Anthraquinones are a class of aromatic compounds with a 9,10-dioxoanthracene core. So far, 79 naturally occurring anthraquinones have been identified which include emodin, physcion, cascarin, catenarin, and rhein. A large body of literature has demonstrated that the naturally occurring anthraquinones possess a broad spectrum of bioactivities, such as cathartic, anticancer, anti-inflammatory, antimicrobial, diuretic, vasorelaxing, and phytoestrogen activities, suggesting their possible clinical application in many diseases. Despite the advances that have been made in understanding the chemistry and biology of the anthraquinones in recent years, research into their mechanisms of action and therapeutic potential in autoimmune disorders is still at an early stage. In this paper, we briefly introduce the etiology of autoimmune diabetes, an autoimmune disorder that affects as many as 10 million worldwide, and the role of chemotaxis in autoimmune diabetes. We then outline the chemical structure and biological properties of the naturally occurring anthraquinones and their derivatives with an emphasis on recent findings about their immune regulation. We discuss the structure and activity relationship, mode of action, and therapeutic potential of the anthraquinones in autoimmune diabetes, including a new strategy for the use of the anthraquinones in autoimmune diabetes.
Autoimmune diabetes (AID) is a life-threatening metabolic disease that is initiated and progresses through a complex interplay of environmental, genetic, and immune factors. As a result, insulin-producing
In patients and animal models of AID, at disease onset, leukocytes infiltrate into the pancreatic islets [
So far, insulin injection is the only way to control AID; however, it fails to cure the disease and can only ameliorate its complications. Therefore, discovery of novel and effective approaches to cure AID is necessary. Immune therapy, replacement therapy using insulin,
AID development and intervention. During AID onset, leukocytes start to invade pancreatic islets, a condition termed insulitis, followed by diabetes. Diabetes is characterized by hyperglycemia, insulin insufficiency/deficiency, and glucosuria. Polydipsia, polyphagia, and polyuria are found in diabetic patients. Diabetic complications such as retinopathy, nephropathy, foot ulcers, and cardiovascular disease result in fatality of patients. Immunotherapy, replacement therapy, and combinations of both are common approaches to treat AID.
In mammals, 23 chemokine receptors and over 50 chemokines have been discovered (Figure
Chemokines and their cognate receptors. Twenty-three chemokine receptors and their natural ligands are classified into CCR, CXCR, and other categories.
Since T cells and other leukocytes are thought to be essential players in AID [
Animal models are indispensable for dissecting pathogenesis and for preclinical trials in AID despite some difference between animal models and patients. The animal models include streptozotocin- (STZ-) treated mice, nonobese diabetic (NOD) mice, Biobreeding (BB) rats, Long Evans Tokushima Lean (LETL) rats, New Zealand white rabbits, Chinese hamsters, Keeshond dogs, and Celebes black apes [
Naturally occurring anthraquinones (NOAQs) are a group of secondary metabolites structurally related to 9,10-dioxoanthracene (also known as anthracene 9,10-diones) and their glycosides (Table
Chemical structure of NOAQs in different plants.
S. number | IUPAC names | Structure | Species | |||||||
---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | R3 | R4 | R5 | R6 | R7 | R8 | |||
1 | Tectoquinone (2-methyl-AQ) | H | Me | H | H | H | H | H | H |
|
2 | 2-(Hydroxymethyl)-AQ | H | HOCH2 | H | H | H | H | H | H |
|
3 | 2-Methoxy-AQ | H | MeO | H | H | H | H | H | H |
|
4 | 2-Hydroxy-AQ | H | OH | H | H | H | H | H | H |
|
5 | 1-Methoxy-AQ | OH | H | H | H | H | H | H | H |
|
6 | 1-Hydroxy-2-methyl AQ | OH | Me | H | H | H | H | H | H |
|
7 | 1-Hydroxy-2-(hydroxymethyl)-AQ | OH | HOCH2 | H | H | H | H | H | H |
|
8 | 2-(Ethoxycarbonyl)-1-hydroxy-AQ | OH | EtOOC | H | H | H | H | H | H |
|
9 | 1-Methoxy-2-methyl-AQ | MeO | Me | H | H | H | H | H | H |
|
10 | Alizarin (1,2-dihydroxy-AQ) | OH | OH | H | H | H | H | H | H |
|
11 | Alizarin 2-methyl ether |
OH | MeO | H | H | H | H | H | H |
|
12 | Alizarin 1-methyl ether |
MeO | OH | H | H | H | H | H | H |
|
13 | Alizarin 1,2-dimethyldiether |
MeO | MeO | H | H | H | H | H | H |
|
14 | Rubiadin (1,3-dihydroxy-2- |
OH | MeO | OH | H | H | H | H | H |
|
15 | Lucidin (1,3-dihydroxy-2- |
OH | HOCH2 | OH | H | H | H | H | H |
|
16 | Nordamnacanthal (1,3-dihydroxy-2-formyl-AQ) | OH | CHO | OH | H | H | H | H | H |
|
17 | Munjistin (1,3-dihydroxy-2-carboxy-AQ) | OH | HOOC | OH | H | H | H | H | H |
|
18 | 1,3-Dihydroxy-2-(methoxycarbonyl)-AQ | OH | MeOOC | OH | H | H | H | H | H |
|
19 | 2-(Ethoxymethyl)-1,3-dihydroxy-AQ | OH | EtOCH2 | OH | H | H | H | H | H |
|
20 | 1,3-Dihydroxy-2-(methoxymethyl)-AQ | OH | MeOCH2 | OH | H | H | H | H | H |
|
21 | Lucidin dimethyl ether | MeOH | HOCH2 | MeO | H | H | H | H | H |
|
22 | Munjistin dimethyl ether (2-carboxy- |
MeOH | HOOC | MeO | H | H | H | H | H |
|
23 | 2-Benzylxanthopurpurin | OH | PhCH2 | OH | H | H | H | H | H |
|
24 | Anthragallol 3-methyl ether | OH | OH | MeO | H | H | H | H | H |
|
25 | Anthragallol 2,3-dimethyl ether | OH | MeO | MeO | H | H | H | H | H |
|
26 | 2-Carboxy-1-hydroxy-3-methoxy-AQ | OH | HOOC | MeO | H | H | H | H | H |
|
27 | 3-Hydroxy-1-methoxy-2-(methoxymethyl)-AQ | MeO | MeOCH2 | OH | H | H | H | H | H |
|
28 | Anthragallol (1,2,3-trihydroxy-AQ) | OH | OH | OH | H | H | H | H | H |
|
29 | Purpurin (1,2,4-trihydroxy AQ) | OH | OH | H | OH | H | H | H | H |
|
30 | Quinizarin (1,4-dihydroxy-AQ) | OH | H | H | OH | H | H | H | H |
|
31 | 1,4-Dihydroxy-2-(hydroxymethyl)-AQ | OH | HOCH2 | H | OH | H | H | H | H |
|
32 | 2-(Ethoxycarbonyl)-1,4-dihydroxy-AQ | OH | EtOOC | H | OH | H | H | H | H |
|
33 | Christophine (2-(ethoxymethyl)- |
OH | EtOCH2 | H | OH | H | H | H | H |
|
34 | 1,4-Dihydroxy-2-methyl-AQ | OH | Me | H | OH | H | H | H | H |
|
35 | Xanthopurpurin (1,3-dihydroxy-AQ) | OH | H | OH | H | H | H | H | H |
|
36 | Xanthopurpurin 3-methyl ether |
OH | H | MeO | H | H | H | H | H |
|
37 | Xanthopurpurin dimethyl ether (1,3-dimethoxy-AQ) | MeO | H | MeO | H | H | H | H | H |
|
38 | 1-Hydroxy-3-(methoxycarbonyl)-AQ | OH | H | MeOOC | H | H | H | H | H |
|
39 | Pseudopurpurin (3-(carboxy)-1,2,4-trihydroxy-AQ) | OH | OH | HOOC | OH | H | H | H | H |
|
40 | 1,4-Dihydroxy-2-methyl-5-methoxy-AQ | OH | Me | H | OH | MeO | H | H | H |
|
41 | 1,4-Dihydroxy-2-methyl-8-methoxy-AQ | OH | Me | H | OH | H | H | H | MeO |
|
42 | 1,4-Dihydroxy-6-methyl-AQ | OH | H | H | OH | H | Me | H | H |
|
43 | 1,5-Dihydroxy-2-methyl-AQ | OH | Me | H | H | OH | H | H | H |
|
44 | Physcion (1,8-dihydroxy-3-methoxy-6-methyl-AQ) | OH | H | Me | H | H | Me | H | OH |
|
45 | 2-Methyl-1,3,6-trihydroxy-AQ | OH | Me | OH | H | H | OH | H | H |
|
46 | 1,4-Dihydroxy-7-methyl-AQ | OH | H | H | OH | H | H | Me | H |
|
47 | 4,5-Dihydroxy-2-methoxy-7-methyl-AQ | H | Me | H | OH | OH | H | MeO | H |
|
48 | 2,7-Dihydroxy-4-methoxy-3-methyl-AQ | H | OH | Me | MeO | H | H | OH | H |
|
49 | 2-Hydroxy-7-methyl-AQ | H | Me | H | H | H | H | OH | H |
|
50 | 2-Carboxy-4-hydroxy-AQ | H | HOOC | H | OH | H | H | H | H |
|
51 |
3-( |
OH | Me | GluO | H | H | OH | H | H |
|
52 | 3-(6-O-Acetyl- |
OH | Me | 6-OAc- |
H | H | OH | H | H |
|
53 | 3-[(2-O-6-Deoxy- |
OH | Me | 6-dManO-GluO | H | H | OH | H | H |
|
54 | 3-[(3-O-Acetyl-2-O-6-deoxy- |
OH | Me | 3-OAc- |
H | H | OH | H | H |
|
55 | 3-[(6-O-Acetyl-2-O-6-deoxy- |
OH | Me | 6-OAc- |
H | H | OH | H | H |
|
56 | 3-[(3,6-O-Diacetyl-2-O-6-deoxy- |
OH | Me | 3,6-[OAc]2-6-dManO- |
H | H | OH | H | H |
|
57 | 3-[(4,6-O-Diacetyl-2-O-6-deoxy- |
OH | Me | 4,6-[OAc]2-6-dManO- |
H | H | OH | H | H |
|
58 | 3-[(4-O-Acetyl-2-O-6-deoxy- |
OH | Me | 4-OAc-6- |
H | H | OH | H | H |
|
59 | 3-[(6-O-Acetyl-2-O- |
OH | Me | 6-OAc- |
H | H | OH | H | H |
|
60 | Ruberythric acid (1-hydroxy-2-[(6-O- |
OH | XylO- |
H | H | H | OH | H | H |
|
61 | Lucidin primeveroside (1-hydroxy-2-(hydroxymethyl)-3-[(6-O- |
OH | HOCH2 | XylO- |
H | H | OH | H | H |
|
62 | 1-Acetyl-3-[(4-O-6-deoxy- |
MeCO | Me | 6-dManO-GluO | H | H | OH | H | H |
|
63 | 2-[(6-O- |
H | H | H | H | H | H | H | GluO-GluO |
|
64 | 3-[(2-O-6-Deoxy- |
OH | MeOOC | 6-dManO-GluO | H | H | H | H | H |
|
65 | 3-( |
H | HOCH2 | GluO | H | H | H | H | H |
|
66 | 3-( |
H | HOCH2 | GluO | H | H | H | H | OH |
|
67 | 2-( |
OH | GluO | OH | H | H | H | H | H |
|
68 | 3-( |
OH | HOCH2 | GluO | H | H | H | H | H |
|
69 | Emodin (1,3,8-trihydroxy-6-methyl-AQ) | OH | H | Me | H | H | OH | H | OH |
|
70 | Cascarin (emodin 6-O-rhamnoside) | OH | H | Me | H | H | RhaO | H | OH |
|
71 | Rhein (1,8-dihydroxy-3-carboxyl-AQ) | OH | H | HOOC | H | H | H | H | OH |
|
72 | Catenarin (1,4,6,8-tetrahydroxy-3-methyl-AQ) | OH | H | Me | OH | H | OH | H | OH |
|
73 | Aloe-emodin (1,8-dihydroxy 3-hydroxy methyl anthraquinone) | OH | H | CH2OH | H | H | H | H | OH |
|
74 | Chrysophanol (1,8-dihydroxy-3-methyl-AQ) | OH | H | Me | H | H | MeO | H | OH |
|
75 | Rhein-8-glucoside | OH | H | HOOC | H | H | H | H | GluO |
|
76 | Alatinone (1,5,7-trihydroxy-3-methyl-AQ) | OH | H | Me | H | OH | H | OH | H |
|
77 | Diacerein (diacerhein) | OAc | H | HOOC | H | H | H | H | OAc |
|
78 | Fistulic acid | OH | Me | HOOC | OH | H | MeO | MeO | OH |
|
79 | 5-Hydroxy emodin | OH | H | Me | H | OH | OH | H | OH |
|
80 | 1,3-hihydroxy-6,8-dimethoxy-AQ | OH | H | OH | H | H | MeO | H | MeO |
|
81 | 1,3,5,8-Tetrahydroxy-2-methyl-AQ | OH | Me | OH | H | OH | MeO | H | OH |
|
82 | 1,2-Dihydro-1,3,8-trihydroxy-2-methyl-AQ | OH | Me | OH | H | H | H | H | OH |
|
83 | 1,8-Dihydroxy-6-methoxy-2-methyl-AQ | OH | Me | H | H | H | MeO | H | OH |
|
84 | 1,8-Dihydroxy-6-methoxy-3-methyl-AQ | OH | H | Me | H | H | MeO | H | OH |
|
85 | Citreorosein (1,3,8-trihydroxy-6-hydroxymethyl-AQ) | OH | H | CH2OH | H | H | OH | H | OH |
|
86 | Emodic acid (1,6,8-trihydroxy-AQ-3-carboxylic acid) | OH | H | HOOC | H | H | OH | H | OH |
|
87 | Obtusifolin (2,8-dihydroxy-1-methoxy-3-methyl-AQ) | MeO | OH | Me | H | H | H | H | OH |
|
88 | 2-Formyl-1,3,8-trihydroxy-AQ | OH | CHO | OH | H | H | H | H | OH |
|
89 | 3-Formyl-1-hydroxy-8-methoxy-AQ | OH | H | CHO | H | H | H | H | MeO |
|
Glu: glucosyl; dMan: deoxymannosyl; Rha: rhamnosyl; Xyl: xylosyl; Me: methyl; Et: ethyl; Ph: phenyl; Ac: acetyl.
Schema outlining the biosynthesis of anthraquinones. Anthraquinones can be synthesized from acetyl CoA and malonyl CoA via the polyketide pathway (a), or from shikimic acid (b) via the shikimate pathway.
Mode of action of catenarin and other anthraquinones for AID. (a) Upon chemokine binding, a chemokine receptor is activated and induces G protein activation. A cascade of calcium mobilization and activation/phosphorylation of MAPKK/MAPK pathways leads to chemotaxis of leukocytes and, subsequently, insulitis and diabetes. (b) Catenarin and probably other anthraquinones inhibit leukocyte migration mediated by CCR5 and CXCR4 via the inactivation of MAPKs (p38 and JNK), MKKs (MKK6 and MKK7), and calcium mobilization. As a result, anthraquinones can suppress insulitis and diabetes.
NOAQs have widespread applications throughout medicine as well as in industry. Medicinally speaking, they show a wide spectrum of bioactivities. Most of them are best known as laxative compounds for constipation. Apart from laxative activity, emodin, the most studied anthraquinone, has been reported to have cathartic, anti-inflammatory, anticancer, antimicrobial, diuretic, DNA-binding, and vasorelaxant activities [
Recently, NOAQs have been explored for their potential in AID intervention. In one study,
In another study, Shen and colleagues showed that catenarin, cascarin, emodin, and rhein inhibited CXR4-mediated chemotaxis in Jurkat T cells [
NOAQs with antidiabetic activities.
S. number | Name | Classification | Molecular formula | Biological activities |
---|---|---|---|---|
72 | Catenarin | Anthraquinone |
|
Antichemotactic [ |
69 | Emodin | Anthraquinone |
|
Antichemotactic [ |
44 | Physcion | Anthraquinone |
|
Antichemotactic [ |
70 | Cascarin | Anthraquinone |
|
Antichemotactic [ |
71 | Rhein | Anthraquinone |
|
Antichemotactic [ |
77 | Diacerein | Anthraquinone |
|
Antiosteoarthritic [ |
Diacerein is a commercial drug commonly utilized to treat human osteoarthritis. It was developed from its prodrug rhein. Very interestingly, diacerein can be used to treat AID in NOD mice [
There is lack of information about the impact of the other chemokines/chemokine receptors in AID. We showed that NOAQs can target CXCR4 and CCR5 pathways [
Emodin, one of the most well-studied anthraquinones, is frequently present in laxative herbs. Furthermore, emodin is reported to be effective against cancer, constipation, inflammation, microbes, and peptic ulcers [
Several NOAQs show anti-inflammatory activity. Among them, cascarin, catenarin, rhein, physcion, and emodin suppress the chemotactic activity of leukocytes at the insulitis stage of AID development. They suppress chemokine-mediated leukocyte migration towards pancreatic islets leading to a decline in AID development. This suppression involves anthraquinone-mediated inhibition of MAPKK/MAPK pathway. An antiosteoarthritic anthraquinone drug, diacerein, has been shown to prevent AID in a NOD model, suggesting that the antichemotactic activity of the risk-free anthraquinones can likely be exploited for AID and other inflammatory diseases.
Autoimmune diabetes
Naturally occurring anthraquinone
Nonobese diabetic mice
G protein-coupled receptor
Mitogen-activated protein kinase
Mitogen-activated protein kinase
Half maximal inhibitory concentration
Streptozotocin
Biobreeding rats
Long Evans Tokushima Lean rats.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Shih-Chang Chien and Yueh-Chen Wu contributed equally to this work.
The authors thank the authors of the articles cited in this paper.