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Milk thistle (Silybum marianum) is a medicinal plant that has been used for thousands of years as a remedy for a variety of ailments. The main component of S. marianum fruit extract (silymarin) is a flavonolignan called silybin, which is not only the major silymarin element but is also the most active ingredient of this extract, which has been confirmed in various studies. This compound belongs to the flavonoid group known as flavonolignans. Silybin’s structure consists in two main units. The first is based on a taxifolin, the second a phenyllpropanoid unit, which in this case is conyferil alcohol. These two units are linked together into one structure by an oxeran ring. Since the 1970s, silybin has been regarded in official medicine as a substance with hepatoprotective properties. There is a large body of research that demonstrates silybin’s many other healthy properties, but there are still a lack of papers focused on its molecular structure, chemistry, metabolism, and novel form of administration. Therefore, the aim of this paper is a literature review presenting and systematizing our knowledge of the silybin molecule, with particular emphasis on its structure, chemistry, bioavailability, and metabolism.

Background Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. Objective To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. Method In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo ( n  = 41) or silymarin (103.2 mg/d, n  = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. Results Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P  = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P  = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P  = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. Conclusion These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. Trial registration The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043).

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.

Hepatitis C virus (HCV) is a major public health problem being the most common cause of chronic liver disease in Egypt. HCV-induced decompensated liver cirrhosis patients have a median survival of 2 years even with currently used new treatments. Silymarin is the most commonly used herbal product in chronic liver disease for its anti-inflammatory, antiviral, antioxidant, and antifibrotic effects. The aim of this study was to assess the effects of silymarin in high dose on the clinical and biochemical status of chronic HCV-associated decompensated liver cirrhosis. The study was conducted on 62 chronic HCV-decompensated cirrhotic patients. Patients were randomized according to treatment plans: group A, included 31 patients who received silymarin in dose of 1,050 mg/day, and group B, included 31 patients who received silymarin in dose of 420 mg/day. Patients were subjected to baseline history taking, laboratory evaluation, abdominal ultrasound, Child scoring, and quality-of-life (QoL) questionnaire. Follow-up was done every 2 weeks for 12 weeks. Silymarin in high dose had an effect on reducing alanine transaminase, aspartate aminotransferase levels (P ≤ 0.01), as well as improving albumin (P = 0.04), bilirubin (P = 0.02), and international normalized ratio (P = 0.03), thus resulted in improvement in Child score (P = 0.048), however, regular silymarin regimen (420 mg/day) failed to achieve the previous biochemical changes. High-dose regimen of silymarin also had a positive impact on improving QoL. No serious adverse events were reported. Silymarin in high dose is a good choice for improvement of liver biochemical profile and QoL in chronic HCV cirrhotic patients.

Silymarin is the extract of Silybum marianum, or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma.

Silymarin, a mixture of flavonolignan and flavonoid polyphenolic compounds extractable from milk thistle (Silybum marianum) seeds, has anti-oxidant, anti-inflammatory, anti-cancer and anti-viral activities potentially useful in the treatment of several liver disorders, such as chronic liver diseases, cirrhosis and hepatocellular carcinoma. Equally promising are the effects of silymarin in protecting the brain from the inflammatory and oxidative stress effects by which metabolic syndrome contributes to neurodegenerative diseases. However, although clinical trials have proved that silymarin is safe at high doses (>1500 mg/day) in humans, it suffers limiting factors such as low solubility in water (<50 μg/mL), low bioavailability and poor intestinal absorption. To improve its bioavailability and provide a prolonged silymarin release at the site of absorption, the use of nanotechnological strategies appears to be a promising method to potentiate the therapeutic action and promote sustained release of the active herbal extract. The purpose of this study is to review the different nanostructured systems available in literature as delivery strategies to improve the absorption and bioavailability of silymarin.

Two novel nanomicellar formulations were developed to improve the poor aqueous solubility and the oral absorption of silymarin. Polymeric nanomicelles made of Soluplus and mixed nanomicelles combining Soluplus with d-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) were prepared using the thin film method. Physicochemical parameters were investigated, in particular the average diameter, the homogeneity (expressed as polydispersity index), the zeta potential, the morphology, the encapsulation efficiency, the drug loading, the critical micellar concentration and the cloud point. The sizes of ~60 nm, the narrow size distribution (polydispersity index ≤0.1) and the encapsulation efficiency >92% indicated the high affinity between silymarin and the core of the nanomicelles. Solubility studies demonstrated that the solubility of silymarin increased by ~6-fold when loaded into nanomicelles. Furthermore, the physical and chemical parameters of SLM-loaded formulations stored at room temperature and in refrigerated conditions (4 °C) were monitored over three months. In vitro stability and release studies in media miming the physiological conditions were also performed. In addition, both formulations did not alter the antioxidant properties of silymarin as evidenced by the 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) assay. The potential of the nanomicelles to increase the intestinal absorption of silymarin was firstly investigated by the parallel artificial membrane permeability assay. Subsequently, transport studies employing Caco-2 cell line demonstrated that mixed nanomicelles statistically enhanced the permeability of silymarin compared to polymeric nanomicelles and unformulated extract. Finally, the uptake studies indicated that both nanomicellar formulations entered into Caco-2 cells via energy-dependent mechanisms.

We aimed to perform a comprehensive study on the development and characterization of silymarin (Syl)-loaded niosomes as potential drug delivery systems. The results demonstrate significant novelty and promising outcomes in terms of morphology, size distribution, encapsulation efficiency, in vitro release behavior, free energy profiles of Syl across the niosome bilayer, hydrogen bonding interactions, antimicrobial properties, cytotoxicity, and in vivo evaluations. The physical appearance, size, and morphology assessment of free niosomes and Syl-loaded niosomes indicated stable and well-formed vesicular structures suitable for drug delivery. Transmission electron microscopy (TEM) analysis revealed spherical shapes with distinct sizes for each formulation, confirming uniform distribution. Dynamic light scattering (DLS) analysis confirmed the size distribution results with higher polydispersity index for Syl-loaded niosomes. The encapsulation efficiency of Syl in the niosomes was remarkable at approximately 91%, ensuring protection and controlled release of the drug. In vitro release studies showed a sustained release profile for Syl-loaded niosomes, enhancing therapeutic efficacy over time. Free energy profiles analysis identified energy barriers hindering Syl permeation through the niosome bilayer, emphasizing challenges in drug delivery system design. Hydrogen bonding interactions between Syl and niosome components contributed to energy barriers, impacting drug permeability. Antimicrobial assessments revealed significant differences in inhibitory effects against S. aureus and E. coli . Cytotoxicity evaluations demonstrated the superior tumor-killing potential of Syl-loaded niosomes compared to free Syl. In vivo studies indicated niosome formulations’ safety profiles in terms of liver and kidney parameters compared to bulk Syl, showcasing potential for clinical applications. Overall, this research highlights the promising potential of Syl-loaded niosomes as effective drug delivery systems with enhanced stability, controlled release, and improved therapeutic outcomes.

Psoriasis is a chronic inflammatory disorder affecting over 100 million people, requires long-term therapy. Current treatments offer only symptomatic relief. However, phytoconstituents-based therapies like Silymarin (SLM) have shown promising effects. The study aims to develop, optimize, and evaluate a novel stable SLM NLC gel to improve anti-psoriatic activity by enhancing its permeability and retention into the dermal layer. SLM NLC formulation was prepared and optimized using 3 2 full factorial designs. The formulation was evaluated for the particle size, PDI, zeta potential, and % entrapment efficiency, evaluated by Transmission electron microscopy and thermal analysis. The freeze dried and prepared NLC-loaded gel was evaluated for physicochemical parameters, ex-vivo , and i n-vivo studies. SLM-loaded NLC shows 624 nm particle size, 0.41 PDI, 92.95% entrapment efficiency, and -31.6 mV zeta potential. The sphere form of NLCs was confirmed using TEM. Controlled drug release was observed in ex vivo studies, low PASI score compared to disease control. Further, the levels of IL-6, TNF-α, and NF-κB were also reduced. The results are supported by histopathology showing minimal parakeratosis indicated in the SLM NLC-treated group. Prepared NLC-based shows enhance topical penetration and decrease the thickness of psoriatic plaques in the in vivo study. Graphical Abstract

The purpose of this study was to compare the bioavailability between 2 milk thistle–containing dietary supplements, Product B and IsaGenesis, in healthy volunteers. Bioavailability between Product B, originally formulated as a powdered capsule, and IsaGenesis, reformulated as a soft gel, were compared by measuring silybin A and silybin B as surrogate pharmacokinetic markers for differences in absorption and bioavailability. For this randomized, open-label, crossover pharmacokinetic study, 12 healthy volunteers consumed a single-dose serving of each supplement separated by at least a 7-day washout period. Serial blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and analyzed via LC-MS/MS. Rapid absorption and elimination of silybin A and silybin B have been observed after oral administration of both Product B and IsaGenesis. However, the absorption rate and extent, as indicated by mean the Cmax and mean plasma AUC, were significantly higher for the IsaGenesis soft gel formulation. The dose-corrected mean Cmax was 365% and 450% greater for silybin A and B, respectively, relative to powdered Product B. The time to Tmax was reached, on average, at least 1 hour earlier with IsaGenesis relative to Product B for both silybin A and silybin B. The IsaGenesis soft gel formulation provided substantially greater absorption and bioavailability of silybin A and silybin B relative to the powdered Product B supplement. ClinicalTrials.gov Identifier: NCT02529605.