A Review on the Phytochemical and Pharmacological Properties of Rosa laevigata: A Medicinal and Edible Plant

Bai-Lin Li; Jie Yuan; Jie-Wei Wu

doi:10.1248/cpb.c20-00743

Abstract

Rosa laevigata Michx., a medicinal and edible plant in China, has exerted a variety of medicinal values and health benefits. This present review aims to achieve a comprehensive and up-to-date investigation in the phytochemistry and pharmacology of R. laevigata. According to these findings in the literature, approximately 123 chemical ingredients covering triterpenoids, flavonoids, tannis, lignans and polysaccharides, have been characterized from various parts of this species. Among these isolates, 77 triterpenoids have been isolated and thus regarded as the primary and characteristic substance. Based on the chemical structures, most of the obtained triterpenoids can be classified into polyhydroxy triterpenoids and readily divided into four categories: ursane-type, oleanane-type, lupinane-type, as well as seco-triterpenoids. The crude extracts and the purified compounds have demonstrated various pharmacological effects in vitro and in vivo, such as antioxidant activity, immunomodulatory effect, anti-inflammatory effect, liver protection, kidney protection, cardiovascular protection, neuroprotective effect and improvement of diabetic cataract. Noticeably, these pharmacological results of R. laevigata provide evidences for its traditional uses. In addition, these different chemical ingredients existing in the title plant may have synergistic effects. In conclusion, the chemical profiles, including ingredients and structures, together with the modern pharmacological properties have been adequately summarized. These evidences have revealed this plant to be a valuable source for therapeutic foodstuff and more attention should be paid to a better utilization of this plant.

1. Introduction

Rosa laevigata (Fig. 1) commonly known as Cherokee rose, belonging to the genus Rosa (Rosaceae), is an evergreen climbing shrub prevalently distributed over southern regions of China. As a famous folk herb, the fruits, roots, flowers and leaves of R. laevigata have been recorded as source of traditional Chinese medicines. For instance, its fruits, known as “Jin-Ying-Zi” in Chinese, are recorded in the Chinese Pharmacopoeia and prescribed as kidney tonic for the treatment of urinary diseases like wet dreams, urinary incontinence, urinary frequency, as well as menstrual irregularities, leucorrhea and uterine prolapse, and thus widely consumed in China as a component of some Traditional Chinese Medicines (TCMs).¹⁾ Moreover, the Ministry of National Health of China has rated the fruit of R. laevigata a new food resource, and has now developed it as a third-generation wild fruit food. At present, this fruit is extensively used as a foodstuff, such as nourishing oral liquid, fruit wine, vinegar-based beverage, fruit juice and so on. Besides, this fruit is also applied for the extraction of brown pigments used as food additives.²⁾ For long time, the roots of R. laevigata have been commonly used in folk practices of Guangdong, Guangxi and Hunan provinces to cure pelvic inflammation, irregular vaginal bleeding, cervical erosion, and cervicitis.^3,4) Therefore, the roots of this plant have been exploited commercially as the crucial constituents of some famous proprietary TCMs such as San-Jin-Pian, Jin-Ji-Jiao-Nang, and Fu-ke-Qian-Jin-Pian which have been approved for the treatment of gynecological infection and diseases of urinary system.¹⁾ In terms of the leave of R. laevigata, it also has a high medicinal value and broadly utilized to cure burns, skin tumors and ulcers.⁵⁾

Fig. 1. Pictures of R. laevigata: (A) the Plant, (B) Fruits and (C) Roots of R. laevigata as Medicinal Materials Used in TCM

2. Phytochemistry

Due to its significant pharmacological activities, the chemical constituents of R. laevigata have been extensively studied in the past decades. Up to date, approximately 123 ingredients covering triterpenoids, flavonoids, tannis, lignans and polysaccharides, have been isolated from different parts of this species. Among them, triterpenoids have been regarded as the principal and characteristic bioactive substances.

2.1. Triterpenoids

Currently, there are three types of triterpenoids and their derivatives found in R. laevigata: ursolic acid, oleanolic acid, and lupinic acid. Among them, ursolic acid is the majority (Figs. 2–5).

Fig. 2. Ursane-Type Triterpenoids Isolated from R. laevigata

Fig. 3. Oleanane-Type Triterpenoids Isolated from R. laevigata

Fig. 4. Lupinane-Type Triterpenoids Isolated from R. laevigata

Fig. 5. seco-Triterpenoids Isolated from R. laevigata

The first report of triterpenoids from R. laevigata can be traced back to 1991, when 11 chemical components including derivatives of ursolic (1–9, Table 1) and oleanolic acids (10–11, Table 1) were isolated from an acetone extract of the aerial parts of R. laevigata.⁶⁾ Among these compounds, 5 was assigned to be a new compound, with a hydroxyl group positioned at C-11 in the molecule. Noticeably, lots of ursane-type triterpenoids were isolated from R. laevigata, only compound 5 was found to possess hydroxyl group occurring at C-11. Since then, phytochemical researches on R. laevigata have been carried out scarcely. Till 2008, Yuan et al. reported the isolation of two new ursane-type triterpene glucosides featured with a heteroannular diene (12 and 13) from this species by bioassay-guided fractionation.¹⁾ In the period 2010–2014, ongoing chemical investigations of R. laevigata afforded a variety of triterpenoids (15–52, Table 1) which were isolated for the first time from the title plant.^7–11) Apparently, these studies reinforce previous reports in indicating that triterpenoids are the predominant chemical constituents in R. laevigata. In particular, the occurrence of 28 in R. laevigata is more interesting, as it is reported for the first time in the family Rosaceae and may be useful as chemotaxonomic marker for the genus.⁷⁾ Additionally, bioassay-guided fraction led to the isolation of several novel triterpenoids,⁸⁾ for instance, 29 belongs to nortriterpenoid, possessing a conjugated diene between C-12 and C-17, 30 can be classified into triterpene lactone saponin, in whose structure, a six-membered lactone ring was formed between C-20 and C-28, while 31 and 32 are assigned to seco-ursane type triterpenes, bearing a 18,19-seco moiety in the molecules. Although triterpenoids with a p-coumaroyl group substituent were reported rarely, 38–41 were found to own a p-coumaroyl group substituent which was attached at OH-3 exactly.⁹⁾ Interestingly, 43 possessing aldehyde group moiety which occurs rarely in the natural plant, indicated that it might be artefact of the isolation procedure.¹⁰⁾ Moreover, another bioassay-guided isolation carried out by Yan et al. afforded a few of novel triterpenoids: laevigins A–D (44–47).¹¹⁾ Among them, 45 and 46 are newly described 18,19-seco-ursane-type triterpenoid saponins. This finding enriched the structure diversity of 18,19-seco-ursane-type triterpenoids and thus the chemical diversity of R. laevigata. In 2016, a novel skeleton natural product laevigaterpene A (53), featuring a rare 2-hemiacetal moiety in its A ring was found to exist in the title plant.¹²⁾ Additionally, laevigaterpene B (54), a new lupane-type triterpene belonging to aromatic ester triterpene derivative has been characterized in this study.¹²⁾ Besides, phytochemical investigation of roots of R. laevigata carried out by Dai et al. resulted in the isolation of a series of triterpenoids, especially, the following chemical components were obtained from this plant for the first time: 55–70.^13,14)

Table 1. Chemical Ingredients Isolated from the Plant of R. laevigata

Classification	No.	Chemical ingredient	Part of plant	Ref.
Triterpenoids	1	Ursolic acid	Aerial part, Fruit, Leaf	6–8)
	2	2α-Hydroxyursolate	Aerial part, Leaf	6,11)
	3	2α-Methoxyursolate	Aerial part	6)
	4	Tormentate	Aerial part, Fruit, Root	6,7,10,14)
	5	11α-Hydroxytormentate	Aerial part	6)
	6	Tormentic acid β-D-glucopyranosyl ester	Aerial part, Root, Fruit	1,6,7,10)
	7	Tormentic acid 6-methoxy-β-D-glucopyranosyl ester	Aerial part	6)
	8	Euscaphate	Aerial part, Fruit, Leaf, Root	6–8,10,11)
	9	Euscaphic acid β-D-glucopyranosyl ester	Aerial part, Root	1,6,10)
	10	Oleanolic acid	Aerial part, Fruit	6,7)
	11	Hederagenin	Aerial part	6)
	12	2α,3α,24-Trihydroxyurs-12,18-dien-28-oic acid β-D-glucopyranosyl ester	Root	1)
	13	2α,3α,23-Trihydroxyurs-12,19(29)-dien-28-oic acid β-D-glucopyranosyl ester	Root	1)
	14	2α,3β,19α,23-Tetrahydroxyurs-12-en-28-oic acid β-D-glucopyranosyl ester	Root, Fruit, Leaf	1,7,8,17)
	15	Pomolic acid	Fruit, Root	7,16)
	16	2α,3α-Dihydroxyurs-12-en-28-oic acid	Fruit	7)
	17	2α,3α,23-Trihydroxyurs-12-en-28-oic acid	Fruit	7)
	18	2α,3β,23-Trihydroxyurs-12,18-dien-28-oic acid	Fruit	7)
	19	2α,19α-Dihydroxy-3-oxo-urs-12-en-28-oic acid	Fruit	7)
	20	1α,2α,3β,19α-Tetrahydroxyurs-12-en-28-oic acid	Fruit	7)
	21	Myrianthic acid	Fruit, Leaf, Root	7,11,14)
	22	19α-Hydroxyasiatic acid	Fruit, Leaf	7,8,11,17)
	23	Maslinic acid	Fruit, Leaf	7,8)
	24	2α,3α-Dihydroxyolean-12-en-28-oic acid	Fruit	7)
	25	2α,3α,23-Trihydroxyolean-12-en-28-oic acid	Fruit, Leaf	7,8)
	26	2α,3β,19α-Trihydroxyolean-12-en-28-oic acid	Fruit, Root	7,14)
	27	2α,3β-Dihydroxylup-20(29)-en-28-oic acid	Fruit	7)
	28	2α,3β,23-Trihydroxylup-20(29)-en-28-oic acid	Fruit, Leaf	7,8)
	29	2α,3β,23-Trihydroxy-12,17-dien-28-norursane	Leaf	8)
	30	3β-[(α-L-Arabinopyranosyl)oxy]-20β-hydroxyursan-28-oic acid δ-lactone	Leaf	8)
	31	2α,3β,23-Trihydroxy-19-oxo-18,19-seco-12,17-dien-28-norursane	Leaf	8)
	32	2α,3α,23-Trihydroxy-19-oxo-18,19-seco-urs-11,13(18)-dien-28-oic acid	Leaf	8)
	33	2α,3β-Dihydroxyolean-13(18)-en-28-oic acid	Leaf	8)
	34	2α,3α,19α,23-Tetrahydroxyolean-12-en-28-oic acid	Leaf	8)
	35	3β,23α-Dihydroxyursan-28-oic acid δ-lactone	Leaf	8)
	36	Betulinic acid	Fruit, Root	9,10)
	37	2α,3β-Dihydroxylup-20-en-28-acid methyl ester	Fruit	9)
	38	3-O-trans-p-Coumaroyl alphitolic acid	Fruit	9,12)
	39	3-O-cis-p-Coumaroyl alphitolic acid	Fruit	9,12)
	40	3-O-trans-p-Coumaroyl maslinic acid	Fruit	9,12)
	41	3-O-cis-p-Coumaroyl maslinic acid	Fruit	9,12)
	42	Nigaichigoside F2	Root	10)
	43	Rubuside J	Root	10)
	44	Laevigin A	Leaf	11)
	45	Laevigin B	Leaf	11)
	46	Laevigin C	Leaf	11)
	47	Laevigin D	Leaf	11)
	48	3β-Hydroxyursan-28-oic acid δ-lactone	Leaf	11)
	49	Lup-20(29)-en-28-ol	Leaf	11)
	50	2α,3β,23-Trihydroxy-urs-12-en-28-O-β-D-glucopyranoside	Leaf	11)
	51	2α,3β,23-Trihydroxy-urs-11,13-dien-28-O-β-D-glucopyranoside	Leaf	11)
	52	Isopinfaenoic acid-28-O-β-D-glucopyranoside	Leaf, Root	11,14)
	53	Laevigaterpene A	Fruit	12)
	54	Laevigaterpene B	Fruit	12)
	55	Arjunetin	Root	13,14)
	56	Cecropiacic acid 3-methyl ester	Root	13,16)
	57	2-Acetyl tormentic acid	Root	13,16)
	58	2,3-Dihydroxyurs-12,18-dien-28-oic acid	Root	13,16)
	59	3-E-Feruloyl corosolic acid	Root	13)
	60	Fupenzic acid	Root	13)
	61	2-O-Acetyl euscaphic acid	Root	13)
	62	12,13-Dihydromicromeric acid	Root	13)
	63	(2R,19R) Methyl 2-acetyloxy-19-hydroxyl- 3-oxo-urs-12-en-28-carboxylate	Root	14,16)
	64	Pomonic acid	Root	14,16)
65	18,19-seco-2α,3α-Dihydroxy-19-oxo-urs-11,13(18)-dien-28-oic acid	Root	14)
66	Swinhoeic acid	Root	14)
67	1β-Hydroxyeuscaphic acid	Root	14)
68	2α,3β,19α-Trihydroxy-24-oxo-urs-12-en-oic acid	Root	14)
69	Alpinoside	Root	14)
70	Rubuside B	Root	14)
71	19α-OH-3β-E-Feruloyl corosolic acid	Root	15)
72	2α,3α,20β-Trihydroxyurs-13(18)-en-28-oic-acid	Root	15)
73	2α,3β,20β-Trihydroxyurs-13(18)-en-28-oic-acid	Root	15)
74	18,19-seco-2α,3β,23α-Trihydoxyl-19-oxo-urs-11,13(18)-dien-28-oic acid	Root	16)
75	Rosanortriterpene A	Fruit	18)
76	Rosanortriterpene B	Fruit	18)
77	Rosanortriterpene C	Fruit	19)
Flavonoids	78	Catechin	Leaf, Root	20,22)
	79	Quercetin	Leaf	20)
	80	Naringenin	Leaf	20)
	81	Kaempferol	Leaf	20)
	82	Dihydroapigenin	Fruit	21)
	83	Liquiritigenin	Fruit	21)
	84	(+)-Catechin-8-acetic acid	Root	10)
	85	Guibourtacacidine 4-Me ether	Root	10)
	86	Guibourtacacidine	Root	10)
	87	(+)-Gallocatechin	Root	22)
	88	(2R,3S,4S)-cis-Leucocyanidin	Root	22)
	89	(2R,3S,4S)-cis-Leucofisetinidin	Root	22)
	90	(2S,3R,4R)-cis-Leucofisetinidin	Root	22)
	91	Dehydrodicatechin A	Root	22)
	92	Phloridzin	Root	22)
Tannins	93	Laevigatin A	Pericarp	23)
	94	Laevigatin B	Pericarp	23,24)
	95	Laevigatin C	Pericarp	23)
	96	Laevigatin D	Pericarp	23,24)
	97	Sanguiin H-4	Pericarp	23)
	98	Pedunculagin	Pericarp	23,24)
	99	Casuarictin	Pericarp	23)
	100	Potentillin	Pericarp	23)
	101	Agrimonic acid A	Pericarp	23)
	102	Agrimonic acid B	Pericarp	23,24)
	103	Agrimoniin	Pericarp	23,24)
	104	Laevigatin E	Pericarp	24)
	105	Laevigatin F	Pericarp	24)
	106	Laevigatin G	Pericarp	24)
Lignans	107	Rosalaevin A	Fruit	21)
	108	Rosalaevin B	Fruit	21)
	109	Polystachyol	Fruit	21)
	110	Buddlenol C	Fruit	21)
	111	erythro-Guaiacylglycerol-β-O-4′-coniferyl ether	Fruit	21)
	112	Diasyringaresinol	Fruit	21)
	113	Buddlenol B	Fruit	21)
	114	(−)-Simulanol	Fruit	21)
	115	4-Acetonyl-3,5-dimethoxy-p-quinol	Fruit	21)
	116	(+)-8-Hydroxypinoresinol	Fruit	21)
	117	erythro-Guaiacylglycerol-β-O-4′-sinapyl ether	Fruit	21)
	118	threo-Guaiacylglycerol-β-O-4′-coniferyl ether	Fruit	21)
	119	1,2-(1S,2R)-Bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol	Fruit	21)
	120	Sisymbrifolin	Fruit	21)
Polysaccharides	121	Se-RLFP-1	Fruit	26)
	122	Se-RLFP-2	Fruit	26)
	123	PPRLMF-2	Pulp	27)

More recently, a new triterpenic acid derivative was isolated from the roots of R. laevigata and elucidated as 71. In addition to 71, two known compounds 72 and 73 were obtained from the genus Rosa for the first time.¹⁵⁾ Separation of the MeOH extract of R. laevigata resulted in the characterization of a new 18,19-seco-ursane-type triterpenoid (74).¹⁶⁾ Gao et al. designed a method for the rapid and straight forward preparative scale purification of two polyhydroxy triterpenoids (14 and 22) from the fruits of R. laevigata. This method involves microwave-assisted extraction technology coupled with multi vacuum extraction columns.¹⁷⁾

R. laevigata var. leiocapus acts as a variety of R. laevigata, whose specific morphological characteristics of this species is attributed to its smooth fruits without any thorns. In 2019, as a part of our ongoing research on novel and bioactive triterpenes from Rosa genus, the fruit of R. laevigata var. leiocapus was subjected to a detailed phytochemical investigation, resulting in the isolation of three new nortriterpenes, designated as rosanortriterpenes A–C (75–77). To the best of our knowledge, this represented the first study on the chemical constituents of R. laevigata var. leiocapus.^18,19)

In aggregation, 77 triterpenoids and the derivatives were isolated from R. laevigata till now, including 45 ursane-type triterpenoids, 13 oleanane-type triterpenoids, 8 lupinane-type triterpenoids, as well as 11 seco-triterpenoids. Generally, most of the triterpenoids obtained from R. laevigata can be classified into polyhydroxy triterpenoids, the main differences among them depended on the number of the hydroxyl groups and their substitution positions.

2.2. Flavonoids, Tannins, Lignans and Polysaccharides

Flavonoids, tannins, lignans and polysaccharides are common chemical constituents which occur widely in the natural plant. Totally, 15 flavonoids (78–92), 14 tannins (93–106), 14 lignans (107–120) and three polysaccharides (121–123) have been isolated from R. laevigata up to now.

At present, there are many reports involved the flavonoids from R. laevigata, however, most of them are focused on the extraction and content determination of total flavonoids, studies on the isolation and identification of flavonoid monomers are few. Four flavonoids shown to be 78–81 were characterized from the leaves of R. laevigata.^20,21) Interestingly, 78 is flavan-3-ol and occurs in a range of plants, it is considered as the main building-block to form condensed tannins. Another two analogues, identified as 82 and 83, were reported by Li et al.²¹⁾ The structures of (+)-catechin-8-acetic acid (84) and guibourtacacidine 4-Me ether (85), assigned to be new compounds, together with a known flavonoid (86), were identified by Li et al.¹⁰⁾ Additionally, six flavonoids isolated from R. laevigata for the first time were identified as 87–92. Importantly, 92, mainly existing in the species of Malus (Rosaceae), is useful as chemotaxonomic marker for the rosaceous plant species.²²⁾

To date, 14 tannins (93–106) including seven new hydrolyzable tannins, laevigatins A–G (93–96, 104–106), were isolated from R. laevigata.^23,24) In general, tannins isolated from R. laevigata were dimeric ellagitannins closely related to agrimoniin (103), in whose structure, two glucose cores were linked through a dehydrodigalloyl group. For instance, chemical conversions of 101 to 93, and of 103 to 94 and 95, as well as of 96 to 102, could be achieved in the structure characterization of 93–96. Besides, the structure of 103 was finally confirmed by the partial hydrolysis of 103 with tannase to give 104.

A total of 14 lignans (107–120) have been isolated from the fruits of R. laevigata, however, only two lignans characterized as rosalaevins A–B (107 and 108), were designated as new lignans. The remain known lignans were respectively identified as 109–120 by comparison of their NMR data with those reported in the literatures.²¹⁾

Although the fruit of R. laevigata is rich in polysaccharides (approximately 260.5 mg/g),²⁵⁾ few phytochemical researches have been carried out on the isolation of polysaccharides from R. laevigata till now. 121 and 122 determined to be two new selenium (Se)-containing polysaccharides, were isolated through an effective and rapid approach in which microwave-assisted aqueous two-phase extraction (MA-ATPE) with a polyethylene glycol (PEG)/ammonium sulfate system was developed.²⁶⁾ Their chemical structures were determined by weight-average molecular mass, acid hydrolysis and Se-content analysis, as well as NMR spectroscopy studies. 121 was found to be mainly composed of mannose, glucose, galactose and xylose in a molar ratio of 1.4 : 7.9 : 1.0 : 1.5, while 122 was composed of mannose, rhamnose, glucose, galactose and xylose (12.6 : 1.0 : 38.3 : 5.6 : 19.6). In addition, a novel acid polysaccharide (123) with the molecular weight of 1.37 × 10⁵ Da and a triple-helix conformation was purified from the pulp of R. laevigata fruit, which had 16 types of glycosidic linkages. Its primary chemical structure was characterized by monosaccharide composition, methylation, IR and NMR analysis.²⁷⁾

3. Pharmacology

As a medicinal and edible homologous plant, R. laevigata has been proved to have a variety of pharmacological activities both in vivo and in vitro. Table 2 summarizes the key pharmacological activities reported for this species as well as the individual compounds related to them.

Table 2. Summary of the Key Pharmacology Studies Conducted with R. laevigata-Derived Compounds or Extract

Pharmacological activity	Chemical ingredient	Major findings	Ref.
Antioxidative activity	Compounds 107–109, 112–114 and 119	All these compounds exhibited strong effects against the DPPH radical, which were stronger than or similar to that of L-ascorbic acid used as positive control; compounds 109, 112 and 119 exhibited better antioxidant activities in the FRAP assay, while compounds 109 and 112 were most active in the beta-carotene linoleate model system.	21)
Antioxidative activity	Brown pigment	It exhibited a potent radical scavenging activity, with a concentration-dependent inhibition of hydroxyl radical and superoxide free radical at low concentrations.	29)
Immunomodulation	PPRLMF-2 (123)	PPRLMF-2 exerted the immunoregulatory activities by markedly enhancing phagocytosis, the secretion and mRNA expression of cytokines in RAW264.7 cells; its mechanisms of action contributed to the activation of the MAPKs and NF-κB signaling pathways.	27)
Anti-inflammation	Compounds 8, 14, 21, 22, 25, 31, 33 and 47	These compounds could inhibit the transcriptional activity of NF-κB and decrease production of IL-10, TNF-α, IL-1β, and IL-6 in RAW264.7 macrophages stimulated by LPS to varying degrees.	8)
	Compounds 75–77	These compounds can effectively inhibit NO production induced by LPS in RAW264.7	18,19)
	Whole plant extract	Pretreatment of R. laevigata could remarkably attenuate allergic asthma in the chronic inflammation mice model through decreasing inflammatory cells, the secretion of IgE and related cytokines in a dose-dependent pattern.	39)
Hepatic protection	Total flavonoids (TFs)	TFs could resist liver damage caused by CCl₄, LPS, Propionibacterium acnes, paracetamol, ischemia/reperfusion injury and high-fat diet; TFs could reduce the incidence of liver lesions, and improve liver cell DNA fragmentation and mitochondrial ultrastructure changes; the mechanisms of action involved the activation of PPARs and PGC-1α.	44–49)
Hepatic protection	Total saponins (RLTS)	RLTS could protect the liver injury induced by CCl₄ through a similar mechanism of action; RLTS exerted anti-fibrotic effects via regulating the signalling pathways of TGFβ/Smad, FAK-PI3K-Akt-p70S6K and MAPKs; the realization of RLTS in matrix degradation attributed to down-regulation of MMPs; RLTS could induce autophagy and suppress inflammation to treat acetaminophen-induced liver damage.	38,50–52)
Renal protection	Fruit extract	R. laevigata fruit extract exerted a renal protective effect through significantly ameliorating renal dysfunction in diabetic rats; with treatment of R. laevigata, the activity of superoxide dismutase and total antioxidant capacity of kidney-damaged rodents increased while the levels of MDA and ROS reduced.	55)
Renal protection	Total flavonoids (TFs)	TFs have significant protective effect against ameliorate renal ischemia-reperfusion injury (IRI) by affecting the Sirt1/Nrf2/NF-κB signalling pathway; the effect of the plant extract against renal IRI depended on Sirt1.	56)
Cardiovascular and cerebrovascular protection	Total flavonoids (TFs)	Oral administration of TFs with high-dose led to the decreases of TC, TG, LDL-C, while the increase of HDL-C; TFs possessed the protective effect against the damage of human umbilical vein endothelial cells through increasing the protein expression of procaspase-3 and Bcl-2, and decreasing the expression of Bak, Bax, Bid and p53; the antithrombotic effect of TFs was verified by the evidence that oral administration of TFs could markedly reduce the whole blood viscosity, platelet aggregation, along with prolong thrombin and prothrombin time.	61,62,64)
Cardiovascular and cerebrovascular protection	Flavonoid-rich extract (FRE)	Oral administration of f FRE significantly improved the survival rate and obviously prevented cerebral ischemia–reperfusion (I/R) induced disability and histopathological damage; the mechanisms of FRE on the protective effects in I/R injury was verified to be decreasing DNA fragmentation, up-regulating Bcl-2, and down-regulating Apaf1, FasL, Fas, p53, Bid, Bax, and cytochrome C, as well as regulating MAPK pathways.	63)
Neuroprotection	Total flavonoids (TFs)	TFs exhibited a good effect on H₂O₂-induced oxidative damage of nerve cells owing to its protection against cell apoptosis, DNA and mitochondrial damage; TFs could significantly reduce the release of cytochrome c into the cytoplasm, the level of intracellular Ca²⁺ in the mitochondria, as well as the production of intracellular ROS; TFs displayed the down-regulation of IL-1, IL-6, COX-2, TNF-α, NF-κB, AP-1, Fas, FasL, Bak, CYP2E1, caspase-3, -9, and p53, up-regulation of the expressions of Bcl-2 and Bcl-xl, along with the inhibition of the phosphorylation level of p38, JNK and ERK.	66)
	Polysaccharides (121 and 122)	121 showed obvious neuroprotective activity at a concentration of 100 µg mL⁻¹ by relieving oxidative stress in SH-SY5Y neuroblastoma cells.	26)
	Triterpenoids (14 and 22)	14 and 22 showed acetylcholinesterase inhibitory activity with IC₅₀ values of 29.22 and 45.47 µM, respectively and neuroprotective effects against H₂O₂-induced SHSY5Y cell death.	17)
Improvement of diabetic cataract	Pulp extract (RLE)	RLE treatment exerted protective effects on SRA01/04 cells via decreasing the production of ROS and elevating the levels of MMP in these cells; the expression level of HO-1 was significantly elevated in SRA01/04 cells after the RLE treatment; HO-1 induction was necessary for the function of RLE and mediated by the PI3K/Akt and Nrf2/ARE signaling pathways.	70)

3.1. Antioxidative Activity

The data from these antioxidant assays clearly show that multiple components of R. laevigata have good antioxidant activities against oxidative stress, and thus this edible fruit can be considered as a good source of natural antioxidants.^21,28,29) In general, flavonoids are an important part of antioxidant research on R. laevigata, but those pharmacological studies are often not limited to the superficial measurement of antioxidant capacity, so the relevant content will be presented in the following specific sections. It is noteworthy that the antioxidant capacities of lignans and brown pigment in R. laevigata are extraordinary.^21,29,30) The detailed results were summarized in Table 2.

3.2. Immunomodulation

Immune stimulation is considered to be an important means to improve the defence mechanism of the elderly and cancer patients.^31–34) Evidences have provided important implications of R. laevigata as an attractive immunomodulatory agent to activate the immune vitality of macrophages. In the immunomodulatory activity assays, an acid polysaccharide (123) was verified to exert the immunoregulatory activities by markedly enhancing phagocytosis, the secretion and mRNA expression of cytokines in RAW264.7 cells.²⁷⁾ The mechanism of its immunoregulation is related to the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-κB) signalling pathways.^27,35,36) Specifically, the scavenger receptor (SR), glucan receptor (GR), toll-like 2 receptor (TLR-2), and toll-like 4 receptor (TLR-4) were identified as the main pattern recognition receptors of 123 to upregulate the phospho-extracellular signal-regulated kinase (p-ERK), phospho-c-Jun N-terminal kinase (p-JNK), phospho-p38 (p-p38), and phospho-p65 (p-p65) in this study.

3.3. Anti-inflammation

In the anti-inflammatory study of R. laevigata, triterpenoids have received the most attention and their anti-inflammatory mechanism can mainly be attributed to inhibit the abnormal activation of NF-κB signalling pathway caused by lipopolysaccharide (LPS) and other stimulants.^8,37,38) Taking compound 21 as an instance, it exhibited moderate inhibitory activity on the release of tumour necrosis factor-alpha (TNF-α), Interleukin (IL)-1β, IL-6, and IL-10 with IC₅₀ values of 14.32, 8.53, 8.04, and 10.38 µM, respectively, while the IC₅₀ value was measured as 23.21 µM for the inhibition on NF-κB transcriptional activity. In addition, the triterpenoids derivatives from the fruit of R. laevigata var. leiocapus also exhibited promising anti-inflammatory effects.^18,19) What is more, pretreatment of R. laevigata extract could remarkably attenuate allergic airway inflammation in the chronic inflammation mice model through decreasing inflammatory cells, the secretion of immunoglobulin E (IgE) and related cytokines in a dose-dependent pattern, suggesting the possibility of R. laevigata as a therapeutic agent for allergic asthma via the modulation of IgE and related cytokines.³⁹⁾

3.4. Hepatic Protection

The liver is the largest metabolic organ in the human body while a diverse set of toxic elements causes liver damage and diseases.^40–43) A large number of studies have shown that R. laevigata can be applied as a promising candidate of liver protection and its mechanisms of action were all related to the functions of increasing antioxidant capacity against oxidative stress by raising antioxidant enzymes, suppressing inflammation via affecting NF-κB. In general, the main components of R. laevigata on liver protection are total flavonoids (TFs) and saponins (RLTS). For instance, the protective effect of TFs against CCl₄-induced hepatotoxicity in mice was investigated by Zhang et al.⁴⁴⁾ Their results revealed that TFs could up-regulate the expression of B-cell lymphoma-2 (Bcl-2) and down-regulate the expressions of CYP proteins E1 (CYP2E1), inducible nitric oxide synthase (iNOS), TNF-α, NF-κB, Caspase-3, fibroblast-associated (Fas)/Fas ligand (FasL), Bcl-2-antagonist/killer (Bak) and Bcl associated X protein (Bax) to alleviate liver injury. Moreover, TFs could remarkably decrease the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in mice serum, while increase the activities of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). At the same time, TFs increased the amount of glutathione (GSH) and reduced the amount of malondialdehyde (MDA). Histopathological observation also showed that TFs reduced the incidence of liver lesions, and improved liver cell DNA fragmentation and mitochondrial ultrastructure changes. It was believed that the above effect should be attributed to the activation of peroxisome proliferators-activated receptors (PPARs) and peroxysome proliferator activated receptor-γ coactlvator 1α (PGC-1α) by TFs.⁴⁵⁾ Similar findings also included that TFs could resist liver damage caused by LPS,⁴⁶⁾ Propionibacterium acnes, paracetamol,⁴⁷⁾ ischemia/reperfusion injury⁴⁸⁾ and high-fat diet.⁴⁹⁾ In addition to TFs, RLTS could also protect the liver injury induced by CCl₄ through a similar mechanism of action.^38,50,51) Moreover, RLTS exerted anti-fibrotic effects via regulating the signalling pathways of transforming growth factor-β (TGFβ)/mothers against DPP homolog (Smad), focal adhesion kinase 1 (FAK)-phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-p70S6 Kinase (p70S6K) and MAPKs. Further research also indicated that the realization of RLTS in matrix degradation could be attributed to down-regulation of matrix metalloproteinases (MMPs). Besides, Dong et al. conducted the evaluation on the effect of RLTS against acetaminophen-induced liver damage in mice, they found that RLTS could induce autophagy and suppress inflammation to treat acetaminophen-induced liver damage.⁵²⁾

3.5. Renal Protection

Traditionally, the fruit of R. laevigata is believed to possess the effects of improving sperm count and kidney health.²¹⁾ Modern pharmacological studies have demonstrated that this plant does have renal protection effects and supported their application in the ethnomedicines.^53,54) In general, R. laevigata could significantly ameliorate renal dysfunction by affecting the SIR2-like protein 1 (Sirt1)/NF-E2 related factor 2 (Nrf2)/NF-κB signalling pathway as oxidative stress, inflammation and apoptosis were found to be associated with the disease renal injury.^55,56) With treatment of R. laevigata, the activity of superoxide dismutase and total antioxidant capacity of kidney-damaged rodents increased while the levels of MDA and reactive oxygen species (ROS) reduced. More importantly, the research disclosed that the effect of the plant extract against renal injury depended on Sirt1.

3.6. Cardiovascular and Cerebrovascular Protection

Cardiovascular and cerebrovascular disease is the leading cause of death in the world.⁵⁷⁾ The effects of R. laevigata on cardiovascular and cerebrovascular protection are mainly attributed to flavonoids due to their anti-apoptotic, antioxidant and anti-inflammatory properties.^58–60) For instance, Liu et al. found oral administration of TFs with high-dose led to the decreases of total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), while the increase of high density lipoprotein-cholesterol (HDL-C).⁶¹⁾ Jia et al.⁶²⁾ proved the protective effect of TFs against the damage of human umbilical vein endothelial cells induced by hydrogen peroxide. Zhang et al.⁶³⁾ found that oral administration of flavonoid-rich extract (FRE) from R. laevigata significantly improved the survival rate and obviously prevented cerebral ischemia–reperfusion (I/R) induced disability and histopathological damage. Additionally, the antithrombotic effects of TFs were reported by Zhang et al. that oral administration of TFs could markedly reduce the whole blood viscosity, platelet aggregation, along with prolong thrombin and prothrombin time of rats in the acute blood stasis model induced by ice water and adnephrin.⁶⁴⁾

3.7. Neuroprotection

Oxidative stress-induced neuronal death plays an important role in the pathogenesis of neurodegenerative diseases,⁶⁵⁾ suggesting R. laevigata could be developed as a potential candidate for neuroprotection. TFs from R. laevigata has been showed to exhibit a good effect on H₂O₂-induced oxidative damage of nerve cells owing to its protection against cell apoptosis, DNA and mitochondrial damage.⁶⁶⁾ Additionally, the polysaccharide (121) showed obvious neuroprotective activity by relieving oxidative stress in SH-SY5Y neuroblastoma cells,²⁶⁾ while two polyhydroxy triterpenoids (14 and 22) were proved to show acetylcholinesterase (AChE) inhibitory activity and neuroprotective effects against H₂O₂-induced SHSY5Y cell death.¹⁷⁾ In particular, 14 and 22 caused a 92 and 89% inhibition on the target enzyme at high concentration, which was consistent with the results in AChE molecular docking studies.

3.8. Improvement of Diabetic Cataract

More and more evidences suggested that abnormal ROS metabolism may be an important factor leading to diabetic cataract.^67–69) Liu et al. investigated the effects of R. laevigata extract (RLE) on ROS production and matrix metalloproteinases (MMPs) in lens epithelial cells cultured under high glucose condition. The results revealed the RLE treatment to exert protective effects on SRA01/04 cells, and the mechanism of action is to reduce the production of ROS and increase the level of MMPs by affecting PI3K/Akt and Nrf2/antioxidant response element (ARE) signalling pathways.⁷⁰⁾ Although there are few pharmacological studies on the treatment of diabetic cataract, it also indirectly indicates that R. laevigata has multiple pharmacological effects.

4. Conclusion

R. laevigata is a kind of medicine and food homologous plant that has been used for a long time. The present review summarizes this medicinal plant comprehensively from the aspects of photochemistry and pharmacology. To date, previous studies on phytochemical investigation in various parts of R. laevigata have exposed the presence of triterpenoids, flavonoids, tannins, ligands and polysaccharides in this plant. Among these isolates (123 ingredients in total), 77 triterpenoids have been isolated and thus regarded to be main and characteristic substance of this plant, and could be taken as typical chemotaxonomic markers for identification of R. laevigata from the phytochemical point of view. Currently, the obtained triterpenoids can be divided into four categories based on their structures: ursane-type (totaling 45 compounds), oleanane-type (totaling 13 compounds), lupinane-type (totaling 8 compounds), as well as seco-triterpenoids (totaling 11 compounds). In general, most of the triterpenoids obtained from R. laevigata can be classified into polyhydroxy triterpenoids, the main differences among them depended on the number of the hydroxyl groups and their substitution positions. Most of the pharmacological researches on R. laevigata are mainly focused on its fruits while other tissues such as leaf, stems and roots have received relatively less attention. According to the literature reports, R. laevigata exhibited antioxidant activity, immunomodulatory effect, anti-inflammatory effect, liver protection, kidney protection, cardiovascular protection, neuroprotective effect, and improvement of diabetic cataract. Interestingly, these pharmacological results provide evidences to prove the correlations between folk medication experience and pharmacological activity research, for example, R. laevigata has been regarded as a valuable kidney tonifying medicinal diet, while modern pharmacological studies show that R. laevigata can significantly improve renal insufficiency by regulating Sirt1/Nrf2/NF-κB signalling pathway.⁵⁶⁾ In addition, these different chemical ingredients existing in the title plant may have synergistic effects. For instance, both TFs and RLTS from R. laevigata could exert the liver protective effects through increasing the body’s antioxidant capacity as well as suppressing inflammation and apoptosis.^44–52) In conclusion, pharmacological studies on crude extracts and chemical ingredients of R. laevigata have revealed this plant to be a valuable source for therapeutic foodstuff.

5. Future Perspective

Although considerable progress has been made in the phytochemistry and pharmacology of R. laevigata, there are still some important areas to be explored in order to better understand its pharmacological effects and clinical efficacy. (i) Till now, pharmacological studies on the title plant have mainly focus on the total flavonoids, and thus the evidence of medicinal value of other types of compounds is still lacking, especially triterpenoids, which have been proved to be the dominant substances existing in R. laevigata. Consequently, the pharmacological researches of other components should be strengthened to support their application in ethnic medicine. (ii) The evaluation of biological activities of R. laevigata are principally focus on anti-inflammatory and anti-oxidation actions, and even other pharmacological studies were carried out around these two factors. Hence the in-depth mechanism of action remains to be investigated with modern pharmacological techniques. (iii) Toxicological studies of R. laevigata are limited. The current data only provide study on subchronic toxicity of total flavonoids from R. laevigata fruit at oral doses of 500, 1000 and 2000 mg/kg/d in rats. In the high dose group, the decreased adrenal gland weight and platelet counts, along with the increased intercellular space of myocardial cells and the relative heart weight were observed, therefore, the dose of 500 mg/kg/d was considered as no-observed-adverse-effect-level.⁷¹⁾ However, the toxicity of other components has not been reported, hence, extensive toxicity and safety assessment should be conducted to determine the side effects, acute and chronic toxicity. (iv) Obviously, triterpenoids (especially ursane-type triterpenes) are the principal and characteristic bioactive substances occurring in this species. However, polysaccharides have been documented as the standard for the quality control of R. laevigata in Chinese Pharmacopoeia (2020 Edition). According to our opinion, total triterpenoids should be considered as new standard in the new version of Chinese Pharmacopoeia. (v) In literature review, it was found that there were few studies on chemistry and pharmacology which were consistent with the efficacy of traditional Chinese medicine theory of R. laevigata. Above all, let’s take the best-known efficacy of R. laevigata, renal protective and fertility-improving function, as an example. In traditional Chinese medicine theory, the fruit of R. laevigata is believed to possess the effects of improving sperm count and kidney health. Although it has been reported that the fruits of this plant could protect the kidney through affecting the Sirt1/Nrf2/NF-κB signaling pathway, articles focus on this aspect are still scarce, and the animal models used are not diversified. Moreover, to the best of our knowledge, there is no report on the improvement of sexual dysfunction by this plant. More importantly, to date, there is no single monomer compound has been proved to be responsible for these efficacies. In addition, during the investigation on the pharmacological researches in this plant, most of the activities could be attributed to the antioxidant and anti-inflammatory activities. Therefore, appropriate experimental models in vivo and in vitro should be selected pertinently in future research in order to better combine the pharmacological activities with the traditional medication experience. Additionally, specific monomer compounds should be demonstrated to be responsible for the studied pathological models. To be emphasized once again, the in-depth mechanism of action remains to be investigated with modern pharmacological techniques.

Acknowledgments

Copyright of Fig. 1 was generously provided by holders of the online medicine store. Figures 1A–C were separately from: https://item.taobao.com/item.htm?spm=a1z0k.7386009.0.d4919233.e132879BO3aT0&id=578749350050&_u=t2dmg8j26111; https://item.taobao.com/item.htm?spm=a1z0k.7386009.0.d4919233.e1326879BO3aT0&id=598579539499&_u=t2dmg8j26111. This work was financially supported by the National Natural Science Foundation (No. 81903509).

Conflict of Interest

The authors declare no conflict of interest.

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