The genus Rumex (Polygonaceae):an ethnobotanical,phytochemical and pharmacological review

Jing?Juan Li,Yong?Xiang Li,Na Li,Hong?Tao Zhu,Dong Wang and Ying?Jun Zhang,3*

1 State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,People’s Republic of China

Abstract Rumex L.,a genus in Polygonaceae family with about 200 species,is growing widely around the world.Some Rumex species,called "sorrel" or "dock",have been used as food application and treatment of skin diseases and hemostasis after trauma by the local people of its growing areas for centuries.To date,29 Rumex species have been studied to contain about 268 substances,including anthraquinones,flavonoids,naphthalenes,stilbenes,diterpene alkaloids,terpenes,lignans,and tannins.Crude extract of Rumex spp.and the pure isolates displayed various bioactivities,such as antibacterial,anti?inflammatory,antitumor,antioxidant,cardiovascular protection and antiaging activities.Rumex species have important potential to become a clinical medicinal source in future.This review covers research articles from 1900 to 2022,fetched from SciFinder,Web of Science,ResearchGate,CNKI and Google Scholar,using “Rumex” as a search term ("all fields") with no specific time frame set for the search.Thirty?five Rumex species were selected and summarized on their geographical distribution,edible parts,traditional uses,chemical research and pharmacological properties.

Keywords: Polygonaceae,Rumex L.,Anthraquinones,Phenolics,Pharmacological properties

1 Introduction

RumexL.,the second largest genus in the family Polygonaceae,with more than 200 species,is mainly distributed in the northern temperate zone [1].It is mostly perennial herbs with sturdy roots,paniculate inflorescences,and triangular fruits that are enveloped in the enlarged inner perianth.The name "Rumex" originated from the Greek word–"dart" or "spear",alluding to the shape of leaves [2].The other explanation from Rome–"rums" alludes to the function that the leaves could be sucked to alleviate thirst [3].R.acetosa,a typical vegetable and medicinal plant,whose name ’acetosa’ originated from the Latin word "acetum",described the taste of the plant as vinegar.Currently,many oxalic acids have been reported fromRumex,verifying its sour tastes [4].

Rumexspecies have had a valued place as global folk medicine,e.g.,in Southern Africa,America,India,China,and Turkey.The earliest medicinal record ofRumexspp.in China was in "Shennong’s Herbal Classic",in whichRumexwas recorded for the treatment of headed,scabies,fever,and gynecological diseases.Roots ofRumex,also called dock root,have been reported for its therapeutic capacity of bacterial infections,inflammatory,tumor and cardiovascular diseases [5,6].Recently,pharmacological study showed thatRumexspecies displayed apparent antibacterial and antifungal effects [7],and were employed in the management of skin scabies and inflammation [8,9].The processedRumexexhibited different chemical profiles and bioactivities [10,11].Leaves,flowers and seeds of someRumexplants are edible as vegetables,while in some regions,theRumexplants are regarded as noxious weeds because oxalic acid makes them difficult to be digested [12].

To date,268 components from 29Rumexspecies have been reported.Anthraquinones,flavonoids,tannins,stilbenes,naphthalenes,diterpene alkaloids,terpenes,and lignans were as the main chemical components,with a broad spectrum of pharmacological activities,such as anti-inflammatory,antioxidant,antibacteria,antitumor,and antidiabetic activities [13–17].In addition to important role ofRumexin the traditional applications,researchers also regardRumexas a potential effective medicine of many diseases.This article has reviewed a comprehensive knowledge on the distribution,traditional uses,chemistry and bioactivity progress ofRumex,and their therapeutic applications and utilizations were provided.

2 Geographical distributions,local names,parts used and traditional uses

The genusRumexwith more than 200 species,is distributed widely in the world and has been used traditionally in many regions,e.g.,Asia,America,Europe and other continents.Many of them known as "sorrel" or "dock"have a long history of food application and medicinal uses for the treatment of skin diseases,and hemostasis after trauma by the local people of its growing areas.For example,R.acetosais commonly used medicinally for diuretics around the world [4].R.maritimusandR.nepalensis,used as laxatives,have long-term medicinal applications in India as substitutes forRheum palmatum(Polygonaceae),which is usually used to regulate the whole digestive system.Moreover,Indians have also recorded nineRumexplants as astringent agents,includingR.acetosa,R.acetosella,R.crispus,R.dentatus,R.hastatus,R.maritimus,R.nepalensis,R.scutatus,andR.vesicarius[18].All seven species includedR.acetosa,R.trisetifer,R.patientia,R.crispus,R.japonicus,R.dentatusandR.nepalensis,called "jinbuhuan",have been used for hemostasis remediation in China [19].R.thyrsiflorus,rich in nutrition,has been used as food by Europeans in history and as folk medicine due to its obvious antiinflammatory activity [20].R.lunariahas been used to treat diabetes by Canarian medicine [16].The leaves of more than 14Rumexspp.,such asR.acetosa,R.hastatus,R.thyrsiflorus,R.aquaticus,R.crispus,R.gmelini,R.patientia,R.vesicarius,R.ecklonianus,R.abyssinicus,R.confertus,R.hymenosepalus,R.alpinusandR.sanguineus(Table 1) could be eaten freshly or cooked as vegetables in the folk of many places [5,6].In Table 1,the geographical distributions,local names,parts used and traditional uses of 35Rumexspecies are summarized.

Table 1 Traditional uses of Rumex plants

Table 1(continued)

Table 1(continued)

3 Chemical constituents

To date,268 compounds including 56 quinones (1–56),57 flavonoids (57–113),25 tannins (114–138),6 stilbenes (139–144),22 naphthalenes (145–166),6 terpenes(167–172),3 diterpene alkaloids (173–175),14 lignans(176–189) and 79 other types of components (190–268) were isolated and reported from 29Rumexspecies(Table 2).

Table 2 The summary of compounds in Rumex

Table 2(continued)

Table 2(continued)

Table 2(continued)

Table 2(continued)

Table 2(continued)

Table 2(continued)

Table 2(continued)

3.1 Quinones

Quinones are widely found inRumex,particularly accumulated in the roots.56 quinones (Fig.1) including anthraquinones,anthranones,andseco-anthraquinones and their glycosides and dimers were isolated and identified from more than 17Rumexspecies (Table 2).Among them,anthraquinoneO-andC-glycosides with glucose,galactose,rhamnose,and 6-hydroxyacetylated glucose as commonly existing sugar moieties,were normally found inRumex.Three anthraquinones,chrysophanol (1),emodin (8) and physcion (18) are commonly used indicators to evaluate the quality ofRumexplants [22].Some new molecules were also reported.For example,xanthorin-5-methylether (30) was isolated fromR.patientiafor the first time [23,24],and two new antioxidant anthraquinones,obtusifolate A (45) and B (46) were isolated fromR.obtusifolius[25].

Fig.1 Structures of quinones (1—56)

The anthranones often existed in pairs of enantiomers,whosemeso-position is commonly connected with aC-glycosyl moiety.The enantiomers,rumejaposides A (21) and B (22),E (25) and F (26),G (27) and H (28)were reported fromR.dentatus,R.japonicus,R.nepalensisandR.patientia[26–28].Three hydroxyanthrones,chrysophanol anthrone (7),emodin anthrone (17),physcion anthrone (20),whose C-10 were reduced as an alphatic methylene,were isolated from the roots ofR.acetosafor the first time [29],while a new anthrone,rumexone (31) was reported from the roots ofR.crispus[30].Two anthranones,10-hydroxyaloins A (39) and B(40) were reported fromRumexfor the first time [31].A new 8-ionized hydroxylated 9,10-anthraquinone namely,rumpictusoide A (56) was isolated from the whole plant ofR.pictus[183].Moreover,two new oxanthroneC-glucosides 6-methoxyl-10-hydroxyaloins A (41) and B (42)were isolated from the roots ofR.gmelini[32].

Seco-anthraquinones are oxidized anthraquinones with a loop opened at C-10,resulting in the fixed planar structure of anthraquinone destroyed and causing of a steric hindrance between the two left benzene rings.So far,only twoseco-anthraquinone glucosides,nepalensides A(49) and B (50) were reported from the roots ofR.nepalensis[33].

3.2 Flavonoids

Flavonoids are one of the most important bioactive components existing widely in plant kingdom.To date,57 flavonoids (57–113) including flavones,flavanols,chromones and their

glycosides were reported fromRumex(Fig.2,Table 2).They are mostly derived from kaempferol (63) and quercetin (71) connecting with glucosyl,rhamnosyl,galactosyl and arabinosyl moieties at different positions.For example,kaempferol (63) together with seven glycosides,-3-O-β-D-glucoside (64),-3-O-α-L-rhamnoside (65),-3-O-α-L-rhamnosyl-(1→6)-β-D-galactoside(66),-3-O-α-L-arabinosyl-(1→6)-β-D-galactoside (67),-3-O-(2’-O-acetyl-α-L-arabinosyl)-(1→6)-β-D-galactoside (68),-7-O-β-D-glucoside (69) and-7-O-α-L-rhamnoside (70)[14,23,34–42],and quercetin (71) together with 11 derivatives,-3-O-β-D-glucoside (72),-3-O-β-D-glucuronide(73),-3-O-β-D-glucosyl(1→4)-β-D-galactoside (74),-3-O-α-L-rhamnoside (75),-3-O-α-L-arabinoside(80),-3-O-α-L-arabinosyl-(1→6)-β-D-galactoside(81),-3-O-[2’-O-acetyl-α-L-arabinosyl]-(1→6)-β-Dgalactoside (82),-7-O-β-D-glucoside (83),-7-O-α-L-rhamnoside (84),3-O-methyl quercetin (97) and-3,3’-dimethylether (113) [14,23,27,35,37,38,40–50,148],were reported from severalRumexplants.

Fig.2 Structures of flavonoids (57–113)

Moreover,a new chromone glucoside,2,5-dimethyl-7-hydroxychromone-7-O-β-D-glucoside (95) was isolated from the root ofR.gmelini[31],and five chromones,7-hydroxy-2,3-dimethyl-chromone (90),5-methoxy-7-hydroxy-1(3H)-chromone (91),5,7-dihydroxy-1(3H)-chromone (92),2,5-dimethyl-7-hydroxychromone-7-O-β-D-glucoside (95)and 2,5-dimethyl-7-hydroxychromone (96) were reported fromR.gmelini,R.nepalensis,R.patientiaandR.cristatus[31,51–53].

Catechin (105) and epicatechin (107) are commonly distributed inR.patientia,the roots ofR.rechingerianus,the whole plant ofR.crispus,and the leaves ofR.acetosa[34,37,39,49,54,55].Moreover,a variety of flavan-3-ols,105,107,epicatechin-3-O-gallate (110),epigallocatechin-3-O-gallate (111) were isolated fromR.acetosa[49,56].

3.3 Tannins

Tannins,which may be involved with the hemostasis activity,are abundant inRumexplants.So far,25 condensed tannins (114–138) (Fig.3,Table 2) were reported from the genusRumex.

Fig.3 Structures of tannins (114–138)

Chemical investigations on the EtOAc fraction of acetone–water extract of the aerial parts ofR.acetosashowed thatR.acetosawas rich in tannins.Five new condensed tannin dimers,epiafzelechin-(4β→8)-epicatechin-3-O-gallate (127),cinnamtannin B1-3-O-gallate(132) and epiafzelechin-(4β→6)-epicatechin-3-O-gallate(135),and trimers,epiafzelechin-(4β→8)-epicatechin-(4β→8)-epicatechin (114),and epicatechin-(2β→7,4β→8)-epiafzelechin-(4α→8)-epicatechin (132),were reported.In addition,some procyanidins and propelargonidins,epiafzelechin-(4β→8)-epicatechin-(4β→8)-epicatechin (114),epicatechin-(4β→8)-epicatechin-(4β→8)-catechin (115),procyanidin C1 (116),epicatechin-(4β→6)-catechin (121),procyanidin B1-B5(120,122–125),and epicatechin-(4β→8)-epicatechin-3-O-gallate (126),were also isolated [56,107].

3.4 Stilbenes

So far,6 stilbenes have been separated fromRumex(139–144) (Fig.4,Table 2).Resveratrol (139) isolated fromR.japonicaHoutt was found for the first time from the Polygonaceae family [108].It has been widely applied in cardiovascular protection and as antioxidation agent [109].Resveratrol (139),(Z)-resveratrol (140)and polydatin (141) were obtained fromRumexspp.[14,32,35,45,110,111].5,4’-Dihydroxy-3-methoxystilbene (142),3,5-dihydroxy-4’-methoxystilbene (143) and 5,4’-dihydroxy-stilbene-3-O-α-arabinoside (144) were separated from the roots ofR.bucephalophorus[77].

3.5 Naphthalenes

Naphthalenes are also widely distributed inRumex.At present,22 naphthalenes including naphthol,α-naphthoquinones and their derivatives have been identified fromRumex(145–166) (Fig.4,Table 2).Nepodin(145) and nepodin-8-O-β-D-glucoside (146) are widespread inRumex[31,45,112,113].In addition,145,nepodin-8-O-β-D-(6’-O-acetyl)-glucoside (147),rumexoside (154),6-hydroxymusizin-8-O-β-D-glucopyranoside(158) and hastatuside B (164) were isolated fromR.hastatus[35,110,114].2-Methoxystypandrone (152)was isolated fromR.japonicusandR.maritimus[115,116].Notably,some naphthalenes containing Cl,2-acetyl-4-chloro-1,8-dihydroxy-3-methylnaphthalene-8-O-β-D-glucoside (155) and patientoside B (156) were isolated fromR.patientia[117].Moreover,3-acetyl-2-methyl-1,5-dihydroxyl-2,3-epoxynaphthoquinol (153),3-acetyl-2-methyl-1,4,5-trihydroxyl-2,3-epoxy-naphtho-quinol(159) and 3-acetyl-2-methyl-1,5-dihydroxyl-7-methoxyl-2,3-epoxynaphthoquinol (160),which contain the ethylene oxide part of the structure,were rarely found inRumex,and they were reported fromR.patientia,R.japonicusandR.nepalensis[51,65,118,119].4,4’-Binaphthalene-8,8’-O,O-di-β-D-glucoside (157) was isolated fromR.patientia[120].

Fig.4 Structures of stilbenes (139–144) and naphthalenes (145–166)

3.6 Terpenes

Until now,only six terpenes have been reported fromRumex(Fig.5,Table 2).Four pentacyclic triterpenes,i.e.,tormentic acid (167),myrianthic acid (168) and 2α,3α,19α-trihydroxy-24-norurs-4(23),12-dien-28-oic acid (169) and (4R)-23-epoxy-2α,3α,19α-trihydroxy-24-norurs-12-en-28-oic acid (170) were obtained from the EtOAc fraction of the stems ofR.japonicus.Of them,169 and 170 were two new 24-norursane type triterpenoids,whose C-12 and C-13 were existed as double bonds[121].A ursane (α-amyrane) type triterpene,taraxasterol acetate (171) was isolated fromR.hastatus.[63].And lupeol (172) was isolated from the roots ofR.nepalensisfor the first time [122].

Fig.5 Structures of terpenes (167–172)

3.7 Diterpene alkaloids

So far,only three hetisane-type (C-20) diterpene alkaloids,orientinine (7,11,14-trihydroxy-2,13-dioxohetisane,173),acorientine (6,13,15-trihydroxyhetisane,174) and panicudine (6-hydroxy-11-deoxy-13-dehydrohetisane,175) were reported from the aerial part ofR.pictus.They might be biosynthesized from tetra-or penta-cyclic diterpenes [75] (Fig.6,Table 2).

Fig.6 Structures of diterpene alkaloids (173–175)

3.8 Lignans

Fourteen lignans (176–189) were summarized fromRumex(Fig.7,Table 2).A new lignan,3-methoxyarctiin-4’-O-β-D-xyloside (178),and two known ones,arctiin(176) and 3-hydroxy-arctiin (177),were obtained fromR.patientia[23].Six lignan glycosides,schizandriside(183),(-)-isolariciresinol-9-O-β-D-xylopyranoside (184),(-)-5-methoxyisolariciresinol-9-O-β-D-xylopyranoside(185),(+)-5-methoxyisolariciresinol-9-O-β-D-xylopyran oside (186),(+)-lyoniside (187) and nudiposide (188)were reported fromR.hastatusfor the first time [111].

Fig.7 Structures of lignans (176–189)

3.9 Other compounds

Up to now,79 coumarins,sterides,alkaloids,glycosides and polysaccharide were found in Rumex(190–268) (Fig.8,Table 2).Phenylethyl-O-α-Larabinopyransy-(1→6)-O-β-D-glucoside (190) and 5-methoxyl-1(3H)-benzofuranone-7-glucoside (226)were isolated from R.gmelini for the first time [31].p-Hydroxybenzoic acid (205),p-coumaric acid (206),methyl 3,4-dihydrophenylpropionate (207),vanillic acid (208) and isovanillic acid (209) were isolated from the leaves ofR.acetosa[39].β-Sitosterol (232) and daucosterol (233) are commonly distributed inR.acetosa,R.chinensis,R.crispusandR.gmelini[31,34,39,101].2,6-Dimethoxy-4-hydroxyl benzoic acid (212)was isolated fromR.japonicus[26].Moreover,rumexin(218),caffeic acid (219),1-O-caffeoylglucose (220) and 1-methyl caffeic acid (221) were isolated from the aerial parts of R.aquatica [38].Recently,one new compound(S)-4′-methylnonyl benzoate (223) was reported from R.dentatus [14].Ergosta-6,22-diene-3,5,8-triol (234) was isolated from the EtOAc fraction of R.abyssinicus for the first time [123].Conventional techniques and supercritical fluid extraction (SFE) were compared and the latter yielded great efficiency of phenolics from the roots of R.acetosa [124].

Fig.8 Structures of other compounds (190–268) (Note:268 not given)

Ceryl alcohol (245) fromR.ecklonianus[125],andβ-carotene (254) and lutein (255) fromR.vesicarius[126] were reported.Moreover,anhydroluteins I (256) and II (257) were separated fromR.rugosustogether with 255 [95].From the roots ofR.dentatus,helonioside A (265) was isolated for the first time[48].One new phloroglucinol glycoside 1-O-β-D-(2,4-dihydroxy-6-methoxyphenyl)-6-O-(4-hydroxy-3,5-dimethoxybenzoyl)-glucoside (266) was isolated fromR.acetosa[56].It was the first time that 1-O-β-D-(3,5-dimethoxy-4-hydroxyphenol)-(6-O-galloyl)-glucoside(267) was isolated fromR.nepalensis[33].

Rumexpolysaccharides have rarely been studied,and only one polysaccharide,RA-P (268),which has a 30 kDa molecular weight and consists of D-glucose and D-arabinose,was reported fromR.acetosa[127].

4 LC–MS analysis

The chemical compositions ofRumexspp.were also analyzed by LC–MS techniques.Untargeted metabolomic profiling via UHPLC-Q-TOF–MS analysis on the flowers and stems ofR.tunetanusresulted in the identification of 60 compounds,18 of which were reported from the Polygonaceae family for the first time.Quercetin-3-O-β-D-glucuronide (73) was found to be the most abundant phenolic compound in flowers and epicatechin-3-Ogallate (110) in stems [103].Moreover,44 bioactive components classified as sugars,flavanols,tannins and phenolics were clarified from the flowers and stems ofR.algeriensisbased on RP-HPLC–DAD-QTOF-MS and MS–MS [102].The analysis of sex-related differences in phenolics ofR.thyrsiflorushas shown female plants ofR.thyrsifloruscontain more bioactive components than males,such as phenolic acids and flavonoids,especially catechin (105) [20].

5 Bioactivity

Rumexhas been used as food and medicine in the folk.In addition to important role ofRumexin the traditional application,during the past few decades,it was subjected to scientific investigations of the structure of isolated chemical components and their clinical applications by several research groups.Pharmacological studies onRumexextracts and its pure components revealed a wide range of bioactivities,involving antimicrobial,antiinflammatory,antiviral,renal and gastrointestinal protective effects,antioxidant,antitumor and anti-diabetes effects.

5.1 Antimicrobial

Bioassay-guided isolation on the whole plants ofR.abyssinicusyielded six antimicrobial quinones,chrysophanol(1) and its 8-O-β-D-glucoside (3),emodin (8),6-hydroxyemodin (14),physcion (18) and its 8-O-β-D-glucoside(19),with MIC values of 8—256 μg/mL [123].

Proanthocyanidin-enriched extract from the aqueous fraction of the acetone–water (7: 3) extract of the aerial parts ofR.acetosa(5 μg/mL—15 μg/mL) could interfered with the adhesion ofPorphyromonas gingivalis(ATCC 33,277) to KB cells (ATCC CCL-17) both in vitro and in situ.In silico docking assay,a main active constituent fromR.acetosa,epiafzelechin-3-O-gallate-(4β→8)-epicatechin-3-O-gallate (130) exhibited the ability to interact with the active side of Arg-gingipain and the hemagglutinin fromP.gingivalis[139].

A bacteriostasis experiment of two naphthalenes,torachrysone (150) and 2-methoxy-stypandrone (152) isolated fromR.japonicusroots,showed inhibitory effect on both gram-negative and gram-positive bacteria [152].The antibacterial (Bacillus subtilis,Escherichia coli,Moraxella catarrhalis,etc.) potential of then-hexane,chloroform,aqueous fractions of 14Rumexfrom Carpathian Basin (R.acetosella,R.acetosa,R.alpinus,R.aquaticus,R.crispus,R.patientia,R.pulcher,R.conglomeratus,R.thyrsiflorus,etc.) were investigated by the disc diffusion method.It showed that then-hexane and chloroform fractions of roots ofR.acetosa,R.alpinus,R.aquaticus,R.conglomeratusandR.patientiaexhibited stronger activity against bacteria (inhibition zones >15 mm).Naphthalenes (145,146,151,152) exhibited antibacterial capacity against several bacterial strains (MIC=48—57.8 μM,in case ofM.catarrhalis;MIC=96—529.1 μM,in case ofB.subtilis)than anthraquinones (1,3,8,12,14,18),flavonoids (62,71,80,105,112,113),stilbenes (139,141) and 1-stearoylglycerol (237),etc.,which were isolated fromR.aquaticus[148].

Antimicrobial study demonstrated thatR.crispusandR.sanguineushave the potential for wound healing due to their anti-Acinetobacter baumanniiactivities(MIC=1.0—2.0 mg/mL,R.crispus;1.0—2.8 mg/mL,aerial parts ofR.sanguineus;1.4—4.0 mg/mL,roots ofR.sanguineus) [106].

5.2 Anti?inflammatory

The potential effects of anti-inflammatory of AST2017-01 composing of processedR.crispusandCordyceps militariswhich was widely used in folk medicines in Korea,as well as chrysophanol (1) on the treatment of ovalbumin-induced allergic rhinitis (AR) rats were investigated.The serum and tissue nasal mucosa levels of IgE,histamine,TSLP,TNF-α,IL-1,IL-4,IL-5 and IL-13 were both decreased by treatment with AST2017-01 and 1 (positive control: dexamethasone),indicating thatR.crispusand 1 has the ability to prevent and treat AR [153].The aqueous extract of roots ofR.patientiahas anti-inflammatory action in vivo.The higher dose of extract (150 mg/kg) showed inhibition(41.7%) of edema in rats compared with the positive control,indomethacin (10 mg/kg,36.6%) [21].Methanolic extracts of the roots and stems ofR.roseusexhibited anti-inflammatory functions in intestinal epithelial cells,reducing TNF-α-induced gene expression of IL-6 and IL-8 [154].

The ethanol extract of the roots ofR.japonicuscould be a therapeutic agent for atopic dermatitis.Skin inflammation in Balb/c mice was alleviated with the extract in vivo.Moreover,an in vitro experiment showed that the extract ofR.japonicusdecreased the phosphorylation of MAPK and stimulated NF-κB in TNF-αin HaCaT cells [155].The methanolic extract ofR.japonicusinhibited dextran sulfate sodium (DSS)-induced colitis in C57BL/6 N mice by protecting tight junction connections in the colonic tissue.It was observed thatR.japonicushas the potential to treat colitis [156].Ethyl acetate extract of the roots ofR.crispusshowed anti-inflammatory activity in inhibiting NO production and decreasing the secretion of proinflammatory cytokines [157].

5.3 Antivirus

1,4-Naphthoquinone and naphthalenes fromR.aquaticuspresented antiviral activity againstherpes simplexvirus type 2 (HSV-2) replication infected Vero cells.In which,musizin (145) showed dose dependent inhibitory property,causing a 2.00 log10reduction in HSV-2 at 6.25 μM,on a traditional virus yield reduction test andqPCR assay.It suggested thatR.aquaticushad the potential to treat HSV-2 infected patients [158].

Acetone–water extract (R2,which contains oligomeric,polymeric proanthocyanidins and flavonoids) from the aerial parts ofR.acetosashowed obvious antiviral activities via plaque reduction test and MTT assay on Vero cells.R2 was 100% against herpes simplex virus type-1 at concentrations >1 μg/mL (IC50=0.8 ± 0.04 μg/mL).At concentrations >25 μg/mL (CC50=78.6 ± 12.7 μg/mL),cell vitality was more than 100% reduced by R2 [107].

5.4 The function in kidney and gastrointestinal tract

It is noted that quercetin-3-O-β-D-glucoside (72,QGC)fromR.aquaticuscould alleviate the modle that indomethacin (nonsteroidal anti-inflammatory drugs)induced gastric damage of rats and ethanol extract ofR.aquaticushad a protective effect on the inflammation of gastric epithelial cells caused byHelicobacter pylori.In vivo research suggested that QGC pretreatment could decrease gastric damage by increasing mucus secretion,downregulating the expression of intercellular adhesion molecule-1 and decreasing the activity of myeloperoxidase.The in vitro test found that flavonoids including QGC could inhibit proinflammatory cytokine expression and inhibit the proliferation of an adenocarcinoma gastric cell line (AGS) [159,160].The cytoprotective effect of QGC against hydrogen peroxide-induced oxidative stress was noticed in AGS [161].Moreover,QGC also showed protective efficiency in a rat reflux esophagitis model in a dose-dependent manner (1—30 mg/kg) [162].

Ten anthraquinones chrysophanol (1),chrysophanol-8-O-β-D-glucoside (3),6’-acetyl-chrysophanol-8-O-β-D-glucoside (6),emodin (8),emodin-8-O-β-D-glucoside(12),physcion (18),aloe-emodin (13),rumexpatientosides A (47) and B (48) and nepalenside A (49) fromR.patientia,R.nepalensis,R.hastatusnot only inhibited the secretion of IL-6,but also decreased collagen IV and fibronectin production at a concentration of 10 μM in vitro.On which concentration,they were nontoxic to cells [133].It suggested that anthraquinones have great potential to treat kidney disease.

5.5 Antioxidant properties

An extraction technology to obtain the total phenolics ofR.acetosawas optimized and the antioxidant activity of different plant parts ofR.acetosawas well investigated.It was found that the 80% methanol extract of the roots (IC50=118.8 μM) showed higher scavenging activity to DPPH free radicals than the other parts (leaves:IC50=201.6 μM,flowers and fruits: IC50=230.1 μM,stems: IC50=411.2 μM) [163].The roots ofR.thyrsiflorus[164],ethanol extracts ofR.obtusifoliusandR.crispusshowed antioxidant ability on DPPH,ABTS+and FRAP assays [165].Moreover,R.tingitanusleaves,R.dentatus,R.rothschildianusleaves,R.roseusandR.vesicariusalso showed antioxidant activity on DPPH assay [13,78,105,154,166,167].Phenolics isolated fromR.tunetanusflowers and stems displayed antioxidant properties on DPPH and FRAP assays [103].DPPH,ABTS+,NO2?radical scavenging and phosphomolybdate antioxidant assays verified thatR.acetosellahas antioxidant properties[168].Phenolic constitutions fromR.maderensisdispalyed antioxidant activity after the gastrointestinal digestion process.These components are known as dietary polyphenols and have the potential to be developed as functional products [99].

Moreover,the total antioxidant capacities ofR.crispuswere found to be 49.4%—86.4% on DPPH,ABTS+,NO,phosphomolybdate and SPF assays,which provided the basis to developR.crispusas antioxidant,antiaging and skin care products [169].Later on,the ripe fruits ofR.crispuswere studied and the aqueous extract showed antioxidant activity in vitro [170].Dichloromethane and ethyl acetate extracts ofR.crispusexhibited stronger antioxidant activity,which were associated with the concentration of polyphenols and flavonoids [157].The antioxidant activities of chrysophanol (1),1,3,7-trihydroxy-6-methylanthraquinone (54),przewalskinone B(55) andp-coumaric acid (206) isolated fromR.hastatuswere investigated on a nitric oxide radical scavenging assay,whose IC50values were 0.39,0.47,0.45,and 0.45 mM,respectively [134].

5.6 Antitumor properties

MTT assays on HeLa (human cervical carcinoma),A431(skin epidermoid carcinoma) and MCF7 (human breast adenocarcinoma) cell lines showed thatR.acetosaandR.thyrsifloruscould inhibit the tumor cell proliferation [171].The fruit ofR.crispusshowed cytotoxicity on HeLa,MCF7 and HT-29 (colon adenocarcinoma)cells in vitro [170].The methanolic extract ofR.vesicariuswas assessed for hepatoprotective effects in vitro.CCl4-induced hepatotoxicity was observed at 100 mg/kg bw and 200 mg/kg bw.The plant also has cytotoxicity in HepG2 (human hepatoma cancer) cell lines [172].Dichloromethane extract ofR.crispusroots inhibited the growth and induced cellular apoptosis of HepG2 cells[157].The hexane fraction ofR.rothschildianusleaves showed 98.9% and 97.4% inhibition of HeLa cells and MCF7 cells at a concentration of 4 mg/mL [105].

Different plant parts (stems,roots,flowers and leaves)ofR.vesicariuswere screened for their cytotoxicity by the MTS method on MCF7,Lovo and Caco-2(human colon cancer),and HepG2 cell lines.The stems displayed stronger cytotoxicity in vitro and with nontoxicity on zebrafish development,with IC50values of 33.45—62.56 μM.At a concentration of 30 μg/mL,the chloroform extract of the stems inhibited the formation of ≥ 70% of intersegmental blood vessels and 100% of subintestinal vein blood vessels when treated zebrafish embryos,indicating the chloroform extract ofR.vesicariusstems has apparent antitumor potential [15].

2-Methoxystypandrone (152) fromR.japonicusexhibited antiproliferative effect on Jurkat cells and the potential to treat leukemia,by reducing the mitochondrial membrane potential and increasing the accumulation of mitochondrial reactive oxygen,as shown by flow cytometry [116].The phenolic extract from the flower parts ofR.acetosaexhibited in vitro antiproliferative effects on HaCaT cells.When increasing of the extract concentration from 25 μg/mL to 100 μg/mL,the proliferation ability on HaCaT cells gradually decreased [147].

5.7 Antidiabetes activities

Chrysophanol (1) and physcion (18) from the roots ofR.crispusshowed inhibition onα-glucosidase,with IC50values of 20.1 and 18.9 μM,respectively [180].The alcohol extract ofR.acetoselladisplayed stronger inhibitory activity onα-glucosidase (roots,IC50=12.3 μM;aerial parts,IC50<10 μM),compared to the positive control,acarbose (IC50=605 μM,p<0.05),revealingR.acetosellacould be developed as an antidiabetic agent [168].Moreover,the methanolic extract ofR.lunarialeaves displayed remarkable kinetic of-α-glucosidase activity from the concentration of 3 μM by comparison with blank control [16],and the acetone fraction ofR.rothschildianusleaves showed inhibitory activity againstα-amylase andα-glucosidase (IC50=19.1 ± 0.7 μM and 54.9 ± 0.3 μM,respectively) compared to acarbose (IC50=28.8,37.1 ± 0.3 μM,respectively) [105].

The hypoglycemic effects of oral administration of ethanol extract ofR.obtusifoliusseeds (treatment group)were compared to the control group (rabbits with hyperglycemia).The treatment group could decrease fasting glucose levels (57.3%,p<0.05),improve glucose tolerance and increase the content of liver glycogen (1.5-fold,p<0.01).It also not only reduced the total cholesterol,low-density lipoprotein cholesterol levels and liver enzyme levels,but increased the high-density lipoprotein cholesterol levels.The results showed thatR.obtusifoliushas great potential to treat diabetes [173].In addition,phenolic components ofR.dentatusshowed the ability to ameliorate hyperglycemia by modulating carbohydrate metabolism in the liver and oxidative stress levels and upregulating PPARγin diabetic rats [14].

5.8 Other biological activities

The vasorelaxant antihypertensive mechanism ofR.acetosawas investigated in vivo and in vitro.Intravenous injection (50 mg/kg) of the methanol extract ofR.acetosa(Ra.Cr) leaves caused a mean arterial pressure(MAP) (40 mmHg) in normotensive rats with a decrease of 27.88 ± 4.55% and a MAP (70 mmHg) in hypertensive rats with a decrease of 48.40 ± 4.93%.In endothelium intact rat aortic rings precontracted with phenylephrine(1 μM),Ra.Cr induced endothelium-dependent vasorelaxation with EC50=0.32 mg/mL (0.21—0.42),while in denuded endothelial rat aortic rings,EC50=4.22 mg/mL(3.2—5.42),which was partially blocked with L-NAME(10 μM),indomethacin (1 μM) and atropine (1 μM).In isolated rabbit aortic rings precontracted with phenylephrine (1 μM) and K+(80 mM),Ra.Cr induces vasorelaxation and the movement of Ca2+[174].

The acetone extract ofR.japonicusshowed protective activity against myocardial apoptosis,through the regulation of oxidative stress levels in cardiomyocytes (LDH,MDA,CK,SOD) and the suppression of the expression of apoptosis proteins (caspase-3,Bax,Bcl-2) on in vitro H2O2-induced myocardial H9c2 cell apoptosis [175].

The antiplatelet activity ofR.acetosaand the protective mechanism on cardiovascular system were investigated yet.The extract ofR.acetosashowed inhibition of the collagen-induced platelet aggregation by modulating the phosphorylation of MAPK,PI3K/Akt,and Src family kinases and inhibited the ATP release in a dose dependent manner (25—200 μg/mL) [176].The absorption of fexofenadine was inhibited by the ethanol extract ofR.acetosato decrease the aqueous solubility of fexofenadine[177].The hepatoprotective effect ofR.tingitanuswas investigated by an in vivo experiment,in which the ethanol extract protected effectively the CCl4-damaged rats by enhancing the activity of liver antioxidant enzymes.Moreover,the extract could reduce the immobility time of mice,comparable of the positive drug,clomipramine.The results indicated thatR.tingitanushas antidepressant-like effects [78].

Stimulating the ERK/Runx2 signaling pathway and related transcription factors could induce the differentiation of osteoblasts.Fortunately,chrysophanol (1),emodin (8) and physcion (18) from the aqueous extract ofR.crispuscould suppress the RANKL-induced osteoclast differentiation by suppressing the MAPK/NF-κB/NFATc1 signaling axis and increas the inhibitory factors of NFATc1 [178].

Moreover,the ethanol extract ofR.crispuscould reduce the degradation of collagen by inhibiting matrix metalloproteinase (MMP-1,MMP-8,MMP-13),indicating thatR.crispusexhibited the antiaging function [169].

The anti-Alzheimer effect of helminthosporin (51)fromR.abyssinicuswas investigated in PAMPA-BBB permeability research,showing that 51 inhibited obviously AChE and BChE with IC50values <3 μM.Compound 51 could not only cross the BBB with high BBB permeability,but also bind with the peripheral anion part of the cholinesterase activity site by molecular docking [80].

It is noted,R.crispus,a traditional medicinal herb in the folk with rich retinol,ascorbic acid andα-tocopherol in the leaves,could be used as a complementary diet[179].Moreover,chrysophanol (1) and physcion (18)fromR.crispusroots showed obvious inhibitory activity on xanthine oxidase (IC50=36.4,45.0 μg/mL,respectively) [180].

Inhibition of human pancreatic lipase could reduce the hydrolysis of triacylglycerol into monoacylglycerol and free fatty acids [181].Chrysophanol (1) and physcion (18)fromR.nepalensiswith good inhibitory activity on pancreatic lipase (Pearson’s r=0.801 and 0.755,respectively)showed the obvious potential to treat obesity [182].

6 Conclusion

The genusRumexdistributing widely in the world with more than 200 species has a long history of food and medicinal application in the folk.These plants with rich secondary metabolites,e.g.,quinones,flavonoids,tannins,stilbenes,naphthalenes,terpenes,diterpene alkaloids,lignans and other type of components,showed various pharmacological activities,such as antimicrobial,anti-inflammatory,antiviral,renal and gastrointestinal protective effects,antioxidant,antitumor and anti-diabetes effects.Particularly,quinones as the major components inRumexshowed stronger antibacterial activities and exerted the potential to treat kidney disease.However,detailed phytochemical studies are needed for manyRumexspecies,in order to clarify their bioactive components.Further studies and application may focus on the antitumor,anti-diabetes,anti-microbial,hepatoprotective,cardiovascular and gastrointestinal protective effects.Moreover,the toxicity or side effects forRumexplants and their chemical constituents should be evaluated,in order to make the uses ofRumexmore safety.

Abbreviations

AChE: Acetylcholinesterase;AGS: Adenocarcinoma gastric cell line;AR:Allergic rhinitis;BBB: Blood?brain barrier;BChE: Butyrylcholinesterase;EtOAc:Ethyl acetate;HPLC: High performance liquid chromatograph;IL: Interleukin;UHPLC?Q?TOF?MS: Ultra?high performance liquid chromatography?quad?rupole time?of?flight mass spectrometry;MAPK: Mitogen?activated protein kinase;MIC: Minimum inhibitory concentration;MS: Mass Spectrometry;MTT:3?(4,5?Dimethylthiazol?2?yl)?2,5?diphenyl tetrazolium bromide;NF?κB: Nuclear factor?kappa B;QGC: Quercetin?3-O-β?D?glucoside;TNF?α: Tumor necrosis factor?α.

Acknowledgements

This work was supported by the Ministry of Science and Technology,China(2021YFE0103600) for International Scientific and Technological Innovative Cooperation between Governments.

Author contributions

J?J L,Y?X L,H?T Z,DW collected the related references;J?J L worte the manu?script;NL and Y?J Z reviewed and edited the manuscript.All authors read and approved the final manuscript.

Declarations

Competing interests

The authors declare no conflict of interest.

Author details

1State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,People’s Republic of China.2University of Chinese Academy of Sciences,Beijing 100049,People’s Republic of China.3Yunnan Key Laboratory of Natural Medicinal Chemistry,Kunming Institute of Botany,Chinese Academy of Sci?ences,Kunming 650201,People’s Republic of China.