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

Graphic 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, (9R)-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.


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].
Dendrobium Sw. 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]. Dendrobium plants are mainly distributed in the tropics and subtropics in southern Asia, Oceanica, and elsewhere [4]. According to Plants of the World Online, there are 1,556 accepted Dendrobium species at present [5]. Among them, more than 80 Dendrobium species have been reported in China [4]. However, there are only six Dendrobium species, namely, D. bigibbum var.  [6].
Artificial planting of Dendrobium species has been a great success in China. The total mass of annual cultivated Dendrobium plants in China now exceeds 19 million kg [7]. To better utilize Dendrobium resources 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 IC 50 , EC 50 , or MIC values less than 100 μg/mL were cited. The sap from the pseudobulbs is directly squeezed onto sores to relieve itchy skin [85] Australia -Stems, bulbs Fluid from the stem or bulb is used on skin to treat itching, cuts, sores and minor burns [86] Dendrobium alpestre Royle India Jiwanti Bulbs For treating pimples, boils and other skin eruptions [87] Dendrobium amoenum

Traditional Uses of Dendrobium Species for Treating Dermatological Disorders
Wall. ex Lindl India -Leaves Leaf paste is used to treat skin diseases [88] India Mitha alu Leaves Leaves of D. amoenum pounded with Hedychium wardii C.E.C. Fisch. rhizomes are made into a paste, which is used to treat wounds and various skin diseases [89] Nepal Thuur Pseudobulbs A fresh paste is applied topically on burnt skin [90] Dendrobium aphyllum (Roxb.) C.E.C. Fisch Bangladesh -Leaves A paste or juice of the leaves is used to treat wounds [91] China Dou chun shi hu Whole plants, stems Whole plants are used to treat burns and scalds. Fresh stems are externally used to tread burns and scalds [92,93] India -Leaves Fresh leaf juice is used to treat skin infections [94] Dendrobium

Dendrobium chrysanthum
Wall. ex Lindl India Nauawimu Stems Stem juice is applied on wounds and sores [96] Dendrobium crumenatum Sw Malaysia Daun sepuleh tulang Leaves A poultice made from leaves is used to treat boils and pimples [7] Dendrobium densiflorum Lindl Nepal Sungava Pseudobulbs Fresh pulp is applied to boils and pimples [90] Dendrobium discolor Lindl Australia -Stems A poultice is prepared from young canes to draw a boil. A liniment made from mature canes is used to treat ringworm [97] Dendrobium fimbriatum Hook India -Leaves A paste of fresh leaves is used to treat boils and pimples [94] India a

Mokya tu
Leaves Approximately 10 g of leaves are ground, made into a paste and applied twice a day for 10 days to heal cuts and wounds [98] Dendrobium hancockii

Rolfe China
Xi ye shi hu

Stems
To treat ulcers [99] Dendrobium herbaceum Lindl India Agai Roots Fresh roots are burnt, and 10 g of the resultant ash is mixed with 10 ml mustard oil and applied on affected skin 2 to 3 times daily for several days until symptoms disappear [100] Dendrobium Phenanthrenes D. denneanum Anti-inflammatory (NO: IC 50 41.5 μM) [13] 79 (9R)-1,2,5,9-Tetrahydroxy-9,10-di-  D. palpebrae Antioxidant [69] allergies, while antimicrobial activities are associated with treatments of boils, impetigo, and pimples. Anti-inflammatory and antioxidant activities are the most common activities of Dendrobium extracts and compounds. One hundred thirty-one compounds from Dendrobium plants have been reported to possess anti-inflammatory, antimicrobial, antioxidant, antiaging, anti-psoriasis, and tyrosinaseinhibitory activities ( Table 2)

Anti-Inflammatory Activity
Skin inflammation is the most common complaint of those suffering 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].

Dendrobium chrysanthum Wall. ex Lindl.
A phenanthrene, dendrochrysanene (75), was isolated from the stems of D. chrysanthum collected 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].

Dendrobium crepidatum Lindl. & Paxton
A research was conducted on D. crepidatum stems collected from Yunnan, China. Total alkaloids (yield, 2.3%) were obtained from D. crepidadum stems, which exhibited inhibitory effects 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; IC 50

Dendrobium denneanum Kerr.
A series of phenanthrene derivatives were isolated from D. denneanum stems collected from Sichuan, China, and 2,5-dihydroxy-4-met hoxy-phenan-   [16], it is cited in this review. A pilot study was conducted to evaluate the clinical and immunomodulatory effects of an orally administered extract of D. huoshanense leaves and stems in children with moderate to severe recalcitrant atopic dermatitis (AD). AD is a common inflammatory skin disorder for which few safe and effective 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 from D. huoshanense for 4 weeks and were followed-up for another 4 weeks. The results showed that the polysaccharide from D. huoshanense reduced the levels of some cytokines associated with AD and had beneficial effects on symptoms. No serious adverse effects occurred when the polysaccharide was administered orally for 4 weeks [17].

Dendrobium loddigesii Rolfe
Shihunine (80) was isolated from D. loddigesii stems 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 IC 50 value of 11.5 μg/mL. L-NG-monomethyl arginine citrate (IC 50 7.2 μg/mL) was used as a positive control [18].
Phenanthrenes and bibenzyls were isolated from D. loddigesii stems collected from Guangdong, China. These compounds were evaluated for their inhibitory activities against NO production. Loddigesiinol A (52; IC 50

Dendrobium nobile Lindl.
An alkaloid, anosmine (81), was isolated from D. 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 IC 50 value of 16.1 μg/mL, which was compared with L-NG-monomethyl arginine citrate (IC 50 , 7.2 μg/mL) as a positive control [18].
Phenanthrenes from the methanolic extract of D. nobile stems were evaluated for their potential to inhibit LPSinduced production of NO in murine macrophage RAW 264.  [23].
Ephemeranthol A (63) was isolated from D. nobile stems, 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].

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 cultured D. tosaense stems protected mice from OVA/TNCB-induced skin lesions of atopic dermatitis [30].
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 from D. chrysotoxum stems [34]. This compound could inhibit the activity of srtA in vitro with an IC 50 value of 20.9 μg/mL [35].
Dendrocoumarin (125) and itolide A (126) from D. nobile stems collected from Hainan, China, showed antibacterial activities against Staphylococcus aureus with the same MIC value of 2.5 μg/mL and Micrococcus tetragenus with the same MIC value of 5.0 μg/mL. The positive control was ciprofloxacin, with MIC values of 0.6 and 0.3 μg/mL for the two bacteria, respectively [36].

Antioxidant and Antiaging Effects
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].

Dendrobium denneanum Kerr
The ethanolic extract of D. denneanum [syn. D. aurantiacum var. denneanum (Kerr) Z.H. Tsi] stems collected from Yunnan, China, exhibited DPPH radical scavenging activity with an IC 50 value of 92.6 μg/mL and was compared with α-tocopherol (IC 50 , 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].

Dendrobium denudans D. Don
The methanol extract of D. denudans stems collected from India showed in vitro antioxidant activity by a reducing power assay with an IC 50 value of 10.1 μg/mL. Ascorbic acid (IC 50 , 3.9 μg/mL) was used as a positive control [46].

Dendrobium longicornu Lindl.
The acetonic extract of D. longicornu stems collected from Nepal showed DPPH radical scavenging activity with an IC 50 value of less than 100 μg/mL and was compared with ascorbic acid (IC 50 , < 50 μg/mL) as a positive control [51].

Dendrobium macrostachyum Lindl.
Ethanolic extracts of D. macrostachyum stems and leaves collected from India exhibited DPPH radical scavenging activities with IC 50 values of 10.2 and 31.5 μg/mL, respectively, as compared with the positive control ascorbic acid (IC 50 , 18.4 μg/mL); these extracts also had ABTS radical scavenging activities with IC 50 values of 31.5 and 49.1 μg/ mL, respectively, as compared with the positive control ascorbic acid (IC 50 , 34.9 μg/mL). The activities of the ethanol extracts were better than those of petroleum ether, methanol, or water extracts [52].
Bibenzyls and other phenolic compounds were isolated from D. nobile stems collected from Yunnan, China. Nobilin exhibited DPPH radical scavenging activities. Vitamin C (IC 50 , 18.0 μM) and BHT (IC 50 , 90.9 μM) were used as positive controls. For all phenanthrenes and lignans, an electrondonating methoxy group in the ortho position that donates to the phenolic hydroxy group exhibits enhanced antioxidant activity [57].
The chloroform extract of D. officinale stems collected from Yunnan, China, exhibited ABTS radical scavenging activity with an IC 50 value of 88.8 μg/mL [59].
D. officinale protocorm 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 that D. officinale protocorms 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 of D. officinale (syn. D. candidum) stems possess a certain preventive effect on photoaging, and the effect of ultrafine powder is better than that of fine powder [68].

Dendrobium signatum Rchb.f.
D. signatum leaves collected from Thailand were extracted with ethanol by sonication-maceration for 30 min. The extract showed DPPH radical scavenging activity, with a measured IC 50 value of 97.2 μg/mL, with ascorbic acid used as a reference compound (IC 50 , 21.7 μg/mL) [71].

Dendrobium tosaense Makino
The effects of methanolic extracts obtained from three Dendrobium species propagated in vitro on DPPH scavenging were investigated. The D. tosaense extract was the most active extract, with an IC 50 value of 79.9 μg/mL, as compared with the positive control α-tocopherol (IC 50 , 58.2 μM) [73].

Anti-Psoriasis Activity
Psoriasis is a recurrent skin disease described as keratinocyte hyperproliferation and aberrant differentiation. 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 from D. chrysotoxum [34].

Hair Growth Promoting Effects
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 administered D. 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].

Skin-Moisturizing Effects
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 of D. 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 that D. huoshanense polysaccharides do not cause skin irritation [79].
Polysaccharides from white orchids (Dendrobium cv. 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 effects of a D. nobile stem extract on human skin. The moisturizing abilities after 30 min and 2 h were greater than 1 for the D. nobile stem extract (2.0%) [81].
An in vivo experiment showed that 20 μg/mL ethanolic extract of D. officinale collected from Yunnan, China, exhibited a skin moisturizing effect. After 2.5 h of use, skin hydrature increased by 16% compared with that before use (P < 0.05) [82].

Tyrosinase-Inhibitory Activity
Tyrosinase inhibitors are used for hyperpigmentation and developing skin whitening agents.
At concentrations of 12.5, 25 and 50 μg/mL, the CH 2 Cl 2 extract of D. moniliforme leaves collected from South Korea inhibited melanogenesis in murine melanoma cells (B16F10), implying that D. moniliforme is effective against hyperpigmentation disorders and that it is considered a possible antimelanogenic agent in topical application [83].
Ethanolic extracts of Dendrobium cv. Sonia flowers and Dendrobium cv. Sonia pink flowers collected from Thailand showed tyrosinase inhibitory activities using l-tyrosine as a substrate. The IC 50 values were 57.4 μg/mL and 83.2 μg/ mL, respectively, as compared with the positive control kojic acid (IC 50 ,151.7 μg/mL) [84].

Conclusion
There are 22 Dendrobium species with traditional uses for treating dermatological disorders by local people in eight countries, and there are 131 compounds from Dendrobium plants reported to possess anti-inflammatory, antimicrobial, antioxidant, antiaging, anti-psoriasis, and tyrosinase-inhibitory activities, which implies that Dendrobium plants are important resources for the discovery of active compounds and the development of new drugs and cosmetics. However, only D. crepidatum, D. denneanum, D. loddigesii, D. nobile, and D. officinale have been extensively studied. More research on other Dendrobium species is needed.