Phenolic Antioxidants of Morus Nigra Roots, and Antitumor Potential of Morusin
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by SZTE Publicatio Repozitórium - SZTE - Repository of Publications Phytochem Rev (2018) 17:1031–1045 https://doi.org/10.1007/s11101-018-9565-1 (0123456789().,-volV)(0123456789().,-volV) Phenolic antioxidants of Morus nigra roots, and antitumor potential of morusin Zoofishan Zoofishan . Judit Hohmann . Attila Hunyadi Received: 8 January 2018 / Accepted: 25 March 2018 / Published online: 31 March 2018 Ó Springer Science+Business Media B.V., part of Springer Nature 2018 Abstract Phenolic compounds are of considerable Keywords Anticancer activity of prenylflavone Á biomedical interest due to their antioxidant properties Black mulberry root bark Á Cancer stem cell Á and potential in the prevention and possibly treatment Ethnopharmacology Á In vivo antioxidant activity of many chronic diseases. The fruits, leaves and root bark of Morus nigra (Moraceae), the black mulberry tree, have a long history of use for various therapeutic purposes in traditional medicine worldwide. The roots Introduction of the plant are known to be a rich source of phenolic compounds with a particularly high chemical diver- The Morus genus, belonging to the Moraceae family, sity. This mini-review compiles the currently available comprises of twenty-four species with one subspecies, knowledge on phenolic compounds reported from and has ca. one hundred known varieties to date Morus nigra roots, and provides a brief overview on (Ercisli and Orhan 2007; Hojjatpanah et al. 2011). the antioxidant activity with a focus on the available Well known as the ‘‘black mulberry tree’’, Morus in vivo evidence. Morusin, a major phenolic antiox- nigra L. has long been valued for its fruit, which has idant of the root bark, has attracted a rapidly increasing also been claimed as a ‘‘super fruit’’ that has various scientific interest for its versatile and potent antitumor health benefits and promotes longevity (Bircher and properties; recent developments in this regard, includ- Bircher 2000). Morus nigra is a wildly growing rustic ing morusin’s promising activity against cancer stem plant that is also present in many gardens and, cells, are also discussed in the paper. similarly to other Morus species and M. alba in particular, it was also used for sericulture (Hanelt et al. 2001; Orwa et al. 2009). Morus nigra often produces leaves of different shapes, and these multilobed leaves can appear on the same branches. The fruit is blackberry-shaped and typically black but sometimes & Z. Zoofishan Á J. Hohmann Á A. Hunyadi ( ) dark blue in color, with a sweet taste. Despite popular Faculty of Pharmacy, Institute of Pharmacognosy, University of Szeged, Eo¨tvo¨s u. 6, H-6720 Szeged, belief, the color of the fruit alone does not determine Hungary the mulberry species; instead, the leaves and wood e-mail: [email protected] characteristics should be taken into account for an exact identification (Orwa et al. 2009). J. Hohmann Á A. Hunyadi Interdisciplinary Centre of Natural Products, University of The plant has a long and remarkable history. Likely Szeged, Szeged, Hungary introduced to Europe originally from Persia, its 123 1032 Phytochem Rev (2018) 17:1031–1045 cultivation on the Continent appears to date back and bark of black mulberry are known folk remedy for thousands of years (Huxley and Taylor 1989). The diabetes, arthritis, and hypertension, and as diuretics ancient Greeks dedicated the fruit to Minerva, the (Abbas et al. 2014; Ribeiro et al. 2017). The root bark goddess of wisdom. Black mulberry was abundant in has anthelmintic activity, and it is also used to treat Italy during the Roman era; it was also depicted in the bronchitis (Mohiuddin et al. 2011), as well as a paintings from Pompeii (Georgics ii verse 121; purgative agent (Hanif and Singh 2012). The roots of Schreiber 1958). Mulberry has also been acknowl- M. nigra contain an outstandingly rich variety of edged in the Bible (I Maccabees 6:34; Luke 17:5-6). phenolic compounds, which compound family is Black mulberry leaves were considered as the feed for likely among the most important constituents related Italian silkworms until 1434 when Morus alba was to the therapeutic benefits associated with traditional introduced from the Levantine lands (Vivarelli and preparations (Manach et al. 1997). Alvisi 1934). During the ‘‘silk revolution’’ in 1608, the The chemistry and pharmacology of Morus species, practice of sericulture was introduced to Britain by and particularly of M. alba, served as the basis of promoting mulberry cultivation (Grieve 1931). several recent reviews (e.g. Chan et al. 2016; Hussain Although its medicinal use was an ancient practice, et al. 2017; Yaun and Zhao 2017), indicating well the it was the growing silk industry that brought this plant very high current scientific interest in these plants. into the spotlight, resulting in the worldwide spreading Bioactive constituents of Sang-Bai-Pi, root bark of of mulberry trees to satisfy industrial needs for various Morus plants, have recently been reviewed mulberry leaves (Lev 2002). Despite black mulberry from a general point of view (Wei et al. 2016). In the is in fact more nutritive than Morus alba, the white present paper, we aim to set a more specific focus on mulberry (Venkatesh and Chauhan 2008), its impor- (i) the phenolic compounds isolated from the roots of tance has finally been surpassed by that because of its M. nigra, (ii) the in vivo evidence supporting their weaker success in feeding silkworms. The nutritive antioxidant activity, and (iii) the antitumor activity of richness of black mulberry, however, still makes it an morusin, a new ‘‘rising star’’ among the major excellent animal feed that also enhances the milk yield phenolic antioxidants of M. nigra root bark. of dairy animals (Dillard and Bruce German 2000). The root bark of M. nigra also plays an important economical role through its use to prepare ‘artificial Phenolic composition of Morus nigra cotton’ textile fiber, paper and clothes (Hanelt et al. 2001; Lim 2012). Besides its use as livelihood, the All Morus species are known as rich sources of long history of Morus nigra includes its therapeutic phenolic compounds including flavonoids, stilbenes, use in practically every era of traditional medicine, 2-arylbenzopyrans, and a variety of Diels–Alder under different names, and with various, frequently adducts (Nomura 1988; Nomura and Hano 1994), different uses in each system (Leonti et al. 2015). and, according to many comparative studies, M. nigra Ancient Egyptians used the plant preparations for appears to be the richest of all in this regard (Ercisli corroding ulcers and dispersing inflamed tumors, and and Orhan 2007; Wang et al. 2007; Ercisli et al. 2009; the bark juice was an antidote to the venom of deadly Arfan et al. 2012). As an example, a comparison with snakes (Pliny the Elder 2015). Morus nigra has been M. alba revealed that M. nigra has a higher content of used in Ayurveda, one of the oldest holistic healing reduced ascorbic acid, titratable acidity, iron, total systems dating ca. 600 B.C. Many M. nigra formula- flavonoids and total monomeric anthocyanins (Jiang tions are still in use in Ayurvedic medicine, e.g. and Nie 2015). against cancer (Tut-i-aswad, containing the fruits) Flavonoids have a remarkable chemical diversity (Ahmad et al. 1985), and for treating sore throat or not only due to their variability in hydroxylation/ laryngitis (Rub-e-toot siyah, containing the root bark) methoxylation pattern, but mainly due to the many (Khare 2010). The roots of Morus plants were possibilities for being further substituted with sugars, recorded in the Chinese pharmacopeia in 500 B.C. prenyl and geranyl groups, esterified with organic collectively known as sang-Bi-Pi often used for acids, etc., and many of these substituents open treating lung heat, cough, edema, and oliguria (Phar- possibilities to further cyclization. In particular, the macopoeia Committee of P. R. China 2010). The roots root bark of Morus nigra contains a remarkable variety 123 Phytochem Rev (2018) 17:1031–1045 1033 of prenylflavonoids (Ferrari et al. 1999, Wang et al. Diels–Alder type adducts 2007, 2008, 2009, Zheng et al. 2010, De Souza et al. 2000, Simonetti et al. 2017, Zelova et al. 2014), as The [4 ? 2]-Cycloaddition of a conjugated diene and presented in Fig. 1. Interestingly, phenolic compounds a dienophile to form a six-membered ring is a well- isolated from the roots of Morus nigra L. showed known Diels–Alder reaction. Many of these classical remarkable differences as compared to those biosyn- compounds are known to occur in the Morus genus, thesized by cell culture of plant, based on a compar- and an immense variety of Diels–Alder type adducts ative study of Ferrari et al. (1999). From the roots, the have so far been reported from the roots of M. nigra,as flavonoids Kuwanon U, Cyclomorusin, Morusin summarized in Fig. 4. Kuwanol E isolated from the hydroperoxide, Morusin, Kuwanon C, Kuwanon E, roots was found to be potent inhibitor of Mycobac- Morusinol, Norartocarpetin and seven Diels–Alder terium tuberculosis protein tyrosine phosphatase B type adducts (Albanol B, Kuwanon O, Kuwanon H, (Mascarello et al. 2013, 2016). Recently, a similar Kuwanon G, Albafuran C, Kuwanon L, and Morace- testing of other constituents of Morus nigra roots, nin D) were isolated. In contrast to this, the callus gave namely Cudraflavanone A, Morusin, Oxyresveratrol, 4-hydroxyisocordoin, oxyresveratrol, resveratrol, and Chalcomoracin, Norartocarpetin, Kuwanon L, Kuwa- six Diels–Alder type adducts (Kuwanon V, Mulber- non G, and Kuwanon H revealed the latter two rofuran E, Kuwanon R, Kuwanon J, Chalcomoracin, compounds as particularly potent inhibitors of above and Kuwanol E). Above the remarkable lack of enzyme of Mycobacterium tuberculosis (Mascarello compounds isolated from both sources, significant et al.