Emodin

Brand names: 1,3,8-trihydroxy-6-methyl-anthraquinone, 1,3,8-trihydroxy-6-methylemodin, 3',4',5',7-tetrahydroxyflavone, Emodin

Usage of Emodin

Reviews of the pharmacology and observed effects of emodin from in vitro and animal studies have been published.(Akkol 2021, Dong 2020)

Antifibrotic effects

Animal and in vitro data

Emodin demonstrated protective activity in animal models of hepatic injury, pancreatitis, renal failure, and pulmonary fibrosis,(Chen 2009, Dang 2008, Gui 2007, Li 2009, Wang 2007, Wang 2007, Wang 2007, Zhang 2005) as well as fibrinolytic activity via activation of plasminogen activator in vitro.(Radha 2008)

Anti-inflammatory/Immune system effects

Animal and experimental data

Experimental models of inflammation, including rat paw edema and ocular surface inflammation, have been used to demonstrate the mechanisms of action of emodin, which involve influence on cytokines and transcription factors.(Chen 2009, Kitano 2007, Liu 2009, Srinivas 2007) Animal studies investigating the effect of emodin on bone remodeling have demonstrated inhibitory effects on the inflammatory and immune signal mediator nuclear factor kappa B (NF-KB).(Kim 2014) Regulation of inflammasone activation and expression of interleukin 1beta (IL-1beta) in a sepsis mouse model cOnfirmed in vitro findings of these processes, which are downstream of NF-KB activation.(Han 2015) A water extract of P. multiflorum that contained emodin effectively protected the liver of rats treated with carbon tetrachloride by diminishing the release of IL-1beta and tumor necrosis factor-alpha (TNF-alpha). No difference was found in TNF-alpha levels between the P. multiflorum water extract and the positive control, silymarin. The water extract was observed to be a stronger inhibitor of TNF-alpha than emodin alone, whereas the effect on IL)-1beta was similar between emodin and the P. multiflorum water extract.(Lee 2012) Other animal and experimental studies have reported similar improvements in TNF-alpha, IL-1beta, and other inflammatory cytokines in plasma as well as various tissues.(Alisi 2012, Lin 2015, Nemmar 2015, Tong 2011, Xue 2015)

Antimicrobial activity

Animal and in vitro data

In vitro studies of cell cultures have shown that emodin possesses antibacterial (Helicobacter pylori, EscheriChia coli, Pseudomonas aeruginosa, Bacilius cereus, and some Staphylococcus aureus strains), virucidal (herpes simplex), and antifungal (Candida) activity.(Chen 2009, Hsiang 2008, Liu 2015, Srinivas 2007) The antibacterial efficacy of emodin against methicillin-resistant S. aureus (MRSA) was confirmed by in vitro and in vivo studies. Emodin exhibited dose-Dependent effects comparable to linezolid and superior to imipenem and Cefepime, with minimum inhibitory concentrations (MICs) between 2 and 8 mcg/mL and minimum bacterial concentrations (MBCs) between 4 and 32 mcg/mL. At 8 and 16 mcg/mL (1 times and 2 times the MBC, respectively), emodin demonstrated reduced viability of MRSA over 16 hours comparable to that with norvancomycin 0.5 mcg/mL (1 times MIC). Resistance did not develop easily with emodin, as no increase in MIC developed after 20 passages of the resistance selection assay, whereas norvancomycin demonstrated 2-fold and 4-fold increases in MIC after 4 and 15 passages, respectively. These data were confirmed using in vivo lethal and sublethal mice models. At 5 and 10 mg/kg, emodin resulted in 50% and 87.5% survival rates, respectively, compared with 12.5% with emodin 2.5 mg/kg and 0% for controls. The mechanism appears to be related to disruption of cell membrane integrity and not the involvement of genes related to cell wall synthesis, lysis, drug accumulation, or beta-lactamase activity. Additionally, bactericidal concentrations did not display cytotoxicity.(Liu 2015)

Antituberculosis activity of emodin extracted from Aloe vera leaf has been reported, with an MIC of 6.25 mcg/mL against Mycobacterium tuberculosis.(Sharma 2017) In vitro, emodin has also been shown to block severe acute respiratory syndrome (SARS) coronavirus spike protein binding to angiotensin-converting enzyme 2, suggesting potential application in treating SARS.(Lin 2015)

Antioxidant activity

Animal and in vitro data

Antioxidant activity has been observed in in vitro and in vivo studies(Alisi 2012, Lee 2012, Liu 2014, Nemmar 2015, Xue 2015) that used rat liver cell lines and rats, respectively. Emodin and/or the water extract of P. multiflorum root, with emodin as the main antioxidant, effectively reduced carbon tetrachloride-induced (CCl4) cytotoxicity. CCl4–induced elevations in AST and ALT levels were reduced by emodin and the water extract; recovery of key antioxidant enzymes, including glutathione peroxidase, glutathione reductase, glutathione S-transferase, and superoxide dismutase (SOD), was also observed. Additionally, emodin and the water extract reduced other biomarkers of lipid peroxidation such as malondiadehyde. Preventative effects of hepatotoxicity were also seen at the histological and organ level.(Lee 2012) Similar results occurred in a nonalcoholic fatty liver disease rat model that also demonstrated improved future response to oxidative stress in emodin-treated groups as well as enhanced activity of concomitant antioxidant therapy with emodin and N-acetylcysteine.(Alisi 2012) An adaptogenic effect of emodin has been demonstrated in a rat stroke model, in which rats were exposed to pulmonary diesel exhaust particles (DEP). Compared with the control group, DEP exposure induced both a decrease in the antioxidant SOD (P<0.01) and an increase in the antioxidant glutathione reductase (P<0.001); both processes were significantly reversed by emodin, indicating an ability to provide an adaptive response.(Nemmar 2015)

Cancer

Animal and in vitro data

The potential applications of emodin in the management of cancer have been reviewed.(Srinivas 2007). Cell cycle inhibition of many human cancer lines has been reported in vitro.(Brown 2007, Cai 2008, Cha 2005, Chen 2009, Fu 2007, Guo 2009, Huang 2009, Kaneshiro 2006, Kuo 2009, Lev-Goldman 2006, Lu 2008, Olsen 2007, Wang 2006, Wang 2007, Yan 2008, Yu 2008) A definitive mechanism of action, however, is unclear.(Srinivas 2007) Apoptosis, as well as antitumor action, has been demonstrated, and a role as an adjunct to chemotherapy has been suggested.(Chen 2009, Guo 2009) Antiangiogenic action has also been revealed.(Kaneshiro 2006, Lu 2008) Direct cytotoxicity is not thought to be responsible for apoptosis, with some researchers suggesting the involvement of signaling pathways, inhibition of kinases, and microsomal enzyme activation.(Kaneshiro 2006, Olsen 2007, Yan 2008) Data from more recent in vitro studies demonstrate emodin's ability to inhibit non–small cell lung cancer (NSCLC) cell growth in a dose- and time-dependent manner. Mechanisms involved the signaling pathway of adenosine monophosphate-activated protein kinase (AMPK) with subsequent inhibition of integrin-linked kinase, both of which are highly expressed in several human malignancies, including NSCLC. Additionally, the combination of emodin with metformin, which is also an AMPK inhibitor, enhanced the effects of emodin.(Tang 2015) Few animal experiments have been conducted(Guo 2009) and limited clinical studies have been identified.(Srinivas 2007, Sanders 2018)

In a breast cancer mouse model, intraperitoneal administration of emodin 40 mg/kg/day for 18 days significantly suppressed lung metastases, although no difference was found between the control and treatment groups in size, weight, and growth rate of primary tumors. A novel mechanism via tumor-associated macrophages was suggested based on reduced accumulation of M2 macrophages in the lungs. These data highlight the role of transcriptional control of macrophage activation and differentiation as a mechanism of metastasis and as a potential target for therapy.(Jia 2014) In vitro studies in bladder cancer cell lines further support the ability of emodin to affect gene transcriptional expression and reverse histone-induced epigenetic dysregulation of genes associated with cancer progression, cell survival, and proliferation. Emodin reversed the oncogenic epigenetic modifications, inhibited the binding affinity of RNA polymerase II, and restored healthy cellular epigenetic processes.(Cha 2015) An additional mechanism may be antilysosomal activity. Emodin-treated HeLa cervical cancer cells demonstrated lysosomal degradation, including increased autophagic vacuoles and cathepsin leakage, inducing apoptosis.(Trybus 2017)

Clinical data

A clinical study (N=240) reported that and aloe-emodin compound combined with chemotherapy improved solid tumor regression and 3-year survival time.(Lissoni 2009)

Cardiac and smooth muscle effects

Animal and in vitro data

In animal models of acute myocardial infarction and reperfusion injury, emodin appeared to have a protective role on the cardiac tissue by unclear mechanisms.(Du 2005, Wu 2007) Anti- and pro-oxidant effects have been described for emodin.(Hei 2006, Srinivas 2007, Wang 2007) In smooth muscle tissue, calcium and potassium efflux mechanisms are affected by emodin.(Wu 2008, Wu 2009, Zheyu 2006)

Because DEPs are a source of particulate air pollution that have been linked to various cardiovascular conditions (ie, angina, myocardial infarction, heart failure), DEP animal models are used to investigate potential therapies and key underlying mechanisms. These mechanisms involve oxidative stress that lead to proinflammatory responses related to atherogenesis. Studies in rats, including a stroke model, have demonstrated that the significant worsening of inflammatory (IL-1-beta, TNF-alpha), oxidative (SOD), and thrombotic (platelet aggregation, aPTT, PT) processes induced by pulmonary DEP exposure were significantly mitigated by administration of emodin 4 mg/kg. DEP exposure induced both pro-oxidant and antioxidant effects such that the antioxidant SOD was decreased significantly with exposure (P<0.01) and the antioxidant glutathione reductase was significantly increased (P<0.001). Emodin significantly reversed both of these processes, indicating an ability to provide an adaptive response.(Nemmar 2015)

Limited by toxicity, clinical studies for effect in cardiovascular disease are lacking.(Li 2020)

CNS effects

Emodin side effects

In liver and kidney cell lines in vitro, concentration- and time-dependent toxicity of emodin has been demonstrated by induction of apoptosis.(Lin 2015) A systematic review of adverse effects of aloe-emodin anthraquinone, cautioning against its use without robust clinical evidence.(Jangra 2022) Similarly, a review including studies to September 2020 has been published for Radix polygoni multiflori.(Li 2020)

Before taking Emodin

In mouse blastocysts, emodin has been shown to impair embryonic development via the intrinsic apoptotic signaling processes resulting in embryonic toxicity at doses of 25, 50, and 75 mcM.Lin 2015

In human male sperm cells, in vitro studies have demonstrated a dose-dependent inhibitory effect of emodin on sperm motility but not sperm viability. Additionally, via progesterone signaling pathways, emodin reduced the ability of sperm to penetrate viscous media reflective of the female reproductive tract. Mechanisms appear to be related to reduced capacitation and acrosome reaction that resulted from a decrease in both intracellular calcium levels in sperm heads and the phosphorylation of protein tyrosine processes necessary for motility.Luo 2015

How to use Emodin

Clinical studies are lacking to provide dosing recommendations.

Animal studies have demonstrated that emodin undergoes extensive glucuronidation after oral dosing that results in extremely low bioavailability (less than 3%). However, coadministration of emodin with piperine has been shown to clinically improve emodin pharmacokinetics, with a 221% increase in area under the curve (AUC), a 258% increase in maximum concentration (Cmax), and a 230% decrease in clearance due to inhibition of glucuronidation.(Di 2015) After oral administration in rats, bioavailability of emodin and other constituents of processed P. multiflorum products were lower compared to the raw product.(Lin 2015)

Warnings

In vitro, mutagenicity of emodin was demonstrated at concentrations of 80 and 120 mcg/mL via thymidine kinase gene mutation analysis.Lin 2015

Overdose of anthraquinone laxatives results in intestinal pain and severe diarrhea with consequent electrolyte imbalance and dehydration. Treatment should be symptomatic, with special attention given to potassium and other electrolyte levels, especially in elderly patients and children.Cortex 2002

The carcinogenicity of emodin has been studied with equivocal results.Srinivas 2007 Emodin paradoxically exhibits an antioxidant action as well as pro-oxidant activityCai 2008 and has shown protective and toxic effects in rat glioma cells.Kuo 2009 No consensus on the mutagenicity of emodin has been achieved; a 2-year study conducted by the National Cancer Institute found equivocal evidence of carcinogenicity in rats.NTP 2001

What other drugs will affect Emodin

Interference with the absorption of other drugs is possible with anthranoid-containing plants, including Senna and Cascara.Cortex 2002, Fugh-Berman 2000

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