Hypericum sampsonii Hance: a review of its botany, traditional uses, phytochemistry, biological activity, and safety

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.

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

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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  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.
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.

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).

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-trionecore 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).

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.

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.

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).

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).

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.
On the other hand, in vivo studies have demonstrated that the alcohol extracts of H. sampsonii had antinociceptive and antiinflammatory 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 carrageenininduced 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 UClike 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.
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-2,6dihydroxybenzophenonel (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.

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).

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 openfield 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.

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).

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).

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 IC 50 value of 35.48 μM (Dung Nguyen et al., 2021).

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.

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.

FIGURE 1
FIGURE 1Photographs of H. sampsonii: the whole plant (A), the lateral view of connate perfoliate leaves (B), and medicinal material (C).

TABLE 1
Vernacular names of H. sampsonii in China.

TABLE 3
Bicyclic Polyprenylated Acylphloroglucinols (BPAPs) isolated from H. sampsonii.and C These compound names are distinguished by the initials of authors because of their different structures while identical names. T
x -Two compounds have the same structure while different names.

TABLE 11
Simple aromatic compounds isolated from H. sampsonii.

TABLE 13 (
Continued) The biological activities of H. sampsonii.

TABLE 13 (
Continued) The biological activities of H. sampsonii.

TABLE 13 (
Continued) The biological activities of H. sampsonii.