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Dendrobium in Diabetes: A comprehensive review of its phytochemistry, pharmacology, and safety

Jack Wan Hei

School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Wan Hung

School of Nursing, LKS Faculty of Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong

Zhang Yanbo

School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong

Zhang-Jin Zhang

School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong

DOI: 10.15761/JTS.1000456

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Abstract

Dendrobium, which is one of the frequently used medicinal herbs in Traditional Chinese Medicine (TCM) for treating diabetes, has aroused lots of attention on its potential alternative in the treatment of diabetes. This review aims to provide a comprehensive study on its phytochemical constituents, safety and pharmacological effects on treating diabetes and its complications with the underlying mechanisms uncovered. A comprehensive search of published medical literature from 2000 to 2020 was conducted by searching PubMed, Science Direct, Scopus, Web of Science and Google Scholar databases with keywords dendrobium, diabetes, phytochemistry, pharmacology and safety were used. Results showed that dendrobium exhibited anti-diabetic effects such as reducing gluconeogenesis, regulating lipid, protecting islet cells, anti-obesity, antioxidant and anti-inflammation on treating diabetes and its complications through the regulation of AMPK-GLUT4-PPARα; cAMP-PKA and Akt/Fox01; cRaf-MEK1/2-ERK1/2; IRS1-PI3K-Akt-Fox01/GSK 3β; MAPK; NF-κB; PI3k/Akt signaling pathway. The main chemical constituents of dendrobium species, which exert anti-diabetic, were polysaccharides. Most of the compounds of dendrobium species improved diabetes by antioxidant activity. No side effect of dendrobium species was reported in experimental studies. Therefore, our study suggested that dendrobium may offer a new potential alterative for prevention and treatment of diabetes and its complication. Well-designed clinical trials are needed for future studies.

Key words

dendrobium, diabetes, phytochemistry, pharmacology, safety

Abbreviations

AC: Adenylate Cyclase; Akt: Protein Kinase B; Ala: Alanine; ALT: Alanine Transaminase; AR: Aldose Reductase; AST: Aspartate Aminotransferase; AUC: The Area Under the Curve; bFGF: Basic Fibroblast Growth Factor; BG: Blood Glucose; BUN: Blood Urea Nitrogen; BW:  Body Weight; CA/CDCA: Cholic Acid/Chenodeoxycholic Acid; CAT: Catalase; CK: Creatine Kinase; Citr: Citrate; Create: Creatine; CREA: Creatinine; CTGF: Connective Tissue Growth Factor; DPPH, 2,2-Diphenyl-1-Picrylhydrazyl; ERG: Electroretinogram; FBG: Fasting Blood Sugar; FFAs: Free Fatty Acids; FN: Fibronectin; FINS: Fasting Insulins; Fox01: Forkhead Box Protein 01; GDH: Glucose Dehydrogenase; Gln: Glutamine; GLU: Glucagon; GLUT1: Glucose Transporter 1; GLUT2: Glucose Transporter 2; GLUT4: Glucose Transporter 4; G6Pase: Glucose-6-Phosphatase; GSK 3β: Glycogen Synthase Kinase 3 Beta; GSH: Glutathione; GSH-PX: Glutathione Peroxidase; GSP: Glucose Regulated Protein; HG: High Glucose; HIF-1α: Hypoxia-Inducible Factor 1-Alpha; HOMA-IR: Homeostasis Model of Assessment Insulin Resistance; Hs-CRP: High-sensitivity CRP; HW/BW: Heart to Body Weight Ratio; ICAM-1: Intercellular Adhesion Molecule 1; IFN-γ: Interferon-γ; IGF-1: Insulin-like Growth Factor 1; IL-1β: Interleukin-1β; IL-6: Interleukin-6; Ile: Isoleucine; INS: Insulin InsR: Insulin Receptor; iNOS: Inducible Nitric Oxide Synthase; KB: Ketone Body; LDL: Low-Density Lipoprotein; LDL-C: Low Density Lipoprotein Cholesterol; LDH: Lactate Dehydrogenase; Leu: Leucine; MDA: Malondialdehyde; MMP 2/9: Matrix Metalloproteinase-9; MT-1: Metallothionein-1; MyD88, Myeloid Differentiation Primary Response 88; 2-NBDG: 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2deoxyglucose; NF-κB: Nuclear-Factor Kappa β; Nqo1: NADPH Quinore Oxidoreductase-1; OGTT: Oral Glucose Tolerance Test; P-AMPK: Adenosine Monophosphate (AMP)-Activated Protein Kinase Phosphorylation; PEPCK: Phosphoenolpyruvate Carboxykinase; PDGF A/B: Platelet-Derived Growth Factor A/B; PGC1α: Alpha Susbunit of Peroxisome Proliferators-Activated Receptor-Gamma Coactivator-1; PKA: protein Kinase A; PI3K: Phosphoinositide-3-Kinase; PPARα: Peroxisome Proliferator-Activated Receptor α; ROS: Reactive Oxygen Species; SCr: Serum Creatine; SOD:  Superoxide Dismutase; Tau: Taurine; TC: Total Cholesterol; Tch: Blood Lipids; TG: Triglycerides; TLR-4: Toll-Like Receptors; TNF-α: Tumor Necrosis Factor-α; T-SOD: Total Superoxide Dismutase; UA: Uric Acid; Val: Valine; VEGF: Vascular Endothelial Growth Factor.

Introduction

Diabetes mellitus is characterized by high blood glucose level as a result of insufficient insulin for the body’s needs [1]. It is generally accepted that type 1 diabetes is due to the pancreas not producing enough insulin while type 2 diabetes is due to the cells of body not responding properly to the insulin produced [2]. Diabetes has become a worldwide major health-care problem as hyperglycemia increase the risk of complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic cardiomyopathy etc [3].

However, diabetes is a chronic disease which cannot be cured and repaired because if the progressive reduction in beta-cell mass and inversible beta cell failure [4]. Due to the advance effect of drugs, current treatment for diabetes is not satisfactory [5]. As traditional Chinese medicinal herbs are relative cost-effective, multi-target and has low risk of advance effect, they become a potential candidate for diabetic drug development [6].

Dendrobium, which is one of the major genera of Orchidaceae, has both ornamental and medicinal value. There are more than 1400 species worldwide and are widely distributed in tropical and subtropical regions such as Asia, Europe and Oceania [7]. In China, there are about 80 kinds of dendrobium which are mainly distributed in the southwest, east and south of China [8].

Dendrobium is an important flower plants with high economic value. Its stems and flowers have been valued as precious food and herb medicine with healthy benefit and therapeutic effects. In traditional Chinese medicine, fresh of dry stems of some species of Dendrobium’s plants are harvested for medicinal purposes, collectively known as SHIHU. Its medicinal value has been first recorded in ancient Chinese medical book “Shen Nong’s Materia Medica” thousands of years ago [9].

Dendrobium is a valuable medicinal herb commonly used for nourishing yin and clearing heat in traditional Chinese medicine theory. It has the functions of moistening lung and benefiting stomach, clearing heat and brightening eyes, tonifying deficiency and strengthening body [10]. Thus, it can be used to benefit stomach, nourish body fluid, moisten lung and relieve cough. Recently, many researchers studied the chemical constituents and pharmacological effects of Dendrobium plants. It was found that the chemical constituents of Dendrobium plants include polysaccharides, alkaloids, bibenzyls, phenols, Phenanthrenes etc [11].

Several studies showed that Dendrobium has anti-aging, anti-cancer, digestion promotion, blood pressure reduction, cataract treatment and vasodilation effect [12]. At present, there are more than 50 kinds of medicinal Dendrobium such as dendrobium officinale, dendrobium huoshenense, dendrobium loddigesii, dendrobium aphyllum, dendrobium candidum, dendrobium crepidatum, dendrobium draconis etc [13].

In this review paper, the search was done in PubMed, Science Direct, Scopus, Web of Science and Google Scholar databases a 20-year period between 2000 to 2020 with keywords search of dendrobium, diabetes, phytochemistry, pharmacology and safety.

Recently, many researchers are interested in studying dendrobium species. However, there is no review paper focusing on the mechanism of therapeutic effects of dendrobium species on diabetes and its complications. Although some studies suggested that dendrobium can treat diabetes, there is lack of studies about the comprehensive mechanism of dendrobium’s anti-diabetic effects. Therefore, our review is the first study to fully understand the role of dendrobium in diabetes by studying its phytochemistry and pharmacological mechanisms on treating diabetes and its various complications. It also provides an interesting and illuminating insights to the readers who intend to perform clinical trials on dendrobium species in the future.

Phytochemistry of dendrobium: Nowadays, more than 50 compounds had been identified and isolated from dendrobium [14]. It was found that the chemical constituents of dendrobium are mainly polysaccharides, alkaloids, phenols, phenanthrenes and alkaloids [15]. The compounds which show anti-diabetic effects are listed in Table 1.

Table 1. The contents of compounds in different species of Dendrobium that exhibited anti-diabetic activities

Species

Compound name

Types

Molecular formula

Molecular weight

IC50

Function

Reference

Dendrobium officinale

DOP-1-1

Polysaccharide

an O-acetylated glucomannan of β-D configuration in pyranose sugar forms

1.78X105 Da

Nil

Anti-inflammation and anti-oxidant

 [57]

Dendrobium officinale

DOPA-1

 

Polysaccharide

D-mannose,D-glucose,a backbone consisting 1,4-linkedβD-Manp and 1,4-linkedβ-D-Glcp with O-acetyl group

394 kDa

Nil

Anti-oxidant

[34]

DOPA-2

Polysaccharide

D-mannose,D-glucose,a backbone consisting 1,4-linkedβD-Manp and 1,4-linkedβ-D-Glcp with O-acetyl group

362 KDa

Nil

Anti-oxidant

Dendrobium huoshenense

DHPD1

Polysaccharide

glucose,arabinose,galactose,mannose,xylose with C-2,C-6 of glycosyl residues

3.2X103 Da

Nil

Antiglycation

[58]

Dendrobium huoshenense

DHPIA

Polysaccharide

Mannose,glucose,a trace of galactose,backbone contain (1 → 4)-linked α-D-Glcp, (1 → 6)-linked α-D-Glcp and (1 → 4)-linked β-D-Manp, with a branch of terminal β-D-Galp

6700 Da

Nil

Anti-oxidant

[59]

Dendrobium loddigesii

loddigesiinols A(1)

Phenanthnenes

C6H14O3

Nil

2.6μM

Anti-oxidant

 [60]

loddigesiinols B(7)

Phenanthnenes

C25H22O6

Nil

10.9μM

Anti-oxidant

loddigesiinols D(9)

Stibenes

C17H16O7

Nil

69.7μM

Anti-oxidant

Dendrobium loddigesii

loddigesiinols G

Polyphenols

C31H26O9

Nil

16.7μM

α-glucosidase inhibitory activity

[61]

loddigesiinols H

Polyphenols

C31H26O10

Nil

10.9μM

α-glucosidase inhibitory activity

loddigesiinols I

Polyphenols

C31H26O8

Nil

2.7μM

α-glucosidase inhibitory activity

loddigesiinols J

Polyphenols

C31H28O8

Nil

3.2 uM

α-glucosidase inhibitory activity

Dendrobium aphyllum

aphyllals B

Bibenzyl

C17H20O6

Nil

nil

Anti-oxidant

[62]

Aphyllals A

Phenanthrene

C15H14O4

Nil

nil

Anti-oxidant

Dendrobium candidum

dendrocandins J

Bibenzyl

C31H30O8

Nil

36.8 uM

Anti-oxidant

 [63]

dendrocandins K

Bibenzyl

C30H27O8

Nil

70.2 uM

Anti-oxidant

dendrocandins L

Bibenzyl

C30H22O8

Nil

45 uM

Anti-oxidant

Dendrocandins M

Bibenzyl

C26H29O8

Nil

60.5 uM

Anti-oxidant

dendrocandins N

Bibenzyl

C25H25O7

Nil

87.6 uM

Anti-oxidant

dendrocandins O

Bibenzyl

C25H26O8

Nil

50.4 uM

Anti-oxidant

dendrocandin P

Bibenzyl

C30H28O8

Nil

22.3 uM

Anti-oxidant

dendrocandin Q

Bibenzyl

C30H28O8

Nil

30.3 uM

Anti-oxidant

Dendrobium crepidatum

isocrepidanine

Indolizidine alkaloids

C20H27NO4

Nil

345.4 uM

Hypoglycemic effect

 [64]

Dendrobium draconis

5-methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone

Phenanthrenequinone

C15H12O4

Nil

283.3uM

Anti-oxidant

[65]

Table 1 summarizes compounds which exert anti-diabetic effect in different species of dendrobium. Several chemical structures of these compounds involved in anti-diabetic activity are illustrated in Figure 1-4. These compounds include polysaccharide, phenanthenes, stilbenes, bibenzyl, polyphenol, indolizidine alkaloids. Most of these compounds showing anti-diabetic effects are polysaccharides. Besides, most of these compounds alleviate diabetes by antioxidant activity, implying a potential candidate for studying diabetes in the future.

Figure 1. The contents of compounds in different species of Dendrobium that exhibited anti-diabetic activities

Figure 2. Animal studies about the antidiabetic effects of Dendrobium and its ingredients

Figure 3. The chemical structures and names of compounds isolated from different species of Dendrobium that exhibited anti-diabetic activities

Figure 4. Medicinal plants Dendrobium used in treatment of diabetes and its complications with their mechanism of actions

Pharmacological activities of dendrobium in the management of diabetes

Reducing gluconeogenesis: In normal physiological conditions, liver glycogen synthesis and gluconeogenesis maintain a dynamic equilibrium [16]. However, when liver appears insulin resistance, which is defined as a pathological state that human body cannot respond to insulin normally, liver gluconeogenesis increases and hepatic glycogen synthesis decreases. Then, the balance between gluconeogenesis and glycogen synthesis is disrupted. After that, liver glycogen output increases and high blood glucose levels id resulted eventually. Thus, reducing gluconeogenesis is one of the targets to control blood glucose [17].

Dendrobium mixture, which includes 15 g dendrobium, 20 g astragalus, 8 g schisandra, 15 g pueraria, 15 g salvia, 15 g rehmannia and 8 g earthworms, improved insulin resistance and liver functions via regulating the PI3K/Akt signaling pathways. It is evidenced by Fox01, PEPCK, G6Pase decreased expression and InsR, PI3K, Akt increased expression. Thus, Dendrobium may improve liver glycogen and decrease blood glucose [18].

A water extract of dendrobium officinale was showed to up-regulate energy and amino acid metabolism as well as increase liver glycogen. It can reduce gluconeogenesis [19]. A study conducted by Hong-Yan Wang et al. showed that a polysaccharide from dendrobium huoshanense (GXG) could enhance glycogen synthesis and reduce gluconeogenesis via insulin-mediated IRS1-PI3K-Akt-Fox01/GSK 3βsignaling pathway. This study suggested that Dendrobium may reduce glycogen degradation rate by improving stability of liver glycogen structure [20]. In another study, a polysaccharide of dendrobium officinale (DOP) (100,200,400 mg/kg for 4 weeks) strengthened the fragile diabetic liver glycogen by inhibiting cAMP-PKA signaling pathway. Besides, it inhibited hepatic glycogen degradation and hepatic gluconeogenesis [21].

In brief, dendrobium has been evidenced to alleviate diabetes through reducing gluconeogenesis. The underlying mechanisms may be attributed to the regulation of PI3K/Akt, PI3K-Akt-Fox01/GSK 3β, cAMP-PKA signaling pathway (Figure 5).

Figure 5. The diagram illustrates reducing gluconeogenesis of Dendrobium

Dendrobium alleviates diabetes through reducing gluconeogenesis, glycogen degradation rate and increasing energy and amino acid metabolism as well as glycogen synthesis.

Lipid regulation: Obesity is one of the causes of type 2 diabetes as lipid deposition in liver may lead to insulin resistance [22]. Besides, lipotoxicity may increase islet cell apoptosis and restrict the muscle’s usage of glucose capacity. Thus, it is important for diabetic patient to prevent dyslipidemia [23].

An extract of dendrobium nobile lindl. (DNLA) (15mg/kg for 18 weeks) was demonstrated to reduce the absorption of cholesterol by decreasing CA/CDCA ratio and increase the excretion of cholesterol by enhancing the taurine-conjugated bile acids [24]. A study conducted by Qiong Zhang et al. suggested that the extract of dendrobium finbriatium (100mg/kg,200 mg/kg for 4 weeks) could reduce lipid accumulation and lipotoxicity-induced hepatocyte apoptosis in rat. It also prevented islet cell apoptosis [25].

In a cell study of Xue-Wen Li et al., a shihurine-rich extract of D. loddigesii decreased the intracellular accumulation of oil droplets and triglycerides. It also increased 2-NBDG uptake of 3Ts-L1 cells [26]. Another study about dendrobium nobile lindl. revealed that an alkaloid of DNLA could increase lipid metabolism gene expression and decrease lipid synthesis regulator Srebp 1 [27].

Collectively, dendrobium alleviates diabetes by regulating the absorption and excretion of cholesterol. It can also reduce the toxicity of bile acids and lipid accumulation (Figure 6).

Figure 6. The diagram illustrates lipid regulation of Dendrobium

Dendrobium alleviate diabetes by reducing the lipid accumulation, the toxicity of bile acids, absorption of cholesterol as well as increasing excretion of cholesterol.

Protecting islet cells: The pancreas, which is a mixed gland formed by exocrine tissue, can synthetize and secrete inactive digestive enzymes. The endocrine tissue of pancreas is represented by the islets of Langerhaous consisted of alpha, gama, epsilon and beta cells [28]. Apoptosis is a form of beta cells death that happen in diabetes. A vitro study of a shihumine-rich extract of D. loddigesii showed that after 9 weeks of administration, the quantity of islet cells and the adipose cell size increased by up-regulating AMPK-GLUT4-PPARα signaling pathway. The expression of cleaved caspase-3 was also inhibited. Thus, it could prevent islet cell apoptosis [29].

In summary, dendrobium alleviates diabetes by protecting islet cells through the regulation of AMPK-GLUT4-PPARα signaling pathway. Dendrobium can protect islet cells and prevent islet cell apoptosis (Figure 7).

Figure 7. The diagram illustrates lipid regulation of Dendrobium.

Anti-oxidant: Oxidative stress is defined as an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage [30]. If excess reactive oxygen species is produced,β-cell maturation and apoptosis increases. Then insulin synthesis and secretion will be decreased. Both diabetes and obesity can increase the production of reactive oxygen species, resulting in oxidative stress [31].

A rich polyphenol extract of D. loggigesii (DJP) (25 mg/kg,50 mg/kg,100mg/kg for 8 weeks) was demonstrated to reduce the oxidative stress in db/db mice [32]. Another study using 1g/kg of the extract from dendrobium officinale to fed STZ rat for 5 weeks. Although there was no effect on blood glucose level and bodyweight, the glutathione peroxidase (GSH-PX) increased, implying the protective effects of this extract of dendrobium was related to antioxidant activity [33].

A cell study separated two polysaccharide fractions (DOPA-1 and DOPA-2) from stems of dendrobium officinale and tested the ability against H2O2-induced oxidative injury, DOPA-1 and DOPA-2 were found to suppress apoptosis and ameliorate oxidative lesions [34]. Another study about Alkaloids of dendrobium nobile lindl. (DNLA) showed that it could increase the expression of antioxidant gene MT-1 and Nqo1 in livers of mice through Nrf2-antioxidant pathway [27].

In short, dendrobium exerts anti-oxidant effects through Nrf2-antioxidant pathway. It also increases glucose metabolism genes and anti-oxidant genes. Dendrobium exerts anti-oxidant effects through increasing glucose metabolism genes and anti-oxidant genes (Figure 8).

Figure 8. The diagram illustrates anti-oxidant of Dendrobium

Anti-inflammation: Low-grade inflammation can lead to insulin resistance and is a main cause of Type 2 diabetes as pro-inflammatory macrophages may reduce the insulin sensitivity of liver, skeletal muscle and pancreatic β cells [35].

A rich polyphenol extract of D. loddigesii (DJP)was demonstrated to have anti-inflammation effect by reducing IL-6 and TNF-α [32]. Another study suggested that the extract of dendrobium fimbriation (DFE) could downregulate 588 differentially expressed genes (DEGs) and 74% of them were related to inflammatory, implying it may have anti-inflammation effect [25].

In brief, Dendrobium showed anti-inflammation effect by regulating NF-κβ signaling pathway. Dendrobium showed anti-inflammation effect by regulating NF-κβ signaling pathway (Figure 9).

Figure 9. The diagram illustrates anti-inflammation of Dendrobium.

Diabetic cardiovascular complications: Cardiovascular complications are notable causes of death in diabetic patients [26]. Diabetic cardiomyopathy is a serious diabetic complication as it is notable causes of death in diabetic patients. It is mainly manifested as myocardial dysfunction without other heart disease and may eventually lead to heart failure [36]. Chronic sustained hyperglycemia and insulin resistance may induce myocardial infarction and chronic pressure overload in diabetic patients with diabetic cardiomyopathy [37]. A dendrobium officinale extract (DOE), after 8 weeks of (75mg/kg, 150mg/kg, 300mg/kg) administration, was demonstrated that it could inhibit oxidative stress, cardiac lipid accumulation and pro-inflammatory cytokines in order to reduce cardiac fibrosis [38]. In a cell study conducted by Jing-yi Zhang et al., dendrobium officinale polysaccharides (DOY-GY) could exert cardioprotective effects on H2O2 induction-H9C2 cardiomyocytes through PI3K/Akt and MAPK pathways [39]. Collectively, dendrobium alleviates diabetic cardiovascular complications by reducing inflammation, cardiac fibrosis, cardiac oxidative stress, myocardial injury and apoptosis. The underlying mechanism may be associated with PI3K/Akt and MAPK pathways. Dendrobium alleviates diabetic cardiovascular complications by reducing inflammation, cardiac fibrosis, cardiac oxidative stress, myocardial injury and apoptosis (Figure 10).

Figure 10. The diagram illustrates diabetic cardiovascular complications of Dendrobium

Diabetic nephropathy: Diabetic nephropathy is an important chronic micro-vascular complication of diabetes and may lead to end-stage renal disease [40]. Diabetic nephropathy is induced by diabetes and kidney dysfunction will be developed by disturbing renal tubular, glomeruli and its filtration barrier. Kidney functions continues to decline until end-stage renal failure was resulted [41]. Diabetes influences body’s metabolism and blood circulation, generating excess reactive oxygen species. which injure glomeruli and cause albuminuria [42]. The glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane and the epithelial podocytes, becomes more damaged in the progression of diabetic nephropathy. After administrating dendrobium candidum (0.2,0.4,0.8g/kg) for 8 weeks, it was found that it could improve pathological change in kidney and alleviate diabetic nephropathy by regulating VEGF, GLUT-1 and CTGF expression [43].

In vitro and vivo study of diabetic nephropathy, a methanolic extract of dendrobium monilfone (DM) was demonstrated to exert lipid lowering effect in HFD-induced obesity in mice as well as to inhibit the kidney cell damage induced by oxidative stress [44].

Another study using the extract of dendrobium officinale (5 ml/kg,10 ml/kg) for 4 weeks, result showed that it could alleviate diabetic nephropathy by preventing insulin resistance and reducing TLRs and inflammatory response [45]. Glucomannans, which is an extract of dendrobium officinale stem, could balance the disturbed glucose, lipid, amino acid metabolism and normalize the architecture of kidney corpuscle and tubular system after 4 weeks of drug (160 mg/kg) administration [46].

In summary, dendrobium alleviates diabetic nephropathy by reducing inflammation, oxidative stress, insulin resistance, renal dysfunction and diabetic kidney lesion. Dendrobium improves diabetic nephropathy by reducing oxidative stress, renal dysfunction, insulin resistance, inflammatory response and diabetic kidney lesions (Figure 11).

Figure 11. The diagram illustrates diabetic nephropathy of Dendrobium

Diabetic retinopathy: Diabetic retinopathy is a common diabetic complication. It is characterized by hard exudates, microaneurysms, macular edema and retinal hemorrhage [47]. The ethanol extract of D. Chrysotoxum (30 mg/kg,300 mg/kg for 1 month) was demonstrated to breakdown the blood retinal barrier, inhibit retinal inflammation and prevent the decrease of tight junction protein such as occludin and claudin-1 [48]. In vivo and vitro study by Zengyang Yu et al., erianin, which was extracted from dendrobium chrysotoxum Lindl., could inhibit retinal neoangiogenesis by abrogating HG-induced VEGF expression. It could also block ERT1/2-mediated HIF-α activation in retinal endothelial and microglial cells [49]. Another study also found that the ethanol extract of dendrobium chrysotoxum Lindl could alleviate retinal angiogenesis and ameliorate retinal inflammation by inhibiting NFκβ signaling pathway [50]. To conclude, dendrobium alleviates diabetic retinopathy by reducing retinal neoangiogenesis and tight junction protein. It can also reduce pro-angiogenic factor and inflammation. Dendrobium alleviates diabetic retinopathy by reducing inflammation, retinal neoangiogenesis, tight junction proteins and pro-angiogenic factor (Figure 12).

Figure 12. The diagram illustrates diabetic retinopathy of Dendrobium

Diabetic Cataract: Cataract is the leading cause for impaired vision and blindness in patients with diabetes [51]. Hyperglycemia-associated increase in osmotic pressure and oxidative damage are the main causes for the development and progression of diabetic cataract [52].

In a cell study conducted by Jie Wu et al., a gigantol from dendrobium chrysotoxum Lindl. was showed to inhibit AR gene expression and aldose reductase in Human lens epithelial cells (HLECs) [53]. Another study showed that gigantol from dendrobium aurantiacum var dennam could prevent galactose-induced damage to the rat lens by repressing the gene expression and activity of AR & iNOS. It could also delay lens turbidity and keep lens transparent [54].

To sum up, dendrobium alleviates diabetic cataract by reducing damage of osmotic pressure stress and oxidative damage. Dendrobium improves diabetic cataract by reducing oxidative damage and damage caused by osmotic pressure stress (Figure 13).

Figure 13. The diagram illustrates diabetic cataract of Dendrobium

Safety of Dendrobium: In the “Shen Nong’s Materia Medica”, dendrobium is classified as “Top-tier” medicinal herb which is regarded as an effective medicinal herb without observable toxicity. The safety of medicinal herb is important because the intake of heavy metal elements into human body is harmful. One study conducted by Yingdan Yuan et al. showed that the dosage of 12g d-1 dendrobium, which is prescribed in the Chinese Pharmacopoeia 2010 edition, is in accordance with the recommended daily intake of trace elements recommend by the Food and Drug Administration of the United States [55]. Another study by Li-Chan Yang et al. assessed the 90 days oral toxicity and genetic safety of the aqueous extract of Dendrobium Taissed Tosnobile in 90 sprague-dawley (SD) rats, no abnormal changes were observed in clinical signs and body weight. Also, no significant difference between treatment and control group was found in biochemistry parameter, urinalysis and hematology throughout the study period [56-65]. Therefore, when taken according to the dosage prescribed by the pharmacopoeia does not cause any adverse effects and trace elements poisoning.

Conclusion and outlook

Dendrobium is one of the most frequent used medicinal herbs for treating diabetes in TCM clinical practices. Table 2 and Table 3 summarizes its hypoglycemia effects in animal studies and cell-based studies. In recent studies, there are more than 50 compounds isolated and identified from dendrobium. The types of compounds, which show anti-diabetic activities, include polysaccharide, phenanthenes, stilbenes, bibenzyl, polyphenol, indolizidine alkaloids. Most of the compounds showing anti-diabetic effects are polysaccharides. The signaling mechanisms of dendrobium treating diabetes may be involved in the regulation of AMPK-GLUT4-PPARα; cAMP-PKA and Akt/Fox01; cRaf-MEK1/2-ERK1/2; IRS1-PI3K-Akt-Fox01/GSK 3β; MAPK; NF-κB; PI3k/Akt which are illustrated in Figure 2.

Table 2. Animal studies about the antidiabetic effects of Dendrobium and its ingredients

Species

Extract

Topic

Duration

Model

Pathways

Results

Dendrobium nobile Lindl.

(Si Huang, et al. 2019)

DNLA

Hepatic lipid homeostasis

18 weeks

C57BL/6 mice

Reducing cholesterol absorption and increasing cholesterol excretion

Reducing liver TC,TG; Increasing hydrophilicity; Reducing hepatic level of free bile acids(LCA,DCA,CA,CDCA); Increasing taurine-conjugated bile acids (TMCAs, TCDCA,TUDCA,THDCA); Reducing CA/CDCA ratio; Up-regulating Cyp27al,Cyp3all,Fxr,Shp.

Dendrobium officinale kimura & Migo (Hong Zheng, et al. 2017)

 

DOWE

Type 2 diabetes

4 weeks

STZ

Up-regulating energy and amino acid metabolism

Reducing BG; Increasing liver glycogen; Increasing Citr, GIN, Creat, Ala, Leu, Ile, Val, Gln, GSH, Tau in liver

Dendrobium loggigesii (Xue-Wen Li, et al. 2019)

DLS

Type 2 diabetes

8 weeks

db/db mice

Up-regulating AMPK-GLUT4-PPARα

Reducing BW, FBG, serum lipid level; Improving oral glucose; Increasing serum INS level; Decreasing TG & TC; Increasing quanties of islet cells; Increasing adipose cell size; Inhibiting expression of cleaved caspase-3; Increasing P-AMPK, PPARα, GLUT4.

Dendrobium aurantiacum var. denneanum (Hua Fang, et al.2015)

Gigantol

Diabetic cataract

60 days

Wistar rats

Reducing osmotic pressure and ameliorating oxidative damage

Repressing the gene expression and ability of AR & iNOS; keep lens transparent; delay lens turbidity; Reducing amount of AR and iNOS in lens epithelial cells.

Dendrobium candidum (Jingzhi Chang et al.2019)

Nil

Diabetic nephropathy

8 weeks

STZ

Regulating expression of VEGF, GLUT-1, CTGF

Reducing kidney index, SCr, BUN,24 hr urine protein; Decreasing VEGF; Decreasing GLUT-1 & CTGF renal cortex expression; Improving pathological changes in kidney

Dendrobium chrysotoxum lindl. (Zengyang Yu et al.2015)

DC

Diabetic retinopathy

1 month

STZ

Inhibiting retinal inflammation and preventing the decrease of tight junction protein

Decreasing breakdown of blood retinal barrier; Increasing expression of occludin & cludin-1 protein; Reducing the increased retinal mRNA expression of ICAM-1,TNFα,IL-6,IL-1β; Alleviating the increased ICAM-1 and phosphorylated p65,IκB,IκB kinase; Reducing the increased serum level of TNFα,IFN-γ,IL-6,IL-1β,IL-8,IL-12,IL-2,IL-3,IL-10

Dendrobium huoshanense (Hong-Yan Wang et al.2019)

GXG

Type 2 diabetes

5 weeks

STZ

Regulating insulin-mediated IRS1-PI3K-Akt-Fox01/GSK 3β signaling

Reduce FBG, glycosylated serum protein & serum INS; Improving glucose tolerance & insulin sensitivity; Improving pancreaticβ-cell quantity and function; Improving regulation of hepatic glucose metabolism; Up-regulating IRS1-PI3K-Akt phosphorylation; Down-regulating FoxO1/GSK 3βphosphorylation; Enhancing glycogen synthesis; Reducing gluconeogenesis.

Dendrobium mixture (XinJun Lin, et al.2018)

Nil

Type 2 diabetes

12 weeks

Wistar rats.

Regulating PI3k/Akt signaling pathway

Reducing FBG, GSP, InsR, Tch, TG, ALT, AST; Reducing Fox01, PEPCK, G6Pase; Increasing InsR, PI3K, Akt; Improving liver function & insulin resistance

Dendrobium moniliforne (Woojung Lee, et al.2012)

DM

Diabetic nephropathy

9 weeks

Male C57BL/6 mice

Inhibiting kidney cell damage induced by oxidative stress

Reducing elevated serum glucose, TC, renal lipid accumulation; Reducing renal dysfunction biomarkers like SCr & renal collagen IV deposition

Dendrobium nobile Lindl. (Yun-Yan Xu, et al.2017)

DNLA

Diabetic liver

8 days

male kunming mice

Increasing liver glucose and lipid metabolism gene metabolism

Increasing PGC1α mRNA and protein levels; Increasing glucose metabolism gene Glut2, FoxO1; Increasing fatty acidβ-oxidation genes Acox1 & Cpt1a; Reducing lipid synthesis regulator Srebp1; Increasing lipolysis gene ATGL; Increasing antioxidant gene MT-1 & Nqo1 in liver; Increasing PPARα & GLUT4; Increasing Nrf2-antioxidant gene expressions

Dendrobium officinale kimura et Migo (Ming Zhao, et al.2018)

DO

Diabetic nephropathy

4 weeks

STZ

Preventing insulin resistance and reducing TLRs & inflammatory response

Decreasing glomerular volume; Reducing urinary glucose, albuminuria, SCr, albuminuria/SCr, Bun; Reducing the expression levels of CaN, TLR-4, MyD88, hs-CRP, TNF-α, IL-6, the level of FINS, GLU, HOMA-IR.

Dendrobium officinale kimura et Migo(Zhihao Zhang, et al.2016)

DOE

Diabetic cardiomyopathy

8 weeks

STZ

Inhibiting oxidative stress, pro-inflammatory cytokines and cardiac fibrosis

Reducing HW/BW; Reducing CK,LDH,TC,TG; Reducing MDA,T-SOD; Reducing cardiac injury; Reducing cardiac lipid accumulation and deposition of collagen; Downregulating TGF-β,collagen-1,FN,NF-κB,TNF-α,IL-1β

Dendrobium officinale kimura et Migo (Yage Liu, et al. 2020)

DOP

Type 2 diabetes

4 weeks

STZ

Regulating glycogen-mediated cAMP-PKA and Akt/FoxO1 signaling pathway

Inhibiting hepatic glycogen degradation & hepatic gluconeogenesis; Reversing the instability of liver glycogen structure; Suppressing serum glycogen; Reducing BW, FBG, OGTT; Restoring pancreatic islet morphology; Reducing insulin-positive cell ratio in pancreatic islet cells; Inactivating AC & reducing the expression of PKA.

Dendrobium officinale kimura et Migo (Shao-zhen Hou, et al. 2016)

DO

Type 1 diabetes

5 weeks

STZ

Inhibiting oxidative stress

Reducing TC, TG, BUN, CREA; Increasing the amplitudes of ERGa- and b- waves and Ops; Hypoalgesia and histopathological changes of vital organs induced by hyperglycemia; Increasing GSH-PX

Dendrobium loggigesii (Xue-Wen Li, et al. 2018)

DJP

Type 2 diabetes

8 weeks

db/db mice

Reducing inflammation & oxidative stress

Reducing BG, BW, LDL-C; Increasing insulin level; Improving fatty liver & DN; Reducing MDA; Increasing SOD, CAT, GSH; Reducing IL-6, TNF-α; Reducing intestinal flora balance; Increasing Bacteroidetes to firmicute ratios

Dendrobium chrysotoxum lindl. (Zengyang Yu, et al. 2016)

Erianin

Diabetic retinopathy

2 months

STZ

Inhibiting retinal neoangiogenesis

Abrogating retinal neovascularization

Dendrobium chrysotoxum lindl. (Chen-Yuan Gong, et al. 2014)

DC

Diabetic retinopathy

2 months

STZ

Inhibiting NF-κB signaling pathway

Ameliorating increased retinal vessels; Reducing increased retinal mRNA expression of VEGF & VEGFR2; Decreasing elevated serum VEGF level; Reducing retinal mRNA expression of MMP 2/9; Reducing serum levels of MMP2/9, IL-1β, IL-6, IGF-1, bFGF, PDGF A/B; Decreasing increased phosphorylation of p65; Reducing increased expression of ICAM-1

Dendrobium officinale kimura et Migo (Haihong Chen, et al. 2019)

Glucomannans

Diabetic kidney disease

4 weeks

STZ

Normalizing the architecture of kidney corpuscle and tubular system

Reducing FBG, serum INS, glycated serum protein; Reducing concentrations of serum LDL, TC, TG, nonesterified fatty acid; Reducing UA, Creat, urea in serum, glycosuria, KB, protein in urine; Normalizing the architecture of glomerulus.

Dendrobium aphyllum (Huifan Liu, et al. 2019)

DAP

Type 2 diabetes

30 days

kunming mice

Up regulating the expression of glucose transporters

Decreasing BP; Increasing enzyme activities, G6Pase, GDH; Upregulating GLUT1, GLUT2 in colon. Incrementing 4 types short chain fatty acids and the health-promoting microbiota diversity

Dendrobium fimbriatum (Qiong Zhang, et al. 2020)

DFE

Type 2 diabetes

4 weeks

Sprague-Dawley rats

Prevent β cell apoptosis and decreasing hepatic lipid accumulation

Reducing FBG; Reducing AUC value of blood glucose level; Increasing serum & pancreatic INS; Reducing serum FFAs; Downregulating 588 differentially expressed gene,74% related to inflammatory; Preventing islet cell apoptosis; Improving energy metabolism, lipid transport, oxidoreductase activity in liver; Reducing lipid accumulation & lipotoxicity-induced hepatocyte apoptosis.

Table 3. Cell-based studies about the antidiabetic effects of Dendrobium and its ingredients

Species

Extract

Topic

Model

Pathways

Results

Dendrobium loggigesii (Xue-Wen Li, et al.2019)

DLS

Type 2 diabetes

3T3-L1 cell

Up-regulating AMPK-GLUT4-PPARα

Decreasing intracellular accumulation of oil droplets; Decreasing TG; Increasing 2-NBDG uptake.

Dendrobium moniliforne (Woojung Lee, et al.2012)

DM

Diabetic nephropathy

LLC-PK1 renal epithelial cells

Inhibiting kidney cell damage induced by oxidative stress

Increasing DPPH radical scavenging activity; Reducing LLC-PK1 kidney cell damage induced by oxidative stress

Dendrobium chrysotoxum lindl. (Zengyang Yu, et al.2016) 

Erianin

Diabetic retinopathy

 

RF/6A cells & microglia BV-2 cells

Suppressing cRaf-MEK1/2-ERK1/2 and PI3K-Akt signaling cascades in retinal endothelial cells

Blocking high glucose-induced VEGF, HIF-1α translocation into nucleus, ERK1/2 activation; Inhibiting HG-induced tube formation and migration; Inhibiting HG-induced VEGF expression; Inhibiting ERK1/2-mediated HIF-1α activation; Abrogating VEGF-induced angiogenesis

Dendrobium chrysotoxum lindl. (Jie Wu, et al.2017)

Gigantol

Diabetic cataract

Human lens epithelial cells

Inhibiting AR gene expression

Reducing AR gene expression; Bounding to insert AR gene base pairs of the double helix

Dendrobium officinale kimura et Migo (Jing-yi Zhang, et al.2017)

DOP-GY

Diabetic cardiomyopathy

 

H9c2 cardiomyocytes

Exerting cardioprotective effects via PI3K/Akt and MAPK pathways

Increasing survival rate; cutting LDH leakage; Reducing lipid peroxidation damage; Improving activity of endogenous antioxidant enzymes; Inhibiting production of ROS; Declining mitochondrial membrane potential; Downregulating pro-apoptosis protein; Upregulating anti-apoptosis protein

Dendrobium officinale kimura et Migo (Kaiwei Huang, et al.2016)

DOPA-1 & DOPA-2

Oxidative stress

RAW 264.7 macrophages

Ameliorating H2O2-induced oxidative injury

Activating splenocyte & macrophage; Promoting cell viability; Suppressing apoptosis; Ameliorating oxidative lesions.

Moreover, dendrobium can reduce gluconeogenesis, regulate lipid, protect islet cells, anti-obesity, antioxidant and anti-inflammation. It can also treat various diabetic complications such as diabetic cardiovascular, diabetic nephropathy, diabetic retinopathy and diabetic cataract.

Dendrobium is considerably safe and well tolerate at the recommend dose as there are no side effects had been reported in clinical trial. However, as there are insufficient clinical trial studies the effect of dendrobium on diabetes, further investigation, especially well-planned randomized clinical trial, are still needed to study the effect of dendrobium on treating diabetes.

This study combines the experimental evidence of dendrobium both in vivo and in vitro with TCM theory. Result shows that dendrobium may offer a new therapeutic promise to cure diabetes and its complications. Potential chemical structure with anti-diabetic effects is also demonstrated for further investigation. Well-designed clinical trials are anticipated in the future studies.

Conflict of interest

The authors declare no competing interests.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Editorial Information

Editor-in-Chief

Terry Lichtor
Tsuyoshi Hirata
Shinya Mizuno
Giacomo Corrado

Article Type

Review Article

Publication history

Received: March 29, 2021
Accepted: April 23, 2021
Published: April 26, 2021

Copyright

©2021 Hei JW. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Jack Wan Hei, Wan Hung, Zhang Yanbo, Zhang-Jin Zhang (2021) Dendrobium in Diabetes: A comprehensive review of its phytochemistry, pharmacology, and safety 7: DOI: 10.15761/JTS.1000456.

Corresponding author

Professor Zhang-Jin Zhang

School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1. The contents of compounds in different species of Dendrobium that exhibited anti-diabetic activities

Figure 2. Animal studies about the antidiabetic effects of Dendrobium and its ingredients

Figure 3. The chemical structures and names of compounds isolated from different species of Dendrobium that exhibited anti-diabetic activities

Figure 4. Medicinal plants Dendrobium used in treatment of diabetes and its complications with their mechanism of actions

Figure 5. The diagram illustrates reducing gluconeogenesis of Dendrobium

Figure 6. The diagram illustrates lipid regulation of Dendrobium

Figure 7. The diagram illustrates lipid regulation of Dendrobium.

Figure 8. The diagram illustrates anti-oxidant of Dendrobium

Figure 9. The diagram illustrates anti-inflammation of Dendrobium.

Figure 10. The diagram illustrates diabetic cardiovascular complications of Dendrobium

Figure 11. The diagram illustrates diabetic nephropathy of Dendrobium

Figure 12. The diagram illustrates diabetic retinopathy of Dendrobium

Figure 13. The diagram illustrates diabetic cataract of Dendrobium

Table 1. The contents of compounds in different species of Dendrobium that exhibited anti-diabetic activities

Species

Compound name

Types

Molecular formula

Molecular weight

IC50

Function

Reference

Dendrobium officinale

DOP-1-1

Polysaccharide

an O-acetylated glucomannan of β-D configuration in pyranose sugar forms

1.78X105 Da

Nil

Anti-inflammation and anti-oxidant

 [57]

Dendrobium officinale

DOPA-1

 

Polysaccharide

D-mannose,D-glucose,a backbone consisting 1,4-linkedβD-Manp and 1,4-linkedβ-D-Glcp with O-acetyl group

394 kDa

Nil

Anti-oxidant

[34]

DOPA-2

Polysaccharide

D-mannose,D-glucose,a backbone consisting 1,4-linkedβD-Manp and 1,4-linkedβ-D-Glcp with O-acetyl group

362 KDa

Nil

Anti-oxidant

Dendrobium huoshenense

DHPD1

Polysaccharide

glucose,arabinose,galactose,mannose,xylose with C-2,C-6 of glycosyl residues

3.2X103 Da

Nil

Antiglycation

[58]

Dendrobium huoshenense

DHPIA

Polysaccharide

Mannose,glucose,a trace of galactose,backbone contain (1 → 4)-linked α-D-Glcp, (1 → 6)-linked α-D-Glcp and (1 → 4)-linked β-D-Manp, with a branch of terminal β-D-Galp

6700 Da

Nil

Anti-oxidant

[59]

Dendrobium loddigesii

loddigesiinols A(1)

Phenanthnenes

C6H14O3

Nil

2.6μM

Anti-oxidant

 [60]

loddigesiinols B(7)

Phenanthnenes

C25H22O6

Nil

10.9μM

Anti-oxidant

loddigesiinols D(9)

Stibenes

C17H16O7

Nil

69.7μM

Anti-oxidant

Dendrobium loddigesii

loddigesiinols G

Polyphenols

C31H26O9

Nil

16.7μM

α-glucosidase inhibitory activity

[61]

loddigesiinols H

Polyphenols

C31H26O10

Nil

10.9μM

α-glucosidase inhibitory activity

loddigesiinols I

Polyphenols

C31H26O8

Nil

2.7μM

α-glucosidase inhibitory activity

loddigesiinols J

Polyphenols

C31H28O8

Nil

3.2 uM

α-glucosidase inhibitory activity

Dendrobium aphyllum

aphyllals B

Bibenzyl

C17H20O6

Nil

nil

Anti-oxidant

[62]

Aphyllals A

Phenanthrene

C15H14O4

Nil

nil

Anti-oxidant

Dendrobium candidum

dendrocandins J

Bibenzyl

C31H30O8

Nil

36.8 uM

Anti-oxidant

 [63]

dendrocandins K

Bibenzyl

C30H27O8

Nil

70.2 uM

Anti-oxidant

dendrocandins L

Bibenzyl

C30H22O8

Nil

45 uM

Anti-oxidant

Dendrocandins M

Bibenzyl

C26H29O8

Nil

60.5 uM

Anti-oxidant

dendrocandins N

Bibenzyl

C25H25O7

Nil

87.6 uM

Anti-oxidant

dendrocandins O

Bibenzyl

C25H26O8

Nil

50.4 uM

Anti-oxidant

dendrocandin P

Bibenzyl

C30H28O8

Nil

22.3 uM

Anti-oxidant

dendrocandin Q

Bibenzyl

C30H28O8

Nil

30.3 uM

Anti-oxidant

Dendrobium crepidatum

isocrepidanine

Indolizidine alkaloids

C20H27NO4

Nil

345.4 uM

Hypoglycemic effect

 [64]

Dendrobium draconis

5-methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone

Phenanthrenequinone

C15H12O4

Nil

283.3uM

Anti-oxidant

[65]

Table 2. Animal studies about the antidiabetic effects of Dendrobium and its ingredients

Species

Extract

Topic

Duration

Model

Pathways

Results

Dendrobium nobile Lindl.

(Si Huang, et al. 2019)

DNLA

Hepatic lipid homeostasis

18 weeks

C57BL/6 mice

Reducing cholesterol absorption and increasing cholesterol excretion

Reducing liver TC,TG; Increasing hydrophilicity; Reducing hepatic level of free bile acids(LCA,DCA,CA,CDCA); Increasing taurine-conjugated bile acids (TMCAs, TCDCA,TUDCA,THDCA); Reducing CA/CDCA ratio; Up-regulating Cyp27al,Cyp3all,Fxr,Shp.

Dendrobium officinale kimura & Migo (Hong Zheng, et al. 2017)

 

DOWE

Type 2 diabetes

4 weeks

STZ

Up-regulating energy and amino acid metabolism

Reducing BG; Increasing liver glycogen; Increasing Citr, GIN, Creat, Ala, Leu, Ile, Val, Gln, GSH, Tau in liver

Dendrobium loggigesii (Xue-Wen Li, et al. 2019)

DLS

Type 2 diabetes

8 weeks

db/db mice

Up-regulating AMPK-GLUT4-PPARα

Reducing BW, FBG, serum lipid level; Improving oral glucose; Increasing serum INS level; Decreasing TG & TC; Increasing quanties of islet cells; Increasing adipose cell size; Inhibiting expression of cleaved caspase-3; Increasing P-AMPK, PPARα, GLUT4.

Dendrobium aurantiacum var. denneanum (Hua Fang, et al.2015)

Gigantol

Diabetic cataract

60 days

Wistar rats

Reducing osmotic pressure and ameliorating oxidative damage

Repressing the gene expression and ability of AR & iNOS; keep lens transparent; delay lens turbidity; Reducing amount of AR and iNOS in lens epithelial cells.

Dendrobium candidum (Jingzhi Chang et al.2019)

Nil

Diabetic nephropathy

8 weeks

STZ

Regulating expression of VEGF, GLUT-1, CTGF

Reducing kidney index, SCr, BUN,24 hr urine protein; Decreasing VEGF; Decreasing GLUT-1 & CTGF renal cortex expression; Improving pathological changes in kidney

Dendrobium chrysotoxum lindl. (Zengyang Yu et al.2015)

DC

Diabetic retinopathy

1 month

STZ

Inhibiting retinal inflammation and preventing the decrease of tight junction protein

Decreasing breakdown of blood retinal barrier; Increasing expression of occludin & cludin-1 protein; Reducing the increased retinal mRNA expression of ICAM-1,TNFα,IL-6,IL-1β; Alleviating the increased ICAM-1 and phosphorylated p65,IκB,IκB kinase; Reducing the increased serum level of TNFα,IFN-γ,IL-6,IL-1β,IL-8,IL-12,IL-2,IL-3,IL-10

Dendrobium huoshanense (Hong-Yan Wang et al.2019)

GXG

Type 2 diabetes

5 weeks

STZ

Regulating insulin-mediated IRS1-PI3K-Akt-Fox01/GSK 3β signaling

Reduce FBG, glycosylated serum protein & serum INS; Improving glucose tolerance & insulin sensitivity; Improving pancreaticβ-cell quantity and function; Improving regulation of hepatic glucose metabolism; Up-regulating IRS1-PI3K-Akt phosphorylation; Down-regulating FoxO1/GSK 3βphosphorylation; Enhancing glycogen synthesis; Reducing gluconeogenesis.

Dendrobium mixture (XinJun Lin, et al.2018)

Nil

Type 2 diabetes

12 weeks

Wistar rats.

Regulating PI3k/Akt signaling pathway

Reducing FBG, GSP, InsR, Tch, TG, ALT, AST; Reducing Fox01, PEPCK, G6Pase; Increasing InsR, PI3K, Akt; Improving liver function & insulin resistance

Dendrobium moniliforne (Woojung Lee, et al.2012)

DM

Diabetic nephropathy

9 weeks

Male C57BL/6 mice

Inhibiting kidney cell damage induced by oxidative stress

Reducing elevated serum glucose, TC, renal lipid accumulation; Reducing renal dysfunction biomarkers like SCr & renal collagen IV deposition

Dendrobium nobile Lindl. (Yun-Yan Xu, et al.2017)

DNLA

Diabetic liver

8 days

male kunming mice

Increasing liver glucose and lipid metabolism gene metabolism

Increasing PGC1α mRNA and protein levels; Increasing glucose metabolism gene Glut2, FoxO1; Increasing fatty acidβ-oxidation genes Acox1 & Cpt1a; Reducing lipid synthesis regulator Srebp1; Increasing lipolysis gene ATGL; Increasing antioxidant gene MT-1 & Nqo1 in liver; Increasing PPARα & GLUT4; Increasing Nrf2-antioxidant gene expressions

Dendrobium officinale kimura et Migo (Ming Zhao, et al.2018)

DO

Diabetic nephropathy

4 weeks

STZ

Preventing insulin resistance and reducing TLRs & inflammatory response

Decreasing glomerular volume; Reducing urinary glucose, albuminuria, SCr, albuminuria/SCr, Bun; Reducing the expression levels of CaN, TLR-4, MyD88, hs-CRP, TNF-α, IL-6, the level of FINS, GLU, HOMA-IR.

Dendrobium officinale kimura et Migo(Zhihao Zhang, et al.2016)

DOE

Diabetic cardiomyopathy

8 weeks

STZ

Inhibiting oxidative stress, pro-inflammatory cytokines and cardiac fibrosis

Reducing HW/BW; Reducing CK,LDH,TC,TG; Reducing MDA,T-SOD; Reducing cardiac injury; Reducing cardiac lipid accumulation and deposition of collagen; Downregulating TGF-β,collagen-1,FN,NF-κB,TNF-α,IL-1β

Dendrobium officinale kimura et Migo (Yage Liu, et al. 2020)

DOP

Type 2 diabetes

4 weeks

STZ

Regulating glycogen-mediated cAMP-PKA and Akt/FoxO1 signaling pathway

Inhibiting hepatic glycogen degradation & hepatic gluconeogenesis; Reversing the instability of liver glycogen structure; Suppressing serum glycogen; Reducing BW, FBG, OGTT; Restoring pancreatic islet morphology; Reducing insulin-positive cell ratio in pancreatic islet cells; Inactivating AC & reducing the expression of PKA.

Dendrobium officinale kimura et Migo (Shao-zhen Hou, et al. 2016)

DO

Type 1 diabetes

5 weeks

STZ

Inhibiting oxidative stress

Reducing TC, TG, BUN, CREA; Increasing the amplitudes of ERGa- and b- waves and Ops; Hypoalgesia and histopathological changes of vital organs induced by hyperglycemia; Increasing GSH-PX

Dendrobium loggigesii (Xue-Wen Li, et al. 2018)

DJP

Type 2 diabetes

8 weeks

db/db mice

Reducing inflammation & oxidative stress

Reducing BG, BW, LDL-C; Increasing insulin level; Improving fatty liver & DN; Reducing MDA; Increasing SOD, CAT, GSH; Reducing IL-6, TNF-α; Reducing intestinal flora balance; Increasing Bacteroidetes to firmicute ratios

Dendrobium chrysotoxum lindl. (Zengyang Yu, et al. 2016)

Erianin

Diabetic retinopathy

2 months

STZ

Inhibiting retinal neoangiogenesis

Abrogating retinal neovascularization

Dendrobium chrysotoxum lindl. (Chen-Yuan Gong, et al. 2014)

DC

Diabetic retinopathy

2 months

STZ

Inhibiting NF-κB signaling pathway

Ameliorating increased retinal vessels; Reducing increased retinal mRNA expression of VEGF & VEGFR2; Decreasing elevated serum VEGF level; Reducing retinal mRNA expression of MMP 2/9; Reducing serum levels of MMP2/9, IL-1β, IL-6, IGF-1, bFGF, PDGF A/B; Decreasing increased phosphorylation of p65; Reducing increased expression of ICAM-1

Dendrobium officinale kimura et Migo (Haihong Chen, et al. 2019)

Glucomannans

Diabetic kidney disease

4 weeks

STZ

Normalizing the architecture of kidney corpuscle and tubular system

Reducing FBG, serum INS, glycated serum protein; Reducing concentrations of serum LDL, TC, TG, nonesterified fatty acid; Reducing UA, Creat, urea in serum, glycosuria, KB, protein in urine; Normalizing the architecture of glomerulus.

Dendrobium aphyllum (Huifan Liu, et al. 2019)

DAP

Type 2 diabetes

30 days

kunming mice

Up regulating the expression of glucose transporters

Decreasing BP; Increasing enzyme activities, G6Pase, GDH; Upregulating GLUT1, GLUT2 in colon. Incrementing 4 types short chain fatty acids and the health-promoting microbiota diversity

Dendrobium fimbriatum (Qiong Zhang, et al. 2020)

DFE

Type 2 diabetes

4 weeks

Sprague-Dawley rats

Prevent β cell apoptosis and decreasing hepatic lipid accumulation

Reducing FBG; Reducing AUC value of blood glucose level; Increasing serum & pancreatic INS; Reducing serum FFAs; Downregulating 588 differentially expressed gene,74% related to inflammatory; Preventing islet cell apoptosis; Improving energy metabolism, lipid transport, oxidoreductase activity in liver; Reducing lipid accumulation & lipotoxicity-induced hepatocyte apoptosis.

Table 3. Cell-based studies about the antidiabetic effects of Dendrobium and its ingredients

Species

Extract

Topic

Model

Pathways

Results

Dendrobium loggigesii (Xue-Wen Li, et al.2019)

DLS

Type 2 diabetes

3T3-L1 cell

Up-regulating AMPK-GLUT4-PPARα

Decreasing intracellular accumulation of oil droplets; Decreasing TG; Increasing 2-NBDG uptake.

Dendrobium moniliforne (Woojung Lee, et al.2012)

DM

Diabetic nephropathy

LLC-PK1 renal epithelial cells

Inhibiting kidney cell damage induced by oxidative stress

Increasing DPPH radical scavenging activity; Reducing LLC-PK1 kidney cell damage induced by oxidative stress

Dendrobium chrysotoxum lindl. (Zengyang Yu, et al.2016) 

Erianin

Diabetic retinopathy

 

RF/6A cells & microglia BV-2 cells

Suppressing cRaf-MEK1/2-ERK1/2 and PI3K-Akt signaling cascades in retinal endothelial cells

Blocking high glucose-induced VEGF, HIF-1α translocation into nucleus, ERK1/2 activation; Inhibiting HG-induced tube formation and migration; Inhibiting HG-induced VEGF expression; Inhibiting ERK1/2-mediated HIF-1α activation; Abrogating VEGF-induced angiogenesis

Dendrobium chrysotoxum lindl. (Jie Wu, et al.2017)

Gigantol

Diabetic cataract

Human lens epithelial cells

Inhibiting AR gene expression

Reducing AR gene expression; Bounding to insert AR gene base pairs of the double helix

Dendrobium officinale kimura et Migo (Jing-yi Zhang, et al.2017)

DOP-GY

Diabetic cardiomyopathy

 

H9c2 cardiomyocytes

Exerting cardioprotective effects via PI3K/Akt and MAPK pathways

Increasing survival rate; cutting LDH leakage; Reducing lipid peroxidation damage; Improving activity of endogenous antioxidant enzymes; Inhibiting production of ROS; Declining mitochondrial membrane potential; Downregulating pro-apoptosis protein; Upregulating anti-apoptosis protein

Dendrobium officinale kimura et Migo (Kaiwei Huang, et al.2016)

DOPA-1 & DOPA-2

Oxidative stress

RAW 264.7 macrophages

Ameliorating H2O2-induced oxidative injury

Activating splenocyte & macrophage; Promoting cell viability; Suppressing apoptosis; Ameliorating oxidative lesions.