Phytochemistry Reviews
https://doi.org/10.1007/s11101-023-09870-3(0123456789().,-volV() 0123458697().,-volV)
Phytochemistry, data mining, pharmacology, toxicology
and the analytical methods of Cyperus rotundus L.
(Cyperaceae): a comprehensive review
Bian-Xia Xue . Ru-Shang He . Jia-Xin Lai . Nana Ama Mireku-Gyimah .
Li-Hua Zhang . Hong-Hua Wu
Received: 30 May 2022 / Accepted: 12 April 2023
 The Author(s), under exclusive licence to Springer Nature B.V. 2023
Abstract Cyperus rotundus L. has been widely used rotundus were systematically collated and classified,
in the treatment and prevention of numerous diseases concerning monoterpenoids, sesquiterpenoids, flavo-
in traditional systems of medicine around the world, noids, phenylpropanoids, phenolics and phenolic
such as nervous, gastrointestinal systems diseases and glycosides, triterpenoids and steroids, diterpenoids,
inflammation. In traditional Chinese medicine (TCM), quinonoids, alkaloids, saccharides and others. Their
its rhizomes are frequently used to treat liver disease, pharmacological effects on the digestive system,
stomach pain, breast tenderness, dysmenorrheal and nervous system, gynecological diseases, and other
menstrual irregularities. The review is conducted to bioactivities like antioxidant, anti-inflammatory, anti-
summarize comprehensively the plant’s vernacular cancer, insect repellent, anti-microbial activity, etc.
names, distribution, phytochemistry, pharmacology, were summarized accordingly. Moreover, except for
toxicology and analytical methods, along with the data the data mining on the compatibility of C. rotundus in
mining for TCM prescriptions containing C. rotundus. TCM, the separation, identification and analytical
Herein, 552 compounds isolated or identified from C. methods of C. rotundus compositions were also
systematically summarized, and constituents of the
essential oils from different regions were re-analyzed
Bian-Xia Xue, Ru-Shang He, Jia-Xin Lai have contributed using multivariate statistical analysis. In addition, the
equally to this work and should be considered co-first authors.
toxicological study progresses on C. rotundus
Supplementary Information The online version contains revealed the safety property of this herb. This review
supplementary materials available at https://doi.org/10.1007/ is designed to serve as a scientific basis and theoretical
s11101-023-09870-3. reference for further exploration into the clinical use
and scientific research of C. rotundus.
B.-X. Xue  R.-S. He  J.-X. Lai 
L.-H. Zhang  H.-H. Wu (&)
State Key Laboratory of Component-Based Chinese
Medicine, Institute of Traditional Chinese Medicine,
Tianjin University of Traditional Chinese Medicine, 10
Poyanghu Road, West Area, Tuanbo New Town, Jinghai
District, Tianjin 301617, People’s Republic of China
e-mail: wuhonghua2011@tjutcm.edu.cn
N. A. Mireku-Gyimah
Department of Pharmacognosy and Herbal Medicine,
School of Pharmacy, College of Health Sciences,
University of Ghana, Legon-Accra, Ghana
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Graphical Abstract
Keywords Cyperi rhizome  Association rules  SFE Supercritical fluid extraction
Gynecological diseases  Sesquiterpenoids  Essential HSCCC High-speed counter-current
oil  GC–MS chromatography
UFLC-MSn Ultra-fast liquid chromatography
mass spectrometry
Abbreviations
HR-MS High resolution mass spectrometry
CyRh Cyperi rhizoma
NMR Nuclear magnetic resonance
TCM Traditional Chinese medicine
HD Hydrodistillation
CMs Chinese medicines
SPME Solid phase micro extraction
ChP Chinese Pharmacopoeia
PLE Pressurized liquid extraction
EOCR The essential oil of C. rotundus
HR-ESI–MS High resolution-electrospray
TLC Thin-layer chromatography
ionization mass spectrometry
PTLC Preparative thin-layer
EI-MS Electron impact mass spectrometry
chromatography
FAB-MS Fast atomic bombardment mass
HPTLC High-performance thin-layer
spectrometry
chromatography
Q-TOF–MS Quadrupole-time of flight mass
MPLC Medium pressure liquid
spectrometry
chromatography
MS–MS Tandem mass spectrometry
HPLC High performance liquid
UHPLC- Ultra-high performance liquid
chromatography
QTOF-MS chromatography quadrupole-time of
PHPLC Preparative high-performance liquid
flight mass spectrometry
chromatography
GC–MS Gas chromatography-mass
UHPLC Ultra-high performance liquid
spectrometry
chromatography
GC Gas chromatography
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Phytochemistry Reviews
GC-FID Gas chromatography-flame H2O2 Hydrogen peroxide
ionization detector ABTS 2,20-Azinobis (3-
GC-O-MS Gas chromatography–olfactometry- ethylbenzothiazoline-6-sulfonic
mass spectrometry acid) diammonium salt
PDA Flame ionization detector AChE Acetylcholinesterase
DAD Diode array detection MAO Monoamine oxidase
UV Ultraviolet–visible spectra MIC Minimum inhibitory concentration
IR Infrared spectra MBC Minimum bactericidal concentration
PIXE Particle induced X-ray emission LD50 Median lethal concentration and
ICP-MS Inductively coupled plasma mass median lethal dose
spectrometry EC50 Concentration for 50% of the
HCA Hierarchical clustering analysis maximal effect
PCA Principal component analysis CC50 The 50% cytotoxic concentration
CD Circular dichroism IC50 Half maximal inhibitory
COVID-19 Coronavirus disease 2019 concentration
TOF Total oligomeric flavonoid BMI Body mass index
TPC Total phenolic GABA c-Aminobutyric acid
DPPH 1,1-Diphenyl-2-picrylhydrazyl AP-1 Activator protein-1
SOD Superoxide dismutase
HO-1 Heme oxygenase-1
GSH-Px Glutathione peroxidase Introduction
MDA Malondialdehyde
PTZ Pentylentetrazole Cyperus rotundus L. (family: Cyperaceae), an erect,
SARS-CoV- Severe acute respiratory syndrome glabrous, grasslike, fibrous-rooted, herbaceous plant
2 coronavirus with slender, scaly creeping rhizomes, is widely
5-LOX 5-Lipoxygenase distributed in temperate, tropical and sub-tropical
COX-2 Cyclooxygenase-2 regions, such as China, India, South Africa, Korea,
PGE2 Prostaglandin E2 Japan, Egypt, Iran and other countries (Chang et al.
IL-1 Interleukin 1 2012; Aeganathan et al. 2015; Liu et al. 2016; Janaki
IL-6 Interleukin 6 et al. 2018; Sabir et al. 2020). C. rotundus has a long
TNF-a Tumor necrosis factor-a history as an herbal remedy in several nations, and
NF-jB Nuclear factor-kappa B accordingly has been collated into the native medical
iNOS Nitric oxide synthase systems in various countries and prefectures. In China,
LPS Lipopolysaccharide the rhizomes of C. rotundus officially referred to as
TPA 12-O-Tetradecanoylphorbol-13- ‘‘Xiangfu’’ (Cyperi rhizoma, CyRh) according to the
acetate 2020 Edition of Chinese Pharmacopoeia (ChP) and
NO Nitric oxide initially recorded in ‘‘Mingyi Bielu’’, is a gynecolog-
TST Tail suspension test ical herb commonly used in Traditional Chinese
FST Forced swimming test Medicine. And it is frequently recommended for the
HBV Hepatitis B virus treatment of epigastric pain, breast aches, irregular
DCFH 2,7-Dichlorofluorescein menstruation, dysmenorrhea and amenorrhea (Chi-
EtOAc Ethyl acetate nese Pharmacopoeia Committee of China, Edition
EECR Ethanol extract of C. rotundus 2020). In India Ayurveda, C. rotundus, also known as
MECR Methanolic extract of C. rotundus ‘‘Motha’’ and ‘‘Mutha’’, is used for the treatment of
CYP450 Cytochrome P450 diarrhea, dysentery, diabetes, arthritis, leprosy, bron-
ROS Reactive oxygen species chitis, amenorrhea, dysmenorrhea, fever and blood
AD Alzheimer’s disease disorders (Babiaka et al. 2021). In West Asia, C.
CNS Central nervous system rotundus is applied in folk medicine for the treatment
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Phytochemistry Reviews
of leprosy, fever, thirst and blood illnesses. In Egypt, In the past decades, several reviews related to C.
C. rotundus is used in traditional medicine as an rotundus have been published. However, most of them
anthelmintic, aphrodisiac, diuretic, sedative, carmina- focused on the traditional uses, phytochemistry and
tive, stimulant and tonic, and for treating renal colic pharmacological aspects (Sivapalan 2013; Pirzada
and stomach pains (Samra et al. 2020). Apart from the et al. 2015; Al-Snafi 2016; Kumar et al. 2017; Bajpay
above, C. rotundus also is the raw material of some et al. 2018; Kabir and Abbasi 2018; Kamala et al.
perfumes and mosquito repellents. 2018; Babiaka et al. 2021; Kandikattu et al. 2021;
Till now, the presence of monoterpenoids (menthane- Bezerra and Pinheiro 2022; Kandikattu et al. 2021; Lu
, pinane-, iridoid glycosides, etc.), sesquiterpenoids et al. 2022; Rita Yadav et al. 2022). There is no
(eudesmane-, patchoulane-, cadinane-, guaiane-, aro- comprehensive overview concerning the separation,
modendrane-, eremophilane-, caryophllane-, rotundane-, identification and analytical techniques of the chem-
etc.), flavonoids (flavone-, flavonol-, isoflavone-, ical components of C. rotundus, not to mention an in-
biflavonoids-, etc.), phenylpropanoids (simple phenyl- depth data excavation of C. rotundus’s common
propanoids-, coumarins-, and lignans-), phenolics and compatibility with other Chinese medicines (CMs).
phenolic glycosides, triterpenoids and steroids, diter- For instance, Kumar et al. summarized C. rotundus’s
penoids, quinonoids, alkaloids, saccharides and other traditional uses and pharmacological effects (Kumar
constituents in C. rotundus has been amply demon- et al. 2017). Medicinal applications, phytochemistry
strated by a large number of phytochemistry investi- and pharmacology of C. rotundus were worked on
gations (Sivapalan 2013; Pirzada et al. 2015; Kabir (Sivapalan 2013; Pirzada et al. 2015; Kamala et al.
and Abbasi 2018). Essential oil is the indispensable 2018; Kandikattu et al. 2021). Plant morphology,
substance contained in the rhizomes, tubers and aerial distribution, phytochemical constituents and pharma-
parts of C. rotundus, and it provides the characteristic cological activities of C. rotundus were focused on
odor and flavor of this herb (Zoghbi et al. 2008; Kilani- (Al-Snafi 2016; Bajpay et al. 2018; Kabir and Abbasi
Jaziri et al. 2009; Chang et al. 2012). Moreover, the 2018). Babiaka et al. reported in detail the bioactivities
major constituents, such as a-cyperone, a-rotunol, b- and mechanisms involved in certain C. rotundus
rotunol, cyperotundone, cyperene, nootkatone, and components (Babiaka et al. 2021). Lu et al. concen-
isocyperol, were frequently described to be isolated trated on an overall summary on the pharmacological
from the essential oil and the extracts of C. rotundus effects of the chemical constituents and extracts in C.
rhizomes (Sivapalan 2013; Sonwa and König 2001; rotundus (Lu et al. 2022).
Ahn et al. 2015; Xu et al. 2015). In this paper, a comprehensive literature investiga-
Extensive modern pharmacological evidences have tion on C. rotundus was accomplished by retrieving a
revealed that C. rotundus possesses a variety of series of electronic databases, including PubMed,
biological activities including neuroprotective (Jebas- Google Scholar, SciFinder, ScienceDirect, Web of
ingh et al. 2014; Dabaghian et al. 2015), anti- Science, Huabeing database, CNKI, Traditional Chi-
inflammatory (Rocha et al. 2020), antipyretic (Deng nese Medicine Resource Network. This present over-
et al. 2012), analgesic (Ahmad et al. 2012), sedative view intended to compile an overall knowledge on
(Srivastava et al. 2013), anticonvulsant (Khalili et al. phytochemistry, pharmacology, separation, identifica-
2011), gastroprotective (Thomas et al. 2015), anthel- tion and analytical methods, as well as data mining of
mintic (Al-Massarani et al. 2016; Janaki et al. 2018), C. rotundus. Unlike previous reviews in phytochem-
antidiarrheal (Uddin et al. 2006; Daswani et al. 2011), istry and pharmacology, this paper goes further in the
anti-cancer (Saad et al. 2018; Susianti et al. 2018), following aspects. To make the content more thor-
anti-obesity (Majeed et al. 2022), antioxidant (Khalili ough, advances in phytochemistry, pharmacology and
et al. 2011), anti-bacterial (Ahmad et al. 2012), anti- toxicology from 1941 to 2022 were reviewed, 552
malarial (Thebtaranonth et al. 1995), anti-diabetic chemical constituents isolated or identified from C.
(Singh et al. 2015), wound healing (Puratchikody et al. rotundus have been systematically collated and clas-
2006; Srivastava et al. 2013), anti-cytotoxic (Sayed sified for the first time. And the pharmacological and
et al. 2007), anti-depressant (Lin et al. 2015; Hao et al. toxicological studies of C. rotundus on the digestive
2017), anti-HBV (Parvez et al. 2019), and lactogenic system, nervous system and gynecological diseases
(Badgujar and Bandivdekar 2015) activity. and other activities have been summarized
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accordingly. Moreover, the separation, identification The wide distribution ofC. rotundus throughout the
and analytical methods of the chemical constituents of world has given it a unique name in different regions.
C. rotundus were systematically summarized for the To facilitate a comprehensive investigation and
first time. Furthermore, the chemical compositions of research by future researchers, it is essential to provide
C. rotundus essential oils from different regions have a systematic summary involving a variety of vernac-
been re-analyzed by multivariate statistical analysis. ular names of C. rotundus. Table 2 thus provides a
Additionally, data mining has been carried out for the detailed summary of the diverse common names of C.
first time on the compatibility of C. rotundus in TCM. rotundus used by different regions.
Distribution and synonyms Data mining in TCM
Owing to its adaptation to a broad range of soil In China, TCM prescriptions briefly refer to an orderly
textures, altitudes, climates, soil pH, and moisture combination of CMs following the principles of CMs
levels, C. rotundus, commonly known as ‘‘The recipe (Sovereign and subject Musa acts) for the
World’s Worst Weed’’, may thrive in a variety of treatment of a specific disease under the guidance of
locations and ecosystems. It is unquestionably a global TCM theory. C. rotundus, known as ‘‘Xiangfu’’ or
species, prospering in tropical, subtropical, and tem- ‘‘Xiangfuzi’’ in China which enrolled as ‘‘Cyperi
perate regions and especially well in Asia, Africa, rhizome’’ (CyRh) of Latin name in ChP, is dominantly
Europe and America. Table 1 gives a full summary of native to the middle and lower reaches of the Yangtze
the regions where C. rotundus is located and Fig. 1 River and the Huanghe River, with the optimum
depicts colorfully its extensive distribution. quality in Zhejiang and Shandong provinces. It was
Table 1 The distribution of C. rotundus around the world
Continent Nation References
Eastern China, Japan, Korea, India, Nepal, Pakistan, SriLanka, Lawal and Oyedeji (2009), Pirzada et al. (2015), Al-Snafi
Asia Myanmar, Thailand, Vietnam, Indonesia, Malaysia, (2016), Yagi et al. (2016), Bajpay et al. (2018), Samra
Philippines et al. (2020)
Africa Algeria, Egypt, Libya, Morocco, Tunisia, Western Sahara,
Chad, Djibouti, Eritrea, Ethiopia, Somalia, Sudan, Kenya,
Tanzania, Uganda, Burundi, Equatorial, Guinea, Gabon,
Rwanda, Democratic Republic of Congo, Benin, Burkina
Faso, Cote D’Ivoire, Ghana, Guinea, Mali, Mauritania,
Niger, Nigeria, Senegal, Sierra Leone, Togo, Angola,
Malawi, Mozambique, Zambia, Zimbabwe, Botswana,
Namibia, South Africa, Swaziland
Middle Kazakhstan, Kyrgyzstan, Turkmenistan, Uzbekistan
Asia
Western Afghanistan, Iran, Iraq, Saudi Arabia, Yemen, Palestine,
Asia Lebanon, Syria, Turkey
Europe Austria, Switzerland, Albania, Bulgaria, Croatia, Greece,
Romania, Serbia, Slovenia, France, Portugal, Spain
North United States of America (USA), Mexico
America
Southern Brazil, Bolivia, Colombia, Ecuador, Peru, Argentina
America
Caucasus Armenia, Azerbaijan, Russian Federation
Pacific Marshall Islands, Micronesia, Northern Mariana Islands
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Fig. 1 The distribution of C. rotundus around the world. (The colours on the map were used only to distinguish between different
countries)
originally recorded in the book ‘‘Mingyi Bielu’’ and methods of data mining and comprehensive results
possesses the effects of soothing liver-Qi stagnation have been presented in the supplementary materials.
and alleviating depression, regulating Qi for protect- The results showed that 2712 TCM prescriptions
ing the stomach as well as regulating menstruation and containing CyRh or its processed products were
relieving menstrual pain, making it the most com- adopted, with 449 CMs enrolled in the ChP. The top
monly available CM for regulating the flow of Qi to 10 CMs with the greatest frequency in combination
alleviate depression. In ‘‘Compendium of Materia with CyRh were Angelicae sinensis radix (Danggui),
Medica’’, it was described that Xiang Fu is ‘the chief Glycyrrhizae radix et rhizome (Gancao), Chuanxiong
commander of the treatment for Qi diseases and the rhizome (Chuanxiong), Citri reticulatae pericarpium
leading general of the treatment for female diseases’, (Chenpi), Paeoniae radix alba (Baishao), Atractylodis
and it is frequently applied as a medicine for soothing macrocephalae rhizome (Baizhu), Poria (Fuling),
liver-Qi stagnation and relieving depression. Since Aucklandiae radix (Muxiang), Amomi fructus (Sharen),
ancient times, it has been known as ‘‘holy medicine’’ Citri reticulatae pericarpium viride (Qingpi) (Fig. 2a
in gynecology. At present, big data processing and and supplementary Table S1). The CMs in combina-
analysis techniques, especially data mining and net- tion with CyRh mostly fell into the effect classifica-
work pharmacology, have been greatly applied to the tions of tonic, regulating the circulation of Qi,
study of the material basis, mechanism of action and invigorating Blood Circulation, clearing Heat and
medication pattern of TCM. Therefore, data mining relieving Exterior syndrome (Fig. 2c, supplementary
(Rao et al. 2021; Wang et al. 2021a; Xue et al. 2022) Table S3), with natures of Warm (Fig. 2d, supple-
has been performed in this section on the TCM mentary Table S4), flavors of Pungent, Bitter as well
prescriptions containing raw CyRh or its processed as Sweet (Fig. 2e, supplementary Table S4), and
product, in order to better explore the combination channel tropisms of Spleen, Liver, Lung, Stomach,
pattern characteristics of CyRh in TCM for better Heart and Kidney (Fig. 2f, supplementary Table S5).
clinical application. The detailed materials and In traditional recipes of TCM prescriptions, CyRh is
frequently used for treatments of diseases of (I) the
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Table 2 Various vernacular names of C. rotundus
Language Synonyms References
Arabic Sa’ed, Soadekufi Lawal and Oyedeji (2009), Pirzada et al. (2015), Al-Snafi
Chinese Xiangfu, Suo cao, Xiang fu zi (2016), Kumar et al. (2017), Bajpay et al. (2018), Kabir
and Abbasi (2018)
English Nut grass, Purple nutsedge, Java grass, Rhizoma cyperi,
Coco-grass, Ground-almond, Nut sedge, Nut-grass,
Purple nut, Sedge, Purple nut-grass, Red nut sedge, Java-
grass, Purple nut sedge
Indian Motha, Mutha, Musta, Nagagmotha, Nagarmothaya,
Nagarmotha, Nagaramothaya, Keyabon, Korakizanna,
Barik motha, Bimbal, Muthakasu, Varida, Koranari-
gadde
French Souchet rond
German Knolliges Zypergras
Italian Zigolo infestante
Japanese Hamasuge
Korean Hyangbuja
Portuguese Alho-bravo, Capim-alho, Capim-dandá, Tiririca, Tiririca-
vermelha
Spanish Castañuela, Cipero, Coquito, Juncia real
Swedish Nötag
Burmese Vomonniu
Malayan Mushkezamin
Persian Mushkzenezamin
Sanskrit Chakranksha, Charukesara
Urdu Saad kufi
Spleen system, (II) women’s menstrual, leucorrhea regulating the circulation of Qi. The result suggested
and miscellaneous diseases, (III) fetuses, parturients that Xiangfu (C. rotundus) may be commonly com-
and their diseases and (IV) the Brain system and bined with CMs with efficacies of tonic, regulating the
(V) the Liver system (Fig. 2b, supplementary circulation of Qi, or invigorating Blood circulation in
Table S2), and is generally consistent with the results TCM prescriptions, basically in line with those results
of modern pharmacological studies of CyRh in vivo of the above frequency statistics and can be corrob-
and in vitro. orated with each other.
Association rules were provided by the Apriori Based on the association rules, among the various
algorithm as presented in Fig. 3 and supplementary TCM clinical diseases treated by TCM prescriptions
Tables S6–S9. It has revealed the overall compatibility containing CyRh, the most common diseases of the
patterns of the core CMs in the TCM prescriptions Spleen system, women’s menstrual, leucorrhea and
containing CyRh in Fig. 3 and supplementary miscellaneous diseases as well as fetuses, parturients
Table S6. The CMs combinations with the highest and their diseases were selected for analysis of
support were Xiangfu-Danggui, Xiangfu-Gancao, medication patterns.
Xiangfu-Chuanxiong, Xiangfu-Chenpi, Xiangfu- The results demonstrated that in the traditional
Baishao, Xiangfu-Baizhu. Among them, the Danggui application for treating diseases of the Spleen system,
and Chuangxiong belong to drugs for invigorating the core combination of CMs was Mu Xiang Fen Qi
blood circulation, Gancao, Baishao and Baizhu belong recipe, with slight variations depending on the health
to tonics, while Chenpi is one of the CMs for condition of the patient (Fig. 3b, supplementary
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Fig. 2 The results of frequency statistics for the recipes of TCM prescribed excluding data of CyRh; d Natures of CMs
prescriptions containing CyRh. a The CMs prescribed with prescribed excluding data of CyRh; e Flavors of CMs prescribed
frequency percentage above 5% excluding data of CyRh; excluding data of CyRh; f Channel tropisms of CMs prescribed
b Indication classifications; c Effect classifications of the CMs excluding data of CyRh
Table S7). The CMs combinations with the highest system diseases, Xiangfu (C. rotundus) is regularly
support were Xiangfu-Chenpi, Xiangfu-Gancao, compatible with CMs for regulating the circulation of
Xiangfu-Muxiang, Xiangfu-Sharen, Xiangfu-Baizhu Qi, tonics and aromatics for resolving Dampness. It is
(Chenpi and Muxiang belong to CMs for regulating well known that Xiangfu, Chenpi, Muxiang, Sharen,
the circulation of Qi, Gancao and Baizhu belong to and Baizhu all serve the spleen and stomach meridians
tonics, Sharen is one of the aromatics for resolving in TCM. Gancao is usually applied as an adjuvant and
Dampness), revealing that in the treatment of spleen dispatcher herb in TCM prescriptions to moderate the
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Fig. 3 Representative network display for association rules of system diseases; c The CMs prescribed for the women’s
the CMs in TCM prescriptions containing CyRh. a The CMs menstrual, leucorrhea and miscellaneous diseases; d The CMs
with high-frequencies; b The CMs prescribed for the Spleen prescribed for the fetuses, parturients and their diseases
violent and irritant effects of medicines, and at the support were Xiangfu-Danggui, Xiangfu-Chuanxiong,
same time can strengthen the spleen. It is evident that Xiangfu-Baishao, Xiangfu-Shudihuang, Xiangfu-
the data mining results and the traditional uses of TCM Baizhu, Xiangfu-Gancao (Shudihuang belong to ton-
both were mutually verified, explaining the reason- ics), which reveals that in the treatment of women’s
ability and reliability of the data mining findings. diseases, Xiangfu is often compatible with tonics and
On the other hand, the outcomes of the association medicines for invigorating Blood circulation. It is
rules between women’s menstrual, leucorrhea and notable that Si Wu Tang, which consists of Chuanx-
miscellaneous diseases and fetuses, parturients and iong, Danggui, Baishao and Shudihuang, is a classic
their diseases were extremely similar (Fig. 3c and d, recipe of TCM prescriptions for invigorating blood,
supplementary Tables S8–9). And the core combina- the blood tonic and the treatment of menstrual
tion of CMs was Siwu Tang for curing both of their irregularities, and has been recognized as the ‘‘Pre-
diseases in TCM. The association rule analysis results ferred Prescription of Gynecology’’ by succeeding
showed that the CMs combinations with the highest generations of TCM medical practitioners. More
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importantly, Baizhu is traditionally recognized in The results of the cluster analysis presented in
TCM for its effect on the calming fetus and Xiangfu is Fig. 4 indicated that CMs with the same medicinal
regarded as the ‘‘Sacred Medicine of Gynecology’’ in properties are more likely to cluster into one class,
TCM. This explains to some extent in the aforemen- which is consistent with the above association rule
tioned results of the data mining, that Xiangfu has results.
been frequently prescribed by combinations with In conclusion, CyRh, in TCM, is traditionally
Danggui, Chuanxiong, Baishao, Shudihuang, Baizhu used for treating diseases concerning the digestive
and Gancao in the TCM system. system, gynecology and nervous system such
as stomach pain, abdominal pain, depression,
Fig. 4 Hierarchical cluster analysis of the CMs in TCM c Hierarchical cluster analysis for the CMs prescribed for the
prescriptions containing CyRh. a Hierarchical cluster analysis women’s menstrual, leucorrhea and miscellaneous diseases;
of the CMs with high-frequencies; b Hierarchical cluster d Hierarchical cluster analysis for the CMs prescribed for the
analysis of the CMs prescribed for the Spleen system diseases; fetuses, parturients and their diseases
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Phytochemistry Reviews
amenorrhea, dysmenorrhea, menoxenia as well as carbohydrates, aliphatic compounds and several trace
breast tenderness. The plant which is called ‘‘the elements have also been found to be existent in this
general medicine to treat Qi disease, and the chief plant. Figure 5 and Table 4 distinctly illustrate the
medicine to treat women’s diseases’’, exactly corre- multiplicity of chemical constituents of C. rotundus.
sponds to the results of the data mining described In this part, a total of 552 compounds fromC. rotundus
above. Referring to two important and authoritative have been summarized, with 350 and 202 compounds
criterions, (I) the Chinese national standard ‘Clinic isolated or characterized, respectively. Their detailed
terminology of traditional Chinese medical diagnosis chemical information including the name, formula,
and treatment-Diseases’ (GB/T 1675.1–1997) and (II) molecular weight and the originated plant parts are
International Classification of Diseases (ICD-10), summarized in supplementary Tables S10–17, and
modern pharmacological studies related to traditional their chemical structures are presented in supplemen-
applications of TCM were systematically summa- tary Fig. S1–23.
rized, as detailed in Table 3. Anti-cervical cancer
(Mannarreddy et al. 2017; Saad et al. 2018; Susianti Monoterpenoids
et al. 2018; Lin et al. 2019), anti-breast cancer (Park
et al. 2014; Mannarreddy et al. 2017; Simorangkir The simple monoterpenes and their oxygenated
et al. 2019; Wang et al. 2019; Ma et al. 2020; Samra derivatives are an indispensable part of the essential
et al. 2020), anti-ovarian cancer (Ahn et al. 2015; Ryu oil of C. rotundus (EOCR) and are mainly composed
et al. 2015), anti-depressant activity (Pal et al. 2009; of menthane-type (supplementary Fig. S1) and pinane-
Jia and Zou 2014; Lin et al. 2015; Zhou et al. type (supplementary Fig. S2) monoterpenoids. Inves-
2016a, 2016b; Hao et al. 2017), neuroprotective tigation of the available literature indicated that the
activity (Dabaghian et al. 2015; Sutalangka and monoterpenoids isolated from this aromatic herb are
Wattanathorn 2017), hepatoprotective activity predominantly iridoid glycosides, with chemical
(Mohamed 2015; Parvez et al. 2019), against gastric structures shown in supplementary Fig. S3. Using
mucosal damage (Thomas et al. 2015), anti-gastroin- despair mice models, three iridoid glycosides [rotun-
testinal tumors (Al-Shammari et al. 2021) and other duside F (60), rotunduside G (55) and rotunduside H
effects of CyRh have been well evaluated in modern (56)] were shown to exhibit noticeable antidepressant
pharmacological studies. Moreover, CyRh is also used activity by the forced swim test (FST) and the tail
for the treatment of digestive and gynecological suspension test (TST), equivalent to the positive
disorders including amenorrhea and dysmenorrhea in control fluoxetine (Zhou and Fu 2013; Lin et al.
traditional Indian, Tunisian, and South Korean medic- 2015; Zhou et al. 2016a). 10-O-p-Hydroxybenzoylthe-
inal systems. All the above are to some extent unified. viridoside (53), rotundusideB (51), rotunduside C (67)
and senburiside I (66) displayed macrophages respi-
ratory burst (MRB) inhibitory activity to some extent
Phytochemistry (Zhou et al. 2013; Zhou and Zhang 2013; Cheng et al.
2014; Zhang et al. 2014).
Due to its wide distribution worldwide, the phytocon-
stituents of C. rotundus have been extensively Sesquiterpenoids
detected and isolated in many countries over the past
decades. The complexity and structural diversity of the Sesquiterpenoids are the most dominant active con-
chemical composition of this aromatic herb has stituents in EOCR. To date, there are approximately
contributed to its wide-ranging pharmacological 260 sesquiterpenoids that have been isolated and
activities and medicinal values. Numerous studies characterized from C. rotundus, mainly consisting of
have demonstrated that the main component of C. sesquiterpenes and their oxygenated derivatives such
rotundus is the volatile oil, which is also the major as alcohols, ketones and lactones. Notably, most of
pharmacologically active ingredient, consisting of a themwere identified to be separated from the rhizomes
variety of monoterpenes, sesquiterpenes and their or tubers of this plant. The predominant sesquiter-
oxides. In addition, some flavonoids, saponins, alka- penoid skeletons include eudesmane-type (supple-
loids, phenylpropanoids, quinonoids, diterpenoids, mentary Fig. S5), patchoulane-type (supplementary
123
Phytochemistry Reviews
123
Table 3 Modern pharmacological studies related to the traditional use of C. rotundus in TCM
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Estrogen-like In vivo Female C57bl/6 By recovering the levels of Petroleum ether II 3 Rhizomes Kim et al.
effect mice dopamine in the striatum extract (2013)
and behavior performance (50 mg/kg/day)
in MPTP mice and the TH
immunopositive fibers and
cells
Anti-estrogenic In vivo Female Swiss Reduction of the thickness in Methanol extract II 3 Tubers Hendri et al.
effect albino mice the endometrial layers of (3375 mg/kg) (2016)
the uterine wall
Enhance In vivo C57BL/6 female Increase the expression of Water extract II 3 Tubers Choi et al.
endometrial and mice; LIF and enhance adhesion (31.68 mg/kg/day) (2017)
receptivity in vitro Choriocarcinoma of JAr cells onto Ishikawa
JAr cells and cells to improve the
endometrial number of implantation
Ishikawa cells sites in pregnant mice
Anti-uterine In vivo Female sprague By increasing Bax protein Amentoflavone II 3 Rhizomes Ying and Bing
fibroids dawley rats expression and reducing (15, 10 and 5 g/kg) (2016)
Bcl-2 expression from
homodimers Bax/Bax, and
decreasing plasma
estradiol and progesterone
Lactogenic In vivo Lactating dams By increasing the weight and Water extract (300 and III 3 Rhizomes Badgujar and
activity the protein, carbohydrate 600 mg/kg) Bandivdekar
content of mammary gland (2015)
tissue, and stimulating the
synthesis of prolactin
significantly to increase the
milk production
Inhibition to fetal In vivo Female sprague Exhibit inhibitory effects 96% Alcohol extract III 3 Tubers Hendri et al.
growth dawley rats against fetal growth of rats (22.5, 45, 90 mg/kg) (2019);
during pregnancy Busman et al.
(2020)
Regulation of In vivo Mice (Mus Reduce the levels of b3 Essential oil III 3 Tubers Yulianty and
Integrin b3 musculus L.) integrin of uterine mice Sutyarso
during the embryo (2019)
implantation period
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Anti-depressant In vivo Adult swiss albino By enhancing sleeping time Ethanol extract IV 2 Roots and Pal et al. (2009)
activity mice and analgesic, reducing (40, 60 and 80 mg/kg) rhizomes
different behavioral
reflexes, increasing the
brain serotonin and GABA
levels in mice by
anticonvulsant activity
Anti-depressant In vivo Male NIH mice / Rotunduside D, IV 2 Rhizomes Lin et al. (2015)
effect rotunduside E,
rotunduside F
(50 mg/kg)
Anti-depressant In vivo Male NIH mice / Rotunduside G, IV 2 Rhizomes Zhou et al.
effect rotunduside H (2016a)
(50 mg/kg)
Anti-depressant In vivo Male NIH mice / Cyprotuside A and IV 2 Rhizomes Zhou et al.
effect Cyprotuside B (2016b)
(50 mg/kg)
Antidepressant In vivo Mice Reduction of the immobility Ethanol extract IV 2 Roots Jia and Zou
effect time in the TST and FST (2014)
Antidepressant In vivo Wistar rats Inhibition of brain MAO Water extract IV 2 Whole Hao et al.
effect activity in rats (200, 400 and 800 mg/ plant (2017)
kg)
Potential In vivo Adult male Wistar Amelioration of the CA1 Ethanol extract IV 2 Rhizomes Dabaghian
neuroprotective rats pyramidal cell loss due to (100 mg/kg/day) et al. (2015)
effects transient global ischemia/
reperfusion injury
Neuroprotective In vivo Male Wistar rats Enhance memory, increase 95% Ethanol extract IV 2 Aerial part Sutalangka and
and cognitive- neuronal density, decrease (100, 200 and 300 mg/ Wattanathorn
enhancing AChE activity, decrease kg) (2017)
effects oxidative stress status and
activate pERK1/2 CP1-
treated in rats
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Potential against In vivo Male Wistar rats Improvement of spatial Ethanol extract IV 2 Tubers Rabiei et al.
Alzheimer’s learning and memory in (100 and 200 mg/kg) (2013)
disease rats might be related to the
mediation of the
cholinergic nervous system
and exhibit potent
antioxidant activity by
regulating the enzyme
levels such as SOD, CAT,
GPx and GR in brain tissue
Potential against In vivo Wistar male rats The increase of escape 80% Ethanol extract IV 2 Powder Mehdizadeh
Alzheimer’s latency and traveled (400 mg/kg) et al. (2017)
disease distance, improvement of
the learning impairment
and improvement of AD-
induced cognitive
dysfunction
Potential against In vivo Male Wistar rats The increase of spatial Chloroform fraction IV 2 Rhizomes Shakerin et al.
Alzheimer’s memory, neuronal (250, 500, and (2020)
disease differentiation in the 750 mg/kg)
hippocampus
Against Hypoxia In vivo Inbred male Wistar The protection against the Ethanol extract IV 2 Tubers Jebasingh et al.
injury rats cognitive impairments, (200 and 400 mg/kg) (2014)
muscular coordination
defects and the locomotor
activity
Against Hypobaric In vivo Sprague–Dawley Amelioration of hypobaric TOF Extract IV 2 Roots Kandikattu
hypoxia rats hypoxia-induced memory (150, 300 and 600 mg/ et al. (2017)
impairment and kg)
neurodegeneration in the
hippocampus through its
anti-stress effects
Against In vivo Albino Wistar rats Protective effect against Methanol extract IV 2 Tubers Hussein et al.
neurotoxicity esfenvalerate by (100 mg/kg) (2020)
ameliorating levels of
antioxidant enzymes,
acetylcholine esterase, and
inflammatory markers
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Hepatoprotective In vivo Wister rats Anti-hepatotoxic, anti- 80% Ethanol extract V 1 Rhizomes Parvez et al.
activity hepatitis B virus and (IC50: 100 lg/mL) (2019)
modulation of hepatic
CYP450
Hepatoprotective In vivo Adult male albino By improving the activity of EtOAc fraction V 1 Rhizomes Mohamed
activity rats SGOT, SGPT, and total (100 mg/kg) (2015)
bilirubin, scavenging free
radicals for the
lipoperoxidants, reactive
oxygen species (ROS) and
NO and maintaining the
liver antioxidative defense
systems
Against non- In vivo Male C57BL/6 Reduction of the expression The hexane fraction V 1 Rhizomes Oh et al. (2015)
alcoholic fatty mice levels of hepatic lipogenic
liver disease genes
Cytoprotective In vivo Female Sprague– Effects on protecting the Water extract I 1 Rhizomes Zhu et al.
effects against Dawley rats stomach, delay gastric (1250, 2500, 4000 mg/ (1997)
gastric motility, and delayed kg)
ulceration gastric emptying of resin
pellets
Against gastric In vivo Male Wistar rats By inhibiting oxidative 70% Methanol extract I 1 Rhizomes Thomas et al.
mucosal damage stress, increasing the (250 and 500 mg/kg) (2015)
activity of SOD, cellular
glutathione and GSH-Px
and inhibiting the lipid
peroxidation in the gastric
mucosa of ulcerated
animals
Potential anti- In vitro Cervical cancer Reduction of the expression TOF Extraction II 3 Tubers Saad et al.
cervical cancer (HeLa) cells and levels of OCT3/4, MMP2 (50–500 lg/mL, the (2018)
human and MMP9 best concentration of
glioblastoma inhibition: 350 lg/
(AMGM) cells mL)
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Potential anti- In vitro HeLa cervical / The hydrodistilled II 3 Tubers Susianti et al.
cervical cancer cancer cells essential oil (2018)
(IC50:
35.062 ± 11.258 lg/
mL)
Potential anti- In vitro HeLa human Induction of gene expression Ethanol extract II 3 Rhizomes Lin et al. (2019)
cervical cancer cervical cancer which is associated with (IC50: 300 lg/mL)
cells apoptosis and cell-cycle
arrest
Potential anti- In vitro HeLa cervical / Methanol extract II 3 Rhizomes Mannarreddy
cervical cancer cancer cells (IC50: 6.83 ± 0.79 lg/ et al. (2017)
mL)
Potential anti- In vitro Breast carcinoma / The hydrodistilled II 3 Rhizomes Samra et al.
breast carcinoma (MCF-7) cells essential oil (2020)
(IC50:
170.8 ± 0.567 lg/
mL)
Potential anti- In vitro TNBC cells lines Induction of apoptosis by 95% Ethanol extract II 3 Rhizomes Ma et al. (2020)
triple-negative (MDA-MB-468 arresting the pathways of (MDA-MB-468: IC50:
breast cancer and MDA-MB- carbohydrate metabolism 773.3 lg/mL; MDA-
231) and nucleotide sugar MB-231: IC50:
metabolism and impacting 537.5 lg/mL)
the energy metabolism of
TNBC cells
Potential anti- In vitro TNBC cells lines By arresting cell cycle in G0/ 95% Ethanol extract II 3 Rhizomes Wang et al.
triple-negative (MDA-MB-468 G1 phase induces apoptosis (0, 200, 400, 600, 800, (2019)
breast cancer and MDA-MB- by promoting the 1000 and 1200 lg/
231) expression of BAX and mL)
inhibiting the expression of
BCL-2 3-MA
Potential anti- In vitro Breast carcinoma / Methanol extract II 3 Rhizomes Mannarreddy
breast cancer (MCF-7) cells (IC : 4.52 ± 0.57 lg/ et al. (2017)50
mL)
Potential anti- In vitro MCF-7 cell and By arresting the cell cycle in n-Hexane fraction II 3 Rhizomes Simorangkir
breast cancer Vero cells the G0-G1 phase and (IC : 120.819 lg/mL) et al. (2019)50
inducing apoptosis
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Potential anti- In vitro MDA-MB-231 Activation of both intrinsic Ethanol extract II 3 Rhizomes Park et al.
breast cancer human breast and extrinsic signaling Methanol extract (2014)
carcinoma cells pathways to regulate the (0–500 lg/mL)
caspase-dependent cascade
Potential anti- In vitro Human ovarian / AcOEt fraction II 3 Rhizomes Ryu et al.
ovarian cancer cancer cells (IC50: 74.60 and
(2015)
(A2780) and 177.61 lg/mL)
endometrial
11,12-
adenocar
Dihydroxyeudesm-4-
cinoma (Ishikawa) en-3-one (IC50:
11.06 ± 0.25 and
6.46 ± 0.12 lM)
Potential anti- In vitro Endometrial / Cyperusol A3 II 3 Rhizomes Ryu et al.
ovarian cancer adenocar (86.85 ± 0.41 lM) (2015)
cinoma (Ishikawa)
Potential anti- In vitro Ovarian cancer cell By inducing caspase- n-Hexane fraction II 3 Rhizomes Ahn et al.
ovarian cancer lines (A2780, dependent apoptosis in (IC50: 50.48 ± 1.07,
(2015)
SKOV3 and human ovarian cancer cells 87.34 ± 0.56 and
OVCAR-3) 149.04 ± 0.87 lg/
mL)
EtOAc fraction
(IC50: 74.60 ± 0.52,
80.72 ± 1.92 and
134.75 ± 0.98 lg/
mL)
80% EtOH extract
(A2780: IC50:
135.33 ± 0.14 lg/
mL)
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Potential anti- In vitro Ovarian cancer cell By inducing caspase- 6,9-Diacetoxy II 3 Rhizomes Ahn et al.
ovarian cancer lines (A2780, dependent apoptosis in cyperene (2015)
SKOV3 and human ovarian cancer cells (IC50: 89.75 ± 1.27,
OVCAR-3) 118.63 ± 0.01,
114.45 ± 0.12 lg/
mL)
6-Acetoxy Cyperene
(IC50: 61.69 ± 2.25,
89.17 ± 0.06,
100.42 ± 0.02 lg/
mL)
Potential anti- In vitro Endometrial cancer By inducing caspase- n-Hexane fraction II 3 Rhizomes Ahn et al.
ovarian cancer (Hec1A and dependent apoptosis in (110.62 ± 0.37 and (2015)
Ishikawa) cells human ovarian cancer cells 164.07 ± 0.23 lg/
mL)
EtOAc Fraction
(IC50: 131.43 ± 0.95
and
177.61 ± 0.53 lg/
mL)
Estrogen-like In vitro MCF-7 BUS cells By increasing transcriptional 4a,5a-Oxidoeudesm- II 3 Rhizomes Park et al.
effect activity in estrogen- 11-en-3-one (2019)
sensitive gene (3.75–60 lg/mL)
Potential anti- In vitro Human endometrial / AcOEt fraction II 3 Rhizomes Ryu et al.
endometrial adenocarcinoma (IC50: 177.61 lg/mL) (2015)
adenocarcinoma cells (Ishikawa)
cancer
Neuroprotective In vitro The human Amelioration of the H2O2- Water extract IV 2 Roots Kumar and
effects neuroblastoma induced oxidative stress by (0, 1, 10, 25, 50, and Khanum
cell line (SH- improving the antioxidant 100 lg/mL) (2013)
SY5Y) status, mitochondrial
membrane integrity,
regulating the apoptotic
markers and maintaining
the BDNF level
Phytochemistry Reviews
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Against neuronal In vitro PC12 cells Inhibition of the generation Water extract IV 2 Rhizomes Lee et al.
damage of reactive oxygen species (50 and 100 lg/mL) (2010)
and nitric oxide, reduction
of mitochondrial
membrane potential, and
caspase-3 activity induced
by 6-OHDA, protective
effect against damage to
dopaminergic neurons
Potential anti- In vitro Hepatocellular / The hydrodistilled V 1 Rhizomes Samra et al.
hepatocellular carcinoma essential oil (2020)
carcinoma (HepG2) cells (IC50:
cancer 204.1 ± 1.25 lg/
mL)
Potential anti-liver In vitro Hepatocellular / Methanol extracts V 1 Rhizomes Mannarreddy
cancer carcinoma (IC : 7.66 ± 0.82 lg/ et al. (2017)50
(HepG2) cells mL)
Hepatoprotective In vitro Hepatocellular Anti-hepatotoxic, anti- Ethyl acetate, n- V 1 Rhizomes Parvez et al.
activity carcinoma hepatitis B virus and butanol and aqueous (2019)
(HepG2) cells modulation of hepatic fractions
CYP450 (IC50: 64.24, 94.86,
107.81 lg/mL)
Anti-hepatitis B In vitro HepG2.2.15 cells / Ethyl acetate, aqueous, V 1 Rhizomes Parvez et al.
virus (HBsAg and n-butanol extracts (2019)
HBeAg Elisa) (IC50: 64.24, 94.86,
107.81 lg/mL)
Anti-infectious In vitro E. coli B170, By reducing bacterial Water extract I 1 Tubers Daswani et al.
diarrhea E. coli E134, adherence and regulating (0.52 ± 0.028, (2011)
E. coli B831-2, the production of CT and 2.6 ± 0.14 and
Vibrio cholerae action of LT, directly 5.2 ± 0.28 mg/mL)
C6709 and killing the pathogen to
Shigella flexneri exerts its antidiarrheal
M9OT action
Phytochemistry Reviews
Fig. S6), and cadinane-type (supplementary Fig. S7)
sesquiterpenoids. A summary of the sesquiterpenoid
skeletons in C. rotundus is presented in Fig. 6.
It is worth pointing out that several of the published
pharmacological effects of C. rotundus may be
attributed to the most abundant and major bioactive
components of eudesmane-type, patchoulane-type,
eremophilane-type (supplementary Fig. S10) sesquiter-
penoids, such as a-cyperone (111), isocyperol (96),
nootkatone (235) and valencene (237). Khan et al.
pointed out that a-cyperone (111), isocyperol (96) and
nootkatone (235), valencene (237), b-selinene (97)
expressed a powerful anti-inflammatory effect on
LPS-stimulated RAW 264.7 cells (Khan et al. 2011;
Seo et al. 2014). There are also several research works
showing convincingly that nootkatone (235) and
valencene (237) exerted anti-allergic activity either
in vitro or in vivo and increased the survival rates in
septic mice on account of heme oxygenase-1 induction
(Jin et al. 2011; Tsoyi et al. 2011). Besides, nootkatone
(235) exerted potent DPPH radical scavenging capac-
ity, with IC50 valued 22.03 lM, followed by aristolone
(296) and solavetivone (302), with IC50 values of
24.18 and 31.24 lM, respectively (Priya Rani and
Padmakumari 2012). Some sesquiterpenoids isolated
from Cyperus rotundus tubers were found to possess
varying degrees of antimalarial effects against Plas-
modium falciparum, as exemplified by patchoulenone
(152, EC50: 0.108 M), caryophyllene a-oxide (241,
EC50: 0.345 lM), 10,12-peroxycalamenene (318,
EC50: 2.33 9 10
–3 lM), a-cyperone (111, EC50:
25 lM) and b-selinene (97, EC50: 27 lM) (Weenen
et al. 1990a; Thebtaranonth et al. 1995). In addition,
11,12-dihydroxyeudesm-4-en-3-one (110, EC50:
11.06 ± 0.25 lM) showed a more potent proliferation
inhibitory effect against ovarian cancer A2780 cells
than 6,9-diacetoxy cyperene (143, EC50: 61.69 ±
2.25 lM). Again, 11,12-dihydroxyeudesm-4-en-3-
one (110, EC50: 6.46 ± 0.12 lM) and cyperusol A3
(197, EC50: 86.54 ± 0.41 lM) also exhibited
detectable cytotoxicities against endometrial adeno-
carcinoma Ishikawa cells (Ahn et al. 2015; Ryu et al.
2015). There was an interesting discovery that 4a,5a-
oxidoeudesm-11-en-3-one (105) exerts a dual regula-
tion on estrogen receptor-a and estrogen receptor-b
and possesses both estrogenic and antiestrogenic
effects depending on the E2 concentration (Park
et al. 2019).
123
Table 3 continued
Effect Type of Species/enzymes Mechanism/effect Extract/compound Corresponding International Part of References
study (Dose/IC50) TCM Classification plant
indicationsa of diseasesb
Therapy for In vitro Esophagus cancer, The combination therapy of Alkaloid extract I 1 Rhizomes Al-Shammari
gastrointestinal hepatocellular NDV-alkaloid extract had (100 lg/mL) et al. (2021)
tumors carcinoma, synergistic and enhanced
human rectal anticancer activity, with
cancer upregulating p53 level
a I, The Spleen system; II, Women’s menstrual, leucorrhea and miscellaneous diseases; III, Fetuses, parturients and their diseases; IV, The Brain system; V, The Liver system; b 1,
The digestive system diseases; 2, The nervous system diseases; 3, The gynecological diseases
Phytochemistry Reviews
Fig. 5 Distribution of chemical constituents of C. rotundus. of monoterpenoids; c Distribution of the sub-type of sesquiter-
a Treemap showing the constituent distribution by roughly penoids; d Distribution of the sub-type of flavonoids
compound type from C. rotundus; bDistribution of the sub-type
Additionally, a norsesquiterpenoid norcyperone Flavonoids
(343) and a sesquiterpenoid cyperensol A (344)
characterized with a unique 6/6/5 skeleton, have been Flavonoids are extensively distributed in the plant
isolated and identified from the rhizomes of C. kingdom with a wide variety of biological activities,
rotundus (Xu et al. 2008; Wang et al. 2021b). Again, which have attracted worldwide attention (Bai et al.
three novel sesquiterpenoid alkaloids (supplementary 2019). Flavonoids are mainly found in the rhizomes
Fig. S13) rotundines A–C (352–354) have been and aerial parts such as the leaves of C. rotundus
reported by Jeong et al. (Jeong et al. 2000) to be (Sayed et al. 2007, 2008; Ibrahim et al. 2018). Until
isolated from the methanol extract of the rhizomes of now, a total of fifty-four flavonoids have been isolated
C. rotundus. and identified from C. rotundus, with chemical
structures as displayed in the supplementary
Fig. S14–18. Flavone-type and flavonol-type are the
predominant types of flavonoids isolated from C.
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Phytochemistry Reviews
Table 4 Summary of the chemical constituents in C. rotundus rotundus. Besides these, the isoflavone-type, biflavo-
noids and other types of flavonoids have also been
Type Number of compounds
discovered to be present in C. rotundus. Among them,
Monoterpenoids 94 four biflavone constituents namely amentoflavone
Sesquiterpenoids 260 (393), ginkgetin (394), isoginkgetin (395) and sciado-
Flavonoids 54 pitysin (396), were obtained from the ethanol extract
Saponins 31 of rhizomes of C. rotundus. And amentoflavone
Phenylpropanoids 15 showed a significant effect on anti-uterine fibroids in
Quinonoids 2 pathological rat models (Ying and Bing 2016). 7,8-
Diterpenoids 2 Dihydroxy-5,6-methylenedioxyflavone (362) was iso-
Alkaloids 11 lated from the rhizomes of C. rotundus (Zhou and Fu
Saccharides 3 2013); while vitexin (365), isovitexin (366), orientin
Phenolic and phenolic glycosides 37 (367), epiorientin (368), luteolin 40-O-b-D-glucuronopy-
Other types 43 ranoside (370), luteolin 7-O-b-D-glucuronopyra-
Total 552 noside (371), cyperaflavoside (375), myricetin
3-O-b-D-galactopyranoside (382), quercetin 3-O-b-
D-glucopyranoside (383), and myrcetin 3-O-b-D-
Fig. 6 Basic sesquiterpenoid skeletons in C. rotundus
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Phytochemistry Reviews
glucopyranoside (384) were given from the aerial Phenolic compounds and phenolic glycosides
parts of C. rotundus (Sayed et al. 2008; Ibrahim et al.
2018). Compounds 365–368, 370–371 and 382 exhib- Phenolic compounds are largely composed of phenyl-
ited significant antioxidant activities (Sayed et al. propanoids, flavonoids, and some other phenolic acid
2008), and compounds 365, 367, 371, 375, 383, and components. As phenylpropanoids and flavonoids
384 possessed significant 5-lipoxygenase inhibitory have been detailed in the preceding sections, this
activity with IC50 values at 5.1, 4.5, 5.9, 4.0, 3.7, and section focused on some other phenolics or phenolic
2.3 lM, respectively (Ibrahim et al. 2018). As is glycosides as shown in supplementary Fig. S22. For
reported, khellin (403) and visnagin (404) were example, scirpusins A–B (494–495) (Sim et al. 2016)
reported to show strong cytotoxic activities against which were obtained from the 80% EtOH extract of C.
L5178y (mouse lymphoma cells) with ED50 of 4.5 and rotundus rhizomes using bioactivity-guided fraction-
0.9 lg/mL, respectively, and also inhibit significantly ation, remarkably provided in vitro protection against
the growth of the neonate larvae of the pest insect neurotoxins for neuronal cells. In addition, five natural
Spodoptera littoralis to exert the antifeedant activity a-glucosidase inhibitors, cyperusphenol A (497),
(Sayed et al. 2007). mesocyperusphenol A (499), cyperusphenol D (493),
scirpusins A (494) and scirpusins B (495) have been
Triterpenoids and steroids successfully fished out (Cao and Ou 2015) from the C.
rotundus extracts using immobilized enzyme tech-
Saponins in C. rotundus are of considerable impor- nique in combination with UHPLC-QTOF MS
tance in the treatment of inflammation as well as analysis.
depression. Supplementary Fig. S19 displays a sum-
mary of the structures of thirty-one triterpenoids and Other compounds
steroids discovered in C. rotundus. Among them, the
cycloartane glycosides cyprotuside A (435), cyprotu- Apart from the aforementioned, diterpenoids (455–
oside B (436), cyprotuoside C (433), cyprotuoside D 456), quinonoids (457–458), nitrogenous compounds
(434), which were isolated from the 95% aqueous (459–469), carbohydrates (470–472) and some other
ethanol extract of the rhizome of C. rotundus (Yang compounds (510–552) were also detected to be present
and Shi 2012; Zhou et al. 2016b; Lin et al. 2018), with in C. rotundus, as shown in supplementary Fig. S21–
a 9,10-seco-cycloartane framework that has seldom S23. Among them, fulgidic acid (532) could suppress
been reported from a natural source. Cyprotuoside A LPS-induced iNOS, COX-2, TNF-a, and IL-6 expres-
(435) and cyprotuoside B (436) showed remarkable sion effectively by activator protein-1 (AP-1)AP-1
antidepressant activity in the despair mice models inactivation in RAW264.7 macrophages to exert its
(Zhou and Zhang 2013). Furthermore, a classic lupine- anti-inflammatory activity (Shin et al. 2015).
type triterpenoid lupeol (420), to a certain extent,
expressed anti-inflammatory activity and IL-1b inhi-
bitory activity in THP-1 monocytic cells. Separation, identification and analytical methods
Phenylpropanoids Separation techniques
So far, a total of 15 phenylpropanoids have been Presently, various separation techniques have been
isolated or characterized from C. rotundus. They employed for the isolation and purification of chem-
generally consist of simple phenylpropanoids (440– ical components of C. rotundus. Among them, the
451), coumarins (452–453) and lignans (454), as listed conventional separation procedures include silica gel
in supplementary Fig. S20. Among them, p-coumaric column chromatography, sephadex LH-20 column
acid (443), caffeic acid (445), (-)-(E)-caffeoylmalic chromatography, alumina column chromatography,
acid (447) and chlorogenic acid (446) exhibited reversed-phase (ODS, RP-18, MCI, YMC) column
significant antioxidant activities (Sayed et al. 2008). chromatography, macro porous absorption resin (Diaion
HP-20) column chromatography, thin-layer chromatog-
raphy (TLC), preparative thin-layer chromatography
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Phytochemistry Reviews
(PTLC), HPLC with C18 column, semi-preparative sitosteryl-(60-hentriacontanoyl)-b-D-galactopyra-
HPLC and preparative HPLC (PHPLC) (Morimoto noside (427), cyprotuoside C (433), cyprotuoside D
and Komai 2005; Kim et al. 2012; Cheng et al. 2014; (434), cyprotuside A (435) and cyprotuside B (436),
Zhang et al. 2014; Shin et al. 2015; Xu et al. 2015; Liu identification of the structure and especially the
et al. 2016). absolute configuration of the sugar residues (viz.
Moreover, several alternative techniques have been glycones) is typically aided by acid hydrolysis of the
applied in the purification of the secondary metabo- analytes followed by GC comparisons with authentic
lites ofC. rotundus. MPLC (RediSep SiO2) andMPLC standards. Q-TOF–MS aided by available standards
(RediSep C18) were employed to obtain two novel has been carried out for the identification of certain
sesquiterpenoids and three identified ones by Ryu et al. constituents including (E)-cyperusphenol A (497),
(Ryu et al. 2015). Park et al. purified six sesquiter- mesocyperusphenol A (499), cyperusphenol D (493),
penoids from the methanolic extract of C. rotundus scirpusins A–B (494–495), and sugetriol (163) (Sayed
(MECR) rhizomes based on estrogenic activity, et al. 2007; Zhou and Zhang 2013; Cao and Ou 2015;
obtained by a combination of silica gel column Zhou et al. 2016a, 2016b; Lin et al. 2018). On the other
chromatography and cycling HPLC chromatography hand, MS combined with GC is frequently applied for
with JAIGEL-1H and 2H columns (Park et al. 2019). A characterizing the volatile components of C. rotundus
flash chromatographic system equipped with a C18 (Lawal and Oyedeji 2009; Ghannadi et al. 2012;
flash column was adopted to conduct the separation of Eltayeib and Ismaeel 2014; Richa and Suneet 2014;
fulgidic acid (532) (Shin et al. 2015). Supercritical Aeganathan et al. 2015; Samra et al. 2020; Qu et al.
fluid extraction (SFE) and high-speed counter-current 2021).
chromatography (HSCCC) were used for the first time
to acquire high-purity a-cyperone (111) of much Analytical methods
quantities from EOCR (Shi et al. 2009). Xu et al.
obtained thirty-seven sesquiterpenoids based on anti- With the purpose of better qualitative and quantitative
hepatitis B virus activity-oriented isolation by associ- analysis of C. rotundus, numerous techniques includ-
ating common chromatographic separation techniques ing TLC, PTLC, HPTLC, GC, GC–MS, HPLC/
with ultra-fast liquid chromatography-mass spectrom- UHPLC, UPLC-QTOF-MS, LC–ESI–MS/MS, PIXE
etry (UFLC-MSn) and HR-MS (Xu et al. 2015). Sonwa and ICP-MS have been employed. Table 5 and
and König also for the first time performed the pre- supplementary Table S18 summarized in detail the
fractionation of EOCR on a silica column coupled analytical methods of C. rotundus, focusing mainly on
with a condenser and successively isolated (-)- isoro- the analyses of volatile oils, sesquiterpenoids and
tundene (254) by PTLC on silver nitrate precoated some phenolic constituents such as solavetivone
plates (Sonwa and König 2001). (302), aristolone (296), nootkatone (235), scirpusins
A (494), gallic acid (484), etc. The majority of the
Identification techniques analyses of C. rotundus were performed by GC–MS
for qualitative and semi-quantitative analysis of the
The structural identification of the isolated phytocon- essential oil.
stituents from C. rotundus has been performed
successfully using recognized chromatographic and GC analysis
spectroscopic techniques such as TLC, IR, UV, EI-
MS, HR-ESI–MS, MALDI-TOF MS, FAB-MS, HR- Gas chromatography has been widely implemented for
DART-MS, 1D/2D NMR (including 1H NMR, 13C the rapid and efficient detection of volatile or non-
NMR, DEPT, HMBC, HSQC, 1H-1HCOSY, ROESY volatile compounds not limited to the food industry
and NOESY), ECD and X-ray crystallography (Sayed alone but also in the pharmaceutical field. Gas
et al. 2008; Liu et al. 2010; Ito et al. 2012; Zhou and chromatography-flame ionization detector (GC-FID),
Yin 2012; Zhou et al. 2013; Cheng et al. 2014; Lin gas chromatography–olfactometry-mass spectrometry
et al. 2018; Samra et al. 2021). Given the presence of (GC-O-MS), and gas chromatography-mass spectrom-
glycosidic compounds in C. rotundus, such as rotun- etry (GC–MS) were used for the analysis of the
duside G (55), rotunduside H (56), rotunduside A (68), volatile constituents of C. rotundus (Table 5).
123
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123
Table 5 GC–MS determination methods for chemical constituents in C. rotundus
Region Method Analytes Yield Column Mobile Elution Detection/ Plant References
Phase program Chromogenic part
conditions
China-Anhui GC–MS Essential oils (extracted 0.52% DB-1MS capillary column Helium Gradient Relative Rhizomes Qu et al.
by hydrodistillation) (60 m 9 0.25 mm 9 0.25 lm) retention (2021)
indices
calculated
against n-
alkanes
Egypt-Bahtim GC–MS Essential oils (extracted 0.40% DB-5 MS column Helium Gradient Kovats’ Rhizomes Samra et al.
by hydrodistillation) (30 m 9 0.32 mm 9 0.25 lm) retention (2020)
index relative
to n-alkanes
(C8–C22)
Iran-Khuzestan- GC–MS Essential oils (extracted / TRACE-TR-5 capillary column Helium Gradient Kovats’ Rhizomes Janaki et al.
Ahvaz by hydrodistillation) (30 m 9 0.53 mm 9 0.25 lm) retention (2018)
indices
calculated
against
aliphatic
hydrocarbons
(C5–C20)
China-Shandong GC–MS Essential oils (extracted 0.83% HP-5 MS capillary column Helium Gradient Retention Rhizomes Hu et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) Indices (2017);
calculated Zhang et al.
against a (2017)
homologous
series of n-
alkanes (C8–
C24)
Sudan-West GC–MS Essential oils (extracted 2.60% Rtx-5 MS capillary column Helium Gradient Retention index Rhizomes Yagi et al.
Kordofan by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) (RI) relative 2016)
to n-alkanes
(C10–C24)
China-Hainan GC–MS Essential oils (extracted / OV-I Helium Gradient Relative Rhizomes He et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) retention (2015)
index
calculated
against n-
alkanes (C8–
C20)
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Table 5 continued
Region Method Analytes Yield Column Mobile Elution Detection/ Plant References
Phase program Chromogenic part
conditions
India-New Delhi GC–MS Essential oils (extracted / OmegawaxTM 250 Flused silica Helium Gradient / Rhizomes Richa and
by hydrodistillation) capillary column Suneet
(2014)
China-Zhejiang GC–MS Essential oils (extracted 0.78% HP-5 MS column Helium Gradient Retention Rhizomes Liu et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) indices (2016)
calculated
against a
homologous
series of n-
alkanes (C8–
C24)
India-Bareilly GC–MS Essential oils (extracted / DB-1 capillary column Helium Gradient Retention index Rhizome Gupta et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) relative to n- (2016)
alkanes
Sudan-Kordofan- GC–MS Essential oils (extracted 2.90% DB-5 MS Helium Gradient Kovats Rhizomes Eltayeib and
Elrahad by hydrodistillation) (30 m 9 0.32 mm 9 0.25 lm) retention Ismaeel
indices (2014)
calculated
using n-
alkanes (C8–
C20)
Sudan-Kordofan- GC–MS Essential oils (extracted 0.60% DB-5 MS Helium Gradient Kovats Rhizomes Eltayeib and
Elobeid by hydrodistillation) (30 m 9 0.32 mm 9 0.25 lm) retention Ismaeel
indices (2014)
calculated
using n-
alkanes (C8–
C20)
Sudan-Kordofan- GC–MS Essential oils (extracted 1.80% DB-5 MS Helium Gradient Kovats Rhizomes Eltayeib and
Bano by hydrodistillation) (30 m 9 0.32 mm 9 0.25 lm) retention Ismaeel
indices (2014)
calculated
using n-
alkanes (C8–
C20)
China-Shandong GC–MS Essential oils (extracted / HP-5 quartz capillary column Helium Gradient / Rhizomes Li (2013)
by hydrodistillation) (30 m 9 0.32 mm 9 0.25 lm)
China-Hainan GC–MS Essential oils (extracted / HP-5 quartz capillary column Helium Gradient / Rhizomes Li (2013)
by hydrodistillation) (30 m 9 0.32 mm 9 0.25 lm)
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123
Table 5 continued
Region Method Analytes Yield Column Mobile Elution Detection/ Plant References
Phase program Chromogenic part
conditions
Iran-Isfahan GC–MS Essential oils (extracted 0.20% HP-5MS capillary column Helium Gradient Retention Tubers Ghannadi
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) indices et al. (2012)
relative to n-
alkanes
China-Anhui GC–MS Essential oils (extracted 0.40% DB-5 capillary column Helium Gradient / Rhizomes Chen et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) (2011)
Tunisia-Monastir GC–MS Essential oils (extracted 0.50% polar SGE BPX-70 Helium Gradient Kovats indices Tubers Kilani et al.
by hydrodistillation) (60 m 9 0.25 mm 9 0.25 mm) calculated (2008b)
cap. column and apolar Supelco from the
SPB-5 injection of
(50 m 9 0.25 mm 9 0.25 mm) alkanes (C7–
cap. column C31)
China- GC–MS Essential oils (extracted 2.4%(SFE) BP1 quartz capillary column Helium Gradient / Rhizomes Feng et al.
Guangzhou by hydrodistillation (60 m 9 0.22 mm 9 0.25 lm) (2006)
and SFE)
China-Guangxi GC–MS Essential oils (extracted 0.26%–0.97% HP-5 quartz capillary column Helium Gradient / Rhizomes Jin et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) (2006)
China- GC–MS Essential oils (extracted / DB -1701 quartz capillary column Helium Gradient / Rhizomes Lin et al.
Guangzhou with mixed solvent by (30 m 9 0.35 mm 9 1.00 lm) (2006)
ultrasonic)
China-Guiyang GC–MS Essential oils of CyRh 0.82% (raw HP-5 MS quartz capillary column Helium Gradient / Rhizomes Xu et al.
and processed product product), 0.76% (30 m 9 0.32 mm 9 0.25 lm) (2006)
(extracted by (processed
hydrodistillation) product)
Tunisian- GC–MS Essential oils (extracted 0.50% HP-5 fused silica capillary column Helium Gradient Retention Tubers Kilani et al.
Monastir by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) indices (2005a)
relative to a
series of n-
alkanes
Egypt-Guiza GC–MS Essential oils (extracted 0.46% Carbowax 20 M coated capillary Helium Gradient / Tubers El-Gohary
by hydrodistillation) column (2004)
(50 m 9 0.2 mm 9 0.2 lm)
China-Zhejiang GC–MS Essential oils (extracted / HP-1MS quartz capillary column Helium Gradient / Rhizomes Wu (2007)
by hydrodistillation) (50 m 9 0.25 mm 9 0.25 lm)
China- GC–MS Essential oils (extracted 0.25%–0.41% HP-5 MS column Helium Gradient / Rhizomes Lin et al.
Guangdong by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) (2017)
Iraq GC–MS Methanol extracts / Capillary column (InertCap 1MS, Helium Gradient / Tubers Abo-Altemen
30 m 9 0.25 mm 9 0.25 lm) et al. (2019)
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123
Table 5 continued
Region Method Analytes Yield Column Mobile Elution Detection/ Plant References
Phase program Chromogenic part
conditions
India-Mangalore GC–MS n-hexane extracts / Perkin Elmer Elite-5 capillary Helium Gradient / Rhizomes Nidugala
column et al. (2015)
(30 m 9 0.25 mm 9 0.25 lm)
India-Tamilnadu GC–MS Chloroform fraction / DB-5 capillary column Helium Gradient / Rhizomes Aeganathan
(30 m 9 0.25 mm 9 0.25 lm) et al. (2015)
Hawaii GC–MS Essential oils (extracted / DB-5 fused silica capillary column Helium Gradient / Tubers Komai and
by n-hexane) (20 m 9 0.25 mm) Tang
(1989)
India-Tamilnadu GC–MS Ethanol extracts / Elite-5 fused silica capillary Helium Gradient / Leaves Elezabeth
(Soxhlet extraction) column (30 m 9 250 lm and
1D 9 1 lm df) Arumugam
(2014)
Brazil GC–MS Essential oils (extracted 0.40% HP-5 capillary column Helium Gradient Retention Leaves Duarte et al.
by hydrodistillation) (25 m 9 0.2 mm 9 0.33 lm) indices (2007)
relative to
hydrocarbon
standards
China GC–MS Essential oils of CyRh / Agilent 19091S-433column Helium Gradient / Rhizomes Sheng et al.
and processed product (30 m 9 250 lm 9 0.25 lm) (2013)
(extracted by
hydrodistillation)
China-Jiangxi GC–MS Essential oils of CyRh / DB -1701 quartz capillary column Helium Gradient / Rhizomes Hu et al.
and processed product (30 m 9 0.35 mm 9 1.00 lm) (2012)
(extracted by
hydrodistillation)
China GC–MS Essential oils (extracted 0.69%–1.25% DB-1701 quartz capillary column Helium Gradient / Rhizomes Zhao et al.
by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) (2008)
China GC–MS Essential oils (extracted / HP-5MS capillary column Helium Gradient / Rhizomes Tam et al.
by hydrodistillation (30 m 9 0.25 mm 9 0.25 lm) (2007)
(HD), pressurized
liquid extraction (PLE)
and supercritical fluid
extraction (SFE))
China- GC–MS Essential oils (extracted 2.3% (SFE), 0.8% SGE BP1 column Helium Gradient / Rhizomes Li et al.
Guangzhou by hydrodistillation (hydrodistillation) (60 m 9 0.25 lm) (2000)
and SFE)
China and India GC–MS Extraction with hexane/ (?)-Nootkatone DB-5 capillary column Helium Gradient / Rhizomes Jaiswal et al.
ethyl acetate mixture [30.47 lg/10 g (30 m 9 0.25 mm 9 0.25 lm) (2014)
(1:1), (?)-nootkatone (India), 21.72 lg/
10 g (China)]
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123
Table 5 continued
Region Method Analytes Yield Column Mobile Elution Detection/ Plant References
Phase program Chromogenic part
conditions
Algeria GC, GC– Essential oils (extracted 2.70% DB-5 capillary column Helium Gradient Retention index Rhizomes Fenanir et al.
MS by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) relative to n- (2021)
alkanes
South Africa- GC, GC– Essential oils (extracted 0.20% DB-5 capillary column Helium Gradient Retention Rhizomes Lawal and
Empangeni MS by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) indices Oyedeji
relative to n- (2009)
alkanes (C9–
C24)
South Africa- GC, GC– Essential oils (extracted 0.16% DB-5 capillary column Helium Gradient Retention Rhizomes Lawal and
KwaDlangezwa MS by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) indices Oyedeji
relative to n- (2009)
alkanes (C9–
C24)
South Korean- GC, GC– Essential oils (extracted 2.70% RTX-1 capillary column Helium Gradient Authentic Rhizomes Chang et al.
Seoul MS by hydrodistillation) (60 m 9 0.25 mm 9 1.00 lm) sample (2012)
Iran-Ahwaz GC, GC– Essential oils (extracted 1.50% HP-5 MS capillary column Helium Gradient Kovats Aerial Aghassi et al.
MS by hydrodistillation) (30 m 9 0.25 mm 9 0.25 lm) retention parts (2013)
indices
calculated
using n-
alkanes (C9–
C23)
South-India GC-FID, Essential oil (extracted 0.11% FSOT-RSL-200 fused silica Helium Gradient Kovats indices Roots Jirovetz et al.
GC– by hydrodistillation column relative to n- and (2004)
MS and SPME) (30 m 9 0.32 mm 9 0.25 lm) alkanes Tubers
and polar Stabilwax
(30 m 9 0.32 mm 9 0.50 lm)
Brazil-Pará GC-FID, Essential oils (extracted 0.40% DB-5 MS fused silica capillary Helium Gradient Retention Tubers Zoghbi et al.
GC– by hydrodistillation) column indices (2008)
MS (30 m 9 0.25 mm 9 0.25 lm) relative to n-
alkanes
Saudi Arabia- GC-FID, Essential oils (extracted 0.20% Innowax FSC column Helium Gradient Relative Tubers Al-Massarani
Riyadh GC– by hydrodistillation (60 m 9 0.25 mm 9 0.25 lm) retention et al. (2016)
MS and extracted with index
diethyl ether from the calculated
aqueous distillate) against a
series of n-
alkanes
Phytochemistry Reviews
123
Table 5 continued
Region Method Analytes Yield Column Mobile Elution Detection/ Plant References
Phase program Chromogenic part
conditions
Tunisia-Kebili GC-FID, Essential oils (extracted 0.5 ± 0.3% HP-1 column Helium Gradient Retention Tubers Essaidi et al.
GC– by hydrodistillation), (50 m 9 320 lm 9 0.5 lm), Indices (2014)
MS F1: n-pentane, F2: n- HP-innowax columns relative to n-
pentane/diethyl ether (60 m 9 320 lm 9 0.5 lm) alkanes
(95/5) and F3: diethyl
ether further
fractionated from
essential oils
Turkey HS– Essential oils (HS-SPME / Innowax FSC column Helium Gradient Relative Root Eröz Poyraz
SPME– extraction) (60 m 9 0.25 mm 9 0.25 mm) retention et al. (2018)
GC– index (RRI)
MS relative to a
series of n-
alkanes
China HS– Volatile/heat-labile / HP-5 capillary column Helium Gradient Retention index Rhizomes He et al.
SPME– components (SPME (30 m 9 0.25 mm 9 0.25 lm) calculated (2018)
GC– extraction) against alkane
MS standard
solutions of
C8–C20 and
C21–C40
Phytochemistry Reviews
Qualitative and semi-quantitative analyses of HPLC/UHPLC analysis
EOCR by GC–MS were performed and the essential
oils from different regions were compared to identify Liquid chromatography (LC), including HPLC and
the intrinsic material basis for their distinctions. UHPLC, is frequently and consistently utilized as an
Volatile oils of C. rotundus were mostly extracted effective and excellent means for the identification and
by hydro-distillation (HD) (Kilani et al. 2008b; quantitative determination of compounds due to its
Ghannadi et al. 2012; Yagi et al. 2016; Abo-Altemen accessibility, ease of operation, high sensitivity and
et al. 2019), in addition to supercritical fluid extraction reproducibility, good resolution and linearity, and the
(SFE) (Feng et al. 2006; Tam et al. 2007; Cao and Ou ability to analyze a diverse range of components. It is
2015), solid phase micro extraction (SPME) (Tam one of the common techniques used for the quality
et al. 2007; Eröz Poyraz et al. 2018; He et al. 2018), assessment of C. rotundus. In practical terms, certain
pressurized liquid extraction (PLE) (Tam et al. 2007), conditions of analysis, consisting of analytes type,
mixed solvent extraction by ultrasound (Lin et al. mobile phase, mobile phase flow rate, column tem-
2006) and n-hexane extraction (Komai and Tang perature, column type, eluent program and detector,
1989). The yield of volatile oil varies dramatically are critical factors affecting HPLC analysis. Supple-
depending on the region and extraction method. For mentary Table S18 reveals the detailed conditions for
example, by using the hydro-distillation method, the the HPLC approach with regard to the analyses of C.
yield of volatile oil extracted from the rhizomes of C. rotundus.
rotundus in Seoul, South Korea was 2.7% (Chang et al. It could be found that most of the analytes subjected
2012), while the yield of essential oil extracted by the to LC analysis of C. rotundus are the major sesquiter-
same method from the tubers in Isfahan, Iran, was only penoid components, as well as the phenolic compo-
0.2% (Ghannadi et al. 2012). The volatile oil, the nents. The mobile phases are commonly methanol–
characteristic and flavor component, has been taken as water or acetonitrile–water, with the addition of
the crucial marker for the quality control of C. 0.1–0.5% formic acid, acetic acid, or trifluoroacetic
rotundus. Thus, the ChP stipulates that the content of acid to the aqueous phase. Varied columns and
volatile oil should not be less than 1.0% (mL/g) (China different detectors (such as PDA, DAD and MS) are
Pharmacopoeia Committee 2020). It can be concluded now frequently equipped for the qualitive or quanti-
from a number of literature that the DB-5 capillary tative analyses.
column (30 m 9 0.25 mm 9 0.25 lm) and HP-5 MS As is reported, the contents of mesocyperusphenol
capillary column (30 m 9 0.25 mm 9 0.25 lm) are A (499), scirpusins A (494) and b-sitosterol (422)
commonly selected as GC columns for the analysis of were evaluated in C. rotundus from different regions
EOCR (Lawal and Oyedeji 2009; Ghannadi et al. in China by UPLC and HPLC. The results indicated
2012; Hu et al. 2017; Fenanir et al. 2021). It is that the content of active ingredients in C. rotundus
interesting to note that investigations have shown that from Shandong, was relatively higher than those of
the volatile components of the aerial parts of C. other regions, revealing the necessity of selecting
rotundus are quite different from those of its rhizomes authentic and genuine herbs (Cao and Ou 2015; Deng
(Aghassi et al. 2013; Elezabeth and Arumugam 2014). et al. 2016). Zhao et al. established an HPLC method
Flame ionization detector (FID) has gained great for fingerprinting the chemical components in the
popularity over recent years for its excellent response methanolic extracts of eight batches of C. rotundus
and stable signal for hydrocarbons, as well as simple from different regions, as well as similarity evaluation
operation and low cost compared to MS (Jirovetz et al. and clustering analysis (Zhao et al. 2008). Deng et al.
2004; Zoghbi et al. 2008). For example, the GC-FID have developed an approach for effective and rapid
technique was used by Al-Massarani et al. for affinity-based screening of natural a-glucosidase
analyzing the volatile components of C. rotundus inhibitors directly from C. rotundus extracts by
tubers originating from India, Brazil and Saudi Arabia utilizing an immobilized enzyme technique integrated
(Al-Massarani et al. 2016). with UHPLC-QTOF-MS analysis (Deng et al. 2019).
Also, tissue-specific metabolite analyses of C. rotun-
dus from India and China by laser microdissection,
UHPLC-QTOF-MS/MS and additional GC–MS have
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Table 6 Ingredients in essential oils of C. rotundus with relative contents higher than 1% and identification frequency above 3
Compound (No.) Identification Compound (No.) Identification
frequency frequency
Caryophyllene oxide (241) 24 Cyperotundone (154) 4
Cyperene (165) 23 a-Humulene (266) 4
a-Cyperone (111) 21 Mustakone (256) 4
b-Selinene (97) 14 a-Cubebene (319) 4
trans-Pinocarveol (28) 13 a-Calacorene (183) 4
Aristolone (296) 13 Spathulenol (230) 4
a-Copaene (257) 12 Rotundene (251) 4
Myrtenol (37) 12 a-Gurjunene (214) 4
Longiverbenone (284) 12 c-Muurolene (191) 3
a-Pinene (38) 11 Pinocarvone (29) 3
b-Pinene (39) 10 Isocyperol (96) 3
Isolongifolen-5-one (291) 9 Methyl (Z)-5,11,14,17-eicosatetraenoate 3
(545)
Humulene epoxide II (264) 8 Isolongifolene (293) 3
Nootkatone (235) 7 Isoaromadendrene epoxide (226) 3
Myrtenal (35) 7 Cyperene epoxide (161) 3
Verbenone (30) 7 8-Oxo-9H-cycloisolongifolene (305) 3
a-Terpineol (17) 6 a-Ylangene (262) 3
a-Selinene (131) 6 a-Longipinene (286) 3
4-Oxo-a-ylangene (261) 6 Valencene (237) 3
Limonene (1) 6 trans-Carveol (12) 3
Aromadendrene, dehydro- 6 Eudesma-2,4,11-triene (124) 3
(215)
b-Caryophyllene (242) 5 Patchoulenone (152) 3
1,8-Cineole (93) 5 allo-Aromadendrene (228) 3
Aromadendrene epoxide (225) 4
been conducted and the outcomes demonstrated that rotundus (Priya Rani and Padmakumari 2012). With
the content of ( ?)-nootkatone (235) in C. rotundus of the help of TLC, UV (Ultraviolet and visible spec-
India (30.47 lg/10 g), was higher than that of China trophotometer) and IR (Grating Infrared spectropho-
(21.72 lg/10 g) (Jaiswal et al. 2014). Furthermore, tometer), Samariya and Sarin have analyzed
LC–ESI–MS/MS was employed to characterize the qualitatively four compounds obtained by PTLC,
phytochemical composition of the total oligomeric namely quercetin (377), kaempferol (376), myricetin
flavonoid (TOF) of C. rotundus and simultaneously to (380) and catechin (399). By UV spectrophotometer as
determine its total flavonoid and total phenolic (TPC) well as other techniques, quercetin, kaempferol and
content (Kandikattu et al. 2015). myricetin have been analyzed quantitatively. A con-
clusion was reached that the total flavonoid content in
Other analytical methods the leaves of C. rotundus was higher compared to the
roots, with the total quercetin content also higher than
In other aspects, a simple, sensitive and effective the roots (Samariya and Sarin 2013). In addition, PIXE
HPTLC and HPLC method (245 nm) was established and ICP-MS techniques have been applied to analyze
to verify the validity for quantification of solavetivone qualitatively and quantitatively some inorganic ele-
(302), which had been initially isolated from C. ments in C. rotundus. These include Li, Al, Cl, K, Ca,
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Phytochemistry Reviews
Fig. 7 Multivariate statistical analysis on thirty-two essential oils of C. rotundus from different regions. a ‘‘Region-Component’’
network; b Heatmap analysis; c HCA analysis; d PCA analysis
Ti, V, Cr, Mn, Fe, Co, Ni, Cu and Zn (supplementary bioactive substance of C. rotundus, is contained in the
Table S18) (Rao et al. 2019). rhizome, tuber and aerial parts (Zoghbi et al. 2008;
Kilani-Jaziri et al. 2009; Chang et al. 2012). Details of
the chemical composition and structure of EOCR are
Multivariate statistical analysis of the essential oil presented in the supplementary Tables S10–17 and
of C. rotundus supplementary Fig. S1–23. Moreover, chemical con-
stituents that have been reported to be present in
Up until now, numerous works have systematically EOCR by at least two publications were considered
carried out the analysis regarding EOCR from differ- and included in the tables.
ent countries on account of the worldwide distribution In this section, a comprehensive summary of over
(El-Gohary 2004; Kubmarawa et al. 2005; Kilani et al. thirty articles of literature concerning the essential oil
2008b; Zoghbi et al. 2008; Lawal and Oyedeji 2009; profiling ofC. rotundus via the GC–MS is presented in
Chang et al. 2012; Nidugala et al. 2015; Yagi et al. detail as shown in supplementary Table S19. The
2016; Janaki et al. 2018; Abo-Altemen et al. 2019; components displayed only include those with relative
Samra et al. 2020; Fenanir et al. 2021; Qu et al. 2021). content greater than 1%, which were then regarded as
The essential oil, the extremely main and valuable essential ingredients (Table 6). The numbers in Fig. 7
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Phytochemistry Reviews
Fig. 8 The diagram of pharmacological properties of C. rotundus
represent the corresponding region of the C. rotundus The outcomes of HCA (Fig. 7c) and PCA (Fig. 7d)
and details are listed in supplementary Table S21. analysis revealed that the thirty-two batches of C.
These references contain only the GC–MS studies of rotundus could be clustered into four groups, in which
C. rotundus tubers and rhizomes by hydrodistillation. NO14, NO16, NO17 were classified as group I, NO2,
Neither the studies of aerial parts of C. rotundus, nor NO8, NO3, NO22, NO21, NO27, NO18, NO26,
the studies with other analytical means such as SFE, NO20, NO32, NO28, NO5, NO19, NO25, NO30 were
SPME, ultrasonic extraction with organic reagents and treated as group II, NO13, NO15 were classified as
GC-FID are included, so as to allow for a better group III, and the remaining batches were clustered
comparative effect. The detailed methods for multi- into group IV. This phenomenon indicates that the
variate statistical analysis of the essential oil were intrinsic material bases of the C. rotundus originating
provided in the supplementary materials. from different regions of the same country are not
Figure 7a visually indicates that the types of identical. The quality of C. rotundus from diverse
constituents in EOCR vary along with the regions, nations also varies. Especially, the main volatile
and it may be possible for the same components to ingredients, such as a-cyperone and cyperene, can
occur simultaneously in C. rotundus from different also be strongly affected by their geographical origin.
countries, uncovering the difficulty and complexity of This variability might be closely associated with
quality control and assessment for C. rotundus at hereditary factors, growth year, storage time, storage
present. The figure outwardly demonstrated that the conditions, plant parts, herbal processing or not, and
top twelve key compounds in EOCR are caryophyl- environmental factors, specifically soil composition,
lene oxide (241), cyperene (165), a-cyperone (111), b- climatic factors, seasonality and circadian cycle, all of
selinene (97), trans-pinocarveol (28), aristolone (296), which may impact the qualitative and quantitative
a-copaene (257), myrtenol (37), longiverbenone profiling of components in the essential oils.
(284), a-pinene (38), b-pinene (39), isolongifolen-5- A conclusion can be easily drawn from Fig. 7b, that
one (291). a-cyperone (111) and cyperene (165) exist in almost
all regions with relatively high contents, and they
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Phytochemistry Reviews
possess a variety of pharmacological activities (Wee- It is well known that the oxidative stress plays a
nen et al. 1990a; Khan et al. 2011; Jung et al. 2013), vital role in diseases such as epilepsy, neurodegener-
and hence, they were frequently recommended as the ative disorders (Alzheimer’s disease and Parkinson’s
quality control marker of C. rotundus. Besides, disease) (Lee et al. 2010; Rabiei et al. 2013), non-
caryophyllene oxide (241), b-selinene (97) and aris- steroidal anti-inflammatory drug-induced gastric
tolone (296) also play important roles in EOCR mucosal damage (Thomas et al. 2015), hepatic injury
(Ghannadi et al. 2012; Richa and Suneet 2014). (Mohamed 2015) and diabetes (Raut and Gaikwad
2006). C. rotundus shows potential activity in treat-
ments of these oxidative stress-related disease, owing
Pharmacology to its antioxidative activity by regulating the levels of
some biological enzymes (SOD, HO-1, GSH-Px), and
There have been more than ten previous reviews cell factors (MDA) (Baek and Lee 2016). It is recorded
which refer to the pharmacological effects of C. that the rhizome extract of C. rotundus can improve
rotundus, as well as more than hundreds of studies on the level of SOD and decrease the level of MDA in
its pharmacological properties with the first dating pentylentetrazole (PTZ)-induced mice brain, exerting
back to 1959. Hence, the pharmacology of C. rotundus its oxidation resistance property. Epileptic seizure in
has been researched thoroughly, and this section mice was alleviated after the treatment with C.
intends to comprehensively summarize the pharma- rotundus (Khalili et al. 2011).
cological actions of C. rotundus, like anti-inflamma-
tory, antioxidant, apoptotic, antibacterial, digestive Anti-microbial activity
system effects, neuroprotective effects, based on the
experiments in vitro, in vivo and in clinical trials The antimicrobial activities of C. rotundus involves
(Fig. 8, supplementary Table S22). Additionally, anti-bacterial, anti-fungal and anti-viral effects (Al-
novel indications and hot spots of research in recent Massarani et al. 2016; Samra et al. 2020). C. rotundus
years are also included in this summary. inhibited Streptococcus mutans by suppressing the
bacterial growth, adherence activity and water-insol-
Anti-oxidant activity uble glucan synthesis, and, reducing acid production
(Yu et al. 2007). Studies have found the antibacterial
Components in C. rotundus, such as phenolic acids, activity of C. rotundus among different bacterial
alkaloids, quinones, essential oil and sesquiterpenoids species, no matter whether they are Gram-positive or
have shown excellent antioxidant activity (Kandikattu Gram-negative (Kabbashi et al. 2015). It has however
et al. 2015), especially phenolic compounds, including been revealed that inhibition of Gram-positive bacte-
flavonoids, coumarins, and polyphenols (Kilani-Jaziri ria is more sensitive than that of Gram-negative
et al. 2011; Soumaya et al. 2014). For isolated bacteria owing to the differences in the lipopolysac-
compounds, nootkatone (235) exerted the strongest charides of their cell walls (Ouattara et al. 1997; Kilani
DPPH radical scavenging capacity, with IC50 valued et al. 2005a). The anti-viral effect of C. rotundus have
4.81 lg/mL followed by aristolone (296) and solave- been demonstrated only against hepatitis B virus
tivone (302), whose IC50 was valued at 5.28 lg/mL (Parvez et al. 2019).
and 6.82 lg/mL respectively (Priya Rani and Pad- Recently, the screening and prediction of active
makumari 2012). Compared with ethanol and ethyl constituents of herbs by computer simulation technol-
acetate extracts, aqueous extract of C. rotundus has ogy have become a research hotspot. As coronavirus
exhibited the strongest scavenging activity as shown disease 2019 (COVID-19) has spread throughout the
by DPPH assay, with an IC50 value of 418.74 lg/mL world, screening of natural products against M
pro of
(Mohamed et al. 2021). In addition to scavenging SARS-CoV-2 has attracted great attention. Subse-
DPPH free radicals, C. rotundus also showed scav- quently, components of C. rotundus were screened by
enging ability on hydroxyl radical, superoxide radical, molecular docking and successively compared with
xanthine/xanthine oxidase and others (Kilani et al. standard drugs to value the binding of protein–ligand
2008b). interactions. Molecular dynamics was used to assess
that binding, and finally pharmacokinetic properties
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Phytochemistry Reviews
and safety profiles were measured. From this study, b- 2016a, 2016b; Hao et al. 2017), anti-Alzheimer’s
amyrin (411) and stigmasta-5,22-dien-3-ol (424) were (Rabiei et al. 2013; Mehdizadeh et al. 2017; Shakerin
selected as the molecules that potentially inhibit et al. 2020), anticonvulsant (Shivakumar et al. 2009;
SARS-COV-2 Mpro and thus implied their potential Khalili et al. 2011), analgesic (Pal et al. 2009; Ahmad
therapeutic effect against COVID-19 (Kumar et al. et al. 2012; Imam and Sumi 2014), and neuromodu-
2021). latory (Ha et al. 2002; Rafe et al. 2019) effects.
Antidepressant and neuroprotective effects are two
Anti-inflammatory activity dominant activities of C. rotundus with regard to the
CNS system. The ethanol extract and water extract of
In previous studies of pharmacologic activities of C. C. rotundus have shown antidepressant-like action by
rotundus, the extracts and its isolated compounds have the tail suspension test (TST) and the forced swim test
been demonstrated to reduce the levels of the inflam- (FST) in murine models (Jia and Zou 2014; Hao et al.
matory mediators, cytokines, and transcription factors, 2017). Ethanol extract of C. rotundus at doses of 200
like 5-LOX, COX-2, PGE2, IL-1, IL-6, TNF-a (Seo and 400 mg/kg effectively protected against cognitive
et al. 2001; Jung et al. 2013; Ibrahim et al. 2018). It has impairment, locomotor activity and muscle coordina-
also been shown that they could reduce the inflam- tion deficits induced by sodium nitrite-induced
matory response by suppressing the regulation of the hypoxic injury in rats (Jebasingh et al. 2014). Hydro-
NF-jB signal pathway and down-regulating AP-1 alcoholic extract of C. rotundus prolonged the latency
activation (Khan et al. 2011; Jung et al. 2013; Choi of seizure and reduced the duration of seizure in mice
et al. 2014; Shin et al. 2015; Ibrahim et al. 2018). (Khalili et al. 2011).
Furthermore, the generation of NO, which reflects the
degree of inflammation at the cellular level, can be Digestive system effects
reduced after treatment with C. rotundus rhizome
extract by suppressing the expression of iNOS in LPS- The role of C. rotundus in regulating the digestive
stimulated RAW 264.7 cells (Tsoyi et al. 2011). The system is in general agreement with TCM and there
extent of ear edema, cellular infiltrates and ker- have been numerous reports concerning the hepato-
atinocyte hyperproliferation were depressed in arachi- protective (Kumar and Mishra 2005; Mohamed 2015;
donic acid and 12-O-tetradecanoylphorbol-13-acetate Oh et al. 2015; Parvez et al. 2019), gastroprotec-
(TPA)-induced mice after the administration of C. tive(Thomas et al. 2015), anti-diarrhoeal (Uddin et al.
rotundus rhizome ethanolic extract (Rocha et al. 2006), anti-infectious diarrhea (Daswani et al. 2011)
2020). and anti-gastric ulceration (Zhu et al. 1997) effects of
The sesquiterpenoids components of C. rotundus, C. rotundus. For example, Parvez et al. have demon-
to be specific, were found to possess pronounced anti- strated a promising hepatoprotective effect of C.
inflammatory effect (Tsoyi et al. 2011), particularly, rotundus in vivo experiments in rats and also proven
nootkatone (235), a-cyperone (111), valencene (237), that the n-butanol and aqueous fractions ofC. rotundus
and b-selinene (97) (Khan et al. 2011). rhizomes exhibit the most prospective activity against
The anti-inflammatory function of C. rotundus in HBV in vitro in DCFH-damaged HepG2 cells (Parvez
experimental studies has implied that it has the et al. 2019). Furthermore, C. rotundus can dramati-
potential to cure inflammatory skin disorders (Rocha cally inhibit aspirin-induced gastric ulceration and
et al. 2020) and peritonitis (Dang et al. 2011). lipid peroxidation in ulcerated rats in a dose-depen-
dent manner (Thomas et al. 2015). After treatment
Central Nervous system activity with C. rotundus methanol extracts, the frequency of
diarrhea onset in mice decreased (Uddin et al. 2006),
C. rotundus has been reported to exert neuroprotective and at the same time, the cytoprotective effect of the
(Lee et al. 2010; Hemanth Kumar et al. 2013; Kim aqueous decoction of C. rotundus on the ethanol-
et al. 2013; Jebasingh et al. 2014; Dabaghian et al. induced gastric injury was verified (Zhu et al. 1997).
2015; Kandikattu et al. 2017; Sutalangka and Wat-
tanathorn 2017; Hussein et al. 2020), antidepressant
(Jia and Zou 2014; Lin et al. 2015; Zhou et al.
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Phytochemistry Reviews
Anti-cancer activity Toxicology
In recent years, the antitumor activity of C. rotundus Given the importance of understanding the toxicity of
has gradually attracted the attention of researchers and herbal medicines to facilitate their safe use, the
become a hot direction of researches, including those toxicological studies in vivo and in vitro of the
with potential effects against cervical cancer (Man- extracts, essential oil, and isolated compounds from C.
narreddy et al. 2017; Saad et al. 2018; Susianti et al. rotundus have been summarized and presented in
2018; Lin et al. 2019), breast cancer (Park et al. 2014; supplementary Table S23.
Mannarreddy et al. 2017; Wang et al. 2019; Simor- Numerous acute toxicity tests have shown that
angkir et al. 2019; Ma et al. 2020; Samra et al. 2020), essential oil (Biradar et al. 2010), n-hexane extract
ovarian cancer (Ryu et al. 2015; Ahn et al. 2015), (Lemaure et al. 2007), ethanol extract (Akperbekova
esophagus cancer (Al-Shammari et al. 2021), hepato- and Abdullaev 1966; Thanabhorn et al. 2005; Ahmad
cellular carcinoma (Parvez et al. 2019; Samra et al. M et al. 2013; Okwu et al. 2015; Singh et al. 2015; Al-
2020), human rectal cancer (Mannarreddy et al. 2017; Snafi 2016; Rajakrishnan et al. 2020; Shakerin et al.
Al-Shammari et al. 2021), prostate cancer (Man- 2020; Al-Awar and Alqabbani 2021), methanol
narreddy et al. 2017; Samra et al. 2020) and colorectal extract (Soumaya et al. 2013; Imam and Sumi 2014;
cancer (Park et al. 2014; Ahn et al. 2015; Ryu et al. Kabir et al. 2019), and water extract (Krisanapun et al.
2015; Al-Massarani et al. 2016; Ying and Bing 2016; 2012; Badgujar and Bandivdekar 2015) of C. rotundus
Mannarreddy et al. 2017; Abdulghany et al. 2018; didn’t arise any behavioral, biochemical, or histolog-
Susianti et al. 2018; Lin et al. 2019; Simorangkir et al. ical alterations either in mice or in rats. And, there was
2019; Wang et al. 2019; Ma et al. 2020; Samra et al. a subacute toxicity test revealing that the ethanol
2020; Al-Shammari et al. 2021). The ethanol extract of extract of the rhizomes ofC. rotundus didn’t cause any
C. rotundus (EECR) has been demonstrated to possess mortality or behavioral changes after an administra-
a potential effect against human cervical cancer and tion of 1,000 mg/kg daily over 14 days (Thanabhorn
breast cancer in HeLa human cervical carcinoma cells et al. 2005).
and MCF-7 cells (Lin et al. 2019; Simorangkir et al. However, the extract of C. rotundus showed
2019). The EOCRwas found to have cytotoxic activity significant cytotoxicities to various cancer cells,
against the HeLa cervical cells (Susianti et al. 2018). including L1210 (Kilani et al. 2008a), MCF-7 (Man-
narreddy et al. 2017), HeLa (Mannarreddy et al. 2017),
Others HepG2 (Mannarreddy et al. 2017), PC-3 (Man-
narreddy et al. 2017), HT-29 (Mannarreddy et al.
In addition to the above, studies have also uncovered 2017), MDA-MB 231 (Ma et al. 2020), and MDA-MB
the anti-allergic (Jin et al. 2011), antidiabetic ( Raut 468 (Ma et al. 2020) cells, without any observable
and Gaikwad 2006; Lemaure et al. 2007; Singh et al. cytotoxic effects against normal cells, such as LO2
2015; Majeed et al. 2022), antihemolytic (Kilani et al. (Song et al. 2016), MCF-12A (Mannarreddy et al.
2005a), antimalarial (Weenen et al. 1990a, 1990b; 2017), HGF (Moein et al. 2018), and BV-2 cells
Thebtaranonth et al. 1995), antimutagenic (Kilani (Huang et al. 2018). It is worth mentioning that the
et al. 2005a), apoptotic (Kilani et al. 2008a, 2008b; essential oil of C. rotundus didn’t show any significant
Soumaya et al. 2014), estrogenic (Hendri et al. 2016; inhibitory effects on SH-SY5Y cells viability at the
Park et al. 2019), repellent against mosquito (Singh concentration of 50–150 lg/mL, unless above 150 lg/
et al. 2009; Al-Massarani et al. 2016), lactogenic mL (Hu et al. 2017). Similarly, 10–100 lg/mL 70%
(Badgujar and Bandivdekar 2015), against urinary ethanolic extract of C. rotundus didn’t exert any
tract infection (Sharma et al. 2014) and diuretic effects significant cytotoxicities against SH-SY5Y cells,
(Sripanidkulchai et al. 2001) of C. rotundus. instead of a significant decrease of the cell’s viability
once the final concentration was above 100 lg/mL
(Hemanth Kumar et al. 2014). And, 25–100 mg/mL of
the water decoction of C. rotundus didn’t affect PC12
cell’s viability unless the administration concentration
was up to 200 mg/mL (Lee et al. 2010).
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Phytochemistry Reviews
As for other aspects, 4,11-selinnadien-3-one, alkaloids, and etc. And the essential oil is the most
namely a-cyperone (111), from C. rotundus was important and bioactive substance of C. rotundus.
known to be toxic to the bee larvae (Apis florea) with Cyperene (165), a-cyperone (111), caryophyllene
an IC50 of 10.8 ppm (Visetson et al. 2001). And, oxide (241), b-selinene (97), trans-pinocarveol (28),
khellin (403) and visnagin (404) were reported to aristolone (296) are the vitally important components
induce Artemia salina LEACH mortality in the brine of the essential oil in the clue of their relative high
shrimp lethality test (Sayed et al. 2007). In general, a contents in this medicinal plant as illustrated in the
conclusion can be safely drawn that C. rotundus is re-analyzed result (Fig. 7 and supplementary
deemed safe enough for further development and Tables 19–21) by multivariate statistical analysis of
utilization. EOCRs. Furthermore, a-cyperone (111), nootkatone
(235), isocyperol (96), cyperotundone (154), valen-
cene (237) and other compounds of iridoid glycosides,
Conclusion and future perspectives flavonoids and saponins were isolated and considered
to be the main active ingredients of C. rotundus. These
This review provides a comprehensive summary so-called main constituents have been evaluated to
regarding distribution, synonyms, traditional uses, exhibit extensive pharmacological activities as men-
data mining of application in TCM, phytochemistry, tioned above. Interestingly, cyperene (165), a-cyper-
isolation, analysis and identification methods, phar- one (111), isocyperol (96), cyperotundone (154),
macology and toxicology of C. rotundus to provide cyperol (127) not only present in C. rotundus, but
detailed and scientific evidence for its modern indica- also existed specially in other plants of Cyperus
tions and intensive clinical applications in treatments species, such as C. esculentus L., C. distans L.f., and
of different diseases. C. articulatus L. This phenomenon to some extent
explains that why these Cyperus plants with similar
Traditional uses, chemical components chemical components exhibit similar pharmacological
and pharmacological activities activities (including the treatment potentials for gas-
trointestinal disorders, menstrual irregularities, and
C. rotundus have various traditional applications in inflammatory diseases) (Taheri et al. 2021).
different nations, whereas the common important uses Different extracts and fractions of C. rotundus
are for gastrointestinal discomforts, mental disorders, exhibited distinct activities, which could be attributed
menstrual disorders in women and skin problems. to the structural diversity and the uneven distribution
Notably, a data mining of TCM prescriptions contain- of the phytoconstituents present in these extracts and
ing Cyperi rhizoma draws the generally same conclu- fractions. TOF extract exhibited the strongest antiox-
sion as the modern pharmacological research, which idant activity, followed by the other solvent extracts in
concluded that CyRh was commonly prescribed for the order of ethyl acetate[methanol extract[water
the treatment of diseases of (I) the Spleen system, (II) extract (Kilani et al. 2008a, 2005b; Kilani-Jaziri et al.
the women’s menstrual, leucorrhea and miscellaneous 2011). The reason may be the intrinsic contents of the
diseases, (III) the fetuses, parturients and their diseases common antioxidants of phenolic compounds such as
and (IV) the Brain system, (V) the Liver system, flavonoids, tannins and coumarins in those extracts
corresponding to (1) the digestive system diseases, (2) (Hussein et al. 2020). The anti-breast cancer activity of
the nervous system and (3) the gynecological diseases EECR was stronger than MECR in the human breast
in the western medicinal system. As shown in Table 3, carcinoma cell (MDA-MB-231) model (Park et al.
the modern pharmacological effects and bioactivities 2014). The anti-ovarian cancer activity of the n-
of the extracts, fractions and compounds related to the hexane fraction was more potent than that of the ethyl
traditional uses of C. rotundus in TCM are acetate (EtOAc) fraction of EECR followed by EECR
summarized. in the human ovarian cancer cell (A2780) model. The
The main constituents of C. rotundus include IC50 values of the n-hexane and EtOAc fractions were
essential oil, sesquiterpenoids (with diverse skeletons different among different cancer cell lines (Ahn et al.
such as eudesmane, patchoulane, cadinene, caryophyl- 2015). Moreover, n-butanol and aqueous fractions of
lene types), flavonoids, phenolic acids, saponins, C. rotundus showed significant hepatoprotective
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Phytochemistry Reviews
activity against DCFH-induced HepG2 cytotoxicity and the global quality control methods for C. rotundus
compared to other fractions (e.g., hexane, chloroform, should be established accordingly. It is also advisable
and EtOAc fractions). Meanwhile, the EtOAc fraction to study the uses of C. rotundus from different
exhibited highly promising anti-HBV activity, fol- countries separately, where the chemical composition
lowed by n-butanol and aqueous fractions of C. of C. rotundus differs and their pharmacological
rotundus (Parvez et al. 2019). activities vary greatly. In addition, it is currently
In conclusion, the chemical constituents of C. challenging to identify the functional factors of
rotundus could be considered to be mostly from the components in herbal medicine for a specific disease
essential oil, the non-aqueous solvent-soluble (eg. and to assess the contribution weights of functional
ethanol, methanol, ethyl acetate) and the water-soluble factors due to the diversity of phytoconstituents of
components. Different extracts and fractions of C. herbal medicines and the complexity of their mech-
rotundus exhibited distinct activities, which could be anisms of action. To overcome these obstacles, instead
attributed to the structural diversity and the uneven of the classic workflow of phytochemical isolation and
distribution of the phytoconstituents present in these purification followed by activity screenings, several
extracts and fractions. It is noteworthy that a number statistical methods (e.g., fingerprint-efficacy relation-
of literatures have reported the activities of C. ship) and modern molecular networking technologies
rotundus concerning nervous system diseases, diges- (network pharmacology, molecular docking, or
tive system disorders, gynecological disorders, both molecular dynamics simulation), are encouraged to
in vivo and in vitro. To some extent, this phenomenon perform a virtual screening of the active phytochem-
validates the diverse traditional uses of C. rotundus. icals before further phytochemistry and pharmacolog-
However, there are no available clinical trials demon- ical studies.
strating the activities of C. rotundus in these aspects, Recently, as COVID-19 has spread throughout the
and even the in vivo pharmacological evaluations world, studies using molecular docking and molecular
concerning the uses of C. rotundus in the treatment of dynamics have demonstrated the inhibition effect ofC.
gynecological diseases, instead of the numerous rotundus against SARS-CoV-2 Mpro (Kumar et al.
in vitro experiments conducted in several cancer cells 2021) and implied its potential as a therapeutic agent
including HepG2, HeLa, MCF-7, MDA-MB-468, for COVID-19. It might be worthwhile to conduct an
MDA-MB-231, A2780, SKOV3, OVCAR-3, Hec1A, in-depth study on the contribution of C. rotundus
and Ishikawa cells. Consequently, in vivo or even against COVID-19 pandemic in the near future.
clinical trials are needed in the future for further
validation of the efficacies ofC. rotundus in light of its Acknowledgements This work was financially supported by a
grant (No. 21ZYJDJC00080) from the Tianjin Committee of
traditional uses.
Science and Technology of China, the National Key Research
and Development Project of China (No. 2018YFC1707904,
Deficiency and prospect 2018YFC1707905 and 2018YFC1707403) and the Important
Drug Development Fund, Ministry of Science and Technology
of China (No. 2018ZX09735-002).
Due to its wide distribution, the chemical composition
of C. rotundus varies greatly along with the regions,
Authors contribution BXX, RSH and JXL were responsible
and the variations in chemical composition directly led for the data collection. The design of the whole review and
to the differences in the pharmacological effects of C. critical revision of the manuscript were done byHHW,BXX and
rotundus. This makes quality control of C. rotundus NAM, LHZ and HHW assisted with the analysis and
interpretation of the data. BXX and RSH were responsible for
challenging, especially the pharmacological activity-
drafting the manuscript. The drawing of the figures was done by
associated global quality control standards for C. BXX.
rotundus, which unfortunately are not yet available.
Again, there was little in-depth research on the Declarations
potential of those bioactive components for clinical
Conflict of interest The authors declare that there is no con-
uses. And numerous further evidence of their phar-
flict of interest regarding the publication of this paper.
macological effects is still urgently needed. These
remind us that the diverse pharmacological activities
of C. rotundus should be fully developed and utilized,
123
Phytochemistry Reviews
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