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flavanolignans from milk thistle (Silybum marianum L. Gaertner). Phytochem Anal. 2005 Jan-Feb;16(1):7-16. [4]Duan L Silymarin extraction from milk thistle using hot water. Appl Biochem
Biotechnol. 2004 Spring;113-116:559-68.[5] Lee DY, Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk
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21;1(10):1684-9.[7] Manna SK Silymarin [MILK THISTLE] suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol. 1999 Dec
15;163(12):6800-9. [8] Lee DG et al Gram-positive bacteria specific properties of silybin derived from Silybum marianum [Milk Thistle]. Arch Pharm Res. 2003 Aug;26(8):597-600.[9]
Soliman KF In vitro attenuation of nitric oxide production in C6 astrocyte cell culture by various dietary compounds. Proc Soc Exp Biol Med. 1998 Sep;218(4):390-7.[10] Bialecka M. The
effect of bioflavonoids and lecithin on the course of experimental atherosclerosis in rabbits Ann Acad Med Stetin. 1997;43:41-56. [11]Zi X, Novel cancer chemopreventive effects of a
flavonoid antioxidant silymarin [MILK THISTLE]: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha. Biochem Biophys Res Commun. 1997 Oct
9;239(1):334-9.[12]Tyagi A Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and
PARP cleavages. Carcinogenesis. 2004 Sep;25(9):1711-20. Epub 2004 Apr *milk thistle [13]Tyagi AK Silibinin down-regulates survivin protein and mRNA expression and causes caspases
activation and apoptosis in human bladder transitional-cell papilloma RT4 cells. Biochem Biophys Res Commun. 2003 Dec 26;312(4):1178-84.[14] Vinh PQ et al Chemopreventive effects
of a flavonoid antioxidant silymarin [MILK THISTLE] on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res. 2002
Jan;93(1):42-9. [15]Tyagi AK Synergistic anti-cancer effects of silibinin [milk thistle extract] with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast
carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep. 2004 Feb;11(2):493-9.Zi X. Anticarcinogenic effect of a flavonoid antioxidant, silymarin [milk thistle], 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.[17]  Kohno H et al, Silymarin [MILK THISTLE], a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in
male F344 rats. Int J Cancer. 2002 Oct 10;101(5):461-8.[18] Yoo HG Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. Int J Mol Med. 2004
Jan;13(1):81-6.[19] Qi L, Epidermal growth factor receptor mediates silibinin [milk thistle]-induced cytotoxicity in a rat glioma cell line. Cancer Biol Ther. 2003 Sep-Oct;2(5):526-31.[20]
Chu SC Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Mol Carcinog. 2004
Jul;40(3):143-9.[21] Ladas EJ Milk thistle: is there a role for its use as an adjunct therapy in patients with cancer? J Altern Complement Med. 2003 Jun;9(3):411-6.[22] [Davis-Searles PR,
Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum [MILK THISTLE] on antiproliferative end points in human prostate carcinoma cells.
Cancer Res. 2005 May 15;65(10):4448-57] [23] Singh RP A cancer chemopreventive agent silibinin [MILK THISTLE], targets mitogenic and survival signaling in prostate cancer. Mutat Res.
2004 Nov 2;555(1-2):21-32.[23] Thelen P Silibinin down-regulates prostate epithelium-derived Ets transcription factor in LNCaP prostate cancer cells. Planta Med. 2004
May;70(5):397-400.[24] Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin [milk thistle] in prostate cancer cells. J Urol. 2004 May;171(5):1934-8. [25]
Prostate cancer prevention by silibinin [milk thistle]. Curr Cancer Drug Targets. 2004 Feb;4(1):1-11 [26] A flavonoid antioxidant, silymarin [milk thistle], 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. 27 Silibinin [Milk
Thistle] 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. 28 Dhanalakshmi S Silibinin [MILK THISTLE] sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced
growth inhibition and apoptotic death. Int J Cancer. 2003 Sep 20;106(5):699-705. 29 Zi X Silibinin [MILK THISTLE] 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. [30] Singh RP Dietary feeding of [MILK THISTLE] silibinin inhibits advance
human prostate carcinoma growth in athymic mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res. 2002 Jun 1;62(11):3063-9. [31]Tyagi A et al,
Silibinin [MILK THISTLE] strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin Cancer Res. 2002
Nov;8(11):3512-9. [32] Tyagi A Antiproliferative and apoptotic effects of silibinin [MILK THISTLE] in rat prostate cancer cells. Prostate. 2002 Nov 1;53(3):211-7.[33]Katiyar SK et al,
Protective effects of silymarin [milk thistle] against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst. 1997 Apr 16;89(8):556-66][34] Katiyar SK. Silymarin [milk thistle] and skin
cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (Review). Int J Oncol. 2005 Jan;26(1):169-76.[35] Silibinin prevents ultraviolet radiation-caused skin
damages in SKH-1 hairless mice via a decrease in thymine dimer positive cells and an up-regulation of p53-p21/Cip1 in epidermis. Carcinogenesis. 2004 Aug;25(8):1459-65. Epub 2004
Mar 19. [36]A flavonoid antioxidant, silymarin [milk thistle], affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res.
1999 Feb 1;59(3):622-32[36] Yanaida Y et al Dietary silymarin [MILK THISTLE] suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis. 2002
May;23(5):787-94.[37]Silymarin [Milk thistle]: potent inhibitor of cyclic AMP phosphodiesterase. Methods Find Exp Clin Pharmacol. 1985 Aug;7(8):409-13.][38]Crocenzi FA et al, Silibinin
[Milk thistle] prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of cAMP. Biochem Pharmacol. 2005 Apr
1;69(7):1113-20.]
[39] von Schonfeld J Silibinin [Milk thistle], 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.] [40] Maghrani M Study of the hypoglycaemic activity of Fraxinus excelsior and Silybum marianum [Milk thistle]  in an animal model of type 1 diabetes
mellitus. J Ethnopharmacol. 2004 Apr;91(2-3):309-16. [41]  Chlopcikova S Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I.
Silymarin [Milk thistle] and its flavonolignans. Phytother Res. 2004 Feb;18(2):107-10. [42] Katiyar SK. Treatment of silymarin [MILK THISTLE], a plant flavonoid, prevents ultraviolet
light-induced immune suppression and oxidative stress in mouse skin. Int J Oncol. 2002 Dec;21(6):1213-22. [43]Wilasrusmee C et al, Immunostimulatory effect of Silybum Marianum (milk
thistle) extract. Med Sci Monit. 2002 Nov;8(11):BR439-43.[44] Ferenci P et al, Randomized controlled trial of silymarin [Milk thistle]  treatment in patients with cirrhosis of the liver. J
Hepatol. 1989 Jul;9(1):105-13. [45] Arteel G Advances in alcoholic liver disease. Best Pract Res Clin Gastroenterol. 2003 Aug;17(4):625-47.[46] Lieber CS Silymarin [Milk thistle] retards the
progression of alcohol-induced hepatic fibrosis in baboons. J Clin Gastroenterol. 2003 Oct;37(4):336-9.[47]. Dehmlow C. Inhibition of Kupffer cell functions as an explanation for the
hepatoprotective properties of silibinin. Hepatology. 1996 Apr; 23 (4): 749-54. [48]. Wu DF The effects of silymarin [Milk thistle] on hepatic microsomal and mitochondrial membrane fluidity
in mice.  Zhongguo Zhong Yao Za Zhi. 2003 Sep;28(9):870-2. [49] Tanamly MD et al, Randomised double-blinded trial evaluating silymarin [Milk thistle]  for chronic hepatitis C in an
Egyptian village: study description and 12-month results. Dig Liver Dis. 2004 Nov;36(11):752-9. [50]Tedesco D Silymarin, a possible hepatoprotector in dairy cows: biochemical and
histological observations. J Vet Med A Physiol Pathol Clin Med. 2004 Mar;51(2):85-9.[51]  Wang MJ Silymarin [MILK THISTLE] protects dopaminergic neurons against
lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation. Eur J Neurosci. 2002 Dec;16(11):2103-12 [52] Kittur S et al, Neurotrophic and neuroprotective effects of milk
thistle (Silybum marianum) on neurons in culture. J Mol Neurosci. 2002 Jun;18(3):265-9.
[53] Hu Z, Herb-drug interactions: a literature review. Drugs. 2005;65(9):1239-82.][54]DiCenzo R Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy. 2003
Jul;23(7):866-70.[55]  Giese LA. Milk thistle and the treatment of hepatitis. Gastroenterol Nurs. 2001 Mar-Apr;24(2):95-7. [56] Saller R et al, The use of silymarin in the treatment of liver
diseases Drugs. 2001;61(14):2035-63.[57] Ferenci P. et al, Randomized controlled trial of silymarin (milk thistle) treatment in patients with cirrhosis of the liver. J Hepatol. 1989
Jul;9(1):105-13. [58]Silymarin inhibits T-lymphocyte function at low doses but stimulates inflammatory processes at high doses. Planta Med. 2003 Jan;69(1):44-9.[59] Jacobs BP, Milk thistle
for the treatment of liver disease: a systematic review and meta-analysis. Am J Med. 2002 Oct 15;113(6):506-15.[60] Rambaldi A. et al, Milk thistle for alcoholic and/or hepatitis B or C virus
liver diseases. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003620.][61] Physiological responses of a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: III. Silymarin
inhibits T-lymphocyte function at low doses but stimulates inflammatory processes at high doses. Planta Med. 2003 Jan;69(1):44-9.
Milk Thistle has been marketed as a herbal supplement having a  protecting benefits on the liver, they claim milk thistle
can even regenerate the liver cells in most liver diseases such as cirrhosis (hardening of the liver), jaundice and
hepatitis (inflammation of the liver), cholangitis (inflammation of bile ducts resulting in decreased bile flow). Milk Thistle
liver to cleanse itself of damaging substances, such as alcohol, drugs, medications, mercury and heavy metals. Milk
thistle is also promoted as an agent which can cleanse and detoxify  overburdened and stagnant livers, strengthen and
tonify weak livers.

Milk thistle is also suggested to be used as a gentle and mild laxative, as it may be able to increase bile secretion and
flow in the intestinal tract. This herb is also claimed to be able to lubricate and soften the stools to a mild laxative effect-
a balance between constipation and diarrhea.  However, scientific supports to these claims are limited. In the following
section, we review what scientists found about milk thistle - benefits and side effects.
__________________________________________________________________________________________

What are the health benefits of milk thistle?
Milk thistle has been used for centuries for the treatment of liver disease. Milk thistle appears to be safe and have
multiple health benefits on various liver conditions; the available evidence on the mechanisms of action appears
promising [1]. Traditionally, milk thistle is commonly used for liver cirrhosis, alcoholic hepatitis, alcoholic fatty liver, liver
poisoning, and viral hepatitis.

What ingredients in milk thistle contribute to its beneficial effects?
Milk thistle extracts are standardized to a concentration of 70-80% of flavone lignans including isosilybinin, silybinin,
silychristin, and silydianin, which are collectively called silymarin. Silymarin may play a role in displacing toxins binding
to the liver and causing the liver cells to regenerate at a faster rate.

Milk thistle is a flowering herb. Silymarin can be extracted from the seeds (fruit). The seeds are used to prepare
capsules containing powdered herb or seed; extracts; and infusions (strong teas). [NCCAM]

Anti-inflammatory, cytoprotective, anticarcinogenic, anti-oxidative and anti-microbial activities
Milk thistle silymarin has anti-inflammatory, cytoprotective, and anticarcinogenic effects. These effects are probably
related to inhibition of activation of NF-kappa B and the kinases. [7] Milk thistle silybin inhibited RNA and protein
synthesis on gram-positive bacteria. [8] Milk thistle, silymarin, reduced NO production at less than 300 ppm. [9] Milk
thistle extract, silymarin, protects cardiomyocytes against doxorubicin-induced oxidative stress via cell membrane
stabilization effect, radical scavenging and iron chelating potency. {41]

Vascular System
Milk thistle and lecithin have found to have anti-atherosclerotic activity in rabbits. Milk thistle-phospholipid complex
showed a strong anti-atherosclerotic activity. [10] Thus, milk thistle may have benefits on vascular system.

Cancers
Milk thistle silymarin exerts chemopreventive effects against tumorigenicity by inhibiting endogenous tumor promoter
TNF alpha. [11] Milk thistle silibinin and milk thistle silymarin, have shown the anticancer effects in different cancer cells
in multiple studies: BLADDER Milk thistle silibinin modulates cyclin-dependent kinase inhibitors - cyclin-dependent
kinases -cyclin cascade and activates caspase 3 causing growth inhibition and apoptotic death of human bladder
transitional cell carcinoma cells. [12] In another study, milk thistle silibinin decreased survivin levels and
caspases-PARP cleavages, in accord with a strong apoptotic death and growth inhibition of Human bladder
transitional-cell papilloma cells. [13] And, milk thistle silymarin was found to be effective in preventing OH-BBN-induced
bladder carcinogenesis in mice. [14] BREAST An in vitro study has suggested a possible synergism between milk thistle
silibinin and conventional cytotoxic agents for breast cancer treatment. [15] Milk thistle extract may exert a strong
anticarcinogenic effect against breast cancer involving inhibition the threshold kinase activities of cyclin-dependent
kinases and associated cyclins, leading to a G1 arrest in cell cycle progression. [16].COLON Study showed a
chemopreventive ability of milk thistle silymarin against chemically induced colon tumorigenesis.[17] ENDOTHELIAL
CELLS Milk thistle silibinin may exert, at least partly, its anti-cancer effect by inhibiting angiogenesis through induction
of endothelial apoptosis via modulation of NF-kappaB, Bcl-2 family and caspases. [18] Milk thistle silibinin toxicity to
cancer cells is found to involve the epidermal growth factor receptor signaling pathway. [19] LUNG Milk thistle
containing Silibinin exerted a dose-dependent inhibitory effect on the invasion and motility of human lung cancer
cells.[20] LIVER Milk thistle may be useful in the prevention or treatment of liver dysfunction in patients undergoing
anticancer therapy.[21] PROSTATE In prostate cancer, milk thistle silibinin exerts its anti-cancer effect probably via
epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling [23]
Milk thistle extracts possess anticancer activities on human prostate carcinoma. Isosilybin A and B might be the most
effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Researchers
suggested that milk thistle extracts enriched for isosilybin A or B might possess improved potency in prostate cancer
prevention and treatment. [22] Finally, milk thistle silibinin was found to able to down regulate
5alpha-dihydrotestosterone, thus, milk thistle may be beneficial to prostate health. [23] There are eight more
studies showing milk thistle benefits on prostate [24-32]. SKIN In studies of rats, milk thistle extracts provided
substantial protection against different stages of UVB-induced carcinogenesis, possibly via its strong antioxidant
properties. [33] In another study, topical treatment of milk thistle silymarin inhibited
7,12-dimethylbenz(a)anthracene-initiated and several tumor promoters in mouse models. [34] There are two more
studies showing  the anti-tumor activities of milk thistle extracts on skin cancer: [35] TONGUE Feeding of milk thistle
silymarin (500 p.p.m.) during the promotion phase of 4-NQO-induced rat tumorigenesis exerts chemopreventive ability
against tongue squamous cell carcinoma through modification of phase II enzymes activity, cell proliferation, and/or
PGE(2) content. [36] Thus, milk thistle extracts may have benefits on people at risk of certain cancers.

Cholestasis
Milk thistle prevents cholestasis induced by estrogens and taurolithocholate via inhibiting cAMP-phosphodiesterase.  
[38] In 1985, Koch HP reported that milk thistle was a very potent inhibitor of cyclic AMP phosphodiesterase. Milk
thistle's constituents, silybin, silydianin and silychristin, are 12.66 to 52.06 times more active than theophylline. [37]

Diabetes
Milk thistle extracts may be useful in treatment of non-insulin-dependent diabetes mellitus, as silibinin inhibits
glucose-stimulated insulin release in vitro, while not affecting blood glucose concentration in vivo. [39]Aqueous extracts
of milk thistle exhibit potent hypoglycaemic and anti-hyperglycaemic activities in normal and streptozotocin diabetic rats
without affecting insulin secretion. [40]  In a study, researchers treated  diabetics with 200 mg of silymarin three times a
day. After four months, patients had reductions in blood glucose levels. The results are very encouraging and the
researchers planned to do further large multi-centre studies. [Milk thistle may help diabetics -study, Reuters, October
30, 2006.] Thus, milk thistle may have benefits on animals at risk of diabetes.

IMMUNE MODULATION
A study of mice showed milk thistle silymarin could prevent UVB-induced immuno-suppression and oxidative stress
probably by inhibiting the infiltration of leukocytes, and myeloperoxidase activity. [42]

A study demonstrated that milk thistle was immunostimulatory in vitro. Milk thistle 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.  [43]

Liver diseases
CIRRHOSIS A double blind study of 170 patients with cirrhosis demonstrated that silymarin (milk thistle extract)
treatment was effective in patients with alcoholic cirrhosis. [44]  A study has suggested that milk thistle and
S-adenosylmethionine may be effective in alcoholic cirrhosis. [45] FIBROSIS Milk thistle silymarin retarded the
development of alcohol-induced hepatic fibrosis in 12 baboons, consistent with several positive clinical trials. [46]
INJURY The hepatoprotective properties of milk thistle extracts in acute and chronic liver injury is probably related to
inhibition of leukotriene B (4) formation by silibinin [Milk thistle]. [47] The protective effects of milk thistle on liver injury
may be related to the recovery of the membrane fluidities of liver microsome and mitochondria [48] HEPATITIS C A
double-blinded trial of 141 subjects demonstrated that milk thistle extract, silymarin, could improve symptoms and
general well-being of patients suffered from hepatitis C. [49] However, some researchers found that milk thistle extracts
had no benefits on liver health. For instance, milk thistle extract was found to have no hepatoprotective effect on dairy
cows. [50] Thus, milk thistle may benefit people at risk of certain liver issues.

Milk thistle may have protective effects on neural system
In a cell study, milk thistle silymarin significantly inhibited the LPS-induced activation of microglia and the production of
inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide (NO), and reduced the damage to
dopaminergic neurons.[51] In a study, milk thistle extract protected cultured rat hippocampal neurons against oxidative
stress-induced cell death. [52] Thus, milk thistle may have benefits of neuronal protection.
_________________________________________________________________________________________

MILK THISTLE DRUG INTERACTION
Milk thistle decreased the trough concentrations of indinavir in humans. [53] However, another study showed milk thistle
had no apparent effect on indinavir plasma concentrations. [54]  This conflicting data might be due to different milk
thistle product preparation, extraction method, product composition, experimental design or even the purity of milk
thistle.

MILK THISTLE SIDE EFFECTS
Milk thistle appears to be safe and accepted by patients. Only a few cases of milk thistle side effect have been
reported. Citations about milk thistle side effects and safety issues from various researchers are summarized as follows:

[1] Silymarin (milk thistle) with few side effects that has been safely used for centuries to treat liver ailments. [55]

[2] Silymarin (milk thistle) side effects include gastrointestinal disturbances and allergic skin rashes.[56]

[3] In a study of 170 patients with cirrhosis, researchers observed no milk thistle side effect.  [57]

[4] Silymarin (milk thistle) exposure did not produce any signs of overt toxicity or any changes in relative organ weights.
Johnson VJ et al, Physiological responses of a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: III. [58]

[5] Treatment with milk thistle appears to be safe and well tolerated. No reduction in mortality, but improvements in
histology and in biochemical markers of liver function among patients with chronic liver disease were found with milk
thistle supplement. [59]

[6] Milk thistle was not associated with a significantly increased risk of adverse events. [60]

[7] High dose of milk thistle may stimulate inflammatory process (from a mice study). [61]

Note Milk thistle can produce allergic reactions, which tend to be more common among people who are allergic to
plants in the same family (e.g. ragweed, chrysanthemium, marigold, and daisy}.
__________________________________________________________________________________________

CONCLUSIONS
1. Milk thistle has somewhat benefits on liver conditions. But,  its effect on hepatitis C is inconclusive.
2. Milk thistle extracts are well-accepted, with limited side effects.
3. Milk thistle extracts may have benefits of cancer prevention, based on the vitro and animal studies.
--
Milk Thistle Benefits, Milk Thistle Side Effects - ZHION.COM
zhion@zhion.com November 12, 2011
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