Traditional uses, phytochemistry and pharmacology of genus Fritillaria—a review

Genus Fritillaria is one among the biggest genera of family Liliaceae comprising of around 130–165 species. Fritillaria is viewed as a significant genus and a source of significant pharmaceutically active compounds utilized in conventional drugs by folklore. Fritillaria is utilized worldwide as medication and food. Different chemically dynamic components separated from genus Fritillaria, their phytochemistry with structure and pharmacology of these compounds have been extensively reviewed. Fritillaria is utilized for treatment of dyspepsia, chest injury, tuberculosis, cough, asthma, gout, bronchitis, dysuria, sinus, boils, stomatitis, malaria, insanity, anaemia, immunity promoter, remedy for child emaciation, fever, burning sensation, phthisis and broncho-asthma, heart diseases, dysfunction of breathing and nervous system, etc. Different chemical components isolated from genus Fritillaria include around 120 alkaloids, 15 terpenoids as well as saponins, glycosides, volatile components, nucleosides, amino acids, nucleobases, flavonoids, fatty acids and so forth. Many Fritillaria species have been utilized in traditional Chinese medication on account of their effects of clearing heat, moistening the lung, alleviating cough, asthma, tumours, scrofula and so on. Fritillaria is utilized for treatment of dyspepsia, chest injury, tuberculosis, cough, asthma, gout, bronchitis, dysuria, sinus, boils, stomatitis, malaria, insanity, anaemia, immunity promoter, remedy for child emaciation, also for fever, burning sensation, phthisis and broncho-asthma, heart diseases, dysfunction of breathing and nervous system, etc.


Background
Genus Fritillaria L. is one among the largest genera belonging to monocot family Liliaceae comprising of around 130-165 species (Rix 2001;Xiao et al. 2007), native to mild zone of the Northern Hemisphere (Tsukamoto et al. 1989;Hao et al. 2013). The centre of genetics diversity of the genus has been reported to lie in Iran, where subgenra from the central Asia, Mediterranean and Caucasus meet (Rix 1977). Some species are native to Cyprus, Iran and southern Turkey (Ori et al. 1992a), about 18 species are reported endemic to Iran (Khaniki 2003) and about 20 species had been reported in China, till 1980(Chen 1980. Fritillaria is regarded as an important genus in Liliaceae family and a plant source of significant chemically components utilized in conventional prescriptions by folklore of Turkey (Farooq et al. 1994), South East Asia  China, Pakistan and Japan (Kaneko et al. 1981b). Fritillaria species are presently popular in therapeutic plants industry (Day et al. 2014) and floriculture (Turktas et al. 2012). Fritillaria is utilized worldwide as medication and food; typically roasted bulbs of certain species are utilized as food by Native Americans.
Bulbus Fritillaria usually called as " Pei-mu " or " Beimu " in Chinese language and in Japanese as "Bai-mo" (Chi et al. 1936;Kitajima et al. 1982a), obtained from the bulbs of different species of the genus Fritillaria (Liliaceae), has been utilized as an expectorant and antitussive in customary Chinese medication for over 2000 years Rashid and Yaqoob Bull Natl Res Cent (2021) 45:124 Shang and Liu 1995). Officially, natural Beimu is prepared by utilizing the bulbs of nine distinctive Fritillaria species in particular Fritillaria unibracteata Hiao et Hsia, Fritillaria thunbergii Miq., Fritillaria cirrhosa D. Don, Fritillaria delavayi Franch, Fritillaria przewalskii Maxim ex Batal, Fritillaria ussuriensis Maxim., Fritillaria pallidiflora Schrenk, Fritillaria walujewii, and Fritillaria hupehensis Hsiao et K. C. Hsia. In Chinese folk medication, other Fritillaria species were additionally utilized as the sources for Beimu in local regions of China (Shang and Liu 1995).

Traditional uses
Bulbus Fritillaria have been utilized as main Chinese crude drugs and furthermore as an antihypertensive and antiasthmatic drugs from years. Notwithstanding, Fritillaria species vary in their phytochemicals with various pharmacological impacts . In conventional medication, many species of Fritillaria have been utilized by Japanese (Ito et al. 1963;Kaneko et al. 1981b), Pakistani, Turkish (Farooq et al. 1994) and south-east Asian individuals as herbal remedies (Qian and Nohara 1995;Akhtar et al. 2003;Zhou et al. 2010). Fritillaria are utilized worldwide as medication and food; normally roasted bulbs of some species are utilized as food by Native Americans (Orhan et al. 2009). Prior it was exported from Nepal to India and China due to its high therapeutic values (Thomson 2007). Genus Fritillaria have been utilized for long due to their effects of moistening the lung, clearing heat, resolving phlegm, soothing cough, remedy for cough brought about by lung heat and dryness, a cough because of a yin weakness, sputum with blood and a low sputum dry cough. The bulb part of Fritillaria species utilized as decoction or in dried form to cure bronchitis, cough, tumours, struma, asthma, haemoptysis and insufficiency of milk (Perry 1980;Kang et al. 2002). Fritillaria have been utilized to cure numerous lung infections, including tuberculosis, and asthma. Moreover, it is used as a lymphatic decongestant to decrease glandular or nodular breast tissue, goitre, swellings and lymphadenopathy. It has been utilized for the treatment of prolonged hypotension, sensory system, defective breathing and incitement of the heart muscle (Erika and Rebecca 2005a) as well as treating swelling underneath the skin, for example, scrofulous swellings and breast nodules (Da-Cheng et al. 2013). It is likewise detailed that blood platelet conglomeration is restrained by Fritillaria bulbs.
Fritillaria ebeiensis G. D. Yu and G. Q. Ji, local to northwest area of Hubei region, China is utilized as medication for saturating lungs, clearing heat and throat infections, for example cough, tracheitis and asthma, by folklore of China (Li et al. 1994). Fritillaria ebeiensis shows high antitussive and expectorant impacts (Yu et al. 1985). A crude drug known as Ebeibeimu is set up by treating the bulbs of F. ebeiensis with lime and, afterward bleached in sun, serves as a substitute for major conventional Chinese medication Beimu (Wu et al. 1995). Fritillaria cirrhosa, Fritillaria thunbergii and Fritillaria pallidiflora are accounted for to be utilized in various cough status with respect to their potencies in customary Chinese medication, great quality bulbs of well-grown F. cirrhosa, when dried seem white and fine (Bensky and Gamble 1993;Konchar et al. 2011) and bulbs can be utilized as entire or in powdered form as remedies for clearing the lungs from mucus and cooling heat (Bensky et al. 2004;Li et al. 2006aLi et al. , 2009). It has been utilized to cure diseases like asthma and cough in TCM (Traditional Chinese Medicine) for over 2000 years ) and furthermore act expectorant, astringent and demulcent (Uprety et al. 2010). Pharmaceutical investigations of Fritillaria thunbergii Miq. have revealed that it has been utilized to deal with different infections like cough, disposing of mucus, alleviating pain and anti-inflammatory problems (Qian and Xu 1985;Xiao et al. 1992;Zhou et al. 2003). Fritillaria thunbergii Miq. (known as 'Zhe Beimu' in Chinese) is among the main species from genus Fritillaria to be utilized in TCM (Traditional Chinese Medicine) as expectorant and antitussive herb for over 200 years (Li et al. 2006a). F. pallidiflora is an ordinarily utilized plant for cough treatment in TCM. Fritillaria pallidiflora Schrenk generally found in Xinjiang region of China is utilized as an antitussive, expectorant and antiasthmatic medication Li et al. 1993;Zhou et al. 2003). Bulbus Fritillariae ussuriensis (BFU) in view of its antiasthmatic, expectorant and antitussive actions is utilized as food and orthodox medication, scattered all through the Northeast areas of China, including Liaoning, Heilongjiang and Jiling areas and also for treating swollen throat and lung diseases in Chinese medication (Perry 1980). F. maximowiczii (Rinyou-Baimo), local to north-eastern part of China, is referred to act as an alternative for the bulb of various Fritillaria species like Fritillaria thunbergii (Setu-Baimo), Fritillaria unibracteata, Fritillaria taipaiensis (Sen-Biamo) and Fritillaria cirrhosa used to treat cough. In customary traditions, Fritillaria imperialis has been utilized for the treatment of different diseases like asthma, pharyngitis, bronchitis, cough, struma, haemoptysis, dysuria and gland tumour (Bailey 1966;Perry 1980). Its tendrilled bulbs are utilized as a home remedy for haemorrhage, cough and mucus, treatment of abscess, high fever, absence of milk, eye sickness, and rheumatoid arthritis (Aydın et al. 2018) and act as antianxiety/depression (Abbaszadeh et al. 2019). Fritillaria roylei is utilized to prepare an ayurveda drug Ashtavarga (Ashta-eight and varga-group); thus, Ashtavarga is a polyherbal formulation and F. roylei is likewise utilized for the preparation of ashtavarga with name Kakoli (Warrier et al. 1994;Singh 2006;Negi et al. 2007). It additionally shows impacts of cooling and spermopiotic, antirheumatic, antiasthmatic, galactagogue, haemostatic, antipyretic and oxytocic properties (Singh 2006). Its rhizome acts as expectorant, sexual stimulation, spermatogenic and tonic. Restoratively it is utilized for the treatment of dyspepsia, chest injury, tuberculosis, cough, asthma, congenital pulmonary haemorrhage, gout, bronchitis, diarrhoea, dysuria, sinus, boils, stomatitis, malaria, insanity, anaemia, oligospermia (low sperm check), immunity promoter, remedy for child emaciation, antidote for spider poisoning (Balkrishna 2012) and furthermore for fever, burning sensation, phthisis (Singh 2006) andbroncho-asthma (shaheen et al. 2014). It is additionally utilized for the treatment of incitement of the heart muscle, heart diseases, decreased pulse rate, defective breathing and nervous system (Erika and Rebecca 2005b). Fritillaria hupehensis Hsiao et K.C. Hsia, named 'Hubeibeimu' , documented in the pharmacopeia of the people Republic of China, is commonly utilized in orthodox medication and very much found in Northwest region of Hubie, China. Bulbs of Fritillaria unibracteata 'Chuan Bei-Mu' , utilized as cough reliever, antiasthmatic and decongestant agents for long time in conventional Chinese medication also included in the Chinese Pharmacopeia (Liang 2004), are utilized to treat asthma (Shou et al. 2009). One of the sources for BFC (Bulbus F. cirrhosa) is bulbs of Fritillaria wabuensis S. Y. Tang and S. C. Yueh (BFW), which is taken orally to cure cough by customary individuals. It has likewise been broadly utilized in China to cure asthma and cough in clinic because of its positive therapeutic impacts and lesser side effects (Wang et al. 2012). Fritillaria tortifolia X. Z. Duan et X. J. Zheng native plant in Xinjiang Uygur area is utilized as folk medicine in Uygur medication (Hu et al. 2018). Fritillaria species like F. cirrhosa, F. verticillata and F. thunbergii are utilized as cough remedies in conventional Chinese prescriptions (Da-Cheng et al. 2013). Table 1 shows some of the ordinarily utilized species of genus Fritillaria with their folk uses.

Phytochemicals Alkaloids
In excess of 120 alkaloids have been isolated from the genus Fritillaria (Xiao et al. 2007). The significant phytochemicals in Fritillaria species are reported as isosteroidal alkaloids: ebeiedine, ebeienine, ebeiedinone, verticinone, imperialine, verticine, hupehenine and isoverticine. However, quantity and kind of isosteroidal alkaloids differ in numerous Fritillaria species, and clinical results can likewise be unique . The structures of these alkaloids are given in Fig. 1.
A brief account of morphology of some of the species is given below: a. Fritillaria imperialis, commonly called crown imperial, is an impressive plant, grows about 1 m (3 ft) in height. Each bulb produces a thick, stout, upright, ramrod-straight flowering stem which bears lanceshaped, glossy leaves with wavy margins appear in whorls around the lower 1/2 of the stem. It bears a prominent whorl of 3-5 drooping or downward facing, bell-shaped orange or red flowers at the top of the stem, topped by a 'crown' of small pineapple-like tuft of leaf-like bracts. While the wild form is usually Page 31 of 37 Rashid and Yaqoob Bull Natl Res Cent (2021) 45:124 orange-red, various colours are found in cultivation, ranging from nearly a true scarlet through oranges to yellow. All parts of the plant have a skunky order (Fig. 4a). b. Fritillaria cirrhosa is a perennial herb producing bulbs up to 20 mm (0.8 in) in diameter. Stem is up to 60 cm (24 in) tall with oppositely arranged leaves 7-11 in number, sometimes 3-4 whorled and alternate. Leaves are linear to linear lance-shaped with the tip often curved or coiled. The plant bears nodded, bell-shaped, one flower at the top, sometimes flowers are in groups of one or three subtended by three leaflike bracts. Flower stalks (pedicel) shorter than tepals. Tepals are yellowish-green to brownish-purple, usually with a chequered pattern in dull purple. It is in flower from April to May. The species is hermaphrodite (has both male and female organs). Stamens are 2-3 cm long, style is three lobed, capsule is broadly oblong, 25-35 mm long, winged. Seeds are many and are pollinated by insects (Fig. 4b).
c. F. pallidiflora is a perennial reaching up to 38 cm (15 in) in height, stems are thick having broadly lance-shaped bluish leaves scattered up and down the slender stem. Fritillaria pallidiflora bears 1-5 nodding greenish-yellow bell-shaped flowers 3-4 cm in length flowers are usually faintly checkered brownish red inside, pale yellow, nodding bell-shaped flowers. It is in flower from May to June. The species is hermaphrodite (has both male and female organs) and is pollinated by insect (Fig. 4c). d. Fritillaria roylei is a herbaceous plant, 0.5-2 ft tall, flowers are yellowish-green to brownish-purple and usually with a chequered pattern in dull purple. Flowers are broadly bell-shaped, hanging looking down, borne singly on the stems, but sometimes in groups of 2-4. Petals are narrow-ovate, 4-5 cm long. Leaves are linear-lancelike, often long-pointed, 5-10 cm, arranged oppositely or in whorls of 2-6 on the stem. It is in flower from April to May. The flowers are her- Page 32 of 37 Rashid and Yaqoob Bull Natl Res Cent (2021) 45:124 maphrodite (have both male and female organs) and are pollinated by insects (Fig. 4d).

Conclusion
The review highlighted the traditional uses, phytochemistry and pharmacology of different species of genus Fritillaria. Numerous Fritillaria species have been utilized in traditional Chinese medication for more than 2000 years due to their activities of reducing heat, alleviating cough, moistening the lung etc., for the treatment of bronchitis, a low sputum dry cough, asthma, tumours, struma, hemoptysis and insufficiency of milk and so on. Expanding interest in the field of plant as therapeutic assets has prompted significant discoveries of numerous essential compounds like alkaloids, terpenoids, saponins, nucleosides, flavonoids, glycosides, volatile components, nucleosides, amino acids, nucleobases, fatty acids and so on in different Fritillaria species including Fritillaria anhuiensis, Fritillaria cirrhosa, Fritillaria ebeiensis, Fritillaria hupehensis, Fritillaria imperialis, Fritillaria pallidiflora, Fritillaria puqiensis and Fritillaria thunbergii. However, around 80% of the Fritillaria species are yet to be investigated through phytochemical examinations which confine therapeutic and remedial utilization of products of Fritillaria. Fritillaria is utilized worldwide as medication and food traditionally and therapeutically because of its significant effects like anticholinergic action, cholinesterase inhibiting activity, antitussive and expectorant effects as well as neuroprotective action, anti-AChE and anti-BChE action, cytotoxic activity against tumour cell, and defensive action on injured hepatocytes, etc. Genus Fritillaria is utilized for the treatment of dyspepsia, chest injury, tuberculosis, gout, dysuria, sinus, boils, stomatitis, malaria, insanity, anaemia, immunity promoter, remedy for child emaciation, likewise for fever, burning sensation, phthisis and broncho-asthma, heart diseases, dysfunction of breathing and nervous system, etc. It is critical to study more species of genus Fritillaria for finding various compounds with important clinical efficiency and for its liveable utilization as medicinal resources. More significantly, research of Fritillaria ought not be confined to the pharmaceutical studies only but the other detailed studies like biochemistry, genetics, epigenetics, cytology and other fields to explore this important genus completely, which will assume an amazing part in future investigations of Fritillaria.