Hovenia dulcis Thumberg | Encyclopedia MDPI

Hovenia dulcis Thumberg: Comparison

Please note this is a comparison between Version 1 by Gianluca Sferrazza and Version 2 by Vicky Zhou.

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][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][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 1Table 2.

Table 12. 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]	[8,33,34,35,36,37]
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]	[38]
Hepatoprotective effect on CCl	₄	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]	[14,39,40]
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]	[41]
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]	[42,43]
Anticancer effect	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]	[21]
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]	[44,45,46]
Anti-allergic activity	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]	[47]
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]	[48]
Anti-inflammatory effect	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]	[49]
Laxative effect	Branches water extract	Vanillic acid	n.a.	Improving the intestinal transit and the frequency and weight of stools	In vivo	^[27]	[50]
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]	[51]
Anti-microbial activity	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]	[52]
Antidiabetic effect	Peduncles water extract	n.a.	n.a.	Reduces blood glucose concentration and partially recovers pancreatic islets and pancreatic beta cells	In vivo	^[30]	[53]
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]	[54]
Anti-dyslipidemic and anti-adipogenic activities	Hydroalcoholic fruit extract	DHM	n.a.	Reducing total cholesterol and LDL-C in hypercholesterolemic rats	In vivo	^[32]	[55]
Antioxidant effect	Hydromethanolic pseudo-fruits extracts	Phenolic ompounds	n.a.	Scavenging activity and inhibition of lipid peroxidation process	In vitro	[3]
Antioxidant effect	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]	[56,57]
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]	[58]
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]	[10]
Neuroprotective	Methanol stem bark extract	(−)-catechin and (+)-afzelechin	n.a.	Neuroprotective effect against glutamate-induced neurotoxicity	In vitro	^[37]	[9]

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.