Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 1247675 10.3389/fphar.2023.1247675 Pharmacology Review Hypericum sampsonii Hance: a review of its botany, traditional uses, phytochemistry, biological activity, and safety Sun et al. 10.3389/fphar.2023.1247675 Sun Zhanghua 1 2 * † Li Yanzhen 3 † Zhong Ruimin 1 2 * Li Ran 1 2 1 Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Shaoguan, China 2 College of Food Science and Technology, Shaoguan University, Shaoguan, China 3 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China

Edited by: Daqian Wan, Tongji Hospital Affiliated to Tongji University, China

Reviewed by: Changling Hu, North Carolina Agricultural and Technical State University, United States

Hong-Hua Wu, Tianjin University of Traditional Chinese Medicine, China

 *Correspondence: Zhanghua Sun, sysuszh@126.com; Ruimin Zhong, sgu_zrm@sgu.edu.cn

These authors contributed equally to this work

 19 09 2023 2023 14 1247675 26 06 2023 31 08 2023 Copyright © 2023 Sun, Li, Zhong and Li. 2023 Sun, Li, Zhong and Li

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

Ethnopharmacological relevance: Hypericum sampsonii Hance, also known as Yuanbao Cao in Chinese, is a traditional medicinal herb from the Guttiferae family and has been widely used in China to treat various conditions, including dysentery, enteritis, mastitis, scrofula, and contusion.

Aim of the review: This review aims to provide a comprehensive overview of the botany, traditional uses, phytochemistry, biological activity and safety of H. sampsonii and to highlight its potential for medical application and drug development.

Materials and methods: We searched several databases, i.e., Web of Science, SciFinder, PubMed, CBM, CNKI, Google Scholar, etc., for relevant information on H. sampsonii. Additionally, we also consulted some books on Chinese medicine.

Results: To date, 227 secondary metabolites have been isolated from H. sampsonii, including polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, xanthones, flavonoids, naphthodianthrones, anthraquinones and aromatic compounds. These metabolites exhibit various biological activities such as anti-inflammatory, anti-tumor, anti-depressant, anti-oxidant, anti-viral and anti-bacterial effects. PPAPs are considered the main active metabolites with rich biological activities. Despite being known as rich source of PPAPs, the full extent of H. sampsonii biological activities, including their potential as PDE4 inhibitors, remained unclear. Since, previous studies have mainly been based on structural identification of metabolites in H. sampsonii, and efficacy evaluations of these metabolites based on clinical applications of H. sampsonii lack sufficient data. However, current evidence suggest that PPAPs are the most likely material basis for efficacy. From the limited information available so far, there is no evidence of potential safety issues and the safety data are limited.

Conclusion: Collectively, this review provides a comprehensive overview of the botany, traditional uses, phytochemistry, pharmacology, and safety of H. sampsonii, a valuable medicinal plant in China with various pharmacological activities. Based on pharmacological studies, H. sampsonii shows potential for treating gastrointestinal and gynecological disorders as well as traumatic injuries, which aligns with traditional medicinal use due to the presence of PPAPs, benzophenones, xanthones, and flavonoids. Therefore, further studies are needed to evaluate the pharmacological effects and elucidate the pharmacological mechanisms. In addition, pharmacological mechanisms and safety evaluation of PPAPs on animal models need to be clarified. Yet, further comprehensive studies are required to elucidate the phytochemical constituents, pharmacological mechanisms, structure-activity relationships, safety evaluation, and quality standards of this plant. Takentogether, this review highlights the potential of H. sampsonii for medical application and drug development.

 Hypericum sampsonii Hance botany traditional uses phytochemistry biological activities safety section-at-acceptance Ethnopharmacology 1 Introduction

Plants have been used in traditional medicine for centuries to prevent and treat various diseases. Ethnomedicinal plants, which have clinical evidence of efficacy and safety, play an important role in drug discovery and development (Cragg and Pezzuto, 2016; Anand et al., 2019; Choudhari et al., 2020). The Hypericum genus (Guttiferae) boasts over 460 species that are distributed worldwide, with the exception of arctic and desert regions and most tropical lowlands. (Committee, 2007). Some species are widely used in official medicine throughout the world, such as Hypericum perforatum L. (St. John’s wort) (Stojanovic et al., 2013). However, some endemic species of Hypericum have traditionally been used as folk medicine or ethnomedicine in East Asia, particularly in China (Zhang et al., 2020). Hypericum sampsonii Hance (known as “Yuanbao Cao” in Chinese), which is used as a traditional medicine in south of Changjiang River, has been commonly used as a folk medicine with functions of traumatic bleeding, enteritis, dysentery, and acute mastitis (Gong, 2014; Xie et al., 2021).

Recent years have shown, growing interest of researchers in the chemical constituents and pharmacological effects of H. sampsonii. Previous chemical investigation of H. sampsonii reports a series of metabolites including polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, flavonoids, xanthones, naphthodianthrones, anthraquinones, and aromatic compounds (Xie et al., 2021). The previously reported literatures have revealed that H. sampsonii possesses multiple biological properties, including anti-inflammatory, antinociceptive, antitumor, antidepressant, antimicrobial, antiviral, and antioxidant activities (Tian, 2015; Xie et al., 2021). Accordingly, in the present srudy, we have attempted a pharmacological analysis of the whole plant H. sampsonii to understand the primary target of inflammation and to validate the ethnomedicine reports due to its numerous pharmacological activities and traditional claims of anti-inflammatory properties in the intestinal tract (Lin et al., 2022). However, biological activities and molecular mechanisms of constituents in H. sampsonii have not been fully explored, and a comprehensive and systematic review of this plant is lacking. The present study will not only provide motivation to the growing interest in recent years for a better understanding of the indication-discovery strategies but also assist the concept of drug repurposing in the treatment of many other related clinical conditions that may direct guide towords future research plan.

In this review, the botany, traditional uses, phytochemistry, pharmacological action, and safety of H. sampsonii have been summarized along with discussion over future direction and focus of H. sampsonii in the field of pharmacology.

 2 Materials and methods

The relevant information was collected from various search engines: Web of Science, SciFinder, PubMed, CBM, CNKI, Google Scholar, etc. Other literature sources, i.e., classic books of Chinese herbal medicine were also screened to get the maximal information on this plant. The keywords used included H. sampsonii Hance, botany, phytochemistry, pharmacological activity, traditional uses, safety, and other related words. The plant name was also checked with World Flora Online (WFO (2023): Hypericum sampsonii Hance. Published on the Internet; http://www.worldfloraonline.org/taxon/wfo-0000728267. Accessed on: 04 February 2023).

 3 Botany

According to World Flora Online, this name of H. sampsonii Hance (Figure 1) of Hypericaceae family has been accepted, with other four synonyms including Hypericum electrocarpum Maxim, H. electrocarpum f. parvifolium R. Keller, Hypericum esquirolii H. Lév, and Hypericum oshimaense R. Keller, in the genus Hypericum (family Hypericaceae). As a folk medicine, various vernacular names of H. sampsonii have been known in China, such as Hezhang Cao, Shangtianti, Dahuanhun, etc (Table 1).

Photographs of H. sampsonii: the whole plant (A), the lateral view of connate perfoliate leaves (B), and medicinal material (C).

Vernacular names of H. sampsonii in China.

Area Name Ref.
Jiangxi Xiangsi, Dengtai, Shuanghehe, Duiye Cao, Daduiye Cao, Pai Cao, Duijing Cao, Sanxuedan Wu, 1963; Zhang et al. (2020)
Guangxi Daduiye Cao, Yebaozhi, Fanchuan Cao, Xiaohuangxin Cao, Baoxin Cao, Waxin Cao, Yangxingai (Miao people), Shanglianxialiu (Zhuang people), Mawu (Mulam people) Wu, 1991; Zhang et al. (2020)
Fujian Xiangsi, Dengtai, Shuanghehe, Duiye Cao, Yebaozhi, Dangguilian, Xiaolianqiao, Duilian, Ligenxiang, Danggui Cao Zhang et al. (2020)
Zhejiang Baota Cao, Chuanxinjian, Lazhudengtai, Dengtai, Qingting Cao, Honghanlian, Dayeyeyanzi Wu, 1963; Zhang et al. (2020)
Guizhou Xiangsi, Dengtai, Shuanghehe, Duiye Cao, Duiyuelian, Shezhakou Zhang et al. (2020)
Hunan Daduiye Cao, Wangbuliuxing, Liujinu, Shaoxi Cao, Lanchang Cao, Yehanyan, Mangzi Cao, Shekaikou, Yangzi Cao, Yizi Cao, Jiaozhu Cao Zhang et al. (2020)
Hunan Yaowu Zhi
《湖南药物志》
Hubei Daduiye Cao, Wangbuliuxing, Liujinu, Duiyue Cao Zhang et al. (2020)
Sichuan Daduiye Cao, Foxin Cao, Duidui Cao Wu, 1963; Zhang et al. (2020)
Jiangsu Kongxin Cao, chuanxin Cao Zhang et al. (2020)
Guangdong Daduiye Cao Zhang et al. (2020)
Anhui Huangyelianqiao Zhang et al. (2020)
Yunnan Fanchuan Cao Zhang et al. (2020)

H. sampsonii, which look like gold ingot (Yuanbao in Chinese) by the connate perfoliate leaves, is a perennial herb with a height of approximately 0.2–0.8 m. The stem is erect and glabrous, with slender and short fibrous roots. The upright stem is cylindroid, and the upper part is branched. The shape of leaves is oblong to lanceolate or oblanceolate, (2–) 2.5–7 (8) cm long, (0.7–) 1–3.5 cm wide, and the apex is obtuse or rounded, sessile, with entire margins. Leaves are arranged in opposite and basally completely connate, green above and light green below with dense marginal black glands. The leaf midrib passes through the leaf apex, and both sides have four lateral veins oblique upward; the vein network is fine and sparse. Its inflorescences like corymbose, terminal, which form into the cylindrical panicle; the bracts and bractlets are linear-lanceolate or linear, 4 mm long, with an acuminate apex. The flowers are 6–10 (−15) mm in diameter, nearly oblate, and cup-shaped at the base; the buds are ovate with an obtuse apex. The pedicel is slender and 2–3 mm long; the sepals are oblong to oblong-spatulate or oblong-linear with 3–7 (–10) mm in length and 1–3 mm in width; the petals are light yellow, ovate, persistent, about 4–8 (−13) mm long and 1.5–4 (−7) mm wide, with marginal sessile or nearly sessile black glands. There are three stamens, each containing 10–14 stamens; the anther is light yellow with black glands. The ovary is ovoid to narrowly conical, three-celled, and about 3 mm long; the style is 3, about 2 mm long, separated from the base. The capsule is ovate with a length of 6–9 mm and covered with yellowish-brown glands; seeds are small long ovate, about 1 mm long with yellowish-brown. The fluorescence duration is from May to June and the fruiting period is from July to August. The whole plant is collected in summer or autumn, dried, and used for medicinal purposes (Editorial Committee of Flora of China, 1990; Xie, 2014; Li et al., 2019).

H. sampsonii not only favors a warm and humid environment but also tolerant to cold and drought. This plant is usually living on hillsides, roadsides, scrub, grassland, fields, and ditches, with an altitude of 0–1,200 m. It is commonly distributed in the south of the Yangtze River and Taiwan in China, and is also found in Japan, Northern Viet Nam, Eastern Myanmar, and Northeast India. Guangxi, Jiangsu, Zhejiang, and Sichuan are major provinces producing this plant (Editorial Committee of Flora of China, 1990).

 4 Traditional uses

H. sampsonii has been traditionally used as a folk medicine for the treatment of gastrointestinal diseases and traumatic bleeding in China. The medicinal use of this plant was first recorded in the book of Ben Cao Cong Xin (本草从新) in Qing Dynasty, which proposed that it tastes acrid, is cold in nature, functions as nourishing Yin, and can be used to treat haematemesis and epistaxis (Wu, 1957). Textual Research on other monographs of Materia Medica, such as Bai Cao Jing and An Illustrated Book on Plants, records that the plant can be used for treating carbuncle due to toxins, traumatic injury, and deep-rooted breast carbuncles. It has the functions of clearing heat and detoxifying, relaxing tendons and activating collaterals, cooling blood and stopping bleeding. Clinically, H. sampsonii has been used to treat a variety of diseases, such as dysentery, enteritis, infantile fever, infantile convulsion, haematemesis, epistaxis, irregular menstruation, leucorrhea, traumatic bleeding, wounds, mastitis, burns, bedsores, and snakebites, etc (Editorial Board of Chinese Materia Medica, 1999; Xie, 2014; Xu, 2016; Vincent et al., 2021). According to the Gu Shang Zhong Cao Yao Shi Yong Tu Ce (Li et al., 2019), the fresh herb is often processed by pounding or grinding and used to treat traumatic injuries, gouty arthritis, and finger sores. In addition to external application, the whole plant is generally made into a decoction and taken orally for the treatment of rheumatic arthralgia, hemoptysis due to pulmonary trauma, stranguria due to hematuria, dysmenorrhea, and aphthous ulcers, etc. As a common folk medicine, the medicinal uses of H. sampsonii are documented in many local medicinal classics (Table 2). For example, Hunan Yaowu Zhi recorded that the whole plant of H. sampsonii can be used to treat diarrhea.

The traditional and clinical uses of H. sampsonii in China.

Composition a Dosage form Traditional and clinical uses Ref
元宝草(whole plant of Hypericum sampsonii Hance) Unrecorded Treat haematemesis and epistaxis Bencao Congxin
《本草从新》
元宝草(whole plant of Hypericum sampsonii Hance) Decoction, and external use Treat irregular menstruation and relieve itching Fenlei Caoyaoxing
《分类草药性》
元宝草(whole plant of Hypericum sampsonii Hance) Decoction, and external use Treat diarrhea, thrush, nebula, burns, cuts, measles without adeqrate eruption, infantile rectocele, and lactation disturbance Hunan Yaowu Zhi
《湖南药物志》
元宝草(whole plant of Hypericum sampsonii Hance), 金银花(flower of Lonicera japonica Thunb.), 白头翁(roots of Pulsatilla chinensis (Bunge) Regel), 夏枯草(whole plant of Prunella vulgaris Linn., 酢浆草(whole plant of Oxalis corniculata L.), 油茶(leaves of Camellia oleifera Abel) External use Treat aphthosis Hunan Yaowu Zhi
《湖南药物志》
元宝草(whole plant of Hypericum sampsonii Hance), 淫羊藿(leaves of Epimedium brevicornu Maxim), 油松(Pinus tabulaeformis Carr.). Decoction Treat low back pain Hunan Yaowu Zhi
《湖南药物志》
元宝草(whole plant of Hypericum sampsonii Hance),车前子(seeds of Plantago asiatica L.), Gardenia jasminoides Ellis, Akebia quinata (Houtt.) Decne Decoction Treat leucorrhea Hunan Yaowu Zhi
《湖南药物志》
忍冬藤(stem of Lonicera japonica Thunb), 野菊花(flower of Dendranthema indicum (L.) Des Moul.),元宝草(whole plant of Hypericum sampsonii Hance), 冰片(borneol) External use Treat wounds fester Hunan Yaowu Zhi
《湖南药物志》
元宝草(whole plant of Hypericum sampsonii Hance), 东方狗脊(root of Woodwardia orientalis Sw.), 四块瓦(leaves of Chloranthus serratus (Thunb.) Roem.), 槟榔(fruits of Areca catechu Linn.) External use Treat abdominal pain due to worm Hunan Yaowu Zhi
《湖南药物志》
元宝草(whole plant of Hypericum sampsonii Hance), 蜂蜜(honey) Decoction Treat erythral and leukal dysentery, and tenesmus Zhejiang Minjian Caoyao
《浙江民间草药》
元宝草(whole plant of Hypericum sampsonii Hance), 大枣(fruits of Ziziphus jujuba Mill.) Decoction Treat cough due to Yin dificiency Zhejiang Minjian Caoyao
《浙江民间草药》
元宝草(whole plant of Hypericum sampsonii Hance) External application Treat snake bites and finger sores Zhejiang Minjian Caoyao
《浙江民间草药》
元宝草(whole plant of Hypericum sampsonii Hance), 水苏(whole plant of Stachys japonica Miq.), 灯笼草(whole plant of Clinopodium polycephalum (Vaniot) C. Y. Wu et Hsuan ex Hsu), 筋骨草(whole plant of Ajuga ciliata Bunge), 玄参(roots of Scrophularia ningpoensis Hemsl.) Decoction Treat chronic pharyngitis and hoarseness Zhejiang Minjian Changyong Caoyao
《浙江民间常用草药》
元宝草(whole plant of Hypericum sampsonii Hance), 白酒(alcohol),黄酒(rice wine) Decoction, and external use Treat traumatic injury Jiangxi Minjian Caoyao
《江西民间草药》
元宝草(whole plant of Hypericum sampsonii Hance), 白酒(alcohol) Decoction Treat breast carbuncle Jiangxi Minjian Caoyao
《江西民间草药》
元宝草(whole plant of Hypericum sampsonii Hance), 商陆(roots of Phytolacca acinosa Roxb.), 白酒(alcohol) Steeping wine Treat irregular menstruation Guizhou Minjian Fangyaoji
《贵州民间方药集》
元宝草(whole plant of Hypericum sampsonii Hance), 马鞭草(whole plant of Verbena officinalis Linn.) Decoction Treat lochia Guizhou Minjian Fangyaoji
《贵州民间方药集》
元宝草(whole plant of Hypericum sampsonii Hance), 长春花(flowers of Catharanthus roseus (L.) G. Don.), 川芎(roots of Ligusticum chuanxiong Hort.) Steeping wine Treat menstrual pain Guizhou Minjian Fangyaoji
《贵州民间方药集》
元宝草(whole plant of Hypericum sampsonii Hance), 猪肉(pork) Decoction Treat hemoptysis Quanzhou Bencao
《泉州本草》
长春花(flowers of Catharanthus roseus (L.) G. Don.), 益母草(whole plant of Leonurus japonicus Houtt.), 元宝草(whole plant of Hypericum sampsonii Hance), dry wines Decoction Treat irregular menstruation Chongqing Caoyao
《重庆草药》
大叶仙茅(roots of Curculigo capitulata Kuntze), 萱草根(roots of Hemerocallis fulva (L.) L.), 女贞子(fruits of Ligustrum lucidum W.T.Aiton), 异叶鼠李(roots of Rhamnus heterophylla Oliv.), 茺蔚子(seeds of Leonurus japonicus Houtt.), 元宝草(whole plant of Hypericum sampsonii Hance), 金樱子(seeds of Rosa laevigata Michx.), 大枣(fruits of Ziziphus jujuba Mill.) Stewing with chicken Treat irregular menstruation Sichuan Zhongyao Zhi
《四川中药志》
四叶葎(whole plant of Galium bungei Steud.), 地锦草(whole plant of Euphorbia humifusa Willd.), 元宝草(whole plant of Hypericum sampsonii Hance), 地耳草(whole plant of Hypericum japonicum Thunb.), 马鞭草(whole plant of Verbena officinalis Linn.), 酢浆草(whole plant of Oxalis corniculata L.), 鹅不食草(Centipeda minima (L.) A.Braun & Asch.), 天胡荽(Hydrocotyle sibthorpioides Lam.), 飞扬草(whole plant of Euphorbia hirta Linn.), 半边莲(whole plant of Lobelia chinensis Lour.), 白花蛇舌草(whole plant of Hedyotis diffusa Willd.), 墨旱莲(whole plant of Eclipta prostrata (L.) L.), 鬼针草(whole plant of Bidens Pilosa L.), 野甘草(Scoparia dulcis L.), 海金沙(Lygodium japonicum (Thunb.) Sw.) Powder, decoction, or external application Treat soft tissue contusion, traumatic fracture, postoperative infection, snake bites, burns, appendicitis, nephritis, hepatitis, cholecystitis, pancreatitis, etc Yu (1995)
柴胡(roots of Bupleurum chinense DC.), 白芍(roots of Paeonia lactiflora Pall.), 郁金(roots of Curcuma aromatica Salisb.), 枳实(fruits of Citrus aurantium L.), 白术(roots of Atractylodes macrocephala Koidz.), 茯苓(Poria cocos (Schw.)Wolf), 陈皮(seedcase of Citrus reticulata Blanco), 元宝草(whole plant of Hypericum sampsonii Hance), 贯叶连翘(leaves of Hypericum perforatum L.), 甘草(roots of Glycyrrhiza uralensis Fisch.) Decoction Treat generalized anxiety disorder due to Liver-qi stagnation Chen (2020)
柴胡(roots of Bupleurum chinense DC.), 贯叶连翘(leaves of Hypericum perforatum L.), 元宝草(whole plant of Hypericum sampsonii Hance), 当归(roots of Angelica sinensis (Oliv.) Diels), 白芍(roots of Paeonia lactiflora Pall.), 川芎(roots of Ligusticum chuanxiong Hort.), 茯苓(Poria cocos (Schw.)Wolf), 白术(roots of Atractylodes macrocephala Koidz.), 酸枣仁(fruits of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow), 知母(roots of Anermarrhena asphodeloides Bunge), 远志(roots of Polygala tenuifolia Willd.), 甘草(roots of Glycyrrhiza uralensis Fisch.). Decoction Treat Generalized Anxiety Disorder Lin (2018)

All of the plant names have been checked with “World Flora Online” (www.worldfloraonline.org) mentioning the data of accessing that website.

H. sampsonii was also widely utilized as ethnomedicine by national minorities in China. In Sandu Shui Autonomous County located in the south of Guizhou Province of China, the botanical drug was commonly used as the liquor fermentation starter by the Shui people. Besides the edible value, this wild plant also possesses a wide range of medicinal values and can be used to treat irregular menstruation, leucorrhea, dysentery, and fever (Hong et al., 2015b). Furthermore, it was often used as an herbal tea to treat gynaecopathia by the Yao minority (Jin et al., 2018). H. sampsonii was also the medicinal plant traditionally used by Mulam people in Guangxi Province. It was mainly used to treat internal hemorrhage, abnormal menstruation, dysmenorrhea, and bleeding wound (Hu et al., 2020). According to the ethnobotanical data collected from the Maonan minority, H. sampsonii was used for the treatment of traumatic injury, pain, indigestion, chest congestion, and acute icteric hepatitis (Hong et al., 2015a; Xiang et al., 2018).

Additionally, the whole plant of H. sampsonii is most frequently reported as a traditional treatment for various diseases. Commonly, two processing methods (internal use and external application) are used before clinical use or self-medication. Firstly, it is processed by removing impurities and non-medicinal parts together with auxiliary materials such as honey and alcohol. Subsequently, the dried or fresh herb is often made as a decoction for oral administration to treat various diseases. Furthermore, in the second step, the dried herb can be ground or freshly pounded, and applied to the affected area for external use.

 5 Phytochemistry

Chemical investigation of the Hypericum species include a series of phloroglucinol derivatives, naphthodianthrones, xanthones, flavonoids, and other phenols and terpenoids (Zhang et al., 2020). Of these, phloroglucinol derivatives are the main secondary metabolites. H. sampsonii is a rich source of natural products with diverse chemical structures. To date, a total of 223 metabolites including polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, xanthones, flavonoids, bisanthraquinones, and anthraquinones have been separated and identified from H. sampsonii (Supplementary Figure S10).

5.1 Polycyclic polyprenylated acylphloroglucinols (PPAPs)

Phloroglucinols, a type of natural products showing strong oxidizing properties, variable stereochemical structures, and a wide range of pharmacological activities, are decorated with isoprenyl and hydroxyl groups which are substituted at multiple positions on the benzene ring or fused together to form a ring (Xiao and Mu, 2007). PPAPs were highly oxygenated acylphloroglucinol derivatives which decorated with complicated side chains. In the past decades, PPAPs have received extensive attention due to their considerable structural diversity and remarkable biological activities (Yang et al., 2018). Biogenetically, all PPAPs which are derived from a common biosynthetic pathway via different cyclizations of the less complex monocyclic polyprenylated acylphloroglucinols, are generated via three main biosynthetic pathways (Yang et al., 2018). Interestingly, this special class of phloroglucinols has been exclusively isolated from the plants of family Guttiferae (Clusiaceae) and mainly from the genera Hypericum and Garcinia. Up to December 2022, 116 PPAPs comprise the major family of metabolites identified from H. sampsonii (Tables 3, 4, 5). All of the PPAP profiles are generated via three major biosynthetic pathways and may be divided into three groups according to their different scaffolds. Group I are the bicyclic polyprenylated acylphloroglucinols (BPAPs) with major bicyclo [3.3.1]nonane-2,4,9-trione core and related seco-BPAPs. Group II include the caged PPAPs with adamantane (tricyclo [3.3.1.1]decane) and homoadamantane (tricyclo [4.3.1.1]undecane) skeletons. Group III contain other biosynthetically related derivatives which derived from direct cyclizations of monocyclic polyprenylated acylphloroglucinols (MPAPs).

Bicyclic Polyprenylated Acylphloroglucinols (BPAPs) isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
1 7-Epiclusianone C33H42O4 502.70 Root Xiao et al. (2007)
2 Attenuatumione C C38H50O5 586.81 Aerial part Zhu et al. (2015)
3 Hyperattenin C C38H50O5 586.81 Aerial part Zhang et al. (2016)
4 Hyperattenin E C33H43O5 519.70 Aerial part (Tian, 2015)]
5 Hyperforatin F C33H48O5 524.74 Whole plant Chen et al. (2020)
6 Hyperforin C35H52O4 536.80 Aerial part Zheng et al. (2003)
7 Hyperibone A C33H42O5 518.69 Aerial part Zhang et al. (2016)
8 Hyperibone I C33H42O5 518.69 Aerial part Tian (2015)
9 Hypersampsone F C38H48O4 568.80 Aerial part Lin and Wu (2003)
10 Hypersampsone H C38H50O4 570.80 Fruit Zeng et al. (2009)
11 Hypersampsone K C38H50O4 570.80 Fruit Zeng et al. (2012)
12 Otogirinin D C38H50O5 586.81 Aerial part Zhu et al. (2015)
13 Otogirinin E C38H50O6 602.81 Aerial part Tian (2015)
14 Hyperisampsin H C35H42O6 558.72 Aerial part Zhu et al. (2017b)
15 Hyperisampsin I C35H42O6 558.72 Aerial part Zhu et al. (2017b)
16 Hyperisampsin J C38H50O7 618.81 Aerial part Zhu et al. (2017b)
17 Hyperisampsin K C38H50O8 634.81 Aerial part Zhu et al. (2017b)
18 Hyperisampsin L C38H50O8 634.81 Aerial part Zhu et al. (2017b)
19 Hyperisampsin M C38H50O7 618.81 Aerial part Zhu et al. (2017b)
20 Hypersampsone RT C30H36O4 460.61 Aerial part Tian et al. (2014b)
21 Hypersampsone RC C32H42O3 474.68 Aerial part Chen et al. (2014)
22 Hypersampsone ST C38H50O5 586.81 Aerial part Tian et al. (2016)
23 Hypersampsone T C33H42O4 502.70 Aerial part Tian et al. (2016)
24 Hypersampsone U C33H42O5 518.69 Aerial part Tian et al. (2016)
25 Hypersampsone V C33H44O7 552.71 Aerial part Tian et al. (2016)
26 Hypersampsone W C33H44O7 552.71 Aerial part Tian et al. (2016)
27 Sampsonione K C38H50O5 586.81 Aerial part Hu and Sim (2000)
28 Sampsonione L C33H42O5 518.69 Aerial part Hu and Sim (2000)
29 Sampsonione M C38H50O5 586.81 Aerial part Hu and Sim (2000)
30 Sampsonione N C33H42O5 518.69 Root Xiao et al. (2007)
31 Sampsonione O C33H42O5 518.69 Root Xiao et al. (2007)
32 Sampsonione P C33H42O5 518.69 Root Xiao et al. (2007), Huang et al. (2022)

T and C These compound names are distinguished by the initials of authors because of their different structures while identical names.

Caged PPAPs isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
33 28,29-Epoxyplukenetione A C33H40O5 516.68 Aerial part Zhu et al. (2014)
34 Attenuatumione D C38H50O5 586.81 Aerial part Zhang et al. (2016)
35 Cowabenzophenone B C35H44O5 544.73 Aerial part Zhang et al. (2016)
36 Dioxasampsone A C33H42O6 534.69 Aerial part Tian et al. (2014b)
37 Dioxasampsone B C33H42O7 550.69 Aerial part Tian et al. (2014b)
38 Hyperattenin G C35H42O5 542.72 Aerial part Zhang et al. (2016)
39 Hyperattenin I C38H50O6 602.81 Aerial part Zhang et al. (2016)
40 Hypercohone A C33H42O5 518.69 Aerial part Chen et al. (2014)
41 Hyperibone K C33H40O4 500.70 Aerial part Chen et al. (2014)
42 Hypericumone A C32H40O4 488.67 Aerial part Huang et al. (2020)
43 Hyperisampsin A C38H50O6 602.81 Aerial part Zhu et al. (2015)
44 Hyperisampsin B C38H50O5 586.81 Aerial part Zhu et al. (2015)
45 Hyperisampsin C C38H48O5 584.80 Aerial part Zhu et al. (2015)
46 Hyperisampsin D C38H50O7 618.81 Aerial part Zhu et al. (2015)
47 Hyperisampsin E C33H40O5 516.68 Aerial part Zhu et al. (2015)
48 Hyperisampsin F C33H42O6 534.69 Aerial part Zhu et al. (2015)
49 Hyperisampsin G C38H48O5 584.80 Aerial part Zhu et al. (2015)
50 Hyperisampsin N C38H50O7 618.81 Aerial part Zhu et al. (2017b)
51 Hyperisampsin O C38H50O8 634.81 Aerial part Zhu et al. (2017b)
52 Hypersampsone A C35H50O4 534.78 Aerial part Lin and Wu (2003)
53 Hypersampsone B C35H52O4 536.80 Aerial part Lin and Wu (2003)
54 Hypersampsone C C32H46O4 494.72 Aerial part Lin and Wu (2003)
55 Hypersampsone D C38H50O4 570.80 Aerial part Lin and Wu (2003)
56 Hypersampsone E C38H50O4 570.80 Aerial part Lin and Wu (2003)
57 Hypersampsone G C38H50O4 570.80 Fruit Zeng et al. (2009)
58 Hypersampsone I C35H44O4 528.73 Fruit Zeng et al. (2012a)
59 Hypersampsone J C38H48O4 568.80 Fruit Zeng et al. (2012a)
60 Hypersampsone L C38H50O4 570.80 Fruit Zeng et al. (2012a)
61 Hypersampsone M C30H36O4 460.61 Aerial part Tian et al. (2014c)
62 Hypersampsone N C30H36O6 492.61 Aerial part Tian et al. (2014a)
63 Hypersampsone O C33H40O5 516.68 Aerial part Tian et al. (2014a)
64 Hypersampsone P C30H36O4 460.61 Aerial part Tian et al. (2014a)
65 Hypersampsone Q C33H42O5 518.69 Aerial part Tian et al. (2014a)
66 Hypersampsone SC C32H46O4 494.72 Aerial part Chen et al. (2014)
67 Hypersampsone X C33H40O4 500.70 Aerial part Tian et al. (2017b)
68 Hypersampsonone A C38H50O5 586.81 Aerial part Zhang et al. (2016)
69 Hypersampsonone B C35H44O6 560.73 Aerial part Zhang et al. (2016)
70 Hypersampsonone C C38H50O7 618.81 Aerial part Zhang et al. (2016)
71 Hypersampsonone D C39H52O6 616.84 Aerial part Zhang et al. (2016)
72 Hypersampsonone E C35H44O6 560.73 Aerial part Zhang et al. (2016)
73 Hypersampsonone F C38H50O6 602.81 Aerial part Zhang et al. (2016)
74 Hypersampsonone G C38H50O5 586.81 Aerial part Zhang et al. (2016)
75 Hyphenrone N C38H50O6 602.81 Aerial part Zhang et al. (2016)
76 Norsampsone E C29H42O4 454.65 Aerial part Tian et al. (2017b)
77 Otogirinin A C38H49O4 569.81 Aerial part Huang et al. (2020)
78 Otogirinin B C38H50O7 618.81 Aerial part Zhu et al. (2017b)
79 Otogirinin C C38H50O5 586.81 Aerial part Zhu et al. (2017b)
80 Peroxysampsone A C33H42O8 566.69 Root Xiao et al. (2010)
81 Peroxysampsone B C33H42O7 550.69 Root Xiao et al. (2010)
82 Plukenetione B C33H42O5 518.69 Aerial part Chen et al. (2014)
83 Plukenetione A C33H40O4 500.70 Aerial part Tian (2015)
84 Plukenetione C C33H42O7 550.69 Root Xiao et al. (2010)
85 Sampsonione A C38H50O5 586.81 Aerial part Hu and Sim (1998)
86 Sampsonione B C33H42O5 518.69 Aerial part Hu and Sim (1998)
87 Sampsonione C C38H50O5 586.81 Aerial part Hu and Sim (1999b)
88 Sampsonione D C38H48O4 568.80 Aerial part Hu and Sim (1999b)
89 Sampsonione E C35H42O5 542.72 Aerial part Hu and Sim (1999b)
90 Sampsonione F C38H50O5 586.81 Aerial part Hu and Sim (1999b)
91 Sampsonione G C33H42O5 518.69 Aerial part Hu and Sim (1999b)
92 Sampsonione H C35H44O4 528.73 Aerial part Hu and Sim (1999b)
93 Sampsonione I C38H48O5 584.80 Aerial part Hu and Sim (1999a)
94 Sampsonione J C38H48O5 584.80 Aerial part Hu and Sim (1999a)
95 Sampsonione Q C33H40O5 516.68 Root Xiao et al. (2007)
96 Sampsonione R C30H36O5 476.61 Root Xiao et al. (2007)

Other PPAPs isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
97 Hyperhexanone A C39H54O6 618.86 Aerial part Zhu et al. (2016b)
98 Hyperhexanone B C30H42O2 434.66 Aerial part Zhu et al. (2016b)
99 Hyperhexanone F C34H46O6 550.74 Aerial part Zhang et al. (2021)
100 Hypsampsone A C33H40O6 532.68 Aerial part Zhang et al. (2021)
101 Norhypersampsone A C20H24O3 312.41 Aerial part Zhang et al. (2017)
102 Norsampsone A C32H44O3 476.70 Aerial part Tian et al. (2014c)
103 Norsampsone B C32H44O3 476.70 Aerial part Tian et al. (2014c)
104 Norsampsone C C37H52O3 544.82 Aerial part Tian et al. (2014c)
105 Norsampsone D C37H52O3 544.82 Aerial part Tian et al. (2014c)
106 Hypericumone B C30H42O2 434.66 Aerial part Huang et al. (2020)
107 Sampsone A C22H24O6 384.43 Aerial part Xin et al. (2011b)
108 Sampsonol A C33H42O7 550.69 Aerial part Xin et al. (2012)
109 Sampsonol B C33H42O7 550.69 Aerial part Xin et al. (2012)
110 Sampsonol C C29H34O5 462.59 Aerial part Xin et al. (2012)
111 Sampsonol D C29H34O6 478.59 Aerial part Xin et al. (2012)
112 Sampsonol E C27H38O5 442.60 Aerial part Xin et al. (2012)
113 Sampsonol F C26H36O5 428.57 Aerial part Xin et al. (2012)
114 Hypersampson A C37H50O4 558.80 Aerial part Huang et al. (2022)
115 Hypersampson B C37H50O4 558.80 Aerial part Huang et al. (2022)
116 Hypersampson C C37H50O4 558.80 Aerial part Huang et al. (2022)
5.1.1 Bicyclic polyprenylated acylphloroglucinols (BPAPs)

The bicyclic polyprenylated acylphloroglucinols (BPAPs) with major bicyclo [3.3.1] nonane-2,4,9-trione core and related seco-BPAPs (1–32, Table 3) include 32 BPAPs in which the acyl group is located at the C-1 or C-3 position. In 2000, BPAPs (Sampsoniones K-M, 27-29) were first discovered in the ethanolic extract of the aerial parts of H. sampsonii (Hu and Sim, 2000). Since then, BPAPs have been increasingly explored from the roots, fruits, and aerial part of H. sampsonii.

 5.1.2 Caged PPAPs with adamantane or homoadamantane skeletons

It is noteworthy that H. sampsonii is a rich source of caged PPAPs, and about 64 adamantane- and homoadamantane-type derivatives with adamantane (tricyclo [3.3.1.1]decane) and homoadamantane (tricyclo [4.3.1.1]undecane) (33–96, Table 4) have also been isolated from this plant. As early as 1998, Hu and Sim isolated two caged PPAPs (sampsoniones A and B, 85–86) from the aerial parts of H. sampsonii (Hu and Sim, 1998). Subsequently, they discovered sampsoniones C-J (87–94) (Hu and Sim, 1999a; b, 2000). A few years later, sampsoniones Q-R (95–96) were isolated from the root of H. sampsonii (Xiao et al., 2007). Since then, a large number of studies of caged PPAPs which were isolated from H. sampsonii have been reported, primarily focusing on its structure diversity with an unprecedented carbon skeleton. The tetracyclo [6.3.1.1(3,10).0(3,7)]tridecane skeletons and biogenetically related congeners, such as 28,29-Epoxyplukenetione A (33) (Zhu et al., 2014), hyperisampsins A-G (43–49) (Zhu et al., 2014), hyperisampsins N (50), and hyperisampsins O (51) (Zhu et al., 2017a), hypersampsones A-E (52–56) (Lin and Wu, 2003), hypersampsones L-S (60–66) (Zeng et al., 2012b), and hypersampsonones A-G (68–74) (Zhang et al., 2016).

 5.1.3 Other PPAPs

A total of 20 other PPAPs such as spirocyclic PPAPs with octahydrospiro-[cyclohexan-1,5′-indene] core and complicated PPAPs via intramolecular [4 + 2] cycloadditions from MPAPs (97-116, Table 5) have been isolated from H. sampsonii. In 2011, a novel prenylated aromatic lactone (sampsone A, 107) was isolated from the aerial parts of H. sampsonii (Xin et al., 2011). Soon afterwards, six new acylphloroglucinol derivatives, (sampsonols A-F, 108–113), were discovered from the aerial parts of H. sampsonii (Xin et al., 2012). In 2014, four new decarbonyl PPAPs, (norsampsones A-D, 102-105), were isolated from the 60% EtOH extract of the aerial parts of H. sampsonii (Tian et al., 2014c). Recently, three nor-polycyclic polyprenylated acylphloroglucinols with a tetracyclic 6/5/5/6 ring system, (Hypersampones A-C, 114-116), which showed a lipid-lowering activity, were isolated from H. sampsonii. (Huang et al., 2022).

 5.2 Benzophenones

Natural benzophenone derivatives have attracted extensive attention due to their unique structures and extensive biological activities. In accordance with the literature, benzophenones, mainly including simple benzophenone derivatives (SBDS) and polyprenylated benzophenones (PPBS), may be the precursors of some xanthones (Kitanov and Nedialkov, 2001). Currently, there are 33 benzophenones isolated from H. sampsonii (Supplementary Figure S4; Table 6). Among them, two pairs of racemic PPBS, (±)-sampsonin A-B (117–120) were chirally separated from H. sampsonii (Tian et al., 2017a). In addition, seven benzophenone derivatives sampbenzophenones A-G (140–146) were isolated from the aerial parts of H. sampsonii (Zhu et al., 2016a).

Benzophenones isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
117 (−)-Sampsonin A C28H32O4 432.56 Aerial part Tian et al. (2017a)
118 (−)-Sampsonin B C28H32O4 432.56 Aerial part Tian et al. (2017a)
119 (+)-Sampsonin A C28H32O4 432.56 Aerial part Tian et al. (2017a)
120 (+)-Sampsonin B C28H32O4 432.56 Aerial part Tian et al. (2017a)
121 (E)-3-(3,7-dimethylocta-2,6-dienyl)-2,4,6-trihydroxybenzophenone C23H26O4 366.46 Aerial part Zhang et al. (2017)
122 (Z)-3-(3,7-dimethylocta-2,6-dienyl)-2,4,6-trihydroxybenzophenone C23H26O4 366.46 Aerial part Zhang et al. (2017)
123 2,4,6,3′,5′-Pentamethoxylbenzophenone C18H20O6 332.35 Aerial part Qiu et al. (2015)
124 2,4,6-Trihydroxybenzophenone C13H10O4 230.22 Aerial part Lin and Wu (2003)
125 2,4,6-Trihydroxybenzophenone 3-C-geranyl ether C23H26O4 366.46 Aerial part Lin and Wu (2003)
126 2,4,6-Trihydroxybenzophenone 4-O-geranyl ether C23H26O4 366.46 Aerial part Lin and Wu (2003)
127 2,6-Dihydroxy-4,3′,5′-trihymethoxy-benzophenone C16H16O6 304.30 Whole plant Yin et al. (2013)
128 2,6-Dihydroxy-4-[(E)-5-hydroxy-3,7-dimethylocta-2,7-dienyloxy]-benzophenone C23H26O5 382.46 Whole plant Don et al. (2004)
129 2,6-Dihydroxy-4-[(E)-7-hydroxy-3,7-dimethylocta-2-enyloxy]-benzophenone C23H28O5 384.46 Whole plant Don et al. (2004)
130 2-Hydroxy-4,6-dimethoxybenzophenone C15H14O4 258.27 Aerial part Qiu et al. (2015)
131 2-β-D-glucopyranosyl-4,6-dihydroxyphenyl phenyl ketone C19H20O9 392.36 Aerial part Hong et al. (2004)
132 3-(2-Hydroxy-7-methyl-3-methyleneoct-6-enyl)-5-isoprenyl-2,4,6-trihydroxybenzophenone C28H34O5 450.58 Aerial part Zhang et al. (2017)
133 4-Geranyloxy-2,6-dihydroxybenzophenone C23H26O4 366.46 Aerial part Zhu et al. (2016a)
134 4-Geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone C28H34O4 434.58 Aerial part Huang et al. (2020)
135 8-Benzoyl-2,2-dimethyl-6-(E-3,7-dimethyl-2,6-octadi-enyl)-3,5,7-trihydroxy chromane C28H34O5 450.58 Aerial part Zhu et al. (2016a)
136 Garcimangosone D C19H20O9 392.36 Whole plant Chen et al. (2020)
137 Otogirinin F C28H34O5 450.58 Aerial part Tian (2015)
138 Otogirinin G C28H34O5 450.58 Aerial part Zhang et al. (2017)
139 Petiolin F C19H20O10 408.36 Whole plant Dung Nguyen et al. (2021)
140 Sampbenzophenone Ax C28H34O5 450.58 Aerial part Zhu et al. (2016a)
141 Sampbenzophenone B C28H34O5 450.58 Aerial part Zhu et al. (2016a)
142 Sampbenzophenone C C28H34O5 450.58 Aerial part Zhu et al. (2016a)
143 Sampbenzophenone D C23H26O5 382.46 Aerial part Zhu et al. (2016a)
144 Sampbenzophenone E C23H26O6 398.46 Aerial part Zhu et al. (2016a)
145 Sampbenzophenone F C22H26O6 386.44 Aerial part Zhu et al. (2016a)
146 Sampbenzophenone G C23H26O5 382.46 Aerial part Zhu et al. (2016a)
147 Sampsine A C16H16O6 304.30 Aerial part Qiu et al. (2015)
148 Sampsine B C22H26O10 450.44 Aerial part Qiu et al. (2015)
149 Sampsone Fx C28H34O5 450.58 Aerial part Tian (2015)
150 Sampsone G C28H34O5 450.58 Aerial part Tian (2015)

x—Two compounds have the same structure while different names.

 5.3 Xanthones

Xanthones, a class of iso-tricyclic compounds mainly divided into simple xanthones, glycosylated xanthones, prenylated xanthones, and sulfonated xanthones, are known to possess a variety of biological activities, such as antihypertensive, antiviral, and antitumor activities. In addition, the discrepancy in xanthones activity depends on the substituents on the aromatic rings.

In 1985, Chen MT and Chen CM isolated hyperxanthone (178) from the whole plant of H. sampsonii, and firstly discovered 2-hydroxy-3.4-dimethoxyxanthone (164) and isomangiferin (179) in the genus Hypericum (Chen and Chen, 1985). Further study on the constituents in the whole plant of H. sampsonii, Hong et al. also isolated two xanthone sulfonates, 1,3-dihydroxy-5-methoxyxanthone-4-sulfonate (158) and 1,3-dihydroxy-5-O-β-D-glucopyranosylxanthone-4-sulfonate (159) (Hong et al., 2004). The reported metabolites and structures of xanthones are shown in Supplementary Figure S5; Table 7.

Xanthones isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
151 1,3,5,6-Tetrahydroxy-2-prenylxanthone C18H16O6 328.32 Whole plant Don et al. (2004)
152 1,3,5,6-Tetrahydroxyxanthone C13H8O6 260.20 Whole plant Don et al. (2004)
153 1,3,5-Trihydroxy-xanthone C13H8O5 244.20 Aerial part Guo et al. (2007)
154 1,3,6,7-Tetrahydroxy-8-(3-methyl-but-2-enyl)-xanthone C18H16O6 328.32 Whole plant Li et al. (2004)
155 1,3,6,7-Tetrahydroxy-xanthone (Norathyriol) C13H8O6 260.20 Whole plant Don et al. (2004)
156 1,3-Dihydroxy-2-methoxyxanthone C14H10O5 258.23 Whole plant Shi et al. (2016)
157 1,3-Dihydroxy-5-methoxyxanthone C14H10O5 258.23 Whole plant Dong et al. (2015)
158 1,3-Dihydroxy-5-methoxyxanthone-4-sulfonate C14H9O8KS 376.38 Whole plant Hong et al. (2004)
159 1,3-Dihydroxy-5-O-β-D-glucopyranosylxanthone-4-sulfonate C19H17O13SK 524.49 Whole plant Hong et al. (2004)
160 1,6-Dihydroxyxanthone C13H8O4 228.20 Whole plant Don et al. (2004)
161 1,7-Dihydroxy-2-methoxyxanthone C14H10O5 258.23 Whole plant Shi et al. (2016)
162 1,7-Dihydroxy-4-methoxyxanthone C14H10O5 258.23 Whole plant Li et al. (2004)
163 1-Hydroxy-7-methoxy-9H-xanthen-9-one C14H10O4 242.23 Whole plant Chen et al. (2020)
164 2-Hydroxy-3,4-dimethoxyxanthone C15H12O5 272.26 Whole plant Chen and Chen (1985)
165 2-Hydroxy-5-methoxyxanthone C14H10O4 242.23 Whole plant Shi et al. (2016)
166 2-Hydroxyxanthone C13H8O3 212.20 Root Xiao et al. (2008)
167 2-Methoxy-1,5-dihydroxyxanthone C14H10O5 258.23 Aerial part Xin et al. (2011a)
168 2-Methoxyxanthone C14H10O3 226.23 Aerial part Zhang et al. (2017)
169 5′-Demethoxycadensin G C23H18O9 438.39 Whole plant Chen et al. (2020)
170 5-Methoxy-1,3,7-trihydroxy xanthone C14H10O6 274.23 Aerial part Xin et al. (2011a)
171 5-O-methyl-2-deprenyIrheediaxanthone B C19H18O6 342.35 Whole plant Chen et al. (2020)
172 7-Methoxy-1,5,6-trihydroxyxanthone C15H12O6 288.26 Aerial part Xin et al. (2011a)
173 Euxanthone C13H8O4 228.20 Aerial part Hong et al. (2004)
174 Hypericumxanthone A C19H18O6 342.35 Aerial part Xin et al. (2011a)
175 Hypericumxanthone B C23H22O6 394.42 Aerial part Xin et al. (2011a)
176 Hyperixanthone A C28H32O6 464.56 Root Xiao et al. (2008)
177 1,3,5,8-Tetrahydroxy-6-methoxy-7-isoprenylxanthone C19H18O7 358.35 Whole plant Don et al. (2004)
178 Hyperxanthone (5,9-Dihydroxy-3,3-dimethylpyrano [3,2-a]xanthen-12-one) C18H14O5 310.31 Whole plant Chen and Chen (1985)
179 Isomangiferin C19H18O11 422.34 Whole plant Chen and Chen (1985)
180 Jacareubin C18H14O6 326.30 Whole plant Chen et al. (2020)
181 Mangiferin C19H18O11 422.34 Whole plant Chen and Chen (1985)
182 Neolancerin C19H18O10 406.34 Whole plant Don et al. (2004)
183 Padiaxanthone C23H20O6 392.41 Whole plant Don et al. (2004)
184 Patulone C23H24O6 396.44 Whole plant Li et al. (2004)
185 Sampsone C C18H18O8 362.33 Aerial part Xin et al. (2011b)
186 Toxyloxanthone B C18H14O6 326.30 Whole plant Chen and Chen (1985)
5.4 Flavonoids

Flavonoids, including flavanols, biflavonoids, and common flavonoids, constitute an important class of metabolites in H. sampsonii. To date, twelve flavonoids have been isolated and identified from H. sampsonii (Supplementary Figure S6; Table 8). According to the documents, we have found that structures of these metabolites are generally based on the structure quercetin (193), in which the groups usually substitute at the 3- and 3′- positions, while all of saccharide groups located at C-3 in flavonoid glycosides.

Flavonoids isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
187 (+)-Catechin C15H14O6 290.27 Whole plant Chen et al. (2020)
188 3,8″-Biapigenin C30H18O10 538.46 Whole plant Dong et al. (2015)
189 Kaempferol C15H10O6 286.24 Whole plant Don et al. (2004)
190 Kaempferol-3-O-glucopyranoside C21H20O11 448.38 Whole plant Don et al. (2004)
191 Luteolin C15H10O6 286.24 Aerial part Hong et al. (2004)
192 Naringenin C15H12O5 272.26 Whole plant Chen et al. (2020)
193 Quercetin C15H10O7 302.24 Whole plant Don et al. (2004)
194 Quercetin 3-galactoside (Hyperin, Hyperoside) C21H20O12 464.38 Whole plant Zeng et al. (2002)
195 Quercetin 3-O-glucopyranoside C21H20O12 464.38 Whole plant Don et al. (2004)
196 Quercetin-3-O-arabinoside C20H18O11 434.35 Whole plant Chen et al. (2020)
197 Quercitrin C21H20O11 448.38 Whole plant Chen et al. (2020)
198 Rutin C27H30O16 610.52 Whole plant Chen et al. (2020)
5.5 Naphthodianthrones

Naphthodianthrones, one out of the most biologically active substances in H. sampsonii, are mainly represented by hypericin and pseudohypericin (Supplementary Figure S7; Table 9). Hypericin (199), the active metabolite isolated from the flowers and fruits of H. sampsonii, is considered the characteristic constituent for the identification of this plant (Zeng et al., 2002). Subsequently, pseudohypericin (200) was isolated from the aerial parts of H. sampsonii (Zheng, 2005).

Naphthodianthrones isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
199 Hypericin C30H16O8 504.45 Flower and fruit Zeng et al. (2002)
200 Pseudohypericin C30H16O9 520.45 Aerial part Zheng (2005)
5.6 Anthraquinones

Anthraquinones found in H. sampsonii generally include two types of single anthraquinones and bisanthraquinones. As shown in Supplementary Figure S8, compounds 201–204 are single anthraquinones, while compounds 205–207 are bisanthraquinones. The chemical structures of anthraquinones are listed in Table 10.

Anthraquinones isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
201 1,3,6-Trihydroxy-2-methylanthra-quinone C15H10O5 270.24 Whole plant Yin et al. (2013)
202 3-Ethyl-1,8-dihydroxy-6-methoxyanthracene-9,10-dione C17H14O5 298.29 Whole plant Chen et al. (2020)
203 Emodin C15H10O5 270.24 Whole plant Don et al. (2004)
204 Physcion C16H12O5 284.27 Whole plant Qi et al. (2008)
205 R-(−)-skyrin-6-O-β-D-glucopyranoside C36H28O15 700.61 Whole plant Don et al. (2004)
206 R-(−)-skyrin-6-O-β-D-xylopyranoside C35H26O14 670.58 Whole plant Don et al. (2004)
207 S-(+)-skyrin-6-O-β-D-glucopyranoside C36H28O15 700.59 Whole plant Don et al. (2004)
5.7 Simple aromatic compounds

Simple aromatic compounds in the extracts of H. sampsonii refer to the compounds with a benzene ring, which have simple structure and small relative molecular weight. The main compounds are presented in Supplementary Figure S9; Table 11. Xin WB and his co-works found a rare chemical structure sampsone B (218) in the aerial parts of H. sampsonii (Xin et al., 2011).

Simple aromatic compounds isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
208 3,4-Dihydroxybenzoic acid C7H6O4 154.12 Whole plant Kang et al. (2011)
209 3,4-Dihydroxybenzoic acid ethyl ester C9H10O4 182.18 Whole plant Yin et al. (2013)
210 3,4-Dihydroxycinnamic acid C9H8O4 180.16 Aerial part Hong et al. (2004)
211 5,7-Dihydroxy-3-methylchromone C10H8O4 192.17 Whole plant Chen et al. (2020)
212 Benzoic acid C7H6O2 122.12 Aerial part Guo et al. (2005)
213 Caffeic acid methyl ester C10H10O4 194.19 Whole plant Shi et al. (2016)
214 Ferulic acid C10H10O4 194.19 Whole plant Shi et al. (2016)
215 Gallic acid C7H6O5 170.12 Whole plant Chen et al. (2020)
216 Octadecyl ferulate C28H46O4 446.67 Whole plant Chen et al. (2020)
217 P-hydroxybenzoic acid C7H6O3 138.12 Whole plant Kang et al. (2011)
218 Sampsone B C15H16O6 292.29 Aerial part Xin et al. (2011b)
219 Vanillic acid C8H8O4 168.15 Whole plant Shi et al. (2016)
5.8 Other secondary metabolites

In addition to the aforementioned compounds, other compounds including alkaloids, porphyrins, steroids, pentacyclic triterpenoids and so on have been found in H. sampsonii. Chen Q isolated 6-ethoxy-1H-pyrimidine-2,4-dione (220) from the whole plant of H. sampsonii (Chen et al., 2020). Qi JB and his colleagues found chlorophyll A (221) from the extract of H. sampsonii (Qi et al., 2008). Additionally, Chen Q also discovered β-sitosterol (222) from this plant (Chen et al., 2020). And Guo et al. isolated stigmasteol (223) from the aerial parts of H. sampsonii (Guo et al., 2005). Betulinic acid (224), a pentacyclic triterpenoid compound, was also discovered in this botanical drug (Don et al., 2004). Furthermore, this plant was also demonstrated to contain 2-caffeoyloxy-3-hydroxy-3-(3,4-dihydroxyphenyl) propyl alcohol (225) (Don et al., 2004), octacosanol (226) (Guo et al., 2005), and triacontanoic acid (227) (Guo et al., 2005). The variety and structure of other compounds are displayed in Supplementary Figure S10; Table 12.

Other compounds isolated from H. sampsonii.

No. Compound name Molecular formula Molecular weight Part of the plant Ref
220 6-Ethoxy-1H-pyrimidine-2,4-dione C6H8N2O3 156.14 Whole plant Chen et al. (2020)
221 Chlorophyll A C55H72MgN4O5 893.51 Whole plant Qi et al. (2008)
222 β-Sitosterol C29H50O 414.72 Whole plant Chen et al. (2020)
223 Stigmasterol C29H48O 412.70 Aerial part Guo et al. (2005)
224 Betulinic acid C30H48O3 456.71 Whole plant Don et al. (2004)
225 2-Caffeoyloxy-3-hydroxy-3-(3,4-dihydroxyphenyl) propyl alcohol C18H18O8 362.33 Whole plant Don et al. (2004)
226 Octacosanol C28H58O 410.76 Aerial part Guo et al. (2005)
227 Triacontanoic acid C30H60O2 452.81 Aerial part Guo et al. (2005)
6 Biological activities

Recent studies have revealed that several biological activities including anti-inflammatory, anti-tumor, anti-depressant, antiviral, antimicrobial, and antioxidant activities have been documented for extracts and secondary metabolites of H. sampsonii (Tian, 2015). These pharmacological effects have been summarized in Table 13; Figure 2.

The biological activities of H. sampsonii.

Biological activities Extracts/compounds Models Positive control Results Ref
Anti-inflammatory Extracts Dimethyl benzene-induced acute ear edema and carrageenin-induced paw oedema Aspirin Oedema↓ Pei et al. (2004)
7-Epiclusianone (1) Carrageenin-induced paw edema in rats and LPS-induced peritonitis in mice Indomethacin Paw oedema↓, leukocyte recruitment↓ Santa-Cecilia et al. (2011)
Hyperforatin F (13) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 15.26 μΜ, 13.05 μΜ, and 18.05 μΜ, respectively Chen et al. (2020)
Hypericumone A (21) RAW 264.7 cells Andrographolide IC50 = 40.32 μΜ Huang et al. (2020)
Norhypersampsone A (73) RAW 264.7 cells Quercetin IC50 = 30.2 μM Zhang et al. (2017)
Otogirinin A (79) RAW 264.7 cells Andrographolide IC50 = 32.87 μΜ Huang et al. (2020)
Sampsonione J (99) RAW 264.7 cells Andrographolide IC50 = 35.25 μΜ Huang et al. (2020)
Sampsonol C (110) RAW 264.7 cells Indomethacin IC50 = 27.3 μM Xin et al. (2012)
Sampsonol F (113) RAW 264.7 cells Indomethacin IC50 = 29.3 μM Xin et al. (2012)
(E)-3-(3,7-dimethylocta-2,6-dienyl)2,4,6-trihydroxybenzophenone (121) RAW 264.7 cells Quercetin IC50 = 37.1 μM Zhang et al. (2017)
(Z)-3-(3,7-dimethylocta-2,6-dienyl)2,4,6-trihydroxybenzophenone (122) RAW 264.7 cells Quercetin IC50 = 36.5 μM Zhang et al. (2017)
4-geranyloxy-2,6-dihydroxybenzophenone (133) RAW 264.7 cells Quercetin IC50 = 20.3 μM Zhang et al. (2017)
Garcimangosone D (136) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 14.52 μΜ, 17.23 μΜ, and 19.14 μΜ, respectively Chen et al. (2020)
Petiolin F (139) RAW 264.7 cells Cadamonin IC50 = 2.00 μM Dung Nguyen et al. (2021)
Sampsine A (147) RAW 264.7 cells Cadamonin IC50 = 2.40 μM Dung Nguyen et al. (2021)
Sampsine B (148) RAW 264.7 cells Cadamonin IC50 = 2.29 μM Dung Nguyen et al. (2021)
1-hydroxy-7-methoxy-9H-xanthen-9-one (163) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 24.32 μΜ, 26.03 μΜ, 28.03 μΜ, respectively Chen et al. (2020)
2-methoxyxanthone (168) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 34.15 μΜ, 31.76 μΜ, and 37.64 μΜ, respectively Chen et al. (2020)
5′-Demethoxycadensin G (169) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 27.43 μΜ, 22.32 μΜ, and 37.64 μΜ, respectively Chen et al. (2020)
5-O-methyl-2-deprenyIrheediaxanthone B (171) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 19.96 μΜ, 18.92 μΜ, and 22.03 μΜ, respectively Chen et al. (2020)
Jacareubin (180) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 23.40 μΜ, 20.71 μΜ, and 26.65 μΜ, respectively Chen et al. (2020)
Mangiferin (181) RAW 264.7, THP-1, AGS, NKE, MC3T3-E1, EA.hy926, ATDC5, 3T3-L1, primary mouse chondrocyte, human osteoarthritis chondrocyte, human renal glomerulus endothelial cell, and human oral epithelial cells; C57BL/6 mice, Balb/c mice, ICR mice, Swiss albino mice, Kunming mice, SD rats, and Wistar rats Inhibited the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and COX-2, iNOS, IL-8, IRF5; regulated NF-κB, PI3K/AKT, and MAPK/ERK pathways Mei et al. (2021)
(+)-Catechin (187) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 25.31 μΜ, 26.29 μΜ, and 33.20 μΜ, respectively Chen et al. (2020)
3,8″-Biapigenin (188) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 21.15 μΜ, 19.05 μΜ, and 25.34 μΜ, respectively Chen et al. (2020)
Kaempferol (189) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 24.67 μΜ, 23.50 μΜ, and 29.57 μΜ, respectively Chen et al. (2020)
Naringenin (192) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 29.60 μΜ, 25.51 μΜ, and 31.16 μΜ, respectively Chen et al. (2020)
Quercetin (193) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 14.13 μΜ, 10.59 μΜ, and 15.92 μΜ, respectively Chen et al. (2020)
Hyperoside (194) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 24.84 μΜ, 21.70 μΜ, and 26.87 μΜ, respectively Chen et al. (2020)
Quercetin-3-O-arabinoside (197) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 40.32 μΜ, 31.82 μΜ, and 42.75 μΜ, respectively Chen et al. (2020)
Quercitrin (197) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 36.92 μΜ, 30.66 μΜ, and 38.71 μΜ, respectively Chen et al. (2020)
Rutin (198) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 32.35 μΜ, 27.17 μΜ, and 34.20 μΜ, respectively Chen et al. (2020)
3-ethyl-1,8-dihydroxy-6-methoxyanthracene-9, 10-dione (202) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 16.21 μΜ, 14.11 μΜ, and 17.90 μΜ, respectively Chen et al. (2020)
Emodin (203) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 17.06 μΜ, 12.39 μΜ, and 16.73 μΜ, respectively Chen et al. (2020)
3,4-dihydroxybenzoic acid (208) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 29.03 μΜ, 25.91 μΜ, and 30.25 μΜ, respectively Chen et al. (2020)
5,7-dihydroxy-3-methylchromone (211) BV-2 and RAW 264.7 cells Indomethacin IC50 = 35.24 μΜ and 36.02 μΜ Chen et al. (2020)
Gallic acid (215) BV-2, RAW 264.7, and THP-1 cells Indomethacin IC50 = 35.11 μΜ, 32.68 μΜ, and 38.42 μΜ, respectively Chen et al. (2020)
6-ethoxy-1H-pyrimidine-2,4-dione (220) RAW 264.7 cells Indomethacin IC50 = 41.69 μΜ Chen et al. (2020)
Antinociceptive Extracts Acetic acid writhing test and hot-plate test Morphine Writhing responses↓, pain thresold↑ Pei et al. (2004)
7-Epiclusianone (1) Acetic acid-induced writhing responses in mice, formalin test, hot plate test, and open-field test Indomethacin, morphine Writhing episodes↓, licking time↓, pain↓ Santa-Cecilia et al. (2011)
Hyperforin (14) Mice Inhibited the activity of PKC Galeotti et al. (2010)
Antitumor Hyperforatin F (13) SMMC-7721 cells Cisplatin IC50 = 10.00 μΜ Guo et al. (2017)
Hyperforin (14) CLL, CML, AML, U937 cells and breast cancer cells Induced apoptosis Schiavone et al. (2014)
Hyperisampsin J (32) A549, HL-60, SMMC-7721, MCF-7, and SW480 cell lines IC50 = 0.53 μΜ, 0.56 μΜ, 0.58 μΜ, 0.88 μΜ, 2.49 μΜ, respectively Bridi et al. (2018)
1,6-Dihydroxyxanthone (160) Hela cells IC50 = 33.00 μΜ Wang et al. (2013)
Quercetin (193) U138MG, HeLa, U2-OS/MTX300, CWR22RV1, MDA-MB-453, HT-29, myeloid leukemia, and oral cavity cancer cell lines; CF1 mice, F344 rats, Wister rats, Min/+ mice, SD rats, CD-1 mice, and Swiss mice Inhibited the proliferation of cancer cells; modulated the experimental carcinogenesis Murakami et al. (2008), Dajas (2012)
Rutin (198) MDA-MB-231, HTC, HT29, A549, MCF-7, SW480 cell lines; HPV16 transgenic mice, HR-1 hairless mice Induced the apoptosis in cancerous cells; COX2↓, inflammation↓ Imani et al. (2021)
Hypericin (199) U87 MG, U937, and K562 cells Exhibited significant cytotoxic effects Xu et al. (2015), Misuth et al. (2017)
Antidepressant Hyperforin (14) Forced swimming test in rats Imipramine Reduced the immobility time, inhibited the reuptake of neurotransmitters Nahrstedt and Butterweck (2010), Bridi et al. (2018)
Hyperoside (194) Forced swimming test in rats Imipramine Reduced the immobility time Nahrstedt and Butterweck (2010)
Hypericin (199) Forced swimming test in rats Imipramine Reduced the immobility time Nahrstedt and Butterweck (2010)
Antiviral Hyperisampsin A (23) HIV EC50 = 2.97 μM Bridi et al. (2018)
Hyperisampsin D (26) HIV EC50 = 0.97 μM Bridi et al. (2018)
Hypersampsone A (38) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Lin and Wu (2003)
Hypersampsone B (39) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Lin and Wu (2003)
Hypersampsone C (40) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Lin and Wu (2003)
Hypersampsone D (41) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Lin and Wu (2003)
Hypersampsone E (42) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Lin and Wu (2003)
Hypersampsone F (43) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Lin and Wu (2003)
2,6-Dihydroxy-4-[(E)-5-hydroxy-3,7-dimethylocta-2,7-dienyloxy]-benzophenone (128) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Don et al. (2004)
2,6-Dihydroxy-4-[(E)-7-hydroxy-3,7-dimethylocta-2-enyloxy]-benzophenone (129) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Don et al. (2004)
Hyperxanthone (178) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Don et al. (2004)
Kaempferol (189) H5N1 Anti-H5N1 Yin (2014)
Hypericin (199) HSV, HCV, HIV, MCMV, Sindbis virus, infectious bronchitis virus, and novel duck reovirus Exhibited significant inhibitory activity Barnes et al. (2001), Zhang et al. (2022)
Pseudohypericin (200) HIV and HSV Exhibited significant inhibitory activity Barnes et al. (2001)
R-(−)-skyrin-6-O-β-D-xylopyranoside (206) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Don et al. (2004)
2-caffeoyloxy-3-hydroxy-3-(3,4-dihydroxyphenyl) propyl alcohol (225) HBV-producing cell line (MS-G2) Isolated from the anti-HBV part Don et al. (2004)
Antimicrobial Root extract MDR S. aureus Norfloxacin MIC = 64 μg/mL Xiao et al. (2007)
7-epiclusianone (1) MDR S. aureus Norfloxacin MIC = 4 μg/mL Xiao et al. (2007)
Hyperforin (14) MRSA and PRSA MIC <6 μM; MIC = 0.1–1.0 μg/mL Schiavone et al. (2014), Bridi et al. (2018)
Peroxysampsone A (84) S. aureus Norfloxacin Exhibited Comparable activity with the positive drug Xiao et al. (2010)
Sampsone A (89) MRSA MIC = 32 μg/mL Xin et al. (2011b)
4-geranyloxy-2,6-dihydroxybenzophenone (133) Klebsiella pneumoniae, Mycobacterium smegmatis, Pseudomonas aeruginosa, Salmonella gallinarum, and S. aureus Exhibited inhibitory activity Pecchio et al. (2006)
Hypericumxanthone A (174) MRSA MIC = 16 μg/mL Xin et al. (2011b)
Hypericumxanthone B (175) MRSA MIC = 32 μg/mL Xin et al. (2011a)
Quercetin (193) S. aureus, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilu, Streptococcus sanguis, Actinobacillus actinomycetemocomitans, and Prevotella intermedia Exhibited inhibitory activity Nguyen and Bhattacharya (2022)
Hypericin (199) S. aureus Stopped the growth of S. aureus when incubated with 40 μM combined with visible light Wölfle et al. (2014)
Antioxidant Ethyl acetate extract BALB/c mice 5-ASA Regulated the levels of CAT, GSH, MDA, and SOD Lin et al. (2022)
Hyperforin (14) HaCaT cell line Trolox and Nacetylcysteine EC50 = 0.42 μg/mL, higher than Trolox (12 μg/mL) and Nacetylcysteine (847 μg/mL) Wölfle et al. (2014)
Mangiferin (181) DPPH assay IC50 = 35.48 μM Dung Nguyen et al. (2021)
Kaempferol (189) DPPH assay Showed 66% scavenging activity at the concentration of 75 μM Deng et al. (2019)
Quercetin (193) DPPH assay Inhibition of MAO Stojanović et al. (2013)
Rutin (198) SH-SY5Y cell line Increased the production of SOD, CAT and GSH Enogieru et al. (2021)
Hypericin (199) MCF-7 cell line Increased the production of SOD-2 combined with photodynamic therapy Kimáková et al. (2017)
Lipid-lowering Hypersampone A (114) HepG2 cell line Rosiglitazone Inhibited the expression of FAS and ACACA at 5 μM Huang et al. (2022)

Graphical summary of the compounds and pharmacological activities of H. sampsonii.

 6.1 Anti-inflammatory activity

In vitro studies have suggested that extracts of H. sampsonii showed anti-inflammatory activity in lipopolysaccharide (LPS)-treated BV-2, RAW 264.7, and THP-1 cells (Chen et al., 2020). On the other hand, in vivo studies have demonstrated that the alcohol extracts of H. sampsonii had antinociceptive and anti-inflammatory properties. The antinociceptive potential carried out using acetic acid-induced writhing responses in mice and hot-plate test suggested that extracts of H. sampsonii effectively suppressed the writhing symptom and increased the pain threshold of mice. Also, the anti-inflammatory effect was investigated using dimethyl benzene-induced acute ear edema and carrageenin-induced paw edema in rats. Besides, the anti-inflammatory activity have been demonstrated by the reduction of acute ear edema induced by dimethyl benzene and carrageenin-induced paw oedema (Pei et al., 2004). A study of our group to investigate the therapeutic effects and molecular mechanisms of H. sampsonii (HS) in a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model (Lin et al., 2022). These results indicate that HS distinctly alleviated DSS-stimulated UC-like lesions symptoms as evidenced by a significant recovery from body weight, colon lengths, and histological injuries of colons. HS reduced the accumulation of pro-inflammatory cytokines and improved the mRNA level of IL-10. Simultaneously, the colonic mRNA expression levels of IL- 1β, IL-17, iNOS and COX-2 were all significantly suppressed by HS in a dose-dependent manner. Furthermore, HS restored the protein expression of tight junction-associated protein (ZO-1 and occluding). Further studies have also reported that HS can significantly inhibit the protein level of PDE4 and reduced the expressions of PKA and phosphorylated CREB.

Experimental evidence has emerged to indicate that PPAPs are one of the major constituents required for anti-inflammatory effects. Since, it has been reported that a series of compounds isolated from H. sampsonii, including hyperattenin C (3), otogirinin D (12), hyperisampsin I (15), hyperisampsin J (16), sampsonione L (28), hyperattenin G (38), hypersampsone O (63), hypersampsonone A (68), sampsonione A (85), and sampsonione B (86), were found to have significant PDE4D2 inhibitory activity (Zhang et al., 2016). PDE4D2 is one of the subtypes of phosphodiesterase-4 (PDE4), which can specifically hydrolyze cAMP and participate in various physiological responses, and is a promising drug target for inflammatory diseases such as psoriasis and ulcerative colitis. Moreover, the antinociceptive and anti-inflammatory properties have been reported for 7-epiclusianone (1) using animal models (Santa-Cecilia et al., 2011). In addition to PPAPs, other compounds such as benzophenone, xanthones, flavonoids, anthraquinones, and phenols, are also stated to possess anti-inflammatory properties (Chen et al., 2020).

Besides, benzophenone derivatives have also been shown to be important in the anti-inflammatory effects of H. sampsonii. Recently, our group investigated the therapeutic effect and potential mechanisms of 4-geranyloxy-2,6-dihydroxybenzophenonel (4-GDB, 133) on DSS-induced ulcerative colitis in mice (Wang et al., 2023). This study showed that intragastric administration of 4-GDB (20 mg/kg/day) for 8 days significantly attenuated colonic injury, reduced the expression of inflammatory mediators, and improved colonic barrier function in mice with colitis. Furthermore, in vivo and in vitro experiments indicated that 4-GDB could activate cAMP/PKA/CREB and inhibit the NF-κB pathway. Collectively, 4-GDB may be a potential agent for treating UC by regulating the cAMP/PKA/CREB and NF-κB pathways.

 6.2 Antitumor activity

The antitumor activity of H. sampsonii has been evaluated in various cancer cell lines in vitro including A375, MDA-MB-231, SHSY-5Y, and SiHa cell lines (Chen et al., 2020). Studies have suggested that regulation of subcellular localization of retinoid X receptor-alpha (RXR-α) is a potential method to induce tumor cell apoptosis. Zeng et al. have found that H. sampsonii extracts can induce the translocation of RXR-α from the nucleus to the cytoplasm, and promote the apoptosis of NIH-H460, MGC-803, and SMMC-7721 (Jin-Zhang et al., 2006). Besides, the ethanol extract and the chloroform fraction especially were demonstrated for apoptosis-inducing and antitumor properties via inhibiting RXR-α transcription (Han et al., 2007).

Moreover, the antitumor effect has also been documented for a panel of natural products in H. sampsonii, such as 7-epiclusianone (1) (Sales et al., 2015), sampsonione A (85) (Hu and Sim, 1999a), sampsonione I (93) (Hu and Sim, 1999a), mangiferin (181) (Mei et al., 2021), naringenin (192) (Memariani et al., 2021), quercetin (193) (Murakami et al., 2008; Dajas, 2012) and rutin (198) (Imani et al., 2021).

 6.3 Antidepressant activity

Depression is a common mental disorder characterized by syndromes like depressed mood, hopelessness, and even thoughts of suicide. Clinical studies have demonstrated that H. perforatum L. (St. John’s Wort), a member of the Hypericum genus, has significant antidepressant impacts. The extract of this plant was introduced into the market as an antidepressant in Germany in 1988, and became the preferred phytomedicine for the treatment of depressive disorder in European and American regions. Intriguingly, previously reported studies have also isloated an antidepressant active metabolite hyperforin rom H. perforatum and its also present in H. sampsonii (Zheng et al., 2003).

In 2003, the ethanol extracts of H. sampsonii were demonstrated for a significant antidepressant effect on the behavior despair animal models (Wan et al., 2003). It was believed that the total flavonoids of H. sampsonii showed antidepressant activity in the hypothermia experiments induced by reserpine and the forced swimming test. In studies utilizing the forced swimming test, tail suspension test, and open-field test, H. sampsonii extracts, HTX fraction, and mangiferin (181) induced a significant reduction in immobility, and the antidepressant mechanism of HTX might be related to neurotransmitters (Gong, 2014). The antidepressant properties of H. sampsonii have been attributed to various phytochemical constituents, such as hyperforin (6), hyperoside (194), and hypericin (199) (Nahrstedt and Butterweck, 2010; Bridi et al., 2018). However, the precise mechanism of action for the antidepressant capacity of this plant remains indistinct.

 6.4 Antiviral activity

Previous studies have suggested that the extracts and several compounds of H. sampsonii have antiviral activity. For instance, the chloroform and n-butyl alcohol fractions as well as kaempferol (189) were shown to possess antiviral activity against avian influenza virus H5N1 in the Madin Darby Canine Kidney (MDCK) screening experiment (Yin, 2014). Besides, Lin and Wu found that hypersampsone A-F (52–56, 9) isolated from H. sampsonii exhibited anti-HBV activity on the MS-G2 cell line (Lin and Wu, 2003). In addition, the antiviral activity has been reported for hypericin (199) and pseudohypericin (200) against herpes simplex virus types 1 and 2 and HIV-1 in vitro. Hypericin (199) has also exhibited activity against HCV, murine cytomegalovirus (MCMV), Sindbis virus, infectious bronchitis virus, and novel duck reovirus (Barnes et al., 2001; Zhang et al., 2022).

 6.5 Antimicrobial activity

Plants belonging to the Hypericum genus are a crucial source of antimicrobial compounds (Marrelli et al., 2016). Previous evidence indicated that the antibacterial activity has been demonstrated for hyperforin (6) and quercetin (193) against Staphylococcus aureus, Streptococcus mutans, Streptococcus pyogenes, and Corynebacterium diphtheria, etc (Barnes et al., 2001; Nguyen and Bhattacharya, 2022). In studies using MDR S. aureus strain SA-1199B to determine the antibacterial effect of H. sampsonii, the MIC of the petroleum ether extract of the root was up to 64 μg/mL (Xiao et al., 2007). Moreover, 7-epiclusianone (1) induced potent antibacterial activity against SA-1199B with a MIC of 4 μg/mL, while MIC of the positive control (norfloxacin) was 32 μg/mL (Xiao et al., 2007). In other antibacterial experiments, some PPAPs including sampsone A (107) and hypericumxanthone A (174) were shown to exhibit good antibacterial activity on Methicillin-resistant S. aureus (MRSA), with MIC values of 32 μg/mL and 16 μg/mL respectively (Xin et al., 2011).

 6.6 Antioxidant activity

Reactive oxygen species (ROS), the important substances released from neutrophils, play a part in cell signaling and homeostasis. It is, however, important to note, that the overproduction of ROS can initiate the inflammatory cascade and subsequent cell damage as well as tissue dysfunction under oxidative stress (Chen et al., 2009). Research revealed that H. sampsonii showed antioxidant capacity by regulating the content of oxidase (GSH and SOD) (Chen et al., 2009). It has also been reported that the ethyl acetate extract of H. sampsonii could alleviate oxidative stress as indicated by reversing the abnormal levels of CAT, GSH, MDA, and SOD in mice with colitis (Lin et al., 2022). Additionally, the antioxidant activity of mangiferin (181) from H. sampsonii was assessed by means of the DPPH radical scavenging assay with an IC50 value of 35.48 μM (Dung Nguyen et al., 2021).

 7 Safety

Many ancient classics and medicinal books have recorded that the clinical administration dosage of H. sampsonii should be 9–15 g for dried herb or 30–60 g for fresh herb. To further determine the safety of therapeutic doses of H. sampsonii, a previous study by Lin et al. (2022), fed mice with the ethyl acetate extract at a dose of 2000 mg/kg. After 14 days of observation, there was no morphological abnormality in major organs, indicating that the ethyl acetate extract of H. sampsonii showed no toxicity. Although the toxicity studies and the wide range of edible and medicinal values of H. sampsonii may provide a preliminary reference for its high safety in clinical application; however, the potential toxicity cannot be completely excluded.

According to the Chinese Materia Medica, morphological and microscopic examinations as well as physicochemical identification should be used to control the quality of H. sampsonii. Meanwhile, for its medicinal application, it is should also contain hypericin (199) and flavonoids (Editorial Board of Chinese Materia Medica, 1999). Yet, thin-layer chromatography (TLC) identification and content determination as well as other analytical methods have not been employed to control the quality of this plant, indicating a lack of quality standard despite its extensive folk utilization. Besides, there is no indication of potential safety issues. Therefore, further research work is essentially required to meet these standards.

 8 Conclusion and perspectives

As a common botanical drug for the treatment of dysentery, enteritis, and irregular menstruation in folk, H. sampsonii is safe and effective. It is a versatile plant with a complexity of phytochemicals and remarkable pharmacological actions. In this paper, we reviewed the botany, traditional uses, phytochemistry, pharmacological activities, and safety of this species for the first time. It was found that more than 220 chemicals have been isolated and identified from this plant, including PPAPs, benzophenones, xanthones, flavonoids, naphthodianthrones, anthraquinones, and aromatic compounds, among others. Among the identified compounds, PPAPs are the most abundant compounds with novel structures as well as up-and-coming biological characteristics, such as PDE4 inhibitory activity. Although, accumulating studies have shown the progress in the understanding of its anti-inflammatory, anti-tumor, antidepressant, antiviral, antibacterial, and antioxidant properties. However, further studies should focused on the isolation of new compounds and biological screening tests in vitro from H. sampsonii. Yet, it is also important to mention that empirical pharmacologic studies are insufficient to validate the claimed healing properties.

It is noteworthy that H. perforatum L., the most familiar species of the Hypericum genus, has been extensively investigated due to its medicinal values and was listed in the Chinese Pharmacopoeia in 2015. Nevertheless, H. sampsonii has not yet been listed in the Chinese Pharmacopoeia, which potentially prevents in-depth research to a large extent. Taken together, the current pharmacological research on H. sampsonii remains in infancy, and other aspects such as safety evaluation and quality control standards are scanty. This review provided a systematic overview of this plant based on the available research while not comprehensive. Therefore, further studies including pharmacological mechanisms in vitro and in vivo, structure-activity relationship appraisal, safety evaluation, and quality standards should be done. More emerging studies may reveal the scientific connotation of the traditional application and lay the foundation for the development and utilization of H. sampsonii.

 Author contributions

ZS: methodology, writing—original draft, writing—review and editing, funding acquisition, supervision. YL and RL: data curation. RZ: conceptualization, writing—original draft, funding acquisition. All authors contributed to the article and approved the submitted version.

 Funding

This work was supported by the Science and Technology Program of Guangdong Province of China (2022B1212010014) and the Guangdong Province’s Projects of High-Level University Construction Funds (No. A1-2601-21-414-001Z06).

 Conflict of interest

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

 Publisher’s note

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

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1247675/full#supplementary-material

Abbreviations

CNKI, China National Knowledge Infrastructure; IC50, 50% Inhibitory concentration; uM, Micromolar; Pre, isoprenyl; Ger, geranyl; Bz, benzoyl.

 References Anand U. Jacobo-Herrera N. Altemimi A. Lakhssassi N. (2019). A comprehensive review on medicinal plants as antimicrobial therapeutics: Potential avenues of biocompatible drug discovery. Metabolites 9, 258. 10.3390/metabo9110258 Barnes J. Anderson L. A. Phillipson J. D. (2001). St john's wort (Hypericum perforatum L.): A review of its chemistry, pharmacology and clinical properties. J. Pharm. Pharmacol. 53, 583–600. 10.1211/0022357011775910 Bridi H. Meirelles G. d. C. von Poser G. L. (2018). Structural diversity and biological activities of phloroglucinol derivatives from Hypericum species. Phytochemistry 155, 203–232. 10.1016/j.phytochem.2018.08.002 Chen C. L. Huang C. H. Sung J. M. (2009). Antioxidants in aerial parts of Hypericum sampsonii, Hypericum japonicum and Hypericum perforatum . Int. J. Food Sci. Technol. 44, 2249–2255. 10.1111/j.1365-2621.2009.02066.x Chen D. F. (2020). The clinical efficacy observation of huayu changshen decoction in theTreatment of generalized anxiety disorder for liver-qi stagnation type. Fuzhou, China: Fujian University of Traditional Chinese Medicine. Chen J. J. Chen H. J. Lin Y. L. (2014). Novel polyprenylated phloroglucinols from Hypericum sampsonii . Molecules 19, 19836–19844. 10.3390/molecules191219836 Chen M. T. Chen C. M. (1985). Xanthones from Hypericum sampsonii. Heterocycles 23, 2543–2548. 10.3987/r-1985-10-2543 Chen Q. Di L. Zhang Y. Li N. (2020). Chemical constituents with cytotoxic and anti-inflammatory activity in Hypericum sampsonii and the antitumor potential under the view of cancer-related inflammation. J. Ethnopharmacol. 259, 112948. 10.1016/j.jep.2020.112948 Choudhari A. S. Mandave P. C. Deshpande M. Ranjekar P. Prakash O. (2020). Phytochemicals in cancer treatment: From preclinical studies to clinical practice. Front. Pharmacol. 10, 1614. 10.3389/fphar.2019.01614 Committee (2007). “Flora of China,” in Alangiaceae through violaceae (Beijing: Science Press). Cragg G. M. Pezzuto J. M. (2016). Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med. Princ. Pract. 25, 41–59. 10.1159/000443404 Dajas F. (2012). Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol. 143, 383–396. 10.1016/j.jep.2012.07.005 Deng S. P. Yang Y. L. Cheng X. X. Li W. R. Cai J. Y. (2019). Synthesis, spectroscopic study and radical scavenging activity of kaempferol derivatives: Enhanced water solubility and antioxidant activity. Int. J. Mol. Sci. 20, 975. 10.3390/ijms20040975 Don M. J. Huang Y. J. Huang R. L. Lin Y. L. (2004). New phenolic principles from Hypericum sampsonii . Chem. Pharm. Bull. 52, 866–869. 10.1248/cpb.52.866 Dong H. X. Xia C. Liu Y. Fan M. Wu T. Shi J. C. (2015). Study on chemical constituents in Hypericum sampsonii . J. Plant Resour. Environ. 24, 110–112. Dung Nguyen V. Vinh Le B. Thuan Nguyen D. Van Anh Pham T. Han Tran T. Viet Cuong Le C. (2021). Bioactive compounds from the aerial parts of Hypericum sampsonii . Nat. Prod. Res. 35, 646–648. 10.1080/14786419.2019.1586690 Editorial Board of Chinese Materia Medica (1999). Chinese Materia Medica. Shanghai: Science and Technology Publishing House. Editorial Committee of Flora of China (1990). Flora of China. Beijing: Science Press. Enogieru A. B. Haylett W. Hiss D. Ekpo O. (2021). Inhibition of γH2AX, COX-2 and regulation of antioxidant enzymes in MPP+-exposed SH-SY5Y cells pre-treated with rutin. Metab. Brain. Dis. 36, 2119–2130. 10.1007/s11011-021-00746-z Galeotti N. Vivoli E. Bilia A. R. Bergonzi M. C. Bartolini A. Ghelardini C. (2010). A prolonged protein kinase C-mediated, opioid-related antinociceptive effect of st john's wort in mice. J. Pain 11, 149–159. 10.1016/j.jpain.2009.06.013 Gong Y. Z. (2014). Study of antidepressive effect of HTX from Hypericum sampsonii hance. Fuzhou, China: Fujian University of Traditional Chinese Medicine. Guo C. Zheng Q. M. Zheng H. C. (2005). Study of the chemical constituents of Hypericum sampsonii . Pharm. Care Res. 5, 341–344. Guo C. Zheng Q. M. Zheng H. C. (2007). Study on xanthones from Hypericum samponii hance. Chin. Pharm. J., 418–419+436. Guo Y. Zhang N. Chen C. M. Huang J. F. Li X. N. Liu J. J. (2017). Tricyclic polyprenylated acylphloroglucinols from st john's wort, Hypericum perforatum . J. Nat. Prod. 80, 1493–1504. 10.1021/acs.jnatprod.6b01178 Han C. L. Sun D. F. Wu D. J. Guo Y. Q. Wang L. Qi J. B. (2007). Hypericum sampsonii exerts its apoptotic activity on lung cancer cells through binding and inducing RXRa translocation. Med. J. Chin. People's Armed Police Forces, 729–732. Hong D. Yin F. Hu L. H. Lu P. (2004). Sulfonated xanthones from Hypericum sampsonii . Phytochemistry 65, 2595–2598. 10.1016/j.phytochem.2004.08.014 Hong L. Guo Z. Huang K. Wei S. Liu B. Meng S. (2015a). Ethnobotanical study on medicinal plants used by Maonan people in China. J. Ethnobiol. Ethnomed. 11, 32. 10.1186/s13002-015-0019-1 Hong L. Zhuo J. Lei Q. Zhou J. Ahmed S. Wang C. (2015b). Ethnobotany of wild plants used for starting fermented beverages in Shui communities of southwest China. J. Ethnobiol. Ethnomed. 11, 42. 10.1186/s13002-015-0028-0 Hu L. H. Sim K. Y. (1998). Complex caged polyisoprenylated benzophenone derivatives, sampsoniones A and B, from Hypericum sampsonii . Tetrahedron Lett. 39, 7999–8002. 10.1016/s0040-4039(98)01741-9 Hu L. H. Sim K. Y. (1999a). Cytotoxic polyprenylated benzoylphloroglucinol derivatives with an unusual adamantyl skeleton from Hypericum sampsonii (Guttiferae). Org. Lett. 1, 879–882. 10.1021/ol9907825 Hu L. H. Sim K. Y. (2000). Sampsoniones A-M, a unique family of caged polyprenylated benzoylphloroglucinol derivatives, from Hypericum sampsonii . Tetrahedron 56, 1379–1386. 10.1016/s0040-4020(00)00010-7 Hu L. H. Sim K. Y. (1999b). Sampsoniones C-H, a unique family of polyprenylated benzophenone derivatives with the novel tetracyclo 7.3.1.1(3,11).0(3,7) tetradecane-2,12,14-trione skeleton, from Hypericum sampsonii (Guttiferae). Tetrahedron Lett. 40, 759–762. 10.1016/s0040-4039(98)02366-1 Hu R. Lin C. Xu W. Liu Y. Long C. (2020). Ethnobotanical study on medicinal plants used by Mulam people in Guangxi, China. J. Ethnobiol. Ethnomed. 16, 40. 10.1186/s13002-020-00387-z Huang C. Y. Chang T. C. Wu Y. J. Chen Y. Chen J. J. (2020). Benzophenone and benzoylphloroglucinol derivatives from Hypericum sampsonii with anti-inflammatory mechanism of otogirinin A. Molecules 25, 4463. 10.3390/molecules25194463 Huang L. Zhang Z.-Z. Li Y.-N. Yi P. Gu W. Yang J. (2022). Hypersampones A-C, three nor-polycyclic polyprenylated acylphloroglucinols with lipid-lowering activity from Hypericum sampsonii. Org. Lett. 24, 5967–5971. 10.1021/acs.orglett.2c02240 Imani A. Maleki N. Bohlouli S. Kouhsoltani M. Sharifi S. Dizaj S. M. (2021). Molecular mechanisms of anticancer effect of rutin. Phytother. Res. 35, 2500–2513. 10.1002/ptr.6977 Jin B. Liu Y. Xie J. Luo B. Long C. (2018). Ethnobotanical survey of plant species for herbal tea in a Yao autonomous county (jianghua, China): Results of a 2-year study of traditional medicinal markets on the dragon boat festival. J. Ethnobiol. Ethnomed. 14, 58. 10.1186/s13002-018-0257-0 Jin-Zhang Z. De-Fu S. Li W. Xihua C. Jian-Bin Q. Ting Y. (2006). Hypericum sampsonii induces apoptosis and nuclear export of retinoid X receptor-alpha. Carcinogenesis 27, 1991–2000. 10.1093/carcin/bgl046 Kang J. M. Ouyang S. Xiao B. K. Yang J. Y. Huang R. Q. (2011). Isolation and identification of the chemical constituents from the Hypericum sampsonii hance. Lishizhen Med. Mat. Med. Res. 22, 2641–2642. Kimáková P. Solár P. Fecková B. Sačková V. Solárová Z. Ilkovičová L. (2017). Photoactivated hypericin increases the expression of SOD-2 and makes MCF-7 cells resistant to photodynamic therapy. Biomed. Pharmacother. 85, 749–755. 10.1016/j.biopha.2016.11.093 Kitanov G. M. Nedialkov P. T. (2001). Benzophenone O-glucoside, a biogenic precursor of 1,3,7-trioxygenated xanthones in Hypericum annulatum. Phytochemistry 57, 1237–1243. 10.1016/s0031-9422(01)00194-7 Li S. G. Dai Y. L. Li C. R. Xu S. Z. (2019). Gu Shang Zhong Cao Yao Shi Yong Tu Ce. Fuzhou, China: Fujian Science and Technology Publishing House. Li Z. Q. Luo L. Ma G. Y. Huang R. Hu Z. H. (2004). Sampsoniones and xanthones of Hypericum sampsonii from yunnan province. Chin. Tradit. Herb. Drugs 35, 17–20. Lin Q. F. (2018). The clinical efficacy observation of wangyou ningshen decoction to patients with generalized anxiety Disorder. Fuzhou, China: Fujian University of Traditional Chinese Medicine. Lin Y. L. Wu Y. S. (2003). Polyprenylated phloroglucinol derivatives from Hypericum sampsonii . Helv. Chim. Acta 86, 2156–2163. 10.1002/hlca.200390173 Lin Y. Su J. Wang M. Li Y. Zhao Z. Sun Z. (2022). Hypericumsampsonii attenuates inflammation in mice with ulcerative colitis via regulation of PDE4/PKA/CREB signaling pathway. J. Ethnopharmacol. 296, 115447. 10.1016/j.jep.2022.115447 Marrelli M. Statti G. Conforti F. Menichini F. (2016). New potential pharmaceutical applications of Hypericum species. Mini-Rev. Med. Chem. 16, 710–720. 10.2174/1389557515666150709105844 Mei S. H. Ma H. L. Chen X. M. (2021). Anticancer and anti-inflammatory properties of mangiferin: A review of its molecular mechanisms. Food Chem. Toxicol. 149, 111997. 10.1016/j.fct.2021.111997 Memariani Z. Abbas S. Q. Ul Hassan S. S. Ahmadi A. Chabra A. (2021). Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review. Pharmacol. Res. 171, 105264. 10.1016/j.phrs.2020.105264 Misuth M. Horvath D. Miskovsky P. Huntosova V. (2017). Synergism between PKC delta regulators hypericin and rottlerin enhances apoptosis in U87 MG glioma cells after light stimulation. Photodiagn. Photodyn. Ther. 18, 267–274. 10.1016/j.pdpdt.2017.03.018 Murakami A. Ashida H. Terao J. (2008). Multitargeted cancer prevention by quercetin. Cancer Lett. 269, 315–325. 10.1016/j.canlet.2008.03.046 Nahrstedt A. Butterweck V. (2010). Lessons learned from herbal medicinal products: The example of st. John's wort (perpendicular). J. Nat. Prod. 73, 1015–1021. 10.1021/np1000329 Nguyen T. L. A. Bhattacharya D. (2022). Antimicrobial activity of quercetin: An approach to its mechanistic principle. Molecules 27, 2494. 10.3390/molecules27082494 Pecchio M. Solis P. N. Lopez-Perez J. L. Vasquez Y. Rodriguez N. Olmedo D. (2006). Cytotoxic and antimicrobial benzophenones from the leaves of Tovomita longifolia. J. Nat. Prod. 69, 410–413. 10.1021/np050338c Pei J. Yang L. Huang L. F. Wang G. Z. (2004). “Experimental study on antinociceptive and anti-inflammatory effects of three species of sect. Hypericum medicinal plants,” in The fourth national symposium on medicinal botany and botanical medicine (Nanjing, China: China Academic Journal Electronic Publishing House), 201–204. Qi J. B. Wang L. Chen C. Zeng J. Z. Hu C. Q. (2008). Anti-tumor components targeting to RXRα from Hypericum sampsonii . Nat. Prod. Res. Dev., 129–130+169. Qiu Y. Q. Tian W. J. Li C. Dai Y. Yao X. S. (2015). Two new compounds from Hypericum sampsonii . Chin. Tradit. Herb. Drugs 46, 625–628. Sales L. Pezuk J. A. Borges K. S. Brassesco M. S. Scrideli C. A. Tone L. G. (2015). Anticancer activity of 7-epiclusianone, a benzophenone from Garcinia brasiliensis, in glioblastoma. BMC Complement. Altern. Med. 15, 393. 10.1186/s12906-015-0911-1 Santa-Cecilia F. V. Freitas L. A. S. Vilela F. C. Veloso C. D. da Rocha C. Q. Moreira M. E. C. (2011). Antinociceptive and anti-inflammatory properties of 7-epiclusianone, a prenylated benzophenone from Garcinia brasiliensis. Eur. J. Pharmacol. 670, 280–285. 10.1016/j.ejphar.2011.08.032 Schiavone B. I. P. Verotta L. Rosato A. Marilena M. Gibbons S. Bombardelli E. (2014). Anticancer and antibacterial activity of hyperforin and its derivatives. Anti-Cancer Agents Med. Chem. 14, 1397–1401. 10.2174/1871520614999140829122803 Shi L. L. Xu M. P. Tan H. B. Qiu S. X. (2016). Chemical constituents from Hypericum sampsonii . J. Shanxi Univ. 39, 264–268. Stojanovic G. Dordevic A. Smelcerovic A. (2013). Do other Hypericum species have medical potential as st. John's wort (Hypericum perforatum)? Curr. Med. Chem. 20, 2273–2295. 10.2174/0929867311320180001 Stojanović G. Ðorđević A. Šmelcerović A. (2013). Do other Hypericum species have medical potential as St. John's wort (Hypericum perforatum)? Curr. Med. Chem. 20, 2273–2295. 10.2174/0929867311320180001 Tian W. J. Qiu Y. Q. Chen H. F. Jin X. J. Yao X. J. Dai Y. (2017a). Chiral separation and absolute configurations of two pairs of racemic polyprenylated benzophenones from Hypericum sampsonii . Fitoterapia 116, 39–44. 10.1016/j.fitote.2016.10.014 Tian W. J. Qiu Y. Q. Chen J. J. Yao X. J. Wang G. H. Dai Y. (2017b). Norsampsone E, an unprecedented decarbonyl polycyclic polyprenylated acylphloroglucinol with a homoadamantyl core from Hypericum sampsonii. RSC Adv. 7, 33113–33119. 10.1039/c7ra05947g Tian W. J. Qiu Y. Q. Jin X. J. Chen H. F. Yao X. J. Dai Y. (2016). Hypersampsones S-W, new polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii. RSC Adv. 6, 50887–50894. 10.1039/c5ra26332h Tian W. J. Qiu Y. Q. Jin X. J. Chen H. F. Yao X. J. Dai Y. (2014a). Novel polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii. Tetrahedron 70, 7912–7916. 10.1016/j.tet.2014.08.062 Tian W. J. Qiu Y. Q. Yao X. J. Chen H. F. Dai Y. Zhang X. K. (2014b). Dioxasampsones A and B, two polycyclic polyprenylated acylphloroglucinols with unusual epoxy-ring-fused skeleton from Hypericum sampsonii. Org. Lett. 16, 6346–6349. 10.1021/ol503122m Tian W. J. (2015). Study on the chemical constituents of the aerial parts of Hypericum sampsonii . Shenyang, China: Shenyang Pharmaceutical University. Tian W. J. Yu Y. Yao X. J. Chen H. F. Dai Y. Zhang X. K. (2014c). Norsampsones A-D, four new decarbonyl polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii. Org. Lett. 16, 3448–3451. 10.1021/ol501333k Vincent O. M. Nguta J. M. Mitema E. S. Musila F. M. Nyak D. M. Mohammed A. H. (2021). Ethnopharmacology, pharmacological activities, and chemistry of the Hypericum genus. J. Phytopharm. 10, 105–113. 10.31254/phyto.2021.10206 Wan D. Pei J. Zhou M. Wang G. (2003). Antidepressant effect of ethanol extracts from three species of sect. Hypericum medicinal plants in mice. J. Chin. Med. Mat. 26, 187–189. Wang H. F. Wei L. Q. Yan H. Gao X. H. Xu B. S. Tang N. (2013). Antitumor activity and DNA-binding investigations of isoeuxanthone and its piperidinyl derivative. Chem. Pharm. Bull. 61, 599–603. 10.1248/cpb.c12-00500 Wang M. Q. Li Y. Z. Su J. H. Bai J. Y. Zhao Z. X. Sun Z. H. (2023). Protective effects of 4-geranyloxy-2,6-dihydroxybenzophenonel on DSS-induced ulcerative colitis in mice via regulation of cAMP/PKA/CREB and NF-kappa B signaling pathways. Phytotherapy Res. 37, 1330–1345. 10.1002/ptr.7689 Wölfle U. Seelinger G. Schempp C. M. (2014). Topical application of St. John's wort (Hypericum perforatum). Planta Med. 80, 109–120. 10.1055/s-0033-1351019 Wu Q. J. (1963). An illustrated book on plants. Beijing: Zhonghua Book Company. Wu Y. L. (1957). Bencao congxin. Shanghai: Shanghai Medical Publishing House. Wu Z. Y. (1991). Xinhua bencao gangyao. Shanghai: Shanghai Scientific & Technical Publishers. Xiang S. Zhang L. Zou K. (2018). A kind of maonan formula for treating acute icteric hepatitis and preparation method thereof. Peop. Rep. China. Xiao Z. Y. Mu Q. (2007). Advance on chemical investigation of Hypericum. Nat. Prod. Res. Dev., 344–355. Xiao Z. Y. Mu Q. Shiu W. K. P. Zeng Y. H. Gibbons S. (2007). Polyisoprenylated benzoylphloroglucinol derivatives from Hypericum sampsonii. J. Nat. Prod. 70, 1779–1782. 10.1021/np0704147 Xiao Z. Y. Shiu W. K. P. Zeng Y. H. Mu Q. Gibbons S. (2008). A naturally occurring inhibitory agent from Hypericum sampsonii with activity against multidrug-resistant staphylococcus aureus. Pharm. Biol. 46, 250–253. 10.1080/13880200701739405 Xiao Z. Y. Zeng Y. H. Mu Q. Shiu W. K. P. Gibbons S. (2010). Prenylated benzophenone peroxide derivatives from Hypericum sampsonii. Chem. Biodivers. 7, 953–958. 10.1002/cbdv.200900247 Xie M. J. Guo Y. X. Li F. C. Chen H. Y. Lai X. H. Sui J. N. (2021). Research progress on chemical components and pharmacological effects of Hypericum sampsonii and analysis and prediction of its quality markers. Acta Chin. Med. Pharmacol. 49, 40–44. Xie Z. W. (2014). Quan guo Zhong Cao Yao hui bian. Beijing: People's Medical Publishing House. Xin W.-b. Man X.-h. Zheng C.-j. Jia M. Jiang Y.-p. Zhao X.-x. (2012). Prenylated phloroglucinol derivatives from Hypericum sampsonii . Fitoterapia 83, 1540–1547. 10.1016/j.fitote.2012.08.022 Xin W.-B. Mao Z.-J. Jin G.-L. Qin L.-P. (2011a). Two new xanthones from Hypericum sampsonii and biological activity of the isolated compounds. Phytother. Res. 25, 536–539. 10.1002/ptr.3291 Xin W. B. Jin G. L. Mao Z. J. Qin L. P. (2011b). Two unusual phenolic substances and one new xanthone from Hypericum sampsonii. Helv. Chim. Acta 94, 686–692. 10.1002/hlca.201000281 Xu C. (2016). A traditional Chinese medicine preparation for treating infantile convulsion and its preparation method. Peop. Rep. China. Xu Y. X. Wang D. X. Zhuang Z. Z. Jin K. K. Zheng L. Z. Yang Q. (2015). Hypericin-mediated photodynamic therapy induces apoptosis in K562 human leukemia cells through JNK pathway modulation. Mol. Med. Rep. 12, 6475–6482. 10.3892/mmr.2015.4258 Yang X.-W. Grossman R. B. Xu G. (2018). Research progress of polycyclic polyprenylated acylphloroglucinols. Chem. Rev. 118, 3508–3558. 10.1021/acs.chemrev.7b00551 Yin H. J. Li B. Zhou Q. Dong J. X. (2013). A new benzophenone derivatives from Hypericum sampsonii . Nat. Prod. Res. Dev. 25, 875–877. Yin H. J. (2014). Study on the anti-H5N1 constituents of Hypericum sampsonii . Hefei: Anhui Medical University. Yu Y. P. Diamandis E. P. (1995). Prostate-specific antigen in milk of lactating women. Fujian J. TCM 26, 54–58. 10.1093/clinchem/41.1.54 Zeng H. Y. Zhou P. H. Gang P. (2002). Studies on chemical constituents of Hypericum sampsonii . Nat. Prod. Res. Dev. 14, 50–53. Zeng Y.-H. Osman K. Xiao Z.-Y. Gibbons S. Mu Q. (2012). Four geranyl-bearing polyisoprenylated benzoylphloroglucinol derivatives from Hypericum sampsonii . Phytochem. Lett. 5, 200–205. 10.1016/j.phytol.2011.09.009 Zeng Y. H. Mu Q. Xiao Z. Y. Xu Y. Rahman M. M. Gibbons S. (2009). Geranyl bearing polyisoprenylated benzoylphloroglucinol derivatives from Hypericum sampsonii. Chem. Lett. 38, 440–441. 10.1246/cl.2009.440 Zhang J.-S. Zou Y.-H. Guo Y.-Q. Li Z.-Z. Tang G.-H. Yin S. (2016). Polycyclic polyprenylated acylphloroglucinols: Natural phosphodiesterase-4 inhibitors from Hypericum sampsonii . RSC Adv. 6, 53469–53476. 10.1039/c6ra08805h Zhang J. Gao L. Hu J. Wang C. J. Hagedoorn P. L. Li N. (2022). Hypericin: Source, determination, separation, and properties. Sep. Purif. Rev. 51, 1–10. 10.1080/15422119.2020.1797792 Zhang J. S. Huang J. L. Zou Y. H. Liu X. Ahmed A. Tang G. H. (2017). Novel degraded polycyclic polyprenylated acylphloroglucinol and new polyprenylated benzophenone from Hypericum sampsonii . Phytochem. Lett. 21, 190–193. 10.1016/j.phytol.2017.06.023 Zhang R. Ji Y. Zhang X. Kennelly E. J. Long C. (2020). Ethnopharmacology of Hypericum species in China: A comprehensive review on ethnobotany, phytochemistry and pharmacology. J. Ethnopharmacol. 254, 112686. 10.1016/j.jep.2020.112686 Zhang Z. Z. Zeng Y. R. Li Y. N. Hu Z. X. Huang L. J. Gu W. (2021). Two new seco-polycyclic polyprenylated acylphloroglucinol from Hypericum sampsonii . Org. Biomol. Chem. 19, 216–219. 10.1039/d0ob02072a Zheng Q. M. (2005). Pharmacognostical studies on Hypericum sampsonii and other species of Hypericum . Shanghai , China: Second Military Medical University. Zheng Q. M. Qin L. P. Zheng H. C. Chen Y. Zhang C. Zhang Q. Y. (2003). Quantitative phytochemical analysis of 11 Hypericum species growing in China. Acad. J. Second Mil. Med. Univ. 24, 457–459. Zhu H. C. Chen C. M. Zhang J. W. Guo Y. Tan D. D. Wei G. Z. (2017). Hyperisampsins N and O, two new benzoylated phloroglucinol derivatives from Hypericum sampsonii. Chin. Chem. Lett. 28, 986–990. 10.1016/j.cclet.2016.11.014 Zhu H. Chen C. Tan D. Li D. Guo Y. Wei G. (2016a). Sampbenzophenones A-G, prenylated benzoylphloroglucinol derivatives from Hypericum sampsonii. RSC Adv. 6, 86710–86716. 10.1039/c6ra17885e Zhu H. Chen C. Tong Q. Chen X. Yang J. Liu J. (2015). Hyperisampsins H-M, cytotoxic polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii . Sci. Rep. 5, 14772. 10.1038/srep14772 Zhu H. Chen C. Yang J. Li D. Zhang J. Guo Y. (2016b). Hyperhexanone A, a crucial intermediate from bicyclo 3.3.1 - to cyclohexanone monocyclic-polycyclic polyprenylated acylphloroglucinols. Tetrahedron 72, 4655–4659. 10.1016/j.tet.2016.06.035 Zhu H. Chen C. Yang J. Li X.-N. Liu J. Sun B. (2014). Bioactive acylphloroglucinols with adamantyl skeleton from Hypericum sampsonii. Org. Lett. 16, 6322–6325. 10.1021/ol5030579