Mediterranean Herb Guards Vital Liver Functions

The liver performs over 500 life-sustaining functions, including neutralizing toxins.¹

Milk thistle, a plant native to the Mediterranean regions, has long been prized as a treatment for chronic liver ailments.^2,3

Human and animal studies are confirming these benefits.

Researchers are now finding how milk thistle can protect against metabolic syndrome, guard against fatty liver disease, and neutralize the hepatitis C virus.

Maintaining liver function is essential to overall health and longevity. The ability of milk thistle to protect the liver continues to be validated in the published literature.

The most exciting new data reveals that milk thistle may help protect against a broad array of common malignancies.

What Is Milk Thistle and How Does It Work?

Milk thistle seeds contain several compounds that exert beneficial biological effects, the most prominent of which are silybin and silymarin.^2,4

Unlike many pharmaceuticals, milk thistle extracts benefit liver function by multiple mechanisms of action. In this way, milk thistle extracts provide broad-spectrum benefits for supporting overall health.

Milk thistle’s components help the liver cleanse the blood of toxins and shield liver cells from the barrage of free radicals, fats, sugars, and other compounds that lead to common liver ailments.

Metabolic Syndrome and Fatty Liver Disease

Too many Americans are destroying their livers due to obesity and excess ingestion of sugars, starches, and the wrong fats.

This deadly phenomenon is not limited to the United States. Populations around the world who adopt Western eating patterns are experiencing an epidemic of metabolic syndrome. A diagnosis of metabolic syndrome is made when a person has a combination of abdominal obesity, hypertension, loss of blood sugar control, and blood lipid disturbances. While metabolic syndrome affects most organs in the body, it is potentially lethal to the liver.

Metabolic syndrome can change the way liver cells handle the continual flood of sugars and fats coming from the intestinal tract. This river of sugar and fats that accumulates in the liver can lead to non-alcoholic fatty liver disease (NAFLD). Unfortunately, people with non-alcoholic fatty liver disease are usually unaware of this deadly fat buildup in their liver until it is too late.

In its more advanced stages, non-alcoholic fatty liver disease can progress to non-alcoholic steatohepatitis (NASH). Non-alcoholic steatohepatitis is an even more dangerous, progressive condition involving inflammation and fibrosis of liver tissue, producing liver cirrhosis in 20% of people and death in 12%. Non-alcoholic steatohepatitis can also develop into liver failure and may progress to hepatocellular carcinoma, the deadliest and one of the most common forms of liver cancer.⁵

Combatting metabolic syndrome in its earliest stages protects the liver and can prevent the progression to non-alcoholic fatty liver disease and to non-alcoholic steatohepatitis.

Milk Thistle Protects against Fatty Liver Disease

 

Animal studies show that milk thistle and its extracts provide multi-targeted protection of the liver against both non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

For example, the milk thistle compound silybin was more effective than the antidiabetic drug rosiglitazone at stabilizing liver cells’ damaged energy-handling metabolism, while improving insulin resistance and reducing oxidative stress.⁶ Indeed, silybin’s normalization of insulin resistance and reduction of cell damage proved beneficial to both heart and liver tissue in animals with non-alcoholic steatohepatitis.⁷

In addition to reducing insulin resistance, a major factor in progression of non-alcoholic fatty liverdisease to non-alcoholic steatohepatitis, silybin has also been shown to target and reduce central obesity by regulating the expression of key enzymes and genes involved in the breakdown of lipids (lipolysis) and the formation of glucose (gluconeogenesis), leading to enhanced fat breakdown and inhibition of new glucose production.⁸ Milk thistle extract also produces significant reductions in excess liver weight. This reduction in liver weight helps reduce the dangers of fat progression in the liver.⁹

More importantly, silymarin was shown in recent animal studies to suppress activation of liver inflammatory cells, which are implicated in progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis.^10,11 Silybin treatment in a mouse model of non-alcoholic steatohepatitis counteracted this progression by regulating lipid metabolism in liver cells and suppressing oxidative stress-mediated toxicity.¹¹

What You Need to Know

Milk Thistle Benefits the Liver

• The liver is the largest solid internal organ and is critical to all human biological functions.
• A high rate of chemical reactions makes the liver uniquely susceptible to chemical stresses, inflammation, and loss of energy balance functions, leading to a number of deadly and progressive liver disorders.
• Milk thistle, an indigenous Mediterranean plant, has a long history of use as a liver tonic.
• Modern science has demonstrated beneficial effects of milk thistle extracts in liver diseases such as non-alcoholic fatty liver disease and its dangerous sequel, non-alcoholic steatohepatitis, which can, in turn, lead to deadly liver fibrosis and cirrhosis.
• Milk thistle blocks entry of hepatitis C viral particles into liver cells, while intravenous silybin from milk thistle can reduce the viral load in people already infected.
• Their myriad mechanisms of action give milk thistle extracts powerful cancer chemoprotective effects against liver cancers and several other cancer types.
• Exercise and a healthy lifestyle can promote liver health and reduce its threats, and the addition of daily milk thistle supplementation can augment those benefits.

Human Studies

All of the previously discussed health-boosting properties of milk thistle have been demonstrated in humans, particularly when milk thistle is used in combination with vitamin E.

One human study has shown that in patients diagnosed with non-alcoholic fatty liver disease, supplementation with a silybin compound plus vitamin E produced significant improvements in blood markers of liver damage, insulin sensitivity, and the microscopic appearance of liver cells.¹² Overweight and obese participants (approximately 85% of subjects) also saw a 15% improvement in body mass index. In patients who also had hepatitis C viral infection, the supplement improved markers of liver fibrosis.

In a recent European study, patients with metabolic syndrome and non-alcoholic fatty liver disease participated in an open trial of silymarin plus vitamin E.¹³ One group took this nutrient combination for 90 days, while another group received no treatment. All subjects followed a standard regimen of diet and exercise to reduce lifestyle contributions to the disease.

The supplemented group showed significantly greater reductions in abdominal circumference (4.3%), body mass index (2.2%), size of the liver (5.5%), and ultrasound measurements of fat accumulations in their livers (34%), compared with patients in the diet/exercise-only group.¹³

Liver Fibrosis and Cirrhosis

Liver fibrosis results from liver cell injury and leads to eventual liver scarring. Fibrosis is a common condition that can occur with progression of almost all chronic liver diseases.¹⁴ When fibrosis takes over the entire liver, the liver begins to shut down. Physical changes in the liver start to restrict blood flow, cause backup of bile, and produce end-stage liver failure in the condition known as liver cirrhosis.^15,16 The onset of cirrhosis signals a very poor prognosis.¹⁷

Animal studies reveal that milk thistle extracts can be of use in slowing or even preventing liver fibrosis and progression to cirrhosis. Silybin can boost the function and number of mitochondria in liver cells, enhancing the cells’ ability to handle nutrient molecules efficiently.¹⁸ This protects liver cells from the damage induced by many chemical compounds, which can otherwise induce fibrosis.^14,19

An early human study of patients with pre-existing cirrhosis showed that silymarin, 140 mg three times daily, significantly increased four-year survival time from 39% in untreated people to 58% in silymarin- supplemented subjects.²⁰

How Milk Thistle Works

Milk thistle’s bioactive components work on different pathways to provide a broad range of liver support and protection including:

• Free radical protective properties that boost natural intracellular protection systems.^1,46,47
• Suppression of key inflammatory signaling systems resulting in a reduction in markers of inflammation.^1,46-48
• Ability to bind to excess iron, which when stored in the liver, can lead to cell death and dysfunction.⁴⁹
• Increase of vital longevity-promoting control systems, including the potent AMPK (adenosine monophosphate activated protein kinase), which regulates how the body burns and stores fuel molecules such as fats and sugars and cleans up damaged proteins that promote aging.⁴⁸
• Inhibition of the mammalian target of rapamycin (mTOR), a protein that promotes aging at the cellular level.⁴⁸

Hepatitis C Virus Infection

Hepatitis C virus affects an estimated 170 million individuals worldwide and can result in hepatocellular carcinoma,²¹ one of the most aggressive forms of liver cancer.²²

Breakthrough medications that cure most cases of hepatitis C have recently been in the news, mainly because their cost ($84,000) is so overwhelming.

In a promising development, scientists using live-cell imaging and electron microscopy have discovered that silybin has now been shown to inhibit the entry of the hepatitis C virus into liver cells.²¹

Silybin accomplishes this protective benefit by altering the shape and function of cell membrane complexes that the hepatitis C virus uses to attach itself to the cell.²¹ In other words, silybin prevents the hepatitis C virus from lodging and attaching itself in the liver. This finding suggests that silybin might have important preventive effects for people not yet infected with the virus, and possibly for those receiving liver transplants in the hope of preventing reinfection of the graft. Based on these findings, scientists reported that there might be future antiviral benefits of silybin yet to be discovered.

While we are waiting for large-scale human studies regarding silymarin’s anti-hepatitis C benefits, there are promising studies using intravenous silybin.^23-25 Studies in human patients generally show that intravenous silybin is well-tolerated and has an important anti-hepatitis C virus effect by decreasing viral load, even in people who have not responded to standard therapy.^23,24,26-28 In 2015, the first case study was published showing that, in a single patient, intravenous silybin could successfully eliminate the hepatitis C virus after prolonged treatment.²⁹

None of these remarkable findings mean that hepatitis patients should neglect the curative properties of drugs like Sovaldi^®, assuming they can afford it. For helping to heal a damaged liver and further neutralizing hepatitis C infection, milk thistle supplementation should be considered.

Scientists Explore Milk Thistle’s Anti-Aging Benefits

Silymarin was shown to increase the life span of an animal commonly used in aging research, the worm C. elegans, by as much as 25%.⁵⁰ Intriguingly, in a C. elegans model of Alzheimer’s disease, the worms have been modified to produce the toxic beta amyloid protein found in the brains of humans with the disease. The result is that these worms become paralyzed.⁵⁰

Following treatment with silymarin, the animals showed a delay in onset of paralysis, and a resistance to beta amyloid-induced oxidative stress, raising the real possibility that silymarin might have a role in prevention of human Alzheimer’s disease.⁵⁰

Silymarin also has favorable impacts on cancer risk, not only in the liver, but throughout the body. A major portion of this benefit arises from its ability to regulate liver detoxification pathways in a coordinated fashion. This helps to reduce the activation of potential carcinogens, while enhancing their elimination from the body.

Neutralizing Deadly Toxins

The liver receives blood from the intestinal tract, which means that it is the first to be exposed to a variety of toxins that we swallow. There are two major enzymatic liver detoxification systems, known as Phase I and Phase II. Silymarin regulates both of these detoxification systems, which greatly reduces the risk of a carcinogenic compound being released into the body.

Phase I enzymes break down a variety of potentially harmful molecules, including drugs, alcohol, and toxic compounds, rendering them harmless. But, on their way to their final state, those molecules undergo changes to form highly reactive compounds that can induce mutations in DNA, kill cells, produce birth defects, and promote cancer.³⁰ Silymarin’s dual activity protects against these outcomes by inhibiting phase I enzymes and reducing their production of toxic intermediates and by activating phase II enzymes.^30-32

Phase II liver enzymes, on the other hand, modify potentially toxic molecules that promote their secretion in the bile, leading to their eventual excretion from the body. Silymarin promotes Phase II enzyme activity, helping to hasten elimination of toxic and potentially carcinogenic materials.^30-32

These powerful impacts on liver functions ultimately result in lower exposure to potentially cancer-inducing chemicals. This reduces the threat of cancer in parts of the body as distant from the liver as the breast, prostate, and lungs. Silymarin works through a number of important pathways and mechanisms to block the development of cancer.

These anti-cancer activities:

• Induce apoptosis, the programmed cell death process that normally controls excessive growth in tissues. This process of apoptosis is broken in cancer cells, which allows them to reproduce and spread without control.³³
• Block invasion of healthy tissues by cancer cells.³³
• Inhibit a molecular transcription factor known as pSTAT3, which is required for growth and metastasis in breast, colon, prostate, and non-small-cell lung cancers.³⁴
• Regulate the cell division cycle that goes out of control in cancer.³⁵
• Re-activate a colon tumor suppressor gene, CDX2, which is deactivated early in the process of colon carcinogenesis.³⁶
• Become highly concentrated in breast cancer tissue when given orally, delivering it directly to one important site of action.³⁷
• Inhibit glucose transport into cancer cells, starving them of their source of energy.³⁸

Increasing Milk Thistle Absorption

As beneficial as milk thistle is, there is one thing keeping it from reaching its fullest potential: Silybin, the star component of silymarin, does not dissolve well in water.^51,52 That gives it poor bioavailability, meaning it is difficult for it to reach tissues and cells in the body.^53-56

But scientists have now developed a simple but effective technology to overcome silybin’s poor bioavailability. The solution is to mix the silybin with a nutrient called phosphatidylcholine.

Phosphatidylcholine is a major component of cell membranes and can facilitate transport across the cells lining the intestines, making it an ideal “carrier molecule” for silybin.^53,57 Scientists believe that phosphatidylcholine molecularly bonds to the silybin molecule and wraps around it, ushering it through the membranes of cells in the intestinal tract.⁵³

The silybin-phosphatidylcholine complex is absorbed nearly 5 times better than silymarin alone, and its ultimate concentration to the liver, its target organ, is 10-fold greater than silymarin alone.^54-56

In a study of rats exposed to various liver toxins (including dry-cleaning fluid, acetaminophen, and alcohol), silybin plus phosphatidylcholine protected against the telltale rise in plasma levels of liver enzymes (a marker of liver damage), while the same doses of either nutrient alone had no detectable effect.⁵⁸

A series of human trials has found that this complex also has better results than silymarin or silybin alone, lowering serum levels of liver enzymes and producing clinical improvement in studies of liver cirrhosis and hepatitis caused by alcohol, drugs, and viruses.⁵³

Protects against Primary Liver Cancer

Hepatocellular carcinoma is one of the most common and deadliest liver cancers and is increasing worldwide.³¹ Treatment for hepatocellular carcinoma is limited, with liver transplantation being the best option.³⁹ Yet, even with liver transplantation, the prognosis remains grim.^1,31

There is preliminary data suggesting that milk thistle extracts may be chemoprotective against hepatocellular carcinoma.^31,40 In a study of hepatocellular carcinoma in rats, silymarin favorably modified phase I and II liver enzymes and decreased malignant cell proliferation, reduced expression of proteins that interfere with normal cell death by apoptosis, and increased expression of proteins that promote natural apoptotic cell death, all effects that reduce growth and invasiveness of cancers.³¹

Other animal studies demonstrate that silybin slows the growth of implanted human hepatocellular carcinoma tumors, the result of many different mechanisms of action.⁴¹

All of the general anticancer properties of milk thistle extracts bode well for cancer chemoprevention at sites throughout the body. No large human trials have been completed yet, but evidence from animal and basic science studies shows that milk thistle extracts, including silymarin and silybin, can:

• Slow the transition of cell types in lung tissue that precedes emergence of non-small-cell lung cancers.⁴²
• Reduce cancer cell survival and inhibit growth of squamous cell cancers from the human pharynx.⁴³
• Arrest the cell cycle and induce beneficial cancer cell death in human ovarian cancer cells.⁴⁴
• Show affinity for prostate cancer cells and inhibit migration of malignant cells.⁴⁵
• Reduce inflammatory changes and slow the cell replicative cycle in human colorectal cancer cells.³⁵

Summary

The human liver engages in half a thousand unique chemical reactions that influence human health throughout the body. All of that chemical activity exposes liver tissue to unmatched levels of oxidative stress and inflammation, while modern lifestyles pile on abuse in the form of excessive fats, sugars, and chemical toxins.

As a result, liver diseases such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and liver fibrosis/cirrhosis are growing in frequency, as are rates of infection with hepatitis C virus and development of hepatocellular carcinoma. Even cancers in other parts of the body can result from the liver’s improper handling of toxins and carcinogens.

Milk thistle, a flowering plant native to the Mediterranean regions, has long been used as a specific liver tonic. Today, scientific evidence abounds that milk thistle extracts, including silymarin and its chief component, silybin, indeed have multiple health-promoting properties that can benefit liver health.

Studies show that milk thistle extracts can mitigate non-alcoholic fatty liver disease, which can develop as a result of several causes, including metabolic syndrome. Extracts appear to help slow the progress of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis, a deadly consequence of progressive inflammation and fibrosis of the liver. There is early evidence that milk thistle also slows eventual progression of liver diseases to fibrosis and cirrhosis, which are life threatening.

Perhaps most exciting is the volume of pre-clinical data indicating how milk thistle extract may help protect against a broad array of common and deadly malignancies.

Care of the liver is essential for a long and healthy life. A lifestyle that limits ingestion of dangerous fat, sugar, starch, and alcohol calories along with increased physical activity is the first step. Regular supplementation with a high-quality milk thistle extract is an excellent addition to such a regimen.

If you have any questions on the scientific content of this article, please call a Life Extension^® Health Advisor at 1-866-864-3027.

Editor's Note

Science continues to evolve, and new research is published daily. As such, we have a more recent article on this topic: Milk Thistle Promotes Liver Detoxification

References

1. Shulman M, Nahmias Y. Long-term culture and coculture of primary rat and human hepatocytes. Meth Molec Biol. (Clifton, N.J.). 2013;945:287-302.
2. Mastron JK, Siveen KS, Sethi G, et al. Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review. Anticancer Drugs. 2015;26(5):475-86.
3. Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20-6) in F344/N rats and B6C3F1 mice (Feed Studies). Natl Toxicol Program Tech Rep Ser. 2011(565):1-177.
4. Polyak SJ, Ferenci P, Pawlotsky J-M. Hepatoprotective and antiviral functions of silymarin components in HCV infection. Hepatology (Baltimore, Md.). 2013;57(3):1262-71.
5. McCullough AJ. The clinical features, diagnosis and naturalhistory of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8(3): 521-33, viii.
6. Yao J, Zhi M, Minhu C. Effect of silybin on high-fat-induced fatty liver in rats. Braz J Med Biol Res. 2011;44(7):652-9.
7. Salamone F, Galvano F, Marino Gammazza A, et al. Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis. Dig Liver Dis. 2012;44(4):334-42.
8. Yao J, Zhi M, Gao X, et al. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver. Braz J Med Biol Res. 2013;46(3):270-7.
9. Pais P, D’Amato M. In vivo efficacy study of milk thistle extract (ETHIS-094) in STAM model of nonalcoholic steatohepatitis. Drugs R D. 2014;14(4):291-9.
10. Kim M, Yang SG, Kim JM, et al. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. Int J Mol Med. 2012;30(3):473-9.
11. Salamone F, Galvano F, Cappello F, et al. Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Transl Res. 2012;159(6):477-86.
12. Loguercio C, Andreone P, Brisc C, et al. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med. 2012;52(9):1658-65.
13. Sorrentino G, Crispino P, Coppola D, et al. Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study. Drugs R D. 2015;15(1):21-5.
14. Clichici S, Olteanu D, Nagy AL, et al. Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl(4)-treated rats. J Med Food. 2015;18(3):290-8.
15. Available at: http://www.niddk.nih.gov/health-information/health-topics/liver-disease/cirrhosis/pages/facts.aspx. Accessed February 8, 2016.
16. Bataller R, Brenner DA. Liver fibrosis. J Clin Inves. 2005;115(2):209-18.
17. Available at: http://www.medscape.com/viewarticle/572659.Accessed February 8, 2016.
18. Serviddio G, Bellanti F, Stanca E, et al. Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis. Free Radic Biol Med. 2014;73:117-26.
19. Ghaffari AR, Noshad H, Ostadi A, et al. The effects of milk thistle on hepatic fibrosis due to methotrexate in rat. Hepat Mon. 2011;11(6):464-8.
20. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.J Hepatol. 1989;9(1):105-13.
21. Blaising J, Levy PL, Gondeau C, et al. Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking. Cell Microbiol. 2013;15(11):1866-82.
22. El-Tayeh SF, Hussein TD, El-Houseini ME, et al. Serological biomarkers of hepatocellular carcinoma in Egyptian patients. Dis Markers. 2012;32(4):255-63.
23. Barcena R, Moreno A, Rodriguez-Gandia MA, et al. Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period. J Hepatol. 2013;58(3):421-6.
24. Marino Z, Crespo G, D’Amato M, et al. Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period. J Hepatol. 2013;58(3):415-20.
25. Rendina M, D’Amato M, Castellaneta A, et al. Antiviral activity and safety profile of silibinin in HCV patients with advanced fibrosis after liver transplantation: a randomized clinical trial. Transpl Int. 2014;27(7):696-704.
26. Braun DL, Rauch A, Durisch N, et al. Efficacy of lead-in silibinin and subsequent triple therapy in difficult-to-treat HIV/hepatitis C virus-coinfected patients. HIV Med. 2014;15(10):625-30.
27. Ferenci P, Scherzer TM, Kerschner H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology. 2008;135(5):1561-7.
28. Socha L, Karpinska E, Jurczyk K, et al. Rescue therapy with intravenous silibinin in liver transplant recipients with recurrent HCV hepatitis - two case reports. Ann Transplant. 2014;19:161-4.
29. Dahari H, Shteingart S, Gafanovich I, et al. Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics. Liver Int. 2015;35(2):289-94.
30. Kiruthiga PV, Karthikeyan K, Archunan G, et al. Silymarin prevents benzo(a)pyrene-induced toxicity in Wistar rats by modulating xenobiotic-metabolizing enzymes. Toxicol Ind Health. 2015;31(6):523-41.
31. Gopalakrishnan R, Sundaram J, Sattu K, et al. Dietary supplementation of silymarin is associated with decreased cell proliferation, increased apoptosis, and activation of detoxification system in hepatocellular carcinoma. Mol Cell Biochem. 2013;377(1-2):163-76.
32. Liska DJ. The detoxification enzyme systems. Altern Med Rev. 1998;3(3):187-98.
33. Woo SM, Min KJ, Chae IG, et al. Silymarin suppresses the PGE2 -induced cell migration through inhibition of EP2 activation; G protein-dependent PKA-CREB and G protein-independent Src-STAT3 signal pathways. Mol Carcinog. 2015;54(3):216-28.
34. Bosch-Barrera J, Menendez JA. Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat Rev. 2015;41(6):540-6.
35. Eo HJ, Park GH, Song HM, et al. Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells. Int Immunopharmacol. 2015;24(1):1-6.
36. Sangeetha N, Nalini N. Silibinin modulates caudal-type homeobox transcription factor (CDX2), an intestine specific tumor suppressor to abrogate colon cancer in experimental rats. Hum Exp Toxicol. 2015;34(1):56-64.
37. Lazzeroni M, Guerrieri-Gonzaga A, Gandini S, et al. A presurgical study of oral silybin-phosphatidylcholine in patients with early breast cancer. Cancer Prev Res (Phila). 2016;9(1):89-95.
38. Zhan T, Digel M, Kuch EM, et al. Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins. J Cell Biochem. 2011;112(3):849-59.
39. Available at: http://emedicine.medscape.com/article/197319-overview. Accessed February 11, 2016.
40. Ramakrishnan G, Elinos-Baez CM, Jagan S, et al. Silymarin downregulates COX-2 expression and attenuates hyperlipidemia during NDEA-induced rat hepatocellular carcinoma. Mol Cell Biochem. 2008;313(1-2):53-61.
41. Cui W, Gu F, Hu KQ. Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice. World J Gastroenterol. 2009;15(16):1943-50.
42. Cufi S, Bonavia R, Vazquez-Martin A, et al. Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. Food Chem Toxicol. 2013;60:360-8.
43. Su CH, Chen LJ, Liao JF, et al. Increase of phosphatase and tensin homolog by silymarin to inhibit human pharynx squamous cancer. J Med Food. 2013;16(9):778-84.
44. Fan L, Ma Y, Liu Y, et al. Silymarin induces cell cycle arrest and apoptosis in ovarian cancer cells. Eur J Pharmacol. 2014;743:79-88.
45. Snima KS, Arunkumar P, Jayakumar R, et al. Silymarin encapsulated poly(D,L-lactic-co-glycolic acid) nanoparticles: a prospective candidate for prostate cancer therapy. J Biomed Nanotechnol. 2014;10(4):559-70.
46. Ebrahimpour Koujan S, Gargari BP, Mobasseri M, et al. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: a randomized, triple-blind, placebo-controlled clinical trial. Phytomedicine. 2015;22(2):290-6.
47. Feng B, Meng R, Huang B, et al. Silymarin alleviates hepatic oxidative stress and protects against metabolic disorders in high-fat diet-fed mice. Free Radic Res. 2016;50(3):314-27.
48. Lovelace ES, Wagoner J, MacDonald J, et al. Silymarin suppresses cellular inflammation by inducing reparative stress signaling. J Nat Prod. 2015;78(8):1990-2000.
49. Moayedi B, Gharagozloo M, Esmaeil N, et al. A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in beta-thalassemia major patients receiving desferrioxamine. Eur J Haematol. 2013;90(3):202-9.
50. Kumar J, Park KC, Awasthi A, et al. Silymarin extends lifespan and reduces proteotoxicity in C. elegans Alzheimer’s model. CNS Neurol Disord Drug Targets. 2015;14(2):295-302.
51. Kidd P, Head K. A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Altern Med Rev. 2005;10(3):193-203.
52. Dixit N, Baboota S, Kohli K, et al. Silymarin: A review of pharmacological aspects and bioavailability enhancement approaches. Indian J Pharmacol. 2007;39(4):172-79.
53. Kidd PM. Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts. Altern Med Rev. 2009;14(3):226-46.
54. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet. 1990;15(4):333-8.
55. Morazzoni P, Montalbetti A, Malandrino S, et al. Comparative pharmacokinetics of silipide and silymarin in rats. Eur J Drug Metab Pharmacokinet. 1993;18(3):289-97.
56. Morazzoni P, Magistretti MJ, Giachetti C, et al. Comparative bioavailability of Silipide, a new flavanolignan complex, in rats. Eur J Drug Metab Pharmacokinet. 1992;17(1):39-44.
57. Available at: http://www.altmedrev.com/publications/7/2/150.pdf. Accessed February 8, 2016.
58. Conti M, Malandrino S, Magistretti MJ. Protective activity of silipide on liver damage in rodents. Jpn J Pharmacol. 1992;60(4):315-21.