All the time, emodin has been demonstrated to have a potential protective action on cardiovascular system. Currently, mutiple studies substantiate that emodin has several properties, including protecting acute myocardial infarction cells, inhibiting proliferation of VSMC and endothelial cells, dilating blood vessels through two ways of non-endothelium-dependent and endothelium-dependent and stabilizing atherosclerotic plaque [77-80]. Acute myocardial infarction (AMI) mainly involves in the process of partial myocardial ischemic necrosis caused by acute coronary artery occlusion, which is one of primary reasons of human death caused by cardiovascular diseases . Several cytokines, such as TNF, IL-1 and IL-6, play an important role in the inflammatory phenomenon of AMI associated with promoting the formation and rupture of coronary atherosclerotic plaques of the initial factors in AMI. And tumor necrosis factor (TNF), interleukin-6 (IL-6) and other pro-inflammatory cytokines in serum or plasma of AMI patients at acute stage are higher than normal and their levels are closely related to cardiac function classification . Additionally, NF-κB is a nuclear transcription factor commonly associated with inflammatory responses. Recently, Song et al. report that emodin can significantly suppress the expression of tumor necrosis factor (TNF-α) and the activation of NF-κB in the area of local myocardial infarction and play a protective role in mouse models of myocardial ischemia . It is possible that emodin may play a protective role in myocardium by regulating the release of local inflammatory mediators and inhibiting inflammation-mediated tissue damage. Moreover, increasing evidence indicates emodin exerts an inhibitory effect on the formation and progress of vulnerable atherosclerotic plaque (VAP) . For instance, Zhou et al.  found that emodin effectively inhibited the expression of GM-CSF and MMP-9 and stabilized the VAP in the aortic root of ApoE-knockout mice. Meanwhile, emodin has vasodilatory functions by inhibiting the contractile effect of 5-hydroxytryptamine and synergizing the diastolic effect of acetylcholine related to up-regulation of free radicals, hydrogen peroxidation and cGMP, as well as its possible mechanisms of improving microcirculation are associated with inhibiting platelet aggregation and reducing blood viscosity [86, 87].
In conclusion, emodin has a protective effect on the cardiovascular system, and the main mechanism is connected with its anti-inflammation and antioxidation resistance. Although beneficial effects of emodin on the cardiovascular system were proved in numerous experiments in vivo and in vitro, how to apply emodin to the corresponding treatment needs more clinical tests (Table 1).
Tissue/Organs Disease Action Mechanism Reference Epithelium Epithelial ovarian cancer Inhibits integrin-linked kinase and epithelial–mesenchymal transition associated factors  Esophageal cancer
Inhibits AKT and ERK associated with cell proliferation and differentiation  Tongue cancer Induces DNA damage and inhibits DNA repair gene expression; Inhibits gene expression of metalloproteinase-9  Cardiovascular system Myocardial infarction Regulates the release of local inflammatory mediators and inhibits oxidative stress injury  Atherosclerosis Stabilizes vulnerable atherosclerotic plaque; Inhibits platelet aggregation and blood viscosity  Diabetic cardiomyopathy Induces phosphorylation of Akt and GSK-3β in myocardium.  Eyes
Diabetic retinopathy Inhibits aldose reductase (AR) and revascularization  Diabetic nephropathy (DN) Inhibits inflammation-related factors and oxidative stress damages  Pancreas Pancreatic cancer Inhibits pancreatic cancer cell growth and angiogenesis, induces apoptosis  Acute pancreatitis Induces apoptosis of inflammation-related lymphocytes; Inhibits excessive oxidative stress and inflammatory cytokines expression   Oral cavity Dental Caries Inhibits the growth, insoluble glucans synthesis and acid production of S. mutans  Periodontitis Inhibits the levels of NO, inflammatory response and alveolar bone absorption  Lung Lung cancer (A549 and H1299 cells) Induced ER stress and TRIB3/NF-κB pathway  Asthma Restricts Th2-related macrophage polarization and airway inflammation action  Acute Lung Injury Exerts anti-fibrotic activity, reverses epithelial-mesenchymal transition (EMT) and inhibits oxidative stress damage  Pulmonary edema  Nervous system Alzheimer’s disease (AD) Inhibits β-amyloid-induced toxicity by PI3K/Akt and the class III phosphatidylinositol-3-kinase pathways; Exerts direct neuroprotective effect via regulation of hormones, nerve growth factors (NGF) and related-signaling pathway  Parkinson’s disease (PD)    Liver Hepatocellular carcinoma Inhibits MAPK and PI3K/AKT pathways Fatty Liver IInhibits SREBP1 activity via the CaMKK-AMPK-mTOR-p70S6K signaling pathway; Decreases alanine aminotransferase (ALT), hepatic triglycerides and aspartate aminotransferase   Hepatitis B virus (HBV) Inhibits HBV DNA replication  Skeleton Osteoporosis Inhibits bone resorption by OPG and RANKL/RANK pathway 
Table 1. Emodin for different treatents
Recently, emodin has been implicated as a therapeutic medicine for diabetes and its severe complications. Diabetes mellitus (DM) is a chronic disease with increasing prevalence in population growth, aging, urbanization and obesity, which complications increasingly contribute to the mortality of diabetes patients . There are findings suggesting that emodin can protect against diabetic nephropathy (DN), which underlying mechanism may involve inhibition of inflammation-related factors and oxidative stress damages . However, what can be concerned is how to ameliorate the hyposensitive anti-diabetes property because of poor oral bioavailability of emodin. With establishment of the self-microemulsifying drug delivery system (SMEDDS) based on emodin, it attained better suppressive effects on the protein level of renal fibrosis compositions in AGEs-induced GMCs and NRK-52E cells . Emodin that was encapsulated into nanoparticle significantly supressed currents activation of HEK293 cells transfected with the P2X3 receptor mediating DN in the dorsal root ganglia . Furthermore, emodin may have potential therapeutic effects on diabetic retinopathy and cataract patients through inhibiting the activity of aldose reductase and ameliorating retinal neovascularization [92, 93]. For example, it is well-known that emodin has good selectively inhibitory activity against aldose reductase (AR) (IC50 = 2.69 ± 0.90 μmol·L−1) and is stable at 37 °C for at least 7 days, and the 3-hydroxy group of emodin that interacts with Ser302 through hydrogen bonding in the specificity pocket of AR plays an essential role. Meanwhile, recent studies show that aloe-emodin prevents hypoxia-induced retinal neovascularization through inhibition of VEGF, prolyl hydroxylase-2 and HIF-1α [ 94].
From above research results, we can know that emodin could have a distinct therapeutic effect on the complications of diabetes, including diabetic nephropathy, retinopathy and cataract, which potantial mechanisms may link to inhibiting oxidation-related enzyme, revascularization, tissue fibrosis and damages, etc.
Increasing studies address that emodin plays a potential role in the treatment of pancreatitis. Acute pancreatitis is a common disease and mainly ruled by its complications and recurrent attacks. Interestingly, emodin can decrease the expression of preBcell colonyenhancing factor and promote the apoptosis of polymorphonuclear leukocyte neutrophil in severe acute pancreatitis (SAP)-associated acute lung injury (ALI) . Meanwhile, lung oedema induced by SPA of rats was significantly alleviated with the combined treatment of emodin and dexamethasone (DEX) . Excessive oxidative stress induced by acute inflammatory response usually causes tissue damages and plays an important role in the development course of acute pancreatitis. Jin et al. found emodin with the strategy of high concentration effectively diminished oxidative stress in SAP rats, and shown lower levels of serum amylase, HMGB 1 and COX-2 and higher levels of PPAR-γ . In another experiment, Wu et al.  found that treatment with emodin obviously ameliorated pancreatic injury and decreased the release of amylase and inflammatory cytokines such as TNF-α and IL-6.
Therefore, above study results have shown that emodin might become the beneficial treatment medicine in severe acute pancreatitis and its multiple complications via suppressing oxidative stress, immune and inflammatory responses. Although the inhibiting effect of emodin on the complications and recurrent attacks of pancreatitis has been reported in numerous researches, the clinical treatment of emodin in SPA patients is little reported.
The application of emodin in the field of oral treatment mainly presumes on its anti-inflammatory, antibacterial effects and inhibition of osteoclast-induced bone resorption. Dental caries is a bacterial infection-related oral disease prevalent across the world. All the time, Streptococcus mutans (S. mutans) is considered as a crucial pathogen in the pathogenesis of dental caries . The major mechanism of being responsible for the cariogenicity of S. mutans relies on its ability of producing glucosyltransferases (Gtfs), synthesizing insoluble glucans, generating acids and surviving at low pH environment . Interestingly, Pandit et al.  demonstrated that polygonum cuspidatum extract F1, mainly composed of resveratrol, emodin and physcion (approximately 16.2%, 18.9% and 2.07% of the weight of F1, respectively), might be useful in control of dental biofilms and improving the cariostatic properties of fluoride without increasing its exposure. According to study results, emodin (0.5−2 mg·mL−1) effectively inhibits the growth, insoluble glucans synthesis and acid production of S. mutans, and reduces the incidence and severity of carious lesions in rats . These experiments suggest that the natural compound emodin might have a potential prevention and treatment effect on dental caries. Additionally, very recent researches show that periodontitis is a bacteria-induced inflammatory bone loss disease. One of important reasons of alveolar bone destruction is closely associated with inflammatory response caused by oral pathogens, including Porphyromonas gingivalis (P.g), Actinobacillus actinomycetemcomitans (A. a) and Tannerella forsythia (T. f) [103-105]. Interestingly, it was found that the levels of NO in the peripheral blood and gingival tissue were decreased with emodin treatment, and subsequent inflammatory response and alveolar bone absorption were inhibited as well . From above study results, it is obvious that emodin exerts suppressing effects on cariogenic bacteria and metabolic bone resorption, this compound might have the possibility in prevention and treatment of dental diseases, thus further studies on it are still needed.
Emodin has potential therapeutic effects on asthma and several lung damage diseases. The primary mechanism of emodin on asthma may associate with inhibition of airway inflammation reaction. For example, Song et al. found emodin effectively decreased pulmonary inflammatory cells infiltration, mucus secretion and serum IgE production, as well as IL-4-mediated macrophage polarization and STAT6 phosphorylation. Additionally, There are findings showing that emodin alleviates lung injury by suppressing and reversing epithelial-mesenchymal transition (EMT)-like shifts, reducing the accumulation of p-IκBα
, NF-κB and TGF-β1, and activating the Nrf2-antioxidant signaling pathway . Furthermore, it is impossible to ignore the fact that emodin may have an anti-fibrotic effect on COPD patients, for instance, Guan et al.  proved emodin exerted anti-fibrotic activity via inhibiting the levels of TNF-α, IL-6, TGF-β1 and heat shock protein (HSP)-47 induced by Smad2/3 and STAT3 signaling molecules in the lungs of BLM-treated rats.
Therefore, the emodin reduces lung structural distortion and damages through inhibition of massive inflammatory cells infiltration and pro-inflammatory cytokines expansion, and its possible mechanisms on asthma and lung damages may closely associate with its superiority of anti-inflammation, anti-oxidation and immunosuppressive activity.
Recently, emodin has been reported to have a potential nervous system protection effect. The protein misfolding resulting from β-amyloid protein (Aβ) in brain plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) . Liu et al.  found that emodin prevented the cultured cortical neurons from β-amyloid-induced toxicity, which was closely associated with increasing the Bcl-2 regulated by the ER stress and PI3K/Akt pathway. Meanwhile, Sun et al.  found emodin blockaded the β-amyloid-induced autophagy with the activation of the class III phosphatidylinositol-3-kinase and downstream signaling molecules ules ules. In a word, these results provided adequate evidence for the application of emodin in the prevention and treatment of neurodegenerative diseases associated with the misfolding of Aβ. Moreover, Ma et al. proved that emodin normalized the change of the plasma corticosterone level and up-regulated the mRNA and protein expression levels of hippocampal glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) . Additionally, emodin treatment effectively reduced OGD/R-lead to neurotoxicity through potentiating Nrf2/ARE-regulated neuroprotection associated with the AMPK/GSK3β pathway in SH-SY5Y cells as well . Therefore, emodin may produce direct neuroprotective effect via regulation of hormones, nerve growth factors (NGF) and related-signaling pathway . Although these studies in vitro and in vivo indicate that emodin might be useful for treating neurodegenerative disorders, more laboratory and clinical experiments are needed for its clinical treatments.
It is well-known that emodin generates hepatocyte protection action via suppressing fibration. Liver is one of the primary organs participating in the metabolism of human body, there would be plenty of adverse effects produced with disorders of its detoxification, metabolism, excretion and other fuctions. Interestingly, emodin may have hepatoprotective activity at low concentration, for example, Ding et al.  found emodin can alleviate intrahepatic cholestasis by regulating the expression of mRNA and protein of FXR, SHP, UGT2B4, and BSEP. Besides, Feng et al.  demonstrated that emodin significantly alleviated CCl4-induced liver fibrosis by suppressing epithelial-mesenchymal transition (EMT) and transforming growth factor-β1 (TGF-β1) in rats rats. There are findings showing that emodin effectively ameliorates hepatic steatosis through the CaMKK–AMPK–mTOR–p70S6K–SREBP1 signaling pathway, which indicates emodin might be beneficial in patients with non-alcoholic fatty liver diseases . Besides, Liu et al.  found emodin can also ameliorate ethanol-mediated liver steatosis and treat alcoholic liver by down-regulating the levels of alanine aminotransferase (ALT), hepatic triglycerides and aspartate aminotransfeansferase. Thus, we can know that emodin may have a potential prevention and treatment action on hepatofibrosis via inhibiting epithelial-mesenchymal transition as well as the expression levels of several cascade signaling pathways.
However, it is impossible to ignore the phenomenon that emodin might produce hepatotoxicity at a high concentration. Recent study has demonstrated that high-concentration emodin might have potential risk of the hepatotoxicity based on bilirubin metabolism mediated by glucuronidation of UGT1A1 enzyme . Therefore, there are more studies needed to explore effects of emodin on both hepatoprotective activity and hepatotoxicity.
The pharmacology, toxicology and therapeutic potential of anthraquinone derivative emodin
- Received Date: 2019-10-01
- Available Online: 2020-06-01
Abstract: Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) is a derived anthraquinone compound extracted from roots and barks of pharmaceutical plants, including Rheum palmatum, Aloe vera, Giant knotweed, Polygonum multiflorum and Polygonum cuspidatum. The review aims to provide a scientific summary of emodin in pharmacological activities and toxicity in order to identify the therapeutic potential for its use in human specific organs as a new medicine. Based on the fundamental properties, such as anticancer, anti-inflammatory, antioxidant, antibacterial, antivirs, anti-diabetes, immunosuppressive and osteogenesis promotion, emodin is expected to become an effective preventive and therapeutic drug of cancer, myocardial infarction, atherosclerosis, diabetes, acute pancreatitis, asthma, periodontitis, fatty livers and neurodegenerative diseases. This article intends to provide a novel insight for further development of emodin, hoping to reveal the potential of emodin and necessity of further studies in this field.