Citrullus colocynthis: A Treasure of Phytochemical, Pharmacological, Pesticidal and Nematicidal Compounds

Sonam Khatri1, Shaheen Faizi2, Shahina Fayyaz1 and Erum Iqbal1*

1National Nematological Research Centre (NNRC), University of Karachi, Karachi, 75270, Pakistan; 2Husein Ebrahim Jamal (HEJ) Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan.

Received | November 11, 2021; Accepted | December 18, 2021; Published | December 22, 2021

*Correspondence | Erum Iqbal, National Nematological Research Centre (NNRC), University of Karachi, Karachi, 75270, Pakistan; Email: erum_i@yahoo.com

Citation | Khatri, S., Faizi, S., Fayyaz, S. and Iqbal, E., 2021. Citrullus colocynthis: A treasure of phytochemical, pharmacological, pesticidal and nematicidal compounds. Pakistan Journal of Nematology, 39(2): 122-150.

DOI | https://dx.doi.org/10.17582/journal.pjn/2021.39.2.122.150

Keywords | Citrullus colocynthis, Effective compounds, Phytonematodes, Nematicidal properties, Root knot

Introduction

In the current scenario, food security is one of the sustainable development goals as more than 800 million people are chronically starving and millions more are at risk globally (FAO, 2013). Sustainable progress in agriculture and attaining food sufficiency is a central agenda in the global world. Yield and quality of crops grown for human consumption and global food security is menaced by the emergence and propagation of crop pests and pathogens especially weeds, pathogens and animal pests. The food production has been facing the distressing actions of numerous pests like viruses, microbes, fungi, nematodes, insects and parasitic plants, which have triggered noteworthy total economic losses of about 50% of agricultural yield per annum, including 14% and 35% losses in storage and field, respectively (Okwute, 2012).

Among other pests, plant-parasitic nematodes mostly mangle the field as concealed enemies and reduce agricultural harvest. Plant parasitic nematodes inflict direct economic losses of around USD 118000 million in a single 5 years on agriculture (Ahmed et al., 2015). The different varieties of crops are being infected by different genera of phytonematodes, some of them with significant importance are Pratylenchus spp., Tylenchus spp., Belonolaimus spp., Helicotylenchus spp., Paratrichodorus spp., Tylenchorhynchus spp., Criconema spp., Meloidogyne spp., Heterodera spp., Hoplolaimus spp., Tylenchulus spp., Rotylenchulus spp., Xiphinema spp., (Anwar and VanGundy, 1989; Maqbool and Shahina, 2001).

In order to manage phytonematodes, number of managing approaches is being embraced to eradicate them. The most common approach includes the use of synthetic chemicals which possess great history. Up till now, management of phytonematodes in agriculture has been reliant on the routine usage of nematicides, but after the awareness of negative influence of these chemical nematicides, researchers are exploring different methods to be used as substitute (Hallmann et al., 2009; Siddiqui et al., 2009). Due to the adverse effect of chemicals on environment, they are being steadily banned or removed from market (Hague and Gowen, 1987; Sabarwal et al., 2018). The unreliable outcomes of nematicides, chiefly due to greater biodegradation (Karpouzas et al., 2001; Qin et al., 2004; Giannakou et al., 2005), aggravation of asthma (Raanan et al., 2015; Amaral, 2014), imparting a greater threat of developing type 2 diabetes (Azandjeme et al., 2013) and impairment in reproductive systems growth (Martin-Reina et al., 2017), generates a crucial requisite for unconventional nematode management approaches (Nicolopoulou-Stamati et al., 2016). It has become prime concern to search ecologically friendly substitutes to manage plant parasitic nematode populations.

Recently, the research is seriously oriented towards the plant derived products; the extracts derived from plants have been a main interest of researchers to formulate an alternative bio-safe pesticide to replace the conventionally used pesticides (Marrone, 2019). Besides this, phytochemicals are not explored much for their nematicidal properties in spite of the existing urgency for initiation of nematode management measures, which are hardly supported by industry for the development of nematicides (Chitwood, 2002). The number of studies have reported the nematicidal activities of extracts of various plant species against different species of plant parasitic nematodes (Shaukat et al., 2003; Ntalli et al., 2010a, b; Dos Santos et al., 2010; Faizi et al., 2011; D’Addabbo et al., 2011; Leonetti et al., 2011; Caboni et al., 2012).

Many investigators have focused their consideration towards the cucurbitaceae family because fruits, seeds and vegetables are customarily utilized in various ayurvedic preparations (Ajuru and Nmom, 2017). In the plant kingdom, cucurbitaceae family is among the finest hereditarily assorted collection of curative plants (Prashant et al., 2017; Zaini et al., 2011). For the assessment of nematicidal compound, a biologically vital plant Citrullus colocynthis is selected as it is the plant of medicinal importance (Meena and Patni, 2008; Aldamegh et al., 2013). C. colocynthis, a potential and noteworthy for nutraceutical and therapeutic uses, is grown as a wild perennial plant in arid and barren regions of the world including Pakistan (Asyaz et al., 2010; Sawaya et al., 1983).

Taxonomic account of Citrullus colocynthis (Linnaeus) schrader

• Kingdom– Plantae
• Division– Magnoliphtya
• Class– Magnolipsida
• Order– Cucurbitales
• Family– Cucurbitaceae
• Genus– Citrullus
• Species– colocynthis

Bitter apple, egusi, desert gourd are some of the common names of C. colocynthis, belonging to cucurbitacae family (Figure 1). Geographically, it is distributed in the barren areas of India, West Pakistan, Ceylon, and Arabia in the region westward of Mediterranean region (Jafri, 1966). Around 17 genera and 32 species are reported among which 25 medical plants of genus Citrullus are recorded in Pakistan (Nazimuddin and Naqvi, 1984).

 

Chemical constituents of Citrullus colocynthis

Chemically, the fruit and its various parts possess treasure of compounds with remarkable biological functions and activities. Seeds of C. colocynthis are the rich source of edible oil, comprising of 56% and 25% of linoleic acid and oleic acid respectively as major constituents (Sawaya et al., 1983). Flavonoids, glucosides, terpenoids and alkaloids are reported as bioactive chemical components in fruit along with variety of curcurbitacins such as A, B, C, D, E, I, J, K, and L and colocynthosides A and B (Hussain et al., 2014). Other than these, many compounds belonging to different classes have also been identified from different parts of C. colocynthis plants which are listed in Table 1.

Pharmacological properties of Citrullus colocynthis

C. colocynthis was used as an ancient medicine by the ancient Greek and Roman physicians and is used broadly in folk medicine since ancient times (Uma and Sekar, 2014). Many medicinal and pharmacological activities of C. colocynthis like laxative, anti-inflammatory, anti-diabetic, palliative, hair growth, promoting, aborticide, and anti-epileptic were recognized in traditional Iranian medicine (Rahimi et al., 2012). The pharmocological activities of different parts of C. colocynthis are listed in Table 2.

Pesticidal properties of Citrullus colocynthis

C. colocynthis has gained increasing attention and has also emerged as a natural pesticide and its activity against many economically important pest species has been assessed. It has been suggested as influential insecticide in order to protect the ecosystem and improve the quality of public well-being (Niroumand et al., 2016). Many studies support the efficacy of C. colocynthis along with other plants as powerful insecticides but only few studies showed nematicidal properties of C. colocynthis and recommended to evaluate the overall efficacy of these plants in order to save the environment. Table 3 inlists the pesticidal activities of C. colocynthis against various insects and phytonematode pests.

Plants possess the valuable paragon of secondary metabolites which play vital part in many medicinal diseases since ancient times which is also being explored for their use in crop protection as Integrated Pest Management practices (Niroumand et al., 2016). Customarily, different parts of C. colcynthis plant are consumed in the treatment of different ailments; which shows the multidisciplinary action of this plant. This plant has been the area of great interest for researchers in order to establish the medicinal and pesticidal significance of this plant and to discover new bio-active moieties, for which bulk of research is in progress. Plants may provide a prime and importance method in the integrated nematode management (INM) practices as environmental safety and economical as a new alternative to originally chemical nematicides. Botanical nematicides are the source of alternative bio-rational and eco-safe products to toxic synthetic nematicides. Very little work has been done to consider the potential of C. colocynthis to manage phytonematodes.

C. colocynthis is a treasure of numerous bioactive compounds ranging from small hydrocarbons to large and complex flavonoids and terpenoids. It is a rich source of amino acids, hydrocarbons, alcohols, esters, fatty acids, flavonoids and terpenoids specially cucurbitacins. Among these compounds, many have been studied for their nematicidal responses against different species of phytonematodes. Esters like methyl stearate and methyl palmitate had been reported to possess potential to reduce root galls and egg masses, inhibit egg hatching and repel larvae and nematodes in soil (Lu et al., 2020). Many fatty acids which are one of the major constituents of C. colocynthis are already studied for their nematicidal activities. Oleic acid which is the most common fatty acid in nature was found active against Bursaphelenchus lignicolus (Tominaga et al., 1982); hexadecanoic, lauric, caprylic and myristic acid found effective against the phytonematode, Meloidogyne incognita (Ntalli et al., 2010c; Zhang et al., 2012). Nematicidal activity of linoleic, lauric and myristic acid is also reported against saprophytic nematode Coenorhabditis elegans (Gu et al., 2005; Stadler et al., 1994); lactic acid was also concluded to be an effective ovicidal agent against root-knot nematodes (Lee et al., 2014). Besides these, short chained fatty acid like acetic acid is also reported and concluded to be efficient against plant-parasitic species (Favre-Bonvin et al., 1991).

Among alcohols, oleyl alcohol and 1-triacontanol, were found active against Bursaphelenchus lignicolus and Meloidogyne incognita, respectively (Tominaga et al., 1982; Nogueira et al., 1996). Phenolic compounds like gallic acid and methyl eugenol were found to be nematotoxic against the root-knot nematode, Meloidogyne incognita (Seo et al., 2013; Li et al., 2013). Other than this, Coumaric acid and a flavonoid, quercetin showed promising anthelmintic activity against Haemonchus contortus, a nematode parasite of ruminants (Castillo-Mitre et al., 2017).

 

Table 2: Pharmacological activities of different extracts obtained from different parts of C. colocynthis.

S. No.	Activity	Part of plant	Extracts	References
1.	Anti-Cancer Or Anti-Tumor	Seeds Plant Pulp powder	Different extracts Aqueous	Tannin-Spitz et al., 2007; Belkin and Fitzgerald, 1952; Kafshgari et al., 2019
2.	Jaundice	Roots	-	Pravin et al., 2013
3.	Urinary Diseases	Roots	-	Pravin et al., 2013
4.	Rheumatism	Roots Roots	-	Pravin et al., 2013; Batanouny, 1999
5.	Snake Bite	Whole Plant	Methanol	Asad et al., 2012
6.	Anti-asthmatic	Roots Fruit	Powder oral Ethanolic	Savithramma et al., 2007; Genwa et al., 2017
7.	Anti-Inflammatory	Leaves Immature fruit and seeds	Methanol Aqueous Organic solvents	Marzouk et al., 2010; Rajamanickam et al., 2010; Marzouk et al., 2011
8.	Analgesic	Immature fruit and seeds	Organic solvents	Marzouk et al., 2011
9.	Amenorrhea	Roots	-	Batanouny, 1999
10.	Helmintholytic	Leaves	Different	Talole et al., 2013
11.	Osteoarthritis	Roots	Ethanol	Akhzari et al., 2015
12.	Joint Pains	Root	-	Batanouny, 1999
13.	Ophthalmia	Roots	-	Batanouny, 1999
14.	Uterine Pain	Roots	-	Batanouny, 1999
15.	Purgative	Fruit/Pulp	-	Batanouny, 1999
16.	Antipyretic	Fruit	-	Batanouny, 1999
17.	Anti-Malarial	Fruit Fruit pulp	Methanol Ethanolic	Tariq et al., 2016; Feiz et al., 2017
18.	Anti-leishmanial	Plant Fruit	Aqueous Crude methanol	Rani and Dantu, 2015; Tariq et al., 2016
19.	Anti-Ulcers	Seeds Fruits	Aqueous and ethanolic	Gill et al., 2011; Reddy et al., 2012
20.	Hair Loss Treatment	Fruits Fruit	Ethanol and pet. ether Pet.ether	Roy et al., 2007; Dhanotia et al., 2011
21.	Bronchitis	Fruit	-	Gurudeeban et al., 2010a
22.	Nephro protective	Fruit	Ethanolic	Adeyemi et al., 2017
23.	Anti-Gonorrhea.	Fruit/Pulp	-	Uma and Sekar, 2014
24.	Anti-Diabetic	Fruit Seeds	- Oil	Rahbar and Nabipour, 2010; Heydari et al., 2019
25.	Toothache	Roots	-	Qureshi and Bhatti, 2008
26.	Mastitis	Fruit pulp	Ethanol	Singh, 2019
27.	Constipation	Seeds	-	Bahmani et al., 2014
28.	Anti-diarrheal	Fruits	Hydroalcoholic	Dhakad, 2017
29.	Acute stomach ache	Fruits	Oral	Meena et al., 2014
30.	Bowel complaints	Seed oil	-	Meena et al., 2014
31.	Epilepsy	Seed oil	-	Meena et al., 2014
32.	Dropsy	Fruits	Juice	Meena et al., 2014
33.	Boils and pimples	Fruits and roots	Mixture with water	Meena et al., 2014
34.	Hepatitis	Fruit	Decoctation	Meena et al., 2014
35.	Abortion	Pulp (dried and powdered)	Oral	Meena et al., 2014
36.	Anti-Microbial	Leaf Pulp Fruit Plant Whole Plant	Methanol Methanol Chloroform Methnolic Acetone	Gurudeeban et al., 2010b; Shaikh et al., 2016; Kim et al., 2014; Al-Askar et al., 2014; Mahendiran and Umavathi, 2015
			Table continues on next page.............
S. No.	Activity	Part of plant	Extracts	References
37.	Antineoplastic Action	Fruit	-	Faust et al., 1958.
38.	Anti-Implantation	Plant	Ethanolic and benzene	Prakash et al., 1985.
39.	Anti-Oxidant	Pulp Seeds Seeds Immature fruit and seeds Fruit Leaves	Hydro-ethanol Hydro-methanol, ethyl acetate Methanol/water Organic extracts Benzene, chloroform, methanol Different extracts	Dallak, 2011; Benariba et al., 2013; Yasir et al., 2016; Marzouk et al., 2016; Vakiloddin et al., 2015; Nessa and Khan, 2014
40.	Antimyco bacterial activity	Aerial parts and ripe deseeded fruits	Methanol	Mehta et al., 2013
41.	Xanthine oxidase inhibition	Leaves	Different extracts	Nessa and Khan, 2014
42.	Radical scavenging potential	Fruit	Methanolic	Kumar et al., 2008
43.	Anti-fertility effect	Fruit Roots	Ethanol Ethanol	Chaturvedi et al., 2003; Mali et al., 2001
44.	Anti-convulsant	Fruit	Hydroalcoholic extract	Mehrzadi et al., 2016
45.	Lipoxygenase activity	Seed	-	Al-Khalifa, 1996
46.	Antifungal	Fruit, seeds Floral parts Seeds Plant	Aqueous Ethanolic Petroleum ether Various extract	Marzouk et al., 2010b; Hadizadeh et al., 2009; Sari et al., 2014; Bokhari et al., 2013
47.	Hepato protective	Fruit Fruit	Benzene, chloroform, methanolic Ethanolic	Vakiloddin et al., 2015; Adeyemi et al., 2017
48.	Antibacterial	Leaves Roots, stems, leaves and three maturation stages of its fruit and seeds Immature fruits and seeds) Leaves and fruits Pulp Plant	Methanolic Aqueous and diluted acetone Aqueous (water and ethanolic) Aqueous and dealcoholized Different extracts	Gurudeeban et al., 2010; Marzouk et al., 2009; Marzouk et al., 2010b; Najafi et al., 2010. Patel and Trivedi, 1957 Mehni et al., 2014
49.	Anticandidal	Roots, stems, leaves and three maturation stages of its fruit and seeds	Aqueous and diluted acetone	Marzouk et al., 2009
50.	Hypoglycemic	Rind Seedless pulp	Aqueous	Abdel-Hassan et al., 2000; Mohammad et al., 2009
51.	Normo-hypoglycemic	Dried seedless pulp	Ethanol	Mohammad et al., 2009b
52.	Insulinotropic actions	Dried seedless pulp	Ethanol	Mohammad et al., 2009a
53.	Anti-Hyper Lipidemic	Seed powder Dried seedless pulp Pulp	Capsule Ethanol Hydro-ethanol	Rahbar and Nabipour, 2010; Mohammad et al., 2009b; Dallak, 2011
54.	Antihyper glycemic	Seeds	Aqueous	Lahfa et al., 2017
55.	Immuno stimulating activity	Plant	Hot water polysaccharide	Bendjeddou et al., 2003
56.	Anti-obesity	Flesh powder	70% Ethanol	Jemai et al., 2018
57.	Anti-angiogenesis	Fruit	Ethyl acetate	Gaikwad et al., 2019
58.	Anti-arthritic	Fruit	Hydroalcoholic	Kachhawah et al., 2016
59.	Anti-biofilm	Seeds	Ethyl acetate	Almalki and Mohammed, 2016
60.	Anti-depressant	Fruit	Ethanol	Nafisi et al., 2016
61.	Spasmogenic activity	Whole plant	Aquoeus and n-butanol	Faisal et al., 2018
62.	Oral mucosal disease	Pulp powder	Aqueous	Kafshgari et al., 2019
63.	Polycystic ovarian syndrome	Pulp powder	Hydro-ethanolic	Barzegar et al., 2017
64.	Antimetallo proteinases	Peels	Aqueous	Zioud et al., 2019
65.	Wound healing	Different parts	Methanolic	Gupta et al., 2018
66.	Benign prostatic hyperplasia	Fruit	Cucurbitacin E glucoside	Basha et al., 2019
67.	Parkinson's disease	-	-	Chen et al., 2019
68.	Anti-platelets activity	Plant	Hydro-alcoholic	Alhawiti, 2018
69.	Profibrinolytic activity	Plant	Hydro-alcoholic	Alhawiti, 2018

 

Table 3: Pesticidal activities of different extracts obtained from different parts of C. colocynthis.

S. No.	Pests	Part of plant	Extracts/ form	References
1.	Culex quinquefasciatus	Leaf Whole plant	Oleic and linoleic acid	Mullai and Jebanesan, 2007; Rahuman et al., 2008
2.	Aedes aegypti Culex quinquefasciatus	Leaf	-	Rahuman and Venkatesan, 2008
3	Anopheles stephensi Liston	Whole plant	Hexane, diethyl ether, dichloromethane, ethyl acetate	Arivoli et al., 2012
4.	Culex pipiens Culiseta longiareolata	Fruit	Aqueous	Merabti-Brahim et al., 2016
5.	Bactrocera zonata	Fruit	-	Rehman et al., 2009
6.	Aphids, Lipaphis erysimi	Aerial parts	Ethanolic	Soam et al., 2013
7.	Tribolium castaneum	Fruit powder	Ethanolic	Nadeem et al., 2012
8.	Spodoptera littoralis	Fruit	Methylene chloride and hexane.	Rawi et al., 2011
9.	Locust, Chrotogonus trachypterus	Fruit	Methanol	Mollashahi et al., 2017
10.	Cowpea beetle, Callosobruchus maculatus	Seeds	Successive extraction	Dimetry et al., 2015
11.	Dermestes maculatus	Seeds	Hexane / oil	Akpotu et al., 2015
12.	Teteanychus urticae Sitophilus oryzea Sitophilus zeamais	Fruit	4- methylquinoline	Jeon and Lee, 2014
13.	Callosobruchus maculatus; cowpea	Seeds	Chloroform	Dimetry et al., 2007
14.	Aphis craccivora	Fruit	Ethanol	Torkey et al., 2009
15.	Aphid, Rhopalosiphum padi	Root, stem, leaf and fruit	Aqueous	Khalid, 2015
16.	Amphistome parasite, Orthocoelium scoliocoelium	Fruit pulp	Alcohol	Swarnakar and Kumwat, 2014
17.	M. incognita	Fruit	Acetone Water	Muniasamy et al., 2010; Gad et al., 2018
18.	Meloidogyne spp.	Pulp, seeds, whole fruit	Methanol	Rizvi and Shahina, 2014
19.	Haemonchus contortus	Fruit	Crude aqueous methanol extract	Ahmed et al., 2019
20.	Rhipicephalus (Boophilus) Microplus	Roots	Petroleum ether, hexane, methanol	Loach et al., 2019
21.	Spodoptera litura	Fruit	Cucurbitacin E	Ponsankar et al., 2019
22.	Musca domestica (House fly)	Different parts	Aqueous and ethanolic	Farah, 2017

 

Steroids like β-sitosterol and stigmasterol were also investigated for their nematotoxic effect and were found active against an economically important cyst nematode, Heterodera zeae (Bano et al., 2019). Flavonoids, quercetin and isovitexin showed promising activity against Haemonchus contortus and M. incognita respectively (Castillo-Mitre et al., 2017; Atolani et al., 2014). According to a research, a diterpene, phytol is involved in inhibition of root-knot nematodes, induced by the production of tocopherol (Fujimoto et al., 2021). Effect of amino acids is also studied against phytonematodes and as mentioned in Table 1, C. colocynthis also possess variety of amino acids among them the nematicidal evaluation of L-arginine, L-glutamic acid, ascorbic acid, alanine, glycine, histidine, threonine, phenyalinine, valine, l-lysine, leucine, aspartic acid and methionine had been reported and resulted in efficient nematicidal responses (Siddiqui and Shaukat, 2002).

The nematotoxic activity of terpenoids, thymol and citronellol is reported against Caenorhabditis elegans and Ascaris suum (Lei et al., 2010; Abdel-Rahman et al., 2013), whereas ursolic acid, was found to be nematicidal against root-knot nematode, Meloidogyne incognita (Begum et al., 2008). C.colocynthis is an easy source of cucurbitacins which are biologically active component for various pharmacological activities (Chung et al., 2015). As far as the nematicidal investigation of cucurbitacins is concerned, Nemarioc-AL and Nemafric-B are phytonematicides, containing cucurbitacin A and B respectively as active ingredients that are being investigated and developed in South Africa as a substitute for the control of Meloidogyne species (Dube and Mashela, 2017). A research study was also conducted to compare the nematicidal effect of these phytonematicides and their purified active ingredients and concluded that the cucurbitacin-containing phytonematicides were more active against phytonematodes than their purified active ingredients (Dube et al., 2019). In another study, ripe, unripe and powdered form of fruits was investigated for nematicidal activity and was found to be active against larvae of M. incognita (Khatri et al., 2020). From the literature cited above, it is evident that the phytochemicals present in C. colocynthis fruits are lethal for the nematodes and this research data will provide an overview of the type of compounds responsible for mortality of nematodes and will enlighten the new horizons for nematode management other than harmful and most conventional chemical nematicides.

Fatty acids, phenols, esters, alcohols, steroids and terpenoids including cucurbitacins are some of the secondary metabolites isolated from C. colocynthis, nematicidal property of which have been already reported and have proved that application of extracts of different parts of C. colocynthis could serve as a promising candidates for biocontrol of phytonematodes. Practically, the use of this plant is easier as it is a wild plant that grows easily in desert and does not require much water for nourishment, so it could be easily available resource to the poor farmers not as the chemical pesticides, expensive and hazardous to health. Phytonematicides are easily accessible and bio-degradable, are therefore environmentally friendly compared to the synthetic pesticides. It can be said that the use of botanical means may serve as a substitute to the chemicals in order to bring sustainability to agriculture. The dynamic usage of C. colocynthis in medicinal, pesticidal and nematicidal horizons along with its numerous secondary metabolites have established the importance of this plant for future proespects and nominate it as a potential formulation of bio-rational nematicidal solution to include in Integrated Nematode Management (INM) programs. A patent filed in 2019 by Prof. Dr. Shahina Fayyaz, Erum Iqbal, Shaheen Faizi and Sonum Khatri of NNRC product (NNRC-82) composed of C. colocynthis is effective against agricultural pests including nematodes.

Recommended dose of NNRC product (NNRC-82)

Regular application is recommended each after six months for all types of field plants.

• For crop plantation: Apply NNRC-82 @ 2 kg a.i./ ha at sowing.
• For tree plantation: Apply NNRC-82 @ 13 g/m2 (about 9 m2 around the tree trunk) just before flowering.

Novelty Statement

The given information in this review article highlights the importance of Citrullus colocynthis L. Schrad as a promising biological and pesticidal agent useful for the treatment of various medicinal ailments as well as reducing different pests that are harmful for the crop yield and emphasize the need to utilize the useful effect of this plant against nematodes.

Author’s Contribution

Sonam Khatri searched the related articles and wrote the manuscript,Prof. Shaheen Faizi supervised in writing manuscript, Prof. Shahina Fayyaz critically reviewed and help in writing manuscript, Dr. Erum Iqbal helped in compiling the data

Conflict of interest

The authors have declared no conflict of interest.

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