Traditional Uses and Pharmacologically Active Constituents of Dendrobium Plants for Dermatological Disorders:A Review

Yue-Hu Wang

Abstract Dendrobium Sw.is one of the largest genera in the orchidaceous family and includes 900-2000 species.Among them,more than 80 Dendrobium species have been reported in China.However,there are only six Dendrobium species,namely,D.bigibbum var.superbum (syn.D.phalaenopsis),D.chrysanthum,D.fimbriatum,D.loddigesii,D.nobile,and D.officinale(syn.D.candidum),listed in the New Inventory of Existing Cosmetic Ingredients in China Launched.Artificial planting of Dendrobium species has been a great success in China.To better utilize Dendrobium resources for medicinal and cosmetic purposes,we summarize their traditional uses and pharmacologically active compounds for treating dermatological disorders in this review.“Orchidaceae”,“ Dendrobium”,“traditional use”,“ethnobotany”,“dermatological disorder”,and “skin disease”were used as search terms to screen the literature.Cited references were collected between 1970 and 2020 from the Web of Science,China National Knowledge Internet (CNKI),SciFinder,Google Scholar,and Chinese books.From the search,it was found that there are 22 Dendrobium species with traditional uses in dermatological disorders,and 131 compounds from Dendrobium plants have been reported to possess anti-inflammatory,antimicrobial,antioxidant,antiaging,anti-psoriasis,and tyrosinase-inhibitory activities,implying that Dendrobium plants are important resources for the discovery of active compounds and the development of new drugs and cosmetics.D.crepidatum,D.denneanum,D.loddigesii,D.nobile,and D.officinale have been extensively studied.More research on other Dendrobium species is needed.The major active compounds found in Dendrobium species are phenanthrenes,alkaloids,flavonoids,phenylpropanoids,and lignans.Several compounds,such as loddigesiinol A,(S)-5-methoxy-2,4,7,9-tetrahydroxy-9,10-dihydrophenanthrene,(S)-4-methoxy-2,5,7,9-tetrahydroxy-9,10-dihydrophenanthrene,2,5-dihydroxy-4-methoxy-phenanthrene 2- O- β- D-glucopyranoside,(9 R)-1,2,5,9-tetrahydroxy-9,10-dihydrophenanthrene 5- O- β- D-glucopyranoside,(+)-homocrepidine A,and vicenin 2,have significant anti-inflammatory activities and inhibit nitric oxide (NO) production with IC50 values less than 5 μM,and these compounds are worthy of further study.

Keywords Orchidaceae·Dendrobium ·Traditional uses·Dermatological disorders·Anti-inflammatory

1 Introduction

Even though human skin is not the largest organ by weight or functional surface area [1],it is the main interface of the human body with the external environment.The skin meets the environment directly and thus is vulnerable to various types of damage.For this function,the skin possesses remarkable barrier qualities that protect humans from external pathogens and prevent the uncontrolled loss of water from the body.Although mortality rates for skin diseases are generally relatively low,they are often persistent,difficult to treat,can significantly impact quality of life and have a major psychological impact [2].

DendrobiumSw.is one of the most important genera of Orchidaceae.The genus is one of the largest members of the orchidaceous family and includes 900-2000 species [3].Dendrobiumplants are mainly distributed in the tropics and subtropics in southern Asia,Oceanica,and elsewhere [4].According toPlants of the World Online,there are 1,556 acceptedDendrobiumspecies at present [5].Among them,more than 80Dendrobiumspecies have been reported in China [4].However,there are only sixDendrobiumspecies,namely,D.bigibbumvar.superbumRchb.f.(syn.D.phalaenopsisFitzg.),D.chrysanthumWall.ex Lindl.,D.fimbriatumHook.,D.loddigesiiRolfe,D.nobileLindl,andD.officinaleKimura et Migo (syn.D.candidumWall.ex Lindl.),listed in the New Inventory of Existing Cosmetic Ingredients in China Launched (IECIC 2015,Final Version)[6].

Artificial planting ofDendrobiumspecies has been a great success in China.The total mass of annual cultivatedDendrobiumplants in China now exceeds 19 million kg [7].To better utilizeDendrobiumresources for medicinal and cosmetic purposes,we summarize their traditional uses and pharmacologically active constituents for treating dermatological disorders.“Orchidaceae”,“Dendrobium”,“traditional use”,“ethnobotany”,“dermatological disorder”,and“skin disease” were used as search terms to screen the literature.Cited references were collected between 1970 and 2020 from the Web of Science,China National Knowledge Internet (CNKI),SciFinder,Google Scholar,and Chinese books.For pharmacological activities,only extracts or compounds with IC50,EC50,or MIC values less than 100 μg/mL were cited.

2 Traditional Uses of Dendrobium Species for Treating Dermatological Disorders

Traditional uses of 22Dendrobiumspecies for treating dermatological disorders by local people in Australia,Bangladesh,China,India,Indonesia,Liberia,Malaysia,and Nepal are found in the literature (Table 1).

As shown in Table 1,the uses ofDendrobiumplants include treatments of boils [Dendrobium alpestreRoyle,D.crumenatumSw.,D.densifl orumLindl.,D.discolorLindl.,D.fi mbriatum,D.monticolaP.F.Hunt & Summerh.,andDendrobiumsp.(local name:gulubalama boblogie)],cuts (Dendrobium affineSteudel,D.fimbriatum,andD.nobile),burns [D.affine,D.amoenumWall.ex Lindl.,D.aphyllum(Roxb.) C.E.C.Fisch.,D.nobile,andD.polyanthumWall.ex Lindl.],eczema (D.macraeiLindl.andD.polyanthum),impetigo (D.denneanumKerr),infected nails (Dendrobium purpureumRoxb.),itchy skin (Dendrobium affineSteudel),pimples (D.alpestre,D.crumenatum,D.densiflorum,D.fimbriatum,andD.monticola),scalds (D.aphyllumandD.polyanthum),skin allergies (D.macraeiandD.macrostachyumLindl.),sores(D.affine,D.canaliculatumR.Br.,andD.chrysanthum),ringworm (D.discolor),ulcer (D.hancockiiRolfe),and wounds (D.amoenum,D.aphyllum,D.chrysanthum,D.fimbriatum,andD.nobile).The treatments of boils (seven species),burns (five species),pimples (five species),and wounds (five species) are the most common uses (Table 1).

Table 1 (continued)

Plant parts used ofDendrobiumspecies for treating dermatological disorders include aerial parts (one species),bulbs (three species),leaves (eight species),pseudobulbs (six species),pseudostems (one species),roots(three species),seeds (one species),stems (seven species),and whole plants (two species).Leaves,pseudobulbs,and stems are the most common parts used.

3 Pharmacological Activities of Extracts,Preparations,and Chemical Constituents from Dendrobium Plants for Treating Dermatological Disorders

Some extracts,preparations,and chemical constituents fromDendrobiumplants exhibit pharmacological activities related to dermatological disorders,such as antiinflammatory,antimicrobial,antioxidant,antiaging,antipsoriasis,hair growth promoting,skin-moisturizing,and tyrosinase-inhibitory activities.A part of pharmacological activities is related to the traditional uses ofDendrobiumplants.For example,anti-inflammatory activities are associated with treatments of eczema,itchy skin,and skin allergies,while antimicrobial activities are associated with treatments of boils,impetigo,and pimples.

Anti-inflammatory and antioxidant activities are the most common activities ofDendrobiumextracts and compounds.One hundred thirty-one compounds fromDendrobiumplants have been reported to possess anti-inflammatory,antimicrobial,antioxidant,antiaging,anti-psoriasis,and tyrosinaseinhibitory activities (Table 2).These compounds include bibenzyls (1- 44,Figs.1 and 2),phenanthrenes (45- 79,Fig.3),alkaloids (80- 101,Fig.4),flavonoids (102- 108),phenylpropanoids (109- 117),lignans (118- 124),and others(125- 131,Fig.5).

Fig.1 Chemical structures of pharmacologically active bibenzyls (1- 28) from Dendrobium plants (I)

Fig.2 Chemical structures of pharmacologically active bibenzyls (29- 44) from Dendrobium plants (II)

Fig.3 Chemical structures of pharmacologically active phenanthrenes (45- 79) from Dendrobium plants

Fig.4 Chemical structures of pharmacologically active alkaloids (80- 101) from Dendrobium plants

Fig.5 Chemical structures of pharmacologically active flavonoids (102- 108),phenylpropanoids (109- 117),lignans (118- 124) and other active compounds (125- 131) from Dendrobium plants

Table 2 Pharmacologically active compounds (1- 131) from Dendrobium plants

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

3.1 Anti-Inflammatory Activity

Skin inflammation is the most common complaint of those suff ering from dermatological diseases.Inflammatory skin diseases are divided into acute and chronic conditions.Acute skin inflammation is associated with occasional rashes,itching and skin redness and may be caused by ultraviolet or ionizing radiation,allergens or chemical irritants.Chronic inflammatory skin diseases include atopic dermatitis (such as eczema),seborrheic dermatitis,psoriasis,and rosacea.Chronic inflammatory skin diseases may lead to significant and serious disruption of skin immunity [8].

3.1.1 Dendrobium chrysanthum Wall.ex Lindl.

A phenanthrene,dendrochrysanene (75),was isolated from the stems ofD.chrysanthumcollected from Yunnan,China.This compound significantly suppressed the mRNA levels of TNF-α,IL-8,IL10,and iNOS in murine peritoneal macrophages at a concentration of 11.2 μg/mL.The compound may be a potentially useful new anti-inflammatory agent [9].

3.1.2 Dendrobium crepidatum Lindl.& Paxton

A research was conducted onD.crepidatumstems collected from Yunnan,China.Total alkaloids (yield,2.3%)were obtained fromD.crepidadumstems,which exhibited inhibitory eff ects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages,with an IC 50 value of 18.7 μg/mL.The active alkaloids were found to be dendrocrepidine A (85; IC50,39.8 μM),dendrocrepidine B (93; IC50,51.8 μM),dendrocrepidine C (94;IC50,29.7 μM),dendrocrepidine D (95; IC50,40.1 μM),dendrocrepidine E (96; IC50,35.2 μM),(±)-dendrocrepidine F(IC50,38.4 μM),(-)-dendrocrepidine F (97; IC50,13.3 μM),and (+)-dendrocrepidine F (98; IC50,42.7 μM) [10].In another study,the racemic mixture of (±)-homocrepidine A was separated into a pair of enantiomers,(+)-homocrepidine A (82) and (-)-homocrepidine A (83).(±)-Homocrepidine A,(+)-homocrepidine A,(-)-homocrepidine A,and homocrepidine B (84) also inhibited NO production with IC 50 values of 14.7,3.6,22.8,and 27.6 μM,respectively,as compared with the positive control indomethacin (IC50,42.2 μM) [11].In a very recent study,(±)-dendrocrepidine A(IC50,63.8 μM),(+)-dendrocrepidine A (85; IC50,16.1 μM),dendrocrepidine B (86; IC50,14.3 μM),(±)-crepidine (IC50,51.1 μM),(-)-crepidine (87; IC50,29.9 μM),(+)-crepidine(88; IC50,81.9 μM),(±)-dendrocrepidine A (IC50,27.5 μM),(-)-dendrocrepidine A (89; IC50,18.5 μM),(+)-dendrocrepidine A (90; IC50,30.2 μM),(±)-isocrepidamine (IC50,27.4 μM),(-)-isocrepidamine (91; IC50,16.3 μM),and(+)-isocrepidamine (92; IC50,73.0 μM) also exhibited inhibitory eff ects on NO production.Dexamethasone (IC 50 ,47.0 μM) was used as a positive control [12].

3.1.3 Dendrobium denneanum Kerr.

A series of phenanthrene derivatives were isolated fromD.denneanumstems collected from Sichuan,China,and 2,5-dihydroxy-4-methoxy-phenanthrene 2-O-β- D-glucopyranoside (76; IC50,4.6 μM),2,5-dihydroxy-4-methoxy-phenanthrene 2-O-β- Dapiofuranosyl-(1 → 6)-β- D-glucopyranoside (77; IC50,16.9 μM),2,5-dihydroxy-4-methoxy-phenanthrene 2-O-α- L-rhamnopyranosyl-(1 → 6)-β- D-glucopyranoside(78; IC 50 ,41.5 μM),(S)-5-methoxy-2,4,7,9-tetrahydroxy-9,10-dihydrophenanthrene (66; IC50,3.1 μM),(S)-4-methoxy-2,5,7,9-tetrahydroxy-9,10-dihydrophenanthrene (67; IC50,4.2 μM),(9R)-1,2,5,9-tetrahydroxy-9,10-dihydrophenanthrene 5-O-β- D-glucopyranoside (79;IC50,0.7 μM),4-methoxyphenanthrene-2,5-diol (moscatin,45; IC50,6.3 μM),(S)-4-methoxy-9,10-dihydrophenanthrene-2,5,9-triol (65; IC50,27.4 μM),2-methoxy-9,10-dihydrophenanthrene-4,5-diol (57; IC50,7.6 μM),and 9,10-dihydrophenanthrene-2,4,7-triol (56; IC50,32.7 μM)inhibited NO production in LPS-activated mouse macrophage RAW264.7 cells,as compared with the positive control curcumin (IC50,6.2 μM) [13].

3.1.4 Dendrobium findlayanum C.S.P.Parish & Rchb.f.

Seco-dendrobine-type alkaloids and phenolics were isolated fromD.findlayanumstems collected from Yunnan,China.Bibenzyl 6″-de-O-methyldendrof indlaphenol A (38) inhibited NO production in RAW 264.7 cells with an IC50value of 21.4 μM.MG-132 (IC50,0.2 μM) was used as a positive control [14].

3.1.5 Dendrobium heterocarpum Lindl.

3-Hydroxy-4′,5-dimethoxybibenzyl (4),gigantol (7),and dendrocandin I (39) were isolated from whole plants ofD.heterocarpumcollected from Yunnan,China,and these compounds reduced nitric oxide (NO) production in LPSactivated mouse macrophage RAW264.7 cells.At a concentration of 25 μM,the inhibition percentages of these three compounds were 51,52,and 59%,respectively.NGMonomethyl-L-arginine (L-NMMA) was used as a positive control (IC50,34 μM) [15].

3.1.6 Dendrobium huoshanense Z.Z.Tang & S.J.Cheng

Dendrobium huoshanenseZ.Z.Tang & S.J.Cheng was not accepted by “Plants of the Worldonline.” However,because this name is used in theChinese Pharmacopoeia(2020 edition) [16],it is cited in this review.

A pilot study was conducted to evaluate the clinical and immunomodulatory eff ects of an orally administered extract ofD.huoshanenseleaves and stems in children with moderate to severe recalcitrant atopic dermatitis (AD).AD is a common inflammatory skin disorder for which few safe and eff ective systemic treatments are available.Twenty-seven patients aged 4-18 years with AD who did not respond to topical therapy were treated with polysaccharides derived fromD.huoshanensefor 4 weeks and were followed-up for another 4 weeks.The results showed that the polysaccharide fromD.huoshanensereduced the levels of some cytokines associated with AD and had beneficial eff ects on symptoms.No serious adverse eff ects occurred when the polysaccharide was administered orally for 4 weeks [17].

3.1.7 Dendrobium loddigesii Rolfe

Shihunine (80) was isolated fromD.loddigesiistems collected from Yunnan,China.The alkaloid showed antiinflammatory activity using the method of NO production the polysaccharide in RAW 264.7 cells activated by LPS with an IC50value of 11.5 μg/mL.L-NG-monomethyl arginine citrate (IC507.2 μg/mL) was used as a positive control[18].

Phenanthrenes and bibenzyls were isolated fromD.loddigesiistems collected from Guangdong,China.These compounds were evaluated for their inhibitory activities against NO production.Loddigesiinol A (52; IC50,2.6 μM),moscatin (plicatol B,45; IC50,6.4 μM),5-hydroxy-2,4-dimethoxyphenanthrene (46; IC50,5.3 μM),lusianthridin (54; IC50,4.6 μM),rotundatin (64,plicatol C; IC50,29.1 μM),hircinol (55; IC50,29.2 μM),loddigesiinol B(71; IC50,10.9 μM),loddigesiinol D (26; IC50,69.7 μM),(-)-pinoresinol (118; IC50,89.5 μM),and (-)-medioresinol(120; IC50,5.0 μM) inhibited NO production,as compared with the positive controls aminoguanidine (IC50,17.5 μM)and resveratrol (IC50,22.0 μM) [19].

Fifteen compounds were isolated from a preparation ofD.loddigesiioriginating in Yunnan,China.Chrysotoxol A(74; IC50,10.9 μM),neoechinulin A (99; IC50,50.0 μM),3,6,9-trihydroxy-3,4-dihydroanthracen-1-(2H)-one (129 ;IC50,43.8 μM),4,4′-dihydroxy-3,5-dimethoxybibenzyl(5; IC50,49.3 μM),naringenin (104; IC50,26.9 μM),5,4′-dihydroxy-7,3′,5′-trimethoxyflavanone (106; IC50,24.9 μM),5,7,4′-trihydroxy-3′,5′-dimethoxyflavanone(IC50,19.1 μM),batatasin III (1; IC50,21.9 μM),3,3′,5-trihydroxybibenzyl (2; IC50,13.1 μM),trigonopol B(28; IC50,26.3 μM),syringaresinol (122; IC50,1.9 μM),9,10-dihydrophenanthrene-2,4,7-triol (56; IC50,8.6 μM),loddigesiinol B (71; IC50,9.9 μM),loddigesiinol I (72;IC50,7.5 μM),and loddigesiinol J (73; IC50,14.6 μM)inhibited NO production in RAW 264.7 cells activated by LPS when compared with the positive control L-NMMA(IC50,29.0 μM) [20].

3.1.8 Dendrobium moniliforme (L.) Sw.

Denbinobin (68) was isolated fromD.moniliformestems.At 1 μM,this compound significantly inhibited the formation of TNF-αand prostaglandin E2(PGE2) (about 62 and 43% inhibition,respectively) in RAW264.7 cells stimulated with 1 μg/mL of LPS.In N9 cells (murine microglial cell line) stimulated with 10 ng/mL of LPS plus 10 unit/mL of interferon-γ(IFN-γ),denbinobin (3 μM) reduced TNF-αand nitrite formation (about 70 and 44% inhibition,respectively)[21].

3.1.9 Dendrobium nobile Lindl.

An alkaloid,anosmine (81),was isolated fromD.nobile,which was purchased from Guangzhou,China.The compound exhibited anti-inflammatory activity using the method of NO production inhibition in RAW 264.7 cells activated by LPS with an IC50value of 16.1 μg/mL,which was compared with L-NG-monomethyl arginine citrate (IC50,7.2 μg/mL)as a positive control [18].

Phenanthrenes from the methanolic extract ofD.nobilestems were evaluated for their potential to inhibit LPSinduced production of NO in murine macrophage RAW 264.7 cells.3,4,8-Trimethoxyphenanthrene-2,5-diol (51;IC50,20.4 μM),hircinol (55; IC50,26.4 μM),erianthridin(60; IC50,19.5 μM),ephemeranthol A (63; IC50,12.0 μM),5,7-dimethoxyphenanthrene-2,6-diol (50; IC50,35.7 μM),moscatilin (9; IC50,27.6 μM),coelonin (58; IC50,10.2 μM),flavanthridin (61; IC50,34.1 μM),epheneranthol C (62; IC50,17.6 μM),lusianthridin (54; IC50,9.6 μM),and fimbriol B(48; IC50,28.9 μM) inhibited NO production.Aminoguanidine (IC50,17.5 μM) was used as a positive control [22].

Nobilin D (21; IC50,15.3 μM),nobilin E (33; IC50,19.2 μM),nobilone (128; IC50,38.1 μM),chrysotobibenzyl(16; IC50,48.2 μM),moscatilin (9; IC50,36.8 μM),gigantol(7; IC50,32.9 μM),and dendrof lorin (127; IC50,13.4 μM)fromD.nobilestems collected from Yunnan,China,exhibited inhibitory effects on NO production in the murine macrophage-like cell line RAW264.7 activated by LPS and IFN-γ.Resveratrol (IC50,23.5 μM) was used as a positive control [23].

Ephemeranthol A (63) was isolated fromD.nobilestems,and its anti-inflammatory activity was evaluated in Raw 264.7 cells.This compound reduced NO production in a dose-dependent manner.Notably,with pretreatment with 12.5 μg/mL ephemeranthol A,NO production decreased to the level of the cell-only control [24].

3.1.10 Dendrobium officinale Kimura & Migo

Vicenin 2 (vicenin II,108) was suggested to be a common component inD.officinaleleaves of diff erent origins [25].This di-C-glucosylflavone was synthesized,and it inhibited TNF-αexpression and NO production with IC50values of 6.8 and 3.9 μM,respectively,as compared with the positive control apigenin (IC50= 18.5 and 19.0 μM,respectively)[26].

Two types of polysaccharides inD.officinaleleaves,DLP-1 and DLP-2,were obtained by hot water extraction.DLP-1 (5 μg/mL) and DLP-2 (50 μg/mL) were shown to be eff ective in protecting THP-1 cells,a human leukemia monocytic cell line,from LPS-stimulated cytotoxicity and inhibited reactive oxygen species formation.In addition,both DLP-1 (5 μg/mL) and DLP-2 (50 μg/mL) significantly suppressed TLR4,myeloid diff erentiation factor (MyD88),and tumor necrosis factor receptor-associated factor-6 (TRAF-6) mRNA and protein expression in LPS-stimulated THP-1 cells [27].

3.1.11 Dendrobium parishii H.Low

(-)-Dendroparishiol (36) from the whole plant ofD.parishiicollected from Thailand was evaluated for its antiinflammatory eff ects in LPS-stimulated RAW264.7 murine macrophage cells.At 12.5,25 and 50 μg/mL,(-)-dendroparishiol reduced the expression of iNOS and COX-2 in LPStreated RAW264.7 cells [28].

3.1.12 Dendrobium cv.Sonia

Ten compounds were isolated fromDendrobiumcv.Sonia stems collected from Nanjing,China,and their anti-inflammatory activities were evaluated.6-Feruloyloxyhexanoic ester (112; IC50,29.6 μM),pinoresinol (119; IC50,26.3 μM),syringaresinol (122; IC50,27.7 μM),and sesqui-illisimonan A (124; IC50,31.6 μM) exhibited inhibitory activities on NO production.Aminoguanidine (IC50,27.3 μM) was used as a positive control [29].

3.1.13 Dendrobium tosaense Makino

Via oral administration at dosages of 30,100,and 300 mg/kg for one week in an atopic dermatitis murine model,the standardized ethyl acetate extract of culturedD.tosaensestems protected mice from OVA/TNCB-induced skin lesions of atopic dermatitis [30].

3.2 Antimicrobial Activity

Microorganisms can cause skin infections,such as carbuncles,furuncles,cellulitis,impetigo,boils (Staphylococcusaureus),folliculitis (S.aureus,Pseudomonas aeruginosa),ringworm (Microsporumspp.,Epidermophytonspp.,andTrichophytonspp.),acne (Propionibacterium acnes),and foot odor (Brevibacteriumspp.) [31].

Gigantol (7) has been found in 33Dendrobiumspecies[32].This compound showed inhibitory activity againstStaphylococcus aureuswith an MIC value of 82.2 μg/mL[33].

Sortase A (srtA),a transpeptidase in gram-positive bacteria,can anchor surface proteins that play a vital role in the pathogenesis of these bacteria.SrtA is known as a potential antivirulent drug target to treat bacterial infections.Erianin (14) was isolated fromD.chrysotoxumstems [34].This compound could inhibit the activity of srtA in vitro with an IC50value of 20.9 μg/mL [35].Dendrocoumarin (125) and itolide A (126) fromD.nobilestems collected from Hainan,China,showed antibacterial activities againstStaphylococcus aureuswith the same MIC value of 2.5 μg/mL andMicrococcus tetragenuswith the same MIC value of 5.0 μg/mL.The positive control was ciprof loxacin,with MIC values of 0.6 and 0.3 μg/mL for the two bacteria,respectively [36].

3.3 Antioxidant and Antiaging Eff ects

The skin shows obvious signs of aging due to age,ultraviolet radiation exposure,and chemical pollution [37].The changes in the skin are among the most visible signs of aging,including wrinkles,sagging skin,age spots dryness,and the loss of fat,which cause the skin to lose its natural smoothness [38].The sum of the deleterious free radical reactions is a major contributor to the aging process [39].In intrinsically aged skin,the quantity of dermal collagen decreases,and elastin accumulates structural abnormalities [40].

3.3.1 Dendrobium amoenum Wall.Ex Lindl.

Chloroform and acetone extracts ofD.amoenumstems collected from Nepal showed 2,2-diphenyl-1-picrylhydrazyl(DPPH) free radical scavenging activities with IC50values of 36.5 and 53.2 μg/mL,respectively [41].

3.3.2 Dendrobium aphyllum (Roxb.) C.E.C.Fisch.

Aphyllone B (17) from the stems ofD.aphyllumcollected from Yunnan,China,possessed DPPH radical scavenging activity with a scavenging percentage of 88% at a concentration of 100 μg/mL [42].

3.3.3 Dendrobium crepidatum Lindl.& Paxton

Ethanol and acetone extracts ofD.crepidatumstems collected from Nepal showed DPPH free radical scavenging activities with IC50values of 73.9 and 99.4 μg/mL,respectively,as compared with the positive control ascorbic acid(IC50,38.2 μg/mL) [43].

3.3.4 Dendrobium denneanum Kerr

The ethanolic extract ofD.denneanum[syn.D.aurantiacumvar.denneanum(Kerr) Z.H.Tsi] stems collected from Yunnan,China,exhibited DPPH radical scavenging activity with an IC50value of 92.6 μg/mL and was compared withα-tocopherol (IC50,25 μg/mL) as a positive control.Three compounds were obtained by bioguided isolation.Unfortunately,the activities of these compounds were weaker than those of the crude extract [44].

A bibenzyl-rich fraction fromD.denneanumstems collected from Sichuan,China,exhibited DPPH scavenging activity with an EC50of 62.8 μg/mL.Vitamin C (EC50,3.4 μg/mL) was used as a positive control [45].

3.3.5 Dendrobium denudans D.Don

The methanol extract ofD.denudansstems collected from India showed in vitro antioxidant activity by a reducing power assay with an IC50value of 10.1 μg/mL.Ascorbic acid (IC50,3.9 μg/mL) was used as a positive control [46].

3.3.6 Dendrobium draconis Rchb.f.

5-Methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone (69; IC50,283.3 μM or 72.6 μg/mL),hircinol (55 ;IC50,22.3 μM),gigantol (7; IC50,17.7 μM),and 7-methoxy-9,10-dihydrophenanthrene-2,4,5-triol (59; IC50,10.2 μM)were isolated fromD.draconisstems collected from Thailand and exhibited DPPH radical scavenging activities.Quercetin (IC50,2.4 μM) and Trolox (IC50,11.7 μM) were used as positive controls [47].

3.3.7 Dendrobium huoshanense Z.Z.Tang & S.J.Cheng

A polyphenol extract was obtained fromD.huoshanensecollected from Anhui,China,and the extract exhibited DPPH and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging activities with IC50values of 57 and 27 μg/mL,respectively,as compared with the positive control vitamin C [48].

3.3.8 Dendrobium loddigesii Rolfe

A series of phenolic compounds were found inD.loddigesiicollected from Yunnan,China.From its stems,threo-7-O-ethyl-9-O-(4-hydroxyphenyl)propionylguaiacylglycerol (113),crepidatin (15),moscatilin(9),4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (13),4′,5-dihydroxy-3,3′-dimethoxybibenzyl (gigantol,7),tristin (8),dihydroconiferyl dihydro-p-coumarate (114),andp-hydroxyphenethyltrans-ferulate (115) were obtained,and these compounds exhibited significant activities,with DPPH scavenging capacities ranging from 89 to 94% at 100 μg/mL,as compared with the positive control Trolox,which led to an inhibition of 96% at a concentration of 25 μg/mL.Batatasin III (1) significantly stimulated the collagen production activity of human dermal fibroblasts-adult (HDFa)(EC503.2 μg/mL) and was compared with TGF-βas a positive control,with an inhibition of 66% at a concentration of 0.01 μg/mL [49].From complete plants,moscatin (45),9,10-dihydrophenanthrene-2,4,7-triol (56),and crepidatuol B (27) were obtained,and these compounds showed significant activities,with DPPH scavenging capacities ranging from 84 to 95% at 100 μg/mL,as compared with the positive control Trolox,which led to an inhibition of 96% at a concentration of 25 μg/mL [50].

Phenanthrenes and bibenzyls were isolated fromD.loddigesiistems collected from Guangdong,China.Loddigesiinol A (52; IC50,26.1 μM),moscatin (45; IC50,59.8 μM),lusianthridin (54; IC50,62.2 μM),and loddigesiinol C (25;IC50,23.7 μM) showed activities using the DPPH-scavenging assay,as compared to the positive controls resveratrol(IC50,28.7 μM) and aminoguanidine (IC50,21.7 μM) [19].

Fifteen compounds were isolated from a preparation ofD.loddigesiistems collected from Yunnan,China.Chrysotoxol A (74; IC50,23.2 μM),3,6,9-trihydroxy-3,4-dihydroanthracen-1-(2H)-one (129; IC50,22.8 μM),4,4′-dihydroxy-3,5-dimethoxybibenzyl (5; IC50,94.5 μM),5,4′-dihydroxy-7,3′,5′-trimethoxyflavanone (106; IC50,227.7 μM or 78.9 μg/mL),batatasin III (1; IC50,204.9 μM or 50.1 μg/mL),3,3′,5-trihydroxybibenzyl (2; IC50,85.8 μM),trigonopol B (28;IC50,60.1 μM),syringaresinol (122; IC50,31.1 μM),and 9,10-dihydrophenanthrene-2,4,7-triol (56; IC50,14.1 μM)showed DPPH radical scavenging activities.Vitamin C(IC50,29.8 μM) was used as a positive control [20].

3.3.9 Dendrobium longicornu Lindl.

The acetonic extract ofD.longicornustems collected from Nepal showed DPPH radical scavenging activity with an IC50value of less than 100 μg/mL and was compared with ascorbic acid (IC50,＜ 50 μg/mL) as a positive control [51].

3.3.10 Dendrobium macrostachyum Lindl.

Ethanolic extracts ofD.macrostachyumstems and leaves collected from India exhibited DPPH radical scavenging activities with IC50values of 10.2 and 31.5 μg/mL,respectively,as compared with the positive control ascorbic acid(IC50,18.4 μg/mL); these extracts also had ABTS radical scavenging activities with IC50values of 31.5 and 49.1 μg/mL,respectively,as compared with the positive control ascorbic acid (IC50,34.9 μg/mL).The activities of the ethanol extracts were better than those of petroleum ether,methanol,or water extracts [52].

3.3.11 Dendrobium moniliforme (L.) Sw.

The DPPH radical scavenging activities of hexane,chloroform,acetone,and ethanol extracts ofD.moniliformestems collected from Nepal were measured,showing IC50values of 52.7,42.4,49.6,and 58.8 μg/mL,respectively,as compared with the positive control ascorbic acid (IC50,38.2 μg/mL) [53].

Based on bioguided fractionation and isolation,a mixture ofn-pentacosyltrans-ferulate (117) andn-tetracosyltransferulate (116) (1:4) was obtained from tissue culture-raised plants ofD.moniliforme.At 100 μg/mL,the mixture of the alkyl ferulates exhibited DPPH radical scavenging activity(inhibition ＞ 50%) [54].

3.3.12 Dendrobium nobile Lindl.

Flavonoids have been detected in ethyl acetate,n-butanol,and aqueous extracts ofD.nobileleaves collected from Guangdong,China.These three extracts showed DPPH free radical scavenging activities with IC50values of 21,11,and 13 μg/mL,respectively,with Trolox used as a reference compound (IC50,7 μg/mL) [55].

Bibenzyls and other phenolic compounds were isolated fromD.nobilestems collected from Yunnan,China.Nobilin A (22; IC50,87.1 μM),nobilin B (23; IC50,32.2 μM),nobilin C (24; IC50,136.0 μM or 47.4 μg/mL),dihydroconiferyl alcohol (109; IC50,50.9 μM),coniferylaldehyde (110; IC50,127.9 μM or 22.8 μg/mL),3-hydroxy-4-methoxyphenylethanol (130; IC50,64.5 μM),and syringic acid (131; IC50,8.1 μM) exhibited DPPH radical scavenging activities.Vitamin C (IC50,18.0 μM) and BHT (IC50,90.9 μM) were used as positive controls [56].

Nobilin D (21; IC50,19.9 μM),nobilin E (33; IC50,21.0 μM),crepidatin (15; IC50,21.8 μM),dendrobin A (10;IC50,40.3 μM),chrysotoxine (11; IC50,14.0 μM),moscatilin (9; IC50,14.5 μM),gigantol (7; IC5056.4 μM),and dendrof lorin (127; IC50,16.2 μM) fromD.nobilestems exhibited DPPH radical scavenging activities.Vitamin C (IC50,18.0 μM) was used as a positive control [23].

Phenanthrenes and lignans were isolated fromD.nobilestems in Yunnan,China.Fimbriatone (70; IC50,144.5 μM or 40.8 μg/mL),confusarin (47; IC50,12.9 μM),flavanthrinin(49; IIC50,35.7 μM),2,5-dihydroxy-4,9-dimethoxyphenanthrene (53; IC50,34.8 μM),5,7-dimethoxyphenanthrene-2,6-diol (50; IC50,29.7 μM),syringaresinol (122; IC50,9.8 μM),pinoresinol (119; IC50,60.6 μM),medioresinol(121; IC50,27.9 μM),and lirioresinol A (123; IC50,30.9 μM)exhibited DPPH radical scavenging activities.Vitamin C(IC50,18.0 μM) and BHT (IC50,90.9 μM) were used as positive controls.For all phenanthrenes and lignans,an electrondonating methoxy group in theorthoposition that donates to the phenolic hydroxy group exhibits enhanced antioxidant activity [57].

3.3.13 Dendrobium officinale Kimura & Migo

Ethanolic extracts ofD.officinaleflowers,leaves,and stems collected from Zhejiang,China,in which the total flavonoid contents measured were 1.8,0.25,and 0.052%,respectively,were prepared.These extracts showed DPPH scavenging activities with IC50values of 0.2 μg/mL,17.4 μg/mL,and 10.4 μg/mL,respectively,as compared with the positive control vitamin C (IC50,7.5 μg/mL) [58].

The chloroform extract ofD.officinalestems collected from Yunnan,China,exhibited ABTS radical scavenging activity with an IC50value of 88.8 μg/mL [59].

The antioxidant activities ofD.officinale(Syn.D.candidum) collected from diff erent areas of Hainan,China,were compared.Ethanolic extracts of plant samples collected from Sanya,Qiongzhong,and Baoting exhibited the best DPPH radical scavenging activities,with IC50values of 15.9,20.2,and 78.7 μg/mL,respectively [60].

A series of bibenzyls were isolated fromD.officinale(syn.D.candidum) stems collected from Zhejiang,China.Dendrocandin C (18; IC50,34.2 μM),dendrocandin D(19; IC50,34.5 μM),dendrocandin E (12; IC50,15.6 μM)[61],dendrocandin F (29; IC50,55.8 μM),dendrocandin G(30; IC50,32.4 μM),dendrocandin H (34; IC50,19.8 μM),dendrocandin I (39; IC50,21.3 μM) [62],dendrocandin J(31; IC50,36.8 μM),dendrocandin K (32; IC50,70.2 μM),dendrocandin L (35; IC50,45.0 μM),dendrocandin M (37;IC50,60.5 μM),dendrocandin N (42; IC50,87.6 μM),dendrocandin O (43; IC50,50.4 μM),dendrocandin P (40; IC50,22.3 μM),dendrocandin Q (41; IC50,30.3 μM) [63],and(S)-3,4,α-trihydroxy-5,4′-dimethoxybibenzyl (20; IC50,IC50,32.3 μM) exhibited DPPH radical scavenging activities [64].Vitamin C (IC50,23.2 μM) was used as a positive control[61- 64].

Moupinamide (100; IC50,53.8 μM),dihydroconiferyl dihydro-p-cumarate (114; IC50,78.2 μM),dihydroferuloyltyramine (101; IC50,113.5 μM or 35.8 μg/mL),syringic acid(131; IC50,36.5 μM),ferulic acid (111; IC50,64.9 μM),and 3′,5,5′,7-tetrahydroxyflavanone (105; IC50,29.8 μM) fromD.officinale(syn.D.catenatum) stems collected from Zhejiang,China,showed DPPH free radical scavenging activities.Vitamin C (IC50,23.2 μM) was used as a positive control[65].

Eight bibenzyls were isolated fromD.officinale(syn.D.catenatum) stems collected from Shenzhen,China.Dendrocandin U (44),3,4′-dihydroxy-5-methoxybibenzyl (3),and 3,4′,5-trihydroxy-3′-methoxybibenzyl (tristin,8) exhibited significant ABTS radical scavenging activities with IC50values of 10.0,5.3,and 9.0 μM,respectively,as compared with the positive control vitamin C (IC50,6.5 μM).3,4′,5-Trihydroxy-3′-methoxybibenzyl also exhibited DPPH scavenging activity with an IC50value of 34.5 μM.Vitamin C(IC50,14.9 μM) was used as a positive control [66].

D.officinaleprotocorm powder in deionized water (10,25 and 50 mg/mL,external administration) significantly reduced erythema and protected the skin from dryness in a hairless mouse model with UV irradiation-induced skin damage using matrixyl (10 mg/mL) as a positive control.This study demonstrated thatD.officinaleprotocorms can inhibit photodamage in the skin of hairless mice [67].

An in vivo experiment using photoaged model mice was conducted.The results showed that the ultrafine powder and fine powder ofD.officinale(syn.D.candidum) stems possess a certain preventive eff ect on photoaging,and the eff ect of ultrafine powder is better than that of fine powder [68].

3.3.14 Dendrobium palpebrae Lindl.

A fluorenone,dendrof lorin (127),was isolated fromD.palpebraewhole plants collected from Thailand.This compound significantly decreased ROS in H2O2-stimulated RAW264.7 cells in a dose-dependent manner (12.5-50 μg/mL) [69].

3.3.15 Dendrobium secundum (Blume) Lindl.ex Wall.

Five compounds were isolated fromD.secundumstems collected from Thailand.4,5,4′-Trihydroxy-3,3′-dimethoxybibenzyl (13; IC5015.9 μM),moscatilin (9; IC505.1 μM),syringaresinol (122; IC5011.4 μM),and ferulic acid(111; IC5037.5 μM) exhibited DPPH free radical scavenging activities,which were compared with the positive controls quercetin and Trolox (IC50,2.5 and 11.7 μM,respectively)[70].

3.3.16 Dendrobium signatum Rchb.f.

D.signatumleaves collected from Thailand were extracted with ethanol by sonication-maceration for 30 min.The extract showed DPPH radical scavenging activity,with a measured IC50value of 97.2 μg/mL,with ascorbic acid used as a reference compound (IC50,21.7 μg/mL) [71].

3.3.17 Dendrobium speciosum Sm.

Methanolic extract ofD.speciosumleaves collected from Au

stralia containing polyphenols (1.2%) and flavonoids (0.2%)showed DPPH scavenging activity,with a measured IC50value of 26 μg/mL.Trolox was used as a reference compound (IC50,20 μg/mL) [72].

3.3.18 Dendrobium tosaense Makino

The eff ects of methanolic extracts obtained from threeDendrobium speciespropagated in vitro on DPPH scavenging were investigated.TheD.tosaenseextract was the most active extract,with an IC50value of 79.9 μg/mL,as compared with the positive controlα-tocopherol (IC50,58.2 μM) [73].

Based on bioguided fractionation and isolation,quercetin(103) was obtained from tissue culture-raised plants ofD.tosaense.At 100 μg/mL,quercetin exhibited DPPH radical scavenging activity (inhibition ＞ 50%) [54].

3.3.19 Dendrobium williamsonii Day & Rchb.f.

Six compounds were isolated fromD.williamsoniiwhole plants collected from Thailand and evaluated these isolates for their DPPH radical scavenging activities.3,3′-Dihydroxy-4,5-dimethoxybibenzyl (6),moscatilin (9),and apigenin (102) were active,with IC50values of 19.5,8.5,and 19.3 μM,respectively,as compared with the positive controls,quercetin (IC50,8.3 μM) and vitamin C (IC5042.4 μM) [74].

3.4 Anti-Psoriasis Activity

Psoriasis is a recurrent skin disease described as keratinocyte hyperproliferation and aberrant diff erentiation.At concentrations ranging from 12.5 nM to 50 nM,erianin (14)inhibited proliferation and induced apoptosis in a human keratinocyte cell line (HaCaT).Erianin could be recognized as a potential anti-psoriasis drug [75].This compound was previously isolated fromD.chrysotoxum[34].

3.5 Hair Growth Promoting Eff ects

Alopecia is a skin disease characterized by reduced hair[76].The condition has a strong influence on the mental and psychological health of patients [77].

In an in vivo experiment,C57BL/6 J mice were externally administeredD.officinale(Guangdong,China) polysaccharides (DOP,5.0 g/L) for 21 days.The average hair growth score and average quality of C57BL/6 J mice in the DOP group were significantly better than those in the control groups [78].

3.6 Skin-Moisturizing Eff ects

When the water content in the stratum corneum drops to less than 10%,the skin appears dry,loses elasticity,and wrinkles and skin aging accelerates [77].

The moisture retention rate ofD.huoshanense(Anhui,China) polysaccharide on human skin is significantly higher than that of glycerol after external administration for 6 h,8 h and 12 h.The stimulus value of normal skin and damaged skin of rabbits is less than 0.5,indicating thatD.huoshanensepolysaccharides do not cause skin irritation [79].

Polysaccharides from white orchids (Dendrobiumcv.Khao Sanan) flowers cultivated in Thailand were evaluated in vivo for their skin hydration efficacy in human volunteers.The efficacy of white orchid polysaccharides at 0.3% was noted to be superior in terms of skin hydration efficacy than sea weed polysaccharides at 0.2% [80].

An in vivo experiment was conducted to evaluate the moisturizing eff ects of aD.nobilestem extract on human skin.The moisturizing abilities after 30 min and 2 h were greater than 1 for theD.nobilestem extract (2.0%) [81].

An in vivo experiment showed that 20 μg/mL ethanolic extract ofD.officinalecollected from Yunnan,China,exhibited a skin moisturizing eff ect.After 2.5 h of use,skin hydrature increased by 16% compared with that before use(P＜ 0.05) [82].

3.7 Tyrosinase-Inhibitory Activity

Tyrosinase inhibitors are used for hyperpigmentation and developing skin whitening agents.

3,3′,5-Trihydroxybibenzyl (2) fromD.loddigesiistems collected from Yunnan,China,revealed significant inhibitory activity against tyrosinase with an IC50value of 37.9 μg/mL,as compared with the positive control kojic acid (IC50,8.0 μg/mL) [49].

At concentrations of 12.5,25 and 50 μg/mL,the CH2Cl2extract ofD.moniliformeleaves collected from South Korea inhibited melanogenesis in murine melanoma cells(B16F10),implying thatD.moniliformeis eff ective against hyperpigmentation disorders and that it is considered a possible antimelanogenic agent in topical application [83].

Ethanolic extracts ofDendrobiumcv.Sonia flowers andDendrobiumcv.Sonia pink flowers collected from Thailand showed tyrosinase inhibitory activities using L-tyrosine as a substrate.The IC50values were 57.4 μg/mL and 83.2 μg/mL,respectively,as compared with the positive control kojic acid (IC50,151.7 μg/mL) [84].

4 Conclusion

There are 22Dendrobiumspecies with traditional uses for treating dermatological disorders by local people in eight countries,and there are 131 compounds fromDendrobiumplants reported to possess anti-inflammatory,antimicrobial,antioxidant,antiaging,anti-psoriasis,and tyrosinase-inhibitory activities,which implies thatDendrobiumplants are important resources for the discovery of active compounds and the development of new drugs and cosmetics.However,onlyD.crepidatum,D.denneanum,D.loddigesii,D.nobile,andD.officinalehave been extensively studied.More research on otherDendrobiumspecies is needed.

The major active compounds found inDendrobiumspecies are phenanthrenes,alkaloids,flavonoids,phenylpropanoids,and lignans.Several compounds,such as loddigesiinol A,(S)-5-methoxy-2,4,7,9-tetrahydroxy-9,10-dihydrophenanthrene,(S)-4-methoxy-2,5,7,9-tetrahydroxy-9,10-dihydrophenanthrene,2,5-dihydroxy-4-methoxy-phenanthrene 2-O-β- D-glucopyranoside,(9R)-1,2,5,9-tetrahydroxy-9,10-dihydrophenanthrene 5-O-β- D-glucopyranoside,(+)-homocrepidine A,and vicenin 2,have significant antiinflammatory activities and inhibit NO production with IC50values less than 5 μM,and these compounds are worthy of further study.

AcknowledgmentsThis research was funded by the Beijing DR PLANT Biotechnology Co.,Ltd.and the Second Tibetan Plateau Scientific Expedition and Research (STEP) Program of Ministry of Science and Technology of the People’s Republic of China (2019QZKK0502).

Declarations

Conflict of interestThe author declares that there are no conflicts of interest associated with this work.

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