Sedum aizoon L.: a review of its history, traditional uses, nutritional value, botany, phytochemistry, pharmacology, toxicology, and quality control

In China, Russia, Mongolia, Japan, North Korea, and Mexico, Sedum aizoon L. (S. aizoon) is used as an edible plant. Up to now, over 234 metabolites, including phenolic acids, flavonoids, triterpenes, phytosterols, and alkaloids, among others, have been identified. In addition to its antioxidant, anti-inflammatory, anti-fatigue, antimicrobial, anti-cancer, and hemostatic activities, S. aizoon is used for the treatment of cardiovascular disease. This paper provides an overview of the history, botany, nutritional value, traditional use, phytochemistry, pharmacology, toxicology, and quality control of S. aizoon.


Introduction
Sedum aizoon L. (Chinese name:景天三七) is a perennial herbaceous plant that is widely distributed in China, Russia, Mongolia, Japan, North Korea, and Mexico.It is a member of the Sedum genus in the Sedum family (Crassulaceae) (Guo and Lin, 2007).Its name is also consistent with the plant name recorded in "The Plant List" (http://www.theplantlist.org),which is now incorporated into the requirement for traditional medicine in the provinces of Jiangsu and Fujian (Jia et al., 2014).It is one of the renowned "Taibai seven medicine (太白七药)" in the Qinling Mountains, which has the effects of dispersing blood stasis, stopping bleeding, tranquilizing the mind, detoxifying, and analgesia, and is used in the treatment of various kinds of bleeding, palpitations, and insomnia.Growing in blood bleeding.For instance, daily administration of 60-90 g of S. aizoon decoction can treat bleeding symptoms, including hemoptysis, bleeding gums, epistaxis, gingival bleeding, and internal bleeding.The fresh juice was effectively used for the treatment of leukemia, aplastic anemia, thrombocytopenic purpura, hemoptysis, and different forms of bleeding (i.e., gingival, digestive tract, and hematuria) (Chinese herbal medicine research group, 1971).In addition, ancient medical classics, such as Li Shizhen's "Compendium of Materia Medica" (本草纲目), Chen Shiduo's "New Compilation of Materia Medica" (本草新编), and Zhang Xichun's "Intergrating Chinese And Western Medicine" (医学衷中参西录), explicitly stated that S. aizoon had good hemostasis and analgesic function, which was known as "the god medicine for hemostasis" (止血神药).It is also used as a heart and mind tranquillizing agent with an excellent effect on hysteria palpitation, restlessness, hypertension, and rheumatic heart disease (Chen, 2003).Likewise, the detoxifying and clearing heat effects have also been reported.
Of note, S. aizoon has a long history as both an edible and medicinal herb.For example, vegetables with S. aizoon's stems and leaves as metabolites have good nutritional value."Jiu Huang Ben Cao" (救荒本草) in the Ming Dynasty stated that the regular consumption of the fresh, tender stems and leaves of S. aizoon can promote blood circulation and calm the heart.

Morphology
S. aizoon is an annual or perennial, succulent herb, growing in clusters and has a strong ability to bifurcate.S. aizoon has coarse, woody rhizomes that resemble ginseng in form.The stems are erect, cylindrical, and glabrous, which can reach heights of 15-50 cm.At each node, the stems carry just one leaf, which is nearly opposite on both sides.The leaves are 2.5-5 cm long, 5-12 mm wide, obovate or long oval in shape, and broad and thick with more juice.Additionally, they feature a cuneate base, a serrated border toward the apex, a moderately rounded top, and few sessile leaves.The loose, terminal verticillaster contains ten stamens that are around the same length as the petals, five distinct pistils that are slightly longer than the stamens, five orange-yellow petals with lancolate, sharp tips, and five sepals with blunt ends.Follicles are either reddish or brown in color and are grouped in a star pattern.Seeds are obovate, smooth, have wings along the edge, and have a wider apical.Flowers usually bloom in summer.The photos of S. aizoon are pictured and shown in Figure 1.

Pharmacological activities
According to pharmacological studies, S. aizoon has a wide range of pharmacological activities, including antioxidant, antifatigue, and anti-inflammatory activities, improving cardiovascular disease, and other activities.The related biological activities and main effects are listed in Table 2.

Antioxidant activity
S. aizoon has excellent antioxidant activity, as demonstrated by several pharmacological studies in vitro and in vivo.An in-depth in vivo study showed that the juice from the stems and leaves of S. aizoon increased the peroxidase (POD) and superoxide dismutase    Frontiers in Pharmacology frontiersin.org16 (SOD) of the liver in Cyprinus carpio Linnaeus as well as reduced the content of malondialdehyde (MDA), thus preventing the peroxidation damage of the liver cell membrane (Zhang and Wang, 2012).Experimental tests in vivo showed that ethanol extracts of S. aizoon were able to enhance antioxidant enzymes in T1DM mice and successfully alter the Nrf2/Keap1/ARE signaling pathway (Qi et al., 2022).Additionally, 95% ethanol extract of S. aizoon increased the activity of SOD, CAT, and GSH-Px and reduced the contents of MDA and ROS on the rat adrenal pheochromocytoma cell line (PC12) induced by H 2 O 2 , showing a protective effect on the cell (Zhao, 2015).

Anti-fatigue effects
As national fitness activities expand, more individuals participate in sports, and the negative consequences of exercise fatigue on the body become more obvious.The effective recuperation of the body and the rapid removal of exercise exhaustion are becoming increasingly vital to society.The animal experiments (mice) demonstrated that the extracts of S. aizoon (3.6 and 0.9 mL/kg, 30 days) prolonged the time of extreme exercise in mice, reduced the contents of blood urea nitrogen (BUN), lactic acid (LAC), MDA, and lactate dehydrogenase (LDH) in the serum of mice, improved the activity of SOD and GSH-Px, and increased the contents of liver and muscle glycogen of mice (Ding, 2019).In a human clinical trial, it has been found that the administration of the sap (0.225 mL/kg.d,0.9 mL/kg.d,and 3.6 mL/kg.d,28 days) of the aerial part from S. aizoon [5 mL/(60 kg.d), 14 days] reduced the response time of male college students to the stimulus signal, improved fatigue resistance, and accelerated fatigue recovery by decreasing the content of blood perfusion index, cortisol, and creatine kinase in the serum and increasing hemoglobin and the load of final exercise (Ren, 2020).The above studies showed that S. aizoon improved exercise endurance, affected their metabolic activity, and produced anti-fatigue effect.S. aizoon's probable anti-fatigue effects of action are shown in Figure 6.

Hemostatic activity
S. aizoon has an effect comparable to that of Notoginseng Radix in terms of reducing bleeding without causing stasis and nourishing blood.A series of experiments in vivo and in vitro revealed that extracts and preparations of S. aizoon exhibited good hemostatic activities.Previous studies showed that alcohol and aqueous extracts (6, 12 g/kg b.w) of S. aizoon could significantly shorten the bleeding time and clotting time of mice (Chen et al., 2012).The juice of the whole herb from S. aizoon could increase the levels of GP Ⅱb/Ⅲa, P selectin, and ET-1 and the number of platelets and enhance the platelet aggregation and release function of the rats with aspirininduced gastric hemorrhage, thus achieving hemostasis.Since S. aizoon could increase the level of IL-8, it was used in patients with bleeding accompanied by inflammation (Huang, 2014).
S. aizoon combined with other drugs can also be used for the treatment of bleeding diseases.Patients with bleeding peptic ulcers was treated upon treatments with herbs S. aizoon in conjunction with omeprazole (Xu, 2012).After intravenous injection in rabbits and intraperitoneal injection in mice of S. aizoon syrup, the blood coagulation time and bleeding time were decreased (Chinese Academy of Medical Sciences, 1972).The probable hemostatic mechanism is shown in Figure 7.

Sedative and hypnotic effects
Traditional Chinese medicine and its preparations are commonly used to treat sleeplessness, agitation, and other symptoms.They offer the benefits of safety and dependability, as well as fewer toxicity and side effects, as compared to Western medication with sedative and hypnotic properties.Using the mouse model, Guo et al. (2009) showed that the water and alcohol extracts have tranquilizing mind and the calming effects.Later, they also found that the ethyl acetate and butanol extracts could effectively lower the autonomic activity in mice, lengthen sleeping duration in mice, and increase the number of sleeping mice (Guo et al., 2010).
Additionally, the S. aizoon's prescription or in combination with other drugs also possess sedative and hypnotic properties, which are often used to treat sleeplessness, restlessness, and other disorders.For instance, Yangxincao Anshen Granules made with S. aizoon (12, 6 g/kg/d) significantly reduced the spontaneous movements of mice, and the granules, in conjunction with pentobarbital, extended the duration of their sleep, providing good sedative and hypnotic effects without negative side effects (Zhang R. Z. et al., 2015).Similar results have been recorded for the combination between S. aizoon and Semen ziziphus spinosa (Zhang L. et al., 2015).

Anti-cancer activity
S. aizoon's active metabolites and crude extracts with anti-cancer potential have piqued the interests of researchers in recent years.The ethanol extracts isolated from S. aizoon (50, 100, and 200 μg/mL) could lower the survival rate of human liver cancer cells HepG2 and inhibit human hepatocarcinoma proliferation by 11.15%, 41.96%, and 52.04%, respectively.With the increase in concentration, the inhibition rate of liver cancer cells increased, showing a certain dose-effect relationship (Wang et al., 2013).The aqueous extracts of S. aizoon [equivalent to adding 15.9 mg raw drug, containing 31.7 μg gallic acid (60)] could destroy the phospholipid-dominated structures and block nucleic acid synthesis and metabolism, which caused the death of cancer cells, and the killing effect was improved when the drug treatment period was extended (Fu et al., 2008).

Anti-inflammatory effect
In Northeast Asia, S. aizoon has been used as a traditional medicine to treat inflammatory illnesses.Several extracts (PE, EtOAc, and H 2 O) of S. aizoon were administered to LPSstimulated RAW 264.7 cells to investigate anti-inflammatory activities.The phenolic and flavonoid-rich EtOAc extracts reduced NO, TNF-α, and IL-6 production induced by LPS (Lin et al., 2015a).In a study by Kim et al. (2004), methanol extracts of S. kamtschaticum Fischer showed a significant inhibitory effect in the inflammation models of mouse ear edema (50-400 mg/kg for 3 days) and rat paw edema (400-800 mg/kg for 3 days) induced by croton oil and multiple phorbol ester.The cyclooxygenase-2 expression was downregulated.Possible mechanisms of action are given in Figure 10.

Cardioprotective effects
S. aizoon lowered blood pressure, serum CK activity, and AT1 protein expression, reversed myocardial remodeling, and increased AT2 and catalase protein expression (Han et al., 2022).Chen (2000) showed that fresh S. aizoon grass could help stroke victims regain consciousness.It is thought that this herb has evident effects in improving blood circulation, reducing blood stasis, and decreasing blood pressure.Using the method of network pharmacology and molecular docking, studies found that S. aizoon had the effect of treating atherosclerosis and coronary heart disease (Zhu et al., 2022(Zhu et al., , 2023)).
Interestingly, the extract of S. aizoon increased cardiac activity and decreased amphetamine toxicity (Zheng, 1975).According to the study of Wang et al. (2013), S. aizoon had the ability to regulating blood lipid levels and could dramatically lower the mice's liver index and fat coefficient.Additionally, when hyperlipidemia rats were treated with Yangxincao capsules (derived from whole grass extract), the serum levels of TC, TG, and LDL-C were decreased, while HDL-c and its subcomponents (HDL-c, HDL-3-C, and HDL-C/TC) were increased, implying that the mechanism of lipid regulation of S. aizoon was related to the enhancement of the activities of LPL, LCAT, and HDL2-C (Wu et al., 2006).

Other activities
In T1MD mice, it has been shown that S. aizoon extract has the ability to enhance glucolipid metabolism and organ coefficient and decrease liver tissue damage (Qi et al., 2022).In addition, polysaccharides from S. aizoon have an immune-stimulating effect by increasing the thymus index, spleen index, T-and B-lymphocyte transformation proliferation, and NK cell activity of mice, as well as enhancing the percentage values of CD3 + , CD4 + , and CD19 + and the percentage values of CD4+/CD8+ in the peripheral blood.Such effect was associated with the increased secretion of IL-2 and IFN-γ (Huang, 2019).

Acute toxicity
A previous study showed that excessive consumption may cause small hepatic vein occlusion disease with upper quadrant abdominal pain, hepatomegaly, liver dysfunction, and ascites as the main symptoms (Wu et al., 2008;Shao et al., 2015).

Quality control
The quality of traditional Chinese medicine is the basis for ensuring the stability of its efficacy and the safety of its application,  Frontiers in Pharmacology frontiersin.org20 and its standardization and modernization are the important prerequisites for promoting Chinese medicine toward internationalization.In order to better identify the plant, Scholars (Han, 2008) have controlled the quality of S. aizoon from four aspects: morphology, microscopy, TLC, and RAPD.It is required that the water content shall not exceed 10.53%, the ash content shall not exceed 14.70%, and the leaching content shall not be less than 32.57% (Wei et al., 2020).The linear ranges of quercitroside, quercetin, and kaempferol were 0.0029 ~0.183, 0.0016 ~0.1020, and 0.0045 ~0.260 μg/μL, respectively (He and Du, 2016), and those of luteolin and isorhamnetin were 1.12 112.00 and 0.98 ~97.60 μg/mL (Lin et al., 2013), respectively.However, these methods may not be sufficient to evaluate the quality of S. aizoon.
Traditional Chinese medicine (TCM) fingerprints can comprehensively and quantitatively reflect the chemical information contained in TCM and is an effective means of quality control of TCM.Lin et al. (2015b)

Conclusion and future perspectives
This review provides comprehensive and detailed information about the history, traditional uses, botany, phytochemistry, pharmacological activities, and acute toxicity of S. aizoon.So far, more than 200 metabolites have been identified with a variety of pharmacological activities.These modern pharmacological studies supported most traditional uses of S. aizoon as folk medicine.However, gaps still exist in the systematic study of S. aizoon.
First, S. aizoon has many nicknames, which results in being mixed with other herbs.Therefore, molecular biological studies are required to screen out the reference genes for better identification of S. aizoon.
Second, the pharmacological potential of S. aizoon has not yet been fully discovered, which may be further investigated by a combination of in vitro and in vivo bioactivity assays, metabolomics, network pharmacology, and in silico bioactivity prediction methods.In addition, the therapeutic potential of S. aizoon and its bioactive metabolites, safety, efficacy, and potential mechanism of action require further preclinical and clinical studies to validate for future clinical applications.
Third, S. aizoon is widely popular in herbal healthcare as a commonly used medicinal and edible substance and is especially used in immunomodulation and blood lipid regulation.Nevertheless, the use of S. aizoon in combination with other herbs in healthcare products should be strengthened, and studies on improving memory and promoting digestion may be conducted.
Fourth, the spectrum-efficacy relationship of S. aizoon in immunomodulation and anti-inflammatory therapy should be further investigated in order to better uncover its active metabolites.

Glossary
belongs to the genus Sedum of the Crassulaceae family.
Significantly decreased the levels of serum TC, TG, and LDL-C, decreased the level of apoB, and increased the levels of HDL-C and its subcomponents HDL2-C, HDL3-C, and the ratio of HDL-C/TC; significantly increased the activities of LCAT and LPL and the level of apoA in the serum Liu et al. index and spleen index, T-and B-lymphocyte transformation and proliferation, and NK cell activity; increased the percentage values of CD3 + , CD4 + , CD19 + , and CD4+/CD8+ in the peripheral blood Huang (2019) N/A, not applicable or not explicitly stated.

FIGURE 6
FIGURE 6Schematic diagram of anti-fatigue effects of S. aizoon.

FIGURE 10 S
FIGURE 10S.aizoon's probable anti-inflammatory mechanism of action.
used 11 standards to analyze the phytochemical profiles of the active extracts by HPLC fingerprints.Yang et al. (2023) established the HPLC-ECD fingerprint spectra of S. aizoon from different origins and identified 12 metabolites.

TABLE 1
Main active metabolites identified in S. aizoon.

TABLE 1 (
Continued) Main active metabolites identified in S. aizoon.

TABLE 1 (
Continued) Main active metabolites identified in S. aizoon.

TABLE 1 (
Continued) Main active metabolites identified in S. aizoon.

TABLE 1 (
Continued) Main active metabolites identified in S. aizoon.
(Continued on following page)

TABLE 1 (
Continued) Main active metabolites identified in S. aizoon.

TABLE 1 (
Continued) Main active metabolites identified in S. aizoon.
N/A: not applicable or not explicitly stated.

TABLE 2
Biological activities of the S. aizoon extracts and bioactive metabolites.

TABLE 2 (
Continued) Biological activities of the S. aizoon extracts and bioactive metabolites.

TABLE 2 (
Continued) Biological activities of the S. aizoon extracts and bioactive metabolites.