Ray Peat: Links to referenced studies

Emodin

Emodin inhibits proinflammatory responses and inactivates histone deacetylase 1 in hypoxic rheumatoid synoviocytes.

Abstract:

Chronic inflammation of rheumatoid arthritis (RA) is promoted by proinflammatory cytokines and closely linked to angiogenesis. In the present study, we investigated the anti-inflammatory effects of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) isolated from the root of Rheum palmatum L. in interleukin 1 beta (IL-1β) and lipopolysaccharide (LPS)-stimulated RA synoviocytes under hypoxia. Emodin significantly inhibited IL-1β and LPS-stimulated proliferation of RA synoviocytes in a dose-dependent manner under hypoxic condition. Also, enzyme linked immunosorbent assay (ELISA) revealed that emodin significantly reduced the production of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), IL-6 and IL-8], mediators [prostagladin E(2) (PGE(2)), matrix metalloproteinase (MMP)-1 and MMP-13] and vascular endothelial growth factor (VEGF) as an angiogenesis biomarker in IL-1β and LPS-treated synoviocytes under hypoxia. Consistently, emodin attenuated the expression of cyclooxygenase 2 (COX-2), VEGF, hypoxia inducible factor 1 alpha (HIF-1α), MMP-1 and MMP-13 at mRNA level in IL-1β and LPS-treated synoviocytes under hypoxia. Furthermore, emodin reduced histone deacetylase (HDAC) activity as well as suppressed the expression of HDAC1, but not HDAC2 in IL-1β and LPS-treated synoviocytes under hypoxia. Overall, these findings suggest that emodin inhibits proinflammatory cytokines and VEGF productions, and HDAC1 activity in hypoxic RA synoviocytes.

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Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth.

Abstract:

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.

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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

Abstract:

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 α-tocopherol (α-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 α-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.

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

Abstract:

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.

Effects of emodin on synaptic transmission in rat hippocampal CA1 pyramidal neurons in vitro

Abstract:

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 μM). 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.

Emodin inhibits dietary induced atherosclerosis by antioxidation and regulation of the sphingomyelin pathway in rabbits.

Abstract:

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.

Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway.

Abstract:

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.

Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation.

Abstract:

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.

Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells.

Abstract:

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-κB (NF-κB), 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-κB transcriptional activities. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human glioma.

Effect of emodin on cooked-food mutagen activation

Abstract:

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-methyl-imidazo[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.

Abbreviations:

B[a]P = benzo[a]pyrene; DMSO = dimethylsulphoxide; IQ = 2-amino-3-methylimidazo[4,5-f]quinoline; Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole

Regulatory effects of emodin on NF-κappaB activation and inflammatory cytokine expression in RAW 264.7 macrophages

Abstract:

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.

Aloe-Emodin Metabolites Protected N -Methyl-D-Aspartate-Treated Retinal Ganglion Cells by Cu-Zn Superoxide Dismutase.

Abstract:

A high concentration of glutamate in the eyes not only activates N-methyl-D-aspartate (NMDA) receptors, but also is toxic to the retina ganglion cells (RGCs) in glaucomatous patients. Our previous study had found that aloe-emodin sulfates/glucuronides metabolites, an anthraquinone polyphenol, exerted a neuroprotective activity upon RGCs. In order to understand the mechanisms involved in this neuroprotective effect, this study aimed to determine the expressions of RNAs and proteins in various treatments. The proteins expressed in the control group, NMDA-treated group, and aloe-emodin metabolites-cotreated group were separated by two-dimensional gel electrophoresis (2-DE). Protein spots were excised from 2-DE and analyzed by nano-LC-MS/MS (nano-liquid chromatography with mass spectrometry; tandem MS). Quantitative polymerase chain reaction (Q-PCR) was used to investigate the RNA related to these proteins. There were 84 spots with significant differences in various treatments. Among the 84 spots, we identified 9 spots whose functions were closely related to regulate the apoptosis of cells. The results of Q-PCR were not completely unanimous with those of 2-DE. Our results suggested that aloe-emodin metabolites decreased NMDA-induced apoptosis of RGCs by preserving, and inducing, some proteins related to the antioxidation and regulation of cells' energy. Both the level of RNA and protein of superoxide dismutase (Cu-Zn) were significantly elevated after aloe-emodin metabolites were added. The mechanisms of neuroprotection are complicated, and involve not only the transcription and stability of mRNA, but also post-translation protein modifications, degradation, and protein-protein interaction.

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Ameliorating effect of emodin, a constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats

Abstract:

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.

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Effects of emodin and double blood supplies on liver regeneration of reduced size graft liver in rat model

Abstract:

To study the influences of emodin and reconstruction of double blood supplies on liver regeneration of reduced size graft liver in rat model. 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. 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.

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.

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Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agent

Abstract:

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. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 5, 591–608, 2007

Emodin inhibits the mutagenicity and DNA adducts induced by 1-nitropyrene.

Abstract:

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.

Effect of emodin on pancreatic fibrosis in rats

Abstract:

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-β1) was localized by immunochemistry.

RESULTS: In emodin-treated rats, the serum levels of HA and LN were decreased significantly (HA, 62.2 ± 19.3 μg/L vs 112.7 ± 26.5 µg/L, P < 0.05; LN 44.3 ± 10.4 μg/L vs 86.2 ± 16.5 µg/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-β1 was declined, compared with those in control group.

CONCLUSION: Emodin has an anti-fibrotic effect on pancreatic fibrosis in rats. Because of its anti-fibrotic effect, it could be a potential herb for the treatment of chronic pancreatitis.

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Inhibitory effects of emodin on angiogenesis

Abstract:

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.

Emodin-mediated protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic myocardium

Abstract:

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.

Emodin on hepatic fibrosis in rats

Abstract:

OBJECTIVE: To investigate effect of emodin on hepatic fibrosis in rats.

METHODS: The rat hepatic fibrosis model was induced by the subcutaneous injection of 40% CCl4 (twice a week for 6 weeks) dissolved in olive oil. The emodin-treated 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) dissolved in 0.5% sodium carboxymethylcellulose (CMC), except receiving CCl4. Control group received only olive oil and 0.5% CMC. Liver functions were determined by standard procedure. Serum hyaluronic acid and laminin were determined by radioimmunoassay. Liver hydroxyprolines were determined. Histopathological changes were examined by optical microscopy.

RESULTS: Compared with model group, the emodin-treated rats showed (1) liver functions were improved, alanine transaminase (ALT) and alkaline phosphatase (AKP) were obviously reduced, and total protein (TP) and albumin (ALB) were significantly increased; (2) serum hyaluronic acid and laminin were markedly reduced; (3) liver hydroxyproline was significantly decreased; (4) the degrees of fibrosis were reduced. The changes of parameters mentioned above were significant (P < 0.05 or P < 0.01).

CONCLUSION: Emodin has effect on hepatic fibrosis in rats. The hepatoprotective of emodin may be one of mechanisms for liver fibrosis.

Effect of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and FAS activity

Abstract:

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.

Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin

Abstract:

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.

Sensitization of HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase inhibitor emodin

Abstract:

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.

Tyrosine kinase inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells in athymic mice and sensitizes these cells to the inhibitory effect of paclitaxel.

Abstract:

Overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185neu, has been observed in tumors from breast cancer patients. We demonstrated previously that emodin, a tyrosine kinase inhibitor, suppresses tyrosine kinase activity in HER-2/neu-overexpressing breast cancer cells and preferentially represses transformation phenotypes of these cells in vitro. In the present study, we examined whether emodin can inhibit the growth of HER-2/neu-overexpressing tumors in mice and whether emodin can sensitize these tumors to paclitaxel, a commonly used chemotherapeutic agent for breast cancer patients. We found that emodin significantly inhibited tumor growth and prolonged survival in mice bearing HER-2/neu-overexpressing human breast cancer cells. Furthermore, the combination of emodin and paclitaxel synergistically inhibited the anchorage-dependent and -independent growth of HER-2/neu-overexpressing breast cancer cells in vitro and synergistically inhibited tumor growth and prolonged survival in athymic mice bearing s.c. xenografts of human tumor cells expressing high levels of p185neu. Both immunohistochemical staining and Western blot analysis showed that emodin decreases tyrosine phosphorylation of HER-2/neu in tumor tissue. Taken together, our results suggest that the tyrosine kinase activity of HER-2/neu is required for tumor growth and chemoresistance and that tyrosine kinase inhibitors such as emodin can inhibit the growth of HER-2/neu-overexpressing tumors in mice and also sensitize these tumors to paclitaxel. The results may have important implications in chemotherapy for HER-2/neu-overexpressing breast tumors.

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Effects of emodin on Ca2+ signal transduction of smooth muscle cells in multiple organ dysfunction syndrome

Abstract:

We have made several reports on the signal transduction mechanism that emodin enhance the calcium concentrations of smooth muscle cells (SMCs) in the physiological condition by inositol [1, 4 and 5]-friphosphate (IP3). The observation that IP3 concentrations in SMCs were decreased in multiple organ dysfunction syndrome (MODS) prompted us to ask whether emodin can activate SMCs to contract by way of elevating [Ca2+] and thus modulating the critical Ca2+ signal transduction pathways involved in the contraction of the SMCs in the pathological setting of MODS. To test this hypothesis, we used the rat model of MODS to explore the potential roles of emodin in Ca2+ signal transduction in the SMCs of colon in rats. ML-7 [an inhibitor of myosin light-chain kinase (MLCK)] and Calphostin C [an inhibitor of protein kinase C (PKC)] were used to observe the influence of emodin on the muscle strips and SMCs in rats after MODS. Nifedipine (an antagonist of voltage-gated Ca2+ channel), EGTA (removal of extracellular Ca2+), heparine (a specific IP3 receptor antagonist), and ryanodine were used to probe the potential mechanisms involved in emodin-mediated elevation of the global cytoplasmic Ca2+ in SMCs of colon in the rats after MODS. Our results show that emodin is capable of contract the smooth muscles of colon in rats after MODS by MLCK increasing [Ca2+] of SMCs, and by PKC enhancing the calcium sensitivity of SMCs. The mechanism by which emodin triggers elevated [Ca2+] of smooth muscles of colon in rats after MODS is likely to operate through IP3 and RyR receptors in the sarcoplasm. It is hoped that deeper insights into how emodin modulates the critical calcium signaling in SMCs might lead to the potential development of emodin in the treatment of MODS.

Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient mice.

Abstract:

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-γ (PPAR-γ), 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-γ 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.

Effect of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and FAS activity

Abstract:

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.

Occurrence of emodin, chrysophanol and physcion in vegetables, herbs and liquors. Genotoxicity and anti-genotoxicity of the anthraquinones and of the whole plants.

Abstract:

1,8-Dihydroxyanthraquinones, present in laxatives, fungi imperfecti, Chinese herbs and possibly vegetables, are in debate as human carcinogens. We screened a variety of vegetables (cabbage lettuce, beans, peas), some herbs and herbal-flavoured liquors for their content of the 'free' anthraquinones emodin, chrysophanol and physcion. For qualitative and quantitative analysis, reversed-phase HPLC (RP-LC), gas chromatography-mass spectrometry (GC-MS) and RP-LC-MS were used. The vegetables showed a large batch-to-batch variability, from 0.04 to 3.6, 5.9 and 36 mg total anthraquinone per kg fresh weight in peas, cabbage lettuce, and beans, respectively. Physcion predominated in all vegetables. In the herbs grape vine leaves, couch grass root and plantain herb, anthraquinones were above the limit of detection. Contents ranged below 1 mg/kg (dry weight). All three anthraquinones were also found in seven of 11 herbal-flavoured liquors, in a range of 0.05 mg/kg to 7.6 mg/kg. The genotoxicity of the analysed anthraquinones was investigated in the comet assay, the micronucleus test and the mutation assay in mouse lymphoma L5178Y tk+/- cells. Emodin was genotoxic, whereas chrysophanol and physcion showed no effects. Complete vegetable extract on its own did not show any effect in the micronucleus test. A lettuce extract completely abolished the induction of micronuclei by the genotoxic anthraquinone danthron. Taking into consideration the measured concentrations of anthraquinones, estimated daily intakes, the genotoxic potency, as well as protective effects of the food matrix, the analysed constituents do not represent a high priority genotoxic risk in a balanced human diet.