Расторопши: семена ранней потенциальных

SILYMARIN

Overview

Silymarin is a natural compound that is present in species derived from Silybum marianum, which is commonly known as Milk thistle. The plant contains at least seven flavolignans and the flavonoid taxifolin. The most important flavolignans present include silybin, silydianin, and silychristine. Silybin represents between 50% and 70% of the extract from silymarin. The following flavolignan isoforms are known (Figure ​(Figure1):1): silbyna A, silbyna B, isosilbyna A, and isosilbyna B[10]. Silymarin has been used worldwide for many years as a complementary alternative medicine because of the beneficial effects associated with the treatment of hepatic diseases. Silymarin belongs to the Aster family (Asteraceae or Compositae). The mature plant has large brilliant-purple flowers and abundant thorns. The plant grows in places with sufficient sun exposure[11].

The low level of bioavailable flavolignans is known. For example, the level of silymarin absorption is between 20% and 50%. Silybin is the major compound of silymarin and limiting factors such as low solubility in water, low bioavailability, and poor intestinal absorption reduce its efficacy. New soluble silybin-derived biocompounds (silybin bis-hemisuccinate, β-cyclodextrin complex, silybin-N-methyl-glucamine, silybin 11-O-phosphate, and silybin-phosphatidylcholine) have thus been designed[10]. Chronic inflammation occurs in patients with hepatic damage. Thus, for patients with compensatory cirrhosis, hepatitis C, and non-alcoholic hepatic steatosis, the bioavailability of compounds present in silymarin may be affected, which may also explain the low effectiveness of treatment with flavonoids in these patients[12,13].

Sy-Cordero et al[14] isolated four key flavolignans and diastereoisomers (silybin A, silybin B, isosilybin A, and isosilybin B) from S. marianum on a gram-scale. These compounds and two other related analogues are present in extremely minute quantities. The compounds were evaluated for their antiproliferative/cytotoxic activity against human prostate cancer cell lines. Silymarin reduces the incidence of certain cancers[15]. Su et al[16] used silymarin on nasopharyngeal carcinoma cells (NPC-TW01) and found an increase in Bcl-2 expression and a decrease in the activated caspase-3 or apoptosis-inducing factor (AIF) with low-dose (80 μmol/L) treatment.

The molecular targets of silymarin for cancer prevention have been studied. Milk thistle interferes with the expression of the cell cycle regulators and proteins involved in apoptosis. Thus, it can modulate the balance between cell survival and apoptosis. Lee et al[17] reported that silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which is regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in the reduced activation of nuclear factor-kappa B (NF-κB), activator protein-1, and STAT3. These proteins are transcriptional regulators of several proliferative genes in melanomas. Silybin blocks the activation of these transcription factors and induces cell-cycle arrest at the G₁ phase, which inhibits melanoma cell growth in vitro and in vivo. Silymarin suppresses ultraviolet radiation A-induced oxidative stress (OS), which can induce skin damage. Thus, the topical application of silymarin can be a useful strategy for protecting against skin cancer[18].

In previous studies, the inherent hepatoprotective and antioxidant activity of silymarin was shown to be caused by its control of free radicals (FR), which are produced by the hepatic metabolism of toxic substances such as Et-OH, acetaminophen (Paracetamol), or carbon tetrachloride. The FR damage cellular membranes and cause lipoperoxidation (LPO)[19]. The cytoprotective effect in liver is also caused by the inhibition of the cyclooxygenase cycle, leukotrienes, and the production of FR in Kupffer cells in mice. These affects reduce inflammation[20], and it has been suggested that silymarin also performs the following functions: protecting against genomic injury, increasing hepatocyte protein synthesis, decreasing the activity of tumor promoters, stabilizing mast cells, chelating iron, and slowing calcium metabolism, among other activities that have been described in the literature[21].

Silymarin has been reported to have antioxidant, immunomodulatory, anti-fibrotic, anti-proliferative, and antiviral properties. It also affects the synthesis of RNA and DNA. Furthermore, silymarin maintains the integrity of the hepatocyte membrane and impedes the entrance of toxic substances or xenobiotics. Due to its phenolic nature, it is capable of donating electrons to stabilize FR and reactive oxygen species (ROS). Silymarin also affects intracellular glutathione, which prevents lipoperoxidation of membranes[22].

Pure compounds extracted from silymarin have been examined in cell lines infected with the hepatitis C virus (HCV). Polyak et al[23] showed that silymarin inhibits the replication of an infectious HCV genotype 2a strain (JFH1) in hepatoma cell cultures. The most effective compounds were isosilbin A, taxifolin, and silybinin, and these compounds reduced virus infection. The OS level induced by HCV, the tumor necrosis factor (TNF)-α level, and the transcription factor NF-κB were affected by silbyn A and silbyn B treatment. In general, all of the compounds showed antiviral activity and reduced the OS level caused by HCV infection[24].

The use of a silymarin extract in 72 patients with non-alcoholic hepatic steatosis (non-alcoholic fatty liver disease, NAFLD) on a controlled diet led to significantly reduced levels of alanine aminotransferase (ALT) and aspartame aminotransferase (AST) (AST/ALT < 1). Another parameter evaluated was γ-glutamyl transpeptidase (γ-GT). In NAFLD patients, γ-GT is high because of obesity, hyperinsulinemia, inflammation, and changes in the membrane permeability of the hepatocytes. The level of γ-GT decreased due to the silymarin-mediated inhibition of toxins entering the cells. Additionally, silymarin permits the stabilization of hepatocyte membranes. It also reduced the level of TNF-α, which reduces inflammation. A favorable change in the hepatorenal clearance index was also observed, which suggests a reduction in the accumulation of lipids in the liver. All of these results were visible after 6 mo of treatment[4].