The Chemical Structure and Pharmacological Activity of Sesquiterpenoids in Dendrobium Sw.

Abstract

Dendrobium is one of the most important orchids with high medicinal value. The diverse pharmacological activities of Dendrobium are attributed to its rich content of secondary metabolites. Due to the high variety and content of sesquiterpenoids in Dendrobium, more studies on their pharmacological activities have been reported. More than 100 sesquiterpenoids have been isolated from the roots and stems of Dendrobium, and these compounds have been shown to play important roles in a variety of diseases. However, there is a lack of systematic summarization of the chemical structures and pharmacological activities of sesquiterpenoids in Dendrobium Sw. Here, we reviewed the chemical structures of the sesquiterpenoids in Dendrobium plants, classified them according to the skeleton types, and summarized their pharmacological activities and mechanisms of action, with a view to laying a foundation for future studies on their pharmacological activity mechanisms and rational clinical applications.

1. Introduction

Dendrobium Sw. is one of the most widely represented genera of Orchidaceous family. According to the “Plants of the World Online|Kew Science” database, Dendrobium Sw. comprises 1602 species, with the genus primarily cultivated in China, India, the Amanda Islands, Myanmar, Asia, North America, Oceania, and other tropical and subtropical regions. There are more than 80 species of Dendrobium in China, including Dendrobium nobile Lindl. (D. nobile), Dendrobium candidum (D. candidum), Dendrobium huoshanense (D. huoshanense), and others [1].

Dendrobium is used for the treatment of various diseases, medicinal diets, and horticultural ornamentals purposes, and it has a history of use in several countries such as China, Australia, India, and Malaysia. Approximately 30 species of Dendrobium are commonly employed, including D. nobile, D. candidum, D. polyanthum, D. nobile, D. candidum, D. polyanthum, etc. Most notably, China is the first country to use Dendrobium as herbal medicine, with its medicinal applications traceable to the Qin and Han dynasties [2]. In the “Shennong’s Classic of the Materia Medica”, it is recorded that Dendrobium is a top-ranking traditional Chinese medicine that strengthens the “yin” and nourishes the five viscera. It is also named as “the first of the nine immortal medicines” among the many precious Chinese herbs [3]. As evidenced in the extant literature, over 30 species of Dendrobium have been employed in the treatment of various diseases in China [4]. Phytochemical studies have demonstrated that Dendrobium possesses a multitude of pharmacologically active compounds, including alkaloids [5,6,7,8,9,10,11,12,13,14,15], sesquiterpenoids [16,17,18,19,20,21,22,23,24,25], flavonoids [10,19,26], phenanthrenes [20,27,28,29], and polysaccharides [30,31,32]. In particular, sesquiterpenoids in Dendrobium Sw. (DSS), which is abundant and structurally diverse and exhibits potent pharmacological activities, have received increasing attention from researchers [20,33,34].

Sesquiterpenoids are naturally occurring terpenoids comprising 15 carbon atoms in the molecule, containing three isoprene units, and exhibiting a range of skeletal structures, including chains and rings. The components of this class are widely distributed, and the majority of plants continuously synthesize a variety of sesquiterpenoids during their growth and development stages, including Dendrobium Sw. In recent years, research has demonstrated that sesquiterpenoids are the most prevalent and abundant class of compounds in the genus Dendrobium. These compounds have been shown to play a crucial role in neuroprotection [35], immunomodulation [36], the treatment of diabetes [37], anti-tumor activity [38], and other biological processes. Until now, a total of 12 species of Dendrobium have been identified as containing sesquiterpenoids. However, a dearth of systematic syntheses exists regarding the applications of DSS in research. Given the extensive range and diversity of DSS observed in Dendrobium, an exhaustive review of this subject is of paramount importance. Consequently, this review aims to elucidate the current understanding of DSS, encompassing its structural and typological variations, as well as its pharmacological effects. The review will serve as a foundation for future investigations into its pharmacological activities and rational clinical applications.

2. Chemical Structure of DSS

It has been reported that more than 100 sesquiterpenoids have been isolated from the roots and stems of Dendrobium. These sesquiterpenoids can be categorized into the following types: picrotoxane-type, allo-aromadendrane-type, copacamphane-type, cyclocopacamphane-type, cadinene-type, emmotin-type, muurolene-type, axane-type, and ylangene-derived types. Among them, the picrotoxane-type is the most abundant sesquiterpenoid in Dendrobium, which contains more than 70 compounds. This review summarizes the sesquiterpenoid-type constituents isolated from different types of Dendrobium Sw. according to the skeleton type of the compounds.

2.1. Picrotoxane-Type Sesquiterpenoids

Picrotoxane-type sesquiterpenoids are the precursor substance of other sesquiterpenoids in Dendrobium Sw. To date, 75 compounds of picrotoxane-type sesquiterpenoids have been isolated from 12 species of Dendrobium Sw., including D. nobile, Dendrobium tasselii (D. tasselii), and Dendrobium tympani (D. tympani). This type of sesquiterpenoids covers over 50% of the reported sesquiterpenoids. Additionally, the available literature reveals that picrotoxane-type sesquiterpenoids in Dendrobium Sw. are the primary precursors in the biosynthetic pathway of most active alkaloids. It is of significant importance to summarize the class of alkaloid sesquiterpenoids in Dendrobium Sw., as they represent the primary active components in the majority of medicinal Dendrobiums. The picrotoxane-type sesquiterpene substituents can be subdivided into two types according to their characteristics: picrotoxane-type alkaloid sesquiterpenoids and picrotoxane-type nonalkaloid sesquiterpenoids. This section provides a summary of the picrotoxane-type sesquiterpene substituents according to their characteristics.

2.1.1. Picrotoxane-Type Alkaloid Sesquiterpenoids

Picrotoxane-type alkaloidal sesquiterpenoids, also known as dendrobine-type alkaloidal sesquiterpenoids, are represented by the endemic constituent dendrobine of D. nobile [9]. The skeleton of these sesquiterpenoids is the interaction of the C₁₅ position (carboxyl group) with the C₃ position (hydroxyl group), which condenses to form a five-membered lactone ring. Figure 1 shows the structural parentheses of picrotoxane-type alkaloid sesquiterpenoids. This class of sesquiterpenoids exhibits considerable structural diversity, with variations in the skeleton primarily concentrated around the N atom and N heterocycle. The components of this class are distributed more widely in D. nobile [39], D. findlayanum, D. signatum [8], and D. friedericksianum [5]. Additionally, D. nobile, D. signatum, and D. friedericksianum have also been used as a quality marker [9]. The structural information is shown in Figure 2, and the available information on this class of constituents is shown in Table 1 and Figure 3.

Figure 1.

Pictures of 6 species of Dendrobium. (a) D. nobile; (b) D. huoshanense; (c) D. polyanthum; (d) D. crepidatum; (e) D. wardianum; (f) D. candidum.

Figure 2.

Structural skeleton of picrotoxane-type alkaloidal sesquiterpenoids. The numbers in the structure indicate the number of carbon atoms in the molecule.

Table 1.

Information table of picrotoxane-type alkaloid sesquiterpenoids isolated from Dendrobium.

No.	Compounds	Formula	Sources	Refs.
1	Dendrobine	C16H25NO2	D. nobile, D. crepidatum	[22,31,40,41]
2	Mubironine B	C15H23NO2	D. nobile	[41]
3	Dendramine	C16H25NO3	D. nobile	[13,41]
4	(-)-(1R,2S,3R,4S,5R,6S,9S,11R)-11-Carboxy-methyl-dendrobine	C18H27NO4	D. nobile	[40]
5	Dendrine	C19H29NO4	D. nobile	[40]
6	Dendronobiline A	C19H29NO3	D. nobile	[15]
7	N-methyl-dendrobinium	C17H28NO2+	D. nobile	[41]
8	N-isopentenyl-dendrobinium	C21H34NO2+	D. nobile	[41]
9	Dendrobine N-oxide	C16H25NO3	D. nobile	[7]
10	3-Hydroxy-2-oxodendrobine	C16H23NO4	D. nobile	[42]
11	Oxodendramine	C16H23NO4	D. nobile	[42]
12	Dendroxine	C17H25NO3	D. nobile	[12,14]
13	6-Hydroxy-dendroxine	C17H25NO4	D. nobile	[14]
14	4-Hydroxy-dendroxine	C17H25NO4	D. nobile	[14]
15	N-Isopentenyl-dendroxinium	C22H34NO3+	D. nobile	[41]
16	N-Isopentenyl-6-hydroxydendroxinium	C22H34NO4+	D. nobile.	[41]
17	N-Isopentenyl-dendroxinium chloride	C22H34NO3+	D. nobile	[7,41]
18	N-Isopentenyl-6-hydroxydendroxinium chloride	C22H34NO4+	D. nobile	[7,41]
19	N-isopentenyl-dendroxine	C22H34NO3+	D. nobile, D. friedericksianum	[43]
20	N-isopentenyl-6-hydroxy-dendroxine	C22H34NO4+	D. nobil, D. friedericksianum	[43]
21	Nobilonine	C17H27NO3	D. nobile, D. crepidatum	[41]
22	6-Hydroxynobiline	C17H27NO4	D. nobile	[13,40,41]
23	Dendroterpene A	C15H21NO3	D. nobile	[44]
24	Dendroterpene B	C15H21NO4	D. nobile.	[44]
25	7-hydroxydendroterpene B	C15H21NO5	D. signatum	[44]

Figure 3.

Structures of picrotoxane-type alkaloid sesquiterpenoids isolated from Dendrobium.

2.1.2. Picrotoxane-Type Non-Alkaloidal Sesquiterpenoids

Picrotoxane non-alkaloidal sesquiterpenoids are characterized by a higher degree of oxygen substitution, predominantly occurring at the C4, C9, C11, and C12 positions, which often leads to the formation of polyhydroxy structures. These type of components are reported in D. nobile [44], D. candidum [22], D.moniliforme [45], and D. wardianum [18,29], especially in D. nobile and D. wardianum. Picrotoxane non-alkaloidal sesquiterpenoids are similar in skeleton to their alkaloidal sesquiterpenoids counterparts, and they are mainly characterized by having a high number of chiral carbons and the lack of nitrogen atoms in the molecule. Therefore, the absolute configuration of the components of this class is more difficult to determine. The chemical composition information of the picrotoxane class of non-alkaloidal sesquiterpenoids is shown in Table 2, and the specific structures are shown in Figure 4.

Table 2.

Information table of picrotoxane-type non-alkaloid sesquiterpenoids isolated from Dendrobium.

No.	Compounds	Formula	Sources	Refs.
26	Dendronobilin D	C15H24O5	D. nobile	[46]
27	Dendronobilin E	C15H24O5	D. nobile	[46]
28	Dendronobilin B	C15H24O5	D. nobile	[22,46]
29	Dendroside G (7,11-dihydroxy-5-hydroxymethyl-11-isopropyl-6-methyl-9-oxatricyclo [6.2.1.02,6] undecan-10-one-15-O-β-D-glucopyranoside)	C21H34O10	D. nobile	[47]
30	Dendroside F (7-hydroxy-5-hydroxymethyl-11-isopropyl-6-methyl-9-oxatricyclo [6.2.1.02,6] undecan-10-one-15-O-β-D-glucopyranoside)	C21H34O9	D. nobile	[47]
31	Dendrodensiflorol	C15H24O5	D. nobile	[41,48]
32	Dendronobilin L	C15H24O6	D. nobile	[46]
33	7,12-dihydroxy-5-hydroxymethyl-11-isopropyl-6-methyl-9-oxatricyclo [6.2.1.02,6] dendecane-10-one-15-O-β-D-glucopyranoside	C21H34O10	D. nobile	[49]
34	10,12-dihydroxypicrotoxane	C15H28O2	D. nobile	[49,50]
35	6 α,10,12-trihydroxypicrotoxane	C15H28O3	D. nobile	[49,50]
36	Dendronobiloside B	C21H38O8	D. nobile	[51]
37	Dendronobiloside A	C21H34O8	D. nobile	[51,52]
38	Nobilomethylene	C15H20O3	D. nobile	[14]
39	Findlayanin (1R,2S,3R,4S,5R,6S,9R)-2,3,11,12-tetrahydroxypicrotoxan-12(15)-lactone	C15H24O5	D. nobile, D. findlayanum	[22,53]
40	(+)-(1R,2S,3S,4R,5R,6S,9R)-2,4,11-Trihydroxypicrotoxane-3(15)-lactone	C15H24O5	D. nobile	[22]
41	(+)-(1R,2S,3R,4S,5R,6S,9R)-2,11,12-Trihydroxypicrotoxane-3(15)-lactone	C15H24O5	D. nobile	[22]
42	(+)-(1R,2S,3R,4S,5R,6S,9R)-3,11,12-Trihydroxypicrotoxane-2(15)-lactone	C15H24O5	D. nobile	[21]
43	(−)-(1S,2R,3S,4R,5S,6R,9S,12R)-3,11,13-Trihydroxypicrotoxane-2(15)-lactone	C15H24O5	D. nobile	[21]
44	Dendrobiumane B	C15H24O4	D. moniliforme	[45]
45	Dendrobiumane D	C15H24O5	D. moniliforme	[45]
46	Dendrobiumane C	C16H24O4	D. moniliforme	[45]
47	Dendrobiumane E	C15H18O7	D. moniliforme	[45]
48	Dendrowardin A ((1S,2S,3R,4S, 5R,6S,9S)-3,9,11-trihydroxypicrotoxane-2(15)-lactone.)	C15H24O5	D. wardianum	[18]
49	Dendrowardin B ((1R*,2S*,3R*,4S*,5R*,6S*,9R*)-9-carboxy-9-desmethyl-3-hydroxypicrotoxano-2(15)-lactone)	C15H22O5	D. wardianum	[18]
50	Dendrowardin C ((1R*,2S*,3R*,4S*,5R*,6S*,8R*,9R*)-3,8- dihydroxypicrotoxano-2(15),10(11) -dilactone)	C15H20O6	D. wardianum	[18]
51	Dendrowardin D ((1R*,2S*,3R*,4S*,5R*,6S*,9R*,12S*)-3,13-dihydroxypicr otoxano-2(15),10(11)-dilactone.)	C15H20O6	D. wardianum	[18]
52	Dendrowardin E ((1R*,2S*,3S*,4R*,5R*,6S*,9R*)-9-carboxy-9-desmethyl-2,4-dihydroxypicrotoxano-3(15)-lactone)	C15H22O6	D. wardianum	[18]
53	Dendrowardin F ((1R*,3R*,4R*,5R*,6S*,9R*)-9-carboxy-9-desmethyl-4-hydroxypicrotoxano-3(15)-lactone-2-one)	C15H20O6	D. wardianum	[18]
54	Dendrowardin I ((1R*,4S*,5S*,6S*,9S*)-9,11,13,15- tetrahydroxypicrotoxane)	C15H26O4	D. wardianum	[18]
55	Dendrowardin J ((1R*,2S*,3R*,4S*,5R*,6S*, 8R*,9S*)-9,10-cyclo-2,8,11-trihydroxypicrotoxano-3(15)-lactone)	C15H22O5	D. wardianum	[18]
56	Dendrowardin G ((1R*,2S*,3R*,4S*,5R*,6S*,12R*)-2,11,13-trihydroxypic rotoxano-8-en-3(15)-lactone)	C15H22O5	D. wardianum	[18]
57	Dendrowardin H ((1R*,2S*,3R*,4S*,5R*,6S*,12S*)-2,11,13- trihydroxypic rotoxano-8-en-3(15)-lactone)	C15H22O5	D. wardianum	[18]
58	Dendromoniliside B (2α,3α,12-trihydroxypicro- toxane-3(15α)-olid-11-oic acid 2-O-β-D-glucopyranoside)	C21H32O11	D. moniliforme	[54]
59	Dendromoniliside C (2α,3α,8β-trihydroxy-9α- (11)-epoxypicrotoxan-3(15α)-olide 8-O-β-D-glucopyranoside.)	C21H32O10	D. moniliforme	[54]
60	Dendromoniliside D (2α,3α,11,12-tetrahydroxypicrotoxan-3(15α)-olide 11-O-β-D-glucopyranoside)	C21H34O10	D. moniliforme	[54]
61	Crystallinin	C15H22O5	D. crystallinum	[55]
62	Dendronobilin J	C15H22O6	D. nobile	[48,55]
63	Dendronobilin F	C15H22O5	D. nobile	[46]
64	Dendronobilin M	C15H24O6	D. nobile	[54]
65	Dendronobilin C	C15H22O6	D. nobile	[54]
66	Dendrowillin B	C15H20O6	D. williamsonii	[25]
67	Amotin	C15H20O6	D. amoenum	[56]
68	Dendrowillin A	C15H20O7	D. williamsonii	[25]
69	Dengrasusane A	C15H18O7	D. gratiosissimum	[57]
70	Dendroterpene C	C15H20O4	D. nobile	[44]
71	Dendroterpene D	C15H20O5	D. nobile	[44]
72	Dendroterpene E	C15H22O4	D. nobile	[39]
73	Aduncin C	C15H18O6	D. huoshanense	[25]
74	Wardianumine A	C19H31NO4	D. wardianum	[29]
75	Amoenin	C15H22O6	D.amoenum	[56]

Figure 4.

Structures of picrotoxane-type non-alkaloid sesquiterpenoids isolated from Dendrobium.

2.2. Allo-Aromadendrane-Type Sesquiterpenoids

Allo-aromadendrane-type sesquiterpenoid structures are characterized by the presence of a cyclopropane structure. These compounds usually undergo hydroxyl substitution at the C10, C11, and C13 positions, with their glucose often binding at the C13 and C15 positions, resulting in the formation of sesquiterpene glycosides. By analyzing this class of constituents, it can be found that this class of constituents mainly exists in D. nobile and is rarely reported in D. findlayanum and D. moniliforme. The compositional information table and structure is shown in Table 3 and Figure 5.

Table 3.

Information table of allo-aromadendrane-type sesquiterpenoids isolated from Dendrobium.

No.	Compounds	Formula	Sources	Refs.
76	Dendronobilin H	C15H26O3	D. nobile	[46,55]
77	Dendrobiumane A	C15H26O3	D. nobile, D. moniliforme	[48,55]
78	Dendroside A (10β,12,14-trihydroxyalloaromadendrane 14-O-β-D- glucopyranoside)	C21H36O8	D. nobile	[51]
79	Dendroside B (10β,12,14-trihydroxyalloaromadendrane 12,14-di-O-β-D-glucopyranoside.)	C27H46O13	D. nobile	[50]
80	Dendroside D (10β,14-dihydroxy-alloaromadendran-12-oic acid 12,14-di-O-β-D-glucopyranoside)	C27H44O14	D. nobile	[47]
81	10β,12,14-trihydroxyalloaromadendrane	C15H26O3	D. nobile	[50]
82	Dendroside C (10β,13,14-trihydroxyalloaromadendrane 14-O-β-D-glucopyranoside.)	C21H36O8	D. nobile	[50]
83	Soltorvum F	C17H28O4	D. nobile	[55]
84	10β,13,14-trihydroxyalloaromadendrane	C15H26O3	D. nobile	[55]
85	Dendrofindlayanoside A	C21H34O8	D. findlayanum	[52]
86	Dendrofindlayanoside B	C21H36O8	D. indlayanum	[52]

Figure 5.

Structures of allo-aromadendrane-type sesquiterpenoids isolated from Dendrobium.

2.3. Copacamphane- and Cyclocopacamphane-Type Sesquiterpenoids

The structural similarity between cyclocopacamphane-type sesquiterpenoids and copacamphane-type sesquiterpenoids in Dendrobium Sw. is extremely high. The major difference between them is that cyclocopacamphane-type sesquiterpenoids can form ternary rings, mainly at the C8 and C9 positions. In addition, hydroxyl substitution can also occur in this group of components, mainly at the C4 and C8 positions. Detailed information of cyclocopacamphane-type and copacamphane-type sesquiterpenoids is shown in Table 4, and their structures can be seen in Figure 6.

Table 4.

Information table of copacamphane- and cyclocopacamphane-type sesquiterpenoids isolated from Dendrobium.

No.	Compounds	Formula	Sources	Refs.
87	Dendronobilin A	C15H24O3	D. nobile	[55]
88	Dendronobilin K	C15H24O4	D. nobile	[46]
89	(+)-(1R,5R,6S,8R,9R)-8,12-dihydroxy-copacamphan-3-en-2-one	C15H22O3	D. nobile	[21]
90	Dendromoniliside A (2α,12-dihydroxycopacamphan-15-one 2-O-β-D-glucopyranoside)	C21H34O8	D. moniliforme	[54]
91	Dendronobiloside E (5β,12,15-trihydroxy-cyclocopacamphane 12-O-β-D-glucopyranoside)	C21H34O8	D. nobile	[47]
92	Dendrobane A (5β,8β,12-trihydroxy-cyclopacamphane)	C15H24O3	D. nobile	[47]
93	Dendronobilin I	C15H24O3	D. nobile	[46]
94	Dendronobilin N	C15H24O4	D. nobile	[46]
95	Dendrofindlayanobilin A	C15H24O3	D. findlayanum	[52]

Figure 6.

Structures of copacamphane- and cyclocopacamphane-type sesquiterpenoids isolated from Dendrobium.

2.4. Cadinene-Type Sesquiterpenoids

Cadinene-type sesquiterpenoids have been isolated from both D. nobile and D. findlayanum, with five components currently reported. These compounds can usually be combined with glucose moieties to form glycosidic components. The compounds’ information is shown in Table 5 and the structures in Figure 7.

Table 5.

Information table of cadinene-type sesquiterpenoids isolated from Dendrobium.

No.	Compounds	Formula	Sources	Refs.
96	Dendronobiloside C (11,15-dihydroxycadinene 11,15-di-O-β-D-glucopyranoside)	C27H44O12	D. nobile	[50]
97	Dendronobiloside D (14,15-dihydroxycacinen 14,15-di-O-β-D-glucopyranosidle)	C27H44O12	D. findlayanum	[50,58]
98	Cadalene-12-O-β-D-glucopyranoside	C21H28O6	D. nobile	[59]
99	Findlayanosides A ((1R,6R,7S,10S)-muurol-4-ene-1,11,15-triol 15-O-b-D-glucopyranoside)	C21H36O8	D. findlayanum	[58]
100	Findlayanosides B ((1R,6R,7S,10S)-muurol-4-ene- 1,11,15-triol 11-O-b-D-glucopyranoside)	C21H36O8	D. findlayanum	[58]

Figure 7.

Structures of cadinene-type sesquiterpenoids isolated from Dendrobium.

2.5. Other Types of Sesquiterpenoids

In addition, Dendrobium Sw. also contains other types of sesquiterpenoids, including emmotin-type sesquiterpenoids, muurolene-type sesquiterpenoids, axane-type sesquiterpenoids, and ylangene-derived sesquiterpenoids. Their compositional information and structures are shown in Table 6 and Figure 8.

Table 6.

Information table of emmotin-, murolene-, axane-, and ylangene-derived-type sesquiterpenoids isolated from Dendrobium.

No.	Compounds	Formula	Sources	Refs.
101	Dendroside E (1α,13,14-trihydroxyemmotin 14-O-β-D-glucopyranoside)	C21H36O8	D. nobile	[47]
102	Dendronobilin G (9β,10α)-muurol-4-ene-9,10,11-triol	C21H36O8	D. nobile	[46]
103	Bullatantriol	C15H28O3	D. nobile	[60]
104	Dendrofindlayanoside C	C22H36O8	D. findlayanum	[52]

Figure 8.

Structures of emmotin-, murolene-, axane-, and ylangene-derived-type sesquiterpenoids isolated from Dendrobium.

3. Pharmacological Activity

DSS exhibits diverse pharmacological activities, especially sesquiterpene alkaloids and sesquiterpene glycosides. For example, D. nobile, whose pharmacological activities have been studied by focusing on total alkaloids extracted from D. nobile (DNLA) and its representative compound dendrobine, has shown significant effects in blood glucose regulation, neuroprotection, anti-tumor activity, etc. In addition, the pharmacological effects on immunoinflammatory modulation, antiviral, and other aspects of other classes of components in Dendrobium have also been reported, such as sesquiterpene glycoside components. The aim of this section is to summarize the pharmacological activity and mechanism of action of DSS, and to provide research progress for its further product development and clinical application.

3.1. Treatment of Diabetes

DNLA has significant therapeutic effects on diabetes. Its regulation of blood glucose is summarized in three aspects: increasing insulin sensitivity, glycogen synthesis, and decreasing lipid synthesis. DNLA mainly regulates genes and pathways related to glucose metabolism, insulin action, and lipid metabolism to promote the balance of glucose metabolism in the body.

In improving insulin sensitivity, Shihunine, a water-soluble alkaloid in D. meridianum, significantly reduces body weight, fasting blood glucose, and lipid levels in db/db mice. It also significantly improves the oral glucose tolerance test (OGTT) and serum insulin levels. The underlying mechanism may involve the agonistic adenosine monophosphate (AMP)-activated protein kinase phosphorylation (p-AMPK). It also involves increased expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and glucose transporter protein 4 (GLUT4) in liver and adipose tissue [60]. In regulating glycogen synthesis, DNLA increases the expression of PGC1α in both the mRNA and protein levels. Moreover, DNLA enhances the expression of glucose metabolism genes such as glucose transporter protein 2 (GLUT2) and Forkhead box transcription factor O1 (FoxO1) [35]. In addition, D. nobile regulated blood glucose levels in HFD and STZ-induced diabetic rats. Its glucose-lowering mechanism may be associated with the activation of the PI3K/AKT pathway and insulin signaling pathway, which regulate hepatic glycogen synthesis and gluconeogenesis [59]. In the regulation of lipid synthesis, DNLA up-regulates fatty acid β-oxidation genes, including acyl-CoA oxidase 1(Acox1) and Carnitine Palmitoyl-Transferase1A (Cpt1a). Concurrently, a decrease in the lipid synthesis regulator Sterol Regulatory Element Binding Protein-1 (Srebp1) and an increase in the lipolysis gene Adipose Triglyceride Lipase (ATGL) were observed [35].

Furthermore, DNLA also reduced the amount of Th17 in gestational diabetic mice, which can effectively alleviate gestational diabetes in mice and may serve as a potential therapeutic candidate for gestational diabetic patients [61]. The alcoholic extract of D. bulbosum ameliorated hyperglycemia and diabetic complications in STZ-induced diabetic rats by inhibiting the expression of pro-angiogenic factors, including VEGF/VEGFR2, MMP 2/9, PDGF A/B, bFGF, and insulin-like growth factor 1 (IGF-1) [27].

These findings suggest that the sesquiterpenoids in Dendrobium have therapeutic potential for the treatment of diabetes mellitus and may be beneficial in lowering blood glucose, improving insulin resistance, and alleviating diabetes-related complications. Their mechanism of action is shown in Table 7 and Figure 9.

Table 7.

The potential impact of DSS in diabetes mellitus.

Dendrobium Species or Compounds	Model	Effects and Possible Molecular Mechanisms	Refs.
DNLA	8-week-old male Kunming mice	DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and it enhances the Nrf2-antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders.	[37]
D. nobile	HFD/STZ-induced T2DM rat	D. nobile might be associated with liver glycogen synthesis and gluconeogenesis, contributing to improving insulin resistance and abnormal glucose metabolism in T2DM rats.	[27]
Dendrobine	Genetic mouse model of GDM	Reducing the secretion of inflammatory cytokines by T helper 17 (Th17) cells, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and interleukin-17.	[33]
D. chrysotoxum	STZ-induced diabetic rats	Inhibiting the expression of VEGF/VEGFR2, and some other pro-angiogenic factors such as MMP 2/9, PDGF A/B, bFGF, IGF-1.	[62]
D. loddigesii	3T3-L1 cells and db/db mice	Enhancing the expression levels of GLUT-4 and p-AMPK in the adipose tissue and increasing the expression levels of PPARα and p-AMPK in the liver tissue.	[48,58]

Figure 9.

Antidiabetic mechanism of DSS. Solid arrows are direct effects; dashed arrows are indirect effects. P is phosphorylation, red upward arrows are up-regulated; green downward arrows are down-regulated. Glucose transporter 2/4 (GLUT2/4), insulin receptor substrate (IRS1/2), phosphatidylinositol 3-kinase (PI3K), mechanistic target of rapamycin(mTOR), glycogen synthase kinase-3 beta (GSK-3β), protein kinase B (AKT), Forkhead box O (FOXO), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6pase), phosphatidylinositol-4,5-bisphosphate (PIP2), phosphatidylinositol-3,4,5-trisphosphate (PIP3).

3.2. Neuroprotection

DSS protects neurons from neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease. DNLA is the primary sesquiterpene constituent of Dendrobium and has been reported to exert neuroprotective effects in modern pharmacological studies. And its neuroprotective mechanism can be summarized in two aspects: the reduction of protein overaccumulation and the inhibition of inflammatory cytokine production.

DNLA significantly improves streptozotocin-induced damage and loss of hippocampal neurons in rat, activates GSK-3β, and prevents the hyperphosphorylation of Tau proteins [63]. In addition, reports in the literature indicate that DNLA can reduce the levels of BACEl and Aβ in hippocampal neurons [64]. DNLA may protect neuronal synaptic integrity by upregulating the synaptophysin and postsynaptic dense area protein-95 [65]. DNLA improves cognitive dysfunction and neuronal damage in aged SAMP8 mice while reducing abnormal protein accumulation and gene expression [66].

It has been demonstrated that DSS inhibits oxidative stress and neuroinflammation while reducing neurotoxicity [67,68]. Additionally, DSS inhibits oxidative stress and neuroinflammation, reduces neurotoxicity [60], and mitigates brain damage [63,67,69] and neuropathy [63,65,70]. DNLA has been shown to prevent oxidative stress-induced diseases in different neurological disorders, providing an experimental basis for its potential application [67]. DNLA can prevent CIR injury by inhibiting neuronal death, thus providing new therapeutic insights into CIR injury [71].

Furthermore, newly isolated sesquiterpenoids from D. hercoglossum have demonstrated significant neuroprotective properties [16]. In addition, DNLA is distributed in the brain tissue of C57BL/6J mice, indicating that it can cross the blood–brain barrier, thus providing an experimental basis for the neuroprotective effects of sesquiterpenoids in Dendrobium [72]. Their mechanism of action is shown in Table 8 and Figure 10.

Table 8.

The potential impact of DSS on brain pathology.

Dendrobium Species or Compounds	Model	Effects and Possible Molecular Mechanisms	Refs.
DNLA	H2O2-exposed N2A cells	Inhibit the expression of pro-inflammatory and pro-apoptotic factors by blocking JAK-STATs signaling after oxidative stress injury.	[67]
DNLA	LPS-stimulated rats	Attenuates LPS-induced hyperphosphorylation of tau protein in rat hippocampus and protects against LPS-induced apoptosis in rat brain.	[68]
DNLA	Mn-exposed PC12 cells	Alleviation of cell toxicity, apoptotic cell death with the up-regulation of Bax and down-regulation of Bcl-2, improvement of mitochondrial respiratory capacity and oxidative status, modulation of PINK1/Parkin-mediated autophagy flux mitochondria function.	[73]
D. nobile alkaloids	Rat primary cultured cerebral cortical neurons	Amelioration of neuronal damage in brain hypoxia-ischemia.	[69]
DNLA	Bilateral intracerebroventricular (ICV) streptozotocin (STZ) injection in rats	Ameliorate the STZ-induced hippocampal neuron injury, up-regulate the activity of GSK-3β, and inhibit the hyperphosphorylation of Tau protein in rats.	[63]
DNLA	Aβ25-35-induced PC12 cell damage or rat hippocampus primary neurons	Rescue Aβ-mediated synaptic and mitochondrial injury and inhibit amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity.	[65,70]
Alkaloid-enriched extract from D. nobile	Male C57/BL mice pretreated with different concentrations of DNLA underwent transient middle cerebral artery occlusion and reperfusion.	Protect against CIR damage by inhibiting pyroptosis-induced neuronal death.	[71]
DNLA	SAMP8 mice	Improve cognitive dysfunction and ameliorate neuronal injury in aged SAMP8 mice, and attenuate aberrant protein/gene expressions.	[66]
Dendrobium alkaloids	Elderly normal mice or Aβ25–35-induced	Increasing the expression of BDNF, GDNF, and CNTF in the hippocampus and cortex; improving Aβ-induced spatial learning and memory impairment in mice.	[74]
DNLA	Methionine-diet-fed mice	Down-regulate the expression of amyloid-precursor protein (APP), presenilin-1 (PS1), beta-secretase-1 (BACE1), DNA methyltransferase1 (DNMT1), and Aβ1–40) and Aβ1–42) proteins. Increase CPG island methylation levels of APP and BACE1 genes.	[75]
DNLA	APP/PS1 transgenic mice	DNLA was effective in improving cognitive deficits in aged SAMP8 mice, possibly via suppression of ER stress-related PERK signaling pathway; sequential inhibition of calpain 1, GSK-3β, and Cdk5 activities; and eventually reducing the hyper-phosphorylation of Tau. Sequential inhibition of calpain 1, GSK-3β, and Cdk5 activity, and eventually reducing the hyper-phosphorylation of Tau.	[76]
DNLA	Aged SAMP8 mice	DNLA and metformin treatments prevent brain atrophy and improve morphological changes in the hippocampus and cortex, as evidenced by Nissl and H&E staining for neuron damage and loss, and by SA-β-gal staining for aging cells.	[76,77]
DNLA	6-OHDA-treated mice	Prevention and treatment of Parkinson’s disease	[78]
DNLA	CUS-induced rat model of depression	DNLA attenuates HPA activation by decreasing adrenocorticotropic hormones and the expression of corticotropin-releasing hormone receptor-1, and it increases the expression of the glucocorticoid receptor in the brain.	[79]

Figure 10.

Mechanism of neuroprotective action of DSS. Green upward arrows are for upward adjustments, and red downward arrows are for downward adjustments. Microtubule-associated protein tau (tau); microtubule-associated protein tau. Reactive Oxygen Species (ROS), amyloid-β (Aβ), glycogen synthase kinase-3 beta (GSK-3β), interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), interleukin-6 (IL6).

3.3. Anti-Tumor

Alkaloid sesquiterpenes from Dendrobium Sw. possess a novel structure and rich pharmacological effects, particularly in anti-tumor performance, highlighting their potential for new drug development. The representative alkaloid in Dendrobium genus is dendrobine, which is based on the picrotoxane skeleton and has been found to exert inhibitory effects on various tumors [17,80,81,82]. The primary anti-tumor mechanism of dendrobine involves inhibiting the activation of proto-oncogenes and increasing the expression of oncogenes, thus suppressing the abnormal proliferation and differentiation of cells. The related mechanisms are as follows.

Dendrobine, by targeting JNK stress signaling, enhances cisplatin toxicity of in vivo during chemotherapy for non-small cell lung cancer cells [80]. A picrotoxane-type sesquiterpene (dendrowardin E, amotin, aduncin) from D. findlayanum exhibits significant effects in promoting D-galactose-induced proliferation of Human Lens Epithelium Cells (HLECs) [53]. A newly isolated ylangene-type sesquiterpene glycoside from D. findlayanum exhibits toxic activity against human cancer cell lines SMMC-7721, A-549 and MCF-7 [17]. The ethanolic extract of D. fascicularis induced apoptosis by upregulating p53 in HeLa cells and inhibited tumor progression in mice [81]. Interestingly, the anti-tumor-related target gene p53 associated with dendrobine and its classical target gene p21 are closely linked to the development of aging and aging-related diseases [83]. The relevant literature indicates that dendrobine exhibits anti-aging activity. However, the mechanisms of action require further research.

In conclusion, DSS has anti-tumor activity, inhibiting the growth and metastasis of tumor cells while improving the efficacy of chemotherapeutic drugs. In addition, this class of ingredients has anti-aging effects. However, studies on the anti-tumor effects of DSS are largely limited to in vitro experiments. Further validation of its effects and elucidation of its mechanisms are needed. The results of this study provide a scientific basis for the clinical application of DSS and serve as a reference for the development of new anti-tumor and anti-aging drugs. Their mechanisms of action are shown in Table 9 and Figure 11.

Table 9.

The potential impact of DSS on anti-tumor.

Dendrobium Species or Compounds	Model	Effects and Possible Molecular Mechanisms	Refs.
dendrowardin E, amotin, aduncin	Human lens epithelial cells (HLECs) induced by D-galactose	Exhibited significant effects of promoting the proliferation on human lens epithelial cells (HLECs) induced by D-galactose.	[46]
Dendrobin	A549 lung cancer cellsA549 xenograft in nude mice	Stimulation of JNK/p38 stress signaling pathways and, consequently, the induction of apoptosis involving pro-apoptotic proteins Bax and Bim.	[80]
Dendrobin	γ-Irradiation-Induced Cancer Cell Migration	Dendrobine inhibited γ-irradiation-induced migration and invasion of A549 cells by suppressing sulfatase2 (SULF2) expression, thus inhibiting IR- induced signaling.	[82]
findlayanoside C, findlayanoside D	SMMC-7721, A-549 and MCF-7 human cancer cell lines	Cytotoxic activity assays against SMMC-7721, A-549, and MCF-7 human cancer cell lines.	[17]
ethanolic extract of D. chrysanthum	HeLa (human cervical cancer) cells Dalton’s lymphoma (DL)-bearing mice	Mediated through p53-dependent apoptosis.	[81]

Figure 11.

Anti-tumor mechanism of action of DSS. Green upward arrows are for upward adjustments; red downward arrows are for downward adjustments. The white horizontal line in a red circle represent inhibition, and the white cross in a red circle represents activation. P is phosphorylation. Cyclin-Dependent Kinase 1/2 (CDK1/2).

3.4. Immuno and Anti-Inflammatory Activity

DSS was found to have significant immunomodulatory effects. The compounds dendroside A, dendroside D, dendroside F, dendroside G, and dendronobiloside A have promotional effects in the proliferation of T and B lymphocytes [46,47]. In addition, dendronobiloside B showed inhibitory efficacy in terms of immune functions [51] and also showed inhibitory effects on immune function. Dendroside E also exhibits immunologic activity [47].

Dendronbiline D, a compound isolated from D. nobile, exhibited significant anti-inflammatory activity [16]. Three new sesquiterpenoids isolated from D. nobile, namely dendronbiline A, B, and C, exhibited significant anti-inflammatory activity against LPS-treated RAW 264.7 cells. Three new sesquiterpenoids isolated from D. reuteri, namely Dendrobium terpenoids A, B, and C, exhibited inhibitory activity against NO production in LPS-treated RAW 264.7 cells [17]. Dendrobine alleviates liver injury in metabolic dysfunction-associated steatotic liver disease (MASLD). Its mechanism may involve regulating inflammatory and immune responses and affect lipid metabolism by down-regulating inflammatory mediators (e.g., TNF, IL6, IL1B), inhibiting AKT1, suppressing transcriptional signaling, and activating factor 3 (STAT3) [84]. The D. chrysogenum sesquiterpene-RTK axis upregulates ELF4 expression through activation of the ERK1/2 signaling pathway, and ELF4 up-regulation inhibits inflammatory responses through trans-activation of S100A9 [24].

In conclusion, DSS exhibits notable immunomodulatory and anti-inflammatory activities, but the studies on these compounds have primarily been conducted in vitro, and the specific pharmacological activities and mechanisms require further investigation. Their mechanisms of action are shown in Table 10.

Table 10.

The potential impact of DSS on inflammatory immune responses.

Dendrobium Species or Compounds	Model	Effects and Possible Molecular Mechanisms	Refs.
Dendroside D, dendroside F, dendroside G, dendroside A, dendronobiloside A	T and B lymphocytes	Possess anti-tumor and antimutagenic activity.	[47,51]
Dendrohercoglin A–C	RAW 264.7 cells	Cytotoxic activity assays against SMMC-7721, A-549, and MCF-7 human cancer cell lines.	[17]
Dendrobine	Patients who met the diagnostic criteria for MASLD	Downregulating inflammatory mediators like TNF, IL6, IL1B, and inhibiting AKT1 and Signal Transducer and Activator of Transcription 3 (STAT3).	[84]
D. nobile aqueous extract	Mice were treated with a daily alcoholic intragastric for 14 days	DNAE upregulated ELF4 expression through the RTK/ERK1/2 axis. ELF4 inhibits macrophage inflammatory responses via transactivating its upstream target genes S100A9.	[24]

3.5. Other Pharmacological Activities

Studies have shown that the alkaloidal sesquiterpenoid dendrobine possesses viral inhibitory activity and antiviral activity. The mechanism study showed that dendrobardine can inhibit the early steps of viral replication cycle [85]. In addition, dendrowardin E significantly promoted the proliferation of HLECs induced by D-galactose [46].

4. Discussion

The structural classification, pharmacological effects, and mechanism of action of DSS are summarized by a review. Over 100 sesquiterpenoids have been isolated from the roots and stems of 12 Dendrobium species, which can be categorized into 9 types based on their backbone structure. The picrotoxane type is the most abundant and has been reported to possess a greater number of pharmacological activities. These activities include the regulation of blood glucose, neuroprotection, immunomodulation, anti-tumor activity, and anti-inflammatory effects. Dendrobine, a representative sesquiterpenoid compound, was employed as a quality marker for assessing and identifying D. nobile. Clearly, relying on a single indicator is insufficient to evaluate its quality. This indicates that other sesquiterpenes could serve as potential quality markers for DSS, although they are not yet documented in the Chinese Pharmacopoeia. Therefore, future studies on DSS could focus on species with documented usage that have been less extensively studied.

Despite the diverse pharmacological activities of DSS, there are still few reports on its clinical applications and mechanistic studies. Therefore, the specific mechanism of action of DSS remains unclear. Furthermore, in some cases, pharmacological activity may only be observed at high doses of Dendrobium extracts in clinical applications. Consequently, detailed and large-scale clinical studies are necessary to provide sufficient evidence to ensure drug efficacy and patient safety. Due to their commercial value, most studies have focused on the dominant species (D. nobile., D. candidum, D. huoshanense), resulting in the neglect of sesquiterpenoid constituents in other Dendrobium species. In addition, a general lack of systematic studies on the pharmacokinetic aspects of DSS exists, which should be studied in greater depth to improve their bioavailability.

For others, sesquiterpenoids with immunomodulatory effects are primarily classified as picrotoxanes, a non-alkaloidal sesquiterpenoid found in Dendrobium. These sesquiterpenoids are predominantly sesquiterpene glycosides, with most research focusing on their isolation and in vitro studies. However, their pharmacological activities remain largely unexplored, offering a valuable avenue for further investigation and potential advancement in this field. The role of other types of sesquiterpenoids in immunity needs to be further explored. In addition, DSS shows anti-inflammatory activity, but there are few studies on it, so the research on the immunomodulatory and anti-inflammatory activities of this genus is very promising.

5. Conclusions and Future Directions

DSS has been extracted and isolated from various Dendrobium species. However, most studies are focused on a few species of Dendrobium with high commercial value. These studies are primarily focused on a small number of compounds such as alkaloidal sesquiterpenes and sesquiterpene glycosides.

Although there is an increasing number of research reports on DSS, which has shown significant pharmacological activities in the treatment of diabetes and its complications, neuroprotection, anti-tumor effect, and immuno-inflammatory regulation, most of the current studies remain superficial. These studies primarily focus on observing the changes induced by DSS administration, but they fail to clearly explain its underlying mechanisms of action.

The potent pharmacological activity of DSS may be attributed to its structural diversity. These compounds can be classified into nine types according to the skeleton, and the substituent types of these compounds are also extremely diverse. Although the pharmacological effects and mechanisms of action have been explored, they remain insufficiently detailed. Additionally, further refinement is needed in the areas of pharmacotoxicology and pharmacokinetics. However, continued studies on the structural identification and pharmacological activity of DSS may be fruitful in the clinical application and novel drug development of Dendrobium Sw.

Author Contributions

Conceptualization, J.L. and C.G.; methodology, Z.H.; software, Y.H. (Ya Huang); writing—original draft preparation, J.L.; writing—review and editing, X.W.; visualization, Y.W. and J.W.; supervision, D.T., L.Q. and D.W.; project administration, Y.H. (Yuqi He); funding acquisition, X.W. and Y.L. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding Statement

This study was supported by the National Nature Science Foundation of China (82160812, 82304450), the Department of Science and Technology of Guizhou Province (QKHZC[2021]420, QKHPTRC-CXTD [2023]024), Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile (QKJ[2022]048), and Administration of Traditional Chinese Medicine of Guizhou Province (Grant no. 362 QZYY-2024-197).