Background

Cornus officinalis Sieb. et Zucc., commonly known as Shan Zhu Yu/山茱萸 (in Chinese), Asiatic Dogwood, and Japanese Cornel Dogwood, is a deciduous shrub or dungarunga in the genus Cornus (family Cornaceae). It is a heliophilous plant that grows in the warm-temperate zone. The most suitable growth temperature is between 20 and 30 °C, it also has a specific cold resistance that can temporarily grow in − 18 °C low-temperature zone. Cornus officinalis Sieb. et Zucc. can be found in Anhui, Gansu, Jiangsu, Jiangxi, Shandong, Shanxi in China, Korea, and Japan. It usually grows in 400–1500 m high mountain slope, forest or forest edge. Ripening fruits are picked during September and October and dried in the air for medical uses [1, 2].

About 2200 years ago, Cornus officinalis Sieb. et Zucc. fructus (usually known as Corni Fructus) was first recorded in Shen Nong’s Materia Medica (Fig. 1). According to the basic theory of TCM, CF is characterized as replenishing liver and kidney, arresting seminal emission and sweat for its sour, astringent, and tepid properties [1]. It is used to treat four series of clinical symptoms. The first part of symptoms contains vertigo, tinnitus, weakness of the waist and knees which are caused by liver and kidney deficiency. CF is usually combined with Radix Rehmanniae Praeparata, Dioscoreae Rhizoma, Alismatis Rhizoma, Moutan Cortex, Poria to make Liuwei Dihuang Wan (六味地黄丸) replenish liver and kidney Yin [3]. For patients with kidney Yang deficiency, CF helps Cinnamomi Cortex, Aconiti Lateralis Radix Praeparata to reinforce Yang from Yin, e.g., Jingui Shenqi Wan (金匮肾气丸) [4]. The second part of symptoms contains spermatorrhoea and polydipsia. For patients with kidney deficiency, CF is frequently used with Radix Rehmanniae Praeparata, Dioscoreae Rhizoma, Cervi Cornu Pantotrichum, Psoraleae Fructus. For patients with dysfunction of the urinary bladder, CF is often applied with Mantidis Oötheca, Rubi Fructus, Rosae Laevigatae Fructus. The third part of symptom contains hypermenorrhea. CF is usually combined with Radix Rehmanniae Praeparata, Angelica Sinensis, Radix Paeoniae Alba to make Guchong Tang (固冲汤) preserve Primordial Qi and stop Blood [5]. The fourth part of symptoms contains profuse cold sweating, pale complexion, cold limbs, and a feeble pulse. For patients with the Yang depletion syndrome, Ginseng Radix et Rhizoma, Aconiti Lateralis Radix Praeparata, and CF are applied in Laifu Tang (来复汤) to restore Yang from collapse. Medical practices indicate that CF can be combined with either Yin-tonifying or Yang-invigorating herbs to act as the sovereign drug or adjuvant drug in Chinese medicinal formulae and treat different types of TCM syndromes. Besides, CF is primarily made into the honey bolus to treat chronic diseases while is usually made into the decoction to treat acute conditions.

Fig. 1
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Corni Fructus: a crude fruits, b processed fruits

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Chemical constituents

About 90 compounds have been isolated and identified from CF, including terpenoids, flavonoids, tannins, polysaccharides, phenylpropanoids, sterols, carboxylic acids, furans, and mineral substances. Chemical constituents are listed in Table 1. Among them, iridoids, tannins, and flavonoids are the major components. Their chemical structures are shown in Figs. 2, 3, 4 and 5.

Table 1 Chemical constituents identified from CF
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Fig. 2
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Structures of chemical constituents from Corni Fructus

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Fig. 3
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Structures of chemical constituents from Corni Fructus

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Fig. 4
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Structures of chemical constituents from Corni Fructus

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Fig. 5
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Structures of chemical constituents from Corni Fructus

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Terpenoids (1–26) and flavonoids (27–39)

Most terpenoids and flavonoids in CF shared two similar isolation processes. Firstly, CF was percolated with ethanol to acquire the solvent which was then evaporated under reduced pressure. The resulting extract was suspended in water and then partitioned with ethyl acetate for several times. Finally, the extract was subjected to column chromatography over silica gel to yield compounds. Secondly, CF was grounded into powder and then subjected to supercritical carbon dioxide to yield extract. The resulting extract was subjected to GC–MS to identify the chemical components. So far, 26 terpenoids and 13 flavonoids have been isolated and identified from CF. Among terpenoids, the pharmacological activities of sweroside (1), loganin (5), cornuside (23), ursolic acid (24), and oleanolic acid (25) have been further assayed, and a wide range of pharmacological activities has been revealed. Furthermore, two types of flavonoids namely kaempferol (28), quercetin (33), and their derivatives are the essential flavonoids.

Tannins (40–69)

During the isolation process, CF was firstly homogenized in acetone and then filtered to acquire an aqueous solution which was sequentially extracted with diethyl ether and ethyl acetate. The extract was subjected to column chromatography to give compounds. Finally, the chemical structure and molecular weight were determined using nuclear magnetic resonance (NMR) spectroscopy. To date, 30 tannic acids have been isolated from CF. Tsutomu HATANO identified 28 of them. Many tannic acids in this Chinese herb have the large molecular weight, e.g., the molecular weight of Cornusiins A–F and Camptothins A–B are even larger than 1000 Da [6, 7], because dimers and trimers exist in these types of tannic acids.

Polysaccharides (70–79)

Wu and Yin identified most polysaccharides in CF [8, 9]. In their isolation process, hot water or petroleum ether was initially used for combining with assistant ultrasonic and microwave to break the cell wall to isolate polysaccharides. Further separation and purification were achieved by the combination of several techniques, e.g., fractional precipitation, ethanol precipitation, ion-exchange chromatography and affinity chromatography. Finally, infrared spectroscopy analysis and morphological analysis were used to determine the physiochemical and structural features of the polysaccharide.

Other compounds (80–93)

Four phenylpropanoids, two sterols, five carboxylic acids, two furans, and several mineral substances have also been determined. Among them, 5-hydroxymethylfurfural exhibits diverse biological activities. Besides, Chen, Li, and Wen identified 32, 16, and 48 volatile compounds by GC–MS, respectively [10,11,12].

Pharmacological activities

Although just a few chemical constituents from CF are assayed for their biological activities, these components displayed diverse pharmacological activities. Detailed biological activities are summarized in Table 2.

Table 2 Summary of pharmacological activities of CF
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Hypoglycemic activity and diabetic target organs protective activity

Diabetes mellitus (DM) is a group of long-term and chronic metabolic disorders which are associated with high serum glucose levels. Compared with the no treatment diabetic animal model group, CF extract (at 300 mg kg−1 2 day−1 and 400 mg kg−1 day−1 p.o.), loganin, morroniside, and ursolic acid (each at 200 mg kg−1 day−1 p.o.) for 4 weeks can significantly decrease fasting blood glucose and alleviate polyphagia, polydipsia, polyuria, and weight loss [13, 14]. In He’s study, metformin (at 200 mg kg−1 day−1 p.o.) demonstrated better effect [14]. Besides, loganin, morroniside, ursolic acid, and butyl morroniside (each at 100 μmol L−1) can protect the pancreatic β-cells from high glucose-induced excessive oxidative stress and apoptosis [14, 15], may further increase the insulin release. Compared with the insulin treatment, CF extract, (−)-epicatechin-3-O-gallate, and caftaric acid monomethyl ester (each at 50 μmol L−1) can also significantly inhibit α-glucosidase activity to slow down the elevation of serum glucose levels [14, 16, 17] and suppress the hepatic gluconeogenesis by decreasing the protein and mRNA levels of PEPCK in vitro [15, 18].

Also, CF extract, iridoid glycosides, and the single compound can decrease 24 h urine protein and serum levels of urea nitrogen and creatinine. To be specific, loganin, morroniside, and 7-O-galloyl-d-sedoheptulose (each at 20–100 mg kg−1 day−1 p.o.) for 10 days and 8 weeks can significantly inhibit both AGE/RAGE formation [19,20,21,22] and CTGF production [23] in db/db mice or STZ-induced diabetic nephropathy model. They can also significantly alleviate diabetic organ injury by decreasing the production of NF-κB and its downstream synthetases and cytokines [19,20,21,22,23,24,25], increasing antioxidant enzyme production [19, 26, 27], and suppressing apoptotic cell death [27, 28].

Antioxidant activity

Long-term oxidative stress will generate excessive ROS to oxidize protein, lipids, DNA and then cause cell death, tissue damage, and organ dysfunction. Ideal antioxidant drugs are required to regulate the defense system and scavenge excessive ROS. Studies indicated that morroniside (at 1, 10, 100 μmol L−1) for 24 h and total saponins (at 60 and 120 mg kg−1 day−1 p.o.) for 4 weeks regulated Ca2+ and NO release [29, 30], the aqueous extract (at 0.25–2.0 mg mL−1) for 20 h modulated GSH redox cycle [31], the aqueous extract, the ethanol extract (at 0.01–0.1 mg mL−1), morroniside (at 0.05–2 µg mL−1), and ursolic acid (at 0.05–2 µg mL−1) for 24 h promoted antioxidant enzymes syntheses [31,32,33] to inhibit lipid peroxidation [29], 5-hydroxymethylfurfural (at 100–400 μmol L−1) for 3 days decreased ROS release [34], morroniside (at 100 μmol L−1) for 2 days recovered cell cycle to normal state [35]. Mentioned effects significantly together reduced the oxidative stress-induced damages compared with the no treatment group.

Anti-inflammatory activity

Prolonged and incurable inflammation may cause many diseases, e.g., atherosclerosis, cancer, ulcerative colitis. In LPS and TNF-α-induced cell inflammation models, compared with the no treatment group, CF aqueous extract (at 0.2, 1, 5 mg mL−1) and cornuside (at 1, 10, 50 μmol L−1) for 24 h significantly inhibited NF-κB p65 translocation, down-regulated COX-2 and iNOS production, finally decreased PGE2 and NO levels to control excessive inflammatory responses [36,37,38].

Anticancer activity

CF aqueous extract significantly enhanced both the cytotoxicity and superoxide anion scavenging activity of vitamin C at 0.5 and 36 µg mL−1, respectively. Together with CF aqueous extract, vitamin C further inhibited proliferation and induced apoptosis in several human oral squamous cell carcinoma cell lines. Compared with no treatment, the proliferation inhibition rate was at 1.3–71.0% [39]. Furthermore, the aqueous extract (at 1.0 mg mL−1) for 2 days significantly exhibited anti-ER+ human mammary carcinoma activity by inhibiting cell anchorage-independent growth, regulating the metabolism of E2 and E3 [40], and influencing cell cycle progression and cellular apoptosis [41]. Finally, the aqueous extract has been tested for its cancer inhibitory effect in several hepatocellular carcinomas and leukemic cell lines. The study indicated that the aqueous extract inhibited the tumor cell proliferation in a dose-dependent manner at 0.11–0.337 mg mL−1, exhibited oxygen free radicals scavenging activity (at 50 µg mL−1), attenuated xanthine oxidase production (at 2.62 mg mL−1) and lipid peroxidation (at 0.892 mg mL−1) [42]. In this study, CF aqueous extract exhibited the similar effects compared with 5-fluorouracil (at 0.5, 1, 5 µg mL−1).

Neuroprotective activity

Many compounds in CF were further tested for the neuroprotective effects. 7R-O-Methyl-morroniside, 7S-O-methyl-morroniside, 7-O-butyl-morroniside, loganin, and morroniside (each at 10 and 50 μmol L−1) for 1 h significantly protected the neurons against glutamate-induced neurotoxicity up to about 78% compared with the no treatment group [43]. CF aqueous extract (at 60 µg mL−1) significantly inhibited the extracellular Ca2+ influx to increase cell neurite outgrowth [44]. Also, cornuside, isoterchebin, and tellimagrandin II (each at 25–100 μmol L−1) displayed anti-Alzheimer’s disease potential due to their synergetic inhibitory activities against BACE1 and ChE [45].

Cerebral ischemia, multiple sclerosis, and neurodegenerative disorder models are applied in animal experiments. Iridoid glycosides (at 60 and 180 mg kg−1 day−1 p.o.) for 1–4 weeks and morroniside (at 90 and 270 mg kg−1 day−1 p.o.) for 3 days significantly decreased the infarction volume, increased the number of new mature neurons and blood vessels, and improved nervous system function [46, 47]. Also, iridoid glycosides (at 50–180 mg kg−1 day−1 p.o.) for 3–4 weeks can significantly promote NGF and BDNF production [48,49,50], and repair the abnormal functions of microglia, oligodendrocyte, and T cell to maintain the central nervous system homeostasis [48].

Hepatoprotective activity

In hepatitis cell models, 5-hydroxymethylfurfural (at 0.2–1 and 0.79 μmol L−1) for 24 h has been shown to protect hepatocytes from H2O2 induced-cytotoxicity by significantly decreasing NO and intracellular Ca2+ levels, inhibiting abnormal production of apoptosis-related proteins and recovering back to regular cell cycle [51,52,53]. In hepatitis animal models, 7-O-galloyl-d-sedoheptulose (at 20 and 100 mg kg−1 day−1 p.o.) for 6 weeks and CF ethanol extract (at 100–500 mg kg−1 day−1 p.o.) for 1 week significantly decreased the serum marker enzymes of hepatic damage, weakened the oxidative stress by promoting antioxidant enzymes production and inhibiting lipid peroxidation, finally improved hepatic histological injury [54, 55].

Other pharmacological activities

In addition to the mentioned pharmacological activities, CF has also been reported to exert multiple bioactivities. Firstly, sweroside (at 7.5 µg mL−1) for 1 week significantly promoted the proliferation and differentiation of osteoblasts via the regulation of osteocalcin [56]. Also, CF extract (at 0–100 µg mL−1) for 4 days significantly inhibited osteoclast differentiation in a dose-dependent manner via the inhibition of the signaling cascades NF-κB/c-Fos/NFATc1 to improve osteoporosis [57]. Secondly, CF methanol extract (at 3.125–12.5 µg mL−1) for 3 days significantly up-regulated synthesis and activity of tyrosinase, raised TRP-1&2 translation associating with increasing transcription of MITF-M, finally promoted melanogenesis by 36.1% [58]. Thirdly, CF aqueous extract possesses immunomodulatory activity. In C57BL/6 mice that were transplanted with a skin graft from Balb/C donors, CF extract significantly prolonged skin allograft survival synergistically by suppressing Th1 response, promoting regulatory T cell generation, and enhancing its suppressive function [59]. Fourthly, CF shows lung-protective activity via two studies. In the cellular test, oleanolic acid (at 10 and 100 μmol L−1) and ursolic acid (at 100 μmol L−1) for 30 min’ pretreatment significantly down-regulated MUC5AC mucin whose excessive level would impair airway defenses to cause serious airway diseases [60]. In an animal experiment, CF aqueous extract (at 50 and 200 mg kg−1 3 day−1 p.o.) for 5 weeks significantly decreased the production of inflammatory mediators and reduced eosinophil infiltration, finally attenuated allergic airway inflammation and airway hyperresponsiveness [61]. Fifthly, cornuside significantly dilated vascular smooth muscle in phenylephrine-contracted rat aorta via the up-regulation of cGMP level to show its vasorelaxation activity [62]. Finally, among in vitro screening of antiviral drugs for treating hand, foot, and mouth disease (HFMD) infection, CF aqueous extract (at 0.4 µg mL−1) for 2 days significantly inhibited CVA16 replication in cellular level [63].

Conclusion

CF is recognized as a fundamental constituent part of tonifying Yin and Yang prescription because of its harmonious and complementary features according to the basic theory of TCM. It possesses the properties of sour and astringent. Firstly, sour and sweet herbs can be combined to nourish Yin, it can act as the sovereign and ministerial drug among Radix Rehmanniae Praeparata, Dioscoreae Rhizoma, Lycii Fructus, Ligustri Lucidi Fructus, Schisandrae Chinensis Fructus. Also, sour and astringent properties exhibit their function of astringing and storing. It also behaves as the sovereign and the ministerial drug that combines with Euryales Semen, Sepiae Endoconcha, Mantidis Oötheca, Rubi Fructus, Paeoniae Radix Alba to treat spermatorrhea, urorrhagia, metrorrhagia and metrostaxis, and excessive perspiration. Finally, CF can be as the adjuvant and conductant drug to alleviate warm and dry features of Yang-reinforcing drugs.

Chemical constituents from terpenoids, flavonoids, tannins, and furans exhibited diverse biological activities, including hypoglycemic, neuroprotective, heart-protective, hepatoprotective, nephroprotective, testis-protective activities. Pharmacological activities are outlined in Fig. 6. In these studies, bioactive components from CF mainly alleviated the damage of target organs by antioxidant activity, anti-inflammatory activity, and anti-apoptosis activity, i.e., up-regulating the expressions and activities of antioxidant enzymes, down-regulating the levels of cytokines and chemokines, and modulating the abnormal expressions of apoptotic death associated proteins.

Fig. 6
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The various pharmacological activities of the extract and chemical compounds identified from Corni Fructus

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Hypoglycemic activity and alleviating diabetic target organs damage are critical pharmacological activities among the broad spectrum of pharmacological activities of CF. Morroniside, loganin, oleanolic acid, ursolic acid, and 7-O-galloyl-d-sedoheptulose exhibited the similar efficacy compared with the conventional oral hypoglycemic drugs (acarbose and metformin). In vivo studies, they reduced serum glucose levels and alleviated unusual symptoms caused by diabetes. In cellular assays, they protected pancreatic β cell from oxidative damage, increased insulin release, improved insulin resistance, displayed α-glucosidase inhibition activity, and suppressed liver gluconeogenesis. Also, compounds alleviated the high-glucose triggered target organs damage by attenuating oxidative stress, inflammation, and apoptosis, finally kept the essential function of target organs stable. CF has also been widely used to treat DM in clinical work. For example, Jingui Shenqi Wan and Liuwei Dihuang Wan are two classic Chinese medicinal formulae which contain CF. Clinical trials indicated that Jingui Shenqi Wan and Liuwei Dihuang Wan could decrease serum glucose levels, alleviate typical DM symptoms and repair target organs injury [64,65,66,67]. Diverse anti-diabetes and anti-diabetic complication pharmacological activities make CF a potential herb to become the complementary drug for treating DM.

Another significant biological activity is the neuroprotection. In cerebral ischemia rat model and neurodegenerative disorder cellular model, iridoid glycosides (e.g., morroniside) and 5-hydroxymethylfurfural increased the number of new mature neurons and blood vessels and exerted anti-oxidative stress, anti-inflammation, and anti-apoptosis properties. In cerebral ischemia rat model and multiple sclerosis rats and mice models, iridoid glycosides also enhanced the levels of brain-derived neurotrophic factor and nerve growth factor. Current studies showed that the pathogenic mechanisms of neurodegenerative diseases have the close relationship with autophagy deficiency and abnormal proteins aggregate clearance dysfunction [68, 69]. In addition to the anti-apoptotic activity, pharmacological activities of CF on the regulation of autophagy can be further explored. Furthermore, many classic Chinese medicinal formulae have been used to treat neurological disorders belonging to liver and kidney deficiency [70,71,72]. For example, Liuwei Dihuang Wan treats insomnia, Zuogui Wan (左归丸) treats epilepsy and vertigo, Dabu Yinjian (大补阴煎) treats a headache, Zuogui Wan and Dihuang Yinzi (地黄饮子) treats stroke, and Huanshao Dan (还少丹) treats dementia. CF plays a vital role in nourishing liver and kidney Yin in these Chinese medicinal formulae.

However, about 90 compounds have been isolated and identified from CF, only 18% compounds are further assayed for their pharmacological activities in vivo and in vitro. It indicates that pharmacological activities of the remaining 90% chemical components are still unknown yet. Moreover, current studies do not provide enough evidence to verify the drug binding sites of active ingredients of CF. For example, it is difficult to judge whether these active ingredients bind the G protein coupled receptor, ion channels, transmembrane receptor kinases, or nuclear receptors to work. Therefore, more systematic and detailed pharmacological studies on CF need to be fulfilled in the future.