Milk Thistle

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    Milk Thistle


    studies regarding not only its effectiveness for the liver, but also its numerous anti-carcinogenic properties with regards to the pancreas, breast, and prostate tissues, as well as treatment of chemical induced injury to the kidneys, milk thistles potential benefit to the nervous system and its immunostimulatory effects, AND inhibition of glucose-related insulin release... the list goes on much longer than I thought, as I was originally under the impression that it was primarily only a "liver protectant"... well, it's much more than that it seems... again, cheap and effective... more and more some of these herbal extracts are proving to be very effective, especially in conjuction with standard medical treatment. good stuff. make sure yours is standardized silymarin extract (most are).

    1.Analysis of the active components of silymarin.
    J Chromatogr A 2003 Mar 21;990(1-2):239-45

    2.Primary cultures of human hepatocytes as a tool in cytotoxicity studies: cell protection against model toxins by flavonolignans obtained from Silybum marianum.
    Toxicol Lett 2003 Feb 3;137(3):201-12

    3.Immunostimulatory effect of Silybum Marianum (milk thistle) extract.
    Med Sci Monit 2002 Nov;8(11):BR439-43

    4.Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities.
    Phytother Res 2002 Nov;16(7):632-8

    5.The use of alternative medicine in the treatment of hepatitis C.
    Am Clin Lab 2002 May;21(4):19-21

    6.Neurotrophic and neuroprotective effects of milk thistle (Silybum marianum) on neurons in culture.
    J Mol Neurosci 2002 Jun;18(3):265-9

    7.Milk thistle and the treatment of hepatitis.
    Gastroenterol Nurs 2001 Mar-Apr;24(2):95-7

    8.The use of silymarin in the treatment of liver diseases.
    Drugs 2001;61(14):2035-63

    9.Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise.
    Am Fam Physician 2001 Nov 1;64(9):1555-60

    10.Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells.
    Cancer Res 2000 Oct 15;60(20):5617-20

    11.Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents.
    Biochem Pharmacol 2000 Oct 15;60(8):1051-9

    12.Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin.
    Cancer Lett 1999 Dec 1;147(1-2):77-84

    13.Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis.
    J Immunol 1999 Dec 15;163(12):6800-9

    14.Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells.
    J Pharmacol Exp Ther 1999 Sep;290(3):1375-83

    15.Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention.
    Proc Natl Acad Sci U S A 1999 Jun 22;96(13):7490-5

    16.A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells.
    Cancer Res 1998 May 1;58(9):1920-9

    17.Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins.
    Clin Cancer Res 1998 Apr;4(4):1055-64

    18.Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity.
    Cell Mol Life Sci 1997 Dec;53(11-12):917-20

    19.Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha.
    Biochem Biophys Res Commun 1997 Oct 9;239(1):334-9

    20.Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin.
    Hepatology 1996 Apr;23(4):749-54

    21.Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.
    J Hepatol 1989 Jul;9(1):105-13

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    1.Analysis of the active components of silymarin.

    J Chromatogr A 2003 Mar 21;990(1-2):239-45


    Kvasnicka F, Biba B, Sevcik R, Voldrich M, Kratka J.

    Institute of Chemical Technology, Technicka 3, Prague 6, Czech Republic. kvasnicf@vscht.cz

    Silymarin is an antihepatotoxic substance isolated from fruits of Silybum marianum. Possibly due to their antioxidant and membrane stabilizing properties, the compounds have been shown to protect different organs and cells against a number of insults. The content and composition of main silymarin components (silybin, isosilybin, silydianin and silychristin) in various pharmaceuticals were analysed using HPLC and newly developed capillary zone electrophoresis method. Antioxidant properties expressed as total antioxidant status (TAS) of silymarin components were studied. Results of TAS were correlated with electropherograms and chromatograms.
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    2.Primary cultures of human hepatocytes as a tool in cytotoxicity studies: cell protection against model toxins by flavonolignans obtained from Silybum marianum.

    Toxicol Lett 2003 Feb 3;137(3):201-12


    Dvorak Z, Kosina P, Walterova D, Simanek V, Bachleda P, Ulrichova J.

    Institute of Medical Chemistry and Biochemistry, Faculty of Medicine, Palacky University Hnevotinska 3, 775 15 Olomouc, Czech Republic.

    The aim of this study was to evaluate the cytoprotective effects upon primary human hepatocytes of silymarin extract and its main flavonolignans following exposure to the cytotoxic actions of model toxins. The conditions for the hepatocyte intoxication were optimised for allyl alcohol, carbon tetrachloride, D-galactosamine and paracetamol. Silymarin extract, silychristin and silydianin did not exert cytotoxicity (10-100 microM), whereas silybin and isosilybin at higher concentrations and after longer incubation periods were cytotoxic. All main flavonolignans of silymarin tested displayed concentration-dependent cytoprotection against the toxic effects of both allyl alcohol and carbon tetrachloride but neither paracetamol nor galactosamine. The best protection was achieved by silydianin and silychristin and to a lesser degree by silymarin, while silybin and isosilybin were less effective. It is concluded that these differing outcomes result from the varying abilities of the Silybum marianum substances tested to stabilize the cell membrane, exert antioxidant properties and exhibit intrinsic toxicity.
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    3.Immunostimulatory effect of Silybum Marianum (milk thistle) extract.

    Med Sci Monit 2002 Nov;8(11):BR439-43


    Wilasrusmee C, Kittur S, Shah G, Siddiqui J, Bruch D, Wilasrusmee S, Kittur DS.

    The Johns Hopkins University School of Medicine, Department of Surgery SUNY Upstate Medical University.

    BACKGROUND: Herbal products are increasingly used for their effects on the immune system. Milk Thistle, a commonly used herbal product is known to inhibit growth of certain tumors, although the mechanism of this effect remains unknown. Previously we have shown that Milk Thistle extracts stimulate neurons in culture. Since other drugs that affect the neuronal; system also affect the immune system, we investigated the effects of Milk Thistle on the immune system. MATERIAL/METHODS: Standardized Milk Thistle extract was studied in murine lymphocyte proliferation tests using Concanavalin A (ConA) as mitogen for non-specific stimulation and mixed lymphocyte culture (MLC) as allospecific stimulation. Th1 and Th2 cytokine levels in MLC were assayed by two antibody capture ELISA technique. All tests were performed in triplicate and repeated twice. RESULTS: We found that Milk Thistle is immunostimulatory in vitro. It increased lymphocyte proliferation in both mitogen and MLC assays. These effects of Milk Thistle were associated with an increase in interferon gamma, interleukin (IL)-4 and IL-10 cytokines in the MLC (table). This immunostimulatory effect increased in response to increasing doses of Milk Thistle. CONCLUSIONS: Our study has uncovered a novel effect of milk thistle on the immune system. This immunostimulatory effect may be of benefit in increasing the immunity to infectious diseases.
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    4.Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities.

    Phytother Res 2002 Nov;16(7):632-8


    Zuber R, Modriansky M, Dvorak Z, Rohovsky P, Ulrichova J, Simanek V, Anzenbacher P.

    Faculty of Chemical Technology, University of Pardubice, Nam. Cs. Legii 565, 532 10 Pardubice, Czech Republic.

    Silybin and related flavonolignans form a major part of the Silybum marianum extract, silymarin, which has been used to treat liver diseases for hundreds of years. Although regarded as safe, many of the extract constituents remain thus far untested for their possible effects on liver biotransformation enzymes. Cytochromes P450 (CYP) are very important in this regard. We tested the effect of four flavonolignans: silybin, its hemisynthetic derivative dehydrosilybin, silydianin, and silycristin on three specific CYP activities: bufuralol 1'-hydroxylation (CYP2D6), p-nitrophenol hydroxylation (CYP2E1), and nifedipine oxidation (CYP3A4). All flavonolignans displayed dose-dependent inhibition of these activities with IC(50) values in the micromolar range. The inhibition was competitive or mixed as revealed by double reciprocal plots of kinetic experiments. However, the inhibition is not considered to be relevant for therapy because physiological concentrations of the individual flavonolignans do not exceed 0.5 microM. The data support the use of the extract as a dietary supplement. Copyright 2002 John Wiley & Sons, Ltd.
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    5.The use of alternative medicine in the treatment of hepatitis C.

    Am Clin Lab 2002 May;21(4):19-21


    Bean P.

    Rogers Memorial Hospital, Oconomowac, WI, USA. pambean@charter.net

    More than one-third of Americans use herbs for health purposes, yet patients and physicians usually lack accurate information about safety and efficacy of herbal remedies. In recent years, there has been a substantial increase in the use of so-called complementary and alternative therapies by patients with liver disease. Medical professionals and laboratorians need to be informed about popular alternative therapies and be open-minded to the possibility that some benefit may come from some therapies currently regarded as alternative. Silymarin extracted from the milk thistle is most widely subscribed to as a remedy for liver diseases. The beneficial effects of silymarin are most often seen in the patients who had cirrhosis as a result of alcohol abuse. An ongoing clinical trial will provide some insight as to whether milk thistle directly affects HCV. Silymarin has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. The active component of licorice root, glycyrrhizin, has been shown to reduce alanine transaminase and aspartate transaminase values in the serum. This protective function has recently been explained as the inhibitory effects of glycyrrhizin on immune-mediated cytotoxicity against hepatocytes and on nuclear factor (NF)-kappa B, which activates genes encoding inflammatory cytokines in the liver. Finally, some patients with hepatitis C take St. John's Wort and ginger to treat the side effects caused by interferon therapy. An excellent review of this subject was recently published by the NCCAM.
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    6.Neurotrophic and neuroprotective effects of milk thistle (Silybum marianum) on neurons in culture.

    J Mol Neurosci 2002 Jun;18(3):265-9


    Kittur S, Wilasrusmee S, Pedersen WA, Mattson MP, Straube-West K, Wilasrusmee C, Lubelt B, Kittur DS.

    Department of Neurology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. kitturs@upstate.edu

    Herbal products are being increasingly used as dietary supplements and therapeutic agents. However, much more research must be performed in order to determine the biological basis for their putative clinical effects. We tested the effects of milk thistle (Silybum marianum) extract on the differentiation and survival of cultured neural cells. Milk thistle enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC-12 neural cells and prolonged their survival in culture. Milk thistle extract also protected cultured rat hippocampal neurons against oxidative stress-induced cell death. Our data demonstrate that milk thistle extract can promote neuronal differentiation and survival, suggesting potential benefits of chemicals in this plant on the nervous system.
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    7.Milk thistle and the treatment of hepatitis.

    Gastroenterol Nurs 2001 Mar-Apr;24(2):95-7


    Giese LA.

    Gastroenterology nurses and associates will find it helpful to be informed about milk thistle (silybum marianum), a popular, safe and promising herb used by patients with liver disease. Silymarin is a derivative from the milk thistle plant with few side effects that has been safely used for centuries to treat liver ailments. Since the 1970s, there has been a reemergence of the marketing and use of silymarin. Research results of some small studies suggest silymarin has hepatoprotective, antiinflammatory, and regenerative properties producing a beneficial effect for some types of hepatitis. It is unclear, however, whether silymarin might interfere with the effect of interferon or ribavirin. A well-designed, placebo-controlled study of a larger population is needed. It is certainly encouraging that a large collaborative study is currently underway for milk thistle therapy in hepatitis C. This study is funded by NCCAM, the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Research updates are available online at www.nccam.nih.gov and through the NCCAM Clearinghouse at 1-888-644-6226.
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    8.The use of silymarin in the treatment of liver diseases.

    Drugs 2001;61(14):2035-63


    Saller R, Meier R, Brignoli R.

    Abteilung Naturheilkunde, University Hospital Zurich, Switzerland.

    The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis. Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-kappaB. Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p < 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections. Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by -4.2% [odds ratio (OR) 0.75 (0.5 - 1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of-7% [OR: 0.54 (0.3 - 0.9); p < 0.01]. An individual trial reported a reduction in the number of patients with encephalopathy of -8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by -25% (p < 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis. Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the 'final' evidence of the efficacy of silymarin.
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    9.Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise.

    Am Fam Physician 2001 Nov 1;64(9):1555-60


    Riley TR 3rd, Bhatti AM.

    Pennsylvania State University College of Medicine, Hershey, USA. triley@psu.edu

    Chronic liver disease is the 10th leading cause of death in the United States. Hepatitis C virus infection is the most frequent cause of chronic liver disease and the most common indication for liver transplantation. Preventive care can significantly reduce the progression of liver disease. Alcohol and hepatitis C virus are synergistic in hastening the development of cirrhosis; therefore, patients with hepatitis C infection should abstain from alcohol use. Because superinfection with hepatitis A or B virus can lead to liver failure, vaccination is recommended. Potentially hepatotoxic medications should be used with caution in patients with chronic liver disease. In general, nonsteroidal anti-inflammatory drugs should be avoided; acetaminophen in a dosage below 2 g per day is the safest choice. Many herbal remedies are potentially hepatotoxic, and only milk thistle can be used safely in patients who have chronic liver disease. Weight reduction and exercise can improve liver function in patients with fatty liver.
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    10.Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells.

    Cancer Res 2000 Oct 15;60(20):5617-20


    Zi X, Zhang J, Agarwal R, Pollak M.

    Lady Davis Research Institute of Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec, Canada.

    Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention.
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    11.Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents.

    Biochem Pharmacol 2000 Oct 15;60(8):1051-9


    Agarwal R.

    Center for Cancer Causation and Prevention, AMC Cancer Research Center, Denver, CO 80214, USA. agarwalr@amc.org

    Prostate cancer (PCA) is the most common invasive malignancy and leading cause (after lung) of cancer deaths in males. Since PCA is initially androgen-dependent, strategies are targeted toward androgen depletion for its control. However, tumor re-growth mostly occurs following this modality, and is androgen-independent. A loss of functional androgen receptor and an enhanced expression of growth factor receptors (e.g. erbB family members) and associated ligands have been shown to be the causal genetic events in PCA progression. These genetic alterations lead to an epigenetic mechanism where a feed-back autocrine loop between membrane receptor (e.g. epidermal growth factor receptor [erbB1] and associated ligand (e.g. transforming growth factor-alpha) results in an enhanced activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) as an essential component of the uncontrolled growth of PCA at an advanced and androgen-independent stage. Together, we rationalized that inhibiting these epigenetic events would be useful in controlling advanced PCA growth. Dietary polyphenolic flavonoids and isoflavones are being studied extensively as cancer-preventive and interventive agents. Therefore, we focused our attention on silymarin, genistein, and epigallocatechin 3-gallate (EGCG), present in milk thistle, soy beans, and green tea, respectively. The effect of these agents was assessed on the erbB1-Shc-ERK1/2 signal transduction pathway, cell cycle regulatory molecules, and cell growth and death. In androgen-independent human prostate carcinoma DU145 cells, silymarin, genistein, and EGCG resulted in a significant to complete inhibition of transforming growth factor-alpha-caused activation of membrane receptor erbB1 followed by inhibition of downstream cytoplasmic signaling target Shc activation and a decrease in its binding with erbB1, without an alteration in their protein expression. Silymarin and genistein also inhibited ERK1/2 activation, suggesting that these agents impair the activation of erbB1-Shc-ERK1/2 signaling in DU145 cells. In the case of EGCG, a further increase in ERK1/2 activation was observed that was related to its pro-oxidant and apoptotic activities. Silymarin, genistein, and EGCG also resulted in a significant induction of Cip1/p21 and Kip1/p27 and a decrease in cyclin-dependent kinase (CDK) 4, but a moderate inhibition of CDK2, cyclin D1, and cyclin E was observed. An enhanced level of Cip1/p21 and Kip1/27 also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein, and EGCG also resulted in strong cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein also showed cell death. A more profound cytotoxic effect was observed in the case of EGCG, with strong cell death at lower doses and complete loss of viability at higher doses. Together, these results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents. More studies, therefore, are needed with these agents to explore their anticarcinogenic potential against human prostate cancer.
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    12.Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin.

    Cancer Lett 1999 Dec 1;147(1-2):77-84


    Bhatia N, Zhao J, Wolf DM, Agarwal R.

    Center for Cancer Causation and Prevention, AMC Cancer Research Center, Denver, CO 80214, USA.

    Several studies from our laboratory have shown the cancer chemopreventive and anti-carcinogenic effects of silymarin, a flavonoid antioxidant isolated from milk thistle, in long-term tumorigenesis models and in human prostate, breast and cervical carcinoma cells. Since silymarin is composed mainly of silibinin with small amounts of other stereoisomers of silibinin, in the present communication, studies were performed to assess whether the cancer preventive and anti-carcinogenic effects of silymarin are due to its major component silibinin. Treatment of different prostate, breast, and cervical human carcinoma cells with silibinin resulted in a highly significant inhibition of both cell growth and DNA synthesis in a time-dependent manner with large loss of cell viability only in case of cervical carcinoma cells. When compared with silymarin, these effects of silibinin were consistent and comparable in terms of cell growth and DNA synthesis inhibition, and loss of cell viability. Based on the comparable results of silibinin and silymarin, we suggest that the cancer chemopreventive and anti-carcinogenic effects of silymarin reported earlier are due to the main constituent silibinin.
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    13.Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis.

    J Immunol 1999 Dec 15;163(12):6800-9


    Manna SK, Mukhopadhyay A, Van NT, Aggarwal BB.

    Department of Molecular Oncology, Cytokine Research Laboratory, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

    Silymarin is a polyphenolic flavonoid derived from milk thistle (Silybum marianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic effects. How silymarin produces these effects is not understood, but it may involve suppression of NF-kappa B, a nuclear transcription factor, which regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this report, we investigated the effect of silymarin on NF-kappa B activation induced by various inflammatory agents. Silymarin blocked TNF-induced activation of NF-kappa B in a dose- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of Iota kappa B alpha, an inhibitor of NF-kappa B. Silymarin blocked the translocation of p65 to the nucleus without affecting its ability to bind to the DNA. NF-kappa B-dependent reporter gene transcription was also suppressed by silymarin. Silymarin also blocked NF-kappa B activation induced by phorbol ester, LPS, okadaic acid, and ceramide, whereas H2O2-induced NF-kappa B activation was not significantly affected. The effects of silymarin on NF-kappa B activation were specific, as AP-1 activation was unaffected. Silymarin also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Silymarin suppressed the TNF-induced production of reactive oxygen intermediates and lipid peroxidation. Overall, the inhibition of activation of NF-kappa B and the kinases may provide in part the molecular basis for the anticarcinogenic and anti-inflammatory effects of silymarin, and its effects on caspases may explain its role in cytoprotection.
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    14.Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells.

    J Pharmacol Exp Ther 1999 Sep;290(3):1375-83


    Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R.

    Max Planck Institute for Biochemistry, Martinsried, Germany.

    The biochemical influence of flavonolignans from the milk thistle Silybum marianum has been tested on kidney cells of African green monkeys. Two nonmalignant cell lines were selected, with the focus of the work on the fibroblast-like Vero line. Proliferation rate, biosynthesis of protein and DNA, and the activity of the enzyme lactate dehydrogenase (as a measure of the cellular metabolic activity) were chosen as parameters for the effect of the flavonolignans. Silibinin and silicristin show remarkable stimulatory effects on these parameters, mainly in Vero cells; however, isosilibinin and silidianin proved to be inactive. In vitro experiments with kidney cells damaged by paracetamol, cisplatin, and vincristin demonstrated that administration of silibinin before or after the chemical-induced injury can lessen or avoid the nephrotoxic effects. The results warrant in vivo evaluations of the flavonolignan derivatives.
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    15.Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention.

    Proc Natl Acad Sci U S A 1999 Jun 22;96(13):7490-5


    Zi X, Agarwal R.

    Center for Cancer Causation and Prevention, AMC Cancer Research Center, 1600 Pierce Street, Denver, CO 80214, USA.

    Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
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    16.A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells.

    Cancer Res 1998 May 1;58(9):1920-9


    Zi X, Grasso AW, Kung HJ, Agarwal R.

    Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    Prostate cancer (PCA) is the most common nonskin malignancy and the second leading cause of cancer deaths in United States males. One practical and translational approach to control PCA is to define a mechanism-based anticarcinogenic agent(s). Recently, we showed that silymarin, a flavonoid antioxidant isolated from milk thistle, possesses exceptionally high to complete protective effects against experimentally induced tumorigenesis. Because the epidermal growth factor receptor (erbB1) and other members of the erbB family have been shown to play important roles in human PCA, efforts should be directed to identify inhibitors of this pathway for PCA intervention. In this study, we assessed whether silymarin inhibits erbB1 activation and associated downstream events and modulates cell cycle regulatory proteins and progression, leading to growth inhibition of human prostate carcinoma DU145 cells. Treatment of serum-starved cells with silymarin resulted in a significant inhibition of transforming growth factor alpha-mediated activation of erbB1 but no change in its protein levels. Silymarin treatment of cells also resulted in a significant decrease in tyrosine phosphorylation of an immediate downstream target of erbB1, the adapter protein SHC, together with a decrease in its binding to erbB1. In the studies analyzing cell cycle regulatory molecules, silymarin treatment of cells also resulted in a significant induction of cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27, concomitant with a significant decrease in CDK4 expression, but no change in the levels of CDK2 and CDK6 and their associated cyclins E and D1, respectively. Cells treated with silymarin also showed an increased binding of CDKIs with CDKs, together with a marked decrease in the kinase activity of CDKs and associated cyclins. In additional studies, treatment of cells grown in 10% serum with anti-epidermal growth factor receptor monoclonal antibody clone 225 or different doses of silymarin also resulted in significant inhibition of constitutive tyrosine phosphorylation of both erbB1 and SHC but no change in their protein levels. Furthermore, whereas silymarin treatment resulted in a significant increase in the protein levels of both Cip1/p21 and Kip1/p27, monoclonal antibody 225 showed an increase only in Kip1/p27. These findings suggest that silymarin also inhibits constitutive activation of erbB1 and that the observed effect of silymarin on an increase in CDKI protein levels is mediated via inhibition of erbB1 activation only in the case of Kip1/p27; however, additional pathways independent of inhibition of erbB1 activation are possibly responsible for the silymarin-caused increase in Cip1/p21 in DU145 cells. In other studies, silymarin treatment also induced a G1 arrest in the cell cycle progression of DU145 cells and resulted in a highly significant to complete inhibition of both anchorage-dependent and anchorage-independent growth of DU145 cells in a dose- and time-dependent manner. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against PCA and that this effect is likely to involve impairment of erbB1-SHC-mediated signaling pathway, induction of CDKIs, and a resultant G1 arrest.
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    17.Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins.

    Clin Cancer Res 1998 Apr;4(4):1055-64


    Zi X, Feyes DK, Agarwal R.

    Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    There is an increasing interest in identifying potent cancer preventive and therapeutic agents against breast cancer. Silymarin, a flavonoid antioxidant isolated from milk thistle, exerts exceptionally high to complete anticarcinogenic effects in tumorigenesis models of epithelial origin. In this study, we investigated the anticarcinogenic effect of silymarin and associated molecular mechanisms, using human breast carcinoma cells MDA-MB 468. Silymarin treatment resulted in a significantly high to complete inhibition of both anchorage-dependent and anchorage-independent cell growth in a dose- and time-dependent manner. The inhibitory effects of silymarin on cell growth and proliferation were associated with a G1 arrest in cell cycle progression concomitant with an induction of up to 19-fold in the protein expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21. Following silymarin treatment of cells, an incremental binding of Cip1/p21 with CDK2 and CDK6 paralleled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E-associated kinase activity with no change in CDK2 and CDK6 expression but a decrease in G1 cyclins D1 and E. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against breast cancer and that this effect possibly involves an induction of Cip1/p21 by silymarin, which inhibits the threshold kinase activities of CDKs and associated cyclins, leading to a G1 arrest in cell cycle progression.
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    18.Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity.

    Cell Mol Life Sci 1997 Dec;53(11-12):917-20


    von Schonfeld J, Weisbrod B, Muller MK.

    Department of Gastroenterology, Medical Clinic, Essen, Germany.

    Silymarin can be extracted from the milk thistle, and silibinin is the main component of the plant extract. Possibly due to their antioxidant and membrane-stabilizing properties, the compounds have been shown to protect different organs and cells against a number of insults. Thus liver, kidney, erythrocytes and platelets have been protected from the toxic effects of ethanol, carbon tetrachloride, cold ischemia and drugs, respectively. The effect of silibinin on endocrine and exocrine pancreas, however, has not been studied. We therefore investigated whether silibinin treatment attenuates cyclosporin A (CiA) toxicity on rat endocrine and exocrine pancreas. Groups of 15 male Wistar rats were treated for 8 days with CiA and/or silibinin. On day 9, endocrine and exocrine pancreatic functions were tested in vitro. At the end of the treatment period, blood glucose levels in vivo were significantly higher in rats treated with CiA while silibinin did not affect glucose levels. In vitro, insulin secretion was inhibited after treatment with silibinin, but amylase secretion was not affected. After treatment with CiA both insulin and amylase secretion were reduced. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion. Despite CiA treatment, amylase secretion was in fact restored to normal with the highest dose of silibinin. Thus silibinin inhibits glucose-stimulated insulin release in vitro, while not affecting blood glucose concentration in vivo. This combination of effects could be useful in the treatment of non-insulin-dependent diabetes mellitus. Furthermore, silibinin protects the exocrine pancreas from CiA toxicity. As this inhibitory effect is probably unspecific, silibinin may also protect the exocrine pancreas against other insult principles, such as alcohol.
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    19.Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha.

    Biochem Biophys Res Commun 1997 Oct 9;239(1):334-9


    Zi X, Mukhtar H, Agarwal R.

    Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    In this study we describe exceptionally high protective effects of silymarin, a flavonoid antioxidant isolated from milk thistle, against 12-O-tetradecanoylphorbol 13-acetate (TPA)- and okadaic acid (OA)-caused tumor promotion in SENCAR mouse skin. Pre-application of silymarin to that of TPA in 7, 12-dimethylbenz(a)anthracene (DMBA)-initiated mouse skin resulted in almost complete protection in terms of tumor incidence (85%) as well as multiplicity (94%). In OA-caused tumor promotion studies, application of silymarin prior to that of OA in DMBA-initiated mouse skin resulted in a complete protection against tumorigenicity. We next assessed the effect of silymarin on TPA- and OA-caused induction of mRNA expression of tumor necrosis factor alpha (TNF alpha) which is an endogenous tumor promoter and a central mediator of tumor promotion in vivo in the case of both TPA and OA tumor promotion. Topical application of silymarin on mouse skin prior to that of TPA or OA resulted in a highly significant to complete inhibition in a dose-dependent manner against both TPA- and OA-caused induction of TNF alpha mRNA expression in mouse epidermis. These results indicate that silymarin exerts novel chemopreventive effects against tumorigenicity by inhibiting endogenous tumor promoter TNF alpha. Additional studies are warranted in other tumor models to further evaluate the cancer chemopreventive effect of silymarin and to define the involvement of TNF alpha as a molecular target for such an effect.
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    20.Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin.

    Hepatology 1996 Apr;23(4):749-54


    Dehmlow C, Erhard J, de Groot H.

    Institut fur Physiologische Chemie, Universitatsklinikum, Essen, Germany.

    The flavonoid silibinin, the main compound extracted from the milk thistle Silybum marianum, displays hepatoprotective properties in acute and chronic liver injury. To further elucidate the mechanisms by which it acts, we studied the effects of silibinin on different functions of isolated rat Kupffer cells, namely the formation of superoxide anion radical (02-), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), and leukotriene B(4) (LTB(4)). Production of 02- and NO were inhibited in a dose-dependent manner, with an 50 percent inhibitory concentration (IC(50)) value around 80 micro mol/L. No effect on TNF-alpha formation was detected. Opposite effects were found on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid metabolism. Whereas no influence on PGE(2) formation was observed with silibinin concentrations up to 100 micro mol/L, a strong inhibitory effect on LTB(4) formation became evident. The IC(50)-value for inhibiting the formation of this eicosanoid was determined to be 15 micro mol/L silibinin. The strong inhibition of LTB(4), formation by silibinin was confirmed in experiments with phagocytic cells isolated from human liver. Hence, while rather high concentrations of silibinin are necessary to diminish free radical formation by activated Kupffer cells, significant inhibition of the 5-lipoxygenase pathway already occurs at silibinin concentrations which are achieved in vivo. Selective inhibition of leukotriene formation by Kupffer cells can at least partly account for the hepatoprotective properties of silibinin.
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    21.Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.

    J Hepatol 1989 Jul;9(1):105-13


    Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B.

    1st Department of Gastroenterology and Hepatology, University of Vienna, Austria.

    Silymarin, the active principle of the milk thistle Silybum marianum, protects experimental animals against various hepatotoxic substances. To determine the effect of silymarin on the outcome of patients with cirrhosis, a double blind, prospective, randomized study was performed in 170 patients with cirrhosis. 87 patients (alcoholic 46, non-alcoholic 41; 61 male, 26 female; Child A, 47; B, 37; C, 3; mean age 57) received 140 mg silymarin three times daily. 83 patients (alcoholic 45, non-alcoholic 38; 62 male, 21 female; Child A, 42; B, 32; C, 9: mean age 58) received a placebo. Non-compliant patients and patients who failed to come to a control were considered as 'drop outs' and were withdrawn from the study. All patients received the same treatment until the last patient entered had finished 2-years of treatment. The mean observation period was 41 months. There were 10 drop outs in the placebo group and 14 in the treatment group. In the placebo group, 37 (+2 drop outs) patients had died, and in 31 of these, death was related to liver disease. In the treatment group, 24 (+4 drop outs) had died, and in 18 of these, death was related to liver disease. The 4-year survival rate was 58 +/- 9% (S.E.) in silymarin-treated patients and 39 +/- 9% in the placebo group (P = 0.036). Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated 'Child A' (P = 0.03). No side effects of drug treatment were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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    Great post , nice to find an herb to threat some liver diseases out there
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    I thought yoiu said you had no extra time there biggin

    Nice job bro!
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    yeah, well... I'm a nerd, what can I say... doesn't really take too long to compile this stuff... organizing and highliting is a different matter, but oh well... yeah, I should be studying for finals. mebbe some sort of subconscious diversionary tactic... ? (... must... procrastinate...)
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    yeah im doing the same biggin, procrastinating for Calculus and **** hehe
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    great stuff...i staeted takin this about a month ago....nice to know its backed up by science...cool. btw...i remember finals..heh
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    Yeah, I always take milk thistle and saw palmetto when "on". Thanks Biggin' for letting me know I am doing the right thing. As I am too lazy to do the homework myself.
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    LOL Biggin I feel you bro. Sometimes I wanna study but I'm becoming addicted to AM
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    Also of <a href="http://www.ahrq.org/clinic/epcsums/milktsum.htm">interest</a>.
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