REVIEW article

Front. Pharmacol., 28 May 2021

Sec. Ethnopharmacology

Volume 12 - 2021 | https://doi.org/10.3389/fphar.2021.679378

Comprehensive Review of Phytochemical Constituents, Pharmacological Properties, and Clinical Applications of Prunus mume

  • 1. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

  • 2. Department of Pharmacy, General Hospital of Central Theater Command, Wuhan, China

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Abstract

Prunus mume is one of the most ancient medicinal herbs and health foods commonly used in Asian countries. It is widely used as a constituent of many medicinal preparations and as a food ingredient for its beneficial health effects. In this review, we retrieved reports from PubMed, embase, Scopus, and SciFinder databases, to collect extensive scientific evidence on the phytochemical constituents, pharmacological properties, and clinical applications of Prunus mume. The literature review revealed that approximately 192 compounds have been isolated from different parts of the plant, and their molecular structures have been identified. The pharmacological properties of the plant, including anti-diabetic, liver-protective, antitumor, antimicrobial, antioxidant, and anti-inflammatory activities, as well as their underlying mechanisms, have been clarified by in vitro and in vivo studies. Clinical studies, although very limited, have been highlighted in this review to provide a reference for further exploration on therapeutic applications of the plant.

Introduction

Prunus mume (Siebold) Siebold&Zucc (P. mume) (=Armeniaca mume) is an Asian plum species belonging to the Rosaceae family. It is known as wu mei (Chinese:乌梅) in China, Japanese apricot or ume in Japan, and maesil or oumae in Korea. The plant is commonly cultivated throughout most of China, and is native to Japan and Korea. The fruit of the plant has been used as a medicinal herb and health food in East Asian countries for more than 2000°years. In China, the dried fruit of P. mume is listed in the earliest pharmacopoeia of traditional Chinese medicine (TCM), Shen Nong Ben Cao Jing, compiled during the Han Dynasty, in approximately AD 220. In Japan, the earliest record is found in a medical monograph called Ishinho (published in AD 984). According to the Chinese pharmacopoeia records, the dried ripening fruit of P. mume can be taken to relieve various physical disorders, such as chronic cough caused by lung deficiency, chronic infectious diarrhea, vomiting, or abdominal pain caused by Ascaris infection, dysfunctional uterine bleeding, inadequate secretion of saliva or body fluids. It is also used as a component of many formulas, such as wu mei wan (first recorded in Shang Han Za Bing Lun, compiled during AD200–210), Er Chen Tang and Chang Shan Yin (recorded in Tai Ping Hui Min He Ji Ju Fang, compiled during AD 1078–1085) to treat different kinds of diseases based on classical theories of TCM. As a common commercial food product, the fruit of P. mume is used to prepare pickled plums, plum sauce, plum juice, and plum liquor, which can be consumed as a snack, condiment, or beverage. To date, phytochemical studies have discovered numerous chemical components of the plant, mainly phenolics (Xia et al., 2011; Mitani et al., 2013), flavonoids (Yan et al., 2014a), and organic acids (Gao, 2012). Modern pharmacological studies have disclosed various biological activities and bioactive mechanisms of P. mume and its formulas, including antidiabetic (Kishida et al., 2013; Ko et al., 2013), hepatoprotective (Hokari, 2012; Beretta et al., 2016), antitumoral (Hattori et al., 2013; Cho et al., 2019), anti-inflammatory (Morimoto et al., 2009; Mitani et al., 2013), and antimicrobial (Lee and Stein, 2011; Seneviratne et al., 2011) activities. Bailly (2020) reviewed anticancer properties of P. mume extracts, however, no comprehensive review on the phytochemical and pharmacological properties of P. mume is available.

Herein, we conducted a comprehensive and systematic review to summarize the scattered studies on the phytochemical and pharmacological properties and the clinical applications of P. mume to provide a scientific basis for future research directions and better utilization of the plant.

Data Sources and Search Strategies

A comprehensive literature search was conducted through electronic databases, including PubMed, embase, Scopus, and SciFinder databases. The search time interval was from database inception to 31, Mar 2020. The search strategy used for the PubMed database was “Prunus mume” [tiab] or “Fructus mume” [tiab] or “Chinese plum” [tiab] or “Japanese apricot” [tiab] or “Asian plum” [tiab] or “Oriental plum” [tiab] or “MK 615” [tiab] or maesil [tiab] or oumae [tiab] or ume [tiab] or“Armeniaca mume” [tiab]. The search was limited to English-language and Chinese publications. A PubMed alert was set up for new relevant results.

Database searches initially identified 361 records from Pubmed, 273 records from embase, 540 records from Scopus, and 282 records from the SciFinder database. The duplicate references were removed by Endnote. Only the studies focusing on the phytochemical constituents, pharmacological properties, and clinical applications were selected by two independent reviewers.

Phytochemical Constituents

Phytochemical studies of P. mume have led to the isolation and identification of many types of natural products, including phenolics, organic acids, steroids, terpenes, lignans, furfurals, benzyl glycosides, cyanogenic glycosides, and alkaloids from different parts of P. mume. In total, 192 chemical compounds found in the P. mume were listed in Table 1. The phenolic components, abundantly present in P. mume flower, flower bud, fruit, wood, petal, and seed, are complex, and can be subdivided into phenylpropanoid sucrose esters, hydroxycinnamoylquinic acid derivatives, flavonoids, and other phenolics; the structures of these compounds (1–96) are shown in Figures 1–4. The fruit is the most studied part of the plant, contains mainly therapeutic chemical compounds including organic acid (compounds 92–123), steroids and terpenes (compounds 124–138), lignans (compounds 154–157), furfurals (compounds 158–162), benzyl glycosides (compounds 163–167), cyanogenic glycosides and alkaloid (compounds 168–171). The structures of these compounds are shown in Figures 5–10, respectively.

TABLE 1

NoCompounds nameChemical formulaSourceContent (%w/w)Harvest regionReferences
Phenylpropanoid sucrose esters
1Prunose IC31 H38 O18Flowers0.016JapanYoshikawa et al. (2002)
2Prunose IIC29 H36 O17Flower0.0084JapanYoshikawa et al. (2002)
3Prunose IIIC29 H36 O17Flowers0.0084JapanFujimoto et al. (2014)
4Mumeose AC23 H30 O14Flower buds0.00032ChinaNakamura et al. (2013a)
5Mumeose BC25 H32 O15Flower buds0.0010ChinaNakamura et al. (2013a)
6Mumeose CC27 H34 O16Flower buds0.00050ChinaNakamura et al. (2013a)
7Mumeose DC31 H38 O18Flower buds0.00047ChinaNakamura et al. (2013a)
8Mumeose EC31 H38 O18Flower buds0.00032ChinaNakamura et al. (2013a)
9Mumeose FC27 H34 O16Flower buds0.0011ChinaFujimoto et al. (2013)
10Mumeose GC27 H34 O16Flower buds0.0017ChinaFujimoto et al. (2013)
11Mumeose HC27 H34 O16Flower buds0.0005ChinaFujimoto et al. (2013)
12Mumeose IC29 H36 O17Flower buds0.0003ChinaFujimoto et al. (2013)
13Mumeose JC33 H40 O19Flower buds0.0033ChinaFujimoto et al. (2013)
14Mumeose KC25 H32 O15Flower buds0.0012ChinaNakamura et al. (2013b)
15Mumeose LC29 H36 O17Flower buds0.0008ChinaNakamura et al. (2013b)
16Mumeose MC31 H38 O18Flower buds0.0027ChinaNakamura et al. (2013b)
17Mumeose NC31 H38 O18Flower buds0.0043ChinaNakamura et al. (2013b)
18Mumeose OC31 H38 O18Flower buds0.0003ChinaNakamura et al. (2013b)
19Mumeose pC23 H30 O14Flower buds0.0002ChinaFujimoto et al. (2014)
20Mumeose QC23 H30 O14Flower buds0.0003ChinaFujimoto et al. (2014)
21Mumeose RC23 H30 O14Flower buds0.0010ChinaFujimoto et al. (2014)
22Mumeose SC23 H30 O14Flower buds0.0020ChinaFujimoto et al. (2014)
23Mumeose TC29 H36 O17Flower buds0.0002ChinaFujimoto et al. (2014)
24Mumeose UC29 H36 O17Flower buds0.0012ChinaFujimoto et al. (2014)
25Mumeose VC31 H38 O18Flower buds0.0054China(Fujimoto et al., 2014)
262,3,4′,6′-tetra-O-acetyl-3-O-(E)-p-coumaroylsucroseC29 H36 O17Flower buds0.0127ChinaFujimoto et al. (2013)
273-O-FeruloylsucroseC22 H30 O14Fruits0.00004KoreaYan et al. (2014a)
28α-d-Glucopyranoside, 3-O-[3-(4-hydroxyphenyl)-1-oxo-2-propenyl]-β-d-fructofuranosylC21 H28 O13Fruits0.00002KoreaYan et al. (2014b)
29Chlorogenic acidC16 H18 O9Flowers0.0006JapanYan et al. (2014c)
30Chlorogenic acid methyl esterC17 H20 O9Flower buds0.11ChinaNakamura et al. (2013a)
315-O-(E)-p-coumaroylquinic acid methyl esterC17 H20 O8Flower buds0.0014ChinaNakamura et al. (2013a)
325-O-(E)-p-coumaroylquinic acid ethyl esterC18 H22 O8Flower buds0.0031ChinaNakamura et al. (2013a)
33Mumeic acid-A methyl esterC24 H24 O10Flower buds0.0034ChinaNakamura et al. (2013a)
34Mumeic acid-AC23 H22 O10Flower buds0.0039ChinaNakamura et al. (2013a)
355-O-(E)-feruloylquinic acid methyl esterC18 H22 O9Flower buds0.0013ChinaNakamura et al. (2013a)
36trans-Chlorogenic acidC16 H18 O9Flower buds0.11ChinaNakamura et al. (2013a)
37Chlorogenic acid ethyl esterC18 H22 O9Flower buds0.038ChinaNakamura et al. (2013a)
385-O-(E)-p-coumaroyl quinic acidC16 H18 O8Flower buds0.015ChinaNakamura et al. (2013a)
39Isochlorogenic acidC16 H18 O9Fruits0.00005KoreaYan et al. (2014a)
404-O-Caffeoylquinic acidC16 H18 O9SeedsNMNMXia et al. (2011)
414-O-Caffeoylquinic acid methyl esterC17 H20 O9Fruits0.00025KoreaJin et al. (2012)
425-O-Caffeoylquinic acidC16 H18 O9SeedsNMNMXia et al. (2011)
435-O-Caffeoylquinic acid methyl esterC17 H20 O9Fruits0.00025KoreaJin et al. (2012)
Flavonoids
44RutinC27 H30 O16FlowersNMChinaYoshikawa et al. (2002)
45Quercetin 3-O-neohesperidosideC27 H30 O16Flowers0.0024ChinaYoshikawa et al. (2002)
462″-O-AcetylrutinC29 H32 O17Flowers0.0039ChinaYoshikawa et al. (2002)
472″-O-Acetyl-3′-O-methylrutinC30 H34 O17Flowers0.0008ChinaYoshikawa et al. (2002)
48Quercetin 3-O-rhamnosyl (1→6)galactosideC27 H30 O16Flowers0.0016ChinaYoshikawa et al. (2002)
49Isorhamnetin 3-O-rhamnosideC22 H22 O11Flowers0.0013ChinaYoshikawa et al. (2002)
50Quercetin 3-O-(2″-O-acetyl)-β-d-glucopyranosideC23 H22 O13Flower buds0.0016ChinaNakamura et al. (2013b)
51Isorhamnetin 3-O-β-d-glucopyranosideC22 H22 O12Flower buds0.017ChinaNakamura et al. (2013b)
52Quercetin 3-O-(6″-O-acetyl)-β-d-glucopyranosideC23 H22 O13Flower buds0.0010ChinaNakamura et al. (2013b)
53Quercetin 3-O-(6″-O-benzoyl)-β-d-galactopyranosideC28 H24 O13Flower buds0.00059ChinaNakamura et al. (2013b)
54Isorhamnetin 3-O-β-d-galactopyranosideC22 H22 O12Flower buds0.0006ChinaNakamura et al. (2013b)
55Mumeflavonoside AC24 H24 O13Flower buds0.0004ChinaNakamura et al. (2013b)
56KaempferolC15 H10 O6Fruits0.00125ChinaGuo et al. (2009)
57IsoquercitrinC21 H20 O12Fruits0.00007NMYan et al. (2014a)
58QuercetinC15 H10 O7FlowersNMChinaZhang et al. (2008)
59IsoquercitrinC21 H20 O12FlowersNMChinaZhang et al. (2008)
60Kaempferol-3-O-β-d-galactopyranosideC21 H20 O11FlowersNMChinaZhang et al. (2008)
61IsorhamnetinC16 H12 O7FlowersNMChinaZhang et al. (2008)
62GenkwaninC16 H12 O5WoodNMNMPoonam et al. (2011)
63Flavone,7-hydroxy-3,4′,5-trimethoxy-,β-d-glucopyranosideC24 H26 O11WoodNMNMHasegawa (1959)
64MumeninC22 H22 O11WoodNMNMHasegawa (1959)
65PrudomeninC23 H24 O12WoodNMNMHasegawa (1969)
66GenisteinC15 H10 O5Fruits0.00055ChinaGuo et al. (2009)
672β,3β-epoxy-5,7,3′,4' -tetrahydroxyflavan-(4α→8)-epicatechinC30 H24 O12Fruits0.00002NMYan et al. (2014a)
682β,3β-epoxy-5,7,4′-trihydroxyflavan-(4α→8)-epicatechinC30 H24 O11Fruits0.00004NMYan et al. (2014a)
69Cyanidin 3-rutinosideC27 H31 O15Petals2.6ChinaZhao et al. (2006)
70Cyanidin3-O-(6″- O-α-rhamnopyranosyl-β-glucopyranosideC34 H35 O20Petals5.0ChinaZhao et al. (2006)
71Cyanidin 3-O-(6″ -O-galloyl-β-glucopyranoside)C28 H25 O15PetalsNMChinaZhao et al. (2004)
72Cyanidin3-O-(6″ -O-E-feruloyl-β-glucopyranoside)C31 H29 O14PetalsNMChinaZhao et al. (2004)
73(-)-EpicatechinC15 H14 O6Fruits0.00022NMYan et al. (2014a)
74LeucocyanidolC15 H14 O7FruitsNMNMPoonam et al. (2011)
75(+)-cyanidanolC15 H14 O6WoodNMNMHasegawa (1959)
76NaringenineC15 H12 O5WoodNMNMHasegawa (1959)
77Liquiritigenin-7-O-β-D-glucosideC21 H22 O9Fruits0.00015KoreaJin et al. (2012)
78PruninC21 H22 O10WoodNMNMHasegawa (1959)
79Flavanone,3,5,7-trihydroxy-4′,8-dimethoxy-,7-β-d-glucopyranosideC23 H26 O12WoodNMNMHasegawa (1969)
Other phenolics
80(E)-caffeic acidC9 H8 O4Flower buds0.0016ChinaFujimoto et al. (2013)
81(E)-p-coumaric acidC9 H8 O3Flower buds0.0007ChinaFujimoto et al. (2013)
82(E)-ferulic acidC10 H10 O4Flower buds0.0015ChinaFujimoto et al. (2013)
83(S,R)-1-O-CaffeoylglycerolC12 H14 O6Flower buds0.0011ChinaFujimoto et al. (2013)
84(S,R)-1-O-FeruloylglycerolC13 H16 O6Flower buds0.0043ChinaFujimoto et al. (2013)
85Methyl (E)-4-hydroxycinnamateC10 H10 O3Fruits0.00003KoreaYan et al. (2014a)
86o-CresolC7 H8 OFruitsNMNMKameoka and Kitagawa (1976)
87p-CresolC7 H8 OFruitsNMNMKameoka and Kitagawa (1976)
88GuaiacolC7 H8 O2FruitsNMNMKameoka and Kitagawa (1976)
89Protocatechoic acidC7 H6 O4FruitsNMNMCho et al. (2019)
90Syringic acidC9 H10 O5FruitsNMNMCho et al. (2019)
91p-TyrosolC8 H10 O2Fruits0.00005KoreaYan et al. (2014a)
921-O-(3-hydroxy-4-methoxybenzoyl)-β-d-glucopyranoseC14 H18 O9Flower buds0.0005ChinaFujimoto et al. (2013)
93EugenolC10 H12 O2FruitsNMJapanMiyazawa et al. (2009)
94PrunateC19 H22 O6Fruits0.00001KoreaJeong et al. (2006)
95cis-p-coumaric acidC9 H8 O3FruitsNMJapanMitani et al. (2013)
96HypericinC30 H16 O8FlowersNMChinaZhang et al. (2008)
Organic acids
972-Monomethyl citrateC7 H10 O7Fruits0.00420KoreaYan et al. (2014b)
981,5-Dimethyl citrateC8 H12 O7Fruits0.00042KoreaYan et al. (2014c))
99Benzoic acidC7 H6 O2FlowersNMChinaZhang et al. (2008)
100Propanedioic acidC3 H4 O4FruitsNMChinaGuo et al. (2007)
101Citric acidC6 H8 O7Fruits0.00073ChinaWang et al. (2019)
102Succinic acidC4 H6 O4FruitsNMChinaGao (2012)
103Maleic acidC4 H4 O4FruitsNMChinaGao (2012)
104Fumaric acidC4 H4 O4FruitsNMChinaGao (2012)
105Oxalic acidC2 H2 O4FruitsNMChinaGao (2012)
106Ascorbic acidC6 H8 O6FruitsNMChinaGao (2012)
107Acetic acidC2 H4 O2FruitsNMChinaGao (2012)
108Malic acidC4 H6 O5FruitsNMChinaGao (2012)
109Tartaric acidC4 H6 O6FruitsNMChinaGao (2012)
110Lactic acidC3 H6 O3UnknownChen et al. (2006)
111Lauric acidC12 H24 O2FruitsNMNMKameoka and Kitagawa (1976)
112Valeric acidC5 H10 O2FruitsNMNMKameoka and Kitagawa (1976)
113Caproic acidC6 H12 O2FruitsNMNMKameoka and Kitagawa (1976)
114Stearic acidC18 H36 O2FruitsNMNMKameoka and Kitagawa (1976)
115Butyric acidC4 H8 O2FruitsNMChinaGuo et al. (2007)
116Heptanoic acidC7 H14 O2FruitsNMChinaGuo et al. (2007)
1172-Methylbutanoic acidC5 H10 O2FruitsNMChinaGuo et al. (2007)
118Palmitic acidC16 H32 O2FruitsNMJapanMiyazawa et al. (2009)
119Linolenic acidC18 H30 O2FruitsNMChinaGuo et al. (2007)
1203-Methylbutanoic acidC5 H10 O2FruitsNMChinaGuo et al. (2007)
121Linoleic acidC18 H32 O2FruitsNMChinaGuo et al. (2007)
122Formic acidC H2 O2FruitsNMChinaGuo et al. (2007)
123Propionic acidC3 H6 O2FruitsNMChinaGuo et al. (2007)
Steroids and terpenes
124CitrostadienolC30 H50 OFruits0.00002KoreaYan et al. (2015)
12524-Ethyl-lophenolC30 H52 OFruits0.00004KoreaYan et al. (2015)
126β-sitosterolC29 H50 OFruits0.0014KoreaYan et al. (2015)
127DaucosterolC35 H60 O6Fruits0.00305KoreaYan et al. (2015)
128Ursolic acidC30 H48 O3Fruits0.00455KoreaYan et al. (2015)
129UvaolC30 H50 O2Fruits0.00013KoreaYan et al. (2015)
130Corosolic acidC30 H48 O4Fruits0.00015KoreaYan et al. (2015)
131CycloeucalenolC30 H50 OFruits0.00005KoreaYan et al. (2015)
13224-MethylenecycloartanolC31 H52 OFruits0.00038KoreaYan et al. (2015)
133Oleanolic acidC30 H48 OFruitsNMNMPoonam et al. (2011)
134γ-tocopherolC28 H48 O2Fruits0.00012KoreaYan et al. (2015)
135α-tocopherolC29 H50 O2Fruits0.00044KoreaYan et al. (2015)
136α-tocopherylquinoneC29 H50 O3Fruits0.00002KoreaYan et al. (2015)
1371,2-Bis(γ-tocopherol-5-yl)ethaneC58 H98 O4Fruits0.00003KoreaYan et al. (2015)
138PhytolC20 H40 OFlowersNMNMPoonam et al. (2011)
Amino acids
139l-aspartic acidC4 H7 N O4Fruits0.0000005KoreaKim et al. (2014)
140α-amino-n-butyric acidC4 H9 N O2Fruits0.0000006KoreaKim et al. (2014)
141GlycineC2 H5 N O2Fruits0.00000004KoreaKim et al. (2014)
142l-alannineC3 H7 N O2Fruits0.0000004KoreaKim et al. (2014)
143l-SerineC3 H7 N O3Fruits0.000001KoreaKim et al. (2014)
144l-glutamic acidC5 H9 N O4Fruits0.0000004KoreaKim et al. (2014)
145l-LysineC6 H14 N2 O2Fruits0.00000008KoreaKim et al. (2014)
146l-LeucineC6 H13 N O2Fruits0.0000002KoreaKim et al. (2014)
147l-PhenylalanineC9 H11 N O2Fruits0.00000002KoreaKim et al. (2014)
148l-AsparagineC4 H8 N2 O3Fruits0.00001KoreaKim et al. (2014)
149l-HistidineC6 H9 N3 O2Fruits0.00000015KoreaKim et al. (2014)
150l-ValineC5 H11 N O2Fruits0.0000002KoreaKim et al. (2014)
151l-ThreonineC4 H9 N O3Fruits0.0000003KoreaKim et al. (2014)
152l-isoleucineC6 H13 N O2Fruits0.00000002KoreaKim et al. (2014)
153l-ArginineC6 H14 N4 O2Fruits0.00000029KoreaKim et al. (2014)
Lignans
154(+)-lyoniresinolC22 H28 O8Fruits0.00013KoreaYan et al. (2014a)
155(+)-pinoresinolC20 H22 O6Fruits0.00002KoreaYan et al. (2014a)
156(+)-syringaresinolC22 H26 O8Fruits0.00022KoreaYan et al. (2014a)
157(+)-mediaresinolC21 H24 O7Fruits0.00003KoreaYan et al. (2014a)
Furfurals
158FurfuralC5 H4 O2FruitsNMJapanMiyazawa et al. (2009)
1595-Hydroxymethyl-2-furaldehydeC6 H6 O3Fruits0.001KoreaJin et al. (2012)
1605-Hydroxymethyl-2-furaldehydebis (5-formylfurfuryl) acetalC18 H16 O8FruitsNMKoreaJang et al. (2018)
1615-Methyl-2-furfuralC6 H6 O2FruitsNMNMKameoka and Kitagawa (1976)
1625-[β-d-Fructopyranosyl-(2→6)-α-D-glucopyranosyloxymethyl]-2-furancarboxaldehydeC18 H26 O13Fruits0.00006KoreaYan et al. (2014a)
Benzyl glycosides
163Benzyl-β-d-glucopyranosideC13 H18 O6Flowers0.0022KoreaYan et al. (2014a)
164Phenylmethyl6-O-α-l-arabinofuranosyl-β-d-glucopyranosideC18 H26 O10Fruits0.00883KoreaYan et al. (2014a)
165Benzyl β-primeverosideC18 H26 O10Fruits0.00242KoreaYan et al. (2014a)
166Benzylalcohol O-α-l-arabinopyranosyl-(1→6)-β-d-glycopyranosideC18 H26 O10Fruits0.00012KoreaYan et al. (2014a)
167Benzyl gentiobiosideC19 H28 O11Fruits0.00012KoreaYan et al. (2014a)
Cyanogenic glycosides
168AmygdalinC20 H27 N O11Fruits0.00116ChinaWang et al. (2019)
169PrunasinC14 H17 N O6Fruits0.0002KoreaJin et al. (2012)
Alkaloids
1702,2,6,6-Tetramethyl-4-oxo-1-piperidinooxyC9 H16 N O2FruitsNMNMRen et al. (2004)
171TriacetonamineC9 H17 N OFruitsNMNMRen et al. (2004)
Other compounds
172PhytolC20 H40 OFlowers0.0009JapanYoshikawa et al. (2002)
173Eugenyl glucosideC16 H22 O7Flowers0.050JapanYoshikawa et al. (2002)
174Chavicol β-D-glucosideC15 H20 O6Flowers0.0014JapanYoshikawa et al. (2002)
175β-d-Glucopyranosyl benzoateC13 H16 O7Fruits0.00015KoreaYan et al. (2014a)
1763,4,5-Trimethoxyphenyl-β-d-glucopyranosideC15 H22 O9Fruits0.00039KoreaYan et al. (2014a)
177Rhodioloside EC21 H38 O11Fruits0.00008KoreaYan et al. (2014a)
178BenzaldehydeC7 H6 OFruitsNMJapanMiyazawa et al. (2009)
179LinaloolC10 H18 OFruitsNMJapanMiyazawa et al. (2009)
180α-terpineolC10 H18 OFruitsNMJapanMiyazawa et al. (2009)
181p-CymeneC10 H14FruitsNMJapanMiyazawa et al. (2009)
182SqualeneC30 H50Fruits0.00050ChinaWang et al. (2019)
183Ceryl alcoholC26 H54 OFruitsNMNMPoonam et al. (2011)
184Benzyl alcoholC7 H8 OFruitsNMNMKameoka and Kitagawa (1976)
185Isoamyl alcoholC5 H12 OFruitsNMNMKameoka and Kitagawa (1976)
1862,3-Dimethylmaleic anhydrideC6 H6 O3FruitsNMNMKameoka and Kitagawa (1976)
187cis-3-hexen-1-olC6 H12 OFruitsNMNMKameoka and Kitagawa (1976)
188Ethyl benzoateC9 H10 O2FruitsNMNMKameoka and Kitagawa (1976)
189Patchouli alcoholC15 H26 OFruitsNMNMIchikawa et al. (1989)
190Rhodioloside EC21 H38 O11Fruits0.00008KoreaYan et al. (2014a)
191α-methoxy-2,5-furandimethanolC7 H10 O4Fruits0.00005KoreaYan et al. (2014b)
192Butyl glucosideC10 H20 O6Fruits0.0011KoreaYan et al. (2014c)

List of 192 compounds isolated from P. mume.

NM = Not mentioned in ref.

FIGURE 1

FIGURE 1

Structures of the phenylpropanoid sucrose esters (1–28) form P. mume.

FIGURE 2

FIGURE 2

Structures of the hydroxycinnamoylquinic acid derivatives (29–43) form P. mume.

FIGURE 3

FIGURE 3

Structures of the flavonoids acid derivatives (44–79) form P. mume.

FIGURE 4

FIGURE 4

Structures of other phenolics (80–96) form P. mume.

FIGURE 5

FIGURE 5

Structures of the Organic acid derivatives (97–123) form P. mume.

FIGURE 6

FIGURE 6

Structures of the steroids and terpenes (124–138) form P. mume.

FIGURE 7

FIGURE 7

Structures of the lignans (154–157) form P. mume.

FIGURE 8

FIGURE 8

Structures of the furfurals (158–162) form P. mume.

FIGURE 9

FIGURE 9

Structures of the benzyl glycosides (163–167) form P. mume.

FIGURE 10

FIGURE 10

Structures of the cyanogenic glycosides (168–171) form P. mume.

Pharmacological Properties and Clinical Applications

Metabolic Diseases

Diabetes Mellitus

DM is one of the most common metabolic diseases in the world. It is characterized by hyperglycemia as result of abnormal insulin secretion and insulin resistance. Obesity, which is normally associated with hyperglycemia and insulin resistance, is a high-risk factor for DM. One study found that a water extract of P. mume fruit and Lithospermum erythrorhizon root synergistically improved insulin sensitivity and prevented visceral adiposity in a high-fat diet (HFD)-fed ovariectomized rats model (Ko et al., 2013). A 70% ethanol extract of P. mume fruit was described as able to increas glucose uptake in C2C12 myotubes by activating the peroxisome proliferator-activated receptor (PPAR)-γ. The extract also significantly improved fasting glucose levels and glucose intolerance, reduced body weight, liver and adipose tissue weight without affecting food intake in HFD-fed mice (Hwang et al., 2012; Shin et al., 2013). A 70% ethanol extract of P. mume leaves also decreased blood glucose levels in a dose-dependent manner, and the polyphenol compounds were conjectured to account for these activities (Lee et al., 2016). In another study, phenolic extracts of P. mume inhibited small intestinal disaccharidase activity and suppressed postprandial elevation of blood glucose levels in rats (Kishida et al., 2013). A TCM formula called “wumei wan” in Chinese has also been reported to improve insulin resistance (IR) in type 2 DM rats, which might be related to up-regulation of protein and mRNA expression levels of the insulin receptor (Insr), insulin receptor substrate 1 (Irs-1), glucose transporter4 (Glut-4), and β-arrestin-2 in the liver and skeletal muscle (Li et al., 2013).

Clinically, in a multicenter randomized controlled pilot trial, 85 subjects diagnosed with type 2 DM, were randomized to receive either wumei wan or metformin. After a12-weeks intervention, the P. mume formula wumei wan decreased the fasting plasma glucose (FPG), postprandial glucose (PPG), and glycosylated hemoglobin (HbAlc) levels as effectively as the hypoglycemic agent metformin. In addition, the formula could significantly decrease the body mass index (BMI) when the patient’s BMI was greater than 23, but not when the BMI was below 23 (Tu et al., 2013).

Furthermore, the phenolic compounds 9∼13, 29, 30, 33, 34, 47 extracts from the flower buds of P. mume inhibited aldose reductase, reduced sorbitol accumulation in eye lenses and retinas, and had the potential to prevent diabetic complications such as cataract (Yoshikawa et al., 2002; Fujimoto et al., 2013).

Altogether, these studies demonstrated that P. mume could prevent obesity, maintain glucose metabolism, prevent diabetic complications, and bring therapeutic benefit to the patients with type 2 DMs.

Hypolipidemic Effects

Squalene synthase plays an important role in the cholesterol biosynthesis pathway. Inhibiting this enzyme in hypercholesterolemia can lower not only plasma cholesterol but also plasma triglyceride levels. Chlorogenic acid isolated from P. mume fruit inhibited squalene synthase in pig liver homogenate with an IC50 level of 100 nm (Choi et al., 2007). In HFD-fed mice, the 70% ethanol extract of P. mume fruit decreased serum triglyceride (TG) levels significantly (Hwang et al., 2012; Shin et al., 2013). Furthermore, in HFD-fed rats fed with P. mume concentrate for four°weeks, the total lipid, total cholesterol, and TG serum levels, and the atherogenic index decreased significantly compared with the HFD model control group; while, the serum level of high-density lipoprotein (HDL)-cholesterol was significantly higher than the HFD model control group (Chyun et al., 2012). Therefore, the plant may act as a potential therapeutic agent for hypercholesterolemia.

Gout

Gout is a metabolic disorder characterized by recurrent acute arthritis, hyperuricemia, and deposition of sodium urate in and around the joints, sometimes with the formation of uric acid calculi. The enzyme xanthine oxidase (XO) can oxidize hypoxanthine and xanthine to uric acid, thus playing an important role in the catabolism of purines, which are associated with the metabolic disorders of hyperuricemia and gout (Wang et al., 2010). P. mume can be used to treat gouty arthritis in combination with other herbal medicines based on clinical experience in TCM (Chen et al., 2007). Animal studies have also shown that a methanol extract of P. mume fruit, with the seeds removed (70 and 140 mg/kg, 7°days) decreased serum and liver uric acid levels, elevated urinary uric acid levels, and reduced hepatic XO activity in mice with potassium oxonate induced hyperuremia (Yi et al., 2012).

Osteoporosis

Osteoporosis is a metabolic disease that frequently occurs in aging communities. This degenerative disease is characterized by a progressive loss of bone mineral density (BMD) and deterioration of the bone micro-architecture, causing an increased risk of fracture (Bi et al., 2006). Currently, therapies for osteoporosis are focused on inhibiting osteoclastic activity, stimulating osteoblastic activity, and decreasing oxidative stress (Arai et al., 2007). MC3T3-E1 is a classic cell model of the osteoblastic phenotype. Treatment of MC3T3-E1 cells with the water-soluble fraction of P. mume increased osteogenic mRNA expression of bone morphogenetic protein (BMP-2), osteopontin (OPN), RUNX2, and increased alkaline phosphatase (ALP) activity, which is a marker of the early period of osteoblastic differentiation, and therefore induced cell proliferation and differentiation. Moreover, the Alizarin Red staining assay demonstrated that P. mume increased calcium deposition, and therefore had an accelerative effect on the mineralization of cells (Kono et al., 2011). Other research groups have explored the antioxidant and anti-osteoporosis activities of compounds isolated from P. mume fruit using murine pre-osteoblastic MC3T3-E1 cells and pre-osteoclastic RAW 264.7cells. These studies showed that phenolic and lignans compounds such as compounds 19∼21, 30, 39, 154∼156 exhibited peroxyl radical-scavenging activities in a dose-dependent manner. The benzyl glycoside compound 166 and flavonoid compounds 44, 45, 57, 67, 68, 73 significantly stimulated the differentiation of pre-osteoblastic MC3T3-E1 cells by increasing collagen synthesis and mineralization (Yan et al., 2014a; 2014b). Moreover, some phenylpropanoid sucrose esters, organic acids, lignans and glycoside compounds 30, 39, 98, 154, 163, 169 possessed significant inhibitory activity against osteoclast differentiation by suppressing tartrate-resistant acid phosphatase (TRAP) activity in pre-osteoclastic RAW 264.7cells (Yan et al., 2015). These results show that P. mume may be an excellent source of anti-osteoporosis activity that can be used to prevent osteoporosis.

Digestive System Diseases

Liver Protection

In recent years, many preclinical studies have demonstrated the antioxidant (Xia et al., 2010; Kang et al., 2016) and anti-inflammatory (Morimoto et al., 2009; Mitani et al., 2013) effects of P. mume. Oxidative stress and inflammatory reactions are key risk factors of some chronic liver diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and viral hepatitis (Oyanagi et al., 1999; Lieber, 2001; Ekstedt et al., 2006), thus the hepatoprotective effects of P. mume have been investigated in both animal and clinical models.

MK615 is a commercial product extract from the fruit of P. mume that is rich in hydrophobic substances. Hokari (2012) revealed that d-galactosamine hydrochloride (D-GalN) (600 mg/kg, single intraperitoneal injection) induced hepatopathy in a rat model. MK615 treatment (4 ml/kg per day for 7°days) significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) plasma levels and reduced hepatic injury. In the same report, a case series study was carried out to evaluate the clinical effects of MK615. Fifty-eight enrolled patients with liver disorders, including hepatitis C, NAFLD, and autoimmune liver disease, orally took MK615 solution 13 g every day for 12°weeks. After a 12-weeks intervention, the serum ALT and AST levels of these patients decreased significantly compared with the pretreatment baseline levels.

In another randomized double-blind placebo-controlled study, 45 healthy subjects with transaminase levels between 20 and 40°UI/L were enrolled, and two doses of a food supplement containing a standardized extract of P. mume were administered. After 3°months of treatment, the liver enzyme (ALT, AST, and gamma-glutamyl transferase [γGT]) levels, lipid profile parameters (HDL cholesterol, LDL/HDL ratio, and triglycerides), glycemia, oxidative parameters (reduced or oxidized plasma cysteine (Cys), plasma CysGly, erythrocyte glutathione (GSH), plasma GSH, and plasma neopterin/creatinine ratio) were significantly improved vs. the placebo group and the pretreatment baseline (Beretta et al., 2016).

In the alcoholic liver injury mouse model, the P. mume formula also exhibited hepatoprotective effects (Chen et al., 2016). Khan et al. (2017) investigated the molecular mechanism using a metabolic approach. The three-way hierarchical cluster analysis showed that 101 features were statistically different among the alcohol and P. mume pretreatment groups. The relative concentrations of compounds such as phosphatidylcholine and Saikosaponin BK1 increased significantly in the P. mume treatment group. These compounds are responsible for the hepatoprotective effects of P. mume by inhibiting the reactive oxygen species (ROS)-mediated p53 and mitogen-active protein kinase (MAPK) signaling pathways.

Helicobacter pylori-Related Chronic Gastritis

Epidemiological evidence has indicated a significant relationship between Helicobacter pylori (H. pylori) infection and chronic gastritis (Uemura et al., 2001). Some studies have found that P. mume extract has direct bactericidal activity against H. pylori both in vitro and in vivo (Fujita et al., 2002; Otsuka et al., 2005; Miyazawa et al., 2006). A clinical case series study, which enrolled 18 H. pylori-positive subjects, demonstrated that drinking 130 ml 1% concentrated fruit juice of P. mume twice a day for two°weeks, resulted in a slight fall in the urea breath test (UBT) values (Nakajima et al., 2006). Enomoto et al. (2010) carried out a study to examine the associations between P. mume intake and H. pylori-related chronic gastritis. The results showed that in the 458 non-elderly H. pylori-positive subjects (age range 30–64°years), the H. pylori antibody titers and serum PG-II levels were significantly lower in the high dose P. mume intake group compared with the low dose intake group. Thus, P. mume extract was shown to have a potential protective effect against H. pylori related chronic gastritis.

Dysmotility Disease

P. mume is believed to improve gastrointestinal dysmotility and dyspepsia in traditional medicine in Eastern countries. Some scientific studies have provided evidence for the efficacy of such folk remedies. Tamura et al. (2011) found that P. mume contains both soluble and insoluble fibers and can increase fecal output and fecal lipid excretion significantly. A methanol extract of P. mume was reported to modulate the pacemaker activities of interstitial cells of Cajal (ICCs) and was proposed as a potential gastroprokinetic agent for regulating gastrointestinal motility (Lee et al., 2017). The improvement in gastrointestinal motility also brought benefits to constipation and gastroesophageal reflux diseases (GERD), according to several animal and clinical experiments (Na et al., 2012). Jung et al. (2014) carried out a double-blind, randomized, placebo-controlled trial, in which patients experiencing constipation consumed P. mume fruit extract 7.2 g (n = 28) or a placebo (n = 29) twice a day for eight°weeks. The colon transit time and defecation function were evaluated by questionnaire. The results showed a significant decrease in total colon transit time and abdominal pain during defecation in the group that consumed P. mume compared with the placebo group. In a community cohort study, the frequency scale for symptom of GERD (FSSG) questionnaire was used to investigate the effects of P. mume consumption on GERD symptoms. Of a total of 1303 subjects, 392 were categorized into the P. mume daily intake group, 911 were included in the no or occasional intake group. The results showed that the total FSSG score and FSSG dysmotility score were significantly lower in the P. mume daily intake group compared with no or occasional intake (Maekita, 2015).

Inflammatory Bowel Disease

Oxidative stress and inflammatory reactions are the major etiologies of IBD. Oxidative stress due to excessive ROS triggers inflammatory reactions of the gut wall and causes tissue-disruptive disease (Ko and Auyeung, 2014). Many studies have reported the free radical-scavenging (Matsuda et al., 2003; Xia et al., 2010), antioxidant (Karakaya et al., 2001; Kang et al., 2016), and anti-inflammatory properties of P. mume (Choi et al., 2007; Morimoto et al., 2009). Some studies have assessed further beneficial effects of P. mume extract or formulation on different IBD mouse models. The results showed that P. mume treatment decreased immunoglobulin M (IgM) and immunoglobulin E (IgE) levels, reduced COX-2, tumor necrosis factor alpha (TNF-α), interferon (IFN-γ), interleukin (IL)-12, and IL-17 levels in the colon tissue of colitis mouse models, alleviated dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced histological changes and inflammatory responses (Liu et al., 2009; Zhang et al., 2011; Lee et al., 2014; Lee S. Y. et al., 2017; Kim et al., 2021). All these studies show that P. mume may represent a potential new therapeutic agent for IBD treatment.

Nervous System Diseases

The human hippocampus is associated with cognitive function such as learning, memory, and emotional control (Burgess et al., 2002). A mixture of P. mume concentrate, disodium succinate and Span80 (3.6:4.6:1 ratios) improved the spatial memory of normal rats in the Morris water maze test, the effects being linked to the MAPK/ERK (extracellular signal-regulated kinase) signaling pathway that results in the phosphorylation of cyclic adenosine monophosphate (cAMP)-response-element-binding protein (CREB) through tropomyosin receptor kinase B (TrkB) and/or the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor (Kim et al., 2008).

Chronic cerebral hypoperfusion (CCH) can cause white matter and hippocampal damage and is a key etiological factor in vascular dementia (VaD). The permanent bilateral common carotid artery occlusion (BCCAo) animal model has been widely used to study CCH-relevant nervous system diseases (Farkas et al., 2007). Jeon et al. (2012) used the BCCAo rat model to study the effects of P. mume extract on cognitive deficits caused by CCH. The results showed that an aqueous extract of P. mume (200 mg/kg, 40°days) reduced microglial activation, decreased p-ERK expression, prevented nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in rat hippocampus, and improved the spatial learning of rats in the Morris water maze task. Likewise, an ethanol extract of P. mume alleviated inflammatory responses and cholinergic dysfunction by attenuating white matter lesions, decreasing expression of pro-inflammatory mediators, inhibiting microglial and astrocytic activation, and down-regulating toll-like receptor 4 (TLR4) and p38MAPK signaling (Jeon, 2015; Lee et al., 2015; Kim et al., 2016).

In addition, P. mume can also benefit neurodegenerative diseases such as Alzheimer’s disease. Kim et al. (2015) found that an ethanol extract of P. mume attenuated memory impairment in the scopolamine-induced mouse model. Park et al. (2016) examined the effects of P. mume on cognitive impairments in 5XFAD transgenic mice with five typical Alzheimer mutations. After a 90-days treatment, the P. mume group performed better in the Morris water maze task, the object/location novelty recognition test, and contextual fear-conditioning compared with the model group.

Cardiovascular Disease

Different study groups have found that the fruitjuice concentrate of P. mume markedly improved blood fluidity in different micro-channel instruments (Chuda et al., 1999; Kubo et al., 2005). The polyacylated sucrose, citric acid, and mumefural derivatives of P. mume showed inhibitory effects on collagen-, arachidonic acid-, and ADP-induced platelet aggregation in vitro (Yoshikawa et al., 2002; Kubo et al., 2005). An herbal mixture of Phyllostachys pubescens leaves and P. mume fruits also showed inhibitory effects on platelet aggregation in vitro (Dong-Seon et al., 2013; Son et al., 2017). In the arteriovenous shunt thrombosis rat model and the carrageenan-induced mice tail thrombosis model, the mixture dose-dependently reduced the weight or length of tail thrombosis, respectively. The mechanism study showed that the mixture upregulated intracellular cAMP levels, inhibited the release of granule contents containing serotonin, platelet-activating factor (PAF), and thromboxane A2 (TXA2), and decreased the intracellular concentration of calcium ion. The mixture also exerted inhibitory effects by deactivating the collagen receptor glycoprotein VI (GPVI), blocking ligand binding to the receptor, inhibiting the downstream signaling pathway and the ERK activation pathway, and inhibiting the conversion of fibrinogen to fibrin (Dong-Seon et al., 2013; Son et al., 2017).

Utsunomiya et al. (2002) found that a fruit juice concentrate of P. mume markedly inhibited angiotensin II and H2O2-induced epidermal growth factor (EGF) receptor transactivation, inhibited ERK activation, and mitigated angiotensin II-induced vascular remodeling. The chlorogenic acid derived from P. mume decreased angiotensin converting enzyme (ACE) levels in rat plasma (Ina et al., 2003). Jo et al. (2019) studied the vasodilatory effects of a 70% ethanol extract of P. mume branches on isolated rat aortic rings. The authors showed the vasorelaxant effect of the extract was endothelium dependent. The extract affected the nitric oxide (NO) cyclic guanosine monophosphate (cGMP) pathway, the prostacyclin pathway, the muscarinic receptor pathway, potassium channels, and might represent a promising anti-hypertensive treatment.

Clinically, a 12-weeks double-blind randomized placebo-controlled pilot trial evaluated the anti-hypertensive effects of P. mume. The study recruited 15 participants with normal or normal high blood pressure (BP) (systolic blood pressure [SBP],130–139 mmHg; diastolic blood pressure [DBP], 85–89 mmHg) or hypertension grade 1 (SBP, 140–159 mmHg; DBP, 90–99 mmHg) and taking no anti-hypertensive agents. After a 12°weeks-intervention, the P. mume group showed a lower, albeit not significant, SBP compared with the control group (Takemura et al., 2014). These results require confirmed in clinical trials with a larger patient sample.

These results suggest that P. mume may useful as an herbal remedy to treat and prevent some cardiovascular diseases.

Antitumor Effects

The antitumor effects of P. mume have been an important focus of pharmacological studies of the plant in recent years. MK615 and other compounds extracted from P. mume have exhibited anti-proliferative activity in vitro on many human cancer cell lines (Jeong et al., 2006), for example, the human hepatocellular carcinoma cell lines HuH7, HepG2, and Hep3B (Okada et al., 2007; Sakuraoka et al., 2010); human colon cancer cell lines SW480, COLO, and WiDr (Mori et al., 2007; Cho et al., 2019); human pancreatic cancer cell lines PANC-1, PK-1, PK45H, and MIAPaCa-2 cells (Toshie, 2008; Hattori et al., 2013); human malignant melanoma cell lines SK-MEL28 and A375 cells (Tada et al., 2012); human breast cancer cell lines MDA-MB-468 and MCF-7 cells (Nakagawa et al., 2007); human lung cancer cell lines A549 and PC14 cells (Sunage et al., 2011); and human leukemia cell lines HIMeg, HL-60, and Su9T01 cells (Shen et al., 1995; Kai et al., 2011). The proposed antitumor mechanisms, involved directly suppressing Aurora A and Aurora B kinase activity, inhibition of NF-κB activation (Toshie, 2008), triggering of apoptosis and autophagy (Mori et al., 2007), inducing accumulation of ROS in cancer cells but not in normal endothelial cells (Hattori et al., 2013), inhibition of the ERK1/2 and DNA binding-1 (Id-1) pathways, decreasing Bcl-2 expression (Tada et al., 2012), and suppressing hypoxia tolerance by up-regulation of E-cadherin in cancer cells with mutant KRAS (Nishi et al., 2020).

Anti-neoplastic in vivo studies have also shown that MK615 significantly inhibited the growth of human cancer cells in xenograft mice. The effects might be associated with the antioxidant capacity of MK615 (Hattori et al., 2013). Fermented P. mume and probiotic treatment also alleviated the 12-dimethylbenz [a]anthracene and 12-O-tetradecanoyl phorbol-13-acetate-induced skin carcinogenesis by mitigating oxidative stress (Lee et al., 2013). In addition, a recent study found that MK615 activated T cell-mediated immunity through programmed death-ligand 1(PD-L1) down-regulation (Yanaki et al., 2018).

When a P. mume extract was combined with other anticancer drugs, the drugs showed additive and synergistic effects in different pharmacological models. For example, MK615 enhanced the apoptosis activity of bendamustine in lymphoma cell lines (Inoue et al., 2017). The triterpene extract from P. mume augmented the suppressive effects of 5-fluorouracil on esophageal cancer cell xenografts in the peritoneal cavity of a severe combined immunodeficient (SCID) mouse (Yamai et al., 2012). A MK615 and gemcitabine combined treatment was more effective than single treatments in inhibiting the growth of human pancreatic cancer cell xenografts in athymic nude mice (Hattori et al., 2013).

In a clinical setting, Matsushita et al. (2010) described a patient with malignant melanoma who was administered 13 g daily oral doses of MK615 for 5°months, and whose cutaneous in-transit metastatic lesions were significantly reduced, and the apoptotic index of tumor cells significantly increased. In another case report, a hepatocellular carcinoma (HCC)-recurrent patient was administered 6.15 g MK615 twice daily. After 3°months of treatment, the alpha-fetoprotein level decreased, and both the lymph nodes and pulmonary metastases decreased in size (Hoshino et al., 2013). A phase I clinical trial found that patients showed good tolerance to gemcitabine when it was combined with MK615 (Moriyama et al., 2018). A randomized placebo-controlled clinical trial recruited 208 breast cancer patients with diarrhea caused by lapatinib and capecitabine (Xing et al., 2018). The patients were randomized and assigned to two groups given either 100 mg ethanol extract of P. mume or placebo, respectively. Diarrhea and gastrointestinal symptoms were assessed using the seven-point Likert scale, two scale forms assessed quality of life of patients, and the SF-36 questionnaire, and Hospital Anxiety and Depression Scale (HADS) were used to evaluate the effects of P. mume on diarrhea of those patients. After six°weeks of treatment, the average scores of the Likert scale and HADS were reduced and SF-36 scores were improved significantly in P. mume extract treated group when compared to the control group. The results demonstrated that the ethanol extract of P. mume relieved diarrhea and gastrointestinal symptoms and improved life quality of breast cancer patients with diarrhea caused by lapatinib and capecitabine. Choi et al. (2002) found that consumption of P. mume extracts with a nitrate- and amine-rich diet inhibited endogenous nitrosamine formation in humans, and thus resulted in a lower cancer risk. Overall, numerous studies have shown that P. mume possesses antitumor properties and can be used as complimentary therapy for malignant tumors, but the effective constituents and the mechanism of action are worthy of further confirmation.

Antimicrobial and Antiviral Activity

Several studies have suggested that P. mume possesses a wide range of antibacterial activities. Two independent research groups found that P. mume extracts inhibited common periodontal bacteria, such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and cariogenic bacteria such as Streptococcus mitis, S. sanguis, and S. mutans in vitro (Wong et al., 2010; Seneviratne et al., 2011). It also inhibited bacteria biofilm formation in the mouth cavity (Morimoto-Yamashita et al., 2011). In a six-month randomized single-blinded parallel-controlled clinical trial, a mouthrinse containing P. mume showed beneficial effects in patients with fixed orthodontic appliances by decreasing the bleeding index (Chen et al., 2012).

Some studies showed that the herbal combination of P. mume, Schizandrae Fructus, and Coptidis Rhizoma inhibited some Salmonella and Escherichia coli (E. coli) strains in vitro and in vivo (Kwon et al., 2008; Lee and Stein, 2011). P. mume also inhibited vero-toxin release from some E. coli strains (Sakagami, 2001). Mitani et al. (2018) attributed the antimicrobial activity of P. mume on enterobacteria to the phenolic compounds it contains, but not to the free citric acid. Besides its effects on enterobacteria, P. mume also inhibited the growth of Klebsiella pneumoniae strains, partly by down-regulating the mRNA levels of the capsular polysaccharide (CPS) biosynthesis genes, decreasing CPS production, and reducing bacterial resistance to the host’s immune system (Lin et al., 2013).

In antiviral studies, a fruitjuice concentrate of P. mume inhibited human influenza A virus infection before viral adsorption in Mard in Darby canine kidney (MDCK) cells, presumably through activity of a heat-stable lectin-like molecule (Yingsakmongkon et al., 2008). Furan derivatives and phenolics extract might be the active antiviral components of P. mume relevant to the inhibition of multiplication of influenza pandemic virus and several other RNA and DNA viruses (Sriwilaijaroen et al., 2011; Ikeda et al., 2019). A recent study showed that the umesu phenolics obtained from P. mume inhibited the multiplication of herpes simplex virus (HSV) and might prevent superficial HSV infections (Nishide et al., 2019).

Immunomodulatory Effects

Jung et al. (2010) found that continuous feeding with fermented P. mume and probiotics for four°weeks increased the macrophage ratio in peripheral blood and the T lymphocyte ratio in the spleen in Institute of Cancer Research (ICR)-bred mice. This specific diet also significantly increased antibody production and enhanced the mRNA expression of TNF-α and INF-γ in the splenocytes of experimentally infected mice by killing Bordetella bronchiseptica. The immune-enhancing effect of the diet has also been proven in broiler chicks infected with Salmonella gallinarum (Jung et al., 2010a). In another study, an ethanol extract of P. mume increased the IL-12p40 concentration in the serum and the T cell ratio in the spleen in C57BL/6 J mice (Tsuji et al., 2014). Furthermore, in the tumor-bearing mouse, MK615 treatment enhanced the CD4+/CD8+ ratios following irradiation and reduced tumor volume compared with the irradiated only group (Al-Jahdari et al., 2010). In the field of organ transplantation rejection, Lu et al. (2018) found that an herbal formula containing P. mume inhibited both the mammalian target of rapamycin (mTOR) and the NF-κB signaling pathways and significantly inhibited murine skin allograft rejection. The results of all these studies indicated that P. mume has dual-directional regulatory effects on mammalian immune system.

Anti-Inflammatory and Antioxidant Activities

P. mume was found to have anti-inflammatory activity in various investigations. Extracellular high-mobility group box-1 protein (HMGB1) is a potent inflammatory agent that can promote the release of pro-inflammatory mediators such as TNF-α. The triterpenoid compounds extracted from P. mume, such as oleanolic acid (compound 133), inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated RAW246.7 cells via the Nrf2/HO-1 pathway (Kawahara et al., 2009). MK615 or a water extract of P. mume inhibited the production of cytokines induced by LPS in RAW246.7 cells and in gingival fibroblast cells. The action was mediated by inhibiting the phosphorylation of ERK1/2, p38MAPK, and c-Jun N-terminal kinases (JNK), and blocking LPS-triggered NF-κB activation (Choi H-J. et al., 2007; Morimoto et al., 2009; Morimoto-Yamashita et al., 2015). In the atopic dermatitis animal model, treatment with fermented P. mume with probiotics significantly inhibited the development of skin lesions and decreased the peripheral eosinophil ratio and serum concentrations of IgE. In addition, the mRNA expression levels of IL-4, and TNF-α in the spleen were reduced, while the serum concentrations of IL-10 increased (Jung et al., 2010b).

Different radical-scavenging tests, such as the 2,2-diphenyl-1-picrylhydrazyl (DPHH) test and the superoxide anion radical test, are frequently used methods for determining the antioxidant activities of compounds. Numerous studies have shown that compounds extracted from different parts of the P. mume plant exhibited radical-scavenging effect in the DPHH and tests (Karakaya et al., 2001; Matsuda et al., 2003; Zhang et al., 2015; Pi and Lee, 2017). Hydrogen peroxide (H2O2) can increase the generation of intracellular ROS leading to DNA damage and apoptosis. An ethanol extract of P. mume fruit activated the Nrf2/HO-1 pathway and attenuated H2O2-induced oxidative stress and apoptosis in the murine skeletal muscle myoblast cell line C2C12 (Kang et al., 2016). Compounds derived from P. mume seeds also protected granulose cells from H2O2- induced apoptosis and promoted estradiol secretion (Kono et al., 2014). In a recent study, Jang et al. (2018) found that a new compound isolated from P. mume increased the concentrations of aldehyde dehydrogenase (ALDH) and Werner’s syndrome protein (WRN) in a dose-dependent manner and protected human bronchial epithelial cells and human epidermal keratinocytes from cigarette smoke-induced oxidative damage and DNA damage.

Inflammatory and oxidative stress are the etiology of many diseases. The anti-inflammatory and antioxidant activities of P. mume may be the underlying cause of its pharmacological properties. However, most of the antioxidant studies we collected are in vitro-based studies. Only a clinical experiment assessed oxidative parameters in the study (Beretta et al., 2016), thus the antioxidative properties of P. mume need to be confirmed by more studies in vivo in the future.

Other Pharmacological Activities

Besides the pharmacological effects mentioned above, some scattered studies have reported additional activities induced by P. mume. Compounds in the P. mume extract, especially acylated quinic acid, inhibited melanogenesis and showed no cytotoxicity in theophylline-stimulated B16 melanoma cells (Nakamura et al., 2013a; Pi and Lee, 2017), indicating that P. mume might possess a skin-whitening effect. Interestingly, the effect can be strengthened by fermentation with Poria cocos mycelium (Kang et al., 2019). In folk remedies, P. mume has been reported to promote salivation. Some formulations, such as San Gan Hua Yin, which contain P. mume, can significantly improve the salivary flow rate and mitigate the severity of xerostomia in cancer patients (Murakami et al., 2009). Diets supplemented with P. mume extract significantly reduced serum ammonia concentration, elevated hepatic and muscle glycogen concentrations, increased lactate dehydrogenase, citrate synthase, and glutathione peroxidase activities, and decreased creatine kinase activity in skeletal muscles, and as a result, ameliorated exercise-induced fatigue, improved running endurance in rats. The function might relate to enhancing the oxidative capacity of skeletal muscle and inducing the muscle to prefer fatty acids for fuel use rather than amino acids or carbohydrates (Kim et al., 2008; Kim et al., 2020). A cross-sectional pilot study found that patients who receiving P. mume regularly had a significantly lower odds ratio (OR) for the presence of allergy symptoms. In the same study, oral treatment with P. mume extract attenuated the passive cutaneous anaphylaxis (PCA) reaction and mast cell degranulation in IgE-sensitized mice. The anti-allergic activity might relate to compounds including vanillin, syringic acid, protocatechuic aldehyde, lyoniresinol, and p-coumaric acid (Kono et al., 2018). Ina et al. (2002) found that the chlorogenic acid extract from P. mume reduced bradykinin and prostaglandin E2 production, inhibited acetic acid-induced writhing behavior in mice, and showed analgesic effects. The compound also relieved the tension caused by ether stresses in menopausal model rats, because it recovered catecholamine levels and decreased the adrenocorticotropic hormone (ACTH) levels in the plasma of model rats (Ina et al., 2004).

Toxicity and Safety

A systematic toxicology study evaluated the safety of the ethanol extract of P. mume. The oral acute test showed no lethal effects in rats and mice at the maximum tolerated dose of 20 g/kg. In the subacute toxicity test, no adverse effects were observed at doses greater than 3.33 g/kg body weight for 30°days. In addition, no mutagenic or genotoxic effects were observed in the experiments, including the Ames test, the micronucleus test, and the sperm abnormality test (Lu et al., 2009). The safety profile of mumefural, a bioactive compound derived from the heated fruit of P. mume, was also investigated by acute and subacute oral toxicity experiments. The results indicated that the approximate lethal dose of mumefural in ICR mice was >5 g/kg (Kim et al., 2020).

On the other hand, a few clinical studies evaluated the safety of P. mume during the experiments, and no adverse events were observed (Hoshino et al., 2013; Takemura et al., 2014). These studies demonstrated that P. mume could be used safely as a dietary supplement.

However, in recent years, several studies have found that P. mume peamaclein (also known as gibberellin-regulated protein or GRP) is a cross-reactive allergen between P. mume and peach (P. persica), and could cause food-dependent exercise-induced anaphylaxis (Iijima et al., 2015; Inomata et al., 2016; Yamanaka et al., 2019). It might be necessary to remind individuals who are allergic to peaches to avoid eating P. mume.

Conclusions and Future Perspectives

As an important medicinal herb and food commodity, the Japanese apricot or Chinese plum (P. mume) has aroused the interest of numerous researchers. In this review, we conducted an exhaustive search of the literature describing the phytochemical and pharmacological properties of P. mume. We found that 192 compounds have been isolated from different parts of the plant, including phenolics, organic acids, steroids, terpenes, benzyl glycosides, cyanogenic glycosides, furfurals, lignans, alkaloid, amino acids, and some other compounds. Numerous studies disclosed the pharmacological activities of P. mume, including its anti-diabetic, antihyperlipidemic, lowering uric acid, anti-osteoporosis, hepatoprotection, anti-H. pylori, stimulating intestinal motility, anti-inflammatory, antioxidant, improving blood fluidity effects, as well as its inhibiting platelet aggregation, anti-tumor, antimicrobial, antiviral, immunomodulation, skin whitening, stimulating salivary secretion, anti-fatigue, anti-allergic, and analgesic properties.

Several studies have established connections between the chemical compositions and the pharmacological properties of the plant. For example, the phenolic compounds confer its antidiabetic (Lee et al., 2016), antimicrobial (Mitani et al., 2018), antiviral (Ikeda et al., 2019), and anti-oxidative (Xia et al., 2010) activities; organic acid components exert hypolipidemic (Choi et al., 2007) and antibacterial (Gao, 2012) effects; and steroids and terpenes inhibit osteoclast differentiation (Yan et al., 2015). However, most of the pharmacological studies of P. mume are based on crude extracts, refined preparations such as MK615, and formulas containing P. mume such as wu mei wan or TCM decoctions. Thus, studies elucidating the relationships between the pharmacodynamics and the bioactive constituents of the plant still require further investigation.

Among the pharmacological properties of P. mume, the antidiabetic (Tu et al., 2013) and hepatoprotective effects (Hokari, 2012; Beretta et al., 2016), and the inhibitory effects on chronic gastritis (Enomoto et al., 2010) and gastroesophageal reflux (Maekita, 2015), blood pressure lowering effects (Takemura et al., 2014), and antitumor activities (Matsushita et al., 2010; Hoshino et al., 2013)are particularly notable. Because these pharmacological properties have been proven not only by in vitro and in vivo experiments but also by several clinical studies. However, most clinical studies have only involved small-sample clinical trials or case reports. Thus, to provide strong evidence of clinical applications, well-designed randomized controlled trials, cohort studies, nested case-control studies, and real-world studies need to be carried out appropriately in the future.

With regard to the safety profile of P. mume, existing studies have provided only limited information. More systematic toxicology studies still need to be carried out in the future on the aqueous extraction of P. mume, refined products such as MK 615, and pharmacodynamic components of the plant. The side-effect associating to the P. mume usage observed in the clinical experiments also needs to be identified and reported in future clinical studies.

In terms of quality control, the information about the harvest season and the maturity level of the fruit, the quantitative studies of the index components are scarcely in the existing studies. These should be emphasized in the future to promote the reproducibility of the studies.

In summary, this review provided a comprehensive information regarding P. mume, raised limitations of existing studies, and proposed future research directions, and has established a groundwork for further utilization and development of the plant.

Statements

Author contributions

GD and JL conceived the manuscript, X-PG and YT wrote and revised the manuscript, Y-YS collected the date and revised the manuscript. All authors approved the final version of the manuscript for submission.

Funding

This study was supported by two grants from the Natural Science Foundation of Hubei Province, China (Grant Nos. 2014CKB516 and 2017CFB782).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Summary

Keywords

Prunus mume, pharmacological activities, clinical application, functional mechanism, phytochemical constituents

Citation

Gong X-P, Tang Y, Song Y-Y, Du G and Li J (2021) Comprehensive Review of Phytochemical Constituents, Pharmacological Properties, and Clinical Applications of Prunus mume. Front. Pharmacol. 12:679378. doi: 10.3389/fphar.2021.679378

Received

11 March 2021

Accepted

04 May 2021

Published

28 May 2021

Volume

12 - 2021

Edited by

Michał Tomczyk, Medical University of Bialystok, Poland

Reviewed by

Syed Babar Jamal, National University of Medical Sciences (NUMS), Pakistan

Anthony Bussiere, Stragen Pharma SA, Switzerland

Updates

Copyright

© 2021 Gong, Tang, Song, Du and Li.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Guang Du, ; Juan Li,

†

These authors share first authorship

This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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