Leonurus japonicus (Chinese motherwort), an excellent traditional medicine for obstetrical and gynecological diseases: A comprehensive overview

Abstract

Leonurus japonicus Houtt. is a traditional medicinal herb with significant effects; dating back more than 1800 years, it is widely used in Asia. In traditional Chinese medicine, it is essential in the treatment of menstrual and delivery disorders caused by blood stasis, such as dysmenorrhea, amenorrhea, and postpartum hemorrhage. In the last three decades, many phytochemists, pharmacologists, and doctors have focused on the chemical components, pharmacological activities, and clinical applications of L. japonicus. More than 280 chemical compounds have been isolated from this plant. The effects of most of the terpenoids and alkaloids isolated from the plant have been found to be closely related to the traditional functions of L. japonicus. Owing to its excellent therapeutic effects for obstetrical and gynecological diseases, L. japonicus has been widely used in both ancient and modern times. Nowadays, it has also been developed into a series of Chinese patent medicines in clinics in China. This review summarizes the phytochemistry, pharmacology, and clinical applications of L. japonicus.

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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Review
Leonurus japonicus (Chinese motherwort), an excellent traditional medicine
for obstetrical and gynecological diseases: A comprehensive overview
Lu-Lin Miao
a,b,c
, Qin-Mei Zhou
a,c
, Cheng Peng
a,b,⁎
, Zhao-Hua Liu
d
, Liang Xiong
a,b,c,⁎
a
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese
Medicine, Chengdu 611137, China
b
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
c
Institute of Innovative Medicine Ingredients of Southwest Specialty Medicinal Materials, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
d
Chengdu No. 1 Pharmaceutical Co. Ltd., Chengdu 610031, China
ARTICLE INFO
Keywords:
Leonurus japonicus
Clinical application
Pharmacology
Phytochemistry
ABSTRACT
Leonurus japonicus Houtt. is a traditional medicinal herb with significant effects; dating back more than 1800
years, it is widely used in Asia. In traditional Chinese medicine, it is essential in the treatment of menstrual and
delivery disorders caused by blood stasis, such as dysmenorrhea, amenorrhea, and postpartum hemorrhage. In
the last three decades, many phytochemists, pharmacologists, and doctors have focused on the chemical com-
ponents, pharmacological activities, and clinical applications of L. japonicus. More than 280 chemical com-
pounds have been isolated from this plant. The effects of most of the terpenoids and alkaloids isolated from the
plant have been found to be closely related to the traditional functions of L. japonicus. Owing to its excellent
therapeutic effects for obstetrical and gynecological diseases, L. japonicus has been widely used in both ancient
and modern times. Nowadays, it has also been developed into a series of Chinese patent medicines in clinics in
China. This review summarizes the phytochemistry, pharmacology, and clinical applications of L. japonicus.
1. Introduction
Leonurus japonicus Houtt. (synonyms Leonurus artemisia (Lour.) S.Y.
Hu and Leonurus heterophyllus Sweet.) [1] is widely used as an ethno-
pharmacological medicine in China, Japan, and South Korea. In Chi-
nese, L. japonicus (Chinese motherwort) is named Yi Mu Cao, which
means “good for women” and indicates its traditional function. It was
described in Shennong Bencao Jing, the first pharmacy monograph in
China, and was classified as “the highest grade” with non-toxicity.
Many classic books have documented L. japonicus;Ben Cao Gang Mu
described it as a “panacea in treating diseases about blood.” In modern
times, the aerial parts of L. japonicus are commonly used in Chinese
herbal medicine for regulating menstrual disturbance, dysmenorrhea,
amenorrhea, blood stasis, and postpartum hemorrhage, as well as ac-
tivating blood circulation, diuretics, and dispelling edema [2,3]. Par-
ticularly in promoting blood circulation and removing blood stasis, L.
japonicus shows extraordinary clinical effects.
Owing to its important role in woman’s diseases, scholars have
begun to pay much attention to this plant and conducted in-depth re-
search on its chemical components and pharmacological activities. So
far, over 280 secondary metabolites have been isolated from this plant,
showing vasorelaxant activity [4], coagulant activity [5], cytotoxic
activity [6], angiogenic activity [7], antibacterial activity [8,9], anti-
platelet aggregative activity [6,9–12], and an effect on the uterine
smooth muscle [13]. Meanwhile, many Chinese patent medicines based
on L. japonicus have been developed, including injections, granules,
tablets, mixtures, capsules, soft capsules, ointments, and dripping pills,
which are mainly used for gynecological and obstetrical diseases.
Over the years, several reviews have appeared on L. japonicus,
mainly concerning its chemical constituents and pharmacological ac-
tivities [14–17]. However, there is still a deficiency in reviews of its
clinical application. This review is intended to fill the void and sup-
plement the reviews of its chemical compounds and their pharmaco-
logical activities.
2. Phytochemistry of L. japonicus and pharmacology of its
chemical compounds
Since the 1990s, L. japonicus has been phytochemically investigated
by several research groups, resulting in the identification of more than
https://doi.org/10.1016/j.biopha.2019.109060
Received 18 April 2019; Received in revised form 31 May 2019; Accepted 31 May 2019
⁎
Corresponding authors at: State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu
University of Traditional Chinese Medicine, Chengdu 611137, China.
E-mail addresses: pengchengchengdu@126.com (C. Peng), xiling0505@126.com (L. Xiong).
Biomedicine & Pharmacotherapy 117 (2019) 109060
0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T

Table 1
Chemical compounds from L. japonicus.
No Name Reference
Monoterpenoids
19-Hydroxylinalool-6-O-glucoside [18]
29-Hydroxylinalool-9-O-glucoside [18]
3Ajugoside [19]
4(−)-Loliolide [20]
Sesquiterpenoids
5Staphylionoside E [21]
6(7E,9ξ)-9-Hydroxy-5,7-megastigmadien-4-one [22]
79-Hydroxy-megastigma-4,7-dien-3-one-9-O-glucopyranoside [21]
8Citroside A [21]
9Megastigmane [23]
10 3-Oxo-α-ionone [9]
11 (+)-Dehydrovomifoliol [9]
12 (6S,9R)-Vomifoliol [22]
13 (3S,5R,6S,7E,9R)-5,6-Epoxy-3,9-dihydroxy-7-megastigmene [22]
14 5,6-Epoxy-3-hydroxy-7-megastigmen-9-one [22]
15 (+)-3-Hydroxy-β-ionone [9]
16 (2S,5S)-2-Hydroxy-2,6,10,10-tetramethyl-1-oxaspiro-[4.5]dec-6-en-8-one [9]
17 Chamigrenal [9]
18 β-Chamigrenic acid [11]
19 (−)-(1S*,4S*,9S*)-1,9-Epoxybisabola-2,10-diene-4-ol [9]
20 (−)-(1S*,2S*,3R*)-3-Ethoxycupar-5-ene-1,2-diol [9]
21 Arteannuin B [9]
22 Saniculamoid D [11]
23 7α(H)-Eudesmane-4,11(12)-diene-3-one-2β-hydroxy-13-β-D-glucopyranoside [21]
Diterpenoids
24 Prehispanolone [24,25,26,27,28]
25 Iso-preleoheterin [26,27]
26 Preleoheterin [25,27]
27 13-Epi-preleoheterin [27]
28 16-Oxo-leoheteronone A [29]
29 (+)-(5S,7R,8R,9R,10S,13S,15R)-7-Hydroxy-15-methoxy-9,13;15,16-diepoxylabdan-6,16-dione [10]
30 14,15-Dihydroprehispanolone [24]
31 Leoheteronone B [30]
32 15-Epileoheteronone B [30]
33 Leopersin B [30]
34 15-Epileopersin B [30]
35 Leoheteronone A [30]
36 6β,15α-Dihydroxy-9α,13α:15,16-bisepoxylabdan-7-one [31]
37 6β,15β-Dihydroxy-9α,13α:15,16-bisepoxylabdan-7-one [31]
38 Leoheteronone D [30]
39 15-Epileoheteronone D [30]
40 Leoheteronone E [30]
41 15-Epileoheteronone E [30]
42 Leoheteronone C [30]
43 Leosibirinone A [32]
44 Isoleopersin J [31]
45 15-Epi-isoleopersin J [31]
46 (+)-(5S,7R,8R,9R,10S,13S,15R)-7-Hydroxy-15-ethoxy-9,13;15,16-diepoxylabdan-6-one [10]
47 (−)-(5S,7R,8R,9R,10S,13S,15S)-7-Hydroxy-15-methoxy-9,13;15,16-diepoxylabdan-6-one. [10]
48 (3α,7β,9α,15β)-9,13:15,16-Diepoxy-15-ethoxy-3,7-dihydroxylabdan-6-one [33]
49 (3α,7β,9α,15α)-9,13:15,16-Diepoxy-15-ethoxy-3,7-dihydroxylabdan-6-one [33]
50 (3α,7β,9α,15α)-3-Acetyloxy-9,13:15,16-diepoxy-7-hydroxy-15-methoxylabdan-6-one [33]
51 (−)-(3R,5S,7R,8R,9R,10S,13S,15S)-3-Acetoxy-7-hydroxy-15-methoxy-9,13;15,16-diepoxylabdan-6-one [10]
52 (3α,7β,9α,15α)-3-Acetyloxy-9,13:15,16-diepoxy-15-ethoxy-7-hydroxylabdan-6-one [10,33]
53 (3α,7β,9α,15β)-3-Acetyloxy-9,13:15,16-diepoxy-15-ethoxy-7-hydroxylabdan-6-one [10,33]
54 Leosibirone B [10]
55 15-Epi-leosibirone B [10]
56 Leopersin C [30]
57 15-Epileopersin C [30]
58 3α-Acetoxy-15-O-methylleopersin C [32]
59 (−)-(3R,5S,7R,8R,9R,10S,13R,15R)-3-Acetoxy-7-hydroxy-15-ethoxy-9,13;15,16-diepoxylabdan-6-one [10]
60 (−)-(5S,7R,8R,9R,10S,13R,15R)-7-Hydroxy-15-ethoxy-9,13;15,16-diepoxylabdan-6-one [10]
61 Leopersin G [34]
62 Leoheteronin E [35]
63 Leoheteronin A [34,35]
64 Leoheteronin C [35]
65 Leoheteronin B [35]
66 15-Methoxyleoheteronin B [29,36]
67 Leojapone C [11]
68 Leojaponicin [36]
69 Leojaponicone A [37]
70 Isoleojaponicone A [37]
(continued on next page)
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
2

Table 1 (continued)
No Name Reference
71 Methylisoleojaponicone A [37]
72 Leoheterin [25,35,38,39]
73 Leojapone A [11]
74 Isoleosibirin [40]
75 Hispanolone [27,35]
76 Galeopsin [25,29,30,34,35,39]
77 6β,9α-Dihydroxy-15,16-epoxy-13(16),14-labdadien-7-one [31]
78 15,16-Epoxy-3α,6β,9α-trihydroxylabda-13(16),14-dien-7-one [41]
79 15,16-Epoxy-6β,9α-dihydroxylabda-13(16),14-dien-3,7-dione [41]
80 Hispanone [29,30,35]
81 15,16-Epoxy-3α-hydroxylabda-8,13(16),14-trien-7-one [42]
82 6β-Hydroxy-15,16-epoxylabda-8,13(16),14-trien-7-one [43]
83 Heteronone A [44]
84 Leojapone B [11]
85 Leojaponin [26,27,45]
86 Heteronone B [44,46]
87 Leojaponin C [38,47]
88 (6β)-15,16-Epoxy-15-ethoxy-6,13-dihydroxylabd-8-en-7-one [33]
89 Leojapone D [11]
90 Leojaponin I [22]
91 Leojaponin E [48]
92 Leojaponin F [48]
93 Methoxylsecolabdane [43]
94 Seco-labdane [43]
95 Secoleojaponol [43]
96 8,9-Secohispanolone [29]
97 (−)-ξ8-Acetoxy-15,16-epoxy-8,9-seco-13(16),14-labdadiene-7,9-dione [31]
98 Leojaponin D [38]
99 Leojaponin B [38]
100 Villenol [38]
101 Leoheteronin D [34,35,38]
102 Leoheteronin F [34]
103 Leojaponin K [22]
104 Leojaponin L [22]
105 Leojaponin J [22]
106 Leojaponic acid B [20]
107 (+)-14,15-Bisnorlabda-8-en-7,13-dione [22,36]
108 Leojaponic acid A [20]
109 Methyl 15,16-dinor-7-oxolabda-8-ene-14-oate [36]
110 (−)-3α-Acetoxy-6β-hydroxy-15,16-dinorlabd-8(9)-ene-13-yne-7-one [5]
111 Leonuketal [4]
112 Isoleojaponin [45]
113 Leojaponin G [22]
114 Leojaponin H [22]
115 Leojaponin A [38]
Triterpenoids
116 Phlomistetraol B [49]
117 Leonurusoleanolide A [49,50]
118 Leonurusoleanolide B [49,50]
119 Leonurusoleanolide C [49,50]
120 Leonurusoleanolide D [49,50]
121 Leonurusoleanolide J [49]
122 Leonurusoleanolide G [49]
123 Leonurusoleanolide H [49]
124 Leonurusoleanolide E [49]
125 Leonurusoleanolide F [49]
126 Leonurusoleanolide I [49]
127 (23S)-23-Methoxy-cycloarta-24-en-3β-ol [51]
128 Cycloart-23,25(26)-dien-3β-ol [51]
129 (24R)-Cycloartane-24,25-triol-3β-tetradecanoate [51]
130 22α-Methoxy-20-taraxastene-3β-ol [51]
131 12-Oleanene-3β,21β-diol [51]
132 Oleanolic acid [51]
133 Urjinolic acid [52]
134 β-Amyrenol [52]
135 Leonuronin B [52]
136 Leonuronin A [52]
137 2α,3β,23-Trihydroxyoleana-11,13(18)-dien-28-oic acid [52]
138 12-En-3β-hydroxy-urs-11-one [51]
139 α-Amyrin [51]
140 Zizyberenalic acid [51]
141 20S-17β,29-Epoxy-28-norlupan-3β-ol [51]
142 28-Norlup-20(29)-ene-3β,17β-diol [51]
143 28-Norlup-20(29)-en-3β-hydroxy-17β-hydroperoxide [51]
(continued on next page)
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
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Table 1 (continued)
No Name Reference
144 Lupeol [51]
145 Betulin [51]
146 Betulinic acid [51]
147 Messagenic acid C [51]
148 Dihydrobetulin [51]
149 Cornusalterin D [51]
150 Cornusalterin J [51]
151 Foliasalacin A
4
[51]
Steroids
152 β-Sitosterol [6,35,53]
153 (24S)-Saringosterol [6]
154 (3β,7α)-Stigmast-5-ene-3,7-diol [6]
155 (3β,7α)-7-Methoxystigmast-5-en-3-ol [6]
156 3β-Hydroxy-7α-ethoxy-24β-ethylcholest-5-ene [6]
157 Mono-β-sitosteryl azelate [6]
158 Sitosterol-3-β-D-glucose [22]
159 3-β-O-(2-Acetamido-2-deoxy-β-D-glucopyranosyl)-β-sitosterol [53]
160 β-Sitosterone [6]
161 (24S)-Stigmast-4,28-diene-24-ol-3-one [6]
162 24R-5α-Stigmast-3,6-dione [6]
163 Demethylincisterol A
3
[6]
164 Cyathisterone [6]
165 (22E,24R)-5α,8α-Epidioxyergosta-6,22-dien-3β-ol [5]
166 5α,8α-Epidioxy-23-methyl-(22E,24R)-ergosta-6,22-dien-3β-ol [6]
167 (22E,24R)-5α,8α-Epidioxyergosta-6,9(11),22-trien-3β-ol [5]
168 (24R)-3-β-O-(2-Acetamido-2-deoxy-β-D-glucopyranosyl)-ergosta-5-ene [53]
169 (24S)-3-β-O-(2-Acetamido-2-deoxy-β-D-glucopyranosyl)-ergosta-5-ene [53]
170 3-β-O-(2-Acetamido-2-deoxy-β-D-glucopyranosyl)-ergosta-5,24(28)-diene [53]
Alkaloids, amino acids, and cyclopeptides
171 Cycloleonuripeptide A [54]
172 Cycloleonuripeptide B [54,55]
173 Cycloleonuripeptide C [13,54]
174 Cycloleonuripeptide D [13,55,56]
175 Cycloleonuripeptide E [57]
176 Cycloleonuripeptide F [57]
177 Cycloleonuripeptide G [13]
178 Cycloleonuripeptide H [13]
179 Cycloleonurinin [58]
180 Hapepunine 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside [13]
181 Hapepunine 3-O-β-cellobioside [13]
182 Yibeinoside A [13]
183 Imperialine-3β-D-glucoside [13]
184 N
1
,N
5
,N
10
-Tri-p-(ZZZ)-coumaroylspermidine [13]
185 N
1
,N
5
,N
10
-Tri-p-(EEZ)-coumaroylspermidine [13]
186 Juzirine [13]
187 Leonurine [23,55,59,60]
188 10-Methoxy-leonurine [61]
189 4-Hydroxy-3,5-dimethoxybenzoicacid 5-guanidinopentyl ester [55]
190 Stachydrine [18,59,60,62,63]
191 Choline [18,63]
192 Trigonelline [63]
193 3-Hydroxypyridine [63]
194 3-Hydroxy-2-methylpyridine [63]
195 5-Hydroxy-2-hydroxymethylpyridine [63]
196 Uracil [63]
197 5-Methyluracil [63]
198 Guanosine [59]
199 L-tryptophan [59]
200 L-Phenylalanine [59]
201 Valine [63]
202 N-Isobutyl-L-valine [63]
203 L-Pyroglutamate acid methyl ester [63]
204 Alanine [63]
Flavonoids
205 Genkwanin [32,64,65]
206 Hydroxygenkwanin [61]
207 Luteolin [66]
208 Apigenin [64,65,66,67]
209 Wogonin [68]
210 5,7,3′,4′,5′-Pentamethoxy flavone [68]
211 Cosmosiin [32]
212 Spinosin [13]
213 Linarin [13]
(continued on next page)
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Table 1 (continued)
No Name Reference
214 Apigenin-7-O-β-D-glucopyranoside [13]
215 Kaempferol [66]
216 Quercetin [65,66,68]
217 Myricetin [66]
218 Kaempferol-3-O-β-D-glucopyranoside [69]
219 Kaempferol-3-O-β-D-galactopyranoside [69]
220 Isoquercitrin [32,65,70]
221 Hyperoside [65,69]
222 Kaempferol-7-O-α-L-rhamnoside [62]
223 Kaempferol-3-O-β-D-glucopyranoside-7-O-α-L-rhamnoside [62]
224 Nicotiflorin [32]
225 Kaempferol-3-neohesperidoside [69]
226 Kaempferol-3-O-β-robinobinoside [69]
227 Rutin [18,32,65]
228 Quercetin-3-O-robinoside [65,69]
229 Tiliroside [32,64,67,70]
230 Kaempferol-3-O-(6′′-O-cis-p-coumaroyl)-β-D-glucopyranoside [67]
231 Leonurusoide A [71]
232 Leonurusoide C [71]
233 Leonurusoide E [61,71]
234 Heteronoside [72]
235 Leonurusoide B [71]
236 Leonurusoide D [71]
237 2′′′-Syringylrutin [69,71]
238 Quercetin-3-O-[(3-O-syringoyl-α-L-rhamnopyranosyl)-(1→6)-β-D-glucopyranoside] [64]
239 Daidzein [68]
Phenylpropanoids
240 Ferulic acid [67]
241 4′-Hydroxy-2,3-dihydrocinnamic acid tetracosyl ester [73]
242 2-Feruloyl-4-syringoyl or 5-feruloyl-3-syringoyl glucaric acid [74]
243 2-Syringoyl-4-feruloyl or 5-syringoyl-3-feruloyl glucaric acid [74]
244 3-Feruloyl-4-syringoyl or 4-feruloyl-3-syringoyl glucaric acid [74]
245 Martynoside [67]
246 2-(3,4-Dihydroxyphenyl)-O-α-L-arabinopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→3)-6-O-β-D-glucopyranoside [21]
247 Bergapten [12]
248 Xanthotoxin [12]
249 Isopimpinellin [12]
250 Imperatorin [12]
251 Isogosferal [12]
252 Nodakenin [18]
253 Murrayone [12]
254 Auraptenol [12,50]
255 Osthol [12]
256 Meransin hydrate [12]
257 Isomeranzim [12]
258 Dimethylgomisin J [73]
259 Gomisin K
1
[73]
260 Sesamin [73]
261 (−)-Pinoresinol [22]
262 (−)-Syringaresinol [22]
Other compounds
263 Leonuriside B [70]
264 Leonoside E [21]
265 Cistanoside E [21]
266 Leonoside F [21]
267 Leonuriside A [70]
268 4-Hydroxybenzaldehyde [73]
269 Vanillin [73]
270 Syringic acid [61,66]
271 Syringic acid methyl ester [22]
272 Gallic acid [66]
273 3,4,5-Trimethoxybenzoic acid [22]
274 1-(3-Ethylphenyl) ethane-1,2-diol [20]
275 1,6-Di-O-syringoyl-β-D-glucopyranose [64]
276 Leonurenosid I [18]
277 Leonurenosid II [18]
278 2,6-Dimethyl-2E,7-octadiene-1,6-diol [19]
279 (–)-Nonadeca-5,6-dienoic acid methyl ester [75]
280 Methyl octadeca-5,6-dienoate [75]
281 Arachidic acid [75]
282 Heneicosanoic acid [75]
283 Heptacosanoic acid [75]
284 Methyl myristate [75]
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
5

280 compounds (Table 1). These chemical constituents are mainly
monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, steroids,
alkaloids, flavonoids, and phenylpropanoids. However, only a few of
them have been reported to show bioactivities.
2.1. Phytochemistry and pharmacology of terpenoids
2.1.1. Phytochemistry of monoterpenoids and sesquiterpenoids
So far, only four monoterpenoids (1–4) and 19 sesquiterpenoids
(5–23) have been isolated from L. japonicus (Fig. 1). Among those, the
majority are megastigmane analogs. The other sesquiterpenoid sub-
types include chamigrane, bisabolane, cuparane, chromolaevane, and
eudesmane.
2.1.2. Phytochemistry of diterpenoids
Diterpenoids are a major component in the genus Leonurus. Previous
investigations of L. japonicus have led to the isolation of more than 90
diterpenoids (24–115) (Figs. 2―4), which belong to the labdane type,
except compounds 111–115. More than one third of these are bis-
spirolabdane diterpenoids (24–60) (Fig. 2). These bis-spirolabdanes
share structural similarities; the main differences are the substituents at
carbons C-3, C-6, C-7, C-8, and C-15, as well as different absolute
configurations at chiral carbons, especially at C-13.
In addition to bis-spirolabdane diterpenoids, 37 labdane analogs
(61–97) were identified, with a furan, furolactone, or tetrahydrofuran
ring at the end of the side chain at C-9 (Fig. 3). Compounds 61–71
belong to the furolactone type, and compounds 72–86 belong to the
furan type, while only five tetrahydrofuran-type labdanes (87–91) were
isolated. It should be noted that six unusual 8,9-seco-labdane diterpe-
noids (92–97) were discovered in L. japonicus [29,31,43,48]. In addi-
tion, eight labdane diterpenoids (98–105) were found to possess a side
chain at C-9 with a hydroxyl group at the terminus [22,34,35,38]
(Fig. 4). Compounds 106–110 are unusual dinor- or trinorlabdane di-
terpenoids [5,20,22,36]. Interestingly, leonuketal (111) possesses an
Fig. 1. Structures of monoterpenoids and sesquiterpenoids from L. japonicus.
Fig. 2. Structures of bis-spirolabdane diterpenoids from L. japonicus.
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
6

unprecedented tetracyclic skeleton, which comprises a bridged spir-
oketal moiety fused with a ketal-γ-lactone unit [4]. Compounds
112–114 are halimane diterpenes with a unique cross-conjugated α,β-
unsaturated ketone system [22,45], while compound 115 is a clerodane
diterpenoid characterized by a 4–O–7 bridge [38].
2.1.3. Phytochemistry of triterpenoids
To date, 36 triterpenoids have been isolated from L. japonicus
(Fig. 5), including 11 unusual nortriterpenoids (116–126) that possess
a distinctive 19(18→17)-abeo-28-noroleanane-type spirocyclic skeleton
with a trans- or cis-acyl substituent at C-3 or C-23 [49,50]. Compounds
117,118;119,120;122,123; and 124,125 were found to exist as
equilibrium mixtures of trans- and cis-isomers. It should be mentioned
that ester derivatives of 28-noroleanane-type spirocyclic triterpenoids
were only isolated from fruits of L. japonicus. Other triterpenoids are of
the cycloartane, taraxastane, oleanane, ursane, lupane, euphane, and
dammarane types [51,52].
2.1.4. Pharmacology of terpenoids
Leonurus japonicus is commonly used in Chinese herbal medicine for
regulating menstrual disturbance and invigorating blood circulation in
hematological and gynecological diseases. Related to its traditional
effects, some of the terpenoids showed antithrombotic, vasorelaxant,
and anti-platelet aggregative activities, including (2S,5S)-2-hydroxy-
2,6,10,10-tetramethyl-1-oxaspiro-[4.5]dec-6-en-8-one (16) [9], pre-
hispanolone (24) [24,28], (−)-(3R,5S,7R,8R,9R,10S,13R,15R)-3-
acetoxy-7-hydroxy-15-ethoxy-9,13;15,16-diepoxylabdan-6-one (59)
[10], (−)-(5S,7R,8R,9R,10S,13R,15R)-7-hydroxy-15-ethoxy-9,13;15
,16-diepoxylabdan-6-one (60) [10], and leonuketal (111) [4]. It can be
suggested that terpenoids are the effective substances for promoting
blood circulation and removing stasis. Interestingly, instead of in-
hibiting abnormal platelet aggregation, leojapones A (73), B (84), and
C (67) boosted it significantly, with the promotion rates of 12.90%,
19.24%, and 24.11% [11]. Moreover, (−)-3α-acetoxy-6β-hydroxy-
15,16-dinorlabd-8(9)-ene-13-yne-7-one (110) showed a blood coagu-
lant effect by reducing activated partial thromboplastin times, pro-
thrombin times, and thrombin times, together with increasing fi-
brinogen levels [5]. These reports suggest that the influences on platelet
aggregation of terpenoids, especially diterpenoids, are closely con-
nected with their chemical structures.
Several terpenoids have been demonstrated to have significant anti-
inflammatory activity. Leoheterin (72) and galeopsin (76) both re-
vealed potential anti-inflammatory properties through the prohibition
of proinflammatory factor TNF-α [39]. Hispanone (80) inhibited su-
peroxide anion generation, with a 58.43% suppression ratio, and elas-
tase release, with a 70.06% inhibition suppression ratio. The IC
50
values
were 8.48 μM and 5.42 μM [29]. 15,16-Epoxy-3α-hydroxylabda-
8,13(16), 14-trien-7-one (81) also showed a significant anti-in-
flammatory effect in inhibiting NF-κB phosphorylation and decreased
the gene expressions of iNOS and COX-2, as well as TNF-α secretion on
LPS-stimulated RAW 264.7 macrophages [42]. Leojaponins E and F (91
and 92) inhibited LPS-induced PGE2 production in a dose-dependent
manner at concentrations from 5 to 20 μM [48].
Some terpenoids possess inhibitory effects on acetylcholinesterase
(leopersin G and leoheteronin A, 61 and 63, leojaponicone A, 69, iso-
leojaponicone A, 70, methylisoleojaponicone A, 71) [34,37] and α-
Fig. 3. Structures of labdane diterpenoids from L. japonicus with a furan, furolactone, or tetrahydrofuran ring.
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
7

glucosidase (15-methoxyleoheteronin B, 66) [36]. In addition, leoja-
ponin (85) presented dramatically neuroprotective property in primary
cultured rat cortical cells damaged by glutamate [26]. Five diterpenoids
(85,87,90,105, and 113) could inhibit melanin production in B16F10
melanoma cells at 20 μM, but two similar diterpenoids (104 and 114)
and two sesquiterpenoids (6and 13) promoted melanin production at
the same concentration [22]. Chamigrenal (17) and arteannuin B (21)
showed weak antibacterial activity; the former suppressed proliferation
of three Gram-positive strains containing Macrococcus caseolyticus,
Staphylococcus auricularis, and Staphylococcus aureus, while the latter
acted against Escherichia coli and Enterobacter aerogenes [9]. Leoheterin
(72), leojaponins A–C (115,99, and 87), and villenol (100) could re-
strain IL-2 production in PMA- and ionomycin-activated T cells at a
concentration of 20 μM [38]. 6β-Hydroxy-15,16-epoxylabda-
8,13(16),14-trien-7-one (82) showed potential cytotoxicity against
HeLa cells (IC
50
= 23.75 μM) [31]. Triterpenoids 116–126 were as-
sayed for their cytotoxicity against BGC-823 and KE-97 gastric carci-
noma, Huh-7 hepatocarcinoma, Jurkat T cell lymphoblasts, and MCF-7
breast adenocarcinoma. Only one triterpenoid, leonurusoleanolide J
(121), exhibited significant cytotoxicity, with IC
50
values less than 10
μM [49]. Two oleanane-type triterpenoids, leonuronins A and B(135
and 136), exhibited significant cytotoxicity against HeLa and A549 cells
[52].
2.2. Phytochemistry and pharmacology of steroids
2.2.1. Phytochemistry of steroids
Eleven stigmastanes (152–162) and eight ergostanes (163–170)
have been isolated and characterized from L. japonicus (Fig. 6). Among
these, compound 157 is a β-sitosterol ester derivative of an aliphatic
diacid, and compound 163 is a norergostane [6]. In 2014, four unusual
steroid N-acetylglucosaminides (159 and 168–170) were isolated from
dried fruits of L. japonicus [53].
2.2.2. Pharmacology of steroid compounds
Steroids from L. japonicus are seldom used for assaying activities
that are related to the traditional uses of L. japonicus. β-Sitosterone
(160) and 24R-5α-stigmast-3,6-dione (162) have considerable in-
hibitory activities against ADP-induced platelet aggregation with the
inhibition rates of 17.89% and 31.18%, respectively [6].
2.3. Phytochemistry and pharmacology of alkaloids, amino acids, and
cyclopeptides
2.3.1. Phytochemistry of alkaloids, amino acids, and cyclopeptides
Alkaloids are the main active chemical constituents, with a rela-
tively high content, in L. japonicus. Many subtypes of alkaloids, amino
acids, and cyclopeptides have been isolated (171–204), such as gua-
nidines, spermidines, pyridines, nucleosides, steroidal alkaloids, cy-
clopeptides, and amino acid derivatives (Fig. 7). Compounds 171–179
are proline-rich cyclic nona-, deca-, or dodecapeptides [13,54–58].
Compounds 190–192 are quaternary ammonium alkaloids [59–62].
Among these, stachydrine (190) is a pyrrole alkaloid with a high con-
tent in L. japonicus. In addition, three unusual natural guanidines
(187–189) have been found in L. japonicus. Stachydrine (190) and
leonurine (187) have been studied most extensively.
2.3.2. Pharmacology of alkaloids, amino acids, and cyclopeptides
Alkaloids are important pharmacodynamic material bases of L. ja-
ponicus. Leonurine (187) has a wide range of pharmacological activ-
ities, suitable for the treatment of cardiovascular, nervous, and uterus
diseases, which are closely associated with the traditional functions of
L. japonicus. Yi-Zhun Zhu’s research group conducted exhaustive studies
regarding this compound and achieved a series of good results
[76–80,82–87]. In a study of the effect and mechanism of action of
leonurine on neonatal rat cardiomyocytes treated with hypoxia plus
serum deprivation, leonurine was demonstrated to up-regulate the ex-
pression of anti-apoptosis gene Bcl-2 and Bcl-xl by 1.03 times and 1.07
times and down-regulate the expression of pro-apoptosis genes Bax and
Fig. 4. Structures of labdane diterpenoids with a side chain at C-9 and rearranged diterpenoids from L. japonicus.
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
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Fas by 0.95 times and 0.72 times, respectively, as compared with a
hypoxic control group [76]. These findings suggest that leonurine im-
proves the activity of cardiomyocytes injured by hypoxia. Then, Yi-
Zhun Zhu’s research group developed a comprehensive in-vivo myo-
cardial ischemia rat model and an in-vitro cardiac myocyte H9c2 cell
model to examine the cardioprotective mechanism of leonurine. Their
results revealed that leonurine has direct cardioprotective effects,
mediated through antioxidants [77]. Furthermore, leonurine at a con-
centration of 10
−6
M reduced intracellular Ca
2+
overload and shor-
tened action potential duration. Evaluated using the whole-cell patch-
clamp technique, leonurine was thought to inhibit L-type Ca
2+
chan-
nels and act on the cardiovascular system [78]. Leonurine was also
shown to exhibit an inhibitory effect on the development of athero-
sclerosis in hypercholesterolemic rabbits. It dose-dependently amelio-
rated hemorheological abnormalities and arterial stiffness, as well as
suppressed the production of inflammatory factors and relieved
oxidative stress [79]. In addition, Yi-Zhun Zhu’s research group looked
into the roles and possible mechanisms of leonurine in attenuating
myocardial fibrotic responses in angiotensin-II-stimulated primary
neonatal rat cardiac fibroblasts [80]. Pretreatment with leonurine
(10–20 μM) could prevent cardiac fibrosis and the activation of cardiac
fibroblasts, partly through modulation of a Nox4–ROS pathway.
Recently, another research group has demonstrated that leonurine
protects against age-dependent impairment of angiogenesis [81]. It
increased expression of HIF-1a and VEGF, improved endothelial an-
giogenic function, reduced oxidative stress levels, attenuated mi-
tochondrial damage, and restored mitochondrial function. Liu et al. also
indicated that the anti-inflammatory activity of leonurine demonstrated
in human umbilical vein endothelial cells, partly through the inhibition
of reactive oxygen species and NF-κB signaling pathways, may be useful
for the treatment of inflammatory vascular diseases [82,83].
In addition to these effects on the cardiovascular system, Yi-Zhun
Fig. 5. Structures of triterpenoids from L. japonicus.
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9

Zhu’s group found that leonurine had a significant cerebral protective
effect. It could reduce infarct volume and ameliorate neurological
deficit in middle cerebral artery occluded rats, suggesting a therapeutic
potential for stroke prevention of leonurine [84]. Meanwhile, Yi-Zhun
Zhu’s group also demonstrated, for the first time, to the authors’
knowledge, that cognitive deficit of rats caused by injecting Aβ
1-40
could be attenuated by treatment with leonurine. The mechanism was
also investigated: leonurine could inhibit c-Jun N-terminal kinase and
NF-κB signal transduction to reduce expressions of NO, TNF-α, IL-1β,
and IL-6 [85]. A subsequent study showed that leonurine improved
both recognition and spatial memory, inhibited microgliosis, promoted
neuronal survival, and enhanced CREB/BDNF/TrkB signaling without
affecting the Aβ burden in amyloid-β protein precursor and presenilin-1
(AβPP/PS1) double-transgenic mice [86]. In addition, leonurine was
suggested to be a prospective agent for prevention or moderation, or
both, of the progress of type 2 diabetes by this research group [87].
With respect to uterus contraction, leonurine exhibited bidirectional
regulation effects. In ex-vivo experiments, it was shown to promote
contraction of uterine smooth muscle strips isolated from normal adult
female rats. The contractile activity and tension were increased in a
dose-dependent manner [13]. Another experiment was carried out on
early-pregnant model rats with incomplete termination induced by
mifepristone and misoprostol. Leonurine not only enhanced contractile
frequency and tension, but also increased the level of estradiol (E
2
) in
serum at dosages of 0.5, 1.5, and 4.5 mg/kg. The metrorrhagia volume
decreased significantly at 4.5 mg/kg [88]. In addition, leonurine has
been proven to attenuate hyperalgesia and myometrial infiltration in
mice with induced adenomyosis by down-regulating expressions of p-
P65, COX-2, and OTR [89]. From what has been mentioned above, the
extensive pharmacological effects of leonurine in treating cardiovas-
cular and cerebrovascular diseases and obstetrical and gynecological
diseases are related to the traditional uses of L. japonicus. In recent
years, other activities have been found for leonurine. For example,
leonurine hydrochloride could induce apoptosis of H292 lung cancer
cells through a mitochondria-dependent pathway [90].
Stachydrine (190), accounting for 0.09–1.01% of the total herb
[91], is a main ingredient of L. japonicus and its Chinese patent medi-
cines. The pharmacological activities of stachydrine have been studied
extensively in regard to the traditional effects of L. japonicus. In the
treatment of postpartum hemorrhage, stachydrine hydrochloride could
reduce the volume of uterine bleeding in mice after RU486-induced
abortion by regulating the Th1/Th2/Th17/Treg paradigm [92]. Several
other experiments in vitro demonstrated the effect of stachydrine on
uterus contraction. Dai et al. [93] found that 3 × 10
−5
mol/L of
stachydrine stimulated uterus contraction in guinea pigs. The con-
tractile amplitude was increased, while the contractile frequency was
reduced.
Stachydrine also has significant effects on the vascular endothelium.
It can ameliorate the injury of human umbilical vein endothelial cells
induced by anoxia and reoxygenation; the mechanism by which it does
this may be related to the inhibition of TF expression [94]. Cellular
senescence induced by high levels of glucose is another major factor in
the development of endothelial dysfunction. Stachydrine can down-
regulate p16
INK4a
protein levels and up-regulate SIRT1 expression and
enzyme activity to ameliorate high-glucose-induced endothelial cell
senescence [95]. An in-vivo study demonstrated the ability of stachy-
drine to prevent sunitinib-induced intersegmental blood vessel damage
in transgenic Tg (flk1: EGFP) zebrafish embryos at concentrations of
3.13, 6.25, 12.5, and 25 μM; this may be beneficial for postpartum
recovery [7].
Cardiac hypertrophy is the key starting point for heart failure. Early
intervention in the occurrence of cardiac hypertrophy and fibrosis is a
crucial link to delay or reverse heart failure [96]. Stachydrine has a
therapeutic effect on cardiac hypertrophy induced by various causes, as
evidenced by a large number of trials. Different concentrations of sta-
chydrine (10
−4
, 10
−5
, and 10
−6
mol/L) were used to inhibit the nor-
epinephrine-induced cardiac hypertrophy; results showed that stachy-
drine significantly increased the calcium uptake capacity and
sarcoplasmic reticulum Ca
2+
-ATPase activity in norepinephrine-in-
duced cardiac mast cells in a dose-dependent manner [97]. Another
study indicated that norepinephrine could increase the cell surface
area, protein synthesis, and expression of β-MHC and β/α-MHC ratios
in neonatal rat cardiomyocytes, but these effects were attenuated by
stachydrine. Moreover, stachydrine showed a significant effect on in-
tracellular calcium transients [98]. In addition, atrial natriuretic pep-
tide and brain natriuretic peptide are recognized as characteristic in-
dicators of cardiac hypertrophy [99,100]. In the presence of cardiac
hypertrophy, atrial natriuretic peptide and brain natriuretic peptide are
increased in compensation. Stachydrine could inhibit myocardial cell
hypertrophy of neonatal rats induced by norepinephrine in a time-de-
pendent manner, with the contents of atrial natriuretic peptide and
brain natriuretic peptide markedly decreasing [101]. Zhao et al. re-
vealed that stachydrine suppressed inflammation and oxidative stress to
attenuate isoproterenol-induced fibrosis and cardiac hypertrophy,
mainly by inhibiting NF-κB and JAK/STAT signaling pathways in rats
[102]. Several other reports demonstrated the protective effect of sta-
chydrine against angiotensin II-induced cardiac hypertrophy by sup-
pressing autophagy [103,104].
Fig. 6. Structures of steroids from L. japonicus.
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10

Stachydrine also has a protective effect against myocardial
ischemia-reperfusion injury in rats. Compared with a model group,
stachydrine at dosages of 3, 6, and 12 mg/kg reduced the activity of
creatine kinase, lactic dehydrogenase, and troponin, decreased the
content of malonaldehyde, and increased the superoxide dismutase
activity and NO level [105]. Concerning reperfusion impairment after
cerebral ischemia, stachydrine hydrochloride significantly reduced the
death rate of mice, improved the pathological changes in the hippo-
campus, and inhibited inflammatory reactions [106]. In recent research
reports, stachydrine has been found to have antitumor activity
[107,108].
Compared with studies on the effects of leonurine and stachydrine,
there are relatively fewer studies of other alkaloids. Cycloleonuripeptides
C and D (173 and 174) and imperialine-3β-D-glucoside (183) also in-
creased contractile activity, tension, and frequency in rat uterine muscle
strips [13]. In addition, cycloleonuripeptide D showed potent cycloox-
ygenase inhibitory activity, with 72.6% inhibition rate at 100 μM [56].
Cycloleonuripeptides B and C (172 and 173) had an inhibitory effect on p-
388 lymphocytic leukemia cell growth [54]. Cycloleonuripeptides E and F
(175 and 176) showed weak vasorelaxant effects on a rat aorta that was
precontracted with 3 × 10
−7
M norepinephrine [57]. In anticoagulant
tests, trigonelline (192) clearly prolonged activated partial thromboplastin
time, and both trigonelline and choline chloride (191) inhibited platelet
aggregation [109].
Fig. 7. Structures of alkaloids, amino acids, and cyclopeptides from L. japonicus.
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11

2.4. Phytochemistry and pharmacology of flavonoids
2.4.1. Phytochemistry of flavonoids
Leonurus japonicus is rich in flavonoids, which are a major class of
secondary metabolites; and their concentration is greatest in the leaves
and smallest in roots [110]. As shown in Fig. 8, 35 flavonoids have been
isolated and characterized from L. japonicus; these include 10 flavones
(205–214), 24 flavonols (215–238), and one isoflavone (239). Most of
the flavonols are monoglycosides or diglycosides formed by glycosi-
dation of glucose (Glc), rhamnose (Rha), and galactose (Gal). Although
various acylated flavonol glycosides are widely distributed in the plant
kingdom, syringyl acylated flavonol diglycosides, such as compounds
231–238, are rare.
2.4.2. Pharmacology of flavonoids
By contrast with alkaloids 173,174, and 183, three flavonoids,
spinosin (212), linarin (213), and apigenin-7-O-β-D-glucopyranoside
(214) revealed a remarkable inhibitory effect on rat uterine smooth
muscle, with contractile activity, tension, and frequency decreasing
significantly [13]. Flavonoids from L. japonicus also showed strong
antioxidant activities. Compared with α-tocopheral and butylated hy-
droxytoluene, which were used as controls, luteolin (207), kaempferol
(215), quercetin (216), and myricetin (217) exhibited stronger anti-
oxidative activities [66]. Another study demonstrated that isoquercitrin
(220), rutin (227), and tiliroside (229) had 3.7―5.3 times greater
antioxidant effects than butylated hydroxytoluene [70]. Syringyl acy-
lated flavonol glycosides, such as leonurusoides A–E (231–233,235,
236) and 2′′′-syringylrutin (237) deterred the triglyceride accumulation
in HepG2 cells stimulated by free fatty acid at 10 μM. Their inhibitory
rates were 61.4 ± 10.0%, 52.8 ± 4.2%, 56.9 ± 9.6%, 51.7 ± 6.9%,
49.1 ± 4.9%, and 44.3 ± 4.3%, respectively [71].
2.5. Phytochemistry and pharmacology of phenylpropanoids
2.5.1. Phytochemistry of phenylpropanoids
Phenylpropanoids can be divided into three types: simple phenylpro-
panoids, coumarins, and lignans. Previous chemical investigations have
led to the isolation of seven simple phenylpropanoids (240–246), 11
coumarins (247–257), and five lignans (258–262) (Fig. 9). All of the
simple phenylpropanoids are phenylpropionic acids and their esterifica-
tion derivatives. Compounds 242–244 are unusual glucaric acids with
feruloyl and syringoyl groups, but their structures have not been defini-
tively determined by NMR experiments because of the pseudo-symmetry
of glucaric acids. Six furocoumarins (247–252) and five simple coumarins
(253–257) with substitution of a methoxy and an isopentene group have
been reported. Biphenyl cyclooctene lignans (258 and 259) have been
reported for the first time in the family Labiatae [73].
Fig. 8. Structures of flavonoids from L. japonicus.
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12

2.5.2. Pharmacology of phenylpropanoids
Isogosferal (251) and murrayone (253) both conspicuously pre-
vented the abnormal increase of platelet aggregation induced by ade-
nosine diphosphate [12]. Their inhibitory rates (16.78% and 16.39%)
were very close to those of a positive control (15.26%). 2-Syringoyl-4-
feruloyl glucaric acid or 5-syringoyl-3-feruloyl glucaric acid (243)
showed a moderate hepatoprotective activity [74].
2.6. Phytochemistry and pharmacology of other compounds
2.6.1. Phytochemistry of other compounds
Leonuriside B (263) (Fig. 10) is the first phenylethanoid glycoside
reported from L. japonicus [70]. Another five phenylethanoid glycosides
(245 and 246,Fig. 9;264–266,Fig. 10) were then isolated from aerial
parts of the plant in 2002 and 2003 [21,67]. In addition, several simple
Fig. 9. Structures of phenylpropanoids from L. japonicus.
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13

phenolic acids and their esters, aliphatic acids and their esters, and ali-
phatic alcohols have been isolated. Among those, compounds 279 and 280
are allene derivatives, first reported for the genus Leonurus [75].
2.6.2. Pharmacology of other compounds
A series of hepatoprotective glycosides from L. japonicus, leonoside
E (264), cistanoside E (265), and leonoside F (266), were found in L.
japonicus. All of these have positive activity against D-galactosamine-
induced toxicity in HL-7702 cells at 1 × 10
−5
M administration [21].
Leonurisides A and B (267 and 263) and gallic acid (272) showed
stronger antioxidative activities than α-tocopherol and butylated hy-
droxytoluene [66,70].
3. Application of L. japonicus
3.1. Application of L. japonicus in ancient China
Table 2 shows applications of L. japonicus recorded in classic Materia
Medica books in ancient China. The earliest medicinal documentation of
L. japonicus was in Shennong’s Classics of Materia Medica (Shen Nong Ben
Cao Jing), which recorded that the stems and leaves of the plant could
be used during bathing, added in the ikthang, to treat urticaria. At that
time, the medicine was called Chongwei, which is descriptive of its
flourishing leaves and a great mass of seeds. At the end of the Han
Dynasty (202 B. C. – 220 A. D.), it was found to have a beneficial effect
in treating headache and dysphoria, according to Ming Yi Bie Lu. Since
the Tang Dynasty (618 A. D. – 907 A. D.), people have had a better
understanding of the efficacy of L. japonicus and have begun to use this
herbal medicine to treat obstetrical diseases, such as stillbirth or post-
partum hemorrhage. The records showing that L. japonicus is efficacious
in treating obstetrical diseases have been widely seen in classic Materia
Medica books dating since the Ming Dynasty (1368 A. D. –1644 A. D.). A
compendium of Materia Medica (Bencao Gangmu) indicated that L. ja-
ponicus had good effects in promoting blood circulation, removing
blood stasis, and regulating menstruation. Furthermore, ancient doctors
and herbalists have repeatedly emphasized that L. japonicus is not only
an excellent medicine for the treatment of obstetrical diseases but also
an important drug for the treatment of gynecological diseases. Through
the ages, classic books have documented many prescriptions and cases
of L. japonicus in treating the symptoms of obstetrical and gynecological
diseases. The diseases involved mainly include disturbed fetal move-
ments, miscarriage, dystocia, retention of placenta, retention of lochia,
postpartum hemorrhage, postpartum abdominal pain, postpartum
sweating, and other ill effects associated with childbearing, as well as
uterine bleeding, irregular menstruation, dysmenorrhea, amenorrhea,
and other menstrual diseases. Thus, medical scientists in ancient China
named this herbal medicine as Yi Mu Cao, meaning, literally, “beneficial
herb for women.”
In addition to its use as an obstetrical and gynecological panacea, L.
japonicus has medicinal functions in invigorating blood circulation,
inducing diuresis, and detoxification. Since the Ming Dynasty, its con-
tribution in other diseases, including internal and surgical diseases, skin
diseases, pediatric diseases, and miscellaneous other diseases, has been
well recognized. Leonurus japonicus is used alone or combined with
other herbs in therapies to treat different diseases.
3.2. Modern application of L. japonicus in China
Leonurus japonicus was first recorded in the 1977 edition of the
Pharmacopoeia of the People’s Republic of China (China Pharmacopoeia).
Owing to a lack of textual research, the source of the Chinese herbal
medicine of Leonuri Herba, which was first included in the 1963 edition
of China Pharmacopoeia, is the dried stems and leaves of another species
in the genus Leonurus,L. sibiricus L. Since 1977, L. japonicus has been
included in all eight editions (the 1977, 1985, 1990, 1995, 2000, 2005,
2010, and 2015 editions) of the China Pharmacopoeia, and its functions
have also been revised continuously. It was recorded in the 1977 edi-
tion that L. japonicus was applied in the treatment of irregular men-
struation, dysmenorrhea, amenorrhea, postpartum lochiorrhea, and
edema due to acute nephritis. In the next edition, edema and oliguria
were added to the indications; there were no further revisions until the
2010 edition. In the 2010 and 2015 editions, edema due to acute ne-
phritis was removed from the indications, while sores and ulcers were
added to the indications of L. japonicus.
In modern times, L. japonicus extract and its Chinese patent medi-
cines have a wide range of clinical applications, most of which have a
remarkable effect in invigorating blood circulation and regulating
menstrual disturbance, such as Yi Mu Cao tablets (motherwort tablets),
Yi Mu Cao capsules, fresh Yi Mu Cao capsules, Fufang Yi Mu Cao cap-
sules, Yi Mu Cao granules, Chanfukang granules, Yi Mu Cao injection,
and Yi Mu Cao pills. They are used in the treatment of gynecological
and obstetrical diseases, mainly including postpartum hemorrhage,
postpartum lochiorrhea, irregular menstruation, and subinvolution of
the uterus. Yi Mu Cao injection (motherwort injection) prepared only
from L. japonicus is the best publicized of the Chinese patent medicines
of L. japonicus and is a commonly used drug to contract the uterus and
Fig. 10. Structures of other compounds from L. japonicus.
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
14

stop bleeding in obstetrics and gynecology in China.
Oxytocin is a well-known uterotonic drug for treating postpartum
hemorrhage, but its half-life period is very short (3–4 min) [111], and
the contraction effect on the lower segment of uterine is weak [112]. In
addition, the effect of oxytocin is related to receptor saturation [113].
Motherwort injection, mainly consisting of alkaloids [63], can make up
for these shortcomings [114]. Thus, many literary works report that
motherwort injection and oxytocin are often used together in China.
Compared with oxytocin used alone in cesarean section, the combined
administration of oxytocin and motherwort injection was found to
significantly decrease the average blood loss, both intrapartum and 24 h
after parturition, as well as the incidence of hemorrhage [115]. A meta-
analysis of the effects of motherwort injection and oxytocin on post-
partum hemorrhage in 2424 patients in 13 randomized controlled trials
showed that the combinational use of oxytocin and motherwort injec-
tion reduced the incidence of adverse reactions and bleeding volumes
after cesarean section [116]. Zeng et al. meta-analyzed the efficacy and
safety of motherwort injection combined with oxytocin on postpartum
hemorrhage in natural delivery (2186 patients in 13 randomized con-
trolled trials) and cesarean section (5709 patients in 25 randomized
controlled trials) [117,118]. These results indicated that the combined
use of these two drugs could enhance uterine contraction and reduce
the incidence of hemorrhage and the volume of blood loss through
hemorrhage without additional adverse reactions. In addition to oxy-
tocin, carboprost tromethamine (hemabate) is often also used to treat
postpartum hemorrhage. Deng et al. found that motherwort injection
combined with hemabate could shorten the third stage of labor during
cesarean section, as well as the amount of bleeding and the incidence of
postpartum hemorrhage in high-risk pregnant women [119].
Motherwort injection also has remarkable curative effects for car-
diovascular and cerebrovascular diseases. Experimental pharmacolo-
gists found that motherwort injection had protective effects against
cerebral ischemia in mice and rats and could improve energy metabo-
lism in ischemic brain regions [120]. Clinical studies indicated that
motherwort injection is an effective and safe drug in treating acute
cerebral infarction in the early stage and that its efficacy was better
than that of compound Salvia miltiorrhiza injection. The curative rate of
motherwort injection was 70%, while that of compound S. miltiorrhiza
injection was only 31%. Analysis of biochemical indexes showed that
motherwort injection had better anticoagulant, fibrinogen-reducing,
and lipid-decreasing effects than compound S. miltiorrhiza injection
[121]. In addition, Chen et al. investigated the therapeutic effects of
motherwort injection on arrhythmia in 80 patients with coronary heart
disease. Their results showed that the effective rate of motherwort in-
jection was 87.5% with no obvious adverse reactions, which was sig-
nificantly higher than that of a control group (20 mg of adenosine tri-
phosphate, 100 U of coenzyme A, 1 g of vitamin C, and 0.1 g of vitamin
B
6
) in patients with coronary heart diseases (52.5%) [122].
4. Conclusions
This review summarizes research progress on the phytochemistry,
pharmacology, and clinical application of L. japonicus. The bioactive
chemical components isolated from L. japonicus have fascinated many
phytochemists and pharmacologists. Until now, more than 280 che-
mical components have been isolated and characterized from L. japo-
nicus. Among these, 108 compounds were isolated and reported by our
research group. In Fig. 11, it can be observed that terpenoids and al-
kaloids are major pharmacodynamic components of L. japonicus. Ter-
penoids account for 53.2% of the isolated chemical components and
mainly possess antithrombotic, vasorelaxant, procoagulant, anti-pla-
telet aggregative, neuroprotective, anti-inflammatory, α-glucosidase
and acetylcholinesterase inhibitory, immune regulating, antibacterial,
and cytotoxic activities. Among these terpenoids from L. japonicus, di-
terpenoids are the most studied. Although the number of alkaloids is far
smaller than that of terpenoids, alkaloids show many remarkable ef-
fects, mainly on gynecological and cerebral-cardio vascular diseases.
The effects of terpenoids and alkaloids are closely related to the tradi-
tional efficacy of L. japonicus. According to the previous in-depth stu-
dies, stachydrine and leonurine could be the main active compounds for
treating obstetrical and gynecological diseases. Therefore, more atten-
tion should be paid to the terpenoids and alkaloids contained in L. ja-
ponicus, and studies of these compounds should be strengthened in fu-
ture.
Table 2
Applications of L. japonicus recorded in classic Materia Medica books in ancient China.
Dynasty of ancient China Classic materia medica books Indications of L. japonicus
The Han Dynasty
(202 B. C. – 220 A. D.)
Shennong’s Classics of Materia Medica (Shennong Bencao
Jing)
Urticaria
Supplementary Records of Famous Physicians (Ming Yi Bie
Lu)
Urticaria, headache, and dysphoria
The Northern and Southern Dynasties
(420 A. D. – 589 A. D.)
Variorum of Shennong’s Classics of Materia Medica (Bencao
Jing Ji Zhu)
Urticaria, headache, and dysphoria
The Tang Dynasty
(618 A. D. – 907 A. D.)
Tang Materia Medica (Xinxiu Bencao) Urticaria, headache, dysphoria, stillbirth, postpartum hemorrhage, ulcerative
carbuncle, and venomous snake bites
Guang Ji Fang Infantile emaciation, stillbirth, and dystocia
Supplement to Medica (Bencao Shiyi) Ulcerative carbuncle, acute mastitis, and edema
The Song Dynasty
(960 A. D. – 1279 A. D.)
Taiping Holy Prescriptions for Universal Relief (Taiping
Shenghui Fang)
Acute mastitis, stillbirth, dystocia, postpartum lochiorrhea, postpartum
hemorrhage, and postpartum abdominal pain
Classified Materia Medica from Historical Classics for
Emergency (Jing Shi Zheng Lei Beiji Bencao)
Headache, dysphoria, and postpartum hemorrhage
Augmented Materia Medica (Bencao Yanyi) Various postpartum diseases and dystocia
The Ming Dynasty
(1368 A. D. –1644 A. D.)
Bencao Mengquan Stillbirth, tocolysis, blood stasis, infantile emaciation, acute mastitis, edema, and
dysphoria
Compendium of Materia Medica (Ben Cao Gang Mu) Blood stasis, threatened abortion, irregular menstruation, dystocia, metrorrhagia
and metrostaxis, edema, sore and ulcer
Bencao Zheng Yao Amenorrhea, dysmenorrhea, stillbirth, dystocia, blood stasis, and edema
The Qing Dynasty
(1644 A. D. – 1912 A. D.)
Bencao Qiu Zhen Irregular menstruation, uterine bleeding, blood stasis, dystocia, acute mastitis,
sore and ulcer
Bencao Yi Du Hemorrhage, hematuric strangury, dystocia, metrorrhagia, leukorrhagia, acute
mastitis, sore and ulcer, and constipation
Newly organized Materia Medica (Bencao Xin Bian) Stillbirth, blood stasis, and breast milk stoppage
New Compilation of Materia Medica (Bencao Cong Xin) Hematuric strangury, vaginal bleeding during pregnancy, dystocia, metrorrhagia,
leukorrhagia, sore and ulcer, acute mastitis, edema, constipation
L.-L. Miao, et al. Biomedicine & Pharmacotherapy 117 (2019) 109060
15

Leonurus japonicus was widely used as a traditional Chinese medi-
cine in ancient China, and many ancient books documented its med-
icinal uses. Owing to the further development and extensive application
of modern pharmaceutical technology, various Chinese patent medi-
cines of L. japonicus have been developed and used clinically in China,
especially motherwort injection and motherwort soft capsules.
However, the effective substances and mechanisms of action are seldom
reported. Leonurus japonicus, as an excellent traditional medicine for the
treatment of obstetrical and gynecological diseases, is worthy of more
comprehensive in-depth studies. With the development of science and
technology, it will make greater contributions to the prevention and
treatment of disease.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
Support from the National Natural Sciences Foundation of China
(NNSFC, Grant Nos. 81872991 and 81303209), the Applied Basic
Research Project of Sichuan Province (Grant No. 2019YJ0334), and the
Science and Technology Special Program of Sichuan Administration of
TCM (Grant No. 2017C002) is acknowledged.
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