Abstract
Cyperus rotundus L. has been widely used in the treatment and prevention of numerous diseases in traditional systems of medicine around the world, such as nervous, gastrointestinal systems diseases and inflammation. In traditional Chinese medicine (TCM), its rhizomes are frequently used to treat liver disease, stomach pain, breast tenderness, dysmenorrheal and menstrual irregularities. The review is conducted to summarize comprehensively the plant’s vernacular names, distribution, phytochemistry, pharmacology, toxicology and analytical methods, along with the data mining for TCM prescriptions containing C. rotundus. Herein, 552 compounds isolated or identified from C. rotundus were systematically collated and classified, concerning monoterpenoids, sesquiterpenoids, flavonoids, phenylpropanoids, phenolics and phenolic glycosides, triterpenoids and steroids, diterpenoids, quinonoids, alkaloids, saccharides and others. Their pharmacological effects on the digestive system, nervous system, gynecological diseases, and other bioactivities like antioxidant, anti-inflammatory, anti-cancer, insect repellent, anti-microbial activity, etc. were summarized accordingly. Moreover, except for the data mining on the compatibility of C. rotundus in TCM, the separation, identification and analytical methods of C. rotundus compositions were also systematically summarized, and constituents of the essential oils from different regions were re-analyzed using multivariate statistical analysis. In addition, the toxicological study progresses on C. rotundus revealed the safety property of this herb. This review is designed to serve as a scientific basis and theoretical reference for further exploration into the clinical use and scientific research of C. rotundus.
Graphical Abstract
Supplementary Information
The online version contains supplementary materials available at 10.1007/s11101-023-09870-3.
Keywords: Cyperi rhizome, Association rules, Gynecological diseases, Sesquiterpenoids, Essential oil, GC–MS
Introduction
Cyperus rotundus L. (family: Cyperaceae), an erect, glabrous, grasslike, fibrous-rooted, herbaceous plant with slender, scaly creeping rhizomes, is widely distributed in temperate, tropical and sub-tropical regions, such as China, India, South Africa, Korea, Japan, Egypt, Iran and other countries (Chang et al. 2012; Aeganathan et al. 2015; Liu et al. 2016; Janaki et al. 2018; Sabir et al. 2020). C. rotundus has a long history as an herbal remedy in several nations, and accordingly has been collated into the native medical systems in various countries and prefectures. In China, the rhizomes of C. rotundus officially referred to as “Xiangfu” (Cyperi rhizoma, CyRh) according to the 2020 Edition of Chinese Pharmacopoeia (ChP) and initially recorded in “Mingyi Bielu”, is a gynecological herb commonly used in Traditional Chinese Medicine. And it is frequently recommended for the treatment of epigastric pain, breast aches, irregular menstruation, dysmenorrhea and amenorrhea (Chinese Pharmacopoeia Committee of China, Edition 2020). In India Ayurveda, C. rotundus, also known as “Motha” and “Mutha”, is used for the treatment of diarrhea, dysentery, diabetes, arthritis, leprosy, bronchitis, amenorrhea, dysmenorrhea, fever and blood disorders (Babiaka et al. 2021). In West Asia, C. rotundus is applied in folk medicine for the treatment of leprosy, fever, thirst and blood illnesses. In Egypt, C. rotundus is used in traditional medicine as an anthelmintic, aphrodisiac, diuretic, sedative, carminative, stimulant and tonic, and for treating renal colic and stomach pains (Samra et al. 2020). Apart from the above, C. rotundus also is the raw material of some perfumes and mosquito repellents.
Till now, the presence of monoterpenoids (menthane-, pinane-, iridoid glycosides, etc.), sesquiterpenoids (eudesmane-, patchoulane-, cadinane-, guaiane-, aromodendrane-, eremophilane-, caryophllane-, rotundane-, etc.), flavonoids (flavone-, flavonol-, isoflavone-, biflavonoids-, etc.), phenylpropanoids (simple phenylpropanoids-, coumarins-, and lignans-), phenolics and phenolic glycosides, triterpenoids and steroids, diterpenoids, quinonoids, alkaloids, saccharides and other constituents in C. rotundus has been amply demonstrated by a large number of phytochemistry investigations (Sivapalan 2013; Pirzada et al. 2015; Kabir and Abbasi 2018). Essential oil is the indispensable substance contained in the rhizomes, tubers and aerial parts of C. rotundus, and it provides the characteristic odor and flavor of this herb (Zoghbi et al. 2008; Kilani-Jaziri et al. 2009; Chang et al. 2012). Moreover, the major constituents, such as α-cyperone, α-rotunol, β-rotunol, cyperotundone, cyperene, nootkatone, and isocyperol, were frequently described to be isolated from the essential oil and the extracts of C. rotundus rhizomes (Sivapalan 2013; Sonwa and König 2001; Ahn et al. 2015; Xu et al. 2015).
Extensive modern pharmacological evidences have revealed that C. rotundus possesses a variety of biological activities including neuroprotective (Jebasingh et al. 2014; Dabaghian et al. 2015), anti-inflammatory (Rocha et al. 2020), antipyretic (Deng et al. 2012), analgesic (Ahmad et al. 2012), sedative (Srivastava et al. 2013), anticonvulsant (Khalili et al. 2011), gastroprotective (Thomas et al. 2015), anthelmintic (Al-Massarani et al. 2016; Janaki et al. 2018), antidiarrheal (Uddin et al. 2006; Daswani et al. 2011), anti-cancer (Saad et al. 2018; Susianti et al. 2018), anti-obesity (Majeed et al. 2022), antioxidant (Khalili et al. 2011), anti-bacterial (Ahmad et al. 2012), anti-malarial (Thebtaranonth et al. 1995), anti-diabetic (Singh et al. 2015), wound healing (Puratchikody et al. 2006; Srivastava et al. 2013), anti-cytotoxic (Sayed et al. 2007), anti-depressant (Lin et al. 2015; Hao et al. 2017), anti-HBV (Parvez et al. 2019), and lactogenic (Badgujar and Bandivdekar 2015) activity.
In the past decades, several reviews related to C. rotundus have been published. However, most of them focused on the traditional uses, phytochemistry and pharmacological aspects (Sivapalan 2013; Pirzada et al. 2015; Al-Snafi 2016; Kumar et al. 2017; Bajpay et al. 2018; Kabir and Abbasi 2018; Kamala et al. 2018; Babiaka et al. 2021; Kandikattu et al. 2021; Bezerra and Pinheiro 2022; Kandikattu et al. 2021; Lu et al. 2022; Rita Yadav et al. 2022). There is no comprehensive overview concerning the separation, identification and analytical techniques of the chemical components of C. rotundus, not to mention an in-depth data excavation of C. rotundus’s common compatibility with other Chinese medicines (CMs). For instance, Kumar et al. summarized C. rotundus's traditional uses and pharmacological effects (Kumar et al. 2017). Medicinal applications, phytochemistry and pharmacology of C. rotundus were worked on (Sivapalan 2013; Pirzada et al. 2015; Kamala et al. 2018; Kandikattu et al. 2021). Plant morphology, distribution, phytochemical constituents and pharmacological activities of C. rotundus were focused on (Al-Snafi 2016; Bajpay et al. 2018; Kabir and Abbasi 2018). Babiaka et al. reported in detail the bioactivities and mechanisms involved in certain C. rotundus components (Babiaka et al. 2021). Lu et al. concentrated on an overall summary on the pharmacological effects of the chemical constituents and extracts in C. rotundus (Lu et al. 2022).
In this paper, a comprehensive literature investigation on C. rotundus was accomplished by retrieving a series of electronic databases, including PubMed, Google Scholar, SciFinder, ScienceDirect, Web of Science, Huabeing database, CNKI, Traditional Chinese Medicine Resource Network. This present overview intended to compile an overall knowledge on phytochemistry, pharmacology, separation, identification and analytical methods, as well as data mining of C. rotundus. Unlike previous reviews in phytochemistry and pharmacology, this paper goes further in the following aspects. To make the content more thorough, advances in phytochemistry, pharmacology and toxicology from 1941 to 2022 were reviewed, 552 chemical constituents isolated or identified from C. rotundus have been systematically collated and classified for the first time. And the pharmacological and toxicological studies of C. rotundus on the digestive system, nervous system and gynecological diseases and other activities have been summarized accordingly. Moreover, the separation, identification and analytical methods of the chemical constituents of C. rotundus were systematically summarized for the first time. Furthermore, the chemical compositions of C. rotundus essential oils from different regions have been re-analyzed by multivariate statistical analysis. Additionally, data mining has been carried out for the first time on the compatibility of C. rotundus in TCM.
Distribution and synonyms
Owing to its adaptation to a broad range of soil textures, altitudes, climates, soil pH, and moisture levels, C. rotundus, commonly known as “The World’s Worst Weed”, may thrive in a variety of locations and ecosystems. It is unquestionably a global species, prospering in tropical, subtropical, and temperate regions and especially well in Asia, Africa, Europe and America. Table 1 gives a full summary of the regions where C. rotundus is located and Fig. 1 depicts colorfully its extensive distribution.
Table 1.
The distribution of C. rotundus around the world
| Continent | Nation | References |
|---|---|---|
| Eastern Asia | China, Japan, Korea, India, Nepal, Pakistan, SriLanka, Myanmar, Thailand, Vietnam, Indonesia, Malaysia, Philippines | Lawal and Oyedeji (2009), Pirzada et al. (2015), Al-Snafi (2016), Yagi et al. (2016), Bajpay et al. (2018), Samra 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 Asia | Kazakhstan, Kyrgyzstan, Turkmenistan, Uzbekistan | |
| Western Asia | Afghanistan, Iran, Iraq, Saudi Arabia, Yemen, Palestine, Lebanon, Syria, Turkey | |
| Europe | Austria, Switzerland, Albania, Bulgaria, Croatia, Greece, Romania, Serbia, Slovenia, France, Portugal, Spain | |
| North America | United States of America (USA), Mexico | |
| Southern America | Brazil, Bolivia, Colombia, Ecuador, Peru, Argentina | |
| Caucasus | Armenia, Azerbaijan, Russian Federation | |
| Pacific | Marshall Islands, Micronesia, Northern Mariana Islands |
Fig. 1.
The distribution of C. rotundus around the world. (The colours on the map were used only to distinguish between different countries)
The wide distribution of C. rotundus throughout the world has given it a unique name in different regions. To facilitate a comprehensive investigation and research by future researchers, it is essential to provide a systematic summary involving a variety of vernacular names of C. rotundus. Table 2 thus provides a detailed summary of the diverse common names of C. rotundus used by different regions.
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 (2016), Kumar et al. (2017), Bajpay et al. (2018), Kabir and Abbasi (2018) |
| Chinese | Xiangfu, Suo cao, Xiang fu zi | |
| 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 |
Data mining in TCM
In China, TCM prescriptions briefly refer to an orderly combination of CMs following the principles of CMs recipe (Sovereign and subject Musa acts) for the treatment of a specific disease under the guidance of TCM theory. C. rotundus, known as “Xiangfu” or “Xiangfuzi” in China which enrolled as “Cyperi rhizome” (CyRh) of Latin name in ChP, is dominantly native to the middle and lower reaches of the Yangtze River and the Huanghe River, with the optimum quality in Zhejiang and Shandong provinces. It was originally recorded in the book “Mingyi Bielu” and possesses the effects of soothing liver-Qi stagnation and alleviating depression, regulating Qi for protecting the stomach as well as regulating menstruation and relieving menstrual pain, making it the most commonly available CM for regulating the flow of Qi to alleviate depression. In “Compendium of Materia Medica”, it was described that Xiang Fu is ‘the chief commander of the treatment for Qi diseases and the leading general of the treatment for female diseases’, and it is frequently applied as a medicine for soothing liver-Qi stagnation and relieving depression. Since ancient times, it has been known as “holy medicine” in gynecology. At present, big data processing and analysis techniques, especially data mining and network pharmacology, have been greatly applied to the study of the material basis, mechanism of action and medication pattern of TCM. Therefore, data mining (Rao et al. 2021; Wang et al. 2021a; Xue et al. 2022) has been performed in this section on the TCM prescriptions containing raw CyRh or its processed product, in order to better explore the combination pattern characteristics of CyRh in TCM for better clinical application. The detailed materials and methods of data mining and comprehensive results have been presented in the supplementary materials.
The results showed that 2712 TCM prescriptions containing CyRh or its processed products were adopted, with 449 CMs enrolled in the ChP. The top 10 CMs with the greatest frequency in combination with CyRh were Angelicae sinensis radix (Danggui), Glycyrrhizae radix et rhizome (Gancao), Chuanxiong rhizome (Chuanxiong), Citri reticulatae pericarpium (Chenpi), Paeoniae radix alba (Baishao), Atractylodis macrocephalae rhizome (Baizhu), Poria (Fuling), Aucklandiae radix (Muxiang), Amomi fructus (Sharen), Citri reticulatae pericarpium viride (Qingpi) (Fig. 2a and supplementary Table S1). The CMs in combination with CyRh mostly fell into the effect classifications of tonic, regulating the circulation of Qi, invigorating Blood Circulation, clearing Heat and relieving Exterior syndrome (Fig. 2c, supplementary Table S3), with natures of Warm (Fig. 2d, supplementary Table S4), flavors of Pungent, Bitter as well as Sweet (Fig. 2e, supplementary Table S4), and channel tropisms of Spleen, Liver, Lung, Stomach, Heart and Kidney (Fig. 2f, supplementary Table S5). In traditional recipes of TCM prescriptions, CyRh is frequently used for treatments of diseases of (I) the Spleen system, (II) women's menstrual, leucorrhea and miscellaneous diseases, (III) fetuses, parturients and their diseases and (IV) the Brain system and (V) the Liver system (Fig. 2b, supplementary Table S2), and is generally consistent with the results of modern pharmacological studies of CyRh in vivo and in vitro.
Fig. 2.
The results of frequency statistics for the recipes of TCM prescriptions containing CyRh. a The CMs prescribed with frequency percentage above 5% excluding data of CyRh; b Indication classifications; c Effect classifications of the CMs prescribed excluding data of CyRh; d Natures of CMs prescribed excluding data of CyRh; e Flavors of CMs prescribed excluding data of CyRh; f Channel tropisms of CMs prescribed excluding data of CyRh
Association rules were provided by the Apriori algorithm as presented in Fig. 3 and supplementary Tables S6–S9. It has revealed the overall compatibility patterns of the core CMs in the TCM prescriptions containing CyRh in Fig. 3 and supplementary Table S6. The CMs combinations with the highest support were Xiangfu-Danggui, Xiangfu-Gancao, Xiangfu-Chuanxiong, Xiangfu-Chenpi, Xiangfu-Baishao, Xiangfu-Baizhu. Among them, the Danggui and Chuangxiong belong to drugs for invigorating blood circulation, Gancao, Baishao and Baizhu belong to tonics, while Chenpi is one of the CMs for regulating the circulation of Qi. The result suggested that Xiangfu (C. rotundus) may be commonly combined with CMs with efficacies of tonic, regulating the circulation of Qi, or invigorating Blood circulation in TCM prescriptions, basically in line with those results of the above frequency statistics and can be corroborated with each other.
Fig. 3.
Representative network display for association rules of the CMs in TCM prescriptions containing CyRh. a The CMs with high-frequencies; b The CMs prescribed for the Spleen system diseases; c The CMs prescribed for the women’s menstrual, leucorrhea and miscellaneous diseases; d The CMs prescribed for the fetuses, parturients and their diseases
Based on the association rules, among the various TCM clinical diseases treated by TCM prescriptions containing CyRh, the most common diseases of the Spleen system, women's menstrual, leucorrhea and miscellaneous diseases as well as fetuses, parturients and their diseases were selected for analysis of medication patterns.
The results demonstrated that in the traditional application for treating diseases of the Spleen system, the core combination of CMs was Mu Xiang Fen Qi recipe, with slight variations depending on the health condition of the patient (Fig. 3b, supplementary Table S7). The CMs combinations with the highest support were Xiangfu-Chenpi, Xiangfu-Gancao, Xiangfu-Muxiang, Xiangfu-Sharen, Xiangfu-Baizhu (Chenpi and Muxiang belong to CMs for regulating the circulation of Qi, Gancao and Baizhu belong to tonics, Sharen is one of the aromatics for resolving Dampness), revealing that in the treatment of spleen system diseases, Xiangfu (C. rotundus) is regularly compatible with CMs for regulating the circulation of Qi, tonics and aromatics for resolving Dampness. It is well known that Xiangfu, Chenpi, Muxiang, Sharen, and Baizhu all serve the spleen and stomach meridians in TCM. Gancao is usually applied as an adjuvant and dispatcher herb in TCM prescriptions to moderate the violent and irritant effects of medicines, and at the same time can strengthen the spleen. It is evident that the data mining results and the traditional uses of TCM both were mutually verified, explaining the reasonability and reliability of the data mining findings.
On the other hand, the outcomes of the association rules between women's menstrual, leucorrhea and miscellaneous diseases and fetuses, parturients and their diseases were extremely similar (Fig. 3c and d, supplementary Tables S8–9). And the core combination of CMs was Siwu Tang for curing both of their diseases in TCM. The association rule analysis results showed that the CMs combinations with the highest support were Xiangfu-Danggui, Xiangfu-Chuanxiong, Xiangfu-Baishao, Xiangfu-Shudihuang, Xiangfu-Baizhu, Xiangfu-Gancao (Shudihuang belong to tonics), which reveals that in the treatment of women’s diseases, Xiangfu is often compatible with tonics and medicines for invigorating Blood circulation. It is notable that Si Wu Tang, which consists of Chuanxiong, Danggui, Baishao and Shudihuang, is a classic recipe of TCM prescriptions for invigorating blood, the blood tonic and the treatment of menstrual irregularities, and has been recognized as the “Preferred Prescription of Gynecology” by succeeding generations of TCM medical practitioners. More importantly, Baizhu is traditionally recognized in TCM for its effect on the calming fetus and Xiangfu is regarded as the “Sacred Medicine of Gynecology” in TCM. This explains to some extent in the aforementioned results of the data mining, that Xiangfu has been frequently prescribed by combinations with Danggui, Chuanxiong, Baishao, Shudihuang, Baizhu and Gancao in the TCM system.
The results of the cluster analysis presented in Fig. 4 indicated that CMs with the same medicinal properties are more likely to cluster into one class, which is consistent with the above association rule results.
Fig. 4.
Hierarchical cluster analysis of the CMs in TCM prescriptions containing CyRh. a Hierarchical cluster analysis of the CMs with high-frequencies; b Hierarchical cluster analysis of the CMs prescribed for the Spleen system diseases; c Hierarchical cluster analysis for the CMs prescribed for the women’s menstrual, leucorrhea and miscellaneous diseases; d Hierarchical cluster analysis for the CMs prescribed for the fetuses, parturients and their diseases
In conclusion, CyRh, in TCM, is traditionally used for treating diseases concerning the digestive system, gynecology and nervous system such as stomach pain, abdominal pain, depression, amenorrhea, dysmenorrhea, menoxenia as well as breast tenderness. The plant which is called “the general medicine to treat Qi disease, and the chief medicine to treat women’s diseases”, exactly corresponds to the results of the data mining described above. Referring to two important and authoritative criterions, (I) the Chinese national standard ‘Clinic terminology of traditional Chinese medical diagnosis and treatment-Diseases’ (GB/T 1675.1–1997) and (II) International Classification of Diseases (ICD-10), modern pharmacological studies related to traditional applications of TCM were systematically summarized, as detailed in Table 3. Anti-cervical cancer (Mannarreddy et al. 2017; Saad et al. 2018; Susianti et al. 2018; Lin et al. 2019), anti-breast cancer (Park et al. 2014; Mannarreddy et al. 2017; Simorangkir et al. 2019; Wang et al. 2019; Ma et al. 2020; Samra et al. 2020), anti-ovarian cancer (Ahn et al. 2015; Ryu et al. 2015), anti-depressant activity (Pal et al. 2009; Jia and Zou 2014; Lin et al. 2015; Zhou et al. 2016a, 2016b; Hao et al. 2017), neuroprotective activity (Dabaghian et al. 2015; Sutalangka and Wattanathorn 2017), hepatoprotective activity (Mohamed 2015; Parvez et al. 2019), against gastric mucosal damage (Thomas et al. 2015), anti-gastrointestinal tumors (Al-Shammari et al. 2021) and other effects of CyRh have been well evaluated in modern pharmacological studies. Moreover, CyRh is also used for the treatment of digestive and gynecological disorders including amenorrhea and dysmenorrhea in traditional Indian, Tunisian, and South Korean medicinal systems. All the above are to some extent unified.
Table 3.
Modern pharmacological studies related to the traditional use of C. rotundus in TCM
| Effect | Type of study | Species/enzymes | Mechanism/effect | Extract/compound (Dose/IC50) | Corresponding TCM indicationsa | International Classification of diseasesb | Part of plant | References |
|---|---|---|---|---|---|---|---|---|
| Estrogen-like effect | In vivo | Female C57bl/6 mice | By recovering the levels of dopamine in the striatum and behavior performance in MPTP mice and the TH immunopositive fibers and cells |
Petroleum ether extract (50 mg/kg/day) |
II | 3 | Rhizomes | Kim et al. (2013) |
| Anti-estrogenic effect | In vivo | Female Swiss albino mice | Reduction of the thickness in the endometrial layers of the uterine wall |
Methanol extract (3375 mg/kg) |
II | 3 | Tubers | Hendri et al. (2016) |
| Enhance endometrial receptivity | In vivo and in vitro | C57BL/6 female mice; Choriocarcinoma JAr cells and endometrial Ishikawa cells | Increase the expression of LIF and enhance adhesion of JAr cells onto Ishikawa cells to improve the number of implantation sites in pregnant mice |
Water extract (31.68 mg/kg/day) |
II | 3 | Tubers | Choi et al. (2017) |
| Anti-uterine fibroids | In vivo | Female sprague dawley rats | By increasing Bax protein expression and reducing Bcl-2 expression from homodimers Bax/Bax, and decreasing plasma estradiol and progesterone |
Amentoflavone (15, 10 and 5 g/kg) |
II | 3 | Rhizomes | Ying and Bing (2016) |
| Lactogenic activity | In vivo | Lactating dams | By increasing the weight and the protein, carbohydrate content of mammary gland tissue, and stimulating the synthesis of prolactin significantly to increase the milk production | Water extract (300 and 600 mg/kg) | III | 3 | Rhizomes | Badgujar and Bandivdekar (2015) |
| Inhibition to fetal growth | In vivo | Female sprague dawley rats | Exhibit inhibitory effects against fetal growth of rats during pregnancy |
96% Alcohol extract (22.5, 45, 90 mg/kg) |
III | 3 | Tubers | Hendri et al. (2019); Busman et al. (2020) |
| Regulation of Integrin β3 | In vivo | Mice (Mus musculus L.) | Reduce the levels of β3 integrin of uterine mice during the embryo implantation period | Essential oil | III | 3 | Tubers | Yulianty and Sutyarso (2019) |
| Anti-depressant activity | In vivo | Adult swiss albino mice | By enhancing sleeping time and analgesic, reducing different behavioral reflexes, increasing the brain serotonin and GABA levels in mice by anticonvulsant activity |
Ethanol extract (40, 60 and 80 mg/kg) |
IV | 2 | Roots and rhizomes | Pal et al. (2009) |
| Anti-depressant effect | In vivo | Male NIH mice | / |
Rotunduside D, rotunduside E, rotunduside F (50 mg/kg) |
IV | 2 | Rhizomes | Lin et al. (2015) |
| Anti-depressant effect | In vivo | Male NIH mice | / |
Rotunduside G, rotunduside H (50 mg/kg) |
IV | 2 | Rhizomes | Zhou et al. (2016a) |
| Anti-depressant effect | In vivo | Male NIH mice | / |
Cyprotuside A and Cyprotuside B (50 mg/kg) |
IV | 2 | Rhizomes | Zhou et al. (2016b) |
| Antidepressant effect | In vivo | Mice | Reduction of the immobility time in the TST and FST | Ethanol extract | IV | 2 | Roots | Jia and Zou (2014) |
| Antidepressant effect | In vivo | Wistar rats | Inhibition of brain MAO activity in rats |
Water extract (200, 400 and 800 mg/kg) |
IV | 2 | Whole plant | Hao et al. (2017) |
| Potential neuroprotective effects | In vivo | Adult male Wistar rats | Amelioration of the CA1 pyramidal cell loss due to transient global ischemia/reperfusion injury |
Ethanol extract (100 mg/kg/day) |
IV | 2 | Rhizomes | Dabaghian et al. (2015) |
| Neuroprotective and cognitive-enhancing effects | In vivo | Male Wistar rats | Enhance memory, increase neuronal density, decrease AChE activity, decrease oxidative stress status and activate pERK1/2 CP1-treated in rats |
95% Ethanol extract (100, 200 and 300 mg/kg) |
IV | 2 | Aerial part | Sutalangka and Wattanathorn (2017) |
| Potential against Alzheimer’s disease | In vivo | Male Wistar rats | Improvement of spatial learning and memory in 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 |
Ethanol extract (100 and 200 mg/kg) |
IV | 2 | Tubers | Rabiei et al. (2013) |
| Potential against Alzheimer’s disease | In vivo | Wistar male rats | The increase of escape latency and traveled distance, improvement of the learning impairment and improvement of AD-induced cognitive dysfunction |
80% Ethanol extract (400 mg/kg) |
IV | 2 | Powder | Mehdizadeh et al. (2017) |
| Potential against Alzheimer’s disease | In vivo | Male Wistar rats | The increase of spatial memory, neuronal differentiation in the hippocampus |
Chloroform fraction (250, 500, and 750 mg/kg) |
IV | 2 | Rhizomes | Shakerin et al. (2020) |
| Against Hypoxia injury | In vivo | Inbred male Wistar rats | The protection against the cognitive impairments, muscular coordination defects and the locomotor activity |
Ethanol extract (200 and 400 mg/kg) |
IV | 2 | Tubers | Jebasingh et al. (2014) |
| Against Hypobaric hypoxia | In vivo | Sprague–Dawley rats | Amelioration of hypobaric hypoxia-induced memory impairment and neurodegeneration in the hippocampus through its anti-stress effects |
TOF Extract (150, 300 and 600 mg/kg) |
IV | 2 | Roots | Kandikattu et al. (2017) |
| Against neurotoxicity | In vivo | Albino Wistar rats | Protective effect against esfenvalerate by ameliorating levels of antioxidant enzymes, acetylcholine esterase, and inflammatory markers |
Methanol extract (100 mg/kg) |
IV | 2 | Tubers | Hussein et al. (2020) |
| Hepatoprotective activity | In vivo | Wister rats | Anti-hepatotoxic, anti-hepatitis B virus and modulation of hepatic CYP450 |
80% Ethanol extract (IC50: 100 μg/mL) |
V | 1 | Rhizomes | Parvez et al. (2019) |
| Hepatoprotective activity | In vivo | Adult male albino rats | By improving the activity of SGOT, SGPT, and total bilirubin, scavenging free radicals for the lipoperoxidants, reactive oxygen species (ROS) and NO and maintaining the liver antioxidative defense systems |
EtOAc fraction (100 mg/kg) |
V | 1 | Rhizomes | Mohamed (2015) |
| Against non-alcoholic fatty liver disease | In vivo | Male C57BL/6 mice | Reduction of the expression levels of hepatic lipogenic genes | The hexane fraction | V | 1 | Rhizomes | Oh et al. (2015) |
| Cytoprotective effects against gastric ulceration | In vivo | Female Sprague–Dawley rats | Effects on protecting the stomach, delay gastric motility, and delayed gastric emptying of resin pellets |
Water extract (1250, 2500, 4000 mg/kg) |
I | 1 | Rhizomes | Zhu et al. (1997) |
| Against gastric mucosal damage | In vivo | Male Wistar rats | By inhibiting oxidative stress, increasing the activity of SOD, cellular glutathione and GSH-Px and inhibiting the lipid peroxidation in the gastric mucosa of ulcerated animals |
70% Methanol extract (250 and 500 mg/kg) |
I | 1 | Rhizomes | Thomas et al. (2015) |
| Potential anti-cervical cancer | In vitro | Cervical cancer (HeLa) cells and human glioblastoma (AMGM) cells | Reduction of the expression levels of OCT3/4, MMP2 and MMP9 |
TOF Extraction (50–500 µg/mL, the best concentration of inhibition: 350 µg/mL) |
II | 3 | Tubers | Saad et al. (2018) |
| Potential anti-cervical cancer | In vitro | HeLa cervical cancer cells | / |
The hydrodistilled essential oil (IC50: 35.062 ± 11.258 μg/mL) |
II | 3 | Tubers | Susianti et al. (2018) |
| Potential anti-cervical cancer | In vitro | HeLa human cervical cancer cells | Induction of gene expression which is associated with apoptosis and cell-cycle arrest |
Ethanol extract (IC50: 300 μg/mL) |
II | 3 | Rhizomes | Lin et al. (2019) |
| Potential anti-cervical cancer | In vitro | HeLa cervical cancer cells | / |
Methanol extract (IC50: 6.83 ± 0.79 μg/mL) |
II | 3 | Rhizomes | Mannarreddy et al. (2017) |
| Potential anti-breast carcinoma | In vitro | Breast carcinoma (MCF-7) cells | / |
The hydrodistilled essential oil (IC50: 170.8 ± 0.567 μg/mL) |
II | 3 | Rhizomes | Samra et al. (2020) |
| Potential anti-triple-negative breast cancer | In vitro | TNBC cells lines (MDA-MB-468 and MDA-MB-231) | Induction of apoptosis by arresting the pathways of carbohydrate metabolism and nucleotide sugar metabolism and impacting the energy metabolism of TNBC cells |
95% Ethanol extract (MDA-MB-468: IC50: 773.3 μg/mL; MDA-MB-231: IC50: 537.5 μg/mL) |
II | 3 | Rhizomes | Ma et al. (2020) |
| Potential anti-triple-negative breast cancer | In vitro | TNBC cells lines (MDA-MB-468 and MDA-MB-231) | By arresting cell cycle in G0/G1 phase induces apoptosis by promoting the expression of BAX and inhibiting the expression of BCL-2 3-MA |
95% Ethanol extract (0, 200, 400, 600, 800, 1000 and 1200 μg/mL) |
II | 3 | Rhizomes | Wang et al. (2019) |
| Potential anti-breast cancer | In vitro | Breast carcinoma (MCF-7) cells | / |
Methanol extract (IC50: 4.52 ± 0.57 μg/mL) |
II | 3 | Rhizomes | Mannarreddy et al. (2017) |
| Potential anti-breast cancer | In vitro | MCF-7 cell and Vero cells | By arresting the cell cycle in the G0-G1 phase and inducing apoptosis |
n-Hexane fraction (IC50: 120.819 µg/mL) |
II | 3 | Rhizomes | Simorangkir et al. (2019) |
| Potential anti-breast cancer | In vitro | MDA-MB-231 human breast carcinoma cells | Activation of both intrinsic and extrinsic signaling pathways to regulate the caspase-dependent cascade |
Ethanol extract Methanol extract (0–500 µg/mL) |
II | 3 | Rhizomes | Park et al. (2014) |
| Potential anti-ovarian cancer | In vitro |
Human ovarian cancer cells (A2780) and endometrial adenocar cinoma (Ishikawa) |
/ |
AcOEt fraction (IC50: 74.60 and 177.61 μg/mL) 11,12-Dihydroxyeudesm-4-en-3-one (IC50: 11.06 ± 0.25 and 6.46 ± 0.12 μM) |
II | 3 | Rhizomes | Ryu et al. (2015) |
| Potential anti-ovarian cancer | In vitro |
Endometrial adenocar cinoma (Ishikawa) |
/ |
Cyperusol A3 (86.85 ± 0.41 μM) |
II | 3 | Rhizomes | Ryu et al. (2015) |
| Potential anti-ovarian cancer | In vitro | Ovarian cancer cell lines (A2780, SKOV3 and OVCAR-3) | By inducing caspase-dependent apoptosis in human ovarian cancer cells |
n-Hexane fraction (IC50: 50.48 ± 1.07, 87.34 ± 0.56 and 149.04 ± 0.87 μg/mL) EtOAc fraction (IC50: 74.60 ± 0.52, 80.72 ± 1.92 and 134.75 ± 0.98 μg/mL) 80% EtOH extract (A2780: IC50: 135.33 ± 0.14 μg/mL) |
II | 3 | Rhizomes | Ahn et al. (2015) |
| Potential anti-ovarian cancer | In vitro | Ovarian cancer cell lines (A2780, SKOV3 and OVCAR-3) | By inducing caspase-dependent apoptosis in human ovarian cancer cells |
6,9-Diacetoxy cyperene (IC50: 89.75 ± 1.27, 118.63 ± 0.01, 114.45 ± 0.12 μg/mL) 6-Acetoxy Cyperene (IC50: 61.69 ± 2.25, 89.17 ± 0.06, 100.42 ± 0.02 μg/mL) |
II | 3 | Rhizomes | Ahn et al. (2015) |
| Potential anti-ovarian cancer | In vitro | Endometrial cancer (Hec1A and Ishikawa) cells | By inducing caspase-dependent apoptosis in human ovarian cancer cells |
n-Hexane fraction (110.62 ± 0.37 and 164.07 ± 0.23 μg/mL) EtOAc Fraction (IC50: 131.43 ± 0.95 and 177.61 ± 0.53 μg/mL) |
II | 3 | Rhizomes | Ahn et al. (2015) |
| Estrogen-like effect | In vitro | MCF-7 BUS cells | By increasing transcriptional activity in estrogen-sensitive gene | 4α,5α-Oxidoeudesm-11-en-3-one (3.75–60 μg/mL) | II | 3 | Rhizomes | Park et al. (2019) |
| Potential anti-endometrial adenocarcinoma cancer | In vitro | Human endometrial adenocarcinoma cells (Ishikawa) | / |
AcOEt fraction (IC50: 177.61 μg/mL) |
II | 3 | Rhizomes | Ryu et al. (2015) |
| Neuroprotective effects | In vitro | The human neuroblastoma cell line (SH-SY5Y) | Amelioration of the H2O2-induced oxidative stress by improving the antioxidant status, mitochondrial membrane integrity, regulating the apoptotic markers and maintaining the BDNF level |
Water extract (0, 1, 10, 25, 50, and 100 μg/mL) |
IV | 2 | Roots | Kumar and Khanum (2013) |
| Against neuronal damage | In vitro | PC12 cells | Inhibition of the generation of reactive oxygen species and nitric oxide, reduction of mitochondrial membrane potential, and caspase-3 activity induced by 6-OHDA, protective effect against damage to dopaminergic neurons |
Water extract (50 and 100 μg/mL) |
IV | 2 | Rhizomes | Lee et al. (2010) |
| Potential anti-hepatocellular carcinoma cancer | In vitro | Hepatocellular carcinoma (HepG2) cells | / |
The hydrodistilled essential oil (IC50: 204.1 ± 1.25 μg/mL) |
V | 1 | Rhizomes | Samra et al. (2020) |
| Potential anti-liver cancer | In vitro | Hepatocellular carcinoma (HepG2) cells | / |
Methanol extracts (IC50: 7.66 ± 0.82 μg/mL) |
V | 1 | Rhizomes | Mannarreddy et al. (2017) |
| Hepatoprotective activity | In vitro | Hepatocellular carcinoma (HepG2) cells | Anti-hepatotoxic, anti-hepatitis B virus and modulation of hepatic CYP450 |
Ethyl acetate, n-butanol and aqueous fractions (IC50: 64.24, 94.86, 107.81 μg/mL) |
V | 1 | Rhizomes | Parvez et al. (2019) |
| Anti-hepatitis B virus | In vitro | HepG2.2.15 cells (HBsAg and HBeAg Elisa) | / |
Ethyl acetate, aqueous, n-butanol extracts (IC50: 64.24, 94.86, 107.81 µg/mL) |
V | 1 | Rhizomes | Parvez et al. (2019) |
| Anti-infectious diarrhea | In vitro | E. coli B170, E. coli E134, E. coli B831-2, Vibrio cholerae C6709 and Shigella flexneri M9OT | By reducing bacterial adherence and regulating the production of CT and action of LT, directly killing the pathogen to exerts its antidiarrheal action |
Water extract (0.52 ± 0.028, 2.6 ± 0.14 and 5.2 ± 0.28 mg/mL) |
I | 1 | Tubers | Daswani et al. (2011) |
| Therapy for gastrointestinal tumors | In vitro | Esophagus cancer, hepatocellular carcinoma, human rectal cancer | The combination therapy of NDV-alkaloid extract had synergistic and enhanced anticancer activity, with upregulating p53 level |
Alkaloid extract (100 µg/mL) |
I | 1 | Rhizomes | Al-Shammari et al. (2021) |
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
Due to its wide distribution worldwide, the phytoconstituents of C. rotundus have been extensively detected and isolated in many countries over the past decades. The complexity and structural diversity of the chemical composition of this aromatic herb has contributed to its wide-ranging pharmacological activities and medicinal values. Numerous studies have demonstrated that the main component of C. rotundus is the volatile oil, which is also the major pharmacologically active ingredient, consisting of a variety of monoterpenes, sesquiterpenes and their oxides. In addition, some flavonoids, saponins, alkaloids, phenylpropanoids, quinonoids, diterpenoids, carbohydrates, aliphatic compounds and several trace elements have also been found to be existent in this plant. Figure 5 and Table 4 distinctly illustrate the multiplicity of chemical constituents of C. rotundus. In this part, a total of 552 compounds from C. rotundus have been summarized, with 350 and 202 compounds isolated or characterized, respectively. Their detailed chemical information including the name, formula, molecular weight and the originated plant parts are summarized in supplementary Tables S10–17, and their chemical structures are presented in supplementary Fig. S1–23.
Fig. 5.
Distribution of chemical constituents of C. rotundus. a Treemap showing the constituent distribution by roughly compound type from C. rotundus; b Distribution of the sub-type of monoterpenoids; c Distribution of the sub-type of sesquiterpenoids; d Distribution of the sub-type of flavonoids
Table 4.
Summary of the chemical constituents in C. rotundus
| Type | Number of compounds |
|---|---|
| Monoterpenoids | 94 |
| Sesquiterpenoids | 260 |
| Flavonoids | 54 |
| Saponins | 31 |
| Phenylpropanoids | 15 |
| Quinonoids | 2 |
| Diterpenoids | 2 |
| Alkaloids | 11 |
| Saccharides | 3 |
| Phenolic and phenolic glycosides | 37 |
| Other types | 43 |
| Total | 552 |
Monoterpenoids
The simple monoterpenes and their oxygenated derivatives are an indispensable part of the essential oil of C. rotundus (EOCR) and are mainly composed of menthane-type (supplementary Fig. S1) and pinane-type (supplementary Fig. S2) monoterpenoids. Investigation of the available literature indicated that the monoterpenoids isolated from this aromatic herb are predominantly iridoid glycosides, with chemical structures shown in supplementary Fig. S3. Using despair mice models, three iridoid glycosides [rotunduside F (60), rotunduside G (55) and rotunduside H (56)] were shown to exhibit noticeable antidepressant activity by the forced swim test (FST) and the tail suspension test (TST), equivalent to the positive control fluoxetine (Zhou and Fu 2013; Lin et al. 2015; Zhou et al. 2016a). 10-O-p-Hydroxybenzoyltheviridoside (53), rotunduside B (51), rotunduside C (67) and senburiside I (66) displayed macrophages respiratory burst (MRB) inhibitory activity to some extent (Zhou et al. 2013; Zhou and Zhang 2013; Cheng et al. 2014; Zhang et al. 2014).
Sesquiterpenoids
Sesquiterpenoids are the most dominant active constituents in EOCR. To date, there are approximately 260 sesquiterpenoids that have been isolated and characterized from C. rotundus, mainly consisting of sesquiterpenes and their oxygenated derivatives such as alcohols, ketones and lactones. Notably, most of them were identified to be separated from the rhizomes or tubers of this plant. The predominant sesquiterpenoid skeletons include eudesmane-type (supplementary Fig. S5), patchoulane-type (supplementary Fig. S6), and cadinane-type (supplementary Fig. S7) sesquiterpenoids. A summary of the sesquiterpenoid skeletons in C. rotundus is presented in Fig. 6.
Fig. 6.
Basic sesquiterpenoid skeletons in C. rotundus
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) sesquiterpenoids, such as α-cyperone (111), isocyperol (96), nootkatone (235) and valencene (237). Khan et al. pointed out that α-cyperone (111), isocyperol (96) and nootkatone (235), valencene (237), β-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 capacity, with IC50 valued 22.03 μM, followed by aristolone (296) and solavetivone (302), with IC50 values of 24.18 and 31.24 μM, respectively (Priya Rani and Padmakumari 2012). Some sesquiterpenoids isolated from Cyperus rotundus tubers were found to possess varying degrees of antimalarial effects against Plasmodium falciparum, as exemplified by patchoulenone (152, EC50: 0.108 M), caryophyllene α-oxide (241, EC50: 0.345 μM), 10,12-peroxycalamenene (318, EC50: 2.33 × 10–3 μM), α-cyperone (111, EC50: 25 μM) and β-selinene (97, EC50: 27 μM) (Weenen et al. 1990a; Thebtaranonth et al. 1995). In addition, 11,12-dihydroxyeudesm-4-en-3-one (110, EC50: 11.06 ± 0.25 μM) showed a more potent proliferation inhibitory effect against ovarian cancer A2780 cells than 6,9-diacetoxy cyperene (143, EC50: 61.69 ± 2.25 μM). Again, 11,12-dihydroxyeudesm-4-en-3-one (110, EC50: 6.46 ± 0.12 μM) and cyperusol A3 (197, EC50: 86.54 ± 0.41 μM) also exhibited detectable cytotoxicities against endometrial adenocarcinoma Ishikawa cells (Ahn et al. 2015; Ryu et al. 2015). There was an interesting discovery that 4α,5α-oxidoeudesm-11-en-3-one (105) exerts a dual regulation on estrogen receptor-α and estrogen receptor-β and possesses both estrogenic and antiestrogenic effects depending on the E2 concentration (Park et al. 2019).
Additionally, a norsesquiterpenoid norcyperone (343) and a sesquiterpenoid cyperensol A (344) characterized with a unique 6/6/5 skeleton, have been isolated and identified from the rhizomes of C. rotundus (Xu et al. 2008; Wang et al. 2021b). Again, three novel sesquiterpenoid alkaloids (supplementary Fig. S13) rotundines A–C (352–354) have been reported by Jeong et al. (Jeong et al. 2000) to be isolated from the methanol extract of the rhizomes of C. rotundus.
Flavonoids
Flavonoids are extensively distributed in the plant kingdom with a wide variety of biological activities, which have attracted worldwide attention (Bai et al. 2019). Flavonoids are mainly found in the rhizomes and aerial parts such as the leaves of C. rotundus (Sayed et al. 2007, 2008; Ibrahim et al. 2018). Until now, a total of fifty-four flavonoids have been isolated 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. rotundus. Besides these, the isoflavone-type, biflavonoids and other types of flavonoids have also been discovered to be present in C. rotundus. Among them, four biflavone constituents namely amentoflavone (393), ginkgetin (394), isoginkgetin (395) and sciadopitysin (396), were obtained from the ethanol extract of rhizomes of C. rotundus. And amentoflavone showed a significant effect on anti-uterine fibroids in pathological rat models (Ying and Bing 2016). 7,8-Dihydroxy-5,6-methylenedioxyflavone (362) was isolated from the rhizomes of C. rotundus (Zhou and Fu 2013); while vitexin (365), isovitexin (366), orientin (367), epiorientin (368), luteolin 4′-O-β-D-glucuronopyranoside (370), luteolin 7-O-β-D-glucuronopyranoside (371), cyperaflavoside (375), myricetin 3-O-β-D-galactopyranoside (382), quercetin 3-O-β-D-glucopyranoside (383), and myrcetin 3-O-β-D-glucopyranoside (384) were given from the aerial parts of C. rotundus (Sayed et al. 2008; Ibrahim et al. 2018). Compounds 365–368, 370–371 and 382 exhibited significant antioxidant activities (Sayed et al. 2008), and compounds 365, 367, 371, 375, 383, and 384 possessed significant 5-lipoxygenase inhibitory activity with IC50 values at 5.1, 4.5, 5.9, 4.0, 3.7, and 2.3 μM, respectively (Ibrahim et al. 2018). As is reported, khellin (403) and visnagin (404) were reported to show strong cytotoxic activities against L5178y (mouse lymphoma cells) with ED50 of 4.5 and 0.9 μg/mL, respectively, and also inhibit significantly the growth of the neonate larvae of the pest insect Spodoptera littoralis to exert the antifeedant activity (Sayed et al. 2007).
Triterpenoids and steroids
Saponins in C. rotundus are of considerable importance in the treatment of inflammation as well as depression. Supplementary Fig. S19 displays a summary of the structures of thirty-one triterpenoids and steroids discovered in C. rotundus. Among them, the cycloartane glycosides cyprotuside A (435), cyprotuoside B (436), cyprotuoside C (433), cyprotuoside D (434), which were isolated from the 95% aqueous ethanol extract of the rhizome of C. rotundus (Yang and Shi 2012; Zhou et al. 2016b; Lin et al. 2018), with a 9,10-seco-cycloartane framework that has seldom been reported from a natural source. Cyprotuoside A (435) and cyprotuoside B (436) showed remarkable antidepressant activity in the despair mice models (Zhou and Zhang 2013). Furthermore, a classic lupine-type triterpenoid lupeol (420), to a certain extent, expressed anti-inflammatory activity and IL-1β inhibitory activity in THP-1 monocytic cells.
Phenylpropanoids
So far, a total of 15 phenylpropanoids have been isolated or characterized from C. rotundus. They generally consist of simple phenylpropanoids (440–451), coumarins (452–453) and lignans (454), as listed in supplementary Fig. S20. Among them, p-coumaric acid (443), caffeic acid (445), (-)-(E)-caffeoylmalic acid (447) and chlorogenic acid (446) exhibited significant antioxidant activities (Sayed et al. 2008).
Phenolic compounds and phenolic glycosides
Phenolic compounds are largely composed of phenylpropanoids, flavonoids, and some other phenolic acid components. As phenylpropanoids and flavonoids have been detailed in the preceding sections, this section focused on some other phenolics or phenolic glycosides as shown in supplementary Fig. S22. For example, scirpusins A–B (494–495) (Sim et al. 2016) which were obtained from the 80% EtOH extract of C. rotundus rhizomes using bioactivity-guided fractionation, remarkably provided in vitro protection against neurotoxins for neuronal cells. In addition, five natural α-glucosidase inhibitors, cyperusphenol A (497), mesocyperusphenol A (499), cyperusphenol D (493), scirpusins A (494) and scirpusins B (495) have been successfully fished out (Cao and Ou 2015) from the C. rotundus extracts using immobilized enzyme technique in combination with UHPLC-QTOF MS analysis.
Other compounds
Apart from the aforementioned, diterpenoids (455–456), quinonoids (457–458), nitrogenous compounds (459–469), carbohydrates (470–472) and some other compounds (510–552) were also detected to be present in C. rotundus, as shown in supplementary Fig. S21–S23. Among them, fulgidic acid (532) could suppress LPS-induced iNOS, COX-2, TNF-α, and IL-6 expression effectively by activator protein-1 (AP-1)AP-1 inactivation in RAW264.7 macrophages to exert its anti-inflammatory activity (Shin et al. 2015).
Separation, identification and analytical methods
Separation techniques
Presently, various separation techniques have been employed for the isolation and purification of chemical components of C. rotundus. Among them, the conventional separation procedures include silica gel column chromatography, sephadex LH-20 column chromatography, alumina column chromatography, reversed-phase (ODS, RP-18, MCI, YMC) column chromatography, macro porous absorption resin (Diaion HP-20) column chromatography, thin-layer chromatography (TLC), preparative thin-layer chromatography (PTLC), HPLC with C18 column, semi-preparative HPLC and preparative HPLC (PHPLC) (Morimoto and Komai 2005; Kim et al. 2012; Cheng et al. 2014; Zhang et al. 2014; Shin et al. 2015; Xu et al. 2015; Liu et al. 2016).
Moreover, several alternative techniques have been applied in the purification of the secondary metabolites of C. rotundus. MPLC (RediSep SiO2) and MPLC (RediSep C18) were employed to obtain two novel sesquiterpenoids and three identified ones by Ryu et al. (Ryu et al. 2015). Park et al. purified six sesquiterpenoids from the methanolic extract of C. rotundus (MECR) rhizomes based on estrogenic activity, obtained by a combination of silica gel column chromatography and cycling HPLC chromatography with JAIGEL-1H and 2H columns (Park et al. 2019). A flash chromatographic system equipped with a C18 flash column was adopted to conduct the separation of fulgidic acid (532) (Shin et al. 2015). Supercritical fluid extraction (SFE) and high-speed counter-current chromatography (HSCCC) were used for the first time to acquire high-purity α-cyperone (111) of much quantities from EOCR (Shi et al. 2009). Xu et al. obtained thirty-seven sesquiterpenoids based on anti-hepatitis B virus activity-oriented isolation by associating common chromatographic separation techniques with ultra-fast liquid chromatography-mass spectrometry (UFLC-MSn) and HR-MS (Xu et al. 2015). Sonwa and König also for the first time performed the pre-fractionation of EOCR on a silica column coupled with a condenser and successively isolated (-)- isorotundene (254) by PTLC on silver nitrate precoated plates (Sonwa and König 2001).
Identification techniques
The structural identification of the isolated phytoconstituents from C. rotundus has been performed successfully using recognized chromatographic and spectroscopic techniques such as TLC, IR, UV, EI-MS, HR-ESI–MS, MALDI-TOF MS, FAB-MS, HR-DART-MS, 1D/2D NMR (including 1H NMR, 13C NMR, DEPT, HMBC, HSQC, 1H-1HCOSY, ROESY and NOESY), ECD and X-ray crystallography (Sayed et al. 2008; Liu et al. 2010; Ito et al. 2012; Zhou and Yin 2012; Zhou et al. 2013; Cheng et al. 2014; Lin et al. 2018; Samra et al. 2021). Given the presence of glycosidic compounds in C. rotundus, such as rotunduside G (55), rotunduside H (56), rotunduside A (68), sitosteryl-(6′-hentriacontanoyl)-β-D-galactopyranoside (427), cyprotuoside C (433), cyprotuoside D (434), cyprotuside A (435) and cyprotuside B (436), identification of the structure and especially the absolute configuration of the sugar residues (viz. glycones) is typically aided by acid hydrolysis of the analytes followed by GC comparisons with authentic standards. Q-TOF–MS aided by available standards has been carried out for the identification of certain constituents including (E)-cyperusphenol A (497), mesocyperusphenol A (499), cyperusphenol D (493), scirpusins A–B (494–495), and sugetriol (163) (Sayed et al. 2007; Zhou and Zhang 2013; Cao and Ou 2015; Zhou et al. 2016a, 2016b; Lin et al. 2018). On the other hand, MS combined with GC is frequently applied for characterizing the volatile components of C. rotundus (Lawal and Oyedeji 2009; Ghannadi et al. 2012; Eltayeib and Ismaeel 2014; Richa and Suneet 2014; Aeganathan et al. 2015; Samra et al. 2020; Qu et al. 2021).
Analytical methods
With the purpose of better qualitative and quantitative analysis of C. rotundus, numerous techniques including TLC, PTLC, HPTLC, GC, GC–MS, HPLC/UHPLC, UPLC-QTOF-MS, LC–ESI–MS/MS, PIXE and ICP-MS have been employed. Table 5 and supplementary Table S18 summarized in detail the analytical methods of C. rotundus, focusing mainly on the analyses of volatile oils, sesquiterpenoids and some phenolic constituents such as solavetivone (302), aristolone (296), nootkatone (235), scirpusins A (494), gallic acid (484), etc. The majority of the analyses of C. rotundus were performed by GC–MS for qualitative and semi-quantitative analysis of the essential oil.
Table 5.
GC–MS determination methods for chemical constituents in C. rotundus
| Region | Method | Analytes | Yield | Column | Mobile Phase | Elution program | Detection/Chromogenic conditions | Plant part | References |
|---|---|---|---|---|---|---|---|---|---|
| China-Anhui | GC–MS | Essential oils (extracted by hydrodistillation) | 0.52% | DB-1MS capillary column (60 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Relative retention indices calculated against n-alkanes | Rhizomes | Qu et al. (2021) |
| Egypt-Bahtim | GC–MS | Essential oils (extracted by hydrodistillation) | 0.40% | DB-5 MS column (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | Kovats’ retention index relative to n-alkanes (C8–C22) | Rhizomes | Samra et al. (2020) |
| Iran-Khuzestan-Ahvaz | GC–MS | Essential oils (extracted by hydrodistillation) | / | TRACE-TR-5 capillary column (30 m × 0.53 mm × 0.25 μm) | Helium | Gradient | Kovats’ retention indices calculated against aliphatic hydrocarbons (C5–C20) | Rhizomes | Janaki et al. (2018) |
| China-Shandong | GC–MS | Essential oils (extracted by hydrodistillation) | 0.83% | HP-5 MS capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention Indices calculated against a homologous series of n-alkanes (C8–C24) | Rhizomes | Hu et al. (2017); Zhang et al. (2017) |
| Sudan-West Kordofan | GC–MS | Essential oils (extracted by hydrodistillation) | 2.60% | Rtx-5 MS capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention index (RI) relative to n-alkanes (C10–C24) | Rhizomes | Yagi et al. 2016) |
| China-Hainan | GC–MS | Essential oils (extracted by hydrodistillation) | / | OV-I (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Relative retention index calculated against n-alkanes (C8–C20) | Rhizomes | He et al. (2015) |
| India-New Delhi | GC–MS | Essential oils (extracted by hydrodistillation) | / | Omegawax™ 250 Flused silica capillary column | Helium | Gradient | / | Rhizomes | Richa and Suneet (2014) |
| China-Zhejiang | GC–MS | Essential oils (extracted by hydrodistillation) | 0.78% | HP-5 MS column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention indices calculated against a homologous series of n-alkanes (C8–C24) | Rhizomes | Liu et al. (2016) |
| India-Bareilly | GC–MS | Essential oils (extracted by hydrodistillation) | / | DB-1 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention index relative to n-alkanes | Rhizome | Gupta et al. (2016) |
| Sudan-Kordofan-Elrahad | GC–MS | Essential oils (extracted by hydrodistillation) | 2.90% | DB-5 MS (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | Kovats retention indices calculated using n-alkanes (C8–C20) | Rhizomes | Eltayeib and Ismaeel (2014) |
| Sudan-Kordofan-Elobeid | GC–MS | Essential oils (extracted by hydrodistillation) | 0.60% | DB-5 MS (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | Kovats retention indices calculated using n-alkanes (C8–C20) | Rhizomes | Eltayeib and Ismaeel (2014) |
| Sudan-Kordofan-Bano | GC–MS | Essential oils (extracted by hydrodistillation) | 1.80% | DB-5 MS (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | Kovats retention indices calculated using n-alkanes (C8–C20) | Rhizomes | Eltayeib and Ismaeel (2014) |
| China-Shandong | GC–MS | Essential oils (extracted by hydrodistillation) | / | HP-5 quartz capillary column (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Li (2013) |
| China-Hainan | GC–MS | Essential oils (extracted by hydrodistillation) | / | HP-5 quartz capillary column (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Li (2013) |
| Iran-Isfahan | GC–MS | Essential oils (extracted by hydrodistillation) | 0.20% | HP-5MS capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention indices relative to n-alkanes | Tubers | Ghannadi et al. (2012) |
| China-Αnhui | GC–MS | Essential oils (extracted by hydrodistillation) | 0.40% | DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Chen et al. (2011) |
| Tunisia-Monastir | GC–MS | Essential oils (extracted by hydrodistillation) | 0.50% | polar SGE BPX-70 (60 m × 0.25 mm × 0.25 mm) cap. column and apolar Supelco SPB-5 (50 m × 0.25 mm × 0.25 mm) cap. column | Helium | Gradient | Kovats indices calculated from the injection of alkanes (C7–C31) | Tubers | Kilani et al. (2008b) |
| China-Guangzhou | GC–MS | Essential oils (extracted by hydrodistillation and SFE) | 2.4%(SFE) | BP1 quartz capillary column (60 m × 0.22 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Feng et al. (2006) |
| China-Guangxi | GC–MS | Essential oils (extracted by hydrodistillation) | 0.26%–0.97% | HP-5 quartz capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Jin et al. (2006) |
| China-Guangzhou | GC–MS | Essential oils (extracted with mixed solvent by ultrasonic) | / | DB -1701 quartz capillary column (30 m × 0.35 mm × 1.00 μm) | Helium | Gradient | / | Rhizomes | Lin et al. (2006) |
| China-Guiyang | GC–MS | Essential oils of CyRh and processed product (extracted by hydrodistillation) | 0.82% (raw product), 0.76% (processed product) | HP-5 MS quartz capillary column (30 m × 0.32 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Xu et al. (2006) |
| Tunisian-Monastir | GC–MS | Essential oils (extracted by hydrodistillation) | 0.50% | HP-5 fused silica capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention indices relative to a series of n-alkanes | Tubers | Kilani et al. (2005a) |
| Egypt-Guiza | GC–MS | Essential oils (extracted by hydrodistillation) | 0.46% | Carbowax 20 M coated capillary column (50 m × 0.2 mm × 0.2 μm) | Helium | Gradient | / | Tubers | El-Gohary (2004) |
| China-Zhejiang | GC–MS | Essential oils (extracted by hydrodistillation) | / | HP-1MS quartz capillary column (50 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Wu (2007) |
| China-Guangdong | GC–MS | Essential oils (extracted by hydrodistillation) | 0.25%–0.41% | HP-5 MS column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Lin et al. (2017) |
| Iraq | GC–MS | Methanol extracts | / | Capillary column (InertCap 1MS, 30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Tubers | Abo-Altemen et al. (2019) |
| India-Mangalore | GC–MS | n-hexane extracts | / | Perkin Elmer Elite-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Nidugala et al. (2015) |
| India-Tamilnadu | GC–MS | Chloroform fraction | / | DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Aeganathan et al. (2015) |
| Hawaii | GC–MS | Essential oils (extracted by n-hexane) | / | DB-5 fused silica capillary column (20 m × 0.25 mm) | Helium | Gradient | / | Tubers | Komai and Tang (1989) |
| India-Tamilnadu | GC–MS | Ethanol extracts (Soxhlet extraction) | / | Elite-5 fused silica capillary column (30 m × 250 µm 1D × 1 μm df) | Helium | Gradient | / | Leaves | Elezabeth and Arumugam (2014) |
| Brazil | GC–MS | Essential oils (extracted by hydrodistillation) | 0.40% | HP-5 capillary column (25 m × 0.2 mm × 0.33 μm) | Helium | Gradient | Retention indices relative to hydrocarbon standards | Leaves | Duarte et al. (2007) |
| China | GC–MS | Essential oils of CyRh and processed product (extracted by hydrodistillation) | / | Agilent 19091S-433column (30 m × 250 μm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Sheng et al. (2013) |
| China-Jiangxi | GC–MS | Essential oils of CyRh and processed product (extracted by hydrodistillation) | / | DB -1701 quartz capillary column (30 m × 0.35 mm × 1.00 μm) | Helium | Gradient | / | Rhizomes | Hu et al. (2012) |
| China | GC–MS | Essential oils (extracted by hydrodistillation) | 0.69%–1.25% | DB-1701 quartz capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Zhao et al. (2008) |
| China | GC–MS | Essential oils (extracted by hydrodistillation (HD), pressurized liquid extraction (PLE) and supercritical fluid extraction (SFE)) | / | HP-5MS capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Tam et al. (2007) |
| China-Guangzhou | GC–MS | Essential oils (extracted by hydrodistillation and SFE) | 2.3% (SFE), 0.8% (hydrodistillation) | SGE BP1 column (60 m × 0.25 μm) | Helium | Gradient | / | Rhizomes | Li et al. (2000) |
| China and India | GC–MS | Extraction with hexane/ethyl acetate mixture (1:1), (+)-nootkatone | (+)-Nootkatone [30.47 μg/10 g (India), 21.72 μg/10 g (China)] | DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | / | Rhizomes | Jaiswal et al. (2014) |
| Algeria | GC, GC–MS | Essential oils (extracted by hydrodistillation) | 2.70% | DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention index relative to n-alkanes | Rhizomes | Fenanir et al. (2021) |
| South Africa- Empangeni | GC, GC–MS | Essential oils (extracted by hydrodistillation) | 0.20% | DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention indices relative to n-alkanes (C9–C24) | Rhizomes | Lawal and Oyedeji (2009) |
| South Africa-KwaDlangezwa | GC, GC–MS | Essential oils (extracted by hydrodistillation) | 0.16% | DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention indices relative to n-alkanes (C9–C24) | Rhizomes | Lawal and Oyedeji (2009) |
| South Korean-Seoul | GC, GC–MS | Essential oils (extracted by hydrodistillation) | 2.70% | RTX-1 capillary column (60 m × 0.25 mm × 1.00 μm) | Helium | Gradient | Authentic sample | Rhizomes | Chang et al. (2012) |
| Iran-Ahwaz | GC, GC–MS | Essential oils (extracted by hydrodistillation) | 1.50% | HP-5 MS capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Kovats retention indices calculated using n-alkanes (C9–C23) | Aerial parts | Aghassi et al. (2013) |
| South-India | GC-FID, GC–MS | Essential oil (extracted by hydrodistillation and SPME) | 0.11% | FSOT-RSL-200 fused silica column (30 m × 0.32 mm × 0.25 μm) and polar Stabilwax (30 m × 0.32 mm × 0.50 μm) | Helium | Gradient | Kovats indices relative to n-alkanes | Roots and Tubers | Jirovetz et al. (2004) |
| Brazil-Pará | GC-FID, GC–MS | Essential oils (extracted by hydrodistillation) | 0.40% | DB-5 MS fused silica capillary column (30 m × 0.25 mm × 0.25 µm) | Helium | Gradient | Retention indices relative to n-alkanes | Tubers | Zoghbi et al. (2008) |
| Saudi Arabia-Riyadh | GC-FID, GC–MS | Essential oils (extracted by hydrodistillation and extracted with diethyl ether from the aqueous distillate) | 0.20% | Innowax FSC column (60 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Relative retention index calculated against a series of n-alkanes | Tubers | Al-Massarani et al. (2016) |
| Tunisia-Kebili | GC-FID, GC–MS | Essential oils (extracted by hydrodistillation), F1: n-pentane, F2: n-pentane/diethyl ether (95/5) and F3: diethyl ether further fractionated from essential oils | 0.5 ± 0.3% | HP-1 column (50 m × 320 μm × 0.5 μm), HP-innowax columns (60 m × 320 μm × 0.5 μm) | Helium | Gradient | Retention Indices relative to n-alkanes | Tubers | Essaidi et al. (2014) |
| Turkey | HS–SPME–GC–MS | Essential oils (HS-SPME extraction) | / | Innowax FSC column (60 m × 0.25 mm × 0.25 mm) | Helium | Gradient | Relative retention index (RRI) relative to a series of n-alkanes | Root | Eröz Poyraz et al. (2018) |
| China | HS–SPME–GC–MS | Volatile/heat-labile components (SPME extraction) | / | HP-5 capillary column (30 m × 0.25 mm × 0.25 μm) | Helium | Gradient | Retention index calculated against alkane standard solutions of C8–C20 and C21–C40 | Rhizomes | He et al. (2018) |
GC analysis
Gas chromatography has been widely implemented for the rapid and efficient detection of volatile or non-volatile compounds not limited to the food industry alone but also in the pharmaceutical field. Gas chromatography-flame ionization detector (GC-FID), gas chromatography–olfactometry-mass spectrometry (GC-O-MS), and gas chromatography-mass spectrometry (GC–MS) were used for the analysis of the volatile constituents of C. rotundus (Table 5).
Qualitative and semi-quantitative analyses of EOCR by GC–MS were performed and the essential oils from different regions were compared to identify the intrinsic material basis for their distinctions. Volatile oils of C. rotundus were mostly extracted by hydro-distillation (HD) (Kilani et al. 2008b; Ghannadi et al. 2012; Yagi et al. 2016; Abo-Altemen et al. 2019), in addition to supercritical fluid extraction (SFE) (Feng et al. 2006; Tam et al. 2007; Cao and Ou 2015), solid phase micro extraction (SPME) (Tam et al. 2007; Eröz Poyraz et al. 2018; He et al. 2018), pressurized liquid extraction (PLE) (Tam et al. 2007), mixed solvent extraction by ultrasound (Lin et al. 2006) and n-hexane extraction (Komai and Tang 1989). The yield of volatile oil varies dramatically depending on the region and extraction method. For example, by using the hydro-distillation method, the yield of volatile oil extracted from the rhizomes of C. rotundus in Seoul, South Korea was 2.7% (Chang et al. 2012), while the yield of essential oil extracted by the same method from the tubers in Isfahan, Iran, was only 0.2% (Ghannadi et al. 2012). The volatile oil, the characteristic and flavor component, has been taken as the crucial marker for the quality control of C. rotundus. Thus, the ChP stipulates that the content of volatile oil should not be less than 1.0% (mL/g) (China Pharmacopoeia Committee 2020). It can be concluded from a number of literature that the DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) and HP-5 MS capillary column (30 m × 0.25 mm × 0.25 μm) are commonly selected as GC columns for the analysis of EOCR (Lawal and Oyedeji 2009; Ghannadi et al. 2012; Hu et al. 2017; Fenanir et al. 2021). It is interesting to note that investigations have shown that the volatile components of the aerial parts of C. rotundus are quite different from those of its rhizomes (Aghassi et al. 2013; Elezabeth and Arumugam 2014).
Flame ionization detector (FID) has gained great popularity over recent years for its excellent response and stable signal for hydrocarbons, as well as simple operation and low cost compared to MS (Jirovetz et al. 2004; Zoghbi et al. 2008). For example, the GC-FID technique was used by Al-Massarani et al. for analyzing the volatile components of C. rotundus tubers originating from India, Brazil and Saudi Arabia (Al-Massarani et al. 2016).
HPLC/UHPLC analysis
Liquid chromatography (LC), including HPLC and UHPLC, is frequently and consistently utilized as an effective and excellent means for the identification and quantitative determination of compounds due to its accessibility, ease of operation, high sensitivity and reproducibility, good resolution and linearity, and the ability to analyze a diverse range of components. It is one of the common techniques used for the quality assessment of C. rotundus. In practical terms, certain conditions of analysis, consisting of analytes type, mobile phase, mobile phase flow rate, column temperature, column type, eluent program and detector, are critical factors affecting HPLC analysis. Supplementary Table S18 reveals the detailed conditions for the HPLC approach with regard to the analyses of C. rotundus.
It could be found that most of the analytes subjected to LC analysis of C. rotundus are the major sesquiterpenoid components, as well as the phenolic components. The mobile phases are commonly methanol–water or acetonitrile–water, with the addition of 0.1–0.5% formic acid, acetic acid, or trifluoroacetic acid to the aqueous phase. Varied columns and different detectors (such as PDA, DAD and MS) are now frequently equipped for the qualitive or quantitative analyses.
As is reported, the contents of mesocyperusphenol A (499), scirpusins A (494) and β-sitosterol (422) were evaluated in C. rotundus from different regions in China by UPLC and HPLC. The results indicated that the content of active ingredients in C. rotundus from Shandong, was relatively higher than those of other regions, revealing the necessity of selecting authentic and genuine herbs (Cao and Ou 2015; Deng et al. 2016). Zhao et al. established an HPLC method for fingerprinting the chemical components in the methanolic extracts of eight batches of C. rotundus from different regions, as well as similarity evaluation and clustering analysis (Zhao et al. 2008). Deng et al. have developed an approach for effective and rapid affinity-based screening of natural α-glucosidase inhibitors directly from C. rotundus extracts by utilizing an immobilized enzyme technique integrated with UHPLC-QTOF-MS analysis (Deng et al. 2019). Also, tissue-specific metabolite analyses of C. rotundus from India and China by laser microdissection, UHPLC-QTOF-MS/MS and additional GC–MS have been conducted and the outcomes demonstrated that the content of ( +)-nootkatone (235) in C. rotundus of India (30.47 μg/10 g), was higher than that of China (21.72 μg/10 g) (Jaiswal et al. 2014). Furthermore, LC–ESI–MS/MS was employed to characterize the phytochemical composition of the total oligomeric flavonoid (TOF) of C. rotundus and simultaneously to determine its total flavonoid and total phenolic (TPC) content (Kandikattu et al. 2015).
Other analytical methods
In other aspects, a simple, sensitive and effective HPTLC and HPLC method (245 nm) was established to verify the validity for quantification of solavetivone (302), which had been initially isolated from C. rotundus (Priya Rani and Padmakumari 2012). With the help of TLC, UV (Ultraviolet and visible spectrophotometer) and IR (Grating Infrared spectrophotometer), Samariya and Sarin have analyzed qualitatively four compounds obtained by PTLC, namely quercetin (377), kaempferol (376), myricetin (380) and catechin (399). By UV spectrophotometer as well as other techniques, quercetin, kaempferol and myricetin have been analyzed quantitatively. A conclusion was reached that the total flavonoid content in the leaves of C. rotundus was higher compared to the roots, with the total quercetin content also higher than the roots (Samariya and Sarin 2013). In addition, PIXE and ICP-MS techniques have been applied to analyze qualitatively and quantitatively some inorganic elements in C. rotundus. These include Li, Al, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu and Zn (supplementary Table S18) (Rao et al. 2019).
Multivariate statistical analysis of the essential oil of C. rotundus
Up until now, numerous works have systematically carried out the analysis regarding EOCR from different countries on account of the worldwide distribution (El-Gohary 2004; Kubmarawa et al. 2005; Kilani et al. 2008b; Zoghbi et al. 2008; Lawal and Oyedeji 2009; Chang et al. 2012; Nidugala et al. 2015; Yagi et al. 2016; Janaki et al. 2018; Abo-Altemen et al. 2019; Samra et al. 2020; Fenanir et al. 2021; Qu et al. 2021). The essential oil, the extremely main and valuable bioactive substance of C. rotundus, is contained in the 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 presented in the supplementary Tables S10–17 and supplementary Fig. S1–23. Moreover, chemical constituents that have been reported to be present in EOCR by at least two publications were considered and included in the tables.
In this section, a comprehensive summary of over thirty articles of literature concerning the essential oil profiling of C. rotundus via the GC–MS is presented in detail as shown in supplementary Table S19. The components displayed only include those with relative content greater than 1%, which were then regarded as essential ingredients (Table 6). The numbers in Fig. 7 represent the corresponding region of the C. rotundus and details are listed in supplementary Table S21. These references contain only the GC–MS studies of C. rotundus tubers and rhizomes by hydrodistillation. Neither the studies of aerial parts of C. rotundus, nor the studies with other analytical means such as SFE, SPME, ultrasonic extraction with organic reagents and GC-FID are included, so as to allow for a better comparative effect. The detailed methods for multivariate statistical analysis of the essential oil were provided in the supplementary materials.
Table 6.
Ingredients in essential oils of C. rotundus with relative contents higher than 1% and identification frequency above 3
| Compound (No.) | Identification frequency | Compound (No.) | Identification frequency |
|---|---|---|---|
| Caryophyllene oxide (241) | 24 | Cyperotundone (154) | 4 |
| Cyperene (165) | 23 | α-Humulene (266) | 4 |
| α-Cyperone (111) | 21 | Mustakone (256) | 4 |
| β-Selinene (97) | 14 | α-Cubebene (319) | 4 |
| trans-Pinocarveol (28) | 13 | α-Calacorene (183) | 4 |
| Aristolone (296) | 13 | Spathulenol (230) | 4 |
| α-Copaene (257) | 12 | Rotundene (251) | 4 |
| Myrtenol (37) | 12 | α-Gurjunene (214) | 4 |
| Longiverbenone (284) | 12 | γ-Muurolene (191) | 3 |
| α-Pinene (38) | 11 | Pinocarvone (29) | 3 |
| β-Pinene (39) | 10 | Isocyperol (96) | 3 |
| Isolongifolen-5-one (291) | 9 | Methyl (Z)-5,11,14,17-eicosatetraenoate (545) | 3 |
| 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 |
| α-Terpineol (17) | 6 | α-Ylangene (262) | 3 |
| α-Selinene (131) | 6 | α-Longipinene (286) | 3 |
| 4-Oxo-α-ylangene (261) | 6 | Valencene (237) | 3 |
| Limonene (1) | 6 | trans-Carveol (12) | 3 |
| Aromadendrene, dehydro- (215) | 6 | Eudesma-2,4,11-triene (124) | 3 |
| β-Caryophyllene (242) | 5 | Patchoulenone (152) | 3 |
| 1,8-Cineole (93) | 5 | allo-Aromadendrene (228) | 3 |
| Aromadendrene epoxide (225) | 4 |
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
Figure 7a visually indicates that the types of constituents in EOCR vary along with the regions, and it may be possible for the same components to occur simultaneously in C. rotundus from different countries, uncovering the difficulty and complexity of quality control and assessment for C. rotundus at present. The figure outwardly demonstrated that the top twelve key compounds in EOCR are caryophyllene oxide (241), cyperene (165), α-cyperone (111), β-selinene (97), trans-pinocarveol (28), aristolone (296), α-copaene (257), myrtenol (37), longiverbenone (284), α-pinene (38), β-pinene (39), isolongifolen-5-one (291).
The outcomes of HCA (Fig. 7c) and PCA (Fig. 7d) analysis revealed that the thirty-two batches of C. rotundus could be clustered into four groups, in which NO14, NO16, NO17 were classified as group I, NO2, NO8, NO3, NO22, NO21, NO27, NO18, NO26, NO20, NO32, NO28, NO5, NO19, NO25, NO30 were treated as group II, NO13, NO15 were classified as group III, and the remaining batches were clustered into group IV. This phenomenon indicates that the intrinsic material bases of the C. rotundus originating from different regions of the same country are not identical. The quality of C. rotundus from diverse nations also varies. Especially, the main volatile ingredients, such as α-cyperone and cyperene, can also be strongly affected by their geographical origin. This variability might be closely associated with hereditary factors, growth year, storage time, storage conditions, plant parts, herbal processing or not, and environmental factors, specifically soil composition, climatic factors, seasonality and circadian cycle, all of which may impact the qualitative and quantitative profiling of components in the essential oils.
A conclusion can be easily drawn from Fig. 7b, that α-cyperone (111) and cyperene (165) exist in almost all regions with relatively high contents, and they possess a variety of pharmacological activities (Weenen et al. 1990a; Khan et al. 2011; Jung et al. 2013), and hence, they were frequently recommended as the quality control marker of C. rotundus. Besides, caryophyllene oxide (241), β-selinene (97) and aristolone (296) also play important roles in EOCR (Ghannadi et al. 2012; Richa and Suneet 2014).
Pharmacology
There have been more than ten previous reviews which refer to the pharmacological effects of C. rotundus, as well as more than hundreds of studies on its pharmacological properties with the first dating back to 1959. Hence, the pharmacology of C. rotundus has been researched thoroughly, and this section intends to comprehensively summarize the pharmacological actions of C. rotundus, like anti-inflammatory, antioxidant, apoptotic, antibacterial, digestive system effects, neuroprotective effects, based on the experiments in vitro, in vivo and in clinical trials (Fig. 8, supplementary Table S22). Additionally, novel indications and hot spots of research in recent years are also included in this summary.
Fig. 8.
The diagram of pharmacological properties of C. rotundus
Anti-oxidant activity
Components in C. rotundus, such as phenolic acids, alkaloids, quinones, essential oil and sesquiterpenoids have shown excellent antioxidant activity (Kandikattu et al. 2015), especially phenolic compounds, including flavonoids, coumarins, and polyphenols (Kilani-Jaziri et al. 2011; Soumaya et al. 2014). For isolated compounds, nootkatone (235) exerted the strongest DPPH radical scavenging capacity, with IC50 valued 4.81 μg/mL followed by aristolone (296) and solavetivone (302), whose IC50 was valued at 5.28 μg/mL and 6.82 μg/mL respectively (Priya Rani and Padmakumari 2012). Compared with ethanol and ethyl acetate extracts, aqueous extract of C. rotundus has exhibited the strongest scavenging activity as shown by DPPH assay, with an IC50 value of 418.74 µg/mL (Mohamed et al. 2021). In addition to scavenging DPPH free radicals, C. rotundus also showed scavenging ability on hydroxyl radical, superoxide radical, xanthine/xanthine oxidase and others (Kilani et al. 2008b).
It is well known that the oxidative stress plays a vital role in diseases such as epilepsy, neurodegenerative disorders (Alzheimer’s disease and Parkinson’s disease) (Lee et al. 2010; Rabiei et al. 2013), non-steroidal anti-inflammatory drug-induced gastric mucosal damage (Thomas et al. 2015), hepatic injury (Mohamed 2015) and diabetes (Raut and Gaikwad 2006). C. rotundus shows potential activity in treatments of these oxidative stress-related disease, owing to its antioxidative activity by regulating the levels of some biological enzymes (SOD, HO-1, GSH-Px), and cell factors (MDA) (Baek and Lee 2016). It is recorded that the rhizome extract of C. rotundus can improve the level of SOD and decrease the level of MDA in pentylentetrazole (PTZ)-induced mice brain, exerting its oxidation resistance property. Epileptic seizure in mice was alleviated after the treatment with C. rotundus (Khalili et al. 2011).
Anti-microbial activity
The antimicrobial activities of C. rotundus involves anti-bacterial, anti-fungal and anti-viral effects (Al-Massarani et al. 2016; Samra et al. 2020). C. rotundus inhibited Streptococcus mutans by suppressing the bacterial growth, adherence activity and water-insoluble glucan synthesis, and, reducing acid production (Yu et al. 2007). Studies have found the antibacterial activity of C. rotundus among different bacterial species, no matter whether they are Gram-positive or Gram-negative (Kabbashi et al. 2015). It has however been revealed that inhibition of Gram-positive bacteria is more sensitive than that of Gram-negative bacteria owing to the differences in the lipopolysaccharides of their cell walls (Ouattara et al. 1997; Kilani et al. 2005a). The anti-viral effect of C. rotundus have been demonstrated only against hepatitis B virus (Parvez et al. 2019).
Recently, the screening and prediction of active constituents of herbs by computer simulation technology have become a research hotspot. As coronavirus disease 2019 (COVID-19) has spread throughout the world, screening of natural products against Mpro of SARS-CoV-2 has attracted great attention. Subsequently, components of C. rotundus were screened by molecular docking and successively compared with standard drugs to value the binding of protein–ligand interactions. Molecular dynamics was used to assess that binding, and finally pharmacokinetic properties and safety profiles were measured. From this study, β-amyrin (411) and stigmasta-5,22-dien-3-ol (424) were selected as the molecules that potentially inhibit SARS-COV-2 Mpro and thus implied their potential therapeutic effect against COVID-19 (Kumar et al. 2021).
Anti-inflammatory activity
In previous studies of pharmacologic activities of C. rotundus, the extracts and its isolated compounds have been demonstrated to reduce the levels of the inflammatory mediators, cytokines, and transcription factors, like 5-LOX, COX-2, PGE2, IL-1, IL-6, TNF-α (Seo et al. 2001; Jung et al. 2013; Ibrahim et al. 2018). It has also been shown that they could reduce the inflammatory response by suppressing the regulation of the NF-κB signal pathway and down-regulating AP-1 activation (Khan et al. 2011; Jung et al. 2013; Choi et al. 2014; Shin et al. 2015; Ibrahim et al. 2018). Furthermore, the generation of NO, which reflects the degree of inflammation at the cellular level, can be reduced after treatment with C. rotundus rhizome extract by suppressing the expression of iNOS in LPS-stimulated RAW 264.7 cells (Tsoyi et al. 2011). The extent of ear edema, cellular infiltrates and keratinocyte hyperproliferation were depressed in arachidonic acid and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice after the administration of C. rotundus rhizome ethanolic extract (Rocha et al. 2020).
The sesquiterpenoids components of C. rotundus, to be specific, were found to possess pronounced anti-inflammatory effect (Tsoyi et al. 2011), particularly, nootkatone (235), α-cyperone (111), valencene (237), and β-selinene (97) (Khan et al. 2011).
The anti-inflammatory function of C. rotundus in experimental studies has implied that it has the potential to cure inflammatory skin disorders (Rocha et al. 2020) and peritonitis (Dang et al. 2011).
Central Nervous system activity
C. rotundus has been reported to exert neuroprotective (Lee et al. 2010; Hemanth Kumar et al. 2013; Kim et al. 2013; Jebasingh et al. 2014; Dabaghian et al. 2015; Kandikattu et al. 2017; Sutalangka and Wattanathorn 2017; Hussein et al. 2020), antidepressant (Jia and Zou 2014; Lin et al. 2015; Zhou et al. 2016a, 2016b; Hao et al. 2017), anti-Alzheimer’s (Rabiei et al. 2013; Mehdizadeh et al. 2017; Shakerin et al. 2020), anticonvulsant (Shivakumar et al. 2009; Khalili et al. 2011), analgesic (Pal et al. 2009; Ahmad et al. 2012; Imam and Sumi 2014), and neuromodulatory (Ha et al. 2002; Rafe et al. 2019) effects. Antidepressant and neuroprotective effects are two dominant activities of C. rotundus with regard to the CNS system. The ethanol extract and water extract of C. rotundus have shown antidepressant-like action by the tail suspension test (TST) and the forced swim test (FST) in murine models (Jia and Zou 2014; Hao et al. 2017). Ethanol extract of C. rotundus at doses of 200 and 400 mg/kg effectively protected against cognitive impairment, locomotor activity and muscle coordination deficits induced by sodium nitrite-induced hypoxic injury in rats (Jebasingh et al. 2014). Hydro-alcoholic extract of C. rotundus prolonged the latency of seizure and reduced the duration of seizure in mice (Khalili et al. 2011).
Digestive system effects
The role of C. rotundus in regulating the digestive system is in general agreement with TCM and there have been numerous reports concerning the hepatoprotective (Kumar and Mishra 2005; Mohamed 2015; Oh et al. 2015; Parvez et al. 2019), gastroprotective(Thomas et al. 2015), anti-diarrhoeal (Uddin et al. 2006), anti-infectious diarrhea (Daswani et al. 2011) and anti-gastric ulceration (Zhu et al. 1997) effects of C. rotundus. For example, Parvez et al. have demonstrated a promising hepatoprotective effect of C. rotundus in vivo experiments in rats and also proven that the n-butanol and aqueous fractions of C. rotundus rhizomes exhibit the most prospective activity against HBV in vitro in DCFH-damaged HepG2 cells (Parvez et al. 2019). Furthermore, C. rotundus can dramatically inhibit aspirin-induced gastric ulceration and lipid peroxidation in ulcerated rats in a dose-dependent manner (Thomas et al. 2015). After treatment with C. rotundus methanol extracts, the frequency of diarrhea onset in mice decreased (Uddin et al. 2006), and at the same time, the cytoprotective effect of the aqueous decoction of C. rotundus on the ethanol-induced gastric injury was verified (Zhu et al. 1997).
Anti-cancer activity
In recent years, the antitumor activity of C. rotundus has gradually attracted the attention of researchers and become a hot direction of researches, including those with potential effects against cervical cancer (Mannarreddy et al. 2017; Saad et al. 2018; Susianti et al. 2018; Lin et al. 2019), breast cancer (Park et al. 2014; Mannarreddy et al. 2017; Wang et al. 2019; Simorangkir et al. 2019; Ma et al. 2020; Samra et al. 2020), ovarian cancer (Ryu et al. 2015; Ahn et al. 2015), esophagus cancer (Al-Shammari et al. 2021), hepatocellular carcinoma (Parvez et al. 2019; Samra et al. 2020), human rectal cancer (Mannarreddy et al. 2017; Al-Shammari et al. 2021), prostate cancer (Mannarreddy et al. 2017; Samra et al. 2020) and colorectal cancer (Park et al. 2014; Ahn et al. 2015; Ryu et al. 2015; Al-Massarani et al. 2016; Ying and Bing 2016; Mannarreddy et al. 2017; Abdulghany et al. 2018; Susianti et al. 2018; Lin et al. 2019; Simorangkir et al. 2019; Wang et al. 2019; Ma et al. 2020; Samra et al. 2020; Al-Shammari et al. 2021). The ethanol extract of C. rotundus (EECR) has been demonstrated to possess a potential effect against human cervical cancer and breast cancer in HeLa human cervical carcinoma cells and MCF-7 cells (Lin et al. 2019; Simorangkir et al. 2019). The EOCR was found to have cytotoxic activity against the HeLa cervical cells (Susianti et al. 2018).
Others
In addition to the above, studies have also uncovered the anti-allergic (Jin et al. 2011), antidiabetic ( Raut and Gaikwad 2006; Lemaure et al. 2007; Singh et al. 2015; Majeed et al. 2022), antihemolytic (Kilani et al. 2005a), antimalarial (Weenen et al. 1990a, 1990b; Thebtaranonth et al. 1995), antimutagenic (Kilani et al. 2005a), apoptotic (Kilani et al. 2008a, 2008b; Soumaya et al. 2014), estrogenic (Hendri et al. 2016; Park et al. 2019), repellent against mosquito (Singh et al. 2009; Al-Massarani et al. 2016), lactogenic (Badgujar and Bandivdekar 2015), against urinary tract infection (Sharma et al. 2014) and diuretic effects (Sripanidkulchai et al. 2001) of C. rotundus.
Toxicology
Given the importance of understanding the toxicity of herbal medicines to facilitate their safe use, the toxicological studies in vivo and in vitro of the extracts, essential oil, and isolated compounds from C. rotundus have been summarized and presented in supplementary Table S23.
Numerous acute toxicity tests have shown that essential oil (Biradar et al. 2010), n-hexane extract (Lemaure et al. 2007), ethanol extract (Akperbekova and Abdullaev 1966; Thanabhorn et al. 2005; Ahmad M et al. 2013; Okwu et al. 2015; Singh et al. 2015; Al-Snafi 2016; Rajakrishnan et al. 2020; Shakerin et al. 2020; Al-Awar and Alqabbani 2021), methanol extract (Soumaya et al. 2013; Imam and Sumi 2014; Kabir et al. 2019), and water extract (Krisanapun et al. 2012; Badgujar and Bandivdekar 2015) of C. rotundus didn’t arise any behavioral, biochemical, or histological alterations either in mice or in rats. And, there was a subacute toxicity test revealing that the ethanol extract of the rhizomes of C. rotundus didn’t cause any mortality or behavioral changes after an administration of 1,000 mg/kg daily over 14 days (Thanabhorn et al. 2005).
However, the extract of C. rotundus showed significant cytotoxicities to various cancer cells, including L1210 (Kilani et al. 2008a), MCF-7 (Mannarreddy et al. 2017), HeLa (Mannarreddy et al. 2017), HepG2 (Mannarreddy et al. 2017), PC-3 (Mannarreddy et al. 2017), HT-29 (Mannarreddy et al. 2017), MDA-MB 231 (Ma et al. 2020), and MDA-MB 468 (Ma et al. 2020) cells, without any observable cytotoxic effects against normal cells, such as LO2 (Song et al. 2016), MCF-12A (Mannarreddy et al. 2017), HGF (Moein et al. 2018), and BV-2 cells (Huang et al. 2018). It is worth mentioning that the essential oil of C. rotundus didn’t show any significant inhibitory effects on SH-SY5Y cells viability at the concentration of 50–150 μg/mL, unless above 150 μg/mL (Hu et al. 2017). Similarly, 10–100 μg/mL 70% ethanolic extract of C. rotundus didn't exert any significant cytotoxicities against SH-SY5Y cells, instead of a significant decrease of the cell’s viability once the final concentration was above 100 μg/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).
As for other aspects, 4,11-selinnadien-3-one, namely α-cyperone (111), from C. rotundus was known to be toxic to the bee larvae (Apis florea) with an IC50 of 10.8 ppm (Visetson et al. 2001). And, khellin (403) and visnagin (404) were reported to induce Artemia salina LEACH mortality in the brine shrimp lethality test (Sayed et al. 2007). In general, a conclusion can be safely drawn that C. rotundus is deemed safe enough for further development and utilization.
Conclusion and future perspectives
This review provides a comprehensive summary regarding distribution, synonyms, traditional uses, data mining of application in TCM, phytochemistry, isolation, analysis and identification methods, pharmacology and toxicology of C. rotundus to provide detailed and scientific evidence for its modern indications and intensive clinical applications in treatments of different diseases.
Traditional uses, chemical components and pharmacological activities
C. rotundus have various traditional applications in different nations, whereas the common important uses are for gastrointestinal discomforts, mental disorders, menstrual disorders in women and skin problems. Notably, a data mining of TCM prescriptions containing Cyperi rhizoma draws the generally same conclusion as the modern pharmacological research, which concluded that CyRh was commonly prescribed for the treatment of diseases of (I) the Spleen system, (II) the women's menstrual, leucorrhea and miscellaneous diseases, (III) the fetuses, parturients and their diseases and (IV) the Brain system, (V) the Liver system, corresponding to (1) the digestive system diseases, (2) the nervous system and (3) the gynecological diseases in the western medicinal system. As shown in Table 3, the modern pharmacological effects and bioactivities of the extracts, fractions and compounds related to the traditional uses of C. rotundus in TCM are summarized.
The main constituents of C. rotundus include essential oil, sesquiterpenoids (with diverse skeletons such as eudesmane, patchoulane, cadinene, caryophyllene types), flavonoids, phenolic acids, saponins, alkaloids, and etc. And the essential oil is the most important and bioactive substance of C. rotundus. Cyperene (165), α-cyperone (111), caryophyllene oxide (241), β-selinene (97), trans-pinocarveol (28), aristolone (296) are the vitally important components of the essential oil in the clue of their relative high contents in this medicinal plant as illustrated in the re-analyzed result (Fig. 7 and supplementary Tables 19–21) by multivariate statistical analysis of EOCRs. Furthermore, α-cyperone (111), nootkatone (235), isocyperol (96), cyperotundone (154), valencene (237) and other compounds of iridoid glycosides, flavonoids and saponins were isolated and considered to be the main active ingredients of C. rotundus. These so-called main constituents have been evaluated to exhibit extensive pharmacological activities as mentioned above. Interestingly, cyperene (165), α-cyperone (111), isocyperol (96), cyperotundone (154), cyperol (127) not only present in C. rotundus, but also existed specially in other plants of Cyperus species, such as C. esculentus L., C. distans L.f., and C. articulatus L. This phenomenon to some extent explains that why these Cyperus plants with similar chemical components exhibit similar pharmacological activities (including the treatment potentials for gastrointestinal disorders, menstrual irregularities, and inflammatory diseases) (Taheri et al. 2021).
Different extracts and fractions of C. rotundus exhibited distinct activities, which could be attributed to the structural diversity and the uneven distribution of the phytoconstituents present in these extracts and fractions. TOF extract exhibited the strongest antioxidant activity, followed by the other solvent extracts in the order of ethyl acetate > methanol extract > water extract (Kilani et al. 2008a, 2005b; Kilani-Jaziri et al. 2011). The reason may be the intrinsic contents of the common antioxidants of phenolic compounds such as flavonoids, tannins and coumarins in those extracts (Hussein et al. 2020). The anti-breast cancer activity of EECR was stronger than MECR in the human breast carcinoma cell (MDA-MB-231) model (Park et al. 2014). The anti-ovarian cancer activity of the n-hexane fraction was more potent than that of the ethyl acetate (EtOAc) fraction of EECR followed by EECR in the human ovarian cancer cell (A2780) model. The IC50 values of the n-hexane and EtOAc fractions were different among different cancer cell lines (Ahn et al. 2015). Moreover, n-butanol and aqueous fractions of C. rotundus showed significant hepatoprotective activity against DCFH-induced HepG2 cytotoxicity compared to other fractions (e.g., hexane, chloroform, and EtOAc fractions). Meanwhile, the EtOAc fraction exhibited highly promising anti-HBV activity, followed by n-butanol and aqueous fractions of C. rotundus (Parvez et al. 2019).
In conclusion, the chemical constituents of C. rotundus could be considered to be mostly from the essential oil, the non-aqueous solvent-soluble (eg. ethanol, methanol, ethyl acetate) and the water-soluble components. Different extracts and fractions of C. rotundus exhibited distinct activities, which could be attributed to the structural diversity and the uneven distribution of the phytoconstituents present in these extracts and fractions. It is noteworthy that a number of literatures have reported the activities of C. rotundus concerning nervous system diseases, digestive system disorders, gynecological disorders, both in vivo and in vitro. To some extent, this phenomenon validates the diverse traditional uses of C. rotundus. However, there are no available clinical trials demonstrating the activities of C. rotundus in these aspects, and even the in vivo pharmacological evaluations concerning the uses of C. rotundus in the treatment of gynecological diseases, instead of the numerous in vitro experiments conducted in several cancer cells including HepG2, HeLa, MCF-7, MDA-MB-468, MDA-MB-231, A2780, SKOV3, OVCAR-3, Hec1A, and Ishikawa cells. Consequently, in vivo or even clinical trials are needed in the future for further validation of the efficacies of C. rotundus in light of its traditional uses.
Deficiency and prospect
Due to its wide distribution, the chemical composition of C. rotundus varies greatly along with the regions, and the variations in chemical composition directly led to the differences in the pharmacological effects of C. rotundus. This makes quality control of C. rotundus challenging, especially the pharmacological activity-associated global quality control standards for C. rotundus, which unfortunately are not yet available. Again, there was little in-depth research on the potential of those bioactive components for clinical uses. And numerous further evidence of their pharmacological effects is still urgently needed. These remind us that the diverse pharmacological activities of C. rotundus should be fully developed and utilized, and the global quality control methods for C. rotundus should be established accordingly. It is also advisable to study the uses of C. rotundus from different countries separately, where the chemical composition of C. rotundus differs and their pharmacological activities vary greatly. In addition, it is currently challenging to identify the functional factors of components in herbal medicine for a specific disease and to assess the contribution weights of functional factors due to the diversity of phytoconstituents of herbal medicines and the complexity of their mechanisms of action. To overcome these obstacles, instead of the classic workflow of phytochemical isolation and purification followed by activity screenings, several statistical methods (e.g., fingerprint-efficacy relationship) and modern molecular networking technologies (network pharmacology, molecular docking, or molecular dynamics simulation), are encouraged to perform a virtual screening of the active phytochemicals before further phytochemistry and pharmacological studies.
Recently, as COVID-19 has spread throughout the world, studies using molecular docking and molecular dynamics have demonstrated the inhibition effect of C. rotundus against SARS-CoV-2 Mpro (Kumar et al. 2021) and implied its potential as a therapeutic agent for COVID-19. It might be worthwhile to conduct an in-depth study on the contribution of C. rotundus against COVID-19 pandemic in the near future.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
This work was financially supported by a grant (No. 21ZYJDJC00080) from the Tianjin Committee of Science and Technology of China, the National Key Research and Development Project of China (No. 2018YFC1707904, 2018YFC1707905 and 2018YFC1707403) and the Important Drug Development Fund, Ministry of Science and Technology of China (No. 2018ZX09735-002).
Authors contribution
BXX, RSH and JXL were responsible for the data collection. The design of the whole review and critical revision of the manuscript were done by HHW, BXX and NAM, LHZ and HHW assisted with the analysis and interpretation of the data. BXX and RSH were responsible for drafting the manuscript. The drawing of the figures was done by BXX.
Declarations
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Bian-Xia Xue, Ru-Shang He, Jia-Xin Lai have contributed equally to this work and should be considered co-first authors.
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