Emo)din

Emodin

Emodin is an active natural anthraquinone derivative component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L., Senna obtusifolia [(L.) H.S.Irwin & Barneby], Fallopia japonica [Houtt. (Ronse Decr.)], Kalimeris indica (L.) Sch.Bip. Ventilago madraspatana (Gaertn.), Rumex nepalensis (Spreng.), Fallopia multiflora [(Thunb.) Haraldson], Cassia occidentalis [(L.) Link], Senna siamea [(Lam.) Irwin et Barneby] and Acalypha australis (L.). Glycyrrhiza Uralensis is added as to ‘buffer’ the ‘cold’ nature of emodin. Traditionally D Huang (Rheum palmatum) was considered to injure the stomach due to its ‘cold’ nature and this formula reflects our respect for those traditions.

Aloe-emodin is an active natural anthraquinone derivative, and is found in the roots and rhizomes of numerous Chinese medicinal herbs (including Rheum palmatum L) and exhibits anti-cancer effects on many types of human cancer cell lines. Administration of rhubarb (Emodin) can effectively reverse severe acute pancreatitis (SAP) by regulating the levels of IL-15 and IL-18 (Yu & Yang, 2013).

Influenza A Virus

Lasting activations of toll-like receptors (TLRs), MAPK and NF-κB pathways can support influenza A virus (IAV) infection and promote pneumonia. In this study, we have investigated the effect and mechanism of action of emodin on IAV infection using qRT-PCR, western blotting, ELISA, Nrf2 luciferase reporter, siRNA and plaque inhibition assays. The results showed that emodin could significantly inhibit IAV (ST169, H1N1) replication, reduce IAV-induced expressions of TLR2/3/4/7, MyD88 and TRAF6, decrease IAV-induced phosphorylations of p38/JNK MAPK and nuclear translocation of NF-κB p65. Emodin also activated the Nrf2 pathway, decreased ROS levels, increased GSH levelss and GSH/GSSG ratio, and upregulated the activities of SOD, GR, CAT and GSH-Px after IAV infection. 

Suppression of Nrf2 via siRNA markedly blocked the inhibitory effects of emodin on IAV-induced activations of TLR4, p38/JNK, and NF-κB pathways and on IAV-induced production of IL-1β, IL-6 and expression of IAV M2 protein. Emodin also dramatically increased the survival rate of mice, reduced lung edema, pulmonary viral titer and inflammatory cytokines, and improved lung histopathological changes. In conclusion, emodin can inhibit IAV replication and influenza viral pneumonia, at least in part, by activating Nrf2 signaling and inhibiting IAV-induced activations of the TLR4, p38/JNK MAPK and NF-κB pathways (Dai JP et al, 2017).

Cancer - Apoptosis

Despite its possible genotoxicities, a number of studies have demonstrated that Emodin inhibits growth and proliferation of various cancer cells in vitro and in vivo in animal models. Quinones are well known highly redox active molecules capable to form a redox cycle with their semiquinone radicals leading to formation of ROS. Thus, it has been suggested that the quinoid structure of Emodin could be activated to the semiquinone radical intermediate, which in turn could react with oxygen to produce ROS and ROS-induced apoptosis (Huang et al., 2007).

Emodin also induces apoptotic responses in the human hepatocellular carcinoma cell lines (HCC) Mahlavu, PLC/PRF/5 and HepG2. The addition of emodin to these three cell lines led to inhibition of growth in a time- and dose-dependent manner. The enhancement of the generation of ROS, DeltaPsim disruption and caspase activation may be involved in the apoptotic pathway induced by emodin (Jing et al., 2002).

Cervical Cancer

Emodin (1, 3, 8 - trihydroxy - 6 - methylanthraquinone) is an active herbal component traditionally used in China for treating various ailments. Emodin exerts anti-proliferative effects in many cancer cell lines including human cervical cancer cell lines through the inhibition of DNA synthesis and induction of apoptosis as demonstrated by increased nuclear condensation, annexin binding and DNA fragmentation (Srinivas, 2003)

Emodin induces apoptosis of human cervical cancer hela cells via intrinsic mitochondrial and extrinsic death receptor pathway

Wang Y, Yu HZ, Zhang Y et al. Cancer Cell International, vol. 13, no. 1, article 71, 2013.

Background: Emodin is a natural anthraquinone derivative isolated from the Rheum palmatum L. Aim: The aim of the present study was to investigate the effect of emodin on the apoptosis of the human cervical cancer line HeLa and to identify the mechanisms involved. Methods: Relative cell viability was assessed by MTT assay after treatment with emodin. Cell apoptosis was detected with TUNEL, Hoechst 33342 staining and quantified with flow cytometry using annexin FITC-PI staining. Results: The percentage of apoptotic cells was 0.8, 8.2, 22.1, and 43.7%, respectively. The mRNA levels of Caspase-9, -8 and −3 detected by Real-time PCR after treatment with emodin were significantly increased. Emodin increased the protein levels of Cytochome c, Apaf-1, Fas, FasL, and FADD but decreased the protein levels of Pro-caspase-9, Pro-caspase-8 and Pro-caspase-3. Conclusion: We conclude that the emodin inhibited HeLa proliferation by inducing apoptosis through the intrinsic mitochondrial and extrinsic death receptor pathways.

Lung Cancer

Additionally, emodin was found to decrease tyrosine phosphorylation of HER-2/neu and preferentially suppress the proliferation of HER-2/neu-overexpressing non-small cell lung cancer cells. The combination of emodin with approved anti-cancer drugs such as cisplatin synergistically inhibit the proliferation of HER-2/neu-overexpressing lung cancer cells. This suggests that emodin can sensitize these cells to chemotherapeutic drugs (Zhang & Hung, 1996).

Breast Cancer

In particular, emodin has been found to be effective in the inhibition of breast cancer cells when administered with paclitaxel, a commonly used chemotherapeutic agent for breast cancer patients. The combination of emodin and paclitaxel synergistically inhibits the growth of HER-2/neu-overexpressing breast cancer cells in vitro, inhibiting tumour growth and prolonging survival in mice bearing xenografts of human tumour cells (Zhang et al., 1999).

It has been suggested that the quinoid structure of Emodin could be activated to the semiquinone radical intermediate, which in turn could react with oxygen to produce ROS and ROS-induced apoptosis (Huang et al., 2007).

Colon Cancer

In vitro, emodin induced cell morphological changes, decreased the percentage of viability, induced G2/M phase arrest and increased ROS and Ca(2+) productions as well as loss of mitochondrial membrane potential (ΔΨ(m)) in LS1034 cells. In vivo, emodin effectively suppressed tumour growth in tumour nude mice xenografts bearing LS1034.The potent in vitro and in vivo antitumor activities of emodin suggest that it might be developed for treatment of colon cancer in the future (Ma et al., 2012).

Multiple Myeloma

Emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukaemia 1 (Mcl-1), through inhibition of interleukin-6–induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other antiapoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. Induction of apoptosis by emodin was almost abrogated in Mcl-1–overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. Hence, emodin inhibits interleukin-6–induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a promising target for treating myeloma. This indicates emodin may be a promising new potent anticancer agent for the treatment of multiple myeloma patients (Muto et al., 2007).

Oral Cancer

(35) Aloe-emodin is a natural anthraquinone compound from the root and rhizome of Rheum palmatum. Aloe-emodin inhibits KB cancer cells in a dose-dependent manner, resulting in cell cycle arrest at the G2/M phase. Aloe-emodin has anti-cancer effects on oral cancer, which may lead to its use in chemotherapy and chemoprevention of oral cancer (Xiao et al., 2007).

Pancreatic Cancer

Pharmacological studies have demonstrated that emodin exhibits anti-cancer effects on several human cancers. The molecular mechanisms by which emodin exerts antiproliferative and anti-metastatic activity on pancreatic cancer both in vitro and in vivo may be related to the down-regulation of NF-κB and its regulated molecules such as survivin and MMP-9 proteins. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human pancreatic cancer (Liu et al., 2011).

Multi Drug Resistance (MDR)

Emodin has been found to reverse MDR in cancer cells, for which there is a biological basis for the application of emodin as a biochemical modulator to potentiate the effects of antitumor drugs and reverse the multidrug resistance in cancer cells (Jiang & Zhen, 1999).

Liver Cancer

The antiproliferative activity of aloe-emodin is through p53-dependent and p21-dependent apoptotic pathway in human hepatoma cell lines; hence, aloe-emodin may be useful in liver cancer prevention (Kuo et al., 2002).

Tumour Cell Adhesion

Emodin inhibits tumour cell adhesion through the disruption of the membrane lipid raft-associated integrin-signalling pathway (Huang et al., 2006).

Therapy Associated Toxicities

Recent research has suggested that plant polyphenols such as emodin may be used to sensitize tumour cells to chemotherapeutic agents and radiation therapy by inhibiting pathways that lead to treatment resistance. Such agents have also been found to be protective from therapy-associated toxicities (Garg et al., 2005).

Cancer: Multiple Myeloma

Action: Inhibits interleukin-6, activates of caspase-3 and caspase-9

Muto et al., (2007) show that emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukaemia 1 (Mcl-1). Emodin inhibited interleukin-6-induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other antiapoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. To clarify the importance of Mcl-1 in emodin-induced apoptosis, the Mcl-1 expression vector was introduced into the human myeloma cells by electroporation. Induction of apoptosis by emodin was almost abrogated in Mcl-1-overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. In conclusion, emodin inhibits interleukin-6-induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, our results show emodin as a new potent anticancer agent for the treatment of multiple myeloma patients (Muto et al., 2007).

Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer.

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a natural occurring anthraquinone derivative isolated from roots and barks of numerous plants, moulds, and lichens. It is found as an active ingredient in different Chinese herbs including Rheum palmatum and Polygonum multiflorum, and has diuretic, vaso-relaxant, anti-bacterial, anti-viral, anti-ulcerogenic, anti-inflammatory, and anti-cancer effects.

The anti-inflammatory effects of emodin have been exhibited in various in vitro as well as in vivo models of inflammation including pancreatitis, arthritis, asthma, atherosclerosis and glomerulonephritis. As an anti-cancer agent, emodin has been shown to suppress the growth of various tumour cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal, leukaemia, and lung cancers. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-κB, casein kinase II, HER2/neu, HIF-1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer.

This review summarizes reported anti-inflammatory and anti-cancer effects of emodin, and re-emphasizes its potential therapeutic role in the treatment of inflammatory diseases and cancer (Shrimali et al., 2013).

Anticancer effect of aloe-emodin on cervical cancer cells involves G2/M arrest and induction of differentiation.

The aim of this study was to investigate the effects of aloe-emodin, a natural compound from the root and rhizome of Rheum palmatum, on the growth of human cervical cancer cells, HeLa.

HeLa cells were treated with various concentrations of aloe-emodin for 1-5 d, and cell growth was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay. The long-term growth effect was investigated by crystal violet assay. The distributions of the cell cycle and apoptosis were analysed by flow cytometry. The alkaline phosphatase (ALP) activity was analysed by a chemical analyser. Finally, Western blotting was used to indicate the abundant changes of protein kinase C (PKC), c-myc, cyclins, cyclin-dependent kinases (CDK), and proliferating cell nuclear antigen (PCNA).

Aloe-emodin inhibited the growth of HeLa cells in a dose-dependent manner at concentrations ranging between 2.5 and 40 micromol/L. The flow cytometric analysis showed that HeLa cells were arrested at the G2/M phase. This effect was associated with the decrease in cyclin A and CDK2, and the increase in cyclin B1 and CDK1. More importantly, the ALP activity was found to be increased by aloe-emodin treatment, and accompanied by the inhibition of PCNA expression. In addition, aloe-emodin suppressed the expression of PKCalpha and c-myc. These findings provide a possible mechanistic explanation for the growth inhibitory effect of aloe-emodin on HeLa, which includes cell cycle arrest and inducing differentiation (Guo et al., 2007).

Effect of emodin on human kidney fibroblast proliferation

Emodin inhibited the proliferation of human kidney's fibroblasts by inhibiting the cell DNA synthase and delaying the progress of cell cycle. These findings might provide part of experimental basis for the clinical use of emodin (Ning et al., 2000).

Renal Fibroblasts and Myofibroblasts in Chronic Kidney Disease

Renal interstitial fibrosis is considered the hallmark of progressive renal disease. In particular, many studies have determined that the extent of tubulointerstitial involvement correlates better with renal function deterioration than glomerular changes do, thus the extent of damaged tubulointerstitial area in any given renal biopsy has important implications for the renal prognosis of the patients. Tubulointerstitial fibrosis is characterized by the accumulation of extracellular matrix (ECM) components including collagen types I, III, and IV, as well as proteoglycans and fibronectin. Fibroblasts are considered the primary matrix-producing cells in the kidney and hence they are clinically relevant as principal mediators of renal fibrosis associated with progressive renal failure (Strutz F & Zeisberg, 2006). 

Effects of crude rhubarb on serum IL-15 and IL-18 levels in patients with severe acute pancreatitis

Administration of rhubarb (Emodin) can effectively reverse severe acute pancreatitis (SAP) by regulating the levels of IL-15 and IL-18. (Yu & Yang, 2013).

Antitrichomonal action of emodin in mice.

Emodin, an active component contained in the root and rhizome of Rheum palmatum L. (Polygonaceae), was found to have an inhibitory effect on the pathogenicity of Trichomonas vaginalis in mice. Emodin delayed the development of subcutaneous abscesses due to infection of this parasite. Also, it cures the intravaginal infection of trichomonads through oral administration. In cell cultures, it reduced the cytotoxic effect of this parasite towards mammalian cells. This inhibition was markedly reversed by the coexistence of free radical scavengers, indicating the possible mediation of free radicals (Wang, 1993).

Emodin and Diabetes – Insulin – Metabolic diseases

Emodin, is a natural product extracted from various Chinese herbs including Rheum palmatum. Emodin is an agent that could reduce the impact of Type 2 diabetes. Findings published in the British Journal of Pharmacology August 2010 show that giving emodin to mice with diet-induced obesity lowered blood glucose and serum insulin, improved insulin resistance and lead to more healthy levels of lipid in the blood. Emodin also decreased body weight and reduced central fat mass.

"If repeated in humans, all of these changes would be beneficial for people affected by Type 2 diabetes or other metabolic diseases associated with insulin resistance," says lead author Dr Ying Leng, who works in the Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China.

Research is increasingly showing that an enzyme known as 11β-HSD1 plays a role in the body's response to sugar contained in a person's diet. When someone eats sugar-containing food a lot of glucose floods into the blood stream. In response, the body releases insulin and this hormone triggers various actions that help to clear excess glucose from the blood. The body, however, also has another set of hormones known as glucocorticoids, which have the opposite effect to insulin. And this is where 11β-HSD1 fits in, because this enzyme increases glucocorticoids' ability to act.

The Chinese research study found that emodin extract is a powerful and chosen inhibitor of 11β-HSD1 enzyme. In this way, the anti-insulin action of glucocorticoids hormone is curbed in the body. This effect assists in reducing the blood sugar level and improve the condition of insulin resistance in type 2 diabetics.

Summing up it was found that emodin could lower glucose level in blood glucose, bring down the use of insulin in blood, improved the resistance of insulin efficacy in type 2 diabetics and brought the fat levels in the blood to healthy states. There was also weight loss along with a decline in fat mass at the centre of the body (Ying Feng, 2010).

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