Keywords:Sedum aizoon L., pharmacological activities, quality control, hemostatic activity, active metabolites

3.1 History

S. aizoon was first recorded in “Jiu Huang Ben cao” (救荒本草) (Ming Dynasty), which is the earliest book with agronomy and botany as its monograph on the history of China. Later, it was also included in many other famous works on Chinese herbal medicine, including “Wild Vegetables Bo lu” (野菜博录) (Ming Dynasty), “Plants Ming Shi Tu Kao” (植物名实图考), and “Discussion on varieties of Chinese medicinal materials” (中药材品种论述).

The medicinal parts ofS. aizoon were roots and grass inS. aizoon, andS. kamshaticum.S. aizoon has more than 60 synonyms and is distributed in more than 20 provinces or autonomous regions. In addition, the herb and the syrup were included in the Pharmacopoeia of the People’s Republic of China (Part I) (1977 edition) (Chinese Pharmacopoeia Committee, 2005).

3.2 Traditional uses

In folk medicine, the flat and sweet whole herb and the roots ofS. aizoon are widely used for dispersing blood stasis and stopping blood bleeding. For instance, daily administration of 60–90 g ofS. 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 thatS. 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 withS. 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 ofS. aizoon can promote blood circulation and calm the heart.

5.1 Geographical repartition

S. aizoon belongs to the genusSedum of theCrassulaceae family. There are approximately 600 species widely distributed in the temperate and subtropical regions of the northern hemisphere with Mexico being the largest center of origin and diversity ofSedum species.

5.2 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 ofS. aizoon are pictured and shown inFigure 1.

TABLE 1.

6.1 Flavonoids

So far, 48 flavonoid metabolites (1–48) with definite structure have been isolated and identified fromS. aizoon, which are grouped into flavonols (1–36), isoflavones (37–39), flavones (40–43), flavanonols (44–47), and flavan-3-ol (48). Among flavonols, rhamnazin-3-O-β-D-glucopyranoside (4), myricitrin (10), myricetin-3-O-α-L-arabinopyranoside (14) (Xiong et al., 2019), herbacetin-8-O-β-D-glucopyranoside (26), herbacetin-3-O-β-D-glucopyranosyl-8-O-α-L-arabinopyranoside (27), herbacetin-3-O-α-L-rhamnopyranosyl-8-O-α-D-lyxopyranoside (28), herbacetin-3-O-α-L-arabinopyranosyl-8-O-β-D-xylopyran-oside (29), gossypetin-3-O-β-D-glucopyranosyl-8-O-β-D-xylopyranoside (31), and 3′-methoxyl-gossypetin-3-O-β-D-glucopyranosyl-8-O-β-D-xylopyranosie (35) (Xu et al., 2015) were obtained mainly from the aerial part ofS. aizoon. Later,Xu et al. (2019) successfully identified four flavonols [i.e., trifolin (1), rutin (2), astragalin (32), and isoquercitrin (5)], two flavones [i.e., lonicerin (43) and scutellarein (46)], and one isoflavone [i.e., genistein (39)] in the leaves and stems ofS. aizoon. Two new prenylated isoflavones, sedacin A (37) sedacin B (38), and two flavonols, sedacin C (6″-O-(E)-feruloyl quercetin) (33) and sedacin D (6″-O-(E)-feruloyl isorhamnetin) (34), were isolated from the whole plant ofS. aizoon (Li W. L. et al., 2011). Among them, sedacin A and sedacin B had the function of scavenging DPPH and ABTS+ free radicals (Li J. X. et al., 2011). Rhamnetin-3-O-β-D-glucopyranoside (3), quercetin-3-O-α-L-arabinopyranoside (8), isorhamnetin-3-O-β-D-xylopyranoside (22), and isorhamnetin-3-O-α-L-arabinopyranoside (23) have also been detected in rhizomes (Li et al., 2020a). Four flavanonols (44–47) with rare dimeric structures, with the character of an iriflophene unit and a flavonoid unit connecting via a furan ring, were isolated from the roots and identified using NMR, IR, UV, HRESIM, DEPT, HSQC, HMBC, and CD methods. In addition, studies were conducted to assess the activity of these four substances, and they revealed that 5a-(3,4-dihydroxyphenyl)-1,3,8,10,10b-pentahydroxy-9-(4-hydroxybenzoyl)-5a,10b-dihydro-11H-benzofurochromen-11-one (46) and 1,8,10,10b-tetrahydroxy-5a-(4-hydroxy-3-methoxyphenyl)-9-(4-hydroxybenzoyl)-3-methoxy-5a,10b-dihydro-11H-benzofuro[2,3-b]chromen-11-one (47) had good anti-proliferative activitiesin vitro against the tumor cell lines BXPC-3, A549, and MCF-7 (Li et al., 2017). The structures of flavonoids fromS. aizoon are displayed inFigure 2.

6.2 Phenolic acids

Phenolic acids are the most important chemical derivatives of plant secondary metabolites. Currently, 31 phenolics (49–78) have been found fromS. aizoon, including phenolic acids (49–58, 60), lignans (61), phenylpropanoids (59, 62–63), and other phenolics (64–78). Two phenolic acids, namely, sedumol (49) and 4-methoxy-3,5-dihydroxybenzoic acid (56) (Han et al., 2021), were obtained from the 95% ethanol extract ofS. aizoon^’s whole grass. Other phenolic acids, including vanillic acid (50) (Lin, 2014), protocatechuic acid (51), cis-4-coumaric acid (52), p-hydroxybenzoic acid (54) (Xiong et al., 2019), and caffeic acid (53) (Lin et al., 2014), were isolated from the aerial part ofS. aizoon. Isolariciresinol-9-O-β-D-glucopyranoside (61) is classified as cyclolignans, which was obtained from the 70% ethanol extract via silica gel column chromatography (300–400 mesh). 2-O-(trans-caffeoyl)-malic acid 1,4-dimethyl ester (59) (Xiong et al., 2019), echinochlorin A (62) (Li et al., 2020a), 1-O-sinapoyl glucopyranoside (63) (Xu et al., 2015), and chrysophanol-8-O-β-D-glucoside (64) (Li et al., 2008) have been identified inS. aizoon. The structures of phenolic acids fromS. aizoon are displayed inFigure 3.

6.3 Triterpenes and phytosterol

6.4 Alkaloids

Eight alkaloids (91–98) have been isolated and identified fromS. aizoon. In 1996,Kim et al. (1996) examined the alkaloids inSedum species and discovered the presence of three alkaloids, namely, sedinine (91), sedamine (92), and despun methylisopelletierine (93) inS. aizoon. Thymine (95) was obtained from the ethyl acetate fraction of aqueous extracts ofSedum aizoon L. In the study ofGao et al. (2006), three pyrrolizidine alkaloids (PAs), namely, senecionine (96), seneciphylline (97), and integerrimine (98) were identified in the extracts ofS. aizoon’s root, which had strong hepatotoxicity. The structures of alkaloids fromS. aizoon are displayed inFigure 5.

TABLE 2.

7.1 Antioxidant activity

S. aizoon has excellent antioxidant activity, as demonstrated by several pharmacological studiesin vitro andin vivo. An in-depthin vivo study showed that the juice from the stems and leaves ofS. aizoon increased the peroxidase (POD) and superoxide dismutase (SOD) of the liver inCyprinus 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 testsin vivo showed that ethanol extracts ofS. 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 ofS. 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 H₂O₂, showing a protective effect on the cell (Zhao, 2015).

7.2 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 ofS. 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 fromS. 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 thatS. aizoon improved exercise endurance, affected their metabolic activity, and produced anti-fatigue effect.S. aizoon’s probable anti-fatigue effects of action are shown inFigure 6.

7.3 Hemostatic activity

S. aizoon has an effect comparable to that ofNotoginseng Radix in terms of reducing bleeding without causing stasis and nourishing blood. A series of experimentsin vivo andin vitro revealed that extracts and preparations ofS. aizoon exhibited good hemostatic activities. Previous studies showed that alcohol and aqueous extracts (6, 12 g/kg b.w) ofS. aizoon could significantly shorten the bleeding time and clotting time of mice (Chen et al., 2012). The juice of the whole herb fromS. 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 aspirin-induced gastric hemorrhage, thus achieving hemostasis. SinceS. 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 herbsS. aizoon in conjunction with omeprazole (Xu, 2012). After intravenous injection in rabbits and intraperitoneal injection in mice ofS. aizoon syrup, the blood coagulation time and bleeding time were decreased (Chinese Academy of Medical Sciences, 1972). The probable hemostatic mechanism is shown inFigure 7.

7.4 Antimicrobial activity

The crude extracts fromS. aizoon have antimicrobial activity. According to transcriptome and RNA sequencing analyses, the ethanol extracts extracted fromS. aizoon had significant antimicrobial activities againstB. cinerea (Wang K. et al., 2022),Aeromonas (Xu et al., 2019), postharvest citrus blue mold (Luo et al., 2020),Shewanella putrefaciens (Wang et al., 2020), andPseudomonas fragi (Wang H. X. et al., 2022). Studies revealed that alcohol extracts had a good inhibitory ability against 20 strains of multidrug-resistantPseudomonas aeruginosa (MIC50 value = 0.125 g/mL) (Zhang et al., 2012;Wang H. et al., 2023),Staphylococcus aureus,Staphylococcus epidermidis, andMicrococcus (MIC value = 0.125 g/mL). However, the inhibitory impact on three types of fungus, includingCandida tropicalis,Candida parapsilosis, andCandida albicans, was very poor, with MIC values above 0.5 g/mL (Zhang et al., 2011).

Furthermore, monomer metabolites isolated fromS. aizoon also have antimicrobial activity.Xu et al. (2015) revealed that herbacetin-3-O-α-L-rhamnopyranosyl-8-O-α-D-lyxopyranoside (28), myricetin-3-O-β-D-glucopyranoside (12), and gossypetin-3-O-β-D-glucopyranosyl-8-O-β-D-xylopyranoside (31) exhibited more potency against Gram-positive than against Gram-negative bacteria.S. aizoon’s probable antimicrobial actions are shown inFigure 8.

7.5 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, theS. 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 withS. 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 betweenS. aizoon andSemen ziziphus spinosa (Zhang L. et al., 2015).

7.6 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 fromS. 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 ofS. 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).

Among the active metabolites tested, myricetin-3-O-D-glucopyranoside (12) obtained from the aerial portion ofS. aizoon exhibited an effect on cell proliferation against HepG2, MCF-7, and A549 tumor cells, with IC50 values of 46.30, 75.27, and 49.76 mol/L, respectively (Xu et al., 2015).Li et al. (2017) found that 5a-(3,4-dihydroxyphenyl)-1,3,8,10,10b-pentahydroxy-9-(4-hydroxybenzoyl)-5a,10b-dihydro-11H-benzofuro chromen-11-one, an iriflophene unit, and a quercetin unit connecting via a furan ring (44) and 1,8,10,10b-tetrahydroxy-5a-(4-hydroxy-3-methoxyphenyl)-9-(4-hydroxybenzoyl)-3-methoxy-5a,10b-dihydro-11H-benzofuro[2,3-b]chromen-11-one, an iriflophene unit, and a rhamnazin unit connecting via a furan ring (47) isolated from the roots ofS. aizoon exhibited cytotoxic activities against BXPC-3, A549, and MCF-7 tumor cell lines, with IC50 ranging from 24.84 to 37.22 μmol/L.S. aizoon’s probable anti-cancer actions are shown inFigure 9.

7.7 Anti-inflammatory effect

In Northeast Asia,S. aizoon has been used as a traditional medicine to treat inflammatory illnesses. Several extracts (PE, EtOAc, and H₂O) ofS. aizoon were administered to LPS-stimulated 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 byKim et al. (2004), methanol extracts ofS. 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 inFigure 10.

7.8 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 freshS. 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 thatS. aizoon had the effect of treating atherosclerosis and coronary heart disease (Zhu et al., 2022,2023).

Interestingly, the extract ofS. aizoon increased cardiac activity and decreased amphetamine toxicity (Zheng, 1975). According to the study ofWang 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 ofS. aizoon was related to the enhancement of the activities of LPL, LCAT, and HDL2-C (Wu et al., 2006).

7.9 Other activities

In T1MD mice, it has been shown thatS. aizoon extract has the ability to enhance glucolipid metabolism and organ coefficient and decrease liver tissue damage (Qi et al., 2022). In addition, polysaccharides fromS. 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).

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