Phytochemistry and pharmacology of Curculigo orchioides Gaertn: A review

Curculigo orchioides Gaertn. is a rare rasayana herb (family Amaryllidaceae) popularly known as “Kali Musli”. Traditionally used in Ayurvedic medicine as an aphrodisiac and adaptogen, the plant is native to India. There is evidence that the plant contains mucilage, phenolic glycosides, saponins, and aliphatic compounds. This folk medicine can treat a wide range of ailments, including impotency, aphrodisiacs, tonics, jaundice, and skin conditions. There are also many scientists who have investigated its antioxidant, anticancer, and hepatoprotective properties. Curculigo was isolated for its chlorophenolic glucosides, curculigine, phenolic glycosides, orcinosides, and polysaccharides. As an herbal medicine, Curculigo ’ s quality can be controlled through new analyzing methods. Furthermore, Curculigo has been investigated for its pharmacological activity against diabetes, bacteria, inflammation, osteoporosis, oxidative stress, cancer, and neurodegeneration. Scientific methods were gradually developed for the application of herbal medicine. A more comprehensive pharmacological study of the genus Curculigo is needed to determine its medicinal value. An updated and comprehensive review of the medicinal plant C. orchioides Gaertn is presented here describing traditional uses, phytochemistry, pharmacology, and toxicology, and understanding its future research and development prospects.


INTRODUCTION
The traditional Indian medical system is called Ayurveda.There is a long history of disease management in Ayurvedic practice dating back about 3000 years (Hankey, 2001).The Ayurvedic healing process relies heavily on plantbased preparations (Sastri, 2002).In Ayurvedic medicine, approximately 90% of the preparations are derived from plants (Kumar et al., 2017).There are many Asia's subtropical regions, including China and India, where Curculigo orchioides grows as a perennial herb of the Amaryllidaceae family (Bafna and Mishra, 2005;Jiao et al., 2009;Wang et al., 2012).Curculigo orchioides Gaertn, of the Amaryllidaceae family has different names such as Golden Eye Grass, Talamuli, Kalimusli, Nilappani, and Nilapanaiin English, Sanskrit, Hindi, Malayalam, and in Tamil, respectively (Joy et al., 2004).
Originally native to India, C. orchioides occur everywhere, especially in rocky areas, especially at sea level and up to 2,300 m above the sea level (Mehta and Nama, 2014).Tonic medicine has been used for centuries with the rhizome of C. orchioides by the Chinese since the Tang Dynasty for the maintenance of health, energy, and nourishment of renal and hepatic systems.The root of C. orchioides was commonly used in the treatment of impotence, limb limping, lumbar and knee joint arthritis, and diarrheal water (Chauhan et al., 2010).Jaundice, asthma, urinary and skin diseases, and bladder and kidney infections were treated with C. orchioides in the Ayurvedic System of Medicines (Khare, 2007).

Rhizomes of C. orchioides contain eight cyclodipeptides, such as
, and cyclo-(Leu-Ser), which are previously known (Chen et al., 2017).The aqueous leaf extract of the plant was observed to contain different alkaloids and phenolic compound from the post preliminary phytochemical analysis using Fourier-transform infrared spectrophotometer (Umar et al., 2021).The presence of alkaloids, phenols, and saponins could be a plausible explanation for the observed toxic effects of C. orchioides' AL extract in organismal-level toxicity in Drosophila (Kushalan et al., 2022a(Kushalan et al., , 2022b)).

Immunomodulatory activity
Adaptation to hypoxia and high temperatures is improved by C. orchioides ethanol extract.Extracts from C. orchioides have been found to be sedative, anticonvulsant, and androgen-like.In mice, immunological activity increased as well  et al., 2003).Although polysaccharides stimulate splenocyte proliferation, they do not affect thymocyte proliferation.Using ConA-induced splenocyte proliferation as a model, polysaccharides demonstrated an inhibitory effect on thymocyte and spleenocyte proliferation in vitro.Mice with immunosuppression had larger thymuses and spleens as a result of these effects (Zhou et al., 1996).
It has been suggested that the methanolic extract of C. orchioides (MECO) Gaertn's could be used to prevent the cytotoxic effects of drugs.When the extract was administered to normal mice or cyclophosphamide-induced immunosuppressed mice, humoral antibodies, DTH, and leukocytes increased depending upon the dose (Bafna and Mishra, 2006).One of the contents of C. orchioides rhizomes, Curculigo saponin, acycloartane-type triterpene saponin, enhanced the number of lymphocytes of the spleen remarkably in mice without affecting antibody production (Lacaille-Dubois and Wagner, 1996).Polysaccharides resulted in increased spleen and thymus indexes in normal mice, along with increased hemolytic index and thicker plantar tissue in serum; Mice immune function is enhanced by polysaccharides, according to these results (Ji, 2011).
Mice peritoneal mast cells were significantly inhibited from degranulating by an extract of C. orchioides rhizome in ethanol and mice exposed to 48/80-induced systemic anaphylaxis.Anti-inflammatory properties of C. orchioides are attributed to their inhibitory effects on mast cell degranulation and mast cellderived immediate-type allergic reactions (Venkatesh et al., 2009).

Estrogenic activity
Total glucosides from C. orchioides were found to increase the thymus, uterus, and spleen indices, testosterone levels, and estrogen levels, and decrease luteinizing hormone levels in perimenopause model mice (Cao et al., 2016;Miao et al., 2017).Curculigo orchioides also alleviate streptozotocin-induced hyperglycaemia in male rats, improving sexual dysfunction as well.The effects of the treatment were observed in male sexual behaviour, penile erection index, seminal fructose content, and sperm counting the test samples (Thakur et al., 2012).It increases steroid synthesis and restores sexual function by enhancing the spermatogenesis process.It could also facilitate hormone absorption into the gonads if C. orchioides was administered (Chauhan et al., 2007).

Anti-osteoporosis activity
The rhizomes of C. orchioides are asserted to strengthen bones and tendons (Cao et al., 2008).The proliferation of bone marrow stromal cells was enhanced by 100 mM curculigoside, osteogenic genes were enhanced, and osteoprotegerin secretion was increased (Shen et al., 2013).A study indicates that cuculigoside A chemical compound inhibits the inflammatory cytokines TNF-a, IL-1a, IL-6, and COX-2 production by rat calvarial osteoblasts induced with dexamethasone and regulates osteoblast COX-2 expression, proliferation, and differentiation (Zhu et al., 2015a(Zhu et al., , 2015b)).
The chlorophenolic glucosides (Curculigine M, Curculigine N, and Curculigine O) isolated from the dried rhizomes of C. orchioides Gaertn showed moderate effect on osteoblast proliferation against MC3T3-E1 cell line by using MTT assays (Wang et al., 2018).A novel homogeneous heteropolysaccharide, COP70-3, was isolated and purified from the crude polysaccharide (CO70) isolated from the rhizomes of C. orchioides (0.94 and 1.87 nM) significantly improved the osteogenic mineralization rate and has favorable anti-osteoporosis activity in vitro (Wang et al., 2018).Curculigoside was able to alleviate bone loss induced by oxidative stress resulting from iron overload, suggesting its potential use for the treatment of primary osteoporosis and bone loss in iron-overload-related diseases (Zhang et al., 2019a(Zhang et al., , 2019b)).The major bioactive component of found in the plant's rhizomes, curculigoside, a phenolic glycoside, exhibits neuroprotective and anti-osteoporotic properties (Zhu et al., 2021).COP50-4, a crude polysaccharide (CO50) from C. orchioides shows great potential for the treatment of osteoporosis (Yu et al., 2022).

Antidepressant activity
The immobility time of the forced swimming test, osmotic fragility test, and tail suspension test was significantly reduced by curculigoside treatment.In the hippocampus of chronic mild stress rats, serotonin, dopamine, and norepinephrine levels significantly increased along with brain-derived neurotrophic factor (BDNF) protein expression following the treatment.There is evidence that curculigoside can treat depression in this way (Wang et al., 2016).

Neuroprotective activity
Acetylcholinesterase was effectively inhibited by the extracts of C. orchioides rhizomes, suggesting their potential use in the treatment of Alzheimer's disease (Pratap and Shantaram, 2019).Curculigoside remarkably reduced NMDA-induced loss of neuron cells, apoptosis, necrosis, excitotoxicity, and reactive oxygen species (ROS) production in cultured cortical neurons.The inhibitory properties of curculigoside in cultured cortical neurons may cause the production of intracellular ROS to be reduced and apoptosis may be inhibited.When neurons are exposed to NMDA-induced neuronal excitoxicity, curculigoside prevents them from dying and reduces their apoptosis and necrosis (Tian et al., 2012).
Spectrophotometry and autobiography were used to evaluate the anti-acetylcholinesterase activity of C. orchioides extracts in vitro.The anti-acetylcholinesterase role of rhizome extract methanol in the treatment of Alzheimer's disease appears to be explained by its inhibition of the acetylcholinesterase enzyme (Pratap, 2020).Using curculigoside A, rats with Alzheimer's can be effectively treated because it inhibits apoptosis in hippocampal neurons and reduces cellular damage (Li et al., 2019).In vitro, curculigoside A modulated VCAM-1/Egr-3/CREB/VEGF signalling in cerebroendothelial cells, providing stroke and brain injury therapies by neurovascular repair (Zhu et al., 2015).
It was demonstrated that OG decreased over activity of the hypothalamic-pituitary-adrenal axis and reduced depressive behavior in chronic unpredictable mild stress rats by up-regulating BDNF expression and phosphorylating ERK1/2 (Ge et al., 2014).Mice showed reduced anxiety-like behaviors after administration of OG, but no sedation was seen (Wang et al., 2016).

Hepatoprotective activity
Aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and gamma-glutamyl transpeptidases were reduced in rats exposed to carbon tetrachloride.Food consumption and weight gain were increased by MECO rhizomes.In addition to lowering liver and serum protein levels, serum lipids, cholesterol, and phospholipids were normalized.These studies showed that C. orchioides rhizome has hepatoprotective properties (Venukumar and Latha, 2002).

Nephroprotective activity
Treatment of cyclophosphamide-induced hepatotoxicity and intestinal toxicities with C. orchioides does not compromise cyclophosphamide's chemotherapeutic efficacy.When administered along with cyclophosphamide, the whole plant extract of C. orchioides significantly decreased serum creatinine levels and blood urea nitrogen levels.Induced urotoxicity and nephrotoxicity by cyclophosphamide are alleviated by C. orchioides (Murali and Kuttan, 2016)

Antidiabetic activity
Alloxan-induced diabetic rats and glucose-loaded diabetic rats were shown to be antihyperglycemic with aqueous and ethanol extracts (Chauhan et al., 2007).Using streptozotocin-nicotinamide-induced diabetic nephropathy rats, extracts of C. Orchiodies using ethanol and hydroalcoholreduced hyperglycemia-induced lipid changes, oxidative stress, and renal dysfunction (urea, creatinine, and andalbumin) (Singla and Singh, 2020).Curculigo orchioides was shown to inhibit adipogenesis and enhance glucose uptake in 3T3-L1 adipocytes in an ethanolic extract in a cell-based assay (Gulati et al., 2015).

Anti-microbial activity
As well as being antimicrobial against Bacillus anthracis and Bacillus subtilis, oil of C. orchioides rhizomes inhibited Fusarium solani, Salmonella newport, Staphylococcus aureus, Salmonella pullorum, and Aspergillus flavus, Fusarium moniliforme, and Cladosporium species (Jaiswa et al., 1984).The C. orchioides extract prepared by steam distillation process showed antibacterial activity significantly against several Gram-positive bacteria (Staphylococcus epidermidis and S. aureus) and Gram-negative bacteria (Salmonella typhimurium, Pseudomonas aeruginosa, and Escherichia coli).Antiseptic properties make the extract ideal for preventing bacterial infections (Nagesh and Shanthamma, 2009).
With a minimum inhibitory concentration value of 49 g/ml, C. orchioides alcohol extract inhibited methicillin-resistant P. aeruginosa, whereas Gram-negative bacteria were not affected (Marasini et al., 2015).Curculigo orchioides leaf extracts contain phytochemical-loaded silver nanoparticles which are effective against S. aureus and P. aeruginosa, but less effective against Klebsiella pneumonia and E. coli (Perumal et al., 2017).

Anti-asthmatic activity
Goat tracheal chains and guinea pig ileum are relaxed by C. orchioides ethanol extract.Curculigo orchioides ethanol extract significantly reduced bronchoconstriction and passive paw anaphylaxis in guinea pigs, rats, and mice with haloperidol-induced catalepsy, suggesting an antiasthmatic effect (Pandit et al., 2008).

Anti-stress activity
In forced swimming and tail suspension tests, Curculigo orichioides ethanol extract at 200 mg/kg reduced immobility times.It increased mobility in actophotometer-based tests.Ethanolic extract of C. orchioides' rhizomes increased resistance to heat [50 and 70 infrared (IR) units] in IR testing and rotarod testing.It provides strong evidence that ethanolic extracts have antistress activity (Chauhan et al., 2021).

Anti-cancer activity
Aqueous fresh root extract and methanolic dried root extract showed significant cytotoxicity activity on the human lung adenocarcinoma NCI-H-522 cancer cell line.The cytotoxicity may be attributed to the alkaloids and phenols present in it (Aloysius et al., 2020).A new chlorophenolic glucosides curculigines P, isolated from the dried rhizomes of C. orchioides showed the most potent inhibitory effect on 5α-reductase activity by a HaCaT-based bioassay and, hence, may be useful in benign prostatic hyperplasia (Deng et al., 2021).
Ethyl acetate fractions of C. orchioides Gaertn down regulated the levels of antiapoptotic Bcl-2 expression and upregulated the expression of apoptotic proteins caspase-3 and caspase-8 through an intrinsic ROS-mediated mitochondrial dysfunction pathway (Hejazi et al., 2018).The plant extract when administered in combination with cyclophosphamide enhanced the anticancer properties of cyclophosphamide and ameliorated its toxic side effects (Murali and Kuttan, 2015).Silver nanoparticles using C. orchioides rhizome extracts showed efficacy against human breast cancer cell line (MDA-MB-231) after 48 hours of incubation (Kayalvizhi et al., 2016).Polysaccharides from C. orchioides showed a significant anti-tumor effect on cervical cancer in vivo and in vitro by enhancement of immune function and induction of apoptosis (Xia et al., 2016).

Anti-gout activity
Two heterocyclic phenolic derivatives, orcinosides I and J, displayed xanthine oxidase inhibitory activities with IC 50 values 0.25 and 0.62 mM, respectively.Hence, they may have anti-gout effect (Chen et al., 2017).

Anti-malarial activity
Silver nanoparticles using C. orchioides rhizome extracts showed the highest mortality rate against the malarial vectors such as Anopheles subpictus and Culex quinquefasciatus (Kayalvizhi et al., 2016).

CONCLUSION
This review aims to summarize the existing phytochemistry and pharmacological activities of plant C. orchioides which is a perennial herb, belonging to the family Amaryllidaceae.The content gives a brief proof of the traditional uses of this plant.The plant is reported to show immuno-modulatory, anti-oxidant, hepatoprotective, neuroprotective nephrpprotective, anti-inflammatory, anti-gout, anti-arthritis, anti-cancer, antimicrobial, anti-bacterial, anti-malarial, anti-diabetic, anti-stress, and antihypertensive activities.These effects may be attributed to the anti-oxidant principles present in them.Many authors and researchers reported the phytochemical, pharmacological, and toxicological results which may provide suitable data for further scientific research.

AUTHORS' CONTRIBUTIONS
All authors made substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal and agree to be accountable for all aspects of the work.All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

Table 1 .
Effect of C. orchioides in many metabolic ailments.