Phytochemicals and potential health effects of Sambucus williamsii Hance (Jiegumu)

Sambucus williamsii Hance (Jiegumu) is traditionally used in Chinese medicine to treat bone and joint diseases. The major phytochemicals in S. williamsii are lignans, terpenoids, and phenolic acids, together with trace amounts of essential oils, minerals, amino acids, and natural pigments. In this review, a database search for studies published from 1990 to November 2015 was conducted using PubMed, the China Academic Journals Full-Text Database, and Google Scholar with the keywords “Sambucus williamsii Hance”, “Sambucus williamsii”, “Sambucuswilliamsii + clinic”, “Sambucuswilliamsii + biology”, “Sambucuswilliamsii + chemicals”, and “Jiegumu”, which covered chemical studies, cell culture studies, animal experiments, and clinical studies. This article reviewed the compounds isolated from S. williamsii that may reduce the risk of cancer, and exert antifungal, antioxidant, anti-inflammatory, bone fracture healing, and antiosteoporotic effects. Electronic supplementary material The online version of this article (doi:10.1186/s13020-016-0106-9) contains supplementary material, which is available to authorized users.

comparisons, based on nucleotide sequences of the internally transcribed spacer region of nuclear ribosomal DNA, preliminary morphology, and a combination of the two data sets [13]. The family was reported to comprise at least 115 species and a large number of subspecific taxa [14,15]. However, a recent revision by Bolli [16] recognized only nine species, with the remainder being synonymized or reduced to subspecific ranks. In China, there are five naturally occurring species within the Sambucus Linn. genus: S. williamsii and its varieties var. williamsii and var. miquelii (Nakai), Sambucus adnata Wall. (Xuemancao), Sambucus sibirica Nakai (Xiboliya Jiegumu) and Sambucus chinensis Lindl. (Jiegucao); and one introduced variety, Sambucus nigra Linn. (Xiyang Jiegumu) [17].
Sambucus williamsii is a shrub or small tree growing to a height of 5-6 m (Fig. 2a) that is widely distributed in northeastern China. The aging branches become reddish-brown and exhibit narrowly elliptic lenticels on their surface (Fig. 2b). The leaves are imparipinnate with 2-or 3-jugate leaflets, which are ovate-orbicular or narrowly elliptic at 5-15 × 1.2-7 cm, and irregularly serrate margins (Fig. 2c). The stems terminate in a cymose panicle of 5-11 × 4-14 cm in diameter, with numerous white or yellowish flowers (Fig. 2d). The fruit is a small glossy red berry of 3-5 mm in diameter (Fig. 2e). Sambucus williamsii flowers from April to May, and the seeds ripen from September to October. The plant is mostly located along mountain slopes, scrub, stream sides, and roadsides at altitudes of 540-1600 m, and has high environmental adaptability [1,17].
An extract of the stem prevented reductions in bone mass and bone strength induced by estrogen deficiency in ovariectomized (OVX) rats and mice [25][26][27], increased proliferation and differentiation of UMR-106 cells [4,5,30,46], and induced differentiation of pluripotent stem cells into neurons [47]. A stem extract of S. williamsii exerted beneficial effects on the microarchitecture of trabecular bone and inhibitory effects on urinary calcium excretion in OVX mice by upregulating the ratio of osteoprotegerin to receptor activator of nuclear factor-κB ligand expression in bone obtained from OVX mice [26]. The stem extract exerted free radical-scavenging properties [23], reversed damage to the function of INS-1E β cells induced by alloxan, and increased insulin excretion [24], while the stem bark extract showed antifungal activities by damaging the fungal plasma membrane [2,3,22,48]. The root bark extract exerted healing effects on rabbit bone fractures [6,31,34], inhibitory effects on xylene-induced mouse ear edema and carrageenan-induced rat paw edema, and analgesic properties in rats and mice [33]. A mechanistic study showed that an ethanol extract of the root bark promoted MC3T3-E1 cell proliferation and differentiation through the bone morphogenetic protein 2/Smad/p38/c-Jun N-terminal kinase/runt-related transcription factor 2 signaling pathway [35]. The fruit oil exhibited immune-boosting [36], anticancer [38], and memory-improving [39] effects in mice, and antihyperlipidemic [37,40] and antiaging [37] effects in rats. Furthermore, the leaves extract exhibited antibacterial [44] and anti-inflammatory [45] effects. The details of the bioactivities and chemical components in various parts of S. williamsii are listed in Additional file 1 [2-7, 20-34, 36-67].

Health effects of lignans
These biphenolic compounds have similar structures to estrogens. They are the major source of phytoestrogens in the diets of Western populations and are primarily found in fiber-rich foods such as seeds, grains, vegetables, and fruits [70].
In the human gut, plant lignans are converted by intestinal bacteria into two enterolignans, enterolactone (ENL) and enterodiol (END), that exhibit biological activities and are absorbed into the bloodstream [71,72]. Lignans also exhibit antiosteoporotic and antifungal effects [3] and can reduce the risk of cancer [73].

Osteoprotective effects
The potential therapeutic effects of S. williamsii on postmenopausal osteoporosis in animal models and their underlying mechanisms of action [25][26][27] have been investigated. The active compounds with potential osteoprotective effects were identified by biological assayguided fractionation [27,46,74]. Specifically, an ethanol extract of the stem of S. williamsii exhibited protective effects on trabecular bone mass and mechanical strength of cortical bone in OVX rats fed a normal diet and mice fed a phytoestrogen-free AIN-93M diet [25,26]. Moreover, the chemicals including lignans, phenolic acids and triterpenoids in the ethanol extract of S. williamsii stem stimulated osteogenesis by promoting osteoblastic proliferation and differentiation [25,27,46,68].
A combination of 50 and 95 % aqueous ethanolic fractions from a crude extract of S. williamsii stem purified on a reverse-phase macroporous resin column was the mixture exhibiting the most potent antiosteoporotic activity [27]. Further isolation of the S. williamsii active fraction by a series of chromatography steps and preparative highperformance liquid chromatography led to the separation and identification of 55 lignans [27,28,46,49,63].

Anticancer activity
Several studies [76,77] showed that increased dietary lignan intake and/or increased levels of ENL and/or END might protect against or reduce the risk of breast, colon, and prostate cancers, and reduce hair loss. Lignans and their related metabolites were believed to be partly responsible for the growth inhibition of human prostate cancer cell lines [77]. ENL and END significantly inhibited the growth of prostate cancer PC-3 and LNCaP cells with 50 % inhibitive concentration at 57 and 100 μM respectively [77]. Treatment of human colon cancer SW480 cells with ENL and END, either alone or in combination, resulted in dose-and time-dependent decreases in cell number [78].
The administration of plant lignans, which were further metabolized to ENL and END, inhibited or delayed the onset of mammary cancer [71]. Although the mechanism of the anticarcinogenic action of ENL is not yet fully understood, there is intriguing evidence for ENL as a modulator of estrogen signaling [71]. Consumption of lignans such as lariciresinol (11) and pinoresinol (1) was associated with a significant reduction in breast cancer risk according to the clinical results of premenopausal women in Mexico [79].

Health benefits of phenolic acids
Vanillic acid (61) exerts estrogen-like actions in osteoblastic-like cells through a nongenomic estrogen receptor signaling pathway involving the mitogen-activated protein kinase pathway [80]. The compound also exhibits antibacterial [81] and antimicrobial [82] activities and chemopreventive effects in experimentally induced carcinogenesis [83]. The protective effects of vanillic acid on myocardial infarction were studied in isoproterenol-induced cardiotoxic rats [84]. The free radicalscavenging, antioxidant, and anti-inflammatory activities of vanillic acid reduced isoproterenol-induced oxidative stress, downregulated myocardial interleukin-1β, interleukin-6, and tumor necrosis factor-α gene expression, and inhibited inflammation, thereby preventing cell death and protecting the myocardium [84].
Ferulic acid (64) possesses high antioxidant capacity and exhibits a longer residence time in rats than vitamin C [85]. Ferulic acid exhibits a wide range of therapeutic effects against many chronic conditions, including inflammation, cancer, apoptosis, diabetes, cardiovascular diseases, and neurodegenerative diseases [86]. It may also assist in plant host defense against pathogens and pests [87].
Protocatechuic acid (68) is an effective agent in reducing the carcinogenic actions of diethyl nitrosamine in the liver [88], 4-nitroquinoline-l-oxide in the oral cavity [89], azoxymethane in the colon [90], N-methyl-N-nitrosourea in the glandular stomach tissue [91], and N-butyl-N-(4hydroxybutyl) nitrosamine in the bladder [92]. Protocatechuic acid also exhibits protective effects against the oxidative damage induced by tert-butyl hydroperoxide in rat primary hepatocytes by quenching free radicals [93]. Syringaldehyde (65) has six times higher antioxidant activity than protocatechuic acid [94]. Furthermore, syringaldehyde exerts antifungal activity against Candida guilliermondii [95], and exhibits antioncogenic activity through its inhibitory actions on murine pulmonary and hepatic microsomes [96]. Syringaldehyde shows stimulatory effects on both proliferation and alkaline phosphatase activity in UMR-106 cells [5]. 4-Hydroxybenzoic acid (67) exerts a hypoglycemic effect and increases serum insulin levels and liver glycogen contents in normal rats after oral administration at 5 mg/kg [97].

Health benefits of aliphatic compounds
Linoleic acid (103) extracted from S. williamsii seed oil with a yield of 65.81 % possesses antioxidant, antiglycemic, and hypolipidemic activities [7]. It exerts free radicalscavenging activity at 61.9 mg/mL, inhibits the activity of α-glucosidase at 1.5-25 mg/mL, and significantly improves serum lipid levels in hyperlipidemic mice [7].
Saturated aliphatic compounds are known to have harmful effects on human health, but only trace amounts of  [104,105] and causes cardiac cells to undergo apoptosis [106]. It also causes insulin resistance in the brain by impairing the ability of insulin to activate intracellular signaling pathways [107], and accelerates obesity with diets containing high amounts of hexadecanoic acid [107].

Other compounds
Fifty essential oils in S. williamsii were extracted by steam distillation and identified by gas chromatographymass spectrometry, as listed in Table 1. Among them, cis-3-hexenyl-3-methylbutanoate and salicylic acid methyl ester were the major components [60].

Conclusions
This article reviewed the phytochemicals identified from S. williamsii, together with their biological activities and potential health benefits. Although several biological activities were ascribed to S. williamsii, the most important beneficial effects identified to date, based on