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Sferrazza, G.; Brusotti, G. Hovenia dulcis Thumberg. Encyclopedia. Available online: https://encyclopedia.pub/entry/7666 (accessed on 13 April 2024).
Sferrazza G, Brusotti G. Hovenia dulcis Thumberg. Encyclopedia. Available at: https://encyclopedia.pub/entry/7666. Accessed April 13, 2024.
Sferrazza, Gianluca, Gloria Brusotti. "Hovenia dulcis Thumberg" Encyclopedia, https://encyclopedia.pub/entry/7666 (accessed April 13, 2024).
Sferrazza, G., & Brusotti, G. (2021, March 02). Hovenia dulcis Thumberg. In Encyclopedia. https://encyclopedia.pub/entry/7666
Sferrazza, Gianluca and Gloria Brusotti. "Hovenia dulcis Thumberg." Encyclopedia. Web. 02 March, 2021.
Hovenia dulcis Thumberg
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Hovenia dulcis Thunberg is an herbal plant, belonging to the Rhamnaceae family, widespread in west Asia, USA, Australia and New Zealand, but still almost unknown in Western countries. H. dulcis has been described to possess several pharmacological properties, such as antidiabetic, anticancer, antioxidant, anti-inflammatory and hepatoprotective, especially in the hangover treatment, validating its use as an herbal remedy in the Chinese Traditional Medicine. These biological properties are related to a variety of secondary metabolites synthesized by the different plant parts. Root, bark and leaves are rich of dammarane-type triterpene saponins; dihydrokaempferol, quercetin, 3,3′,5′,5,7-pentahydroflavone and dihydromyricetin are flavonoids isolated from the seeds; fruits contain mainly dihydroflavonols, such as dihydromyricetin (or ampelopsin) and hovenodulinol, and flavonols such as myricetin and gallocatechin; alkaloids were found in root, barks (frangulanin) and seeds (perlolyrin), and organic acids (vanillic and ferulic) in hot water extract from seeds. Finally, peduncles have plenty of polysaccharides which justify the use as a food supplement.

Hovenia dulcis Thumberg traditional medicine pharmacology

1. Introduction

Hovenia dulcis Thunberg is an herbal plant belonging to the Rhamnaceae family. It is indigenous and widespread in East Asia, where is commonly known as Chinese Raisin Tree, Coral Tree, Japanese Raisin Tree, Korean Raisin Tree, Oriental Raisin Tree, while in USA, Australia, New Zealand and Central Africa, it has been introduced as an ornamental plant [1]. Among the Genus Hovenia, H. dulcis Thunb., H. acerba Lindl. and H. dulcis var. tomentella are known as herbal remedies in the ancient medicine; particularly, H. dulcis extracts are used in the Chinese Traditional Medicine in the treatment of several diseases. The whole plant extract is helpful in the hangover syndrome, decreasing alcohol concentration in blood, promoting clearing of alcohol and elimination of free radicals and avoiding dysfunction linked to alcohol abuse [1][2]. Fruits and peduncles possess antimicrobial, antioxidant and antidiabetic activities, while seeds can be used in the treatment of alcohol intoxication for their diuretic properties. In Japan, China and Korea, fruits are also used as ingredients for food supplements and nutraceuticals [3][4]. All these biological properties can be related to the variety of secondary metabolites synthesized by the different plant parts. In 2003, Xu et al. summarized the phytochemical composition of medicinal plants belonging to genus Hovenia [5], highlighting the presence of the following chemical families: triterpenoids, flavonoids, alkaloids, polysaccharides and organic acids. In particular, root, bark and leaves of H. dulcis are rich of dammarane-type triterpene saponins; dihydrokaempferol, quercetin, 3,3′,5′,5,7-pentahydroflavone and dihydromyricetin are flavonoids isolated from the seeds; fruits contain mainly dihydroflavonols such as dihydromyricetin (or ampelopsin) and hovenodulinol, and flavonols such as myricetin and gallocatechin; alkaloids were found in root, barks (frangulanin) and seeds (perlolyrin), and organic acids (vanillic and ferulic) in hot water extract from seeds. Finally, peduncles have plenty of polysaccharides [6].

2. Pharmacological Activities of H. dulcis Extracts

The biological activities of H. dulcis crude extracts and secondary metabolites isolated from them highlighted promising pharmacological effects in vitro and in vivo, the details of which are described below and summarized in Table 1.

Table 1. Summary of H. dulcis pharmacological activities.

Pharmacological Activity ** Active extract Compounds/Fraction Supposed to be Responsible Positive Control Effect/Proposed Mechanism Type of Evidence Reference
Alcohol detoxification effect Water and ethanol fruit, semen and stem bark extracts Hovenodulinol n.a. Reducing alcohol
and aldehyde concentration in blood, saliva exhaled breath through the increase of ADH, ALDH and GST activity
In vitro, in vivo and clinical [7][8][9][10][11][12]
Anti-hangover effect Water fruit extract n.a. n.a. Changes of IL-6, IL-10, IL-10/IL-6 ratio in serum Clinical [13]
Hepatoprotective effect on CCl4 liver injury Methanol fruit extract DHM Glycyrrizhin and silymarin Reduction of AST, ALT and mRNA expression of TIMP-1 In vitro and in vivo [14][15][16]
Hepatoprotective effect on alcohol induced liver injury Ethanol fruit and water semen seu fructus extracts n.a. Sylimarin Modulate GSH, SOD, CAT and Nrf2 activities regulation of markers involved in lipogenic (SREBP-1c, SCD1, ACC1, FAS, PPARγ, DGAT2) and fatty acid oxidation (PPARα, ACO1, CPT1) process in liver (CRP, TNF-α and IL-6) In vivo [17]
Anticancer effect Hydro-methanolic and ethanol fruit extracts n.a. n.a. Cytotoxicity against in vitro against different cancer cell lines In vitro [18][19]
Branches ethanol extract DHM n.a. Anti-angiogenic activity inhibiting HIF-1α, VEGFR2 and downstream signaling: STAT3, PKB or AKT and ERK1/2, MMP-2, MMP-9 and cyclin D1 In vitro and in vivo [20]
Anti-allergic activity Semen seu fructus methanol extract Hovenidulciosides A1, A2, B1 B2 n.a. Inhibitory activity on the histamine release from rat mast cells In vitro [21][22][23]
Ethanol branches extract Taxifolin, dihydro-kaempferol and pinosylvin Cetirizine Inhibition of β-hexosaminidase and histamine release; suppress the FcεRI pathway and inhibits ERK and p38 MAPK. Inhibition of IL-4, TNF-α, PGE2, COX-2, IL-4, NFkB In vitro and in vivo [24]
Anti-inflammatory effect Semen seu fructus ethanol extract DHM, taxifolin, and myricetin Dexamethasone Inhibition of MAPK, AP-1, JAK2/STAT, NF-κB.
Reducing the expression
of NO and iNOS, TNF-α, IL-6 and IL-1β
In vitro [25]
Branches extract Methyl vanillate n.a. Inhibition of TNF-α, IL-6, TARC, MDC, ERK, JNK and p38. Reducing serum IgE and IgG2a levels and the expression of mRNA for Th1- and Th2-related mediators In vivo [26]
Laxative effect Branches water extract Vanillic acid n.a. Improving the intestinal transit and the frequency and weight of stools In vivo [27]
Anti-microbial activity H. dulcis water extract Vanillic and ferulic acids n.a. Antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria and yeast In vitro [28]
Pseudo-fruits extract Catechin and quercetin derivatives n.a. Antimicrobial activity against S. epidermidis, S. aureus and P. aeruginosa In vitro [3]
Antidiabetic effect Ethanol seeds extract Total flavonoids, myricetin and polysaccharides n.a. Inhibitory effect of crude extract and its components against α-amylase and α-glucosidase In vitro [29]
Peduncles water extract n.a. n.a. Reduces blood glucose concentration and partially recovers pancreatic islets and pancreatic beta cells In vivo [30]
Anti-dyslipidemic and anti-adipogenic activities Fruit water extract n.a. n.a. Downregulates PPARγ and increases the phosphorylation of AMPK-α In vitro [31]
Hydroalcoholic fruit extract DHM n.a. Reducing total cholesterol and LDL-C in hypercholesterolemic rats In vivo [32]
Antioxidant effect Hydromethanolic pseudo-fruits extracts Phenolic ompounds n.a. Scavenging activity and inhibition of lipid peroxidation process In vitro [3]
Hot water peduncles extract Polyphenolic–protein–polysaccharide complexes n.a. Demonstrated through ABTS,
DPPH,
NO radical scavenging activities and FRAP methods
In vitro [33][34]
Anti-osteoporotic effect Fruits water extract Methil vanillate n.a. Activation of Wnt/β-catenin pathway in in vivo model; increase of mRNA levels of RUNX2, BMP2, ALP and OCN. Increase the expression of RANKL and decrease OPG In vivo [35]
Immunomodulatory activity Aqueous-ethanol peduncle extract Polysaccharides fraction n.a. Stimulating the proliferation of splenocytes and activating peritoneal macrophages enhancing phagocytosis, NO production and acid phosphatase activity In vitro [36]
Neuroprotective Methanol stem bark extract (−)-catechin and (+)-afzelechin n.a. Neuroprotective effect against glutamate-induced neurotoxicity In vitro [37]
n.a—no data available; ADH—alcohol dehydrogenase; ALDH—aldehyde dehydrogenase; GST—glutathione S—transferase; IL—interleukin; CCl4—carbon tetrachloride; AST—aspartate aminotransferase; ALT—alanine aminotransferase; TIMP-1—tissue inhibitor matrix metalloproteinase-1; GSH—glutathione; SOD—superoxide dismutase; CAT—catalase; Nrf2—nuclear factor erythroid 2-related factor; SREBP-1c—sterol regulatory element-binding protein 1c; SCD1—stearoyl-CoA desaturase-1; ACC1—acetyl-Coenzyme A carboxylase 1; FAS—fatty acid synthase; PPAR—peroxisome proliferator-activated receptor; DGAT2—diacylglycerol O-acyltransferase; ACO1—aminocyclopropane-1-carboxylic acid oxidase; CPT1—carnitine palmitoyltransferase I; CRP—c-reactive protein; TNF-α—tumor necrosis factor-alfa; HIF-1α—hypoxia-inducible factor 1-alpha; VEGFR2—vascular-endothelial growth factor receptor-2; STAT3—signal transducer and activator of transcription 3; PKB or AKT—protein kinase B; ERK1/2—extracellular signal regulated kinase-1/2; MMP—matrix metalloproteinase; FcεRI—high-affinity immunoglobulin E receptor; p38 MAPK—mammalian p38 mitogen-activated protein kinase,; PGE2—prostaglandin E2; COX-2—cyclooxygenase-2; NFkB—nuclear factor kappa-light-chain-enhancer of activated B cells; AP-1—activator protein-1; JAK2/STAT—janus kinase-2/signal transducer and activator of transcription; NO—nitric oxide; iNOS—nitric oxide synthase; TARC—thymus and activation-regulated chemokine; MDC—macrophage-derived chemokine; JNK—c-jun N-terminal kinase; Ig—immunoglobulin; Th1—type 1 T helper; Th2—type 2 T helper; AMPK-α—activated protein kinase-α; LDL-c—low-density lipoprotein-C; ABTS—2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DPPH—2-2-diphenyl-1-picrylhdrazyl; FRAP—ferric ion reducing antioxidant power; Wnt—wingless-related integration site; RUNX2—runt-related transcription factor 2; BMP2—bone morphogenetic protein 2; ALP—alkaline phosphatase; OCN—osteocalcin; RANKL—receptor activator of nuclear κ B ligand; OPG—osteoprotegerin. * no data available on the type of material used. ** Other scientific data are described in the text.

 

 

3. Conclusion and Future Perspectives

Although H. Dulcis extracts are well-known and used in the Chinese Traditional Medicine for the treatment of several diseases and as a food supplement in Japan, China and Korea, little is known about it in Western countries, so far. However, in the recent years, H. dulcis gained growing interest among the scientific community, due to the variety of biological activities, such as antidiabetic, anticancer, antioxidant, anti-inflammatory, hepatoprotective effects and in the hangover treatment, especially.

Secondary metabolites responsible for interesting biological activities are usually secreted from aerial or from non-aerial parts of a plant, unlikely from both of them. On the contrary, in H. dulcis, almost all the plant parts, such as root, bark, leaves, seeds, fruits and pseudo-fruits, are able to produce biologically active extracts. Triterpenoids, flavonoids, alkaloids, polysaccharides, organic acids, saponins, dihydroflavonols and flavonols are the well-known chemical families represented in H. dulcis and responsible for the claimed biological activities.

DHM, a dihydroflavonol belonging to the flavonoids family, resulted to be crucial for most of the pharmacological activities since it is secreted from different plant parts such as fruit, branches, semen seu fructus and seeds. Due to its role in counteracting alcohol intoxication, DHM seems to be a good candidate in alcohol abuse syndrome, but as described, is also involved in other different pharmacological activities.

Hovenodulinol is another dihydroflavonol found to be helpful in the hangover syndrome only, and is secreted from fruit, semen and stem bark.

Pseudo-fruits represent an interesting part of the plant since their activity is correlated with the maturation stage. During the immature stage, a strong antioxidant activity was observed due to the high presence of polyphenolic compounds; on the other hand, nutritional properties reached the maximum at full ripeness, as well as the caloric intake.

In conclusion, H. dulcis has various and useful interesting pharmacological properties and represents a valuable source of active compounds with nutraceutical and pharmaceutical application. However, several issues still need to be explored by basic and clinical research. A better characterization of pharmacological mechanisms of H. dulcis effects is needed in order to elucidate the potential medical application of this plant. Furthermore, despite the good tolerability profile demonstrated, an extensive research on pharmacokinetic and safety profile of H. dulcis extracts is still lacking. The cases of toxic hepatitis reported in Korea suggest to further investigate the potential toxicological mechanisms in order to better characterize the benefit–risk profile of this plant. H. dulcis is of course a promising source of bioactive compounds and a perfect candidate as a food supplement, but the final aim of this review is to underline, once again, that “natural extract” does not mean harmless and misuse has to be avoided. Data shown in this review could be the scientific basis in order to provide knowledge for future studies with the aim to extend the commercialization of the H. dulcis extract-based products also into Western countries.

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