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Article

Phytochemistry, Food Application, and Therapeutic Potential of the Medicinal Plant (Withania coagulans): A Review

by
Muhammad Issa Khan
1,*,
Maria Maqsood
1,
Raakia Anam Saeed
1,
Amna Alam
1,
Amna Sahar
1,2,
Marek Kieliszek
3,
Antoni Miecznikowski
4,
Hafiz Shehzad Muzammil
1 and
Rana Muhammad Aadil
1,*
1
National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan
2
Department of Food Engineering, University of Agriculture, Faisalabad 38000, Pakistan
3
Department of Food Biotechnology and Microbiology, Institute of Food Sciences, Warsaw University of Life Sciences—SGGW, Nowoursynowska 159 C, 02-776 Warsaw, Poland
4
Department of Fermentation Technology, Prof. Waclaw Dabrowski Institute of Agricultural and Food Biotechnology—State Research Institute, Rakowiecka 36, 02-532 Warsaw, Poland
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(22), 6881; https://doi.org/10.3390/molecules26226881
Submission received: 27 September 2021 / Revised: 12 November 2021 / Accepted: 14 November 2021 / Published: 15 November 2021
(This article belongs to the Special Issue Bioactive Metabolites from Medicinal and Food Plants)
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Abstract

:
Herbal plants have been utilized to treat and cure various health-related problems since ancient times. The use of Ayurvedic medicine is very significant because of its least reported side effects and host of advantages. Withania coagulans (Family; Solanaceae), a valuable medicinal plant, has been used to cure abnormal cell growth, wasting disorders, neural as well as physical problems, diabetes mellitus, insomnia, acute and chronic hepatic ailments. This review provides critical insight regarding the phytochemistry, biological activities, and pharmacognostic properties of W. coagulans. It has been known to possess diuretic, anti-inflammatory, anti-bacterial, anti-fungal, cardio-protective, hepato-protective, hypoglycemic, anti-oxidative, and anti-mutagenic properties owing to the existence of withanolides, an active compound present in it. Apart from withanolides, W. coagulans also contains many phytochemicals such as flavonoids, tannins, and β-sterols. Several studies indicate that various parts of W. coagulans and their active constituents have numerous pharmacological and therapeutic properties and thus can be considered as a new drug therapy against multiple diseases.

1. Introduction

Plants are potential sources of medicinal compounds and have been used as ancient healing systems since antiquity. Some medicinal plants are enriched with diverse bioactive constituents. These bioactive constituents have been reported as beneficial to prevent and treat various disorders for maintaining a healthy life. One of the most important medicinal plants of genus Withania is Withania coagulans in the Ayurvedic medicinal system owing to its effective nutraceutical as well as pharmaceutical attributes. It is grown in various regions of the world such as in the Mediterranean region and from North Africa to South Asia [1]. Among twenty-three identified species of genus Withania, only two (W. coagulans and W. somnifera) have economic significance [2]. This plant is widely used to coagulate milk due to the presence of an enzyme in its berries, which is commonly known as an Indian cheesemaker [3]. Figure 1 depicts the leaves, stems, and fruit of the W. coagulans plant. The fruit, roots, and leaves have various therapeutic effects. The main constituents in berries include essential oils, esterases, amino acids, and alkaloids [4]. The healing properties of the plant are attributed to steroid derivative compounds “Withanolides”. There are several withanolides such as coagulin F, coagulanolide, withacoagulin, and coagulin G present in the whole plant [3]. The ripe fruit of the plant is sweet and used for wound healing, asthma and dyspepsia, and as a sedative. In many countries, dry fruit is also used as a traditional treatment for diabetes [5] and as an antibacterial [6], antimicrobial [7], hepatoprotective [8], hypolipidemic [9], antioxidant [10], anti-tumor [11], antidepressant [12], immunosuppressive [13], and anti-inflammatory agent [14]. Seeds are useful for reducing inflammation, as a diuretic, and also in curing ophthalmia, while flower buds showed anthelmintic activity [15,16,17]. Twigs of the plant are used for cleaning teeth, as toothache and blood purifier agents in South Asian regions [3]. By considering the growing utilization of medicinal plants and their application in various indigenous health systems, this review is intended to provide comprehensive knowledge on phytochemistry, food uses, and the therapeutic potential of W. coagulans.

2. Nutritional Profile

W. coagulans is a renowned herb due to its ethnopharmacological properties. It has been utilized as a herbal remedy and is widely distributed in Iran, Pakistan, Afghanistan, and East India. W. coagulans is a good source of macro and micronutrients. The mineral composition of W. coagulans is summarized in Table 1. It contains a small fraction of moisture, protein, fat, and fiber and is also a good source of carbohydrates. Studies also indicate a higher amount of magnesium (greater than Alhagi maurorum, Berberis lyceum, and Tecomella undulate), calcium (greater than Dature alba, A. maurorum, Chenopodium album, B. lyceum, T. undulate), potassium (greater than B. lyceum and T. undulate), and iron (greater than D. alba, B. lyceum, and T. undulata) in W. coagulans [4]. Roots are composed of ash (1.92%), carbohydrates (75.71%), lipids (5.5%), protein (2.95%), and fiber (5.76%). Leaves are composed of ash (3.26%), carbohydrates (65.31%), lipids (5%), protein (2.95%), and fiber (11.76%). Moreover, fruit contains ash (4.21%), carbohydrates (60.14%), lipids (5%), and protein (4.65%) [18].
The berries of the W. coagulans are composed of milk coagulating enzymes, two esterase, free amino acids, and essential oil. Proline, tyrosine, valine, hydroxyproline, glycine, cysteine, asparagine, glutamic, and aspartic acids are the main amino acids that are present in the plant. Major fatty acids include arachidonic acid, stearic acid, palmitic acid, linoleic and oleic acids [3]. Furthermore, n-octatriacont-17-enoic acid, geranilan-10-olyl dihydrocinnamoate (aromatic ester), and geranilan-8-oic acid-10-olyl salicyloxy-2-O-β-d-glucofuranosyl-(6″→1‴)-O-β-d-glucofuranosyl-6‴-n-octadec-9‴′,11‴′″-dienoate (monoterpenic benzyl glucoside) in consort with two already identified fatty acids named as n-dotriacont-21-enoic acid and n-tetratriacontanoic acid were characterized in berries [19]. Similarly, research also detected twenty constituents in the essential oil of the W. coagulans fruit including sesquiterpenes (54%) and esters (21.50%) as dominant compounds followed by the presence of fatty acids (5.5%) such as nonanoic acid, hexanoic acid, methyl ester of hexadecanoic acid, methyl ester of nondecanoic acid, methyl esters of 8,11-octadecadienoic acid, methyl ester of 9-octadecenoic acid, and ethyl ester of linoleic acid, alkanes (9.11%), and the aldehydes (0.32%) in smaller percentage [20]. The un-saponifiable matter of the plant seed is composed of triacontane as well as β-sitosterol and dihydrostigmasterol [21]. In addition, it was reported that seeds are composed of approximately 12–14% of oil. The presence of free sugar (17.8%) in the form of d-galactose and D-arabinose (1:1) in a de-fatted meal of the W. coagulans seeds was also elucidated with maltose present in trace amounts [22]. Higher percentages of β-sitosterol, as well as linoleic acid, were also found and reported for the hypo-cholesterolemic effect of corn oil in combination with W. coagulans [15,23].

3. Phytochemistry

Withania species have been studied extensively by several researchers that subsequently led to the identification, characterization, and isolation of bioactive compounds in different parts of a plant. It includes several steroidal lactones, tannins, flavonoids, and alkaloids [24,25,26]. Ten new phytoconstituents were identified from air-dried W. coagulans fruit extracted with methanol and their structures were based on their chemical and spectral data [27]. Various constituents of W. coagulans were estimated in three different extracts namely, methanolic, hydroalcoholic, and chloroform. It was reported that total phenolic content (55.9 mg/g), total tannins (76.6 mg/g), total flavonoids (0.88 mg/g), and total flavanol (0.25 mg/g) were higher in the methanolic extract as compared to hydroalcoholic and chloroformic [28].
In a study conducted in Iran, the presence of flavonoids (5.70–6.50%), anthocyanins (4.51–9.51 µmol/g), and total phenolics (14.91–23.7 µg gallic acid equivalent (GEA)/mg D.W) were confirmed in W. coagulans [29]. The leaves of W. coagulans demonstrated the levels of total phenolics (58.21 mg GEA/g) and flavonoids (47 mg rutin equivalent (RE)/g), respectively [30]. The important chemical constituents of this medicinal plant are the withanolides, a series of polyhydroxy steroidal lactones, mainly present in the leaves as well as roots. They are composed of C-28 steroidal lactones based on the ergostane structure and the six or five-membered lactone ring is formed by oxidation of C-22 and C-26 [25]. Their concentrations vary from 0.001% to 0.5% of the dry weight [26,31,32,33]. Two major groups include withanolides containing the modified carbocyclic structure and withanolides containing the unmodified skeleton (including the regular β–oriented side chains and the unusual α-oriented side chains). They are classified into seven groups based on being derivatives of ergostane and include 5β,6β–epoxides; 6α,7α–epoxides; 5-enes; intermediate compounds; 5α,6α–epoxides; 6β,7β-epoxides, and phenolic withanolides [31,34].
So far, several withanolides, alkaloids, and sitoindosides (withanolide with glucose molecule at carbon 27) have been reported and isolated from Withania species [24,26,35,36,37,38,39,40,41,42,43,44,45,46]. One of the most salient features that withanolide-producing plants possess is to host an oxygen function in almost all positions of side chains or carbocyclic skeletons. Novel structural variants arise by modifications in either the side chain or in the carbocyclic skeleton [15].

4. Novel Isolated Compounds of W. coagulans

Several compounds have been identified in different parts of W. coagulans including certain coagulans, coagulanolide, and coagulins. Choudhary et al., [40] identified 17β- hydroxywithanolide K: [(20S,22R)14α,17β,20β-trihydroxy-1-oxo-witha-2,5,24-trienolide] and 17β,20β-dihydroxy-1-oxo-witha-2,5,24-trienolide in whole plant. Similarly, Shahwar [47] found withahejarin, withasomniferine-A along with coagulin A. Furthermore, identification and isolation of thirteen coagulins (Coagulin F, G, H, I, J, K, L, M, N, O, P, Q, and R) from the whole plant was reported [41,48,49]. W. coagulans also contains coagulin U along with other metabolites such as methyl-4–benzoate and phytosterols (β-sitosterol, β-sitosterol glycoside). Similarly (22R),20β-hydroxy-1-oxowitha-2,5,24-trienolide and (22R)-14,20-epoxy-17β-hydroxy-1-oxowitha-3,5,25-trienolide which are also important constituents of it [50]. Moreover, 17β,27-dihydroxy-14,20-epoxy-1-oxo-22R-witha-3,5,24-trienolide and 17β-hydroxy-14α,20α-epoxy-1-oxo-(22R)-witha-3,5,24-trienolide were discovered [41]. Coagulin S was also isolated, and its structure was elucidated by using spectroscopic techniques [44]. Coagulansin B and coagulanolide are also amongst the metabolites of W. coagulans [51,52]. Withacoagulin J was identified as well as isolated along with already known withanolide H [53]. Withanolide named as (20R,22R)-14α,17,20β,27-trihydroxy-1-oxowitha-5,24-dienolide-27β-(O-β-d-glucopyranoside was also discovered latterly [53,54]. Furthermore, withacogulanoside-B along with five known withanolides was isolated [55]. The compounds present in different plant parts are given in Table 2. Furthermore, the structures of some withanolides are presented in Figure 2.

5. Application in the Food Industry

Berries of W. coagulans are well known for their milk coagulating potential. Keeping this property in view, the milk coagulating activity of protease from the plant was assessed. A temperature of 70 °C and pH 4 were found to be optimal for enzymatic activity. However, 60 °C was a stable temperature for the activity of the enzyme; SDS-PAGE showed a 66 kDa band [59]. Furthermore, the fruit extract of W. coagulans was utilized to assess the milk coagulating potential which demonstrated the highest impact at pH of 4 and temperature of 65 °C. Additionally, the time for rennet congealing of the extract was observed to be in direct relation with concentrations of NaCl or inversely with enzyme concentrations (protease inhibitors). Moreover, pepstatin-A (aspartic-protease inhibitor) completely inhibited the enzymatic potential of the berry extract [60].
An enzyme aspartic protease was isolated by using fractional ammonium-sulfate precipitation and cation-exchange chromatography from W. coagulans fruit. Furthermore, SDS-PAGE revealed the existence of a monomeric protein with a molecular weight of 31 kDa. The proteolytic activity of the protease enzyme was assessed using casein revealed Km (1.29 mg/mL) and Vmax (0.035 μmol Tyr/min) values for the protease enzyme. Skim milk was utilized to assess the milk coagulating potential of W. coagulans crude fruit extract. Consequently, mass spectrometry and inhibition assays revealed that aspartic protease is the only enzyme involved in milk coagulation. Additionally, the increasing salts concentrations (NaCl, CaCl2) gradually reduced the enzyme activity. Thus, it was concluded that this enzyme may be apt to produce the low salt cheese [61]. The protease was extracted from the berries of the plant and used for the production of white cheese. It was documented that cheese from W. coagulans was more acidic than cheeses prepared from other rennet sources [62].
Buffalo milk mozzarella cheese was developed by using fruits of W. coagulans as milk coagulants. Thus, an aqueous fraction of W. coagulans may be a suitable option for cheese production [63]. Buffalo milk cheese was developed by using an extract of the fruit of W. coagulans and was evaluated in terms of storage conditions (5 months). The highest content of ash, fat, crude protein as well as total solids was observed in cheese prepared with lyophilized berry extract [64]. Cheese preparation was done by using alcoholic and aqueous fractions of W. coagulans at different levels (0.5, 1, and 1.5%) containing plant proteinase [65].
Furthermore, the preparation of cottage cheese from an aqueous fraction of plant showed significantly higher moisture content as well as pH, however, no difference in ash, fat, and crude protein was observed in cheese prepared from calf rennet and W. coagulans [66]. An acceptable quality white cheese can be developed by the utilization of 0.5% alcoholic extract of the plant. The soy milk coagulating potential of W. coagulans extract was assessed in tofu preparation and compared with calcium-sulfate tofu. Sensory analysis revealed no difference between both types of tofu. However, yield as well as moisture content was lower in W. coagulans’s tofu [67].

6. Application in Nanotechnology

Silver nanoparticles (AgNPs) have prodigious potential on behalf of their mechanistic role in biomedical research. Approaches involving green chemistry have gained copious attention recently in plant science for the production of nanoparticles. Keeping in view this fact, leaf extract W. coagulans was utilized for the development of reduced graphene oxide (RGO)/Fe3O4 based nanocomposite with palladium nanoparticles (Pd/RGO/Fe3O4) and resulted in the reduction in 4-nitrophenol in the water at ambient temperature [68]. Silver nanoparticles were developed by using W. coagulans leaf extract and characterization of those nanoparticles was conducted by using UV–Vis, scanning electron microscopy, energy dispersive X-ray analysis, transmission electron microscopy, X-ray powder diffraction, and Fourier transform infra-red. The cumulative result indicated the size of particles as 14 nm having a spherical face-centered cubic structure [69].
Encapsulation of the water extract was performed by developing chitosan nanoparticles coated with food-based starch to retard extract release in the stomach. The release was retarded by 2.5 times by this method, hence exerting hypoglycemic potential [70]. W. coagulans was utilized to develop iron oxide nanorods. Iron oxide nanorods with an average size of 16 ± 2 nm and highly crystalline nature was obtained [6]. Furthermore, Keshari [71] also used W. coagulans extract to develop green silver nanoparticles. Those nanoparticles were crystalline, elemental, and spherical which also showed anti-biotic potential.

7. Therapeutic Potential of W. coagulans

A number of medicinal properties are attributed to W. coagulans such as antifungal, anti-cytotoxic, antidiabetic, hypolipidemic, neuroprotective, anti-inflammatory, anti-cancerous, anthelmintic, antioxidant activity, and wound healing activity [15]. Various pharmacological and therapeutic activities of W. coagulans are attributed to the various plant parts including roots, leaves, and fruits as shown in Figure 3. The anti-inflammatory mechanism of action of cogulin L isolated from W. coagulans is illustrated in Figure 4. Available literature indicates the therapeutic role of W. coagulans and its withanolides is summarized in Table 3.

8. Conclusions

W. coagulans possesses considerable therapeutic potential and has been employed as a remedy against various disorders and diseases due to the presence of withanolides. It also possesses esterases, free amino acids, fatty oils, and essential oils. Medicinal properties of W. coagulans such as hepatoprotective, anti-inflammatory, hypoglycaemic, cardioprotective, free radical scavenging, antimicrobial, central nervous system depressant, immunomodulation, antitumor, and cytotoxic activities have been revealed by several pharmacological studies. However, future studies are needed to explore the mechanisms of action of compounds isolated from W. coagulans in higher animals to confirm their protective activity and safety. Crude extracts from different parts of the plant especially from the fruit have significant medicinal potential. Modern medications can be developed after thorough research into the mechanism of action, bioactivity, toxicity, and pharmacotherapeutic potential of plant-derived beneficial chemicals, as well as clinical trials and standardization.

Author Contributions

All authors contributed equally for original drafting, editing and finalizing of the review paper. Conceptualization, M.I.K. and M.M.; draft preparation, M.I.K., M.M. and R.A.S.; tables and figures preparation, M.M., M.K., A.A., A.S. and H.S.M.; writing—review and editing, M.K., A.M. and R.M.A.; supervision, M.I.K. and R.M.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 26 06881 g001 550
Figure 1. W. coagulans plant. (A): Leaves, (B): Fruits, (C): Stems.
Figure 1. W. coagulans plant. (A): Leaves, (B): Fruits, (C): Stems.
Molecules 26 06881 g001
Molecules 26 06881 g002 550
Figure 2. Structure of Withanolides of W. Coagulans.
Figure 2. Structure of Withanolides of W. Coagulans.
Molecules 26 06881 g002
Molecules 26 06881 g003 550
Figure 3. Graphical representation of the therapeutic potential of W. coagulans in several ailments.
Figure 3. Graphical representation of the therapeutic potential of W. coagulans in several ailments.
Molecules 26 06881 g003
Molecules 26 06881 g004 550
Figure 4. Anti-inflammatory potential of W. coagulans (IκBα: Nuclear factor of kappa light polypeptide gene, iNOS: Inducible NO synthase, NFκB: Nuclear factor of kappa light polypeptide gene, TLR4: Toll-like receptor 4, ERK1/2: Extracellular signal regulator kinase, JNK1/2: c-Jun-N-terminal kinase.
Figure 4. Anti-inflammatory potential of W. coagulans (IκBα: Nuclear factor of kappa light polypeptide gene, iNOS: Inducible NO synthase, NFκB: Nuclear factor of kappa light polypeptide gene, TLR4: Toll-like receptor 4, ERK1/2: Extracellular signal regulator kinase, JNK1/2: c-Jun-N-terminal kinase.
Molecules 26 06881 g004
Table
Table 1. Mineral composition of W. coagulans [4].
Table 1. Mineral composition of W. coagulans [4].
Minerals (mg/kg)
Macro-Minerals
Calcium9260
Magnesium35,280
Potassium2450
Sodium125
Micro-Minerals
Iron98.8
Copper2.2
Zinc40.2
Chromium0.6
Cadmium1.4
Lead1.9
Nickel1.8
Table
Table 2. Important constituents of roots, aerial parts, leaves, and fruits of W. coagulans.
Table 2. Important constituents of roots, aerial parts, leaves, and fruits of W. coagulans.
MoleculesPart of PlantReferences
Withaferin ARoot[35]
(20R,22R)-6α,7α-epoxy-5α,20-dihydroxy-1-oxo-witha-2,24-dienolide)Root[39]
(20S,22R)-6α,7α-epoxy-5α-hydroxy-1-oxo-witha-2,24-dienolide)
Withacoagin: (20R,22R)-5α,20-dihydroxy-1-oxowitha-2,6,24-trienolide)
Coagulin B, Coagulin C, Coagulin D, Coagulin E, Coagulin RAerial parts (leaves and stem), whole plant[48,52]
AmyrinAerial parts (leaves and stem)[50]
Withacoagulin A: (¼(20S,22R)-17β,20β-dihydroxy-1-oxowitha-3,5,14,24-tetraenolide)Aerial parts (leaves and stem)[56]
Withacoagulin B: (¼(20R,22R)-20β,27-dihydroxy-1-oxowitha-3,5,14,24-tetraenolide)
Withacoagulin C: (¼(20S,22R)-14α,15α,17β,20β-tetrahydroxy-1-oxowitha-3,5,24-trienolide)
Withacoagulin D: (¼(20S,22R)-14α,17β,20β,27-tetrahydroxy-1-oxowitha-3,5,24-trienolide)
Withacoagulin E: (¼(20R,22R)-14β,20β-dihydroxy-1-oxowitha-2,5,24-trienolide)
Withacoagulin F: (¼(20R,22R)-14β,20β-dihydroxy-1-oxowitha-3,5,24-trienolide)
Withanolide L
(22R)-14α,15α,17β,20β-tetrahydroxy-1-oxowitha-2,5,24-trien-26,22-olide)
Coagulansin A: (14α,17S,20S,22R)-14,17,20,27-tetrahydroxy-1-oxowitha-2,5,24-trienolide)
Coagulansin B: (3β,14α,20S,22R)-3,14,20-trihydroxy-1-oxowith-5-enolide)
Withanolide P: (¼(17α,22R)-14,17,22-trihydroxy-1-oxoergosta-2,5,24-trien-26-oic acid δ-lactone)(14R,15R,17S,20S,22R)-14,15,17,20-tetrahydroxy-1-oxowitha-2,5,24-trienolide) (14R,15R,17S,20S,22R)-14,15,17,20-tetrahydroxy-1-oxowitha-3,5,24-trienolide)
(14S,17R,20S,22R)-14,17,20-trihydroxy-1-oxowitha-2,5,24-trienolide)
(14S,17R,20S,22R)-14,17,20-trihydroxy-1-oxowitha-3,5,24-trienolide)		Whole plant, aerial parts[52,57]
(5,20α(R)-dihydroxy-6α,7α-epoxy-1-oxo-(5α)witha-2,24-dienolide)Aerial part (leaves)[36]
(Ergosta-5,25-diene-3β,24ξ-diol)Fruit[38]
(3β-hydroxy-2,3-dihydrowithanolide F)Fruit[37]
Withanolide D
(3β,14α,20αF,27-tetrahydroxy-1-oxo-20R,22R-witha-5,24-dienolide)Fruit[58]
Withanolide H: (14α,20αF,27-trihydroxy-1-oxo-20R, 22R-witha-2,5,24-trienolide)
Ajugin EFruit[49]
Ajugin AFruit[50]
Withacoagulin: (20β,27-dihydroxy-1-oxo-(22R)-witha-2,5,24-tetraenolide)Fruit[43]
(20β-hydroxy-1-oxo-(22R)–witha–2,5,24-trienolide)
Coagulanolide (17S,20S,22R)-14α,15α,17β,20β-tetrahydroxy-1-oxowitha-2,5,24-trienolide)Fruit[51]
(20R,22R)-14,20α,27-trihydroxy-1-oxowitha-3,5,24-trienolideFruit[56]
Table
Table 3. Therapeutic potential of W. coagulans.
Table 3. Therapeutic potential of W. coagulans.
Part of PlantType of InterventionExperimental ModelDosageOutcomesReferences
Cardioprotective Potential
FruitMethanolic extractRabbits (1–1.5 kg weight)200 and 600 mg/kg BWImproved lipid profile, HMG-COA reductase, lipase, and
antioxidant activities		[9]
FruitWithacoagulin and coagulin CFemale Albino rats (100–120 g)25 and 50 mg/kg
BW		Antihypertensive impact in a dose-dependent manner[72]
FruitWithacoagulinMale Albino rats (120–150 g)25 mg/kg BWSuperoxide dismutase, catalase, creatinine phosphokinase, and lactate dehydrogenase significantly reduced[73]
Hepatoprotective Activity
FruitMethanolic and aqueous-methanolic
extracts (80%)		Albino rats
(170–220 g)		800 mg/kg BWAn improvement as well as biosynthesis of liver and bile duct specific enzymes. Maintenance of the integrity of the hepatic membrane[8]
Anti-inflammatory and Immune Modulatory Activity
FruitCoagulin LHuman murine cells, mice model
(male Swiss Albino mice)		1, 3, 10 μM (In vitro)
10, 25, and 50 mg/kg BW		Suppression of TLR4 induced immune-mediators including cytokines, growth factors, nitric and superoxide led towards immune-modulatory responses. Moreover, it reduced the degradation of IκBα which in turn inhibited the expression of NF-κB by downregulating the expression of iNOS and release of pro-inflammatory cytokines[14]
FruitEthanolic extract (50%)Broiler chicken
(550 male)		0, 75, and 150 mg/kg dietThe concentration of immunoglobulin G was significantly improved through improving humoral response at the dosage of 150 mg/kg diet[13]
Aerial partsCrude extract (methanol and chloroform in 1:1)Sprague Dawley rats (180–220 g)200, 100 and 50 mg/kg BWAnti-inflammatory impact (70.0%)[74]
PlantMethanolic extract (80%)Wistar rats (150–200 g)250 and 500 mg/kg BWAnti-inflammatory and antioxidant activity[75]
FruitAqueous extractIn vitro analysis-Strong antioxidant and free radical scavenging potential[10]
Antibacterial, Antifungal and Diuretic Activity
Roots and leavesChloroform, ethyl acetate, and aqueous extractBacterial strains
(Gram-positive and Gram-negative)		0.5, 1, 1.5, and 2 mg/mLChloroform leaves and ethyl acetate stem extracts at a dose of 2 mg/mL had significant inhibition activity against bacterial pathogens as compared to aqueous extract[76]
FruitMethanolic extractKlebsiella pneumonia, Escherichia coli, Salmonella paratyphi, Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus20 µg/mLThe highest inhibition by the methanolic extract was reported against Bacillus subtilis at 12 mm[7]
FruitMethanolic extractMale Charles Foster Albino rats (150–200 g)400 mg/kg BWThe nephron-protective role was illustrated by the reduction in levels of free radical, renal function test, and protection from DNA damage[77]
LeavesSilver nanoparticles (leaf extract)Bacterial strains
(Gram-positive and Gram-negative)		5, 10, 15, and 20 µg/mLIt curbed the growth of both gram-positive and negative bacteria[69]
FruitsSilver nanoparticles (fruit extract)Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Salmonella typhi, and Vibrio cholera50 µg/mLPhenolic constituents present in the W. coagulans can reduce silver nitrate into the silver nanoparticles. Moreover, bactericidal and bacteriostatic activity was elucidated[71]
FruitIron oxide nanorods (biological and chemical)Pseudomonasaeuroginosa and Staphylococcus aureus5, 10, and 20 µg/mLThe study indicated that biological nanorods are more effective (30% higher activity) than chemically prepared nanorods. W. coagulans nanoparticles showed significant inhibitory potential against P. aeuroginosa and S. aureus that indicates these nanoparticles are more effective than chemically prepared nanoparticles[6]
FruitAqueous extractIn vitro
(silver carp fillet)		0.5% extract, 1% extract, 1% chitosan, 1% chitosan with 0.5% extract and 1% chitosan with 1% extractChitosan coating of extract demonstrated debility in levels of total bacterial counts and psychrophilic total bacterial counts as well as enhanced shelf life of fish fillets[78]
Hypoglycemic Potential
Whole plantn-butanol and chloroform extractIn vitro and in silicoAjugin E (66.7 ± 3.6 µM), withaperuvin C (407 ± 4.5 µM), withanolid J (683 ± 0.94 µM)Withacogulanoside-B from n-butanol fraction and withaperuvin C as well as 27-hydroxywithanolide I with another 3 known withanolides (chloroform fraction) were identified. Among these, ajugin E showed higher α-glucosidase inhibition potential[55]
FruitEthanolic extractWistar rats and in vitro400 mg/kg BWW. coagulans suppressed the DPP-4 levels (63.2%) in an in vitro model at 14 μg/mL. Furthermore, restoration of pancreatic-endocrinal tissues was observed[5]
Whole plantAqueous extractSprague Dawley rats100 mg/kg BWW. coagulans showed a promising impact on postprandial insulin level and amended the architecture of beta cells of the pancreas[79]
Whole plantAqueous extractMale Sprague Dawley rats (200–300 g)1000 mg/kg BWW. coagulans improved expression of glucagon-like peptide 1 which in turn reduced fasting as well as postprandial glucose levels[80]
FruitAqueous extractIn vitro (mice pancreatic β-cells)
In vivo (Male ICR mice; 28–36 g)		In vitro (1, 2, 5, 10, and 25 μM)
In vivo (50 mg/kg BW)		Secretions of insulin were promoted 2-fold in cells treated with the extract. Furthermore, in vivo testing corroborated to suppress the levels of blood glucose by 60%[70]
FruitAqueous extractIn vitro0–100 µg/mLChromatographic analysis revealed the presence of 17β-hydroxywithanolide K, withanolide F, and coagulin C in fruit fraction that was further illustrated cytotoxic potential against HepG2 cells. Both EAF and WF promoted insulin secretions and inhibition of glucose absorption[81]
BudChloroform extractIn vitro
(L6 rat skeletal muscle cells)		3.906, 7.8125, 15.62,5 31.25, 62.5, 125, 250 and 500 μg/mLW. coagulans bud illustrated significant uptake of glucose via GLUT-4 and activity of PPAR gamma that resulted in enhanced glucose dumping and insulin sensitivity in skeletal muscles[82]
Anticancer Activity
Whole plantHydro-methanolic extractForty male Wistar rats (200–250 g)1000 mg/kg BWW. coagulans extract treatment induced cell apoptosis in the prostate and the expression of cyclooxygenase-2 in the prostatic tissues were effectively reduced[83]
FruitMethanolic extractHuman breast cancer and normal kidney epithelial cell lines20–200 μg/mLMethanolic fruit extract showed substantial anticancer activity by reducing cell viability[11]
LeavesMethanol and chloroform extractCell cultures include normal and cancerous human prostate cell lines10–250 μg/mLExtract exerted its cancer-preventing action by inducing apoptosis, decreasing cell viability, invasion, cell proliferation, and migration of prostate cancerous cells[84]
Whole plantWater and methanol extractForty Wistar rats (200–250 g)250, 500, and 1000 mg/kg BWW. coagulans extract caused decreased malondialdehyde levels and increased total antioxidant capacity levels in the prostate gland[85]
FruitEthanol extractHuman breast cancer cell line0, 10, 20, 40, 80, 160 and 320 µg/mLPlant extract arrested cell cycle at G2/M phase and was found non-hemolytic[86]
Root, leaf, leaf stalk, and fruitMethanolic extractsHuman and rat cancer cell lines20 μg/mLThe leaf stalk extract showed the highest cytotoxic activity against all tested cell lines[87]
LeafSilver nanoparticles(leaf extract)Cervical cancerous hyper-triploid cell-lines0.25–30 mg/L Silver nanoparticles containing withanolides unveiled cytotoxic and apoptotic potential[69]
Other Health Benefits
Whole
plant		Hydroalcoholic extractMale Wistar rats (48)250, 500, and 1000 mg/kg BW/dayResults showed a significant decrease in sperm count, gonadosomatic index, and sperm viability[85]
Whole
plant		Ethanolic extractsVermicidal activity against
Pheretima posthuma earthworm		75 and 100 mg/mLW. coagulans extract exhibited remarkable anti-helminthic activity against P. posthuma[17]
FruitAlcoholic extractSwiss Albino mice200, 500, and 1000 mg/kg BWFruit extract was evaluated as an antidepressant as it reduced the immobility and increased the mobility in rats through tail suspension test[88]
RootEthanol water (3:1) extractMale Wistar rats500 and 1000 mg/kg BWNeuro-protective potential against oxidative stress-induced injury was illustrated with enhancement in the number of intact neurons and suppression in the number of TUNEL neurons in the hippocampal region[89]
RootsMethanol and water (3:1)Male Wistar rats (220–250 g)1000 mg/kg BWPreischemic extract administration effectively increased the antioxidant status (catalase, glutathione peroxidase, and superoxide dismutase level) and reduced the malondialdehyde level in the striatum brain region.[90]
Whole plantMethanol and chloroform (1:1).Sprague-Dawley rats (180–220 g)200, 100, and 50 mg/kg BWThe antinociceptive potential of W. coagulans estimated via hot plate assay elucidated pain reduction by 65.3% and 62% by writhing assay[74]
FruitsMethanolic extractMice100 and 250 mg/kg BWStudy results suggested analgesic and sedative activity of W. coagulans[91]
FruitAlcoholic extractSwiss Albino mice200 mg/kg, 500 mg/kg, and 1000 mg/kgThe alcoholic extract did not exhibit an antidepressant effect in rats, but it showed a depressive effect on mood[92]
FruitAlcoholic extractSwiss Albino mice200, 500 and 1000
mg/kg BW		Rota road test also exhibited central nervous system depressant activity[88]
FruitAlcoholic extractSwiss Albino mice200, and 1000
mg/kg BW		Results showed no considerable association between W. coagulans fruit extract and catalepsy[93]
FruitHydroalcoholic extract (50% ethanol)Male one-day-old broiler chickens (600)0, 100, or 200 mg/kg dietNon-significant impact on the mineralization of tibia bone was illustrated. Dietary calcium level was declined by 30% and total antibodies level was not influenced significantly[94,95]
FruitHydroalcoholic extractMale one-day-old broiler chickens (550)150 and 75 mg/kg dietW. coagulans and W. somnifera administration increased the bone mineralization[96]
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Khan, M.I.; Maqsood, M.; Saeed, R.A.; Alam, A.; Sahar, A.; Kieliszek, M.; Miecznikowski, A.; Muzammil, H.S.; Aadil, R.M. Phytochemistry, Food Application, and Therapeutic Potential of the Medicinal Plant (Withania coagulans): A Review. Molecules 2021, 26, 6881. https://doi.org/10.3390/molecules26226881

AMA Style

Khan MI, Maqsood M, Saeed RA, Alam A, Sahar A, Kieliszek M, Miecznikowski A, Muzammil HS, Aadil RM. Phytochemistry, Food Application, and Therapeutic Potential of the Medicinal Plant (Withania coagulans): A Review. Molecules. 2021; 26(22):6881. https://doi.org/10.3390/molecules26226881

Chicago/Turabian Style

Khan, Muhammad Issa, Maria Maqsood, Raakia Anam Saeed, Amna Alam, Amna Sahar, Marek Kieliszek, Antoni Miecznikowski, Hafiz Shehzad Muzammil, and Rana Muhammad Aadil. 2021. "Phytochemistry, Food Application, and Therapeutic Potential of the Medicinal Plant (Withania coagulans): A Review" Molecules 26, no. 22: 6881. https://doi.org/10.3390/molecules26226881

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