Nutritional constituents of mulberry and their potential applications in food and pharmaceuticals: A review

Mulberry is a fast growing deciduous plant found in wide variety of climatic, topographical and soil conditions, and is widely distributed from temperate to subtropical regions. Due to presence of valuable phytochemical constituents, mulberry as a whole plant has been utilized as a functional food since long time. Mulberry fruits are difficult to preserve as they have relatively high water content. Therefore for proper utilization, different value-added products like syrups, squashes, teas, pestil sand köme, pekmez (turkuish by-products), yogurts, jams, jellies, wines, vinegar, breads, biscuits, parathas, and many more are made. In overseas, these value-added products are commercially sold and easily available, though in India, this versatile medicinal plant is still missing its identity at commercial and industrial scale. Leaves of mulberry are economically viable due to their important role in the sericulture industry since ancient times. Mulberries or its extracts exhibit excellent anti-microbial, anti-hyperglycaemic, anti-hyperlipidemic, anti-inflammatory, anti-cancer effects and is used to combat different acute and chronic diseases. Different parts of Morus species like fruits, leaves, twigs, and bark exhibit strong anti-tyrosinase inhibition activity that makes it a suitable candidate in cosmetic industries as a whitening agent. The current review provides a comprehensive discussion concerning the phytochemical constituents, functionality and nutraceutical potential of mulberry and as a common ingredient in various cosmetic products.


Introduction
Mulberry belongs to the Morus genus of Moraceae family and is dispersed extensively in diverse climatic and environmental circumstances ranging from tropical to temperate. Moraceae, also known as the mulberry or fig family, is a family of flowering plants of more than twenty-four species with one subspecies and at the minimum hundred identified varieties. The term Morus is derived from the Latin word 'mora', which means delay, most likely because of the slow development of its buds. It is an economical and widespread woody plant and has an enormous economic value other than sericulture leading to its several unique and special features. Morus alba (white mulberry), Morus nigra (black mulberry) and Morus rubra (red mulberry) are all commonly accepted worldwide species of genus Morus as they exhibit maximum medicinal properties. Amongst all the species, M. alba is a dominant species (Ercisli and Orhan, 2007). Roots, leaves, bark, stem twigs, and fruits of mulberry possess valuable bioactive constituents that can be explored in food, health care, and cosmetic industries. Conventionally, it is believed that fruits of mulberry, particularly black and red varieties are advantageous to the human body (Ercisli and Orhan, 2007). Almost all varieties of mulberry plant are traditionally recognized in Unani, Ayurveda, and Chinese systems of medicine with several pharmacological properties. Fruits of M. nigra are among the important constituents of Unani medicine known as Tutiaswad, which is believed to have anti-cancerous activities (Nursalam, 2016). In India, mulberry is known as ''KalpaVruksha" since all parts of the plant are used for various purposes and its fruit is commonly named as toot and shahtoot (King's or ''superior" mulberry). Chinese utilizes mulberry fruit as a natural medicine to strengthen the joints, lower the blood pressure, treat fever, protect liver damage, and assist discharge of urine. Its fruits, leaves, and barks in traditional Turkish folk medicine have been utilized as an anti-fever, an expectorant, assists in the discharge of urine, to lower blood pressure, as a folk remedy to treat dental diseases, in dysentery, as a de-worming agent, laxative, anthelmintic, odontalgic, treat diabetes, hypertension, arthritis, and anaemia (Özgen et al., 2009). Azerbaijan people utilize M. nigra fruits in the treatment of ailments like gall bladder, liver, and heart diseases (Farid Alakbarli and Iskandar Aliyev, 2000). The presence of valuable constituents in mulberry leaves and fruits makes the plant suitable to be placed in the category of functional foods that are useful to human health in addition to its basic nutritional function (Kadam, 2019). Leaves of M. nigra are commonly used by women during menopause as a replacement for the conventional hormonal substitute therapy, with a similar effect to that obtained by estrogenic use (de Queiroz et al., 2012). Furthermore, its fruits, roots, and leaves extracts can be utilized in cosmetics globally and is a commonly used constituent in many dermatological creams, bath gels, and many more owing to its exceptionally high radical scavenging potential. As stated by the Ministry of Health of China in 1985, M. alba was recorded as the first medicinal and edible fruit (Yuan and Zhao, 2017), and its leaves and fruits were considered not only food but also as drugs (Wang et al., 2014). Mulberry fruits are soft and delicate, and harvesting season lasts for a month usually from May-June in most parts of the world and the best growing temperature is between 24 and 28°C (Sharma and Zote, 2010;Dhiman et al., 2020). To properly utilize the mulberry or enhance the storage life, maintain nutritional and organoleptic qualities, and to minimize the waste, the possibility of introducing mulberry as a functional food and nutraceutical is a need of the hour that many researchers are looking forward to. Nonetheless, being exceptionally good in nutrients and comparatively low in fats can be considered a good choice for healthy consumers. An overview of multifunctional role of mulberry is shown in Fig. 1.
Based on the existing literature on the mulberry, it will be interesting to review the effectiveness of this multifunctional plant in attributing different functional properties, when being incorporated in several food products and to explore its nutraceutical applications and dermatological role with special emphasis on tyrosinase inhibition activity.
The current review attempted to provide a holistic insight into the nutraceutical potential of Morus in preventing various healthrelated issues and to investigate the possibilities of using mulberry as a functional food with some formulations and as a common ingredient in many cosmetics.

Botanical description of Morus
Mulberry is typically a deciduous or medium sized woody perennial tree having upright fissured bark and cylindrical stem with a milky sap growing upto 10-13 m tall (Singh et al., 2010, Rahman andKhanom, 2013). Leaves of mulberry vary in shape and size, usually range from 5 to 7.5 cm long and 6-10 cm wide and are mostly deeply lobed, margins serrate, shortly acuminate, apex acute or, base cordate or truncate; 3 basal nerves, lateral nerves forked near the margins. Flowers are yellowish green in colour with chromosome number 2n = 28. Female spikes are ovoid and stalked while as male spikes (catkins) are cylindrical and broad. Male catkins tend to be longer than female catkins. Botanically, mulberry fruit is precisely a cluster of small fruits that are organised longitudinally around the central axis similar to that in blackberry or loganberries. Its fruit or syncarp comprises of numerous drupes that are enclosed in a fleshy perianth, ovoid or sub globose, upto 5 cm long, white to pinkish white, purple or black when ripe (Anonymous, 2001). In terms of morphology and growth habits, mulberry ovary is unicellular with a bifid stigma and analogous to that of other fleshy drupaceous fruits. Scientific classification of Morus species is given in Fig. 2.

Dietary importance of Morus
Fully ripened mulberry fruit has a wonderful mouth-watering taste with a good aroma and flavour. It is appreciated for direct consumption and for making value-added products. Mulberry fruits are recognized for the well-being of human beings due to their high nutritional significance (Sengül et al., 2005). Additionally, mulberry fruits hold a diversity of nutrient elements that play a vital function in human metabolism (Akbulut and Özcan, 2009). M. alba fruit is a good resource of carbohydrate, lipid, protein, vitamins, minerals, and fibers. The quantity of protein in fresh M. alba fruit is greater than that of raspberries (Rao and Snyder, 2010)and strawberries (Giampieri et al., 2012)and comparable to blackberries, (Kaume et al., 2012)whereas the anthocyanin content is higher than blackberry, blueberry, blackcurrant, and redcurrant (Veberic et al., 2015). M. alba fruit contains both essential and non-essential amino acids. Essential amino acid /total amino acid ratio is 42 percent, which is almost equal to certain protein-rich foods such as fish and milk (Jiang and Nie, 2015). Hence, can be considered as an excellent protein source. Chemical structures of some important metabolites are given in Fig. 3. Each variety of Morus species contains a significant amount of vitamin C, however among all varieties M. nigra contains the maximum quantity. The ascorbic acid content in M. alba and M. nigra is 15.81 and 12.81 mg/100g, respectively of fresh fruit weight (Eyduran et al., 2015). Mulberries also contain some important alkaloids that acti-vate macrophages by stimulating the immune system and hence safe guard the human body against health threats . The most important alkaloids isolated from mulberry leaves are 1-deoxynojirimycin (DNJ),1,4-dideoxy-1,4-imino-D-ribitol, and 1,4-dideoxy-1,4-imino-D-arabinitol Li et al., 2011). Primary sugars present in mulberry are fructose and glucose, which increase with ripening (Gundogdu et al., 2011;Mahmood et al., 2012;Eyduran et al., 2015). Amongst the widely recognised varieties, M. alba has the maximum fat content of 1.10% followed by M. nigra with0.95% and M. rubrawith0.85%. Oleic acid, palmitic acid and linolenic acid are the major fatty acids in mulberry fruit (Ercisli and Orhan, 2007). The sequence of fatty acids in M. alba fruit is polyunsaturated fatty acids (PUFA) followed by monounsaturated fatty acid (MUFA) and saturated fatty acids. Among all fatty acids, PUFA is the main fatty acid in mulberry fruits comprising at least 76.68%, which is even higher than that of strawberries (Giampieri et al., 2012;San and Yildirim 2010). There are many organic acids present in mulberry fruits viz citric acid, tartaric acid, malic acid, succinic acid and fumaric acid however, malic acid is primarily found organic acid in all the species (Eyduran et al., 2015). Mulberry is also an excellent source of some important minerals particularly calcium, phosphorus, potassium, magnesium, and sodium. Nonetheless, the mineral content differs among phenotypes (Gungor and Sengul, 2008). Although M. alba, M. nigra and M. rubra belong to same genus however, there are still some differences in their physiochemical parameters. A comparative study of varied physiochemical parameters of mulberry varieties (M. alba, M. nigra and M. rubra) is given in Table 1.

Role of Morus in food industries
The understanding of the relationship between diet and health by customers has now acquired a profound shift in eating pattern and lifestyle transformation. The advent of this consumer understanding has been one of the driving forces in production of food products that can satisfy both basic dietary requirements and health benefits. Mulberry fruits are famous throughout the world for their mouth-watering taste that makes it suitable to consume either in fresh or as an ingredient in value-added products and for culinary uses. It has gained popularity due to consumer awareness and enthusiasm for healthy and low calories foods. This has led to increased demand in food processing industries. The role of mulberry in diverse food areas is mentioned in Table 2. Ripened mulberry fruits are harvested by slightly shaking trees (Singhal et al., 2010). Mulberry fruit is highly perishable making it underutilized, however, there is the scope of value addition by various means. It contains health-promoting polyphenols and is consumed directly or in processed product forms such as juices, syrups, liquors, molasses, jams, wines, and soft drinks. Mulberry fruits are among the berries that can be called as superfood and can be industrially explored for diverse commercially priceless valuable edible products. Several patents have been filed on Morus species for multiple therapeutic applications such as hypoglycaemic, neurodegenerative, hypolipidemic, compounds with anti-tyrosinase inhibition and some formulated value-added products as enlisted in Table 3.
Mulberry may be well exploited in fruit and vegetable industries for making, marmalade, fondant jams, jellies, cakes, breads, parathas, fruit teas, fruit drink pulp, fruit wine, fruit sauce, fruit powder, and chocolate, due to high sugar content. Moreover, these fruits are either used in dried, frozen, or fresh forms in the food industry to yield different syrups, amaretto or vermouth wine, tonic wine, and vinegar. Mulberry seeds can also yield oil. 'Pestil' and 'köme' are the famous traditional Turkish foods, which are prepared from a mulberry, walnut, hazelnut, honey, and flour mixture (Oktay, 2013;Sengül et al., 2005;Ercisli and Orhan 2007). Persian utilize mulberries for making jellies, desserts and sauces. Unripe and immature fruits are utilised for chutney preparations (Jalikopa et al., 2011). Pure and fresh mulberry fruit juice under cold storage environment remains fresh for a duration of three months and bottled juice can stay fresh at ambient temperature for a period of six months to a year. This mulberry juice aids in keeping healthy and smooth skin, prevents irritations, inflammations and throat infections, and has also has laxative properties (Buhroo et al., 2018). It is also used as medicine to reduce fever, cold, diarrhoea, endemic, malaria, and amoebiosis (Kumar and Chauhan, 2008). In China, mulberry is usually available in the form of a paste famous as sangshengao. This paste is dissolved in warm water to make tea that improves kidney and liver functions and enhances the vision and hearing. Chinese people also take young leaves and tender shoots of mulberry as vegetables in some specified regions. Iranian people utilize dehydrated mulberries as a sweetening agent in black tea.
Mulberry fruits can be used to make syrup due to their high sugar content. Mulberry syrup is widely consumed as processed mulberry products in Vietnam. In syrup production, usually fresh mulberry fruit is mixed with cane sugar in a ceramic or glass bottle and can be stored for at least 2 weeks (Quang Trung et al., 2018). Mulberry fruit powder prevents aging of the skin by disturbing the formation of free radicals in cells. It also manages good cholesterol in the human body and balances the absorption of carbohydrates (Liu et al., 2009). Mulberry wine, which is sweet and sour can be produced from over-ripened mulberry fruits (Feng et al., 2015). This functional wine aids in removing unwanted faecal impurities from the body and may help in making the body lean and function as medication to tonify the masculine weakness after diseases. Mulberry wine is well-known in Europe as a name lady's drink. In countries like Armenia, Azerbaijan, and Georgia, mulberry is a famous liquor known as Tut araghi. This drink is placed among the national Azerbaijani type of vodka and little quantity of it protects from stomach and cardiovascular diseases (Farid Alakbarli  M. alba fruit was used as raw material to brew fruit wine. Phenolics present in the wines were detected by HPLC Wang et al., 2015;Yadav et al., 2017;Kim et al., 2008 Sake Mulberry leaves were utilized for the production of sake or rice wine by fermentation with Mauri yeast and product was rich in nutrients, amino acids, and polyphenolics Tan and Li, 2013 Vinegar Vinegar produced from M. alba exhibited powerful antioxidant potential and showed anti-microbial effects Karaagac et al., 2016 Jelly Anthocyanin-rich jelly was developed by adding M. alba fruit containing anthocyanins. The consumption of formulated functional product resulted in a significant decrease in fasting blood cholesterol and LDL in dyslipidemia patients  , 2000). Mulberry fruit is a concentrated source of anthocyanins mainly cyanidin-3-glucoside (C3G) and cyanidin-3-rutinoside (C3R)that can be utilized as a natural colorant in food industries (Du et al., 2008;Aramwit et al., 2010;Zhang et al., 2011).
Recently, the effect of polyphenols in mulberry juice on the oxidation stability and functional properties of myofibrillary and sarcoplasmic proteins in dried minced pork slices during storage and processing was studied. Structural stability was improved to a greater extent by reducing protein aggregation, carbonyl accumulation, and transformation of SH group into S-S group in pork slices (Cheng et al., 2020). Similarly, mulberry extracts demonstrated a protective effect on protein oxidation of dried-minced pork slices (Cheng et al., 2018). Mulberry leaves can be incorporated into wheat flour to make paratha with different mix ratios.
The optimized mix has storage stability of two weeks at room temperature and does not exert any adverse effect on the growth of visceral organs of rats (Srivastava et al., 2003).
One of the special caffeine-free teas made from mulberry leaves is mulberry tea. It is popular in China, Thailand, Japan, and Korea, where it has been used in conventional medicine since ages. Itis famous for enhancing liver and kidney functions, sharpening hearing, and brightening the eyes. This tea also relieves cough, cold, and throat infections, and also inhibits cholesterol oxidation, thereby freeing the arteries from fat deposition, hence avoiding artery hardening (Yu et al., 2018). Because of its anti-diabetic and cholesterol-lowering properties, this functional tea is a very popular drink. In case of a throat infection, a decoction of leaves is often used as a gargle (Buhroo et al., 2018).
Nutritionists and health experts have recently placed M. alba tea in the list of superfoods especially in European countries (Natić et al., 2015;Krishna et al., 2020). Mulberry tea, particularly from M. alba, health benefits are largely due to its naturally occurring ingredient, DNJ. It holds anti-diabetic effects, due to its ability to decrease carbohydrate absorption and helps to regulate the level of blood sugar in diabetes. However, it is necessary to steep it for a suitable period to obtain as many of the benefits of mulberry tea as possible. Brewing of one gram of mulberry leaves in 100 ml of water for 3-5 min at 98°C will lead to effective inhibitory activity against certain enzymes such as maltase (Hansawasdi and Kawabata, 2006).
Thus, it is evident from the above studies that mulberry can be effectively used in the food and beverage industries as an interesting raw material being exceptionally rich in antioxidants with a strong nutritional profile.

Anti-tyrosinase properties of Morus for cosmetic application
Use of tyrosinase inhibitors is becoming increasingly important in the cosmetic industry due to their skin-whitening effects. Tyrosinase is a copper-containing primary regulatory multifunctional enzyme that is responsible for melanin biosynthesis and determines the colour of the skin and hence it can be used as a whitening agent. Excessive melanin deposition induces numerous dermatological disorders, such as melasma and age spots (Mukherjee et al., 2018). Roots and twigs of Morus could be utilized as promising natural agents to counteract tyrosinase activity in cosmetics given in Table4.
Most Asian countries use M. alba (leaves, fruits, root bark and branches) as an ingredient in cosmetics . In a study, ethanolic extract of M. alba fruit was utilized to develop an emulsion-based cream to study its clinical effect on skin melanin, erythema, and moisture content for eight weeks. The formulated cream significantly decreased melanin content without causing any type of skin irritation (Akhtar et al., 2012). In other research, betulinic acid (C 30 H 48 O 3 ) was isolated from M. alba (hexane extract of stem and root bark)which can be utilized as a whitening agent owing to its tyrosinase inhibitory activity (Nattapong and Omboon, 2008). Ethanolic extract of M. nigra exhibits excellent tyrosinase inhibition activity and also be utilised for the formulation of peel-off mask and for acne treatment (Budiman et al., 2017a;Budiman et al., 2019).
Mulberries can help to mitigate skin problems such as reduction in spots and blemishes appearing with age and inhibition of free radical linked oxidative activity thereby bestowing a healthier and shiny appearance to skin and hair. Hence from the above discourse, it is clear that different parts of Morus exhibit excellent tyrosinase inhibition activity, and hence can be included as a nec- essary component of cosmetic products and de-pigmentation agents for the treatment of hyperpigmented disorders.

Nutraceutical applications of Morus
Nutraceuticals have various therapeutic properties that are primarily due to their chemical structure, anti-oxidant, anti-diabetic, anti-hypertensive, hypo-cholesterolemic, anti-microbial, hepatoprotective properties, and many more. Some of the traditional formulations containing mulberry as an ingredient are listed in Table 5 and Table 6 summarizes some findings on nutraceutical applications of Morus plant. The current available literature on the nutraceutical ability of Morus species to improve human health and well-being is presented in this section.

Anti-microbial properties
To date, a significant amount of research related to the antimicrobial properties of natural plants and their associated components is reported. Compound viz chalcomoracin with antimicrobial activity against methicillin-resistant Staphylococcus aureus (S. aureus) was isolated from M. alba leaves (Fukai et al., 2005). In another study, hydro-methanolic extract of stem bark of M. alba exhibited anti-microbial activity against Enterococcus faecalis, (E. faecalis), Escherichia coli (E. coli) S. aureus, Staphylococcus epidermidis (S. epidermidis) and Salmonella typhimurium (S. typhimurium) (Thabti et al., 2014). Budiman et al. 2017b, reported that the ethanolic extract of M. nigra was effective and inhibited the growth of S. epidermidis and Propionibacterium acnes (P. acnes) bacteria. Morin an anti-bacterial compound was isolated from M. alba fruits by LH-20 column chromatography and the structure was elucidated by 13 C NMR and 1 H NMR spectroscopy. The isolated compound showed modest anti-bacterial activity against Streptococcus mutans (S. mutans) at 5 and 2 mg/disc .
Apart from leaves, fruits, stems, and bark of Morus varieties, value-added products from them also exhibited potential anti-microbial activities. M. nigra juice exhibited anti-microbial potential against bacteria Bacillus spizizenii (B. spizizenii) and Pseudomonas aeruginosa (P. aeruginosa) with an inhibition zone of 19.68 mm and 19.87 mm, respectively (Khalid et al., 2011). Vinegar produced from M. alba showed antibacterial effect against S. aureus, S. pyogenes, E. coli, E. faecalis, Erwinia carotovora (E. carotovora) Klebsiella oxytoca (K. oxytoca), Bacillus cereus (B. cereus) and Bacillus subtilis (B. subtilis), anti-fungal activities against Candida albicans (C. albicans). Among all bacteria, S. aureus (28 mm) followed by S. pyogenes (20.6 mm) exhibited the highest zone of inhibition while E. coli showed the lowest zone of inhibition 5.3 mm and for C. albicans 9.6 mm zone of inhibition was observed (Karaagac et al., 2016).

Anti-hyperglycaemic property
Diabetes mellitus (DM) is now considered the third most lifethreatening metabolic condition in the world, characterized by hyperglycaemia (high blood glucose levels) (Wang et al., 2013). There are more than 170 million people affected by this chronic disease globally and it is estimated to rise by 50 percent by the year 2030, with the highest increase forecasted in developing countries like Asia, Africa, and South America.
Various studies have reported the anti-diabetic properties of mulberry. The leaves of M. alba have been included in Chinese traditional medicine since a long time for treatment and prevention of diabetes due to the presence of functional chemical constituents that suppress raised blood sugar levels following a carbohydraterich meal (Miyahara et al., 2004). Polysaccharides in M. alba fruit hold excellent potential for anti-diabetic activity. A significant reduction in fasting serum insulin, homeostasis model of assessment-insulin resistance, fasting glucose level, glycated serum protein, and repairment of impaired pancreatic tissues of the diabetic rats was observed after seven weeks of treatment with M. alba fruit polysaccharides (two fractions)in wister rats (Jiao et al., 2017). Extracted DNJ appreciably decreased blood glucose and insulin levels, reversed insulin resistance, and enhanced serum lipid levels and in high fat diet-induced (HFD) diabetic Kunming mice (Hu et al., 2019). A single dose of M. alba leaves extract with a DNJ concentration of 3, 6, or 9 mg was given to subjects with fasting glucose levelsof100-140 mg/dL. Meanwhile, 6 mg of DNJ for twelve weeks was given to subjects with a fasting glucose level of 110-140 mg/dL. Long-term ingestion of DNJ rich M. alba leaves extract resulted in improved post-prandial glycemic control in patients with damaged glucose metabolism (Asai et al., 2011). Ingestion of diet containing M. alba extract repeatedly may maintain postprandial glucose levels. In a study after eight weeks of repeated ingestion of M. alba extract in KK-Ay mice, fasting plasma glucose (FPG) and insulin levels were measured and found an   appreciable reduction in insulin resistance, and the onset time of urinary glucose excretion was delayed (Tanabe et al., 2011).

Anti-hyperlipidemic activity
Obesity is defined as an unusual deposition of fat that extents risk to health. It is one of the serious concerns prevailing today across the globe as it increases the risk of diabetes, heart disease, and cancer. Beneficial phytoconstituents in mulberry has increased the attention of researchers to explore its best potential for antiobesity characteristics.
The effect of M. alba fruit on the lipid profile of humans in the age group of 30-60 years was studied. After consumption of M. alba fruit for six weeks at a dose of 45 g per day, a significant decrease in the total cholesterol (TC) and low-density lipoprotein (LDL) levels in blood was noted (Sirikanchanarod et al., 2016). Similarly, in another study, on oral administration of DNJ rich M. alba leaves extract at a dose of 12 mg three times per day before meals reduced the level of serum triglycerides (ST) and lipoproteins. DNJ, extracted from M. alba leaves when administered to diet-induced obese mice, was found beneficial for lowering down the levels of plasma triacylglycerol besides activating the b-oxidation system and reducing the lipid accumulation in the liver (Tsuduki et al., 2013). It may also reduce hyperlipidemia by moderating feeding behaviour and endoplasmic reticulum stress in the hypothalamus of mice with HFD obesity in C57BL/6J mice (Kim et al., 2017). Mulberry juice in combination with blueberry juice may aid in decreasing the blood cholesterol, resistance to insulin and leptin secretin attenuated lipid accumulation in HFD-induced obesity C57BL/6 mice (Wu et al., 2013). Isolated oxyresveratrol from M. alba wood monitored the degradation of fatty acids and hepatic lipogenesis to ameliorate non-alcoholic fatty liver fat in HFD mice (Lee et al., 2018). In another study, it was observed that administration of aqueous extract of M. alba fruit for twelve weeks in male Syrian golden hamsters resulted in lowered cholesterol, free fatty acid, and hepatic lipids (Peng et al., 2011).
Recently extract of leaves of M. alba fermented with 10% of Cordyceps militaris significantly stimulated the lipolysis of primary adipocytes at a suitable concentration and hence can be utilised as lipolytic agents to treat obesity (Lee et al., 2020).

Anti-inflammatory activity
The presence of microorganisms (bacteria, viruses, and fungi) in specific tissues and their circulation in the blood can cause one of the complex vascular biological responses called inflammation. It can damage the body if not regulated after a certain period and may cause some chronic diseases like rheumatoid arthritis, cardiovascular diseases, and cancers. Studies have highlighted that regular consumption of natural plants with antiinflammatory activities can help in the treatment of acute chronic inflammation.
Recently novel extraction technique, high hydrostatic pressure was employed as an extraction method in M. alba. High hydrostatic pressure extracts inhibited in vitro release of nitric oxide (NO) and messenger ribonucleic acid (mRNA) expression of nitric oxide synthase 2(NOS2) and reduction of cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-a, which are associated with inflammation in lipopolysaccharide (LPS)-induced RAW264.7 cells (Jung et al., 2019). Similarly, methanolic extract of M. alba root bark blocked NO production through suppressing inducible nitric oxide synthase (iNOS)over-expression in LPS-stimulated RAW264.7 cells (Eo et al., 2014).
Ethanolic extract of M. alba leaves effectively reduces proinflammatory mediators and cytokine production by modulating the LPS-induced activation of macrophage cells by suppressing nuclear factor-jB (NF-jB) activation (Park et al., 2013). Ethanolic extract of stem of M. alba at a concentration of 20 and 40 mg/ml show anti-inflammatory activity in LPS-stimulated RAW264.7 macrophage cell line by inhibition of NO production via suppression of both the protein and iNOS mRNA.
Anthocyanins in M. nigra fruits have been reported to have antiinflammatory activity. C3G and C3R exert an anti-inflammatory effect through inhibition of pro-inflammatory cytokine in xyleneinduced ear edema and carrageenan-induced paw edema in mice . Aqueous extract of M. alba root has strong anti-histamine and anti-allergic activity by inhibiting compound 48/80-induced systemic allergic reaction and histamine release in vitro and in vivo. Mast cell-mediated type allergic reactions are also inhibited by the root extract of M. alba (Chai et al., 2005). Hence, Morus species can be a budding natural source of antiinflammatory drugs.

Anti-cancer action
Cancer, with different forms, is believed as one of the primary fatal diseases prevailing globally and the rate is surpassing with a good number. Recently, many types of cancers have been considered to be among the group of diseases that are common reason for death. Many medications are available in the market to treat different forms of cancer, but successful and safe drugs are rarely available. As compared to synthetic and semi-synthetic compounds, naturally occurring bioactive compounds particularly phenolic compounds are less toxic and safer (Habauzit and Morand, 2012).
Many naturally occurring substances exert their anti-cancer activity through apoptosis of tumor cells and by arresting the cell cycle, which is thought to be the best way to avoid or fight irregular cell growth (Dewanjee et al., 2017). Detailed mechanism of anticancer activity of Morus species is mentioned in Fig. 4. Traditionally, medicine value of the mulberry plant is known to humans from the earliest ages. Clinically, mulberry plant has the potential of inhibition of cell proliferation most likely due to the presence of flavonoids that are highly effective against certain types of cancers. Some studies reported the role of mulberry in cancer prevention in animal models. Purified anti-proliferative lectin from M. alba leaves induced cell death through apoptosis in human breast cancer (MCF-7) and colon cancer (HCT-15) cells by inducing essential morphological changes and DNA fragmentation related to apoptosis (Deepa et al., 2012). The root bark of M. alba contains flavanone glycoside, 5,2 0 -d i-hydroxyflavanone-7,4 0 -di-O-b-D-glucoside (steppogenin-7,4 0 -di-O-b-D-glucoside) has anti-proliferation activity against HO-8910 cells in human ovarian cancer (Zhang et al., 2009).

Neurodegenerative actions
Plants play an important role in treating cognitive disorders. Many medicinal plants exhibit an essential role in the treatment and prevention of numerous neuronal dysfunctions and neurodegenerative diseases. There are numerous studies reported on natural medicinal plants where the isolated bioactive constituents such as polyphenolics and alkaloids can considerably delay neurodegeneration and may improve cognitive function and memory (Mohebbati et al., 2017). Lyophilised ethanolic extract of mulberry fruit protects neuronal cells against oxidative stress-induced apoptosis through the enhancement of production of antioxidant enzymes and brain-derived neurotrophic factor formation by stabilizing the activation of the TrkB/Akt pathway in swiss CD-1 mice (Shin et al., 2019).
The role of antioxidants in M. alba fruits is well documented in many studies. Non-anthocyanins in M. alba fruit like rutin and quercetin have neuroprotective effects besides having multibioactive functions (Shih et al., 2010;Isabelle et al., 2008;Zhang et al., 2009). These non-anthocyanins have an impact on Parkinson's disease (PD) models. Effect of ethanolic extract of M. alba fruit in in vitro and in vivo models of PD was studied on dopaminergic neuron protection using the SH-SY5Y neuroblastoma stressed with 6-hydroxydopamine (6-OHDA) and mesencephalic dopamine neurons stressed with 6-OHDA and 1-methyl-4-phenylpyridinium (MPPþ). The effect of the same extract was also studied on in vivo models, where PD was induced by 1-methyl-4-phenyl-1,2, 3,6-tetra-hydropyridine (MPTP). Symptoms of PD like bradykinesia and MPTP-induced dopaminergic neuronal damage in an immunocytochemical analysis of the substantia nigra pars compacta (SNpc) and striatum (ST) was prevented (Kim et al., 2010).

Miscellaneous activities of Morus species
In traditional medicine, the usage of M. alba is credited toits excellent diuretic properties, which are mainly owed to the free radical scavenging attribute. A mixture made of M. alba fruit (ethanolic extract) and gentamicin with a dosage of 200 mg/kg/day and 80 mg/kg/day, respectively for three weeks controlled the serum uric acid, creatinine, blood urea nitrogen content in rabbits (Ullah et al., 2016). Mulberroside A (stilbene glycoside) from twigs of M. alba at 10, 20, and 40 mg/kg significantly treated renal dysfunction by suppressing the elevated protein and mRNA levels of renal glucose transporter 9(mGLUT9) and urate transporter 1 (mURAT1) in hyperuricemia mice . Morusinol a flavonoid extracted from the root bark of M. alba may significantly inhibit arterial thrombosis that was recently studied for cardiovascular potential . The alcoholic extract of M. alba leaves showed hepatoprotective effect against hepatotoxicity induced by carbon tetrachloride and paracetamol in Swiss albino mice (Hogade et al., 2010). M. alba juice is helpful in the prevention of food-borne viral infection (norovirus infection) by inhibiting the internalization and replication of murine norovirus-1 (MNV-1), wherein it may affect the adherence or internalization of feline calicivirus-F9 (FCV-F9) virions . M. alba juice may also induce anti-stress activity in Balb/c mice through a mechanism of radical scavenging activity (Sakagami et al., 2006).
From current scientific studies, it can therefore be inferred that mulberry exhibits substantial antioxidant capacity in vitro and in vivo, making them promising nutraceuticals.

Conclusion
Natural products are now being re-emphasized in order to address a variety of health issues. The correlation between health and diet is well established, and consumers are becoming more conscious of their eating habits. Investigating these connections has resulted in the creation of functional, nutraceuticals, and pharma foods, which are now dominating the global nutrition market. The current review intended to highlight the significance and application of Morus species in different areas and it becomes amply clear from the above discourse that mulberry is a versatile medicinal plant with enormous vitality. Recent approaches regarding the functional applications revealed that Morus species and their bioactive phytochemicals display a wide variety of biomedical activities, including antioxidants, anti-diabetic, hypo-lipidemic, anti-obesity, antihypertensive, and anti-atherosclerosis, etc. Morus extracts or their constituents particularly flavonoids like chlorogenic acid, quercetin, rutin and isoquercitrin scavenge free radicals exhibiting potential against oxidative stress. Alkaloids like DNJ and fagomine present in M. alba exhibit potential glucosidase inhibition. Compounds like moracin, morusin, kuwanon isolated from wood and stem bark of M. nigra exhibit anti-microbial activity. Tyrosinase inhibition properties of Morus species are comparable to kojic acid that makes it a wonderful ingredient in cosmetics. Chemical compounds like maclurin and morin, mulberroside F, oxyresveratrol and austraone isolated from different parts of M. alba exhibit potential tyrosinase inhibition activity. In addition to its exceptional usage as a nutraceutical in the pharmaceutical industry, it is often used in food industries because of the power source of anthocyanins that exhibit strong antioxidant properties and are used as a natural colouring agent. Being low in calories, this plant can be utilised in the formulation of hypocaloric foodstuffs and can be added as a novel ingredient to enhance the functional properties of existing foods. Value added products like jam, jelly, wine, vinegar, tea, syrup, squash and many more are formulated from Morus that aids industrialists for effective utilization of its fruits and leaves. Additionally mulberry is among the major ingredients in many traditional formulations sold worldwide. Chemical composition of mulberry is already extensively studied, there are still some unidentified biological compounds that require proper exploration. It is necessary, however, to investigate the metabolites produced in vivo and how they exert their biological effects in future studies.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.