of conidia. Another study conducted by Duraipandiyan et al. (2012) proved the antifungal properties of the plant by using different extracts such as methanol, chloroform, and ethyl acetate. The inhibitory action of the extracts has been tested against fungi Curvularia lunata, Scopulariopsis sp., Epidermophyton floccosum, Trichophyton spp., Magnaporthe grisea, and Aspergillus niger, and it was reported that the phytocomponents like eremanthin and costunolide were responsible for this (Maji et al. 2020). Antifungal activity of C. speciosus has been tested against a wide range of fungi, which is shown in Fig. 14. Furthermore, the antifungal activity of Costus speciosus can also be evinced through the research work done by Sulakshna and Rani (2015) where it has been observed that the diameter of the inhibition zone of different fungi increases as the concentration of the prepared stock solutions (with 0.5-2 mg of plant extract) made by using dimethyl sulfoxide, DMSO as solvent, was increased and is shown in Fig. 15.

Anthelminthic activity
One of the most common and serious threats to human health is the problem of worm infestation. Infections caused by the worms, particularly parasitic worms, have chronic effects on human health. Methanolic and aqueous extract of the C. speciosus' aerial parts has been studied against one of the most common and widely spread worms Pheretima posthuma (adult earthworm) (Srivastava et al. 2011). Also, comparative studies were done using the conventional antiworm medication, Albendazole, which is reported to cause paralysis and death of the worm by causing expulsion of the worms as the conductance of the chloride ion gets increased in the membrane of the muscles of the worm and thus there occurs flaccid paralysis due to reduction in excitability and hyperpolarization in the muscles (Borkar et al. 2010). Through these studies, the traditional claims of anthelminthic potential of C. speciosus have been proved as the aqueous and the methanolic extract showed greater potency against the worm than the standard drug, albendazole (Borkar et al. 2010). It is also noteworthy that the aqueous extract was more effective in antiworm activity than the methanolic extract (Fig. 16). Though the available literature shows studies conducted on the common earthworm, it is believed that this leads the path to explore this activity of other harmful parasitic worms as there is a resemblance in the physiology and anatomy of Pheretima with other intestinal worms that cause infections in human beings (Srivastava et al. 2011). Moreover, there is a need to trace the exact mechanism of the anthelminthic activity and Page 19 of 27 Sohrab et al. Bulletin of the National Research Centre (2021) 45:209 accountable phytoconstituents of C. speciosus involved in this activity.

Antibacterial activity
Increasing undesirable side effects of synthetic drugs used as antibiotics has grabbed the attention of the scientists to search for more and more herbal resources that would be employed as replacements for these antibiotics. The rhizomes and leaves of C. speciosus are known to possess a wide variety of compounds that have antibacterial properties. Extensive research done in this context has validated the traditional use of this plant against bacterial infections. In vitro studies were performed by Malabadi (2005) and Sulakshana and Rani (2013) against bacteria such as Staphylococcus aureus, Salmonella, Bacillus subtilis, Shigella, Klebsiella pneumoniae, Pseudomonas, and Escherichia coli using aqueous, hexane, and methanolic extracts of C. speciosus (Shrivastava et al. 2011). By employing the disc diffusion method, another evaluative study was conducted by Arunprasath and Gomathinayagam (2014) using the methanolic and hexane extracts of C. speciosus and proved the antibacterial potential of the plant against Bacillus subtilis, Shigella sp., Escherichia coli, and Staphylococcus aureus. Besides rhizome extract, the leaves of the plant also possess antimicrobial properties as was shown in the studies were done by Vaidya Shingadia (2020), where it was found that among many different fungi, viz. E. coli, Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Bacillus subtilis, being tested, by using the extract of the leaves of C. speciosus, the maximum zone of inhibition (measured in terms of the average diameter of zone inhibition in millimeters), which is the represents the antimicrobial activity, was shown by E. coli and lowest activity by Streptococcus pyogenes. It is believed that the alkaloids such diosgenin might be responsible for such antibacterial properties exhibited by the plant (Ariharan et al. 2012). However, to explore the potential of the plant as bio-medicine and bio-bactericide, more biotechnological approaches should be made.

Anticancer activity
According to the World Health Organization (2018), cancer is reported to be one of the deadliest diseases, causing deaths of around 70% of the population globally, and holds the position of the second leading cause of death in the world. Plant-derived drugs are now being focused as the complementary source of medicine to cure cancer, and it has been shown in studies also those herbal medicines when used in combination with the regular therapeutic drugs show advantageous effects on cancer patients' immune modulation, survival, and quality of life (Yin et al. 2013). Various in vitro and in vivo studies have been done on the phytochemistry of C. speciosus, revealing the presence of some active compounds like Costunolide, Beta-amyrin, Camphene, Lupeol, Zerumbone, Alpha-humulene, and Diosgenin, which shows significant anticancer potential. To combat cancer, there are various up-regulatory and down-regulatory mechanisms that are being followed by these compounds (El-Far et al. 2018), shown in Fig. 17A and B. One of the up-regulatory mechanisms against cancer is through the activity of tumor suppression in which the transcription factor p53 plays a very crucial role as it is known to promote various anticancer activities as the promotion of genes that causes growth arrest (genes of p21) and ultimately inhibits the proliferation of cancerous cells, induction of ROS, and regulation of apoptotic pathways. The active components of C. specious have been studied to investigate their activity against various cancers in humans like lung cancer, osteo carcinoma, melanoma, and cervix carcinoma (El-Far et al. 2018). The extracts of different parts of the plant have been evaluated for their anticancer potential; for example, methanolic, hexane, and ethyl acetate extract of the rhizome showed significant antiproliferative activities against human colon cancer (Baskar et al. 2012). Similarly, when the methanolic extract of the leaf was tested, it was found that there was a reduction in the viability of cancerous cells (Nair et al. 2014). It was reported that the extract of the plant by an increase in the activities of caspase-3 leads to the disturbances in the cell cycle. A bioactive ingredient, Costunolide, which is found significantly in C. speciosus, shows the capability to arrest the cells involved in cancerous activities particularly at their second growth phase and mitotic phase. In addition to this, costunolide also affects the regulation of NF-kβ, the overexpression of which must be prevented; otherwise, the cancerous cells would continue their proliferation and cell survival will be maintained (El-Far et al. 2018). It has been reported by Pitchai et al. (2014) that the downregulation of these NF-kβ (if they are over-expressive) can be done by using Costunolide obtained from C. speciosus and its activity has been testified against human breast cancer. Furthermore, it has been seen that the initiator caspase (e.g., caspase-9) and executioner caspase (like caspase-3) both get overexpressed or their activity was significantly increased, which is needed to destroy cancer cells because these endo-proteases lead the cell to apoptosis (Roy and Manikkam 2015). In the same way, diosgenin, another very important anticancer compound produced in the C. speciosus, also shows the apoptotic activity as it actively participates in increasing the DR-4 levels and endo-proteases (like caspase-3), and this property has been studied against human breast adenocarcinoma with cell line-MCF-7 and human liver cancer (cell line HepG2) where cytotoxicity was observed (El-Far et al. 2018). Detailed illustration of anticancer activity of costunolide present in Costus speciosus is shown in Figs. 18 and 19.

Anti-inflammatory activity
Costus speciosus has been used by traditional folk for ages to treat various inflammatory disorders like bronchitis, fever, rheumatism, and headache. Bioactive components like diosgenin and costunolide have been exploited against various inflammatory diseases as they are known to potentially inhibit the activity of tumor necrosis factoralpha (TNF-α), a cytokine, which is released in response to infection as an alarm for other immune reactions to occur and leads to the inflammation of the concerned tissues or cells. Evaluation of the anti-inflammatory property of diosgenin isolated from C. speciosus was done on RAW 264.7, a macrophage, and it was observed that there was an inhibitory or suppressive effect on the virus and the activity of diosgenin was found similar to the MTX (methotrexate), a commonly used immune system suppressant (Selim and Al Jaouni 2016).
Besides diosgenin, costunolide also shows inhibitory potential against TNF-α, cyclooxygenase, and interleukins by following the mechanisms like protein kinase pathways activated by mitogen and inhibiting NFk-β in the activated microglia (Rayan et al., 2011). Various other bioactive chemical compounds like dehydrodihydrocostus lactone, reynosin, arbusculin A, santamarine, and stigmasterol isolated from C. speciosus' chloroform extract have been studied on the isolated mononuclear cells of the blood to possess anti-inflammatory activity by inducing the reduction in the levels of various interleukins (such as interleukins 1 and 6), prostaglandins TNF-α (Al-Attas et al. 2015).

Antidiabetic activity
According to the report of the National Diabetes and Diabetic Retinopathy Survey (2019) done by the Health and Family Welfare Ministry of the Government of India, the prevalence of diabetes was recorded to be 11.8%. In another report published by the International Diabetes Foundation (IDF) Diabetes Atlas India (2019), alarming figures have emerged, which shows that there are around 77 million diabetes patients present, which compels the country to make some re-evaluations and formulate some effective strategies to fight the disease as the numbers are continuously rising and it has been estimated by IDF that in the next 25 years, this number will increase to over 134 million. Apart from creating several health hazards, this disease takes approximately 10% of the global health expenditure, which is quite a big figure in itself to draw the attention of the scientists to explore both more herbal and cost-effective remedies of the disease. Diabetes mellitus is a disease in which the glucose level in the blood gets increased because of the relative or absolute deficiency or insufficiency of the insulin in the blood. Reflecting the level of glucose in the blood, three conditions are noteworthy while mentioning diabetes-Normo-glycemic, hypoglycemic, and hyperglycemic conditions showing normal, below normal, and too high level (above normal) of glucose in the bloodstream, respectively. For the treatment of diabetes, several drugs like insulin, biguanide, thiazolidinediones, and sulfonylureas are commonly used. Besides these drugs, several medicinal plants are exploited to gain remedies for the disease. Among such medicinal plants is the C. speciosus that exhibits significant antidiabetic properties and is given the name "insulin plant" as a very important antidiabetic agent Diosgenin is found in them (Rani et al. 2012;Sulakshana and Rani 2015). To investigate the antidiabetic potential of C. speciosus, an experimental study was done by Daisy et al. (2008) on male diabetic rats that were induced by streptozotocin causing them to develop hyperglycemia. It was observed that when such diseased rats were administered with methyl acetate extract, hexane extract, and methanolic extract for about 60 days, there occurred a significant reduction in the levels of glucose in the blood plasma as compared to the control group. Among these three extracts, the highest antidiabetic potential and hypoglycemic activity were shown by hexane extract. In addition to this, total cholesterol, glycosylated hemoglobin, and cholesterol level were also decreased (Daisy et al. 2008). A similar study was conducted on male rats induced by Alloxan, and the antioxidant, antihyperlipidemic, and antihyperglycemic activities of the ethanolic extract of C. speciosus were tested and compared with glibenclamide (a standard drug), and results showed that there was a tremendous decrease in blood sugar concentration, which may have occurred due to a decrease in gluconeogenesis and increase in glycogenesis. Moreover, the activity of antioxidant enzymes present in the liver was also found to be improved along with the decrease in cholesterol, plasma lipids, and triacylglycerol (Mosihuzzaman et al. 1994). There are the other numbers of investigations done by various workers to evaluate the anti-diabetic potential of C. speciosus and alterations caused in the biochemistry of the treatment group; for example, α-glucosidase and α-amylase were inhibited by the leaf extract (methanolic extract) of the plant, which ultimately leads to the decrease in the plasma protein glycation by delaying the digestion of carbohydrate and decreasing the absorption of glucose (Perera et al. 2016). Other studies revealed that the antidiabetic component, costunolide, has a stimulatory effect on the beta cells that led to the secretion of insulin (Eliza et al. 2009). Various effects of active constituents like eremanthin and costunolide derived from C. speciosus are shown in Fig. 20.

Conclusions
In this review article, efforts have been made to throw light on the medicinally important plant C. speciosus with regard to its ethnobotanical, phytochemical, and pharmacological properties. The plant exhibits strong antioxidant, anti-inflammatory, anticancer, anticholinesterase, hepatoprotective, diuretic, estrogenic, antispasmodic, antifungal, and