Chinese Journal of

Natural Chinese Journal of Natural Medicines 2018, 16(6): 04010410 Medicines

Rhododendron Molle (): phytochemistry, pharmacology, and toxicology

CAI Yong-Qing1Δ, HU Jian-Hui2Δ, QIN Jie3, SUN Tao4*, LI Xiao-Li5,6*

1 Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China; 2 Student Brigade Ten Team, Second Military Medical University, Shanghai 200433, China; 3 Student Eleven Camp, Third Military Medical University, Chongqing 400038, China; 4 College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; 5 College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; 6 Chongqing Key Laboratory of Drug Metabolism, Chongqing 400016, China

Available online 20 June, 2018

[ABSTRACT] molle G. Don, belonging to the Ericaceae family, is a traditional Chinese medicinal with a wide spectrum of pharmacological effects. This paper aimed to review the phytochemistry, pharmacology and toxicology of R. molle, and to discuss the tendency of future investigations on this plant. A systematic review of literature about R. molle was carried out using re- sources including classic books about Chinese herbal medicine, and scientific data bases including CNKI, Pubmed, SciFinder, Scopus, and Web of Science. Over 67 compounds, including diterpenes, triterpenes, flavonoids, and lignans, had been extracted and identified from R. molle. The extracts/monomers isolated from the root, flower and fruits of this plant were used as effective agents for treating pains, inflammatory diseases, hypertension, and pest, etc. In addition, diterpenes, such as rhodojaponin III, were considered as the toxic agents associated with the toxicities of this plant. These findings will be significant for the discovery of new drugs from this plant and full utilization of R. molle.

[KEY WORDS] Rhododendron molle ; Phytochemistry; Pharmacology; Toxicology [CLC Number] R965 [Document code] A [Article ID] 2095-6975(2018)06-0401-10

investigations on R. molle have demonstrated that it possesses Introduction a wide spectrum of pharmacological activities, including an- Rhododendron molle G. Don (R. molle), belonging to the algesics, anti-inflammatory, anti-hypertensive and insecticidal family of Ericaceae, is a small undershrub distributed in the effects [3-4]. Furthermore, previous researches regarding phy- Yangtze River basin and around the south China [1-2]. In addi- tochemistry of R. molle have been done on the roots, flowers tion, the roots, flowers, and fruits of R. molle have been and the fruits of this plant, and over 67 compounds have been commonly recorded in ancient medical monographs as the isolated and identified from this plant, including diterpenes, traditional herbal medicines in China for analgesics, anti-in- triterpenes, flavonoids, and lignans [3-5]. Besides, R. molle is flammatory and insecticides, etc. [3]. Currently, increasing commonly recognized as a poisonous plant, and previous investigations have reported that the diterpenes are the ma-

jor toxic components of this plant [4-6]. In the present paper, [Received on] 20-Oct.-2017 a systematic review of literatures about R. molle was per- [Research funding] This study was supported by the National Natu- formed using the available resources, such as classic books ral Science Foundation of China (No. 81302797), Research Project of about Chinese herbal medicine, and scientific data bases Chongqing Science and Technology (No. cstc2015jcyjBX0018), and Research Project of Third Military Medical University (No. 2015XZH19). including CNKI, Pubmed, SciFinder, Scopus, and Web of [*Corresponding author] E-mails: [email protected] (LI Xiao-Li); Science, etc. The phytochemistry, pharmacology and toxi- [email protected] (SUN Tao) cology of R. molle were reviewed, which would be signifi- ΔThese authors contributed equally to this work. cant for finding new drugs from R. molle and full utilization These authors have no conflict of interest to declare. of this plant. Furthermore, the possible tendency and per- Published by Elsevier B.V. All rights reserved spective for future researches of R. molle were also dis-

– 401 – CAI Yong-Qing, et al. / Chin J Nat Med, 2018, 16(6): 401410 cussed in this paper. Among these compounds, the diterpenes are the most impor- Phytochemistry tant characteristic constituents in this plant [7-9]. In this section, As a well-known traditional Chinese medicine, many we describe the main chemical constituents of this plant chemical compounds have been isolated from R. molle, mainly (Table 1), including their chemical structures and their iso- including diterpenes, triterpenes, flavonoids and lignans. lation parts of this plant (Figs. 1-5).

Table 1 Chemical compounds isolated from R. molle Classification No. Chemical component Part of plant Reference 1 Rhodomolleins I flower [10] 2 Rhodomolins A flower [17] 3 Rhodomolleins XII flower [10] 4 Rhodomolins C flower [16] 5 Rhodomosides A roots [18-19] 6 Rhodomosides B roots [19] 7 1β-rhodomoside root [22] 8 Grayanotoxin II flower [10, 16] 9 Rhodomolleins XIX flower [21] 10 Rhodomolins B flower [17] 11 Rhodomolleins XI (III) flower [10, 13] 12 Rhodomolleins XIII flower [10] 13 Rhodojaponin VI roots, fruits [10, 12, 22] 14 Rhodomolleins XVI fruits [12] 15 Grayanotoxin I flower [16] 16 Grayanotoxin III flower [11] 17 Rhodojaponin II flower [10] Diterpenes 18 Rhodojaponin III root, flower [13] 19 Rhodomolleins IX flower [10] 20 Rhodomolleins XVIII fruits [12] 21 Rhodomolleins X flower [10] 22 Rhodomolleins XX fruits [21] 23 Rhodomolleins XVII fruits [12] 24 Secorhodomollolides A flower [14] 25 Secorhodomollolides B flower [14] 26 Secorhodomollolides C flower [14] 27 Secorhodomollolides D flower [14] 28 Kalmanol flower [10] 29 Rhodomolleins XV fruits [12] 30 Rhodomolleins XIV flower [10] 31 Rhodomolleins F flower [15] 32 Rhodomolleins G flower [15] 2α, 10α-epoxy-3β, 5β, 6β, 14β, 33 flower [29] 16α-hexahydroxy-grayanane 34 Mollolide A roots [33] 35 Quercetin flower [24] 36 Quercitrin flower [24] Flavonoids 37 Isoquercitrin leave [20] 38 Quercetin-3-O-α-L-arabinoside flower [24] 39 Hyperoside flower [20, 24]

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Continued Classification No. Chemical component Part of plant Reference 40 Quercetin-3-rhamnoside-2"-gallate flower [24] 41 Kaempferol flower [24] 42 Kaempferol-7-O-α-L-rhamnoside flower [24] 43 Isorhamnetin flower [24] 44 Caryatin flower [24] 45 Phloretin flower [25] Flavonoids 46 Phlorezin 4'-methyl ether flower [25] 47 Phloretin 4'-yl-β-D-glucopyranoside flower [25] 48 Phloretin 4'-methyl ether flower [25] 49 Phloretin 6'-methyl ether flower [25] 50 Epicatechin leave [26] 51 Vitexin flower [27] 7S, 8S-threo-4, 9, 9'-trihydroxy-3, 3'-dimethoxy-8- 52 roots [22] O-4'-neolignan-7-O-β-glucopyranoside 7S, 8S-erythro-4, 9, 9'-trihydroxy-3, 3'-dimethoxy- 53 roots [22] 8-O-4'-neolignan-7-O-β-glucopyranoside 7R, 8R-threo-4, 7, 9, 9'-tetrahydroxy-3-methoxy-8- 54 roots [22] Lignans O-4'-neolignan-3'-O-β-glucopyranoside 55 (+)-lyoniresionl roots [22] 56 (+)-lyoniresionl-3α-O-β-glucopyranoside roots [22] 57 (+)-lyoniresionl-3α-O-α-rhamnopyranoside roots [22] 58 (−)-lyoniresionl-3α-O-β-glucopyranoside roots [22] 59 Oleanolic acid flower [27] 60 2α-hydroxy-oleanolic acid flower [27] Triterpenes 61 Asiatic acid flower [27] 62 Taraxerol roots [28] 63 β-sitosterol flower [27] 64 2E, 4Z abscisic acid flower [27] 65 Benzyl glucoside flower [27] Other compounds 66 Steraric acid flower [27] Benzyl 2, 6-dihydroxybenzoate-6-O-α-L-rhamno- 67 flower [29] pyranosyl-(1→3)-β-D-glucopyranoside

Diterpenes rhodomolleins X (21), secorhodomollolides A (24), secor- Diterpenes, existing in numerous natural , have been hodomollolides B (25), secorhodomollolides C (26), secor- reported to possess various pharmacological activities. Previous hodomollolides D (27), kalmanol (28), rhodomolleins XIV investigations have reported that abundant diterpenes are (30), rhodomolleins F (31), rhodomolleins G (32), and 2α, isolated from the roots, flowers, and leaves of R. molle, and 10α-epoxy-3β, 5β, 6β, 14β, 16α-hexahydroxy-grayanane the diterpenes are recognized as the characteristic constituents (33) [10-17]. Furthermore, from other parts of R. molle (roots of this plant. As a known folk medicine, called Rhododendri and fruits), abundant diterpenes have also been isolated and Mollis Flos, the chemical constituents of the flowers of R. identified as rhodomosides A (5), rhodomosides B (6), molle have been comprehensively studied, and researchers 1β-rhodomoside (7), rhodojaponin VI (13), rhodomolleins have obtained various diterpenes from its flowers. These XVI (14), rhodojaponin III (18), rhodomolleins XVIII (20), structurally unique diterpenes are mainly Grayanane type rhodomolleins XX (22), rhodomolleins XVII (23), rhodo- diterpenes, and have a broad spectrum of activities, such as molleins XV (29) mollolide A (34) [18-22] (Fig. 1). anti-nociceptive effect, insecticidal effect, and antihypertensive Flavonoids effects. Diterpenes in this plant mainly include rhodomolleins Flavonoids are common constituents with various phar- I (1), rhodomolins A (2), rhodomolleins XII (3), rhodomolins macological activities in natural plant and herbal world, such C (4), grayanotoxin II (8), rhodomolleins XIX (9), rhodo- as antioxidant, anti-tumor and anti-inflammatory effects [23]. So molins B (10), rhodomolleins XI (III) (11), rhodomolleins far, over 16 common flavonoids have been isolated from the XIII (12), grayanotoxin I (15), grayanotoxin III (16), rhodo- R. molle. In 2009, Liu et al. reported that from the 70% ethanol japonin II (17), rhodojaponin III (18), rhodomolleins IX (19), extract of the flower of R. molle, 9 flavonoids were isolated

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Fig. 1 Chemical structures of the diterpenes isolated from the R. molle and identified as quercetin (35), quercitrin (36), quercetin-3- Lignans O-α-L-arabinoside (38), hyperoside (39), quercetin-3-rhamno- So far, seven interesting ligans have been isolated by Zhi side-2"-gallate (40), kaempferol (41), kaempferol-7-O-α-L- et al. from the roots of R. molle, and their structures have rhamnoside (42), isorhamnetin (43), and caryatin (44) [24]. In been elucidated by spectral analysis, and these ligans are 2008, guiding with anti-inflammatory and antinociceptive mainly neolignans and arylnaphthalenes and ligans [22]. In effects, isoquercitrin (37) was isolated from the leaves of addition, these ligands are identified as 7S, 8S-threo-4, 9, this plant [20]. In addition, WANG et al. have extracted as 9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-7-O-β-glucopy- series of dihydrochalcones from the flowers of R. molle ranoside (52), 7S, 8S-erythro-4, 9, 9'-trihydroxy-3, 3'-dime- guiding by antinociceptive activity, and they were identi- thoxy-8-O-4'-neolignan-7-O-β-glucopyranoside (53), 7R, 8R- fied as phloretin (45), phlorezin 4'-methyl ether (46), phlo- threo-4, 7, 9,9'-tetrahydroxy-3-methoxy-8-O-4'-neolignan-3'- retin 4'-yl-β-D-glucopyranoside (47), phloretin 4'-methyl O-β-glucopyranoside (54), (+)-lyoniresionl (55), (+)-lyonire- ether (48), phloretin 6'-methyl ether (49) [25]. Besides, epi- sionl-3α-O-β-glucopyranoside (56), (+)-lyoniresionl-3α-O- catechin (50) and vitexin (51) were also reported from the α-rhamnopyranoside (57), and (−)-lyoniresionl-3α-O-β-gluco- R. molle [26-27] (Fig. 2). pyranoside (58) (Fig. 3).

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Fig. 2 Chemical structures of the flavonoids isolated from the R. molle

Fig. 3 Chemical structures of the ligans isolated from the R. molle

Triterpenes (64), benzyl glucoside (65), and steraric acid (66) [27]. Addi- In 2004, taraxerol (62) was isolated from the roots of R. tionally, one new compound was extracted from this plant in molle [28]. Furthermore, by using a series of chromatographic 2013 and identified as benzyl 2, 6-dihydroxybenzoate-6-O-α- and spectrum technologies, Wang et al. have isolated 3 triter- L-rhamnopyranosyl-(1→3)-β-D-glucopyranoside (67) [29] (Fig. 5). penes from the flowers of R. molle, and their chemical struc- Pharmacology tures are identified as oleanolic acid (59), 2α-hydroxy- oleanolic acid (60), and asiatic acid (61) [27] (Fig. 4). As a commonly used herbal medicine in China, the roots, Other compounds flowers, and fruits of R. molle are reported to be effective Besides these compounds mentioned above, 4 other com- drugs for treating various diseases. In this section, the mainly pounds have also been isolated from the R. molle and their struc- pharmacological activities of the roots, flowers, and fruits of tures are identified as β-sitosterol (63), 2E, 4Z abscisicacid R. molle are summarized (Table 2).

Fig. 4 Chemical structures of the triterpenes isolated from the R. molle

Anti-nociceptive effect powders of the roots and fruits of R. molle on mice, and found The flower of R. molle is an ancient analgesic for treating that its roots and fruits powders at the dose of 0.2 and 0.5 pains caused by wounding and rheumatic arthralgia in Chi- g·kg−1 (crude herb medicine equivalent) showed notable nese folk medicine [3-4]. Therefore, the anti-nociceptive activ- anti-nociceptive effects [30]. In addition, by using hot plate and ity of the R. molle has been investigated comprehensively. In acetic acid writhing tests on mice, ZHANG et al. have re- 1958, ZHAO et al. researched the anti-nociceptive effects of ported that administration orally of the ethyl acetate extracts

– 405 – CAI Yong-Qing, et al. / Chin J Nat Med, 2018, 16(6): 401410 from the roots of R. molle possess significant anti-nociceptive effects at the doses of 10, 50 and 200 mg·kg−1 [31].

Fig. 5 Chemical structures of other compounds isolated from the R. molle

Table 2 Pharmacological effects of R. molle. Extracts/ Minimal active in vitro Pharmacological effects Detail Reference compounds concentration/dose / in vivo Analgesic effect on test of electric Powders of the roots 0.2 g·kg−1(p.o., crude herb in vivo [30] stimulation on tail in mice and fruits medicine equivalent) Analgesic effect on hot plate and Ethyl acetate extracts of 10 mg·kg−1 (p.o.) in vivo [31] acetic acid writhing tests in mice the roots Anti-nociceptive Analgesic effect on test of electric Rd-II (unidentified) 0.01 mg·kg−1 (i.p.) in vivo [32] stimulation on tail in mice

−1 Analgesic effect on acetic Secorhodomollolide D 5 mg·kg (i.p.) in vivo [14] acid-induced writhing test in mice Mollolide A 20 mg·kg−1 (i.p.) in vivo [33]

Ethanol extracts of the −1 Activating the α-adrenergic receptor 20 μg·mL in vivo [34-35] flowers (intracerebral injection)

Antihypertensive Decreasing heart rate, increasing the diastolic threshold of atrial and ven- −1 [12, tricular, prolonging the refractory Rhodojaponin III 3.5 μg·mL in vivo 36-39] period of atrial and ventricular (intracerebral injection) lowering Ang II and increasing eNOS 0.1 g·rat−1·day−1 (p.o., for 4-8 weeks, crude herb medicine Alleviating symptoms of nephritis equivalent) [40] induced by bovine serum albumin via Powders of the roots in vivo [42] down-regulating the IκB and NF-κB 0.9 g·person−1, 3 times a day, last for 6 months, crude herb Anti-inflammatory medicine equivalent) Anti-inflammatory effects on animal models (histamine induced acute joint 0.65 g·kg−1 (p.o., crude herb swelling, capillary permeability in- Powders of the roots in vivo [41] medicine equivalent) duce by acetic acid and tampon granulation swelling tests) Insecticidal effect on roach Flower extracts 20% extracts-water solution in vitro [43] Feeding-deterrent activities against Sitophilus zeamais and Tribolium Flower extracts 20% extracts-water solution in vitro [44] castaneum Insecticidal effects against Oncome- 0.625 mg·mL−1 (p.o., crude Roots extracts in vitro [45-46] Insecticidal lania and blood flukem iracidium herb medicine equivalent)

−2 Rhodojaponin III PC50 2.8 μg·50mm in vitro

−2 Anti-feedant activity against Leptino- Grayanotoxin I PC50 12.5 μg·50mm in vitro [11] tarsa decemlineata −2 Grayanotoxin III PC50 12.5 μg·50 mm in vitro

−2 Kalmanol PC50 15.0 μg·50mm in vitro

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Continued Extracts/ Minimal active in vitro Pharmacological effects Detail Reference compounds concentration/dose / in vivo

−2 Rhodojaponin III PC50 6.4 μg·50mm in vitro

−2 Anti-feedant activity against Grayanotoxin I PC50 12.0 μg·50mm in vitro [11] Spodoptera frugiperda −2 Grayanotoxin III PC50 12.0 μg·50mm in vitro

−2 Kalmanol PC50 12.5 μg·50mm in vitro

Rhodojaponin III 20 μg·mL−1 in vitro Deterrent effects on Lipaphis erysimi Rhodomollein I 20 μg·mL−1 in vitro Insecticidal [16] −1 Toxicities against wingless-adult Rhodomolin C IC50 24.36 μg·mL in vitro aphid −1 Rhodomolein XVIII IC50 26.92 μg·mL in vitro

−1 Rhodomolins A IC50 37.8 μg·mL in vitro [17] Cytotoxicity on Spodoptera −1 frugiperda Sf-9 cell Rhodomolins B IC50 25.6 μg·mL in vitro

−1 Rhodojaponin III IC50 100 μg·mL in vitro [36] Antipyretic effect on pyretic rabbit 1.3 g·kg−1 (p.o., crude herb induced by injection of microzyme Powders of the roots in vivo [41] medicine equivalent) and peptone

Other pharmacological Selective cytotoxic activity against −1 human hepatoma carcinoma cell line Secorhodomollolide B IC50 0.97 μmol·L in vitro [14] (Bel-7402) Antiviral activity against the Cox- Mollolide A −1 in vitro [33] sackie B3 virus IC50 27.7 μmol·L

The PC95 value means the minimal protective concentration (μg/disk) at which > 95% of the control; IC50 means the half maximal inhibitory concentration

Furthermore, previous investigations have been devoted central antihypertensive effect of EFR was closely correlated to investigate the active constituents for responding anti-no- to activation of the α-adrenergic receptor [35]. In addition, ciceptive effects of R. molle. In 1981, Chen et al. reported that previous researches have demonstrated that intravenous injection they isolated an unidentified compound (Rd-II) which pos- of rhodojaponin III (at least 3.5 μg·mL−1) possessed notable sessed promising analgesic effect from the flowers of R. molle, antihypertensive effect [12, 36-39]. MAO et al. have revealed and the Rd-II at the dose of 0.01 mg·kg−1 could have the equal that decreasing heart rate might be one of the important rea- analgesic effect of pethidine (15 mg·kg−1) [32]. Later, WANG et sons of the antihypertensive effect of rhodojaponin III [37]. al. extracted a compound called Secorhodomollolide D from Besides, LI et al. have indicated that rhodojaponin III could the ethyl acetate extracts of the flowers of R. molle, and this increase the diastolic threshold of atrial and ventricular, and compound (5 mg·kg−1) possessed notable analgesic effect in prolong the refractory period of atrial and ventricular [12, 38-39]. the acetic acid-induced writhing test in mice [14]. Recently, LI What’s more, CHENG et al. have suggested that lowering et al. isolated a novel compound with a special structure Ang II and increasing eNOS is also an important reason for (called mollolide A) from the roots of R. molle, and this com- the antihypertensive effect of rhodojaponin III [36]. pound exhibited a significant analgesic effect (20 mg·kg−1) in the Anti-inflammatory effect acetic acid induced writhing test on mice [33]. In Chinese folk medicine, the flowers, fruits and roots of Antihypertensive effect R. molle are often clinically used to treat inflammatory dis- Antihypertensive effect is another characteristic pharma- eases [4]. In 1990, Xiong et al. reported that the roots of R. cological activity of R. molle, and has been investigated com- molle (0.1−0.8 g·rat−1·day−1, last for 4-8 weeks, crude herb prehensively. Furthermore, recently researches regarding medicine equivalent) could significantly decrease the symp- antihypertensive effect this plant mainly focus on the rhodo- toms of nephritis induced by injection of bovine serum albu- japonin III which is also called rhomotoxin [13]. In 1985, min (BSA). In addition, the authors also evaluated the cura- CHEN ang YU reported that by using intracerebral injection, tive effects of the roots of R. molle (0.9−1.5 g·person−1, 3 ethanol extracts from the flowers of R. molle (EFR, 20 μg·mL−1) times a day, last for 6 months, crude herb medicine equivalent) exhibited significant antihypertensive effect, indicating that on clinical nephritis patients, and obtained a similar result antihypertensive effect of EFR is related to the central nerv- with the rat experiment [40]. Later in 1995, by using inflam- ous system [34]. Later in 1986, CHEN and YAO indicated that matory animal models including histamine induced acute

– 407 – CAI Yong-Qing, et al. / Chin J Nat Med, 2018, 16(6): 401410 joint swelling, capillary permeability induced by acetic acid herb medicine equivalent) decreased the body temperature of and tampon granulation swelling tests, ZENG et al. reported pyretic rabbit induced by injection of microzyme and peptone [41]. that the roots of R. molle (0.65−2.6 g·kg−1, crude herb medi- In addition, secorhodomollolide B isolated from the flowers cine equivalent) showed significant anti-inflammatory activi- of R. mole possesses selective cytotoxic activity against human [41] −1 [14] ties in mice . In 2005, LIU et al. reported that the roots of hepatoma carcinoma cell line (Bel-7402) (IC50 0.97 μmol·L ) . R. molle possessed notable therapeutic effects on experimental Besides, Mollolide A isolated from the R. mole exhibits a nephritis in rats via down-regulating the IκB and NF-κB [42]. significant antiviral activity against the Coxsackie B3 virus −1 [33] Insecticidal effect (IC50 27.7 μmol·L ) . Roach is a worldwide pest, commonly spread various Toxicology diseases, Song et al. have reported that 20% R. molle ex- tracts-water solution could reach over 60% lethality on roach In China, the R. molle is traditionally and commonly recog- [47-48] in 336 h [43]. In 2007, LIU et al. screened 40 of Chi- nized as a toxic plant as other plants in . nese medicinal herbs with the insecticidal or feeding-deterrent Thus, the toxicities of R. molle have been comprehensively re- activities against two stored-grain insects Sitophilus zeamais corded and investigated. and Tribolium castaneum, and results of LIU et al. revealed In 1958, Zhao et al. reported that LD50 of the roots and that the hexane and methanol extracts of flowers of R. molle fruits of R. molle were 5.85 g·kg−1 and 5.13 g·kg−1 (crude herb possessed significant insecticidal and feeding-deterrent activi- medicine equivalent), respectively; in addition, after treating ties against the two insects above [44]. In 2008, an interesting with roots and fruits of R. molle at the doses 0.5−1.0 g·kg−1 research investigated the insecticidal effects of roots of R. (crude herb medicine equivalent), toxic symptoms could be molle against Oncomelania and blood flukem iracidium, and observed in mice, including sleepiness, sweating, paresis, found that its roots extracts (0.625−5 mg·mL−1, crude herb instability of gait, and even convulsion [30]. Furthermore, medicine equivalent) could kill the oncomelania and blood another investigation on dog indicated that extracts of the flukem iracidium within 20 min [45-46]. roots of R. molle (ERRM, 0.17−1.42 g·kg−1·day−1, last for 3 It’s reported that grayane diterpenoids in the R. mole are months) had toxic effects on liver and kidney of dog. ERRM the main activities with insecticidal effects. In 1991, James et al. treatment could result in hepatonecrosis, hepatic cells edema, researched the active constituents with anti-feed ant activity ballooning change and steatosis for the liver, and increase of in the flowers of R. molle by using activity-guided isolation, the permeability of glomerulus, edema and ballooning de- and found that Rhodojaponin III, grayanotoxin I, grayano- generation of renal tubular epithelial cells for the kidney [49]. toxin III and kalmanol possessed notable anti-feedant activities Later in 1996, by studying on dog, Liu et al. reported that against Leptinotarsa decemlineata and Spodoptera frugiperda orally treatment with ERRM (0.17−1.42 g·kg−1·day−1) for 3 −2 −2 with the PC95 values of 2.8 μg·50 mm and 6.4 μg·50 mm , months could lead to decrease of the peripheral blood red 12.5 μg·50 mm−2 and 12.0 μg·50 mm−2, 12.5 μg·5 0 mm−2 and blood cells, hemoglobin and ratios of neutrophils, whereas 12.0 μg·50 mm−2 and 15.0 μg·50 mm−2 and 12.5 μg·50 mm−2, increase of the leukocyte and ratios of leukocyte [50]. Be- respectively [11]. Furthermore, ZHONG et al. isolated 13 gra- sides the toxic effects of extracts of this plant, previous re- yane diterpenoids from the flowers of R. mole, and found that searches also devoted some works to its toxic substance. In rhodojaponin III (20 μg·mL−1) and rhodomollein I (20 μg·mL−1) 2010, through administration orally to mice, Cheng et al. had obvious deterrent effects on Lipaphis erysimi with deter- reported that rhodojaponin III was the major toxic constitu- −1[6] rent rate of 76.64% and 65.06%; rhodomolin C and rhodo- ent of R. molle with the LD50 value of 7.609 mg·kg . molein XVIII possessed significant toxicities against wing- What’s more, previous investigations also reported that the less-adult aphid with the IC50 values of 24.36 and toxic effects of R. molle could be alleviated via some strate- 26.92 μg·mL−1, respectively [16]. Later in 2005, Zhong et al. gies. Yao et al. have reported that Fructus Gardeniae (an reported that another two new grayanane diterpenoids includ- herbal medicine in China) could effectively decrease the ing rhodomolins A and B were isolated from the flowers of R. hepatotoxicity of flowers of R. molle via decreasing serum mole, and they found that rhodomolins A and B possessed levels the ALT, MDA, and TG [51]. significant cytotoxicity on Spodoptera frugiperda Sf-9 cell −1 Future perspectives and conclusion line with the IC50 values of 37.8 and 25.6 μg·mL , respec- tively [17]. In 2011, Cheng et al. also reported that rhodoja- As an important traditional Chinese medicine, R. molle ponin III could strongly inhibit the proliferation of S. has been used for treatment of various diseases, such as pains, frugiperda Sf-9 cell via induction of intracellular Ca2+, pH cardiovascular diseases, inflammatory diseases, and killing changes and cell cycle arrest [36]. pest. Previous researches have reported that R. molle contains Other pharmacological effects abundant diterpenes, triterpenes, flavonoids and lignans, etc; Besides these important above pharmacological effects among these constituents, diterpenes are considered as the and applications of R. mole, this medicinal herb is also could main active components in R. molle, in particular the graya- be commonly used in other ways. In 1995, Zeng et al. indi- nane type diterpenes. cated that treatment with roots of R. mole (1.3 g·kg−1, crude However, there is still not enough systemic data in the

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following fields. First, systemic researches regarding the of Rhododendron molle [J]. J Nat Prod, 2003, 63(9): 1214- clinical research and pharmacokinetics of this plant are still 1217. lacking, and additional data regarding these fields are also [13] Liu ZG, Pan XF, Chen CY, et al. Study on the chemical con- very crucial for full understanding the pharmacological ef- stituents of Rhododendron molle G. Don. [J]. Acta Pharm Sin, fects and potential applications of this plant. Thus, in the fu- 1990, 25(11): 830-833. [14] Wang SJ, Lin S, Zhu CG, et al. Highly acylated diterpenoids ture, more researches should be devoted to the toxicology, with a new 3, 4-secograyanane skeleton from the flower buds clinical research and pharmacokinetics of the extracts/com- of Rhododendron molle [J]. Organic Letters, 2010, 12(7): 1560- pounds in R. molle. Second, the majority works regarding the 1563. pharmacological effects of this plant are just superficial and [15] Zhang ZR, Zhong JD, Li HM, et al. 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Cite this article as: CAI Yong-Qing, HU Jian-Hui, QIN Jie, SUN Tao, LI Xiao-Li. Rhododendron Molle (Ericaceae): phyto- chemistry, pharmacology, and toxicology [J]. Chin J Nat Med, 2018, 16(6): 401-410.

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