Botanical description, phytochemistry, traditional uses, and pharmacology of Crataeva nurvala Buch. Ham.: an updated review

Crataeva nurvala Buch. Ham., an important medicinal plant of the Capparidaceae family, is widely distributed in India and tropical and subtropical parts of the world. It has been reported for its folkloric use in various disorders such as blood purifier, breathing problems, fever, metabolic disorders, wound healing, memory loss, and weak immune system. The present review has focused on the botanical description and ethnomedicinal and traditional uses of C. nurvala along with its reported pharmacological activities. Chief chemical constituents and pharmacological aspects of C. nurvala have been deeply explored to unravel the unexplored folklore/ethnomedicinal uses of this plant so that the researchers working on this plant may be able to find new insights to continue further investigation on this plant. The pharmacological aspects like anti-diabetic, anti-inflammatory, anti-nociceptive, anti-diarrheal, anti-fertility, anti-pyretic, and anti-cancer potentials evaluated by various in vitro/in vivo methods on this plant have been reported. Various traditional uses have been reported that need to be scientifically investigated in depth and several pharmacological activities have been reported for the C. nurvala, but more detailed and mechanism-based studies linked to a particular lead compound need to be targeted in the future. Moreover, this plant has not been completely assessed on the basis of its safety and efficacy on humans. It is expected that this review will compile and improve the existing knowledge on the potential utilization of C. nurvala in complementary and alternative medicine.


Background
According to an estimate, 75% of the overall population practices plants or their extracts for their curative capabilities [1]. Furthermore, around 80% of the developing countries of the world rely on traditional medicines, mainly plants or their products, for their basic healthcare needs [2]. In the present situation, it is estimated that medicinal plants, as well as their products contribute up to 50% of all drugs being used in medical practices [3].
Since the beginning of human life, plants and plantderived compounds have been utilized in several diseases or ailments throughout the world. In the present time, most of people in this world still have faith in their traditional herbal medicine (medicinal plants and or their derived materials) for their routine health-related problems. World Health Organization (WHO) states that this "traditional medicine" implies the knowledge and practices of herbal healing for the prevention, diagnosis, and elimination of physical, mental, or social imbalance [4]. Plants have always been an exemplary source of drugs and many of the currently available drugs have been derived directly or indirectly from them. About 25% of the drugs prescribed worldwide come from plants, 121 such active compounds being in current use. Of the 252 drugs considered basic and essential by WHO, 11% are absolutely of plant origin and a significant number are synthetic drugs derived from natural precursors. Some of important drugs obtained from plants include artemisinin from Artemisia annua L., atropine from Atropa belladonna, digoxin from Digitalis sp., quinine and quinidine from Cinchona sp., morphine and codeine from Papaver somniferum, and vincristrine and vinblastine from Catharanthus roseus [5][6][7].
The genus Crataeva was named in honor of the Greek botanist "Crataevas" and includes about 70 species dispersed mainly in the warmer parts of the world. Among them, C. nurvala displays the highest bio-diversity in India [8]. C. nurvala has been an important ingredient of various herbal formulations. "Uriflow" a commercial herbal formulation comprising C. religiosa bark has shown remarkable performance in removing renal and bladder stones. The efficacy of "Himplasia" a polyherbal formulation of Himalaya herbal healthcare has been reported in enlarged prostate problem [9]. "Renaloka" product of Himalaya herbal health care is prescribed and used in for urinary tract infection [10]. Another preparation named "Varunal" containing Crataeva in combination with Eclipts, Picrorrhiza, Achillea, Cichorium, Solanum, Arjuna, and Cassia is useful in the treatment of arthritis, ascites, edema, hepatitis, and urinary stones [11].

Geographical description
It is a medium-sized, ornamental, deciduous tree, 6-10 m tall, found either wild or cultivated throughout India, especially in the semi-arid regions [12]. This plant is one of the eleven species within the family Capparidaceae, including trees, shrubs, and, rarely, herbs, which are distributed in the warm, tropical, and occasionally arid regions of both hemispheres [13]. This plant is distributed in India, Sri Lanka, Myanmar, Malaysia, Indonesia, and China. It is also found in Sikkim and Andman and Nicobar Island [14]. It is found mostly along the bank of the river and streams and near the temple sides [15,16]. In India, it is usually cultivated in Assam, Bengal, Central India, and near river banks in Kanara and Malabar. This plant usually grows in the southernmost mountains in the Himalayan range and is indigenous to Karnataka, Kerala, and Tamil Nadu. This plant usually bears flowers in March and fruits in June every year [17][18][19]. C. nurvala regularly grows throughout India along with tropical and subtropical countries of the world [20].  [8,20]. The developed bark is generally 6 to15 cm in length and 3 to10 cm in width with a thickness of 5 to 15 mm. The bark outer side is rough and appears gray to grayish brown whereas the inner side is suave and whitish brown to pale in appearance. Flowers may be whitish cream, pale yellow, or reddish yellow colored, appearing either just before or with the leaves. Fruits are spherical or oval, hard, slim, or scaly berry. Fruits have multiple reniform seeds which are implanted in the yellow and fleshy pulp of the fruit [17,[21][22][23][24].

Histological characteristics
Transverse section of the fully developed stembark displays outer cork with thin-walled, rectangular or tangentially stretched cells, unilayered phellogen, thin walled, tangentially stretched cells and then, widespread secondary cortex, made up of thin-walled, elongated cells which may be polygonal or tangential in shape. Plentiful stone cells in groups appear disseminated throughout secondary cortex. Stone cells may be circular to rectangular or elongated in shape and are scattered in the phloem region. Secondary phloem being a broader part comprises of companion cells, parenchyma, sieve tubes, and stone cells. Medullary rays are generally multi-seriate. Some rhomboid-shaped calcium oxalate crystals are seen [24].

Traditional/ethnomedicinal uses
In Ayurveda, C. nurvala Buch-Ham is known as Tikta saka (due to bitter taste of leaves), Setu briksh (due to its expulsive property of renal calculus), Kumarak (as its leaves remain younger for many days) and Sweta puspa due to its whitish flower [22,[25][26][27]. According to Bhav Prakash Nighantu, this plant enhances Pitta, soften and expels hardened feces, cures the diseases of Kapha and Vata, and suppresses difficulty in micturation and urolithiasis. It mitigates intestinal growths and Vata and Rakta diseases [28].
In Ayurvedic system of medicine, C. nurvala is widely used in various treatments. This plant has been extensively used in traditional medicines as a blood purifier and in treating cardiac and lung weakness, fever, joint problems, blood flow, memory loss, respiratory complications, metabolic syndromes, wound healing, and weak immune system. Folklore uses recommend its applications as an anti-periodic, bitter tonic, diuretic, laxative, and oxytocic drug [8,29,30].
Leaves are stomachic, very good counter-irritant, rubefacient (external use), febrifuge, and tonic (internal use) and are used in rheumatism [18,31,32]. Leaves along with root paste have been used in abscess, cervical adenitis, edematous wounds, and reducing body fat. Its leaf pulp has been reported to show significant benefit in spleen enlargement, when applied on stomach. The leaf decoction, when administered along with ghee, gets rid of flatulence and stomach pain. This plant also works as an appetizer and cholegogue and hence advantageous in anorexia, helminth infections, hepatic ailments, flatulent dyspepsia, and tumors [24]. In the Philippines, C. nurvala leaves are traditionally used by tribal females during irregular menstruation [8]. This plant is beneficial as an antiinflammatory, anti-pyretic, anthelminthic, demulcent, diuretics, and stomachic; for urinary organs disorders; and as a noble contraceptive for females [33,34].
Both root and bark of C. nurvala are laxative and lithotriptic, promote appetite, and increase biliary secretion. Bark is used in chest infection, fevers, vomiting, urinary stone, thyroid disorder, obesity, cancer, gastric irritation, snake-bite, and convulsions. Stem bark has been widely incorporated in various formulations recommended for kidney stone, prostatic enlargement, and bladder and urinary manifestations. The stem bark is reported to have anti-inflammatory effect and stimulates appetite, bile secretion, and bowel moment [12,18,[35][36][37]. Some of the traditional uses of C. nurvala have been mentioned in Table 1.
Diosgenin Along with C. nurvala, diosgenin is also present in large quantities in many plant species including Costus speciosus, Smilax menispermoidea, species of Paris, Aletris, and Trillum, and in species of Dioscorea [64]. It is used as natural raw material for the preparation of steroidal drugs and contraceptives and reported to have anticancer [65], anti-inflammatory [66], anti-oxidant [67,68], cardiovascular protective [69], hypolipidemic [70], and neuroprotective effects .

Rutin
The name rutin comes from the plant Ruta graveolens, but buckwheat is considered the main natural source [87,88]. It is a glycoside comprising flavonolic aglycone quercetin along with the disaccharide rutinose. The main pharmacological activities of rutin include antioxidant, cardioprotective, cytoprotective, cytotoxic, and neuroprotective activities [89][90][91].

Pharmacological activities
Owing to its widespread traditional and medicinal uses, C. nurvala has been exploited for various pharmacological activities as mentioned below: Anti-inflammatory effect C. nurvala ethanol extract negatively controls signal transduction extracellular kinase signals in rat macrophages, inhibiting the inflammatory response triggered by lipid polysaccharides. Non-cytotoxic concentrations of the extract considerably decrease the production of nitric oxide and interleukin-6, in macrophages inspired by lipid polysaccharides. After decreasing the production of inflammatory mediators using the extract, the kinase activity is controlled by mitogen-activated protein kinase, in particular extracellular signal transduction [95,96]. Studies have reported that lupeol, when administered topically, reduces inflammation caused by 12 Otetradecanoyl phorbol acetate in a mouse ear model and decreases the invasion of cells in the inflammatory tissues of mice by reducing the level of myeliferoxidase (specific markers of neutrophils). Lupeol application (5 to 9.37 mg kg −1 ) has shown to produce maximum inhibition (57.14%) of inflammation [97][98][99][100].

Anti-fertility activity
It has been reported that aqueous and ethanol extracts from the dried stems of C. nurvala Buch-Hum produce a significant effect on infertility in rats. These extracts (300 and 600 mg/kg) displayed partial and complete absorption of implants. The alcoholic extract proved to be more potent than the aqueous one. On the other hand, while evaluating the effect on estrogen level, both extracts were found to increase the uteri weight and caused the vaginal opening in immature mice, thus substantiating its effect on the prevention of pregnancy in mice [8,101].

Anti-arthritic activity
The intraperitoneal administration of isolated lupeol and its esters (50 mg kg −1 ) obtained from C. nurvala showed a protective effect against arthritis induced by FCA in leg swelling in rats and compared with standard indomethacin. Lupeol has been found to temper the action of numerous molecules like cytokines, protease, alphaglucosidase, cFLIP, Bcl-2, and NF-κB [102,103].

Anti-diarrheal activity
The C. nurvala ethanol bark extract (500 mgkg −1 , i.p.) expressively decreased the excreta production and excretion rate compared to rats not treated with castor oil and compared with atropine (3 mg kg −1 ). The extract also significantly slows down intestinal transit and castor oil-induced enteropooling, therefore producing antidiarrheal activity [104].

Cardioprotective activity
In some previous studies, lupeol, isolated from this plant bark when administered (50 mg kg −1 ) for 10 days to investigate protective effect on myocardium against cyclophosphamide (200 mg kg -1 , i.p.), showed cardioprotective effect which might be owing to the anti-oxidant properties of its triterpenes [105][106][107].

Anti-urolithic property
In albino rats, the plant decoction was reported effective in preventing stone formation. It also decreased the pH of urine making it acidic. Therefore, it can be concluded that this plant is useful in reducing the recurrence of urolithiasis [107][108][109]. In another study, lupeol (50 mg/ kg) produced strong in vivo anti-urolithiatic effect. Decoction of this plant (800 mg kg −1 ) also increases contractile strength and decreases the remaining urine load in patients with an enlarged prostate [12].
Anti-nociceptive activity C. nurvala bark ethanol extract (250-500 mg k -1 g, per orally (p.o.) showed the anti-nociception in acetic acidinduced analgesia model, thus indicating its use in the treatment of rheumatic inflammatory conditions [110].
Anti-diabetic activity C. nurvala stembark alcoholic extract significantly decreased blood glucose in alloxan-persuaded diabetic rats. The petroleum ether and ethanol extracts showed significant anti-diabetic effect (p < 0.001), and also prohibited weight loss in diabetic animals [111,112].

Anti-cancer activity
Lupeol (40 mg kg −1 ), when applied topically, not only reduced tumor growth but also increased tumor latent duration in the mice and inhibited tumor growth that directed transduction of the NF-kB 67 signal affecting the invasion of two cervical cancer cells. Its anti-tumor effect was also investigated in human hepatocyte carcinoma cells where it inhibited the growth of cells and caused their death as a result of apoptosis which in turn was caused by a decrease in DR3 expression in cells [113,114].
In an in vitro study, the plant ethanol extract was tested on A549 cell line (human lung cancer), the HeLa cell line (cervix uteri), and the MDA-MB cell line (human adenocarcinoma, mammary gland). Extract showed encouraging anti-cancer effect. Percent cell lysis was found in the range closer to the standard for all the cell lines and optical density at 492 nm as (0.575 to 1.191) almost equal to that of reference standard, i.e., 1.151 and always more than blank. The IC 50 values were obtained to < 10, 13, and 20 μg against A549, HeLa, and MDA-MB cell lines. These findings suggest that C. nurvala bark extract possesses good anti-cancer activity [115].

Anti-pyretic activity
The root bark ethanol extract displayed reduction in temperature against typhoid vaccine-induced pyrexia model in rabbits when compared with paracetamol (100 mg kg −1 , p.o.) at the doses of 200 and 400 mg kg −1 [116].

Anxiolytic activity
Moniruzzaman et al. [29] examined the neuropharmacological potential of methanolic extract of C. nurvala leaves using various behavioral models in animals and identified potentially active phytochemicals in this plant extract. This study showed that this plant extract possesses sedative and anxiolytic potential which could be beneficial in treatment of anxiety and insomnia associated with different psychological disorders [29].

Nootropic activity
Ethanolic extracts of C. nurvala stem bark (100,200, and 400 mg kg −1 body weight) reduced acetyl cholinesterase activity in rat brain when compared with standard drug Piracetam. The results indicate that ethanolic extract of C. nurvala might be useful as a nootropic agent to delay the onset and reduce the severity of symptoms associated with dementia and Alzheimer's disease [108].

Wound healing activity
The C. nurvala root bark ethanol extract (150 and 300 mg kg −1 , p.o.) showed the healing of wound in vivo as well as in vitro [117].
Therefore, further in-depth studies are needed to understand the precise molecular mechanisms underlying the observed pharmacological activities of the isolated the bioactive phytochemical(s).

Conservation of C. nurvala
C. nurvala Buch.-Ham is a medicinally important tree, and the root and stem bark of this tree have been the main ingredients of various pharmaceutical products [118]. Having a high medicinal value with marvelous applications and even if, extensive work has been carried out to exploit the therapeutic significance of this plant, huge prospects still exists in novel areas. Discovering more and newer usages of this plant puts leads to increasing stress on current natural yield of this plant. To encounter the rising demand for plant material, recognizing best genetic varieties and developing mass multiplication rates through conventional and biotechnological/genetic engineering techniques becomes more imperative. Moreover, optimization of climatic conditions and development of suitable agrotechniques would improve the quality and quantity of the overall yield, thus promising a higher compensation to the cultivators. Greater economic earnings by cultivating superior-quality planting material would definitely boost the agrarians to commence commercial cultivation of C. nurvala, hence restricting the overexploitation of this plant in the wild and thereby complementing the conservation process [13].
Future scope of C. nurvala The ethanolic extract of C. nurvala has shown nootropic effect [108] which may reduce the severity of symptoms associated with dementia and Alzheimer's disease. Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Cholinesterase inhibitors are clinically used to improve learning and memory abilities, mood, and behavior in those neurodegenerative diseases [119,120]. Since this drug has anxiolytic potential in previous studies [29], more studies on different parts C. nurvala are required to explore its role in CNS disorders and to elucidate the role of reported chemical constituents in psychosomatic disorders along with mechanism of actions so that this highly exploited ayurvedic medicinal plant can be developed into a medicine with confirmed therapeutic effect on the health.

Conclusion
The profuse growth of C. nurvala in subtropical Himalayan range ensures the availability of this plant at economic cost for its use as herbal complementary medicine. These days, people are heeding back for the utilization of herbal plants in combating routine health problems because of fewer adverse effects and cheap prices as well. The information gathered in this review reveals that C. nurvala, commonly called Varuna, enjoys a respectable place in several materia medica which in turn might be due to its wide range of pharmacological applications in several ailments. Previous research work suggests that this plant or its isolated bioactives can show potential efficacy against chronic conditions like cancer, cardiovascular complications, inflammation, diabetes, and kidney dysfunctions. Betulinic acid, catechin, diosgenin, friedelin, kaempferol, quercetin, and rutin are some of important therapeutically active phytoconstituents of C. nurvala. In this complied work, it seems that C. nurvala and its phytoconstituents may be used as bioactives in the treatment of several ailments and can be developed in to a complimentary herbal medicine.