Protective Cascara Sagrada and Emodin

Also see:
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Protective Bamboo Shoots
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Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
Bowel Toxins Accelerate Aging

Cascara
Dried aged bark of a buckthorn, Frangula purshiana (FRANGULA), that contains the anthraquinone EMODIN and cascarosides. It is used as a laxative (CATHARTICS).
Year introduced: 1991(1975)

Cascara, energy, cancer and the FDA’s laxative abuse by Ray Peat, PhD

Aged Cascara Sagrada Powder from Italy

Emodin has an opposing effect, increasing the metabolic rate. It increases mitochondrial oxygen consumption and ATP synthesis, while decreasing oxidative damage. (Du and Ko, 2005, 2006; Huang, et al., 1995). -Ray Peat, PhD

Life Sci. 2005 Oct 14;77(22):2770-82.
Effects of emodin treatment on mitochondrial ATP generation capacity and antioxidant components as well as susceptibility to ischemia-reperfusion injury in rat hearts: single versus multiple doses and gender difference.
Du Y, Ko KM.
Effects of emodin (EMD) treatment on mitochondrial ATP generation capacity and antioxidant components as well as susceptibility to ischemia-reperfusion (I-R) injury were examined in male and female rat hearts. Isolated-perfused hearts prepared from female rats were less susceptible to I-R injury than those of male rats. I-R caused significant decreases in ATP generation capacity and reduced glutathione (GSH) and alpha-tocopherol (alpha-TOC) levels as well as glutathione reductase, Se-glutathione peroxidase and Mn-superoxide dismutase (SOD) activities. The lower susceptibility of female hearts to myocardial I-R injury was associated with higher levels of GSH and alpha-TOC as well as activity of SOD than those of male hearts. EMD treatment at 3 daily doses (0.6 or 1.2 mmol/kg) could enhance myocardial mitochondrial ATP generation capacity and antioxidant components in both male and female rat hearts, but it only significantly protected against I-R injury in female hearts. Treatment with a single dose of EMD invariably enhanced mitochondrial antioxidant components and protected against I-R injury in both male and female hearts. The gender-dependent effect of EMD treatment at multiple doses may be related to the differential antioxidant response in the myocardium and/or induction of drug metabolizing enzymes in the liver.

Mol Cell Biochem. 2006 Aug;288(1-2):135-42. Epub 2006 Apr 1.
Effects of pharmacological preconditioning by emodin/oleanolic acid treatment and/or ischemic preconditioning on mitochondrial antioxidant components as well as the susceptibility to ischemia-reperfusion injury in rat hearts.
Du Y, Ko KM.
Using an ex vivo rat heart model of ischemia-reperfusion (I-R) injury, we examined the effect of pharmacological preconditioning by chronic treatment with emodin (EMD)/oleanolic acid (OA) at low dose (25 micromol/kg/day x 15) and/or ischemic preconditioning (IPC) (4 cycles of 5 min ischemia followed by 5 min of reperfusion) on myocardial I-R injury. The results indicated that EMD/OA pretreatment, IPC, or their combinations (EMD+IPC and OA+IPC) protected against myocardial I-R injury, as assessed by lactate dehydrogenase leakage and contractile force recovery. The cardioprotection was associated with a differential enhancement in mitochondrial antioxidant components. The combined EMD/OA and IPC pretreatment produced cardioprotective action in a semi-additive manner. This suggested that EMD/OA pretreatment and IPC protected against myocardial I-R injury via a similar but not identical biochemical mechanism.

J Nat Prod. 1995 Sep;58(9):1365-71.
Effect of anthraquinone derivatives on lipid peroxidation in rat heart mitochondria: structure-activity relationship.
Huang SS, Yeh SF, Hong CY.
Lipid peroxidation was induced in rat heart mitochondria with FeSO4 and the inhibitory effects of various anthraquinone derivatives were compared. Oxygen consumption and malondialdehyde formation were used to quantitate the amount of lipid peroxidation. Emodin [2], alizarin [13], and alizarin complexone [14] significantly inhibited lipid peroxidation; their potency as inhibitors of lipid peroxidation was higher than that of alpha-tocopherol. Structure-activity analysis showed that two hydroxyl groups arranged in either the ortho- or meta-position in the C ring of the anthraquinone nucleus are required for such derivatives to inhibit lipid peroxidation. The diphenyl-p-picrylhydrazyl test showed that alizarin [13] and alizarin complexone [14] are free-radical scavengers while emodin [2] is not. The mechanism for emodin [2] to inhibit lipid peroxidation is most likely due to inhibition on the propagation of lipid peroxyl radicals in the mitochondrial membrane.

Zhongguo Zhong Yao Za Zhi. 2010 Dec;35(24):3348-53.
[Emodin enhances antitumor effect of gemcitabine in model of SW1990 cell xenograft on athymic mouse].
[Article in Chinese]
Wei W, Guo Y, Chen H, Liu D, Guo H, Lin S.
OBJECTIVE:
To evaluate the enhanced effect of gemcitabine by emodin and the possible mechanisms of the enhancement.
METHOD:
Based on the model of SW1990 cell xenograft on athymic mouse, the mice were randomized to four groups with intraperitoneal (IP) injections of different drugs: group N (injecting 0.9% sodium chloride), group E (emodin, 40 mg x kg(-1)), group G (gemcitabine, 125 mg x kg(-1)), and group E + G (emodin 40 mg x kg(-1) and gemcitabine 80 mg x kg(-1) in combination). The tumor volume, tumor weight and body weight of mice were measured during the drug therapy. The mice were sacrificed one week after last injection of drug. Tunel assay were used used to detect the apoptosis of tumor cells. And immunohistochemistry (IHC) and Western blot (WB) were used to detect the variance of the apoptosis relative protein expression of Bax, Bcl-2, and Cytochrome C .
RESULT:
One week after the last administration, the mean tumor volume and tumor weight in group E + G were significantly decreased compared to the other groups. Tunel assay showed group E + G presented apparently more apoptosis than the other groups. Immunohistochemistry (IHC) and Western blot (WB) analysis showed the expression of Cytochrome C in cytoplasmin and Bax in group E + G was apparently upregulated while the expression of Bcl-2 was apparently downregulated compared to the other groups. As a result, Bcl-2/Bax ratio was significantly decreased in group E + G.
CONCLUSION:
Emodin can significantly improve the antitumor effect of gemcitabine on transplanted tumor of SW1990 cell line through apparently enhancing the tumor cell apoptosis by gemcitabine. Downregulation of Bcl-2/Bax ratio and promoting release of Cytochrome C from mitochondria is possibly one of the mechanisms of the augmented apoptosis.

Med Res Rev. 2007 Sep;27(5):591-608.
Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agent.
Srinivas G, Babykutty S, Sathiadevan PP, Srinivas P.
Anthraquinones represent a large family of compounds having diverse biological properties. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a naturally occurring anthraquinone present in the roots and barks of numerous plants, molds, and lichens, and an active ingredient of various Chinese herbs. Earlier studies have documented mutagenic/genotoxic effects of emodin, mainly in bacterial system. Emodin, first assigned to be a specific inhibitor of the protein tyrosine kinase p65lck, has now a number of cellular targets interacting with it. Its inhibitory effect on mammalian cell cycle modulation in specific oncogene overexpressed cells formed the basis of using this compound as an anticancer agent. Identification of apoptosis as a mechanism of elimination of cells treated with cytotoxic agents initiated new studies deciphering the mechanism of apoptosis induced by emodin. At present, its role in combination chemotherapy with standard drugs to reduce toxicity and to enhance efficacy is pursued vigorously. Its additional inhibitory effects on angiogenic and metastasis regulatory processes make emodin a sensible candidate as a specific blocker of tumor-associated events. Additionally, because of its quinone structure, emodin may interfere with electron transport process and in altering cellular redox status, which may account for its cytotoxic properties in different systems. However, there is no documentation available which reviews the biological activities of emodin, in particular, its growth inhibitory effects. This review is an attempt to analyze the biological properties of emodin, a molecule offering a broad therapeutic window, which in future may become a member of anticancer armamentarium.

Cancer Res. 1995 Sep 1;55(17):3890-6.
Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin.
Zhang L, Chang CJ, Bacus SS, Hung MC.
The amplification and overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185neu, have been observed frequently in tumors from human breast cancer patients and are correlated with poor prognosis. To explore the potential of chemotherapy directed at the tyrosine kinase of p185neu, we have found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), a tyrosine kinase inhibitor, suppresses autophosphorylation and transphosphorylation activities of HER-2/neu tyrosine kinase, resulting in tyrosine hypophosphorylation of p185neu in HER-2/neu-overexpressing breast cancer cells. Emodin, at a 40-microM concentration, which repressed tyrosine kinase of p185neu, efficiently inhibited both anchorage-dependent and anchorage-independent growth of HER-2/neu-overexpressing breast cancer cells. However, the inhibition was much less effective for those cells expressing basal levels of p185neu under the same conditions. Emodin also induced differentiation of HER-2/neu-overexpressing breast cancer cells by exhibiting a morphological maturation property of large lacy nuclei surrounded by sizable flat cytoplasm and by showing a measurable production of large lipid droplets, which is a marker of mature breast cells. Therefore, our results indicate that emodin inhibits HER-2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-2/neu-overexpressing cancer cells. These results may have chemotherapeutic implications for using emodin to target HER-2/neu-overexpressing cancer cells.

Oncogene. 1998 Jun 4;16(22):2855-63.
Tyrosine kinase inhibitors, emodin and its derivative repress HER-2/neu-induced cellular transformation and metastasis-associated properties.
Zhang L, Lau YK, Xi L, Hong RL, Kim DS, Chen CF, Hortobagyi GN, Chang C, Hung
We have previously shown that emodin suppresses tyrosine kinase activity of HER-2/neu-encoded p185neu receptor tyrosine kinase. In this study, we examine the relationship between the chemical structure and the activity of emodin and nine derivatives, and identified that one methyl, one hydroxy, and one carbonyl functional groups are critical for the biological activities of emodin. We also found that one of the derivatives 10-(4-acetamidobenzylidene)-9-anthrone (DK-V-47) is more effective than emodin in repressing the tyrosine phosphorylation of p185neu and in inhibiting the proliferation and transformation of HER-2/neu-overexpressing human breast cancer cells. Using mutation-activated HER-2/neu transformed 3T3 cells, we also investigated whether emodin and DK-V-47 can inhibit malignant transformation induced solely by the HER-2/neu oncogene. We found that DK-V-47 is more potent than emodin in suppressing transformation phenotypes of activated HER-2/neu transformed 3T3 cells including anchorage-dependent and -independent growth, metastasis-associated properties. These results clearly indicate that the inhibition of p185neu tyrosine kinase by both emodin and DK-V-47 is capable of suppressing the HER-2/neu associated transformed phenotypes including the ability to induce metastatic potential. Our results also support the chemotherapeutic implications of the use of either emodin or DK-V-47 to target HER-2/neu-overexpressing cancer cells.

Mutat Res. 1995 Jul;329(2):205-12.
Emodin inhibits the mutagenicity and DNA adducts induced by 1-nitropyrene.
Su HY, Cherng SH, Chen CC, Lee H.
Polygonum cuspidatum S. (PC) is frequently used as a laxative and an anticancer drug in Chinese medicine. The inhibitory effect of this herb and its component, emodin, on the direct-acting mutagenicity of 1-nitropyrene (1-NP) was examined using the Ames/microsomal test with Salmonella typhimurium TA98 and the genotoxicity of 1-NP was evaluated using the SOS chromotest with E. coli PQ37. Emodin and water extracts of PC markedly decreased the mutagenicity of 1-NP in a dose-dependent manner in both assay systems. Furthermore, emodin and the extracts of PC significantly inhibited the formation of 1-NP DNA adducts in S. typhimurium TA98 in the 32P-postlabeling study. The results suggest that PC extracts and emodin act as blocking and/or suppressing agents to reduce the direct-acting mutagenicity of 1-NP.

Biochem Cell Biol. 2010 Aug;88(4):767-74.
Apoptosis induced by emodin is associated with alterations of intracellular acidification and reactive oxygen species in EC-109 cells.
Wang QJ, Cai XB, Liu MH, Hu H, Tan XJ, Jing XB.
Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a natural anthraquinone derivative found in several herbal medicines, is highly active in suppressing the proliferation of various tumor cells such as breast, hepatocellular, and lung cancer cells under in vitro conditions. The mechanism of emodin-induced apoptosis in esophagus carcinoma cells, EC-109, is not completely understood. In this study, EC-109 cells treated with emodin underwent rapid apoptosis as judged by morphological changes and flow cytometry analysis. The addition of emodin to EC-109 cells led to the inhibition of growth in a time- and dose-dependent manner. Fluorescence measurements of cells indicated that the intracellular pH (pHi) decreased significantly by 0.47-0.78 units. The results obtained from flow cytometry suggested that bursts of reactive oxygen species took place after the application of emodin. The present study indicates that emodin may be a strong anticancer drug against esophagus cancer cells by causing various early events leading to growth inhibition, including the production of reactive oxygen species and decrease of pHi, which may result in cellular apoptosis.

Life Sci. 2007 Oct 13;81(17-18):1332-8. Epub 2007 Sep 19.
Emodin-mediated protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic myocardium.
Wu Y, Tu X, Lin G, Xia H, Huang H, Wan J, Cheng Z, Liu M, Chen G, Zhang H, Fu J, Liu Q, Liu DX.
Acute myocardial infarction (AMI) is associated with inflammation and apoptosis. Emodin plays an anti-inflammatory role in several inflammatory diseases. Recent studies have demonstrated that emodin protects against myocardial ischemia/reperfusion injury. However, its mechanism underlying its effects remains unknown. In a murine model of AMI, based on ligation of the left coronary artery, administration of emodin reduced myocardial infarct size (MIS) in a dose-dependent manner. Emodin significantly suppressed TNF-alpha expression and NF-kappaB activation in the local myocardial infarction area. Treatment with emodin inhibited myocardial cell apoptosis by inhibiting caspase-3 activation. Therefore, these studies demonstrate that emodin protects against myocardial cell injury via suppression of local inflammation and apoptosis.

Zhonghua Gan Zang Bing Za Zhi. 2001 Aug;9(4):235-6.
[Effects of emodin on hepatic fibrosis in rats].
[Article in Chinese]
Zhan Y, Wei H, Wang Z, Huang X, Xu Q, Li D, Lu H.
OBJECTIVE:
To investigate the effect of emodin on hepatic fibrosis in rats and study its possible mechanism.
METHODS:
The rat hepatic fibrotic model was induced by the subcutaneous injection of 40% CCl(4) (twice a week for 6 weeks). The fibrotic rats were treated with low-dose, mediate-dose and high-dose emodin (20, 40 and 80 mg/kg body weight, once a day for 42 days). Liver function, serum hyaluronic acid, laminin, and liver hydroxyproline were determined, Histopathological changes were examined by optical microscopy. The expression of alpha-smooth muscle actin (alpha-SMA) in liver tissue were detected by immunohistochemical techniques.
RESULTS:
Compared with model group, it revealed that in emodin-treated rats: (1) Liver functions was improved, alanine transaminase (ALT) and alkaline phosphatase (AKP) obviously reduced (P<0.05 or <0.01), total protein (TP) and albumin (ALB) significantly increased (P<0.05 or <0.01). (2) Serum hyaluronic acid and laminin markedly reduced (P<0.05 or <0.01). (3) Liver hydroxyproline were significantly decreased (P<0.05 or <0.01). (4) The degrees of fibrosis were reduced (P<0.05). (5) The expression of alpha-SMA in liver tissue were ameliorated.
CONCLUSIONS:
Emodin has an effect on hepatic fibrosis in rats. The effect may be related to slowing hepatocyte injury and inhibiting liver alpha-SMA expressions.

Br J Pharmacol. 2010 Sep;161(1):113-26.
Emodin, a natural product, selectively inhibits 11beta-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice.
Feng Y, Huang SL, Dou W, Zhang S, Chen JH, Shen Y, Shen JH, Leng Y.
BACKGROUND AND PURPOSE:
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11beta-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice.
EXPERIMENTAL APPROACH:
Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11beta-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice.
KEY RESULTS:
Emodin is a potent and selective 11beta-HSD1 inhibitor with the IC(50) of 186 and 86 nM for human and mouse 11beta-HSD1, respectively. Single oral administration of emodin inhibited 11beta-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11beta-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA.
CONCLUSIONS AND IMPLICATIONS:
This study demonstrated a new role for emodin as a potent and selective inhibitor of 11beta-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes.

Chin Med Sci J. 2009 Dec;24(4):236-40.
Protective effect of emodin against lipopolysaccharides-induced corneal injury in rats.
Chen GL, Liu ZY, Wang J, Gao X, Wei LW, Liu YL.
OBJECTIVE:
To investigate the effect of emodin on lipopolysaccharides (LPS)-induced corneal injury in rats.
METHODS:
Three parallel incisions on the central surface of corneal epithelium were made and LPS was applied on them to induce corneal injury in Wistar rats. All rats were randomly divided into emodin group (n=40) and keratitis group (n=40). Rats in the emodin group received subconjunctival injection of emodin and rats in the keratitis group received its vehicle 30 minutes before LPS exposure. At different time points–1, 3, 6, 12, and 24 hours after LPS exposure, the symptoms of all rats were observed and the severity of their ocular inflammation was examined with a slit lamp microscope, then 8 rats in each group were killed through cervical dislocation and their eyes were enucleated and prepared to observe pathological changes of corneal tissue under a light microscope. The activation of nuclear factor-kappaB (NF-kappaB) under different conditions was determined by Western blot. Immunocytochemistry staining with an antibody against intercellular adhesion molecule-1 (ICAM-1) was performed to identify positive cells in corneal tissues.
RESULTS:
The model of acute keratitis was successfully established in Wistar rats. LPS could induce a typical corneal inflammatory response, such as hyperemia, corneal edema and opacity, which were observed in model rats. Compared with keratitis group, both ocular behaviors and damages of the corneal structure were improved in emodin group. Furthermore, the activation of NF-kappaB and the expression of ICAM-1 induced by LPS were markedly inhibited in emodin group.
CONCLUSION:
Emodin can inhibit the activation of NF-kappaB and the expression of ICAM-1 induced by LPS in corneas, protect against acute corneal injury, and improve symptoms in rats.

Bioorg Med Chem Lett. 2011 Nov 9. [Epub ahead of print]
Emodin inhibits migration and invasion of DLD-1 (PRL-3) cells via inhibition of PRL-3 phosphatase activity.
Han YM, Lee SK, Jeong DG, Ryu SE, Han DC, Kim DK, Kwon BM.
Anthraquinones have been reported as phosphatase inhibitors. Therefore, anthraquinone derivatives were screened to identify a potent phosphatase inhibitor against the phosphatase of regenerating liver-3 (PRL-3). Emodin strongly inhibited phosphatase activity of PRL-3 with IC(50) values of 3.5μM and blocked PRL-3-induced tumor cell migration and invasion in a dose-dependent manner. Emodin rescued the phosphorylation of ezrin, which is a known PRL-3 substrate. The results of this study reveal that emodin is a PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor.

Fundam Clin Pharmacol. 2011 Nov 2. doi: 10.1111/j.1472-8206.2011.01003.x. [Epub ahead of print]
Abrogation of cisplatin-induced nephrotoxicity by emodin in rats.
Ali BH, Al-Salam S, Al Husseini IS, Al-Lawati I, Waly M, Yasin J, Fahim M, Nemmar A.
Nephrotoxicity of the anticancer drug cisplatin (CP) involves the generation of reactive oxygen species in renal cortex, and emodin (a rhubarb anthraquinone) has strong antioxidant and anticancer actions. Therefore, we tested here the possible ameliorative effect of emodin on CP nephrotoxicity in rats. Emodin was given orally (10mg/kg/day for nine consecutive days), and on day 4, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Five days after CP treatment, rats were killed, and blood and urine samples, and kidneys were collected for the assessment of histopathological renal damage and apoptosis, and for biochemical estimation of creatinine and urea concentrations in plasma and urine, several cytosolic antioxidant enzyme activities in kidneys, and urinalyses. CP significantly increased the concentrations of urea and creatinine, and decreased creatinine clearance. It also significantly reduced cortical glutathione concentration and the activity of superoxide dismutase. CP treatment significantly increased urine volume and N-acetyl-β-D-glucosaminidase activity and significantly decreased osmolarity and protein concentrations. Emodin treatment markedly and significantly mitigated all these effects. Sections from saline- and emodin-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with emodin. The concentration of CP in the cortical tissues was not significantly altered by emodin treatment. The results suggested that emodin had ameliorated CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies emodin may be considered a potentially useful nephroprotective agent.

Cell Biochem Biophys. 2011 Oct 30. [Epub ahead of print]
Apoptosis of Dalton’s lymphoma due to in vivo treatment with emodin is associated with modulations of hydrogen peroxide metabolizing antioxidant enzymes.
Singh KB, Trigun SK.
The evolving concept of pro-oxidative mechanism-based antitumor activity of emodin (1,3,8-trihydroxy-6-methyl anthraquinone), derived mainly from in vitro studies, needs to be defined for in vivo tumor models. The present article describes apoptosis and regression of Dalton’s lymphoma (DL) in mice by emodin vis a vis modulations of hydrogen peroxide (H(2)O(2)) metabolizing antioxidant enzymes in the tumor cells in vivo. A non-toxic dose (40 mg/kg bw) of emodin, given intraperitoneally to the DL bearing mice daily up to 12th post DL transplantation day, caused a significant decline (P < 0.05) in the number of viable DL cells and could significantly increase life span of the DL mice (P < 0.01). A significant decline in Bcl2/Bax ratio consistent with the release of mitochondrial cytochrome c release in DL cells from emodin-treated DL mice suggested that emodin could induce mitochondrial pathway of apoptosis in the DL cells in vivo. Apoptosis of DL cells by emodin was further confirmed by the appearance of smaller DNA fragments on DNA ladder analysis. Over activation of both, the Cu-Zn-superoxide dismutases (SOD1) and Mn-SOD (SOD2), has been found correlated with the tumor suppression. Emodin caused significant increases in the expression and activity of SOD1 and SOD2 in the DL cells. H(2)O(2) produced by SODs is degraded by catalase and glutathione peroxidase in the cells. Both these enzymes were observed to be declined significantly with a concomitant increment in H(2)O(2) concentration (P < 0.01) in the DL cells from emodin-treated DL mice. It is concluded that emodin is able to induce mitochondrial pathway of apoptosis in the DL cells in vivo via reciprocal modulations of H(2)O(2) producing and degrading antioxidant enzymes.

Oncol Rep. 2011 Jul;26(1):81-9. doi: 10.3892/or.2011.1257. Epub 2011 Apr 12.
Antiproliferative and antimetastatic effects of emodin on human pancreatic cancer.
Liu A, Chen H, Wei W, Ye S, Liao W, Gong J, Jiang Z, Wang L, Lin S.
Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) is an active constituent isolated from the root of Rheum palmatum L and is the main effective component of some Chinese herbs and plants. Pharmacological studies have demonstrated that emodin exhibits anti-cancer effects on several human cancers. However, the molecular mechanisms of emodin-mediated tumor regression have not been fully defined. This study was performed to investigate the antiproliferative and antimetastatic effects of emodin on pancreatic cancer in vitro and in vivo. Our results showed that emodin induced a higher percentage of growth inhibition and apoptosis in the pancreatic cancer cell line SW1990 compared to that of control, and emodin suppressed the migration and invasion of SW1990 cells in a dose-dependent manner. To investigate the possible mechanisms involved in these events, we performed electrophoretic mobility shift assay (EMSA) and Western blot analysis, and found that emodin significantly down-regulated NF-κB DNA-binding activity, survivin and MMP-9 in SW1990 cells. Moreover, the expression of cleaved caspase-3 was up-regulated in SW1990 cells after treatment with emodin. In addition, a metastatic model simulating human pancreatic cancer was established by orthotopic implantation of histologically intact human tumor tissue into the pancreatic wall of nude mice. Oral administration of emodin significantly decreased tumor weight and metastasis compared to control. Furthermore, the expression of NF-κB, survivin and MMP-9 were also suppressed in tumor tissues after treatment with emodin. Collectively, our results indicated that emodin exerts antiproliferative and antimetastatic activity on pancreatic cancer both in vitro and in vivo, which may be related to 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.

Int J Oncol. 2005 Sep;27(3):839-46.
Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells.
Kim MS, Park MJ, Kim SJ, Lee CH, Yoo H, Shin SH, Song ES, Lee SH.
Emodin, an inhibitor of protein tyrosine kinase, possesses antiviral, immunosuppressive, anti-inflammatory and anticancer effects. In the present study, we investigated the effect of emodin on the hyaluronic acid (HA)-induced invasion of human glioma cells. Emodin significantly inhibited the HA-induced invasion through a Matrigel coated chamber, secretion of matrix metalloproteinase (MMP)-2, and HA-induced secretion of MMP-9 in glioma cells. To investigate the possible mechanisms involved in these events, we performed Western blot analysis using phospho-specific antibodies, and found that emodin inhibited phosphorylation of focal adhesion kinase (FAK), extracellular regulated protein kinase (ERK) 1/2 and Akt/PKB; emodin also suppressed the transcriptional activity of two transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), in glioma cells. In addition, oral administration of emodin suppressed in vivo MMP secretion by glioma tumors in nude mice. Taken together, our results indicate that emodin can effectively inhibit HA-induced MMP secretion and invasion of glioma through inhibition of FAK, ERK1/2 and Akt/PKB activation and partial inhibition of AP-1 and NF-kappaB transcriptional activities. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human glioma.

Yao Xue Xue Bao. 2004 Apr;39(4):254-8.
Inhibitory effects of emodin on angiogenesis.
Wang XH, Wu SY, Zhen YS.
AIM:
To determine the anti-angiogenic activity of emodin.
METHODS:
Chick embryo assay and cultured endothelial cells were used.
RESULTS:
Emodin at doses of 150 and 300 microg/egg caused 37.6% and 63.2% inhibition of angiogenesis, respectively. Emodin was shown to inhibit the proliferation of primary cultured bovine aortic endothelial cells in the absence or presence of basic-fibroblast growth factor (bFGF) or the presence of vascular endothelial growth factor (VEGF) in a dose-dependent manner. The IC50 values by MTT assay were 5.56, 8.40 or 6.91 mg x L(-1), respectively. Emodin at concentrations from 5.4 to 21.6 mg x L(-1) induced apoptosis of endothelial cells for 37.6% to 72.6%. Emodin caused endothelial cell cycle arrest at G2/M phase. After emodin treatment, there was a down-regulation of Cyclin B1, P34cdc2, and Bcl-2 protein expression while the Bax protein expression was unaffected.
CONCLUSION:
Emodin shows anti-angiogenic activity and might be useful for the development of novel anti-cancer therapy.

Biochem Pharmacol. 2004 Jul 15;68(2):361-71.
Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB.
Huang Q, Shen HM, Ong CN.
3-Methyl-1,6,8-trihydroxyanthraquinone (emodin) is an active component from the rhizome of Rheum palmatum, a widely used traditional Chinese herb. In this study, we found that emodin significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced in vitro invasion of human cancer cells including HSC5 and MDA-MB-231 cells. Matrix metalloproteinases (MMPs) are known to be associated with cancer invasion. Zymographic analysis showed that emodin suppressed TPA-induced MMP-9 activity in a concentration-dependent manner. We further demonstrated that emodin reduced the transcriptional activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), two important nuclear transcription factors involved in MMP-9 expression. Emodin suppressed the phosphorylation of two mitogen-activated protein kinases, extracellular signal-regulated protein kinase and c-Jun N-terminal kinase, but not p38 kinase, leading to reduced c-Jun phosphorylation and AP-1 DNA-binding. Moreover, emodin inhibited TPA-induced degradation of inhibitor of kappaBalpha, nuclear translocation of p65, and NF-kappaB DNA-binding activity. Taken together, these results suggest that emodin inhibits the invasiveness of human cancer cells by suppressing MMP-9 expression through inhibiting AP-1 and NF-kappaB signaling pathways.

Life Sci. 2006 Nov 25;79(26):2480-5. Epub 2006 Aug 17.
Emodin inhibits TNF alpha-induced MMP-1 expression through suppression of activator protein-1 (AP-1).
Lee J, Jung E, Lee J, Huh S, Hwang CH, Lee HY, Kim EJ, Cheon JM, Hyun CG, Kim YS, Park D.
Matrix metalloproteinases (MMPs) are the proteases involved in the degradation of the extracellular matrix. MMP-1 is thought to be one of the key enzymes acting in fibrolysis, a process closely related to tissue remodeling. In this study, we found that emodin, an anthraquinone which has been isolated from the rhizome of Rheum palmatum, significantly inhibited TNF alpha-induced MMP-1 gene expression in a concentration-dependent manner. Therefore, we have attempted to characterize the inhibitory mechanism of emodin in TNF alpha-induced MMP-1 expression. Emodin was determined to inhibit TNF alpha-induced activation of AP-1 promoter, an important nuclear transcription factor in MMP-1 expression. Additionally, we detected that emodin suppressed the TNF alpha-induced phosphorylation of two mitogen-activated protein kinases, extracellular signal-regulated protein kinase and c-Jun N-terminal kinase, but it did not suppress the TNF alpha-induced phosphorylation of p38 kinase. In a consistent result, the TNF alpha-induced MMP-1 expression was inhibited by PD98059 (MEK/ERK inhibitor) and SP600125 (JNK inhibitor), but was not inhibited by SB203580, a p38 MAPK inhibitor. Taken together, these results show that emodin suppresses TNF alpha-induced MMP-1 expression through the inhibition of the AP-1 signaling pathway.

Mol Med Report. 2011 Mar-Apr;4(2):221-7. doi: 10.3892/mmr.2011.414. Epub 2011 Jan 3.
Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB.
Liu A, Chen H, Tong H, Ye S, Qiu M, Wang Z, Tan W, Liu J, Lin S.
Many studies have demonstrated that emodin inhibits the growth and induces the apoptosis and chemo-sensitization of various cancer cells in animal models. The aim of this study was to investigate the molecular mechanism of the chemo-sensitization potential of emodin on gemcitabine in pancreatic cancer cell lines via inhibition of nuclear factor-κB (NF-κB). SW1990 and SW1990/GZ cells were treated with: i) emodin (20 µmol/l), ii) NF-κB inhibitor Bay 11-7082 (5 µmol/l), iii) gemcitabine (20 µmol/l), iv) pre-treated with emodin for 24 h followed by coincubation with gemcitabine for 24 h, or v) pre-treated with Bay 11-7082 for 1 h followed by treatment with gemcitabine for 24 h. SW1990 and SW1990/GZ cells were also treated with emodin (20, 40 and 80 µmol/l). Cellular proliferation and apoptosis were detected by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry. NF-κB protein was detected by Western blotting. SW1990/GZ cell morphological changes were observed under optical and fluorescence microscopes. Emodin strongly inhibited the proliferation and induced the apoptosis of both pancreatic cancer cell lines. Furthermore, emodin combined with gemcitabine induced a higher percentage of growth inhibition and apoptosis in both pancreatic cancer cell lines compared to gemcitabine alone. Pre-treatment of SW1990/GZ cells with Bay 11-7082 for 1 h followed by gemcitabine resulted in greater inhibitory and apoptosis rates compared to gemcitabine alone. The resistant pancreatic cell line SW1990/GZ presented higher constitutive NF-κB protein expression compared to the SW1990 cells. Emodin not only down-regulated NF-κB in a dose-dependent manner in SW1990 and SW1990/GZ cells under unstimulated conditions, but also inhibited gemcitabine-induced NF-κB protein expression. Emodin potentiated the antitumor effects of gemcitabine in pancreatic cancer, which was related to the down-regulation of NF-κB.

Yao Xue Xue Bao. 2011 Feb;46(2):146-52.
[Role of nuclear factor-kappaB on emodin-induced sensitization of pancreatic cancer to gemcitabine].
[Article in Chinese]
Liu A, Hu YS, Wang ZH, Tang LL, Ke PY, Lin SZ.
In view of gemcitabine resistance has limited clinical activity of gemcitabine as a cellulotoxic drug in pancreatic cancer patients, this study is designed to investigate the effect of emodin on the sensitivity of pancreatic cancer to gemcitabine as well as its mechanism. After gemcitabine-resistant pancreatic cancer cell line (SW1990/GZ) was established by escalating doses of gemcitabine serially in pancreatic cancer cell line (SW1990). The cellular proliferation was detected by cell counting kit-8 (CCK-8) assay. Flow cytometry (FCM) was used to determine apoptosis of pancreatic cancer cells. The activity of NF-kappaB in pancreatic cancer cells was measured by electrophoretic mobility shift assay (EMSA). Western blotting was used to detect the protein expression of Bcl-2 and Survivin in SW1990/GZ cells. Metastatic model simulating human pancreatic cancer was established by orthotopic implantation of histologically intact human tumor tissue into pancreatic wall of nude mice. Also, immunohistochemistry was used to detect the positive expression of Ki-67, NF-kappaB, Bcl-2 and Survivin in the tumors. The results show that pretreatment of cells with emodin followed by gemcitabine induced a higher percentage of growth inhibition and apoptosis of pancreatic cancer cells than that of gemcitabine alone. In addition to in vitro results, emodin in combination with gemcitabine is much more effective as an antitumor agent compared to either agent alone in the orthotopic tumor model. Further study showed that the emodin with or without gemcitabine significantly down-regulates NF-kappaB and its regulated molecules such as Bcl-2 and Survivin proteins both in vitro and in vivo. It is concluded that inactivation of NF-kappaB signaling pathway by emodin resulting in the chemosensitization of pancreatic cancer to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

Asian J Androl. 2008 Jul;10(4):625-34.
Emodin induces apoptosis in human prostate cancer cell LNCaP.
Yu CX, Zhang XQ, Kang LD, Zhang PJ, Chen WW, Liu WW, Liu QW, Zhang JY.
AIM:
To elucidate effects and mechanisms of emodin in prostate cancer cells.
METHODS:
Viability of emodin-treated LNCaP cells and PC-3 cells was measured by MTT assay. Following emodin treatments, DNA fragmentation was assayed by agarose gel electrophoresis. Apoptosis rate and the expression of Fas and FasL were assayed by flow cytometric analysis. The mRNA expression levels of androgen receptor (AR), prostate-specific antigen (PSA), p53, p21, Bcl-2, Bax, caspase-3, -8, -9 and Fas were detected by RT-PCR, and the protein expression levels of AR, p53 and p21 were detected by Western blot analysis.
RESULTS:
In contrast to PC-3, emodin caused a marked increase in apoptosis and a decrease in cell proliferation in LNCaP cells. The expression of AR and PSA was decreased and the expression of p53 and p21 was increased as the emodin concentrations were increased. In the same time, emodin induced apoptosis of LNCaP cells through the upregulation of caspase-3 and -9, as well as the increase of Bax /Bcl-2 ratio. However, it did not involve modulation of Fas or caspase-8 protein expression.
CONCLUSION:
In prostate cancer cell line, LNCaP, emodin inhibites the proliferation by AR and p53-p21 pathways, and induces apoptosis via the mitochondrial pathway.

Anat Rec (Hoboken). 2011 Mar;294(3):445-52. doi: 10.1002/ar.21352. Epub 2011 Feb 9.
Emodin prolongs recipient survival time after orthotopic liver transplantation in rats by polarizing the Th1/Th2 paradigm to Th2.
Tong H, Chen K, Chen H, Wu H, Lin H, Ni Z, Lin S.
Advances in immunosuppressive drugs have improved the short-term survival of liver transplantation. However, drug toxicities have been a serious problem in patients after long-term administration. Therefore, it is necessary to develop a novel immunosuppressant with low-toxicity. We investigated the immunosuppressive effects of Emodin on acute graft rejection following liver transplantation in rats. The recipient rats of orthotopic liver transplantation were divided into groups as follows: isograft+NS group, allograft+NS group, and allograft+emodin group. The survival time of the recipients in each group was recorded. Histopathological changes in the liver, as well as serum concentrations of IL-2, TNF-α, and IL-10 and their expressions in liver tissue were determined. Our results showed that Emodin treatment prolonged liver allograft survival time and inhibited histopathologic changes of acute graft rejection. The rejection activity index in groups isograft+NS, allograft+NS, and allograft+emodin were 1.52 ± 0.37, 6.95 ± 0.75, and 4.23 ± 0.51, respectively (P < 0.01, isograft+NS group vs. allograft+emodin group and allograft+NS group vs. allograft+emodin group). The serum levels of IL-2 and TNF-α were down-regulated but that of IL-10 was up-regulated by Emodin. Serum levels of IL-2 and TNF-α were higher in allograft+NS group than the allograft+emodin group, but that of IL-10 showed opposite effects (P < 0.05 or 0.01). Changes in the expression of these cytokines in transplanted liver tissue were consistent with changes in serum concentrations. These results demonstrate that Emodin has therapeutic potentials for alleviating acute rejection following liver transplantation in rats and prolonging liver allograft survival. The mechanisms underlying this effect may be associated with polarizing the Th1/Th2 paradigm to Th2.

World J Gastroenterol. 2005 May 21;11(19):2941-4.
Effects of emodin and double blood supplies on liver regeneration of reduced size graft liver in rat model.
Meng KW, Lv Y, Yu L, Wu SL, Pan CE.
AIM:
To study the influences of emodin and reconstruction of double blood supplies on liver regeneration of reduced size graft liver in rat model.
METHODS:
A total of 45 SD-SD rat reduced size liver transplantation models were randomly divided into three groups (A-C). The conventional reduced size liver transplantation was performed on rats in group A, while the hepatic artery blood supply was restored in groups B and C. The emodin (1.5 mg/kg/d) was given by intraperitoneal route in group C only. The recipients were killed on the seventh day after the operation. The proliferative cell nuclear antigen (PCNA), TBil and ALT of serum were detected, and the pathological changes of liver cell were observed.
RESULTS:
The numbers of the rats that survived in A, B, and C group on the seventh day after operation were 14, 13, 13, respectively. The levels of TBil (31.5+/-5.2 micromol/L, 23.2+/-3.1 micromol/L vs 38.6+/-6.8 micromol/L), and ALT (5 351+/-1 050 nKat, 1300+/-900 nKat vs 5779+/-1202 nKat) in serum in groups B and C were lower than those in group A (P<0.05), while the expression of PCNA in groups B or C was higher than that in group A (22.0+/-3.5%, 28.2+/-4.2% vs 18.6+/-3.2%, P<0.05). The deeper staining nuclei, double nuclei, multi-nuclei and much glycogen were observed in liver cells of groups B and C, especially in group C, while fewer were found in liver cells of group A. CONCLUSION: The reconstruction of arterial blood supply is very important for rat liver regeneration after reduced size liver transplantation. Emodin has the effect of promoting liver regeneration and improving liver function in rats after reduced size transplantation. The possible mechanism is improving proliferation of liver cell and protecting liver cells from injury.

Clin Exp Pharmacol Physiol. 2010 Aug;37(8):790-4. Epub 2010 Mar 12.
Emodin attenuates acute rejection of liver allografts by inhibiting hepatocellular apoptosis and modulating the Th1/Th2 balance in rats.
Lin SZ, Chen KJ, Tong HF, Jing H, Li H, Zheng SS.
1. In the present study, we investigated the immunosuppressive effects and mechanisms of action of emodin on acute graft rejection following liver transplantation in a rat model of orthotopic liver transplantation. 2. Rats were divided into three groups: Group A, syngenic control (Brown Norway-to-Brown Norway); Group B, acute rejection group (Lewis-to-Brown Norway); and Group C, emodin-treated group (Lewis-to-Brown Norway treated with 50 mg/kg emodin, 50 mg/kgxd, injected intraperitoneally once a day from days 1 to 5 posttransplantation). The survival time of the recipients in each group was recorded. Histopathological changes in the liver, hepatocellular apoptosis, serum concentrations of interleukin (IL)-2, interferon (IFN)-gamma and IL-4 and their expression in liver tissue were determined. 3. Emodin treatment prolonged liver allograft survival time from 10.9 days in Group B to 25.6 days in Group C. The rejection activity index (calculated according to the Banff Schema) in Groups A, B and C was 1.29 +/- 0.47, 7.58 +/- 0.85 and 4.72 +/- 0.79, respectively (P < 0.01 for Groups A and B vs Group C), whereas the apoptosis index in the three groups was 15.51 +/- 1.47, 39.50 +/- 1.65 and 16.72 +/- 1.73, respectively (P < 0.01 for Groups A and C vs Group B). Serum levels of IL-2 and IFN-gamma were higher, whereas levels of IL-4 were lower, in the acute rejection group (Group B) than in the emodin-treated group (Group C; P < 0.05). Changes in the expression of these cytokines in transplanted liver tissue were consistent with changes in serum concentrations. 4. In conclusion, emodin effectively suppresses acute graft rejection in vivo to prolong the survival of recipient rats. The mechanism underlying this effect may be associated with the prevention of hepatocyte apoptosis and with a changing in the balance of Th1/Th2 cytokines towards Th2.

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008 Jan;28(1):91-3.
[Experimental advance of applying emodin for prevention and treatment of liver diseases].
[Article in Chinese]
Xu XC, Lin SZ.
The experimental researches of applying emodin for prevention and treatment of liver diseases in recent years were reviewed. Emodin can inhibit the growth of liver tumor cells in vitro and in vivo, inducing cell apoptosis is one of its mechanisms. Emodin also has the effects of liver protection, anti-liver fibrosis, and so on, the mechanisms for those effects still need more studies.

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005 Nov;25(11):1030-2.
[Emodin and organ fibrosis].
[Article in Chinese]
Gao ZQ, Wang CH.
The aim of this article was to investigate the mechanisms of emodin in antagonizing against organ fibrosis, and to illustrate that emodin can be an effective Chinese herbal preparation for treatment of organ fibrosis.

Clin Exp Pharmacol Physiol. 2009 Feb;36(2):146-53. Epub 2008 Sep 10.
Inhibitory effect of emodin on bleomycin-induced pulmonary fibrosis in mice.
Chen XH, Sun RS, Hu JM, Mo ZY, Yang ZF, Jin GY, Guan WD, Zhong NS.
1. Currently, there is no satisfactory treatment for pulmonary fibrosis. Emodin, a component in Chinese herbs, has been shown to have an antifibrotic effect on pancreatic fibrosis and liver fibrosis. In the present study, we tested the hypothesis that emodin may attenuate the development of pulmonary fibrosis. 2. Mice were randomly divided into five groups (n = 16 in each). One group was a control group; the remaining four groups were treated with intratracheal instillation of 3 mg/kg bleomycin (BLM). The following day, emodin (5, 10 or 20 mg/kg per day, p.o.) treatment was started for three of the BLM-treated groups and was continued for 21 days. The fourth BLM-treated group (and the control group) received daily 0.5% sodium carboxymethyl cellulose (placebo) by gavage over the same period. 3. Bleomycin challenge provoked severe pulmonary fibrosis, with marked increases in fibrosis fraction, hydroxyproline content and myeloperoxidase activity in lung tissue. Emodin treatment (10 and 20 mg/kg per day, p.o.) attenuated all these biochemical indices, as well as histopathological alterations induced by BLM. Furthermore, in mice injected with BLM, elevated levels of transforming growth factor-beta1, interleukin (IL)-4 and IL-13 were found in bronchoalveolar lavage fluid. These increases were significantly inhibited by 10 and 20 mg/kg per day emodin. 4. In cell culture, exposure of cells to 6.25, 12.5, 25 or 50 micromol/L emodin for 24 h decreased fibroblast proliferation. Treatment of cells with the same concentrations of emodin for 72 h decreased collagen production by fibroblasts. In addition, emodin (6.25, 12.5, 25 or 50 micromol/L) inhibited the steady state expression of alpha1 (I) procollagen and alpha2 (I) procollagen mRNA in a dose-dependent manner. 5. The results of the present study suggest that emodin may be effective in the treatment of pulmonary fibrosis.

Chin J Integr Med. 2010 Apr;16(2):151-6. Epub 2010 May 16.
Effect of emodin in suppressing acute rejection following liver allograft transplantation in rats.
Lin SZ, Tong HF, Chen KJ, Jing H, Yang X, Zheng SS.
OBJECTIVE:
To investigate the mechanism of action of emodin for suppressing acute allograft rejection in a rat model of liver transplantation.
METHODS:
Brown Norway (BW) recipient rats of orthotopic liver transplantation (OLT) were divided into three groups, Group A receiving isografting (with BW rats as donor), Group B receiving allografting (with Lewis rats as donor), Group C receiving allografting and emodin treatment (50 mg/kg daily). They were sacrificed on day 7 of post-transplantation, and their hepatic histology, plasma cytokine levels, and T-cell subset expression were detected.
RESULTS:
Compared with those in Group A, rats: in Group B exhibited severe allograft rejection with a rejection activity index (RAI) of 7.67+/-0.98, extensive hepatocellular apoptosis with an apoptosis index (AI) of 35.83+/-2.32, and elevated plasma levels of interleukin-2 (IL-2), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), CD4(+) and CD4 CD4(+)/CD8(+) ratio. However, recipients in Group C showed a decrease in histological grade of rejection and hepatocellular apoptosis, as well as a decrease in plasma levels of IL-2, TNF-alpha, CD4(+) and CD4(+)/CD8(+) ratio, but elevated levels of IL-10 as compared with the allograft group.
CONCLUSION:
Post-OLT acute rejection could be attenuated by emodin, its mechanism of action may be associated with protecting hepatocytes from apoptosis, polarizing the Th 1 paradigm to Th2, and inhibiting the proliferation of CD4(+) T cell in plasma.

World J Gastroenterol. 2007 Jan 21;13(3):378-82.
Effect of emodin on pancreatic fibrosis in rats.
Wang CH, Gao ZQ, Ye B, Cai JT, Xie CG, Qian KD, Du Q.
AIM:
To establish the rats model of chronic fibrosing pancreatitis and to prove the anti-fibrotic effect of emodin in chronic pancreatitis with fibrosis.
METHODS:
Fifty rats were randomly divided into five groups, 10 rats in each group. Trinitrobenzene sulfonic acid (TNBS) was infused into the pancreatic duct to induce chronic pancreatitis in rats (except for normal group). Emodin-treated rats were fed with different doses of emodin (20, 40 and 80 mg/kg body weight) for 28 d, while normal group and control group received 0.9% sodium chloride solution. Serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. Histopathological alterations were studied by optical microscopy. Expression of collagen was also examined while transforming growth factor-beta-1 (TGF-beta(1)) was localized by immunochemistry.
RESULTS:
In emodin-treated rats, the serum levels of HA and LN were decreased significantly (HA, 62.2 +/- 19.3 microg/L vs 112.7 +/- 26.5 microg/L, P < 0.05; LN 44.3 +/- 10.4 microg/L vs 86.2 +/- 16.5 microg/L, P < 0.05); the degree of fibrosis was ameliorated observably; the expression of collagen in pancreatic tissue was reduced especially in high-dose emodin-treated group (36% +/- 5% vs 42% +/- 6%, P < 0.05); with the increased doses of emodin, the expression of TGF-beta(1) was declined, compared with those in control group.
CONCLUSION:
Emodin has an anti-fibrotic effect

Zhonghua Yi Xue Za Zhi. 2006 Sep 26;86(36):2552-5.
[Effect of emodin on pancreatic fibrosis: experiment with rats].
[Article in Chinese]
Wang CH, Gao ZQ, Ye B, Xie CG, Qian KD, Cai JT, Du Q.
OBJECTIVE:
To study the effect of emodin on pancreatic fibrosis and potential mechanism thereof.
METHODS:
Fifty SD rats were randomly divided into 5 equal groups: normal control group, model control group, low-dose emodin-treated group, mediate-dose emodin-treated group, and high-dose emodin-treated group. The rats of the latter 4 groups underwent infusion of trinitrobenzene sulfonic acid (TNBS) into the pancreatic duct so as to establish models of pancreatic fibrosis. The emodin-treated rats were fed with different doses of emodin (20, 40, and 80 mg/kg body weight), while the normal and model control groups received 0.9% sodium chloride solution instead. Twenty-eight days later the rats were killed, blood samples were collected, and their pancreases were taken out. The serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. The histopathological alterations were studied by optical microscopy. The expression of collagen was examined by Van Gieson staining. Western blotting was used to detect the protein expression of transforming growth factor-beta(1) (TGF-beta(1)).
RESULTS:
(1) The serum level of HA of the low-dose, mediate-dose, and high-dose emodin-treated groups were 87 microg/L +/- 22 microg/L, 78 microg/L +/- 25 microg/L, and 62 microg/L +/- 19 microg/L respectively, all significantly lower than that of the model control group (113 microg/L +/- 27 microg/L, P < 0.05 or < 0.01). The serum levels of laminin in the low-dose, mediate-dose, and high-dose emodin-treated groups were 67 microg/L +/- 14 microg/L, 57 microg/L +/- 12 microg/L, and 44 microg/L +/- 10 microg/L respectively, all significantly lower than that of the model control group (86 microg/L +/- 17 microg/L, P < 0.05 or P < 0.01); (2) The degrees of fibrosis of the emodin-treated groups were obviously ameliorated in comparison with the model control group, the higher the dose of emodin the more improved the pathological changes, especially in the high-dose emodin-treated group (P < 0.05). (3) The percentages of collagen positive cells of the low-dose, mediate-dose, and high-dose emodin-treated groups were 39% +/- 7%, 38% +/- 4%, and 36% +/- 5% respectively, all lower than that of the model control group (42% +/- 6%), with a significant difference between the high-dose emodin-treated group and the model control group (P < 0.05). (4) The protein content of TGF-beta(1) of the low-dose, mediate-dose, and high-dose emodin-treated groups were 44.3% +/- 2.1%, 39.2% +/- 1.8%, and 28.8% +/- 1.6% respectively, all significantly lower than that of the model control group (60.7% +/- 1.7%, all P < 0.05), and the protein content of TGF-beta(1) of the high-dose emodin-treated group was significantly lower than those of the other 2 emodin-treated groups (both P < 0.05).
CONCLUSION:
Emodin has an anti-fibrosis effect on pancreatic fibrosis, which maybe related to the content of TGF-beta(1) protein.

Br J Pharmacol. 2010 Dec;161(7):1628-44. doi: 10.1111/j.1476-5381.2010.00993.x.
Emodin suppresses lipopolysaccharide-induced pro-inflammatory responses and NF-κB activation by disrupting lipid rafts in CD14-negative endothelial cells.
Meng G, Liu Y, Lou C, Yang H.
BACKGROUND AND PURPOSE:
Emodin [1,3,8-trihydroxy-6-methylanthraquinone] has been reported to exhibit vascular anti-inflammatory properties. However, the corresponding mechanisms are not well understood. The present study was designed to explore the molecular target(s) of emodin in modifying lipopolysaccharide (LPS)-associated signal transduction pathways in endothelial cells.
EXPERIMENTAL APPROACH:
Cultured primary human umbilical vein endothelial cells (HUVECs; passages 3-5) were pre-incubated with emodin (1-50 µg·mL(-1) ). LPS-induced expression of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6] and chemokines (IL-8; CCL2/MCP-1) were determined by reverse transcription-PCR and elisa. Nuclear factor-κB (NF-κB) activation, inhibitor of κB (IκB)α degradation and Toll-like receptor-4 (TLR-4) were detected by immunocytochemistry and Western blotting. Cholesterol depletion [by methyl β-cyclodextrin (MBCD), a specific cholesterol binding agent] and cholesterol replenishment were further used to investigate the roles of lipid rafts in activation of HUVECs.
KEY RESULTS:
Emodin inhibited, concentration-dependently, the expression of LPS-induced pro-inflammatory cytokines (IL-1β, IL-6) and chemokines (IL-8, CCL2) and, in parallel, inhibited NF-κB activation and IκBα degradation in HUVECs. However, emodin did not inhibit the NF-κB activation and IκBα degradation induced by IL-1β. The cholesterol binding agent, MBCD, inhibited LPS-induced NF-κB activation in passaged HUVECs [which also lack the LPS receptor, membrane CD14 (mCD14)], showing that lipid rafts played a key role in LPS signalling in mCD14-negative HUVECs. Moreover, emodin disrupted the formation of lipid rafts in cell membranes by depleting cholesterol.
CONCLUSIONS AND IMPLICATIONS:
Lipid rafts were crucial in facilitating inflammatory responses of mCD14-negative HUVECs to LPS. Emodin disrupted lipid rafts through depleting cholesterol and, consequently, inhibited inflammatory responses in endothelial cells.

Chin Med J (Engl). 2002 Jul;115(7):1035-8.
Effect of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and FAS activity.
Zhang C, Teng L, Shi Y, Jin J, Xue Y, Shang K, Gu J.
OBJECTIVE:
To study the effects of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and the possible mechanism.
METHODS:
Cell proliferation was determined by MTT spectrophotometry, cell differentiation was determined by Oil Red O staining,and fatty acid synthase (FAS) activity was determined by spectrophotometry.
RESULTS:
Emodin promoted proliferation of 3T3-L1 preadipocyte at low concentration and inhibited the proliferation at high concentration in a dose-related manner. In contrast, it inhibited cell differentiation into adipocyte at low concentration in a dose-related manner. In vitro emodin inhibited the activity of FAS in a dose-related manner.
CONCLUSIONS:
The effects of emodin on 3T3-L1 cell’s proliferation and differentiation are dose dependent. Emodin inhibits the activity of FAS. Our results suggest that emodin should have a potential to serve as a fat-reducing drug.

Oncogene. 1996 Feb 1;12(3):571-6.
Sensitization of HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase inhibitor emodin.
Zhang L, Hung MC.
Overexpression of the HER-2/neu proto-oncogene which encodes tyrosine kinase receptor p185neu, has been observed frequently in many human cancers, including non-small cell lung cancer (NSCLC), and is correlated with poor patient survival in these cancers. In addition, HER-2/neu overexpression in NSCLC is known to induce chemoresistance. Recently, we demonstrated that emodin, a tyrosine kinase inhibitor, suppresses HER-2/neu tyrosine kinase activity in HER-2/neu-overexpressing breast cancer cells and preferentially represses proliferation of these cells. The work described here was carried out to examine (1) whether the tyrosine kinase activity of p185neu is required for resistance to chemotherapeutic drugs of HER-2/neu-overexpressing NSCLC cells and (2) whether the tyrosine kinase inhibitor emodin can sensitize these cells to chemotherapeutic drugs. We found that emodin decreased tyrosine phosphorylation of HER-2/neu and preferentially suppressed proliferation of HER-2/neu-overexpressing NSCLC cells. Furthermore, the combination of emodin with cisplatin, doxorubicin or etoposide (VP16) synergistically inhibited the proliferation of HER-2/neu-overexpressing lung cancer cells, whereas low doses of emodin, cisplatin, doxorubicin, or VP16 alone had only minimal antiproliferative effects on these cells. These results indicate that tyrosine kinase activity is required for the chemoresistant phenotype of HER-2/neu-overexpressing NSCLC cells and that tyrosine kinase inhibitors such as emodin can sensitize these cells to chemotherapeutic drugs. The results may have important implications in chemotherapy for HER-2/neu-overexpressing cancers.

Cancer Res. 2005 Mar 15;65(6):2287-95.
Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth.
Cha TL, Qiu L, Chen CT, Wen Y, Hung MC.
Hormone-refractory relapse is an inevitable and lethal event for advanced prostate cancer patients after hormone deprivation. A growing body of evidence indicates that hormone deprivation may promote this aggressive prostate cancer phenotype. Notably, androgen receptor (AR) not only mediates the effect of androgen on the tumor initiation but also plays the major role in the relapse transition. This provides a strong rationale for searching new effective agents targeting the down-regulation of AR to treat or prevent advanced prostate cancer progression. Here, we show that emodin, a natural compound, can directly target AR to suppress prostate cancer cell growth in vitro and prolong the survival of C3(1)/SV40 transgenic mice in vivo. Emodin treatment resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Emodin decreased the association of AR and heat shock protein 90 and increased the association of AR and MDM2, which in turn induces AR degradation through proteasome-mediated pathway in a ligand-independent manner. Our work indicates a new mechanism for the emodin-mediated anticancer effect and justifies further investigation of emodin as a therapeutic and preventive agent for prostate cancer.

In Vivo. 1996 Mar-Apr;10(2):185-90.
Oncogene signal transduction inhibitors from medicinal plants.
Chang CJ, Ashendel CL, Geahlen RL, McLaughlin JL, Waters DJ.
Signal transduction is believed to be altered by cellular oncogenes or tumor suppressor genes during the transformation of normal cells into malignant cells. This proposition offers an attractive target for oncogene-based anticancer drug discovery from natural sources. Protein kinases encoded or modulated by oncogenes were used to prescreen the potential antitumor activity of medicinal plants. Protein-tyrosine kinase-directed fractionation and separation of the crude extracts of Polygonum cuspidatum and Koelreuteria henryi have led to the isolation of three different classes of protein-tyrosine kinase inhibitors, anthraquinone, stilbene and flavonoid. The anthraquinone inhibitor, emodin, displayed highly selective activities against src-Her-2/neu and ras-oncogenes.

J Pharm Pharmacol. 2004 Jul;56(7):915-9.
Evaluation of the anti-inflammatory and cytotoxic effects of anthraquinones and anthracenes derivatives in human leucocytes.
Chen RF, Shen YC, Huang HS, Liao JF, Ho LK, Chou YC, Wang WY, Chen CF.
A variety of anthracene- and anthraquinone-related derivatives, modified from three types of lead structures, including 9-acyloxy 1,5-dichloroanthracene (type I), 1,5-bisacyloxy-anthraquinones with O-linked substituents (type II) and 1,5-bisacyloxy-anthraquinones with S-linked substituents (type III), were synthesized and evaluated by an in-vitro bioassay for their anti-inflammatory and cytotoxic effects in human leucocytes. Among these derivatives, type I compounds displayed potent anti-inflammatory activity against phorbol-12-myristate-13-acetate (PMA)-induced superoxide anion production, a bio-marker of inflammatory mediator production by neutrophils, with 50% inhibition (IC50) concentrations (microM) for compounds 1f, 1g, 1h and 1m being 13.8 +/- 3.0, 6.3 +/- 4.1, 33.2 +/- 1.3 and 33.9 +/- 5.7, respectively. Type II and type III derivatives (i. e., 1,5-bisacyloxy anthraquinone-related compounds) and the reference compound, emodin, exhibited relatively minor (20-40%) inhibitory effect against superoxide production by neutrophils. Furthermore, none of these compounds showed a significant cytotoxic effect in human neutrophils. In conclusion, these results suggest that compounds modified from 9-acyloxy 1,5-dichloroanthracence (type I) are more powerful than the other two types as anti-inflammatory drugs. This is the first demonstration that derivatives modified from anthracenes or anthraquinones possess anti-inflammatory activity with no significant cytotoxicity in human neutrophils.

Neuropharmacology. 2005 Jul;49(1):103-11. Epub 2005 Mar 31.
Effects of emodin on synaptic transmission in rat hippocampal CA1 pyramidal neurons in vitro.
Gu JW, Hasuo H, Takeya M, Akasu T.
Rhubarb extracts provide neuroprotection after brain injury, but the mechanism of this protective effect is not known. The present study tests the hypothesis that rhubarb extracts interfere with the release of glutamate by brain neurons and, therefore, reduce glutamate excitotoxicity. To this end, the effects of emodin, an anthraquinone derivative extracted from Rheum tanguticum Maxim. Ex. Balf, on the synaptic transmission of CA1 pyramidal neurons in rat hippocampus were studied in vitro. The excitatory postsynaptic potential (EPSP) was depressed by bath-application of emodin (0.3-30 microM). Paired-pulse facilitation (PPF) of the EPSP was significantly increased by emodin. The monosynaptic inhibitory postsynaptic potential (IPSP) recorded in the presence of glutamate receptor antagonists (DNQX and AP5) was not altered by emodin. Emodin decreased the frequency, but not the amplitude, of the miniature EPSP (mEPSP). The inhibition of the EPSP induced by emodin was blocked by either 8-CPT, an adenosine A1 receptor antagonist, or by adenosine deaminase. These results suggest that emodin inhibits the EPSP by decreasing the release of glutamate from Schaffer collateral/commissural terminals via the activation of adenosine A1 receptors in rat hippocampal CA1 area and that the neuroprotective effects of rhubarb extracts may result from decreased glutamate excitotoxicity.

J Ethnopharmacol. 2009 Jan 21;121(2):313-7. Epub 2008 Nov 17.
Anti-angiogenic effects of rhubarb and its anthraquinone derivatives.
He ZH, He MF, Ma SC, But PP.
Rhubarb root (Dahuang) is often included as an ingredient in traditional Chinese compound prescriptions for the treatment of inflammatory diseases. This application may possibly be mediated through anti-angiogensis and thus would shed light on its potential value in cancer therapy.
AIM OF THE STUDY:
To elucidate the anti-angiogenic properties of rhubarb root, we tested the inhibitory effects of different fractions and a series of anthraquinone derivatives against vessel formation in zebrafish embryos.
MATERIALS AND METHODS:
The 95% ethanol extract and four subsequent fractions (n-hexane, ethyl acetate, n-butanol and aqueous fractions) of rhubarb root and five anthraquinone derivatives were investigated on zebrafish model by quantitative endogenous alkaline phosphatase assay and staining assay.
RESULTS:
Ethyl acetate fraction showed the strongest inhibition of vessel formation by 52%. Three anthraquinones (aloe-emodin, emodin and rhein) displayed potent anti-angiogenic activities.
CONCLUSIONS:
The angiogenic properties of rhubarb root may partly account for its use in inflammatory diseases. The anthraquinones with acidic or polar, hydrophilic substitution at C-6 or C-3 positions played a substantial role in inhibiting angiogenesis. The value of the zebrafish angiogenic model is further supported.

Cell Mol Life Sci. 2005 May;62(10):1167-75.
Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway.
Huang Q, Shen HM, Ong CN.
Enhanced cell migration is one of the underlying mechanisms in cancer invasion and metastasis. Therefore, inhibition of cell migration is considered to be an effective strategy for prevention of cancer metastasis.We found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), an active component from the rhizome of Rheum palmatum, significantly inhibited epidermal growth factor (EGF)- induced migration in various human cancer cell lines. In the search for the underlying molecular mechanisms, we demonstrated that phosphatidylinositol 3-kinase (PI3K) serves as the molecular target for emodin. In addition, emodin markedly suppressed EGF-induced activation of Cdc42 and Rac1 and the corresponding cytoskeleton changes. Moreover, emodin, but not LY294002, was able to block cell migration in cells transfected with constitutively active (CA)-Cdc42 and CA-Rac1 by interference with the formation of Cdc42/Rac1 and the p21-activated kinase complex. Taken together, data from this study suggest that emodin inhibits human cancer cell migration by suppressing the PI3K-Cdc42/Rac1 signaling pathway.

Med Res Rev. 2007 Sep;27(5):609-30.
Anti-cancer properties of anthraquinones from rhubarb.
Huang Q, Lu G, Shen HM, Chung MC, Ong CN.
Rhubarb has been used as a traditional Chinese medicine since ancient times and today it is still present in various herbal preparations. In this review the toxicological and anti-neoplastic potentials of the main anthraquinones from Rhubarb, Rheum palmatum, will be highlighted. It is interesting to note that although the chemical structures of various anthraquinones in this plant are similar, their bioactivities are rather different. The most abundant anthraquinone of rhubarb, emodin, was capable of inhibiting cellular proliferation, induction of apoptosis, and prevention of metastasis. These capabilities are reported to act through tyrosine kinases, phosphoinositol 3-kinase (PI3K), protein kinase C (PKC), NF-kappa B (NF-kappaB), and mitogen-activated protein kinase (MAPK) signaling cascades. Aloe-emodin is another major component in rhubarb found to have anti-tumor properties. Its anti-proliferative property has been demonstrated to be through the p53 and its downstream p21 pathway. Our recent proteomic study also suggests that the molecular targets of these two anthraquinones are different. However, both components were found to be able to potentiate the anti-proliferation of various chemotherapeutic agents. Rhein is the other major rhubarb anthraquinone, although less well studied. This compound could effectively inhibit the uptake of glucose in tumor cells, caused changes in membrane-associated functions and led to cell death. Interestingly, all three major rhubarb anthraquinones were reported to have in vitro phototoxic. This re-evaluation of an old remedy suggests that several bioactive anthraquinones of rhubarb possess promising anti-cancer properties and could have a broad therapeutic potential.

Eur J Pharmacol. 2006 Dec 28;553(1-3):46-53. Epub 2006 Sep 23.
Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation.
Kaneshiro T, Morioka T, Inamine M, Kinjo T, Arakaki J, Chiba I, Sunagawa N, Suzui M, Yoshimi N.
An anthraquinone derivative, emodin, suppresses tumor development both in vitro and in vivo. In this study, we examined the anti-angiogenic activity of emodin and its modifying effect on the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. In cell cultures, emodin inhibited endothelial cell proliferation, migration, and tube formation in a dose-dependent manner. In addition, the mouse dorsal air sac assay revealed the vivo anti-angiogenic potential of emodin. Matrix metalloproteinase-9 (MMP-9) expression, which is critical for the angiogenic process, including migration and tube formation, decreased after exposure to emodin, as determined by polymerase chain reaction with reverse transcription (RT-PCR) and gelatin zymography. Moreover, the phosphorylation of ERK 1/2 decreased after exposure to emodin in a dose-dependent manner. These observations suggest that emodin has the potential to inhibit several angiogenic processes and that these effects may be related to suppression of the phosphorylation of ERK 1/2.

Int J Oncol. 2005 Sep;27(3):839-46.
Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells.
Kim MS, Park MJ, Kim SJ, Lee CH, Yoo H, Shin SH, Song ES, Lee SH.
Emodin, an inhibitor of protein tyrosine kinase, possesses antiviral, immunosuppressive, anti-inflammatory and anticancer effects. In the present study, we investigated the effect of emodin on the hyaluronic acid (HA)-induced invasion of human glioma cells. Emodin significantly inhibited the HA-induced invasion through a Matrigel coated chamber, secretion of matrix metalloproteinase (MMP)-2, and HA-induced secretion of MMP-9 in glioma cells. To investigate the possible mechanisms involved in these events, we performed Western blot analysis using phospho-specific antibodies, and found that emodin inhibited phosphorylation of focal adhesion kinase (FAK), extracellular regulated protein kinase (ERK) 1/2 and Akt/PKB; emodin also suppressed the transcriptional activity of two transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), in glioma cells. In addition, oral administration of emodin suppressed in vivo MMP secretion by glioma tumors in nude mice. Taken together, our results indicate that emodin can effectively inhibit HA-induced MMP secretion and invasion of glioma through inhibition of FAK, ERK1/2 and Akt/PKB activation and partial inhibition of AP-1 and NF-kappaB transcriptional activities. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human glioma.

Food Chem Toxicol. 1991 Nov;29(11):765-70.
Effect of emodin on cooked-food mutagen activation.
Lee H, Tsai SJ.
The herbs Rheum palmatum B and Polygonum cuspidatum S are frequently used as laxatives and anticancer drugs in Chinese medicine. The antimutagenic activity of these herbs as well as their active component emodin was examined in Salmonella typhimurium TA98. The crude extracts and emodin induced a dose-dependent decrease in the mutagenicity of benzo[a]pyrene (B[a]P), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Furthermore, emodin reduced the mutagenicity of IQ by direct inhibition of the hepatic microsomal activation and not by interaction with proximate metabolites of IQ and/or by modification of DNA repair processes in the bacterial cell.

Int J Mol Med. 2005 Jul;16(1):41-7.
Regulatory effects of emodin on NF-kappaB activation and inflammatory cytokine expression in RAW 264.7 macrophages.
Li HL, Chen HL, Li H, Zhang KL, Chen XY, Wang XW, Kong QY, Liu J.
Emodin, an anthraquinones component of Rheum palmatun, has been used for anti-inflammatory purposes. However, its underlying molecular effect(s) on target cells remain to be well clarified. Thus, our current study was aimed at investigating the regulatory mechanism of emodin on liposaccharide-induced inflammatory responses in RAW 264.7 macrophages by RT-PCR, Western blot analysis, immunocytochemical staining and immunofluorescence analysis. It was found that a treatment of 20 microg/ml emodin inhibited the expression of a panel of inflammatory-associated genes, including TNFalpha, iNOS, IL-10, cytosolic IkappaBalpha, IKK-alpha and IKK-gamma, to different extents as well as the nuclear translocation of NF-kappaB (nuclear factor-kappaB). The promoting effect of emodin on the production and translocation of p105 (the precursor of NF-kappaB p50) was time-dependent and reached a maximum at 5 h. Our data suggest that emodin plays its anti-inflammatory roles by regulating inflammatory cytokines, specifically by suppressing NF-kappaB activation.

J Ethnopharmacol. 2007 Jul 25;112(3):552-6. Epub 2007 May 6.
Ameliorating effect of emodin, a constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats.
Lu MC, Hsieh MT, Wu CR, Cheng HY, Hsieh CC, Lin YT, Peng WH.
The aim of the present study was intended to investigate the ameliorating effects of emodin on memory consolidation via cholinergic, serotonergic and GABAergic neuronal systems in rats. First, we evaluated the ameliorating effects of emodin on cycloheximide (CXM)-induced impairment of passive avoidance response in rats. Secondly, we clarified the role of cholinergic, serotonergic or GABAergic system on the ameliorating effect of emodin by using 5-HT1A receptor partial agonist, 5-HT2 receptor antagonist, GABAB agonist, GABAA antagonist and muscarinic receptor antagonist. Emodin protected the rat from CXM-induced memory consolidation impairment. The beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by 8-OH-DPAT (5-HT1A receptor partial agonist) and ritanserin (5-HT2 receptor antagonist), but reduced by scopolamine. These results suggested that the beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by serotonergic 5-HT1A-receptor partial agonist and 5-HT2 receptor antagonist but reduced by muscarinic receptor antagonist.

Tohoku J Exp Med. 2008 May;215(1):61-9.
Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient mice.
Zhou M, Xu H, Pan L, Wen J, Guo Y, Chen K.
Increasing evidence indicated that plaque stabilization is attributed to the composition of the atherosclerotic plaque, and inflammation plays an important role in the formation and progress of vulnerable atherosclerotic plaque (VAP), which is prone to rupture. Emodin, an important component of traditional Chinese herb rhubarb, has obvious anti-inflammatory effect, although its effect on atherosclerotic plaque stabilization is unknown. Apolipoprotein E (ApoE) is an important component of plasma lipoprotein with anti-atherosclerosis function, and the plaque in the aorta of ApoE-deficient mice has been demonstrated with characteristics of VAP. Therefore, this study was designed to determine whether emodin can stabilize the VAP in the ApoE-deficient mice and explain the possible mechanism. After fat-fed for 13 weeks, mice were randomized into three groups (11 animals/group) and intragastrically administrated with emodin, simvastatin or distilled water for 13 weeks, respectively. The plaque stability was evaluated by the morphology and composition of atherosclerotic plaques. Additionally, the expression of peroxisomal proliferator-activated receptor-gamma (PPAR-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 9 (MMP-9) in plaques was determined by the immunohistochemistry method. We showed that emodin could decrease the lipid core area and the ratio of lipid to collagen content in plaques. In addition, emodin significantly inhibited the expression of GM-CSF and MMP-9, whereas it induced the expression of PPAR-gamma in plaques. In conclusion, these results suggest that emodin can stabilize the VAP in the aortic root of ApoE-knockout mice, which is probably due to its anti-inflammatory effect.