BIOCELL BIOCELL BIOCELL BIOCELL 1667-5746 0327-9545 Tech Science Press USA 22065 10.32604/biocell.2023.022065 Review Phytochemistry and ethnomedicinal qualities of metabolites from Phyllanthus emblica L.: A reviewPhytochemistry and ethnomedicinal qualities of metabolites from Phyllanthus emblica L.: a reviewPhyllanthus emblica with a particular focus on its phytochemistry and ethnomedicinal qualities KUMARVIJAY 1# RAMAMURTHYPRAVEEN C. 2# SINGHSIMRANJEET 2# DHANJALDALJEET SINGH 3 PARIHARPARUL 4 BHATIADEEPIKA 5 PRASADRAM 6rpjnu2001@gmail.com SINGHJOGINDER 7joginder.15005@lpu.co.in Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, 284003, India Interdisciplinary Centre for Water Research, Indian Institute of Sciences, Bangalore, 560012, India Department of Biotechnology, Lovely Professional University, Phagwara, Punjab, 144411, India Department of Botany, Lovely Professional University, Phagwara, Punjab, 144411, India Department of Biotechnology, Baba Farid College, Bathinda, Punjab, 151001, India Department of Botany, Mahatma Gandhi Central University, Motihari, 845401, India Department of Microbiology, Lovely Professional University, Phagwara, Punjab, 144411, India Address correspondence to: Ram Prasad, rpjnu2001@gmail.com; Joginder Singh, joginder.15005@lpu.co.in

#These authors contributed equally to this work

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Phyllanthus emblica or Indian gooseberry is an integrated part of Ayurvedic and Traditional Chinese Medicines. For several decades, the well-known ancient herb has been extensively utilized in traditional medicine to cure diseases like fever, diabetes, constipation, jaundice, ulcers, biliousness, anemia, anorexia, and dyspepsia. In the traditional system, Indian gooseberry has various ethnomedicinal applications. In the Ayurvedic system, different methods of administration (anupan) have shown different ethnomedicinal properties of Indian gooseberry. Seventy well-known chemical components in Indian gooseberry have been identified through phytochemical evaluation, among which the flavonoids and phenols are most prominent. From the toxicity perspective, it is considered a safe herb in India, and is taken as a food supplement in European countries. The wide-spectrum pharmacological activities of the crude extracts and isolates of Indian gooseberry are attributed to the predominance of phenols and flavonoids. Thus, it is important to study the exact mechanism of the activity of the phytochemicals in Indian gooseberry, especially in anti-cancer activities. Extract of Indian gooseberry enhances proliferation in several cancer cells in vitro, including stem cells like ovarian cancer (OC) cells, and also has been observed to possess anti-proliferative characteristics in vivo. This review intends to explore the therapeutic potential of Indian gooseberry based on scientific reports and attempts to find the gaps for future research.

 Phyllanthus emblica Amla Vitamin C Antioxidant Stem cells Phytochemistry Pharmacology Introduction

Medicinal plants have been known for their healing properties for decades. Plants have been a major source of medicines since ancient or Vedic times (Dehghan et al., 2016; Chakraborty, 2018; Kumar et al., 2018a). Plants and their secondary molecules are a divine blessing to mankind. Even in the 21st century, traditional medicine is still used in most underdeveloped and developing nations (Newman and Cragg, 2016; Kota et al., 2017; Khan et al., 2018b; Kumar et al., 2018b). Secondary metabolites synthesized by the plants are considered of great therapeutic value owing to their ability to cure diverse diseases (Chakraborty, 2018; Kumar et al., 2018a; Sridevi et al., 2018). In spite of the progressive development in the field of synthetic chemistry, medicines derived from plants or plant products, such as morphine, taxol, atropine, ephedrine, etc, are still in the developing stage (Newman and Cragg, 2016; Sridevi et al., 2018). The majority of the plant-derived drugs are of therapeutic importance and are enriched with nutrients (Newman and Cragg, 2016; Chakraborty, 2018).

The unique nutritional, antioxidant, and therapeutic properties of Phyllanthus emblica can be attributed to the predominance of multiclass secondary biomolecules, especially flavonoids and polyphenols (Dehghan et al., 2016; Kumar et al., 2018a; Sridevi et al., 2018; Choudhary and Grover, 2019; Sriwatcharakul, 2020). Almost all Indian gooseberry based products can replace synthetic supplements or antioxidants (Newman and Cragg, 2016).

Antioxidants are crucial constituents of drugs that aid in treating a particular disease and help in capturing free radicals and cease the free radical-associated redox reactions (Chakraborty, 2018; Kumar et al., 2018b).

The current sedentary lifestyles make the sour immune system weak. To restore and heal our system Ayurveda plays a vital role (Govindarajan et al., 2005; Khan et al., 2018b). Each herb and shrub have specific medicinal qualities to cure ailments and restore health. Herbs like Ocimum basilicum, Anethum graveolens, Origanum vulgare, Rosmarinus officinalis, Crocus sativus, Mentha spicata, and Thymus vulgaris are non-toxic if taken fresh or in dried form (Vázquez-Fresno et al., 2019). These herbs can have a higher therapeutic effect in their fresh form (Govindarajan et al., 2005; Khan et al., 2018b; Mukherjee et al., 2018; Srinivasan et al., 2018). The extraordinary nutritional value of these herbs and medicinal plants is a treasure to society. Many yet undetermined nutritional elements need further study. These herbs rejuvenate our whole system and are not specific to certain organs or bodies (Variya et al., 2016; Yadav et al., 2017; Khan et al., 2018b; Mukherjee et al., 2018; Srinivasan et al., 2018).

According to Ritucharya, an ayurvedic practice, if medicinal plants are consumed in their season of availability, it revitalizes one’s health. The role of ‘rasayana’ drugs comes to our rescue. Among the rasayana drugs, P. emblica, commonly called Indian gooseberry, is the drug of choice as it helps in restoring strength and energy (Govindarajan et al., 2005; Khan et al., 2018a; Srinivasan et al., 2018). Indian gooseberry belongs to the family Euphorbiaceae. It is enriched with vitamin C and known to possess different activities like anti-inflammatory, anti-diabetic, hepatoprotective, immunomodulatory, radiomodulatory, and antioxidant properties (Govindarajan et al., 2005; Khan et al., 2018a; Mukherjee et al., 2018; Srinivasan et al., 2018; Kaur et al., 2021). Owing to the above-mentioned properties, more exploration has become the primary target to gain better insight into the P. emblica. Therefore, the current review aims to provide critical information about P. emblica related to its cultural significance, phytochemical constituents, and pharmacological activities.

 Data Extraction Ayurvedic literature about Indian gooseberry

The information on Indian gooseberry regarding its toxicological effects, phytochemistry, pharmaceutical application, and ethnomedicinal usage was obtained from library and online sources like ScienceDirect, Google Scholar, SciFinder, PubMed, etc., for the period 2000 to 2020.

 Literature about Indian gooseberry

Amalaki consists of fresh fruit pulp of medium-sized P. emblica tree, a native of deciduous forests, at altitudes up to 1300 m and cultivated in home-yards and gardens (Krishnaveni and Mirunalini, 2010; Poltanov et al., 2009; Variya et al., 2016; Yadav et al., 2017). P. emblicais known by various other names like Sanskrit: Amitaphala, Amalaka; Assamese: Amlaku Amlakhi, Bengali: Dhatri, Amla, English: Emblic myrobalan, Phyllanthus emblica Gujrati: Amala, Ambala; Hindi: Aonla, Amla; Kashmiri: Embali, Kannada: Nellikayi; Amli; Marathi: Avalkathi, Anvala; Malayalam: Nellikka; Oriya: Anala; Ainla, Punjabi: Amla, Aula; Tamil: Nellikkai; Nelli, Telugu: Usirika; and in Urdu: Amlaj, Amla (API, 2010; Variya et al., 2016; Yadav et al., 2017). The main properties and actions of P. emblica in Ayurveda are rasa (taste): madhura (sweet), amla (sour),tikta (bitter); guna (properties): laghu (light), ruksa (rough); virya (potency): sita (cold); vipaka (final transformation): madhura (sweet). Itstherapeutic uses include raktapitta (haemorrage), amlapitta (gastric trouble), and prameha (diabetes mellitus) (API, 2010; Variya et al., 2016; Yadav et al., 2017).

In Ayurvedic terminology, amla is known as “Amalaki”, which means “Dhatri or Nurse”, as it possesses the ability to reinstate health like a caring mother (Caldecott, 2006; Mir et al., 2005). It is the only plant to control all three doshas (fault or disease) (Vata, Pitta, and Kapa), which shows its Ayurvedic significance (Caldecott, 2006). The Indian gooseberry tree is revered and adored by many Hindus since it is believed that the god Vishnu resides on the plant. Indian gooseberry is a part of almost all Ayurvedic formulations. The main application and mode of administration of Indian gooseberry are described in Fig. 1.

Therapeutic applications of <italic>Phyllanthus embelica</italic> in Ayurveda.

The well-known formulations of Indian gooseberry are amla churn, triphala churn, trikattu churn, amalaki rasayan, etc. (API, 2010; Caldecott, 2006). Unripe Indian gooseberry fruit can control the inflammation of the conjunctiva (Kirtikar and Basu, 1935). Consumption of Indian gooseberry fruit pickles before meals can stimulate the appetite (Nadkarni, 1954; Priya and Islam, 2019). The colon functions and intestinal flow can be improved when fresh Indian gooseberry juice is administrated with ghee (ghrta). The decoction process using the dry Indian gooseberry powder can treat ophthalmia and is hemostatic and antidiarrheal (Nadkarni, 1954; Caldecott, 2006). The combination of jaggery (guda) with dried powder of Indian gooseberry fruits is useful in jaundice, biliousness, anemia, anorexia, and dyspepsia (Sharma, 2002). Indian gooseberry has shown its wide applications in hair fall, fever, diabetes, and heart ailments. It is known for its immune-boosting applications through the actions of its antioxidant. As per Sarangadhara Samhita, the combination of amla, citraka, haritaki, pippli, and saindhava can cure all types of fevers (Srikantha Murthy, 1984). When Indian gooseberry is administrated in a combination of draksa, sugar, and honey, it can cure nausea and vomiting (Caldecott, 2006). Rasayana of Indian gooseberry is effective against chronic lung and heart diseases, strength, intelligence, vigor resembling an elephant, wisdom, infertility, and mental disorders (Srikantha Murthy, 1984; Sharma, 2002).

 Cultural and Religious Significance

From ancient times, in India, Indian gooseberry has been worshipped as Mother Earth as it is believed to nurture mankind (Mir et al., 2005; Ur-Rehman et al., 2007). Various parts of the Indian gooseberry plant are used in worship rituals across India. VratKaumudi and Kartik Mahatma (Goddess of Hindus) order to worship this tree, and the leaves of this tree are offered to deities on auspicious days (Yadav et al., 2017). In Indian states like Himachal Pradesh, Indian gooseberry is worshipped mostly in the month of Kartik as chaste and propitious (Ur-Rehman et al., 2007; Variya et al., 2016). Moreover, it is utilized in Ayurveda, Unani, and Siddha systems in India, China, Tibet, and Sri Lanka to treat different ailments.

 Phytochemical Constituents

The main phyto-elements (per 100 g) present in the Indian gooseberry are listed in Table 1 and Fig. 2. It contains a variety of various chemical components such as carbohydrates, mucic acid, tannins, glycosides, amino acids, flavonol glycosides, alkaloids, phenolic acids, flavones, glycosides, and sesquiterpenoids (Ur-Rehman et al., 2007; Poltanov et al., 2009; Yang and Liu, 2014; Variya et al., 2016; Yadav et al., 2017; Rose et al., 2018). Liquid extract of P. emblica encompasses high vitamin C content (478.56 mg/100 mL) compared to various fruits like grape, lime, apple, and pomegranate. Vitamin C is present in abundant amounts in P. emblica (Zhang et al., 2003; Bansal et al., 2014).

Main phytochemicals of <italic>Phyllanthus emblica</italic> (Indian gooseberry) and their biological activities
Molecule Chemical structure Biological activities Source Class Reference
3-ethygallic acid Antioxidant Fruits Phenol (Variya et al., 2016; Yang and Liu, 2014)
1(β)-O-galloylglucoseR1 = R2 = R3 = R4 = H1(β),6-di-O-galloylglucoseR1 = R2 = R4 = H and R3 = Galloyl1,2,3,6-tetra-O-galloylglucoseR1 = R3 = R4 = Galloyl and R2 = H1,2,3,4,6-penta-O-galloylglucoseR1 = R2 = R3 = R4 = Galloyl Antioxidant, anti-inflammatory, aldose reductase, neuroprotective, and anti-microbial Fruits Phenol and sugar (Bansod, 2012; Bhattacharya et al., 1999; Chang et al., 1995; Chansriniyom et al., 2018; Dhale and Mogle, 2011; Goyal and Bhadauria, 2008; Gupta et al., 2012; Hazra et al., 2010; Liu et al., 2008a, 2008b; Poltanov et al., 2009)
5α,6β-dihydroxysitosterol R = HTrihydroxysitosterolR = OH Antioxidant and cytotoxic Leaves and stem Terpenoids and sterols (Qi et al., 2013; Variya et al., 2016)
Apigenin-7-O-(6-butyryl-β- glucopyranoside) Antioxidant and cytotoxic Leave Flavonoids (Jyothi and Rao, 2011; Pinmai et al., 2008; Rahman et al., 2009)
Ascorbic acid Antioxidant and anti-diabetic Fruits Hydroxyls and ketones (Variya et al., 2016; Yang and Liu, 2014)
Caffeic acid Antioxidant, ant-cancer and anti-hyperlipidemic Fruits Phenolic acids (Baliga and Dsouza, 2011; Mahata et al., 2013)
ChebulaninR1 = R2 = Chebuloyl and R3 = R4 = HChebulagic acidR1 = R2 = Chebuloyl and R3 = R4 = HHDPCorilaginR1 = R2 = H and R3 = R4 = HHDPFurosinR1 = R2 = DHHDP and R3 = R4 = HGeraniinR1 = R2 = DHHDP and R3 = R4 = HHDPGeraniin AcidR1 = H, R2 = HHDP’ and R3 = R4 = HHDPIsostrictininR1 = R4 = H, and R2 = R3 = HHDPTercatainR1 = H, R2 = Galloyl, and R3 = R4 = HHDPPunicafolinR1 = R2 = Galloyl, and R3 = R4 = HHDP Antioxidant, anti-inflammatory, anti-diabetic, anti-cancer and anti-proliferative Fruits Phenols and tannins (Bansod, 2012; Bhattacharya et al., 1999; Chang et al., 1995; Dhale and Mogle, 2011; Gupta et al., 2012; Liu et al., 2008a, 2008b; Poltanov et al., 2009; Zhao et al., 2015)
Chebulic acid Anti-secretory, anti-ulcer, anti-cancer, and cyto-protective Fruits Phenolic acids (Mishra et al., 2013; Variya et al., 2016; Zhao et al., 2015)
Coumaric acid Antioxidant and anti-hyperlipidemic Fruits Phenolic acids (Variya et al., 2016; Yang and Liu, 2014)
Ellagic acid Antioxidant, ant-proliferative, chemo-protective, radio-protective, anti-cancer, estrogenic/anti-estrogenic, and anti-diabetic Whole plant Phenolic acids (Chen and Li, 2006; Jagetia et al., 2002; Papoutsi et al., 2005; Sumitra et al., 2009; Zhao et al., 2015)
Emblicanin-AR1 = R4 = Galloyl, and R2 = R3 = HHDPEmblicanin-BR1 = R4 = HHDP, and R2 = R3 =HHDP’ Antioxidant and anti-diabetic Fruits Phenols and tannins (Deep et al., 2012; Qureshi et al., 2009)
Gallic acid Antioxidant, chemo-protective, radio-protective, anti-inflammatory, anti-cancer anti-diabetic, and anti-proliferative Whole plant Phenolic acid (Variya et al., 2016; Yang and Liu, 2014; Zhao et al., 2015)
L-malic acid 2-O-gallate Antioxidant and anti-atherosclerotic Fruits Phenolic acid (Variya et al., 2016; Yang and Liu, 2014)
Luteolin-7-O-neohesperidoside Anti-inflammatory and anti-diabetic Leave Phenols and tannins (Deep et al., 2012; Jaijoy et al., 2010; Qureshi et al., 2009; Zhang et al., 2004)
Mucic acid 2-O-gallate Anti-proliferative Fruits Phenolic acids (Goyal and Bhadauria, 2008; Zhang et al., 2004)
Mucic acid 1,4-lactone 2-O-gallateR1 = Galloyl, and R2 = R3 = HMucic acid 1,4-lactone 3-O-gallateR1 = R3 = H, and R2 = Galloyl.Mucic acid 1,4-lactone 5-O-gallateR1 = R2 = H, and R3 = Galloyl.Mucic acid 1,4-lactone 3,5 di-O-gallateR1 = H, and R2 = R3 = Galloyl. Antioxidant and anti-proliferative Fruits Phenolic acids (Chang et al., 1995; Dhale and Mogle, 2011; Goyal and Bhadauria, 2008; Zhang et al., 2004)
Myricetin Antioxidant, anti-inflammatory, anti-diabetic, and anti-proliferative Fruits Flavonoids (Variya et al., 2016; Yang and Liu, 2014)
PedunculaginR1 = R2 = HHDP’, and R3 = R4 = HHDP Antioxidant, anti-tumor and anti-inflammatory Fruits Tannins and phenolic acids (Baliga and Dsouza, 2011; Mahata et al., 2013; Verma et al., 2012)
Phyllaemblic acidR1 = R2 = R3 = H, and R4 = THDFPhyllaemblicin-A R1 = R2 = THDF, and R3 = R4 = HPhyllaemblicin-BR1 = R2 = THD, and R3 = R4 = HPhyllaemblicin-CR1 = R2 = THD’, and R3 = R4 = H Antioxidant, protein kinase inhibitor, anti-microbial, anti-cancer; anti-viral, and anti-inflammatory Roots Phenols and sugar (Gopa et al., 2012; Modilal and Pitchai, 2011; Qureshi et al., 2009; Variya et al., 2016; Yang and Liu, 2014; Zhang et al., 2004; Zhao et al., 2015)
PunigluconinR1 = R2 = HHDP, and R3 = R4 = Galloyl Antioxidant Fruits Phenols and tannins (Variya et al., 2016; Yang and Liu, 2014)
Quercetin Antioxidant, anti-inflammatory, anti-cancer, hemo-protective, radio-protective, anti-diabetic, and anti-proliferative Whole plant Flavonoids (Estari et al., 2012; Hazra et al., 2010; Liu et al., 2008a, 2008b; Pinmai et al., 2008; Rahman et al., 2009; Zhao et al., 2015)
Rutin Antioxidant, anti-inflammatory, anti-cancer, hemo-protective, radio-protective, anti-diabetic, and anti-proliferative Whole plant Flavonoids (Estari et al., 2012; Hazra et al., 2010; Liu et al., 2008a, 2008b; Zhao et al., 2015)
5α,6β,7α-7α- acetoxysitosterolR1 = H and R2 = CH3COOβ-sitosterolR1 = H and R2 = H7α-hydroxysitosterolR1 = H and R2 = OH7β-ethoxysiterolR1 = CH3CH2O and R2 = H7-ketositosterolR1 = R2 = O Antioxidant and cytotoxic Leaves and stem Terpenoids and sterols (Qi et al., 2013; Variya et al., 2016)
Stigmast-4-en-3-oneR1 = R2 = HStigmast-4-en-3,6-dioneR1 = R2 = OStigmast-4-en- 6β-ol-3-oneR1 = H and R2 = OH Antioxidant and cytotoxic Leaves and stem Terpenoids and sterols (Qi et al., 2013; Variya et al., 2016)
Stigmast-4-ene-3β,6α-diol Antioxidant and cytotoxic Leaves and stem Terpenoids and sterols (Qi et al., 2013; Variya et al., 2016)
DaucosterolR1 = H and R2 = OH6′-(stigmast-5-en-3-O-β-D-glucopyranosidyl) hexadecanoateR1 = H and R2 = OOC-(CH2)14-CH36′-(stigmast-5-en-7-one-3-O-β-D-glucopyranosidyl) hexadecanoateR1 = OH and R2 = OOC-(CH2)14-CH3 Antioxidant and cytotoxic Leaves and stem Terpenoids and sterols (Qi et al., 2013; Variya et al., 2016)
(3S,10S,13R,17R)-17-((2S,3R,4R,5S)-5-ethyl-3,4-dihydroxy-6-methylheptan-2-yl)-3-hydroxy-10,13-dimethyl-dodecahydro-2H-cyclopenta[a]phenanthren-7(8H,9H,14H)-one Antioxidant and cytotoxic Leaves and stem Terpenoids and sterols (Qi et al., 2013; Variya et al., 2016)
KaempferolR = HKaempferol-3-O-α-L-rhamnopyranosyl-(1-6)-β-D-galactopyranosideR = APP (bonding from the position of arrow head)Kaempferol-3-O-glucosyl (1-2)rhamnosideR = DPP (bonding from the position of arrow head) Antioxidant, anti-inflammatory, anti-cancer, hemo-protective, radio-protective, anti-diabetic, and anti-proliferative Whole plant Flavonoids (Estari et al., 2012; Hazra et al., 2010; Liu et al., 2008a, 2008b; Pinmai et al., 2008; Rahman et al., 2009; Zhao et al., 2015)
Main phyto-elements present in <italic>Phyllanthus emblica</italic> (per 100 g).

The phytochemical composition of P. emblica has been investigated by various researchers in various solvents, including acetone-water (Zhang et al., 2001a, 2001b; Liu et al., 2008a), water (Majeed et al., 2009; Khan et al., 2018a; Tung et al., 2018), fresh juice (Yang and Liu, 2014), enzyme-water (Yokozawa et al., 2007), hydro-alcoholic (Liu et al., 2008b), ethyl acetate (Zhang et al., 2003; Yokozawa et al., 2007), ethanolic (Iqbal et al., 2017), methanol (Ur-Rehman et al., 2007; Liu et al., 2009; Yang et al., 2012), and freeze-dried juice (Majeed et al., 2009). Various other phyto-constituents (in mg/100 mL) of Indian gooseberry juice, including chlorogenic acid (17.43 mg), ellagic acid (71.20 mg), quercetin (2.01 mg), and gallic acid (37.95 mg) from the extract of P. emblica were also reported (Bansal et al., 2014).

Other reported data show the presence of corilagin, 3-ethylgallic acid, chebulagic acid, Glucogallin, iso-strictiniin, quercetin, kaempfero-l,3-O-l-(6-ethyl)-rhamnopyranoside, and various other phenolic compounds like mucic acid 1,4-lactone 3,5-di-O-gallate, mucic acid 2- O-gallate, 1,4-lactone 3-O-gallate, 1,4-lactone 2-O-gallate,mucic acid 1,4-lactone 5-O-gallate, mucic acid, and L-malic acid 2-O-gallate have been extracted from P. emblica (Zhang et al., 2001b; Zhang et al., 2003; Bansal et al., 2014; Yang and Liu, 2014; Variya et al., 2016; Yadav et al., 2017). Two flavonoids, namely Kaempferol-3-O-α-L-(5″-ethyl)-rhamno-pyranoside and Kaempferol-3-O-α-L-(6″-Methyl)-rhamno-pyranoside were isolated and differentiated on the basis of the presence of ethyl (–CH2CH3) and methyl (–CH3) groups (Ur-Rehman et al., 2007). Here both the compounds were extracted from the shoots and leaves of P. emblica using methanol as solvent (Ur-Rehman et al., 2007).Various terpenoid molecules have been reported by researchers; 15 terpenoids with antioxidant and cytotoxic properties were reported by Qi et al. (2013), which were obtained from the stems and leaves of P. emblica (Qi et al., 2013). Recently, two terpenoids, namely ursophyllemblicoside and secofriedelanophyllemblicine were extracted from the roots of P. emblica (Nguyen et al., 2018).

The most common and important chemical constituents of P. emblica with their source and biological activities are presented in Table 1. The phenolic compounds of P. emblica are well known and have well-established biological activities (Nisar et al., 2018). Phytochemical components of P. emblica like ellagic acid, corilagin, chebulagic acid, gallic acid, pyrogallol, and quercetin have been identified by liquid chromatography-mass spectrometryand high-performance liquid chromatography techniques in various extracts of P. emblica (Yang and Liu, 2014; Zhao et al., 2015; Variya et al., 2016). Significant antioxidant and antitumor effects of these phytochemicals have been observed in in-vitro and in-vivo models (Yang and Liu, 2014; Zhao et al., 2015; Variya et al., 2016).

 Pharmacological Activities

Various reports suggest that Indian gooseberry has immune-modulatory, anti-cancer, anti-inflammatory, anti-microbial, anti-diabetic, adaptogenic, and antioxidant properties (Kumar et al., 2018a). The mode of action of P. emblica against various oxidative stresses, cancer, and inflammations is represented in Fig. 3.

Mode of action of <italic>Phyllanthus emblica</italic> against various oxidative stresses, cancer, and inflammations.

P. emblica also prevents various other ailments, such as osteoporosis and hyperlipidemia (Mirunalini and Krishnaveni, 2010). Extracts of dried P. emblica fruits are beneficial for a wide range of ailments, including anemia, digestive problems, asthma, cough, leprosy, and liver disorders, as mentioned in Ayurvedic literature (API, 2010; Patel and Goyal, 2012; Khan et al., 2018b). In Tibetan medical literature, P. emblica is recommended as a diuretic, anti-inflammatory, and antipyretic (Kletter and Kriechbaum, 2001; Yadav et al., 2017; Jantan et al., 2019). The fruiting body of P. emblica has good medicinal and nutritive value. The fruit shows major pharmacological activities (Variya et al., 2016; Yadav et al., 2017; Khan et al., 2018b; Yang et al., 2020).

Cure against diabetes

A proper and balanced diet is of utmost importance in the management of diabetes (type 1 and type 2) and various other metabolic complications (Musman et al., 2019; Sharma et al., 2020). Diabetes is mediated through the stimulation of pancreatic cells, which interferes with the adsorption of dietary glucose (Grover et al., 2002; Platel and Srinivasan, 1997; Srinivasan, 2005). Many non-clinical and clinical studies have been conducted against the anti-hyperglycemic activity of P. emblica (Grover et al., 2002) (Fig. 4). In one clinical trial study, P. emblica was also reported to reduce 2 h post-prandial and fasting blood sugar levels in diabetic patients (Akhtar et al., 2011).

Various activities and mechanism of action of <italic>Phyllanthus emblica</italic> fruit extracts in the cure of diabetes.

For elucidation of the significant role of P. emblica against diabetes and related complications, various studies have been performed on a rat model involving the induction of diabetes by streptozotocin in rats with or without a high-fat diet. The administration of P. emblica incurs significant protection against 5-hydroxyfurfural and low antioxidant levels. The serum adiponectin levels were found to improve, and simultaneously glycosylated proteins were reduced. The study reported the role of P. emblica in improving the metabolism of glucose in diabetes hyperglycemic conditions (Rao et al., 2005).

 Cytoprotective and anti-cancer activity

P. emblica is rich in hydrolysable tannin and polyphenols-derived compounds, which prevent lipid peroxidation and mutagenesis induced by carcinogens (Yang and Liu, 2014; Zhao et al., 2015; Variya et al., 2016). Ellagic acid tannins, and chebulagic acid, extracted from P. emblica, have anti-proliferative and pro-apoptotic activity against cancer cells (Thoidingjam and Tiku, 2019; Balusamy et al., 2020; Fig. 5). They help in scavenging free radicals, therefore, preventing the formation and accumulation of ROS and protecting DNA from damage (Makena and Chung, 2007). P. emblica is also reported to act against carcinogen 3, 4-benzo (a) pyrene in mice,which helps in preventing the negative effects of chromosomal damage (Nandi et al., 1997). Aqueous extract of the fruit of P. emblica also reduces the effect of benzopyrene, which has cytotoxic effects as reported in murine models (Nandi et al., 1997).

Depiction of various components of <italic>Phyllanthus emblica</italic> fruit extracts possessing anti-cancer properties. Anti-inflammatory properties

It has been reported that aqueous extract of P. emblica has the ability to cure several inflammatory disorders, including psoriasis, inflammatory bowel syndrome, atherosclerosis, osteoarthritis, rheumatoid arthritis, etc. Asmawi et al. (1993) reported that the hydro-methanolic extract of leaves of P. emblica possesses excellent anti-inflammatory action against dextran and carrageenan-induced rat paw models (Asmawi et al., 1993). It modulates inflammatory responses by decreasing the synthesis of various chemokines, which inhibit the localization of immune cells to the target area and promotes the synthesis of T cells to overcome the damaging effects (Li et al., 2020; Singh et al., 2015).

 Immuno-modulatory activity

P. emblica also has a unique property of acting as an immuno-modulator which attenuates acquired and innate immunity (Fig. 6). They strengthen the immune system by improving the host defense mechanism (Patil et al., 2012). Products of P. emblica, like dried extract, tonic, syrups, medicines, etc, act as disease-preventing or energy boosting agents that directly work on various immuno-pathogens and support the immune system. Reports also suggest that they are rich in vitamin C, which helps in improving cellular cytotoxicity and natural killer cell activity (NK). The fruits of P. emblica increase the life expectancy (35%) of tumor-affected mice by stimulating proliferation in the splenic activity of a natural killer cell (Suresh and Vasudevan, 1994). It also acts as an immune modulator by inducing DNA fragmentation, decreasing apoptosis and cytoprotection against various pathogenic cells and chromium-induced immunosuppressive and cellular stresses. A dosage of 100 mg/mL of P. emblica also restores the decreased level of gamma interferon and interleukin (IL)-2 of lymphocyte proliferation by chromium-induced immunosuppressive and cellular stress (Ram et al., 2002; Nair et al., 2018; Li et al., 2020). A study by Singh et al. (2013) showed that the aqueous extract of P. emblica serves as an immune-modulatory agent in thymocyte cells of mice against oxidative stress and cytotoxicity caused by arsenic (Singh et al., 2013).

Regulation of immuno-modulatory and anti-hyperlipidemic properties by <italic>Phyllanthus emblica</italic> fruit extracts. Anti-hyperlipidemia and related metabolic syndrome

Phyto-constituents and flavonoids obtained from the extract of P. emblica are also reported to possess hypolipidemic potential (Dwivedi and Aggarwal, 2009; Hakimi et al., 2019). Kim et al. (2005) proposed the anti-hyperlipidemic effects of P. emblica on rats supplemented with cholesterol under copper-induced stresses. A decrease in the concentration level of oxidized LDL was observed, which prevents atherosclerosis in model organisms (Kim et al., 2005; Usharani et al., 2019).

 Anti-mutagenic activity

Other secondary metabolites, such as terpenoids, phenolates, flavonoids glycosides, etc, are also reported in P. emblica, which have high anti-mutagenic properties. It inhibits mutagenicity and activation of 4-nitro-O-phenylenediamine, 2-acetamidofluorene, and 20-methylcholanthrene, which induces sarcoma (Jose et al., 1997). It works by inhibiting the phase I enzymes, establishing an important role against mutagenicity in various model organisms (Haque et al., 2001; Bhattacharjee et al., 2020).

 Uses in Ophthalmology

Retinal disorders including glaucoma, retrolental fibroplasia, diabetic retinopathy, retinitis pigmentosa, cataract, and macular degeneration are the major conditions that cause blindness worldwide. Antioxidant property and free radical scavenging potential of P. emblica are reported to manage ophthalmic issues such as redness, itching, burning, lacrimation, eyesight, etc. (Head, 2001, 1999; Rizvi et al., 2013; Nashine et al., 2019; Prasad and Srivastava, 2020).

Other uses

Earlier findings indicate that the fruit extracts of P. emblica possess wide-spectrum pharmacological activities and show synergistic activity in combination with vitamins (A, C, E) and green tea (Jain et al., 2011; Kamal et al., 2012). The potential role of P. emblica in cardioprotection has also been well-comprehended in the literature highlighting its high antioxidant activity against isoproterenol, and the corresponding results indicate substantial enhancement in contractile and hemodynamic functions when the dose range of 100–500 mg/kg of body weight was administrated orally (Ojha et al., 2012). The presence of phytophenols like flavonoids and tannins in P. emblica fruits acts against oxidative stress in alcohol-induced hepatic injury (Reddy et al., 2010). P. emblica also has a protective effect against its related toxicity during metal-induced stresses. Singh et al. (2014) concluded that the protective effects of P. emblica against necrosis, apoptosis, DNA damage, and oxidative damage aredue to arsenic (As) in liver cells of mice at a dosage of 500 mg/kg of body weight per day for 30 days (Singh et al., 2014).

Earlier findings indicate that the fruit extracts of P. emblica possess wide-spectrum pharmacological activities and show synergistic activity in combination with vitamins (A, C, E) and green tea (Jain et al., 2011; Kamal et al., 2012). The potential role of P. emblica in cardioprotection has also been well-comprehended in the literature highlighting its high antioxidant activity against isoproterenol, and the corresponding results indicate substantial enhancement in contractile and hemodynamic functions when the dose range of 100–500 mg/kg of body weight was administrated orally (Ojha et al., 2012). The presence of phytophenols like flavonoids and tannins in P. emblica fruits acts against oxidative stress in alcohol-induced hepatic injury (Reddy et al., 2010). P. emblica also has a protective effect against its related toxicity during metal-induced stresses. Singh et al. (2014) concluded that the protective effects of P. emblica against necrosis, apoptosis, DNA damage, and oxidative damage aredue to arsenic (As) in liver cells of mice at a dosage of 500 mg/kg of body weight per day for 30 days (Singh et al., 2014).

Extract of P. emblica showed anti-resorptive and anti-osteoclastic activity by showing changes in Interleukin 6 (IL-6), nuclear factor (NF-) and FS-7-associated surface antigen (Fas) expression by activating apoptosis of osteoclasts cells without changes in osteoclastogenesis (Penolazzi et al., 2008; Pompo et al., 2014). It regulates glucose 6-phosphate dehydrogenase activity and has a good aphrodisiac effect (Panda and Kar, 2003). A polyherbal formulation of P. emblica, i.e., Chayavanprasha, is used as a tonic for sexual vitality (Dweck et al., 2002).

 Conclusion and Future Research

Recent studies concluded that P. emblica is a miracle tree. Every part (i.e., leaf, stem, heartwood, and roots) of this plant is very beneficial. Maximum research has been performed on the fruit, and there are a few reports on the leaves and roots. Thus, there is a need to explore the therapeutic properties of leaves and stem because while the fruits are seasonal, their medicine is required throughout the year. P. emblica contains more than 100 phytochemicals of different classes with the dominancy of phenols and tannins. However, many compounds are unidentified, which is an important aspect of future research. Further, detailed investigations of their biological activities in individual or mixed forms are other important aspects of future research. Until now, most experiments have been performed on animal and in-vitro models, highlighting the need for clinical studies with well-established facts. We rarely found ant published clinical studies on the therapeutic effects of P. emblica. Many reports claim that pharmacological activities like anti-cancer, anti-hyperlipidemia, and anti-hyperthyroidism are attributed to the antioxidant activities of P. emblica. Detailed research is required for the characterization and isolation of these compounds. After a detailed review, we found that few compounds have proven safety efficacy and medicinal properties. For example, ellagic acid, corilagin, chebulagic acid, gallic acid, and quercetin have proven anti-cancer and anti-proliferative activities. So, it has become essential to unravel the bio-molecular mechanism of the action of these both compounds as well as their physiological effects.

We are thankful to Director General, Central Council for Research in Ayurvedic Sciences, for his motivation and other facilities. Dr. Simranjeet Singh would like to acknowledge DBT HRD Project & Management Unit, Regional Center for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana for Research Associateship (DBT-RA).

 Funding Statement

The authors received no specific funding for this study.

 Author Contributions

Vijay Kumar: Conceptualization, Data curation, Methodology, Writing–original draft, Writing–review & editing. Praveen C Ramamurthy: Conceptualization, Supervision, Validation, Visualization, Writing–review & editing. Simranjeet Singh: Methodology, Writing–original draft, Writing–review & editing. Daljeet Singh Dhanjal, Parul Parihar and Deepika Bhatia: Data Validation, Visualization. Writing–original draft, Writing–review & editing. Ram Prasad and Joginder Singh: Methodology, Writing–original draft, Writing–review & editing.

 Ethics Approval

Not applicable.

 Conflicts of Interest

The authors declare that they have no conflicts of interest to report regarding the present study.

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