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Milk Thistle in Liver Diseases: Past, Present, Future
Abstract
Silybum marianum or milk thistle (MT) is the most well-researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin-induced liver diseases.
... Currently, the commercial cultivation of milk thistle for therapeutic purposes takes place in Europe, Egypt, China, and Argentina (Sulas et al. 2016). For more than 2000 years, people have used milk thistle as a medicinal ingredient in treating issues involving the liver and gallbladder (Abenavoli et al. 2010;Keshavarz Afshar et al. 2015). The biological homoeostasis and oxidant/antioxidant balance of chickens can be disrupted by the numerous short-and long-acting stressors, such as heat stress, immunological challenges, bacterial diseases, and farming practices, leading to oxidative stress and potentially negative impacts on growth performance and meat quality (Egresi et al. 2020;Lin et al. 2022). ...
... The efficiency of various milk thistle products, as well as the potential health benefits they offer, can be affected by differences in the amounts of silymarin and other chemical elements that they contain. Table 1 summarises the general chemical composition and silymarin content of different milk thistle products (Abenavoli et al. 2010;Aziz et al. 2021;Šťastník, Jůzl, et al. 2019;Stastnik et al. 2020;Sulas et al. 2016). ...
... Thus, we tried to present Table 1. Chemical composition and silymarin content of milk thistle products (Abenavoli et al. 2010;Aziz et al. 2021;Carrier et al. 2003;Šťastník, Jůzl, et al. 2019;Stastnik et al. 2020;Sulas et al. 2016 Chemical composition of milk thistle depends mostly on plant quality. Agricultural technique, soil quality, climate, weather, seed treatment, and pressing all affect the quality of the plant and its expellers. ...
In recent years, many countries have prioritised on using innovative supplements in poultry nutrition. Natural substances can be fed in poultry production with a better level of safety and specific impacts. The majority of these impacts are reflected in final products with added value that are healthy, functional, and free of any antibiotic residue. This review article intends to highlight the nutritional uses and favourable health features of milk thistle (Silybum marianum) and its influence on poultry production. In this regard, milk thistle is abundant in chemical bioactive substances, such as silymarin and has a variety of biological properties, including immuno-stimulating and antioxidant activities. The inclusion of milk thistle in poultry diets increases their growth and productivity. Milk thistle components can improve immune response, antioxidant indices, kidney and liver function, blood haematology, lipid profile and then the physiological status of birds. Thus, milk thistle and its derivatives as feed supplements can meet the desires of producers for augmented poultry performance and the consumer demands to produce poultry under environmentally friendly conditions. Finally, the present review study concluded that supplementation of milk thistle as a natural feed additive may affect the antioxidant, immunity, blood biochemistry, and productive performance in poultry.
... It grows as a wild plant in southern Europe, western Asia and northern Africa (Hassan El-Mallah et al., 2007). Milk thistle is produced for the content of the silymarin complex in its fruits (achenes) (Habán, 2009;Abenavoli et al., 2010). The fruits also contain an important amount of fatty oil (Moudrý, 2011). ...
... Milk thistle is grown commercially mainly in Germany, China, Argentina, Romania, and Mediterranean countries (Abenavoli et al., 2010). Recently, the area of milk thistle cultivation increased in Bulgaria, Poland and Czech Republic (Andrzejewska et al., 2011;Koláčková et al., 2014). ...
... This active substance positively affects liver tissue; helps treat diseases of the gall bladder, including hepatitis and cirrhosis. It protects the liver against intoxication by mushroom toxins and alcohol, as well as snake poison and pest bites (Habán 2009;Abenavoli et al., 2010). Milk thistle has an antioxidant effect; it supports gallbladder function, eases digestive problems, and helps against depression and fatigue (Racz et al., 1990;Pares et al., 1998;Bruneton, 1999). ...
... Chemically it is composed of 4 flavonoids, silybin, isosilybin, silydianin and silychristin (Pradhan and Girish, 2006). Silybin is the major component constituting 50 to 70% of silymarin and exhibit greater biological activities (Ludovico et al., 2010). Pradhan and Girish (2006) reported that milk thistle has hepatoprotective and hepatorestorative functions and protects liver and kidney from both exo-and endo-toxins. ...
... These findings clearly showed the hepatoprotective effect of milk thistle extract (Table 1). Abenavoli et al. (2011) and Ludovico et al. (2010) reported similar hepatoprotective property of milk thistle which is in agreement with findings of the present study. Wang et al. (2010) also reported the hepatoprotective property of silibinin, which is the active ingredient of milk thistle. ...
Milk thistle was added in aflatoxin B1 contaminated poultry feed to investigate and compare its hepatoprotective effects with a commercial toxin binder. Two hundred and forty, day-old broilers were randomly allocated into four major groups A, B, C and D. Group A was kept as control, having aflatoxin free feed, while group B was fed aflatoxin contaminated feed, group C was raised on aflatoxin contaminated feed with toxin binder " Mycoad" @ 3g/kg of feed, while group D was provided aflatoxin contaminated feed along with milk thistle @10g/kg of feed. Aflatoxin B1 was present at the level of 80 μg/kg feed during the first week and 520 μg/kg feed in the remaining experimental period. Serum total protein was significantly (P<0.05) higher in group D, followed by group A, C and B. Serum enzymes including, alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values were significantly (P<0.05) lower in group D, followed by C, A and B, which are indicative of hepatoprotective role of milk thistle. Body weight gain and feed intake was decreased by aflatoxin contaminated feed (group B) in comparison with group A and group D. Milk thistle supplementation improved body weight gain and feed intake and was similar to toxin binder treated birds. Average feed conversion ratio (FCR) was significantly (P<0.05) higher (poor) in group B and were the same in all other groups. Present study demonstrated that milk thistle can potentially be used as mycotoxin binder and to minimize the adverse effects of toxin contaminated feed in broilers production.
... Current consensus recommends that dietary modifcation, exercise, and weight loss as the major treatment option for NAFLD to reduce liver fat and improve IR [86,87]. Besides, considering that silymarin has antioxidant, antiinfammatory, immunomodulatory, antifbrotic, and hepatoprotective activities and stimulates protein synthesis and liver tissue regeneration [88], silymarin may be used for the treatment of NAFLD. Notably, it seems that silymarin can also inhibit H. pylori activity [89][90][91][92]. ...
... 88.7%, p = 0.000) NOTE: Weights are from random effects analysis ...
Background and aims:
Helicobacter pylori (H. pylori) and nonalcoholic fatty liver disease (NAFLD) have become increasingly recognized, both of which affect human health globally. The association of H. pylori infection with NAFLD remains unclear.
Methods:
PubMed, EMBASE, and Cochrane Library databases were searched. Only a random-effects model was used. Odds ratios (ORs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for the combined estimates of raw data. Adjusted ORs (aORs) and hazard ratios (aHRs) with 95% CIs were calculated for the combined estimates of data adjusted for confounders.
Results:
Thirty-four studies with 218573 participants were included. Based on unadjusted data from 26 cross-sectional studies and 3 case-control studies, H. pylori infection was significantly associated with the presence of NAFLD (OR = 1.26, 95% CI = 1.17-1.36, P < 0.001). Based on adjusted data from 15 cross-sectional studies and 1 case-control study, H. pylori infection was significantly associated with the presence of NAFLD (aOR = 1.25, 95% CI = 1.08-1.44, P < 0.001). Compared with control subjects without NAFLD, patients with moderate (OR = 1.67, 95% CI = 1.17-2.39, P = 0.005) and severe (OR = 1.71, 95% CI = 1.30-2.24, P < 0.001) NAFLD, but not those with mild NAFLD (OR = 1.14, 95% CI = 0.9-1.45, P = 0.286), had significantly higher proportions of H. pylori infection. The association of H. pylori infection with the occurrence of NAFLD was statistically significant based on adjusted data from 3 cohort studies (aHR = 1.18, 95% CI = 1.05-1.34, P = 0.007), but not based on unadjusted data from 3 cohort studies (RR = 1.41, 95% CI = 0.80-2.48, P = 0.237).
Conclusion:
H. pylori infection is associated with NAFLD, especially moderate and severe NAFLD. The impact of H. pylori eradication on the prevention of NAFLD should be further explored.
... Silymarin is an extract obtained from the seeds of Silybum marianum (L.) Gaertn (milk thistle) [27]. This mixture contains 65-80% flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin) with small amounts of flavonoids and polyphenolic compounds [28][29][30]. Most of the beneficial effects of silymarin are attributed to its predominant and primary active ingredient, silybin, which is present in proportions of roughly 30% [30,31].Silybin is a pure, chemically defined substance [32]. ...
... It is thought that antioxidants should be used to reduce the acute and chronic hepatoxic effects caused by tacrolimus. Silymarin, fungal poisoning are used therapeutically to reduce even bacterial endotoxins, viral hepatitis, and alcohol-induced liver damage [28]. However, no studies on the protective effects of silymarin against tacrolimus hepatotoxicity could be found. ...
Abstract Background Tacrolimus (FK506) is an immunosuppressive agent and has toxic side effects such as nephrotoxicity, hepatotoxicity, and neurotoxicity. In our study, we aimed to investigate the protective effect of silymarin on renal and hepatic toxicity considered to be tacrolimus related. Methods In this 6-week experimental study, 46 eight-week-old healthy male rats were used. The groups comprised the Control (healthy rats, n = 6), Tac (tacrolimus 1 mg/kg, n = 8), silymarin 100 mg/kg (SLI 100 mg/kg n = 8), Tac + SLI 100 (tacrolimus 1 mg/kg + SLI 100 n = 8), SLI 200 (SLI 200 mg/kg n = 8), and Tac + SLI 200 (tacrolimus 1 mg/kg + SLI 200 mg/kg n = 8). After 6 weeks, all rats were sacrificed, and the tissue follow-up procedure was performed for kidney and liver tissues, histopathology, and in situ TUNEL analysis. Blood samples were analyzed for the total antioxidant capacity (TAC), total oxidant capacity (TOC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), albumin, total bilirubin, creatine. Results Histopathological findings of kidney and liver tissue of rats were determined to increase statistically in Tac group compared to SLI 1 00 and SLI 200 groups (P 0.05). The in situ TUNEL method showed that the tacrolimus increased apoptosis while the silymarin decreased it. TOC levels increased statistically in Tac groups compared to silymarin-treated groups (P 0.05), the lowest was measured in the Tac group. The ALT, AST, GGT, total bilirubin, and creatine values were higher in the Tac group than in the silymarin groups (P 0.05). Conclusion In our study, we determined that tacrolimus caused damage to kidney and liver tissue. Histopathological, biochemical and apoptotic findings show that silymarin has a protective effect against nephrotoxicity and hepatotoxicity caused by tacrolimus.
... Le Chardon-Marie (Silybum marianum (L.) Gaertn) est une plante herbacée annuelle à bisannuelle de la famille des Astéracées reconnaissable à ses feuilles vert pâle et épineuses marbrées de blanc ( Figure 62A). L'usage médicinal du Chardon-Marie remonte à plus de 2 000 ans pour le traitement d'une grande variété de pathologies du foie, de la rate et de la vésicule biliaire grâce à ses puissantes activités anti-oxydantes et anti-inflammatoires (Abenavoli et al., 2010(Abenavoli et al., , 2018. Les effets protecteurs du Chardon-Marie ont été récemment démontrés contre les cancers, maladies neurodégénératives, auto-immunes, cardiovasculaires et métaboliques (Oi et al., 2012;Lee et al., 2013). ...
... De manière intéressante, le TGF-β1 régule l'expression du microARN-21 au niveau transcriptionnel et post-transcriptionnel, en stimulant notamment la maturation du pri-microARN-21 en pré-microARN-21 via l'interaction des protéines Smad avec la sous-unité p68 du complexe Microprocesseur, contenant Drosha (Davis et al., 2008(Davis et al., , 2010Zhong et al., 2011;Wang et al., 2012c). Yang (Abenavoli et al., 2010;Cheung et al., 2010;Dheeraj et al., 2018). De façon surprenante, nous avons récemment montré que l'effet modulateur de la SM sur l'expression du microARN-21-5p n'est pas dépendant de la SB mais de la SC dans les cellules HaCaT traitées par le TGF-β1. ...
Les microARNs jouent un rôle essentiel dans la morphogénèse et l’homéostasie cutanée. Cette classe d’ARN non codant contrôle plusieurs voies de signalisation en régulant l’expression de réseaux entiers de gènes cibles. Ils sont donc considérés comme des cibles biologiques de choix pour les stratégies de criblage de composés bioactifs. Au laboratoire, nous avons conçu une sonde d’imagerie bioluminescente inductible par les microARNs, dénommée RILES pour « RNAi-Inducible Luciferase Expression System » qui se prête particulièrement bien au criblage cellulaire de librairies de composés synthétiques. Au cours de ce doctorat, nous avons placé le système RILES sous contrôle de l’axe de régulation TGF-β1/microARN-21 choisi pour son rôle central dans la ré-épithélialisation cutanée. Le criblage d’une extractothèque de 37 extraits bruts de plantes nous a permis d’identifier trois extraits bruts de plantes, dont celui du Chardon Marie (Silybum marianum (L.) Gaertn) qui a fait l’objet d’études mécanistiques et fonctionnelles poussées.Nous avons montré que l’effet de l’extrait de Chardon-Marie sur le microARN-21 est dépendant d'un complexe contenant six flavonolignanes, appelé silymarine (SM). Des études d’immunoprécipitation de la protéine Argonaute 2 couplée à laRT-qPCR ont permis de révéler un mécanisme de régulation original du microARN-21 par cet extrait. Le séquençage àhaut débit du transcriptome (RNA-seq) des kératinocytes en réponse au traitement par le TGF-β1 et la SM a permis demettre en évidence trois signatures d’expression génique majeures associées à la différenciation kératinocytaire, aucycle cellulaire et de façon inattendue au métabolisme des lipides. Nous avons montré que la SM bloque le cycle cellulaire en phase G0/G1, inhibe la différenciation des kératinocytes via l’inhibition de l’expression de Notch3 et active la synthèse des lipides en inhibant la phosphorylation d’AMPK et en augmentant l’activité transcriptionnelle de PPARγ. Parailleurs, la SM ralentit la migration cellulaire en perturbant la transition épithélio-mésenchymateuse et inhibe les réponses inflammatoires en bloquant l’activité transcriptionnelle de NF-ƙB. Du fait de ces propriétés biologiques, pour certaines nouvelles, nous avons évalué l’effet thérapeutique de la SM contre le développement du psoriasis en plaques induit par l’imiquimod chez la souris. Nos résultats indiquent que la SM pourrait représenter une alternative prometteuse « naturelle » aux traitements pharmacologiques actuels pour la prise en charge de cette pathologie.
... Silibinin (SIL) is the major active component of silymarin, which is a flavonoid extract from milk thistle seeds (Biedermann et al., 2014). SIL possesses various biological activities, including antioxidant, anti-inflammatory, anticancer, and anti-fibrotic activities (Abenavoli et al., 2010;Bosch-Barrera and Menendez, 2015;Mizuno et al., 2020;Fallah et al., 2021). SIL has been reported to be an effective compound against multiple cancers, diabetes, Alzheimer's disease, and hepatic diseases (Bosch-Barrera et al., 2017;Chu et al., 2018;Liu et al., 2019;Shen et al., 2019). ...
Inflammatory bowel diseases (IBDs) are characterized by chronic relapsing intestinal inflammation that causes digestive system dysfunction. For years, researchers have been working to find more effective and safer therapeutic strategies to treat these diseases. Silibinin (SIL), a flavonoid compound extracted from the seeds of milk thistle plants, possesses multiple biological activities and is traditionally applied to treat liver diseases. SIL is also widely used in the treatment of a variety of inflammatory diseases attributed to its excellent antioxidant and anti-inflammatory effects. However, the efficacy of SIL against IBDs and its mechanisms remain unclear. In this study, using Drosophila melanogaster as a model organism, we found that SIL can effectively relieve intestinal inflammation caused by dextran sulfate sodium (DSS). Our results suggested that SIL supplementation can inhibit the overproliferation of intestinal stem cells (ISCs) induced by DSS, protect intestinal barrier function, acid-base balance, and intestinal excretion function, reduce intestinal reactive oxygen species (ROS) levels and inflammatory stress, and extend the lifespan of Drosophila . Furthermore, our study demonstrated that SIL ameliorates intestinal inflammation via modulating the c-Jun N-terminal kinase (JNK) signaling pathway in Drosophila . Our research aims to provide new insight into the treatment of IBDs.
... The mature fruit (hereinafter "seed") of milk thistle contains about 20-30% lipids, 20-30% proteins, 7% water, and less than 1% of other compounds such as sugars, tocopherol, and sterols. Silymarin represents 1.5-3% of dry seed weight (Abenavoli et al. 2010). Due to the high lipid content (20-30%) in milk thistle seeds, the first step in preparation of silymarin is the extraction of the seeds with n-hexane for 6 h, while in the second step silymarin is obtained by extraction of defatted material with methanol for 5 h (Aziz et al. 2021;Marceddu et al. 2022;Wianowska and Wisniewski 2015). ...
... 8,9 Silymarin is derived from milk thistle (Silybum marianum) and comprises a mixture of flavonolignans (silybin, silydianin, and silychristin) and flavonoids (tamoxifen and quercetin). 10 It has been reported that silymarin exerts considerable antiinflammatory, anticarcinogenic, antioxidant, and proapoptotic properties. 11,12 In order to impede cancer progression, silymarin serves key functions such as regulating cell cycle, stimulating apoptosis, and inhibiting cancer cell growth, angiogenesis, invasion, and metastasis. ...
Silymarin (SM) exhibits potential therapeutic effects due to having antioxidant activity. However, the low solubility and bioavailability of SM restrict its biological performance. To overcome this limitation, this study aimed to develop a nanoformulation composed of SM and dimethyltindichloride and investigate the effect of SM-loaded Sn nanoparticles on cancer cell growth and survival. An SM−Sn complex was synthesized and then characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), EDS-MAP, dynamic light scattering (DLS), and ζ-potential analysis. After that, the SW480 colorectal cancer cell line was treated with different concentrations of SM and the SM−Sn complex. Cell viability was examined through the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, analyzing apoptosis, and live−dead assay. The lipid peroxidation rate was assessed through the measurement of thiobarbituric acid (TBA). Intracellular reactive oxygen species (ROS) level and cell population in the cell cycle were measured using a flow cytometry instrument. To evaluate the colonization ability of SW480 cells, a colony formation assay was performed. Gene expression analysis was also conducted using a real-time polymerase chain reaction (PCR) technique. The findings of this study revealed the effectiveness of the SM−Sn complex in decreasing SW480 cell viability by inducing cell death-associated mechanisms. We found that the SM−Sn complex increases intracellular ROS level and malondialdehyde (MDA) content. It was also revealed that the SM−Sn complex induces cell cycle arrest and the expression of apoptotic genes. In addition, the SM−Sn complex could effectively hinder SW480 cells from constituting colonies. We conclude that the use of tin(IV) as a scaffold for enhanced delivery of SM could be considered an efficient option for inhibiting cancer cell proliferation and survival.
... Milk thistle (Silybum marianum L., Family: Asteraceae) is an annual/biennial plant, native of Mediterranean area and now growing and cultivated worldwide including Egypt [25][26][27] (Figure 1). It has been used for centuries in medicine, mainly to treat kidney, spleen and liver diseases [28]. ...
The present study aims to determine the bioactive compounds and biological activities of the Silybum marianum ethanolic extract (SME). Also, the potential effects of SME on obesity and other related complications in rats will be investigated. Data of the proximate chemical composition of Silybum marianum seed powder indicated that carbohydrates were the largest compound (67.21%) followed by ash (16.23 ± 1.14 %), crude fat (26.72%), Total protein (22.17%), crude fiber (7.17%) and ash (2.83%). Also, bioactive compounds content of SME indicated that Silymarin was the most largest compound (269.65 mg. g-1) followed by phenolics (127.65 mg gallic acid equivalent. g-1), flavonoids (65.1 mg quercetin equivalent. g-1), tannins (39.49 mg catechine equivalent. g-1), α-tocopherol (27.43 mg. g-1), chlorophyll (11.54 mg. g-1), β-carotene (6.83 mg. g-1) and anthocyanin's (4.29 mg Cyanidin 3-glucoside, CCy3G equivalent.g-1). The samples also exhibited several high biological activities which include inhibition of low density lipoprotein (LDL) oxidation and scavenging of free radicals. Such important biological effects could play important roles in strategies to combat / treat obesity and its complications in rats. SME intervention by 200 to 800 mg/kg bw/day by oral gavages for 8 weeks consecutive days leads to significantly (p≤0.05) decrease the body weight, lower the serum lipid profile parameters (TGs, TC and LDL-c), enhanced the liver functions in obese, and positively manipulate of the obesity-related the histopathological changes of the model (obese) control group. Therefore, data of the present study recommended like of that Silybum marianum extracts to be included in our daily diets, drinks, food supplementation and pharmacological formulae for the obese patients. Cite This Article: Yousif A. Elhassaneen, Amal Z. Nasef, Rawan S. Arafa and Asmaa I. Bayomi, "Bioactive compounds and antioxidant activities of milk thistle (Silybum marianum) extract and their potential roles in the prevention of diet-induced obesity complications.
... Drugs used for ALD therapy include glucocorticoids, pentoxifylline and metadoxine, which have various side effects [3]. Silymarin (Sil), one of the representative agents, can cause gastrointestinal adverse events after chronic administration [1,4]. ...
Alcoholic liver disease (ALD) can be induced by excessive alcohol consumption, and has a worldwide age-standardized incidence rate (ASIR) of approximately 5.243%. Inonotus hispidus (Bull.) P. Karst. (IH) is a mushroom with pharmacological effects. In ALD mice, the hepatoprotective effects of IH were investigated. IH strongly ameliorated alcohol-induced pathological changes in the liver, including liver structures and its function-related indices. Intestinal microbiota and serum metabolomics analysis showed that IH altered the associated anti-inflammatory microbiota and metabolites. According to results obtained from Western blot, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA), IH downregulated the levels of pro-inflammation factors interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α), enhanced the expressions of peroxisome proliferator-activated receptor alpha (PPARα) and 15-hydroxprostaglandin dehydrogenase (15-PGDH), and inhibited the phosphorylated activation of Janus kinase (JAK) 1 and signal transducer and activator of transcription (STAT) 3, confirming the hepatoprotection of IH against alcohol damage via anti-inflammation. This study provides the experimental evidence for the hepatoprotective effects of IH in chronic ALD.
... It is a natural polyphenolic flavonoid compound -flavonoid lignans (Sun et al. 2022). Since its first discovery in 1986, silybin has demonstrated a wide range of pharmacological activities, with good antioxidant activity (Pietrangelo et al. 1995), protection of mitochondrial membrane integrity (Serviddio et al. 2014), regulation of inflammation, influence on cell survival, autophagy, apoptosis, and other biological functions (Abenavoli et al. 2010). Because of its low toxicity, it is widely used in pharmaceutical research and clinic. ...
The aim of this study was to investigate the splenic tissue damage of environmental biological drug avermectin to freshwater cultured carp and to evaluate the effect of silybin on the splenic tissue damage of carp induced by avermectin. A total of 60 carp were divided into 4 groups with 15 carp in each group, including the control group fed with basic diet, experimental group fed with basal diet and exposed to avermectin (avermectin group), experimental group fed with basal diet supplement silybin (silybin group), and experimental group fed with basal diet supplement silybin and exposed to avermectin (silybin + avermectin group). The whole test period lasted for 30 days, and spleen tissue was collected for analysis. In this study, H&E staining, mitochondrial purification and membrane potential detection, ATP detection, DHE staining, biochemical tests, qPCR, immunohistochemistry, and apoptosis staining were used to evaluate the biological processes of spleen tissue injury, mitochondrial function, oxidative stress, apoptosis, and endoplasmic reticulum stress. The results show that silybin protected carp splenic tissue damage caused by chronic avermectin exposure, decreased mitochondrial membrane potential, decreased ATP content, ROS accumulation, oxidative stress, apoptosis, and endoplasmic reticulum stress. Silybin may ameliorate the splenic tissue damage of cultured freshwater carp caused by environmental biopesticide avermectin by alleviating mitochondrial dysfunction and inhibiting PERK-ATF4-CHOP-driven mitochondrial apoptosis. Adding silybin into the diet becomes a feasible strategy to resist the pollution of avermectin and provides a theoretical basis for creating a good living environment for freshwater carp.
Graphical Abstract
... Silybin is the major component constituting 50 to 60 % of silymarin and exhibit greater biological activities (Ludovico et al., 2010). ...
This study was conducted to investigate the effect of milk thistle plant (Silybum marianum) as antioxidant for improving the performance of Bandarah chickens during summer season (15 June-12 September, 2015). A total number of 225 (195 chickens + 30 cocks) aged 32-week of Bandarah chickens were individually weighed and randomly divided into five treatment groups. Each treatment groups was represented by three replicates (13 hens + 2 cocks) and housed (open system) in 15 floor pens until the end of the experiment (44 weeks of age). The first group was served as a control and fed the basal diet without any supplementation. The second one was fed the basal diet supplemented with vitamin E (150 mg VE /kg diet) used as immunomodulator nutrient. The third group was fed the basal diet supplemented with 0.5g of commercial silymarin per kg diet (SLM). The fourth and the fifth groups were fed the basal diets supplemented with 12.5 and 25.0 g of fine grind aerial parts of milk thistle plant (MTh) /kg diet as a natural source of SLM (represented 0.5 and 1g SLM/ kg diet, respectively). Diets were kept isocaloric and cover nutrient requirements. The screening of chemical analysis indicated that MTh contain 188.5 mg/100g sample of total polyphenols and 320.0 mg/100g sample antioxidant activity. The chicken fed the lower level (12.5g/kg diet) of MTh had the best results on egg production, egg mass, feed conversion ratio, and fertility percentage compared with those in the other experimental groups. Supplementation chicken diet with different agents significantly improved antioxidant status, liver function, lipid profile, haematocrit values and heterophils to lymphocyte ratio compared with the control group. Chicken fed diet supplied with different agent significantly increased estrogen and progesterone hormones concentrations compared to control group. Economic efficiency value (EE) indicated that supplementation the chicken diet in summer condition with MTh (12.5g/kg diet) recorded the highest net return (18.59 LE) and EE (51.17) compared with that in the other experimental groups. In conclusion, supplied chicken diet with 12.5 g MTh /kg diet (equal 0.5g SLM /kg diet) improved the chicken performance and the immune status during summer condition and recorded the best net return and economic efficiency.
... It can help reduce inflammation, which otherwise contributes to symptoms such as headaches [22]. Milk thistle has hepatoprotective effects [23]. As alcohol consumption can damage the liver, consuming milk thistle before or after drinking can help reduce A, B). ...
Many hangover cure products containing natural ingredients that are also effective against alcohol-related liver damage or improve liver function have recently become available. In addition to curing liver damage, antioxidants, anti-inflammatory agents, and blood ethanol reduction aids are emerging as relief targets that reduce hangover symptoms. We investigated the ameliorating effect of WON-21 herbal medicinal products by studying the mixing ratio of oriental medicine concept with respect to antioxidant potential, anti-inflammation, and aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) enzyme activities. WON-21 and its components exerted antioxidant and anti-inflammatory effects. Rutin, taxifolin, and quercetin showed superior antioxidant effects compared to the other components. WON-12 effectively reduced iNOS and COX-2 in LPS-stimulated macrophages. Quercetin and apigenin were 2 compounds effective for the inhibition of iNOS and COX-2. WON-21 and quercetin also significantly increased the activities of ALDH and ADH enzymes in a concentration-dependent manner.
... Silybum marianum is a well-known liver-protecting medicinal plant with a history more than 2000 years [17]. Silymarin, active compounds from the fruits of milk thistle, has been known and used for hundreds of years as the hepatoprotective medicine to treat liver diseases including chronic hepatitis, acute viral hepatitis, and alcoholic liver disease [18]. ...
Ferroptosis, an iron-dependent cell death, is caused by lipid peroxidation. Noteworthily, accumulation of iron and lipid peroxidation are found in the proximity of the neuritic plaque, a hallmark of Alzheimer's disease (AD), but the relationship between ferroptosis and neuroinflammation in AD is unclear. Silibinin, extracted from the Silybum marianum, is possibly developed as an agent for AD treatment from its neuroprotective effect, but the effect of silibinin on sporadic AD that accounts for more than 95% of AD remains unclear. To determine whether silibinin alleviates the pathogenesis of sporadic AD and investigate the underlying mechanisms, STZ-treated HT22 murine hippocampal neurons and intracerebroventricular injection of streptozotocin (ICV-STZ) rats, a sporadic AD model, were used in this study. Results show that silibinin not only promotes survival of STZ-treated HT22 cells, but also ameliorates the cognitive impairment and anxiety/depression-like behavior of ICV-STZ rats. We here demonstrate that silibinin evidently inhibits the protein level of p53 as well as upregulates the protein level of cystine/glutamate antiporter SLC7A11 and ferroptosis inhibitor GPX4, but not p21, leading to the protection against STZ-induced ferroptotic damage. Immunofluorescent staining also shows that accumulation of lipid peroxidation induced by ferroptotic damage leads to increased fluorescence of 8-oxo-deoxyguanosine (8-OHDG), a maker of oxidized DNA. The oxidized DNA then leaks to the cytoplasm and upregulates the expression of the stimulator of interferon gene (STING), which triggers the production of IFN-β and other inflammatory cascades including NF-κB/TNFα and NLRP3/caspase 1/IL-1β. However, the treatment with silibinin blocks the above pathological changes. Moreover, in HT22 cells with/without STZ treatment, GPX4-knockdown increases the protein level of STING, indicating that the ferroptotic damage leads to the activation of STING signaling pathway. These results imply that silibinin exerts neuroprotective effect on an STZ-induced sporadic AD model by downregulating ferroptotic damage and thus the downstream STING-mediated neuroinflammation.
... This mixture consists of seven main components: silybin A, silybin B, isocilybin A, isocilybin B, silychristine, silydianin, and taxifoline (Robert et al., 2021). SL, which has hepatoprotective effects, has been used in the treatment of toxin-induced liver disease, acute and chronic viral hepatitis, and alcoholic liver disease (Abenavoli et al., 2010;Alemardan et al., 2013). SL probably protects the liver thanks to its antioxidant, anti-apoptotic, anti-inflammatory, TNF-α-suppressive, and immunomodulatory effects (Alemardan et al., 2013;Polyak et al., 2010). ...
One of the biggest factors that negatively affect the cancer treatment plan is the toxic effects of chemotherapeutics on non-target cells and tissues. This information prompted us to investigate the protective effects of silymarin (SL), a hepatoprotective agent, against the hepatotoxic effects of the anticancer drug paclitaxel (PAC).
Four groups were formed from 28 rats as control, PAC (2 mg/kg), SL (100 mg/kg) and PAC + SL (combination of PAC with SL). After completing the experimental procedures, the tissues collected after anesthesia were analyzed by Western blot, qRT-PCR, biochemical, stereological, immunohistochemical, and histopathological techniques. Administration of PAC significantly increased the expression of tumor necrosis factor-alpha (TNF-α), Bax, cytochrome-c (cyt-c), and active caspase-3, as well as malondialdehyde (MDA) levels in liver tissue and decreased glutathione (GSH) levels compared with the control group. PAC also resulted in a significant increase in serum triglyceride (TG), cholesterol (CH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the control group. Pathological changes such as microvesicular steatosis, the formation of Councilman bodies, an increase in total sinusoidal volume, and a decrease in the total number of hepatocytes were observed in the liver tissue of the PAC group. Almost all analysis results in the PAC + SL group were similar to those in the control group, and no significant pathological alterations were observed in this group.
The data obtained show that SL protects the liver from the harmful effects of PAC, especially thanks to its TNF-α suppressor, anti-inflammatory, anti-apoptotic and antioxidant effects. Based on this result, in cases where PAC is used in cancer treatment, it can be recommended to be used together with SL to prevent harmful effects on healthy liver tissue and to continue treatment uninterruptedly and effectively.
... Silymarin acts as an antioxidant, reducing the free radical formation and lipid peroxidation, has an antifibrotic effect, and can act as a toxin blocker by inhibiting the toxins binding to hepatocyte cell membrane receptors (Wesołowska et al., 2007). Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis, and toxin-induced liver diseases (Abenavoli et al., 2010;Kostek et al., 2012). Research also shows that silymarin and its active ingredient, silibinin, work as antioxidants, scavenging free radicals and inhibiting lipid peroxidation. ...
The impact of excess fat and high-calorie intake on the human body is an acute problem for many economically developed countries. Modelling the effects on the health of rats of supplementing their diet with crushed seeds of Echinacea purpurea (L.) Moench and Sylibum marianum (L.) Gaertn was carried out in a laboratory experiment. In the control group of animals, body weight increased by 700 mg/day, with the addition of E. purpurea seeds – by 1394 mg/day and with the addition of S. marianum seeds – by only 155 mg/day. A hypercaloric diet supplemented with E. purpurea caused a significant decrease in the relative weight of the liver, thymus, spleen, stomach, and brain. The supplementation with S. marianumseeds to the diet of animals significantly reduced only the relative weight of the thymus. Adding E. purpurea to the diet caused a strong increase in blood alkaline phosphatase activity, an increase in the cholesterol content, and a sharp increase in the atherogenic index. The seeds of S.marianumincreased the alkaline phosphatase activity, reduced the glucose concentration, and triglycerides, significantly reduced the atherogenic index and lowered the C-reactive protein concentration in the rats’ blood when compared with the control group. The seeds of E. purpurea contributed to an increase in the erythrocyte and lymphocyte number in the blood, and the seeds of S.marianum – to a decrease in the thrombocyte concentration. The research results show the possibility of wider use of S. marianumfruits as a dietary supplement in the diet of patients with hypertension and impaired liver function.
... Milk thistle belongs to the sunflower family, and is native to northern Africa, some parts of Asia, southern Europe, and both Americas (Soleimani et al., 2019). Numerous studies have demonstrated that milk thistle possesses antioxidant, anti-atherosclerotic, hepatoprotective, antihypertensive, anti-obesity, anti-diabetic, anti-inflammatory and anticarcinogenic activities (Abenavoli et al., 2010;Meddeb et al., 2017;Fanoudi et al., 2018;Tajmohammadi et al., 2018;Shen et al., 2020 andEl Hassanen et al., 2021). The seed of milk thistle has been shown to contain a high amount of oil ranging from 20 to 31%, and to be rich in unsaturated fatty acids, particularly linoleic and oleic acids, which are beneficial to human health (Fathi-Achachlouei & Azadmard-Damirchi, 2009;Dabbour et al., 2014;Kazazis et al., 2014 andHarrabi et al., 2015). ...
Food security is now a threat to Egypt's economy. Egypt relies on large quantities of imports of edible oil. Securing those supplies led Egypt to become one of the top 10 importers of edible oils in the world. This work aimed to investigate the Silybum Marianum seeds (SMS) as a potential novel source of edible oil. Fatty acids composition, physicochemical characteristics, selected bioactive components and nutritional quality of SMS cold-pressed oil (SMSO) were examined. The results showed that SMS is a promising source of crude fat (28.04%). USFAs quantitatively accounted for 82.89% of total fatty acids, with linoleic (C18:2) being the most abundant (50.31%), followed by oleic (C18:1) at 31.76%. Unfortunately, only 0.28% represented linolenic (C18:3). The physicochemical characteristics of SMSO were in accordance with Egyptian Standards for vegetable edible oils. SMSO contained a wide range of bioactive components including silymarin 2530.79 mg/100g, α-tocopherol 307.84 mg/100g, β-carotene 30.52 mg/100g, total phenolic content 2165.83 mg GAE/100g and flavonoids 837.86 mg QE/100g. SMSO exhibited valuable nutritional quality indicators represented in the low (atherogenic and thrombogenic) indices and the high (PUFAs/SFAs, USFAs/SFAs, and hypocholesterolemic/ hypercholesterolemic) rations, while ω6/ω3 ratio was far from the recommended values. From the nutritional standpoint, SMSO is a strong candidate to serve as a functional ingredient of the human diet, whether used alone or blended with oils that are rich in ω-3 PUFAs to achieve a wide spectrum of nutritional and health benefits. Based on the obtained results, milk thistle should be cultivated extensively as an innovative resource of oil to boost edible oil self-sufficiency in Egypt.
... [Asteraceae] plant, has been used to prevent various liver diseases (Polyak et al., 2010). Silymarin has been reported to act as an antioxidant by reducing free radical production and lipid peroxidation, function as a toxin blocker by inhibiting the binding of toxins to the hepatocyte cell membrane receptors (Abenavoli et al., 2010), and reduce the superoxide and peroxynitrite content by its scavenger activity (Papackova et al., 2018). Recent research has shown that silymarin reduces acute toxic liver injury caused by APAP by increasing hepatocyte proliferation, decreasing CYP2E1 activity and expression, and decreasing the production of toxic metabolites (Elsayed Elgarawany et al., 2020;Ihedioha et al., 2020;Yang et al., 2022b). ...
Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.
... 18,19 However, insignificant clinical and biochemical outcomes, 20 toxicity profiles and costs are limiting factors in the availability and use of these agents. 21,22 Overall, with the limitations of the tried agents, there is a definite need of effective and affordable therapies for prevention and management of ALDs. As conventional medicine pursues a more integrated approach to managing disease, select herbs that influence liver function are being revisited and evaluated for their overall health promoting effects. ...
Indian Journal of Clinical Practice, Vol. 33, No. 9, February 2023
Alcoholic liver disease (ALD) is caused by excessive intake of alcohol for many years. The incidence is as high as 25% in the United States, India and several other countries. The disease spectrum varies from fatty liver in initial stages, to hepatitis and finally cirrhosis. Untreated ALD can be fatal. Yet the options for prescription drugs are limited, and not easily available or affordable to the masses worldwide. BV-7310 contains herbal extracts of Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa and Andrographis paniculata. The individual plants are known hepatoprotective agents in Ayurveda. The objective of this study was to investigate the safety and efficacy of BV-7310, a proprietary combination standardized formulation, in subjects with ALD. A multi-centric, double-blind, placebo-controlled, randomized study of 61 subjects was conducted for a period of 12 weeks. Subjects on BV-7310 showed improvement in clinical features of ALD as compared to placebo, including reduction and normalization of transaminases. BV-7310 also reduced bilirubin levels to normal, showing improvement in the detoxifying and excretory capabilities of the liver. No significant adverse events were seen in the treatment group. Based on the data shown, BV-7310 shows promise as a safe and effective hepatoprotective in patients of ALD.
... Resveratrol, with its antiinflammatory and antioxidative properties, also suppresses periodontitis-mediated tissue damages in a rat model [29]. SB, the main active component of silymarin, has been shown to protect organs such as the liver, heart, and nervous system in many studies because of its anti-inflammatory and antioxidative properties [30,31]. It has been well recognized that SB performs protective effects in inflammatory diseases such as rheumatoid arthritis [32], hepatitis [33], and pulmonary fibrosis [34]. ...
Periodontitis is an oral microbiota-induced inflammatory disease, in which inflammation and oxidative stress play a critical role. Silibinin (SB), a Silybum marianum-derived compound, exhibits strong anti-inflammatory and antioxidative properties. We adopted a rat ligature-induced periodontitis model and a lipopolysaccharide- (LPS-) stimulated human periodontal ligament cells (hPDLCs) model to evaluate the protective effects of SB. In the in vivo model, SB reduced alveolar bone loss and apoptosis of PDLCs in the periodontal tissue. SB also maintained the expression of nuclear factor-E2-related factor 2 (Nrf2), a key regulator of cellular resistance to oxidative stress, and attenuated lipid, protein, and DNA oxidative damages in the periodontal lesion area. Meanwhile, in the in vitro model, SB administration reduced the production of intracellular reactive oxidative species (ROS). Furthermore, SB exerted a strong anti-inflammatory property in both in vivo and in vitro models by inhibiting the expression of inflammatory mediators including nuclear factor-κB (NF-κB) as well as nucleotide binding oligomerization domain- (NOD-) like receptor family pyrin domain-containing 3 (NLRP3) and downregulating the levels of proinflammatory cytokines. This study, for the first time, demonstrates that SB exhibits the anti-inflammatory and antioxidative properties against periodontitis by downregulating the expression of NF-κB and NLRP3 and upregulating Nrf2 expression, suggesting a promising potential clinical application of SB in periodontitis.
... Silymarin, a mixture of flavonolignans (with silibinin being the major component 1 ) and some other polyphenolic compounds such as taxifolin 2 , has long been known with diverse hepatoprotective properties such as antioxidant and lipid-lowering effects 3,4 and could improve non-alcoholic fatty liver diseases (NAFLD) 5,6 . The corresponding clinical studies of silymarin have been comprehensively reviewed recently 7 . ...
Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, we investigate the contributions of the gut microbiota to the improvement of liver lipid metabolism by silymarin. We find i) strong and significant microbial shifts upon silymarin but not silibinin treatment; ii) over 60% variations of liver fat are explained by silymarin-induced bacterial B12 production in male rats but not in male germ-free mice; iii) fecal microbiota transplantation confirms their protective roles against liver fat accumulation; iv) upregulation of one-carbon metabolism and fatty acid degradation pathways are observed based on the liver transcriptome analyses; and v) in humans the delta changes of serum B12 associate negatively with the fluctuations of serum triglycerides. Overall, we reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities. Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, the authors reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.
... Silymarin, a milk thistle (Silybum marianum) extract, is largely considered a potent herbal medication to treat hepatotoxicity (Abenavoli et al. 2010). Silymarin's hepatoprotective properties in PTL intoxication have previously been established (Nayak et al. 2011). ...
This study investigated the possible protective role of mulberry leaf (MLE) and olive leaf (OLE) ethanolic extracts against paracetamol (PTL)–induced liver injury in rats compared to silymarin as a reference drug. Initially, MLE and OLE were characterized using gas chromatography–mass spectrometry (GC/MS). Then, forty male Sprague Dawley rats were divided into five groups: the negative control group orally received distilled water for 35 days, the PTL-treated group (PTG) received 500 mg PTL/kg b. wt. for 7 days, the MLE-treated group (MLTG) received 400 mg MLE/kg b. wt., the OLE-treated group (OLTG) received 400 mg OLE/kg b. wt., and the silymarin-treated group (STG) received 100 mg silymarin/kg b. wt. The last three groups received the treatment for 28 days, then PTL for 7 days. The GC–MS characterization revealed that MLE comprised 19 constituents dominated by ethyl linoleate, phytol, hexadecanoic acid, ethyl ester, and squalene. Moreover, OLE comprised 30 components, and the major components were 11-eicosenoic acid, oleic acid, phytol, and à-tetralone. MLE and OLE significantly corrected the PTL-induced normocytic normochromic anemia, leukocytosis, hypercholesterolemia, and hypoproteinemia. Moreover, the MLE and OLE pretreatment considerably suppressed the PTL-induced increment in serum levels of hepatic enzymes, including alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. Furthermore, the PTL-induced depletion in antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, and the rise in hepatic malondialdehyde content were significantly reversed by the MLE and OLE pretreatment. Besides, MLE and OLE pretreatment significantly protected the hepatic tissue against PTL-induced DNA damage, pathological perturbations, and increased caspase 3 and CYP2E1 immunoexpression. Of note, OLTG showed better enhancement of most indices rather than MLTG. Conclusively, these findings imply that OLE, with its antioxidant and antiapoptotic capabilities, is superior to MLE in protecting against PTL-induced liver injury.
... Silymarin (SIL), a free radical scavenger, belongs to the flavonolignan family and is a main constituent of Silybum marianum [22,23]. Silybum marianum has been applied as a medicinal plant to remedy liver and gallbladder diseases in ancient Greek, and to preserve the liver from chemicals and toxins in Europe and Asia [24,25]. ...
Depression is a prevalent global problem since ages, predominately treated with SSRI. Cipralex, is an antidepressant of the SSRIs class used as a remedy for mood, depression and anxiety. Silymarin (SIL), a natural free radical scavenging, has an antioxidant and anti-inflammatory properties. This hypothesis evaluates, for the first time, the role of cipralex on the structure of the endocrine and exocrine components of the pancreas and assess the beneficial effects of SIL on these changes. Forty-five rats were divided into control, cipralex, and cipralex plus SIL groups. During sacrifice, all rats and pancreases were weighed and the ratio of pancreatic weight (PW) to rat weight (RW) was calculated, blood samples were collected to estimate fasting glucose, insulin and amylase levels, the specimens were prepared for histological, immunohistochemical (inducible nitric oxide synthase [iNOS], tumour necrosis factor-alpha [TNF-α], caspase 3, proliferating cell nuclear antigen [PCNA], and anti-insulin antibody), and morphometrical studies. Cipralex group exhibited marked destruction of the pancreatic architecture of the exocrine and endocrine parts, with a dense collagen fiber deposition. Also, there is highly significant decrease (P<0.001) of PW/RT ratio, insulin, and amylase levels, the number and diameter of islets of Langerhans, the number of PCNA positive immunoreactive cells, and the number of insulin positive β-cells. Furthermore, a highly significant increase of glucose level, iNOS, TNF-α, and caspase-3 positive immunoreactive cells in the islets of Langerhans and acinar cells were observed. SIL improves the pancreatic histological architecture, weight loss, biochemical, and immunohistochemical analyses. Administering SIL is advantageous in managing cipralex induced pancreatic injury via its anti-inflammatory, antioxidant, and anti-apoptotic qualities.
... The evaluation of the biochemical, morphological, and histopathological parameters indicated no toxicity and damage concerning the products used in this study. With oral administration in mice, Br has a very low toxicity effect with an LD50 (lethal dose) greater than 10,000 mg/kg (29); IN has no toxic effect up to 1000 mg/kg (30); BU has no toxic effect up to 1.25 g/kg (31); ALA has no toxic effect up to 500 mg/kg (32); SB has no toxic effect up to 20,000 mg/kg (33). ...
Background: Inflammatory Bowel Disease (IBD) is a complex multifactorial disease that includes two Crohn's disease and ulcerative colitis (UC). The UC characterized by inflammation, oxidative stress, and increased intestinal epithelial cell apoptosis. The present study aiming to investigate the protective potential of a combination of five safety products: Bromelain (BR), Silibinin (SB), Alpha-lipoic acid (ALA), Inulin (IN) and Sodium butyrate (BU) against UC.
Methods: Seventy-two male Balb/c mice were divided into 9 groups, and administered for 14 days by a minimum effective dose of BR, SB, ALA, IN, BU or all together (PAC). Mesalazine (MZ) is used to compare the therapeutic effects of the compounds. Colitis was induced by rectal injection of acetic acid (4%) in 12th day. Blood and colon tissue were collected and the expression of inflammatory cytokines, and oxidative stress indices were examined using ELISA methods. The SPSS v.24 was used for data analysis.
Results: All the therapeutic groups including BR, IN, BU, ALA, SB separately, partially improved histopathological changes due to colitis, but PAC treatment prior to colitis induction significantly (p<0.001), and more effectively alleviated the extent and intensity of the histological signs of cell damage including inflammation intensity, macroscopic and microscopic colon damage, and improved colitis. A significant decrease in inflammatory cytokines and oxidative stress indices also observed in the group treated with ALA, SB and PAC.
Conclusion: This new drug combination (PAC) is more beneficial for the prevention of UC better than MZ that is a usual treatment of UC.
... As reported initially, SM alone possesses many valuable effects such as proper scavenging of free radicals and chelating free Cu and Fe, impeding free radical formation by inhibiting free radical-producing enzymes, ensuring the integrity of mitochondria or the cell in cellular stress conditions, keeping an optimal redox balance in the cell, decreasing inflammatory responses by inhibiting NF-ĸB pathways in liver toxicity and various liver diseases included hepatic IR injury in animal and human studies (Wellington, Jarvis, 2001;Abenavoli et al., 2010;Surai, 2015;Wang et al., 2018). SM is also known as a potent pharmacological agent with anti-oxidant and anti-inflammatory properties as well as raising patient serum levels of GSH (Wellington, Jarvis, 2001;Akbari-Kordkheyli et al., 2019;Heidarian, Nouri, 2019). ...
Abstract Liver ischemia-reperfusion (IR) injury is a major clinical trouble encountered in clinical practice. This study aimed to examine the therapeutic effects of silymarin (SM) plus glutathione (GSH) on hepatic IR injury using a rat model of liver IR. Fifty male rats were randomly divided into five groups, each consisting of 10 rats as follows: Sham, IR, SM-IR, GSH-IR and SM plus GSH-IR. All groups except sham were subjected to 30-min ischemia and 24-h reperfusion. The treated groups received 100 mg/kg of SM, GSH and a mixture of SM plus GSH, 60 min prior to the IR. After a period of 24 h, blood and liver samples were collected for biochemical and histopathological evaluations. Pretreatment with SM, GSH and SM plus GSH before hepatic IR significantly decreased IR-induced elevations of aminotransferases, and significantly reduced the histopathological damage scores of the liver in the late phase of IR injury. Moreover, SM plus GSH treatment prior to liver IR significantly suppressed inflammatory process and oxidative stress as demonstrated by attenuations in tumor necrosis factor-α, myeloperoxidase and the thiobarbituric acid-reactive substances. These findings suggest that administration of SM plus GSH prior to liver IR may protect the liver parenchyma from the effects of an IR injury.
... Interestingly, each flavonolignan has been reported to have a different biological activity (Polyak et al., 2010), underlining the pivotal importance of silymarin composition. New perspectives relating to the use of silymarin reside in the prevention or reduction of chemotherapy, as well as of radiotherapy-induced toxicity (Ladas and Kelly, 2003;Abenavoli et al., 2010). Recently, the exploitation of silymarin for the treatment of metabolic syndromes has been reviewed (Tajmohammadi et al., 2018). ...
HIGHLIGHTS
•Two S. marianum chemotypes with considerably different silymarin composition
•S. marianum chemotypes arise from actively regulated metabolic processes
•Chemotype differentiation is regulated by a monogenic hereditable factor
•RNA-Seq was performed during silymarin deposition in the two chemotypes
•Specific dirigent-like transcripts are likely involved in silydianin accumulation
ABSTRACT
Silymarin is the main phytochemical extracted from Silybum marianum (L.) Gaertn. fruits. It is principally composed of six flavonolignans, which can be present in different relative proportions in the distinct S. marianum chemotypes. Few and sometimes contradictory information is available both about silymarin biosynthesis and how the different chemotypes can arise. According to the commonly accepted pathway, the occurrence of random radical coupling of the two flavonolignan precursors is the main driver of chemotype differentiation. In this work we studied two contrasting S. marianum chemotypes at biochemical, genetic, and transcriptional level. By analysing the flavonolignan accumulation process during fruit ripening and the chemotype segregation ratio after crossing, we concluded that S. marianum chemotype differentiation is a metabolically regulated process driven by a monogenic hereditable factor involved in silydianin biosynthesis. Transcriptome sequencing of the fruit shell during active silymarin accumulation revealed that dirigent-like transcripts putatively involved in the selective radical coupling represent the main and strong difference between the two chemotypes, suggesting their possible role in chemotype differentiation process.
... Therefore, all of the participants had taken dienogest for at least 6 months. This dosage was chosen because it is safe and effective in treating liver diseases 26 . The therapeutic doses of silymarin have been considered safe and well-tolerated in humans and it has low risks of drug interactions 27 . ...
To study the effect of silymarin on the Interleukin-6 (IL-6) level, size of endometrioma lesion, pain, sexual function, and Quality of Life (QoL) in women diagnosed with endometriosis. This randomized, double-blind placebo-controlled clinical trial was performed on 70 women with endometriosis which was divided into two groups of intervention and control. The intervention was 140 mg silymarin (or matching placebo) administered twice daily for 12 weeks. The volume of endometrioma lesions, the level of IL-6 concentration in serum, pain, sexual function, and QoL were analyzed before and after the intervention. The means of endometrioma volume (P = 0.04), IL-6 (P = 0.002), and pain (P < 0.001) were reduced significantly in the silymarin group after intervention. However, the QoL and female sexual function did not improve substantially in the two groups (P > 0.05). Silymarin significantly reduced interleukin-6 levels, sizes of endometrioma lesions, and pain-related symptoms. The trial has been registered in the Iranian Registry of Clinical Trials (IRCT20150905023897N5) on 4th February 2020 (04/02/2020) (https://en.irct.ir/trial/42215) and the date of initial participant enrollment was 2nd March 2020 (02/03/2020).
Bulgaria is famous as one of the countries richest in medicinal plants in Europe. Some of them are unique in their action and are Bulgarian or Balkan endemics. Bulgarian medicinal plants contain a high concentration of biologically active components (alkaloids, glycosides, saponins, tannins, flavonoids, lignans, coumarins, essential oils, vitamins, trace elements), thanks to the variety of climatic and soil conditions. In the present study, six species of medicinal plants are selected and studied: St. John's wort (Hypericum perforatum L.), milk thistle (Silybum marianum L.), heath speedwell (Veronica officinalis L.), dwarf everlast (Helichrysum arenarium L.), wild basil (Clinopodium vulgare) and Mursalski tea (Sideritis scardica Griseb.). Aqueous extracts of the mentioned medicinal plants were obtained and analyzed. The quantitative content of total phenolic substances in all extracts was determined by spectrophotometric method with gallic acid standard. Aqueous extracts of the mentioned medicinal plants were obtained and analyzed. The quantitative content of total phenolic substances in all extracts was determined by
spectrophotometric method with gallic acid standard. The total phenolic content is in the between 0.900±0.018 and 0.636±0.001 GAE mg/ml for Mursalski tea and speedwell respectively.
The evaluation of the antioxidant activity of the extracts was done by determining the radical scavenging activity towards DPPH and ABTS. The highest percentage of
inhibition of the DPPH radical was found in the aqueous extract of St. John's wort and wild basil. In the ABTS analysis, results are presented as TROLOX equivalents of antioxidant activity and the highest values were found in St. John's wort – 29.117±0.149 μmol ТЕ/ml, and heath speedwell - 9.642±0.401μmol ТЕ/ml.
The average worldwide human life expectancy is 70 years, with a significantly higher value in Western societies. Many modern diseases are not associated with premature mortality but with a decreased quality of life in aged patients and an excessive accumulation of various toxic compounds in the human body during life. Today, scientists are especially interested in finding compounds that can help increase a healthy lifespan by detoxifying the body. Phytotherapy with specific approaches is used in alternative medicine to remove toxins from the body. Worldwide, research is conducted to identify medicinal plant-derived molecules that, with few or no side effects, may protect the liver and other organs. This review provides updated information about the detoxification process, the traditional and modern use of the most effective medicinal plants, their active metabolites as detoxifying agents, and the mechanisms and pathways involved in the detoxification process. Among medicinal plants with substantial detoxifying properties, a major part belongs to the Asteraceae family (Silybum marianum, Cynara scolymus, Arctium lappa, Helichrysum spp, Inula helenium, and Taraxacum officinale). The most widely used hepatoprotective phytocomponent is silymarin, a standardized extract from the Silybum marianum seeds containing a mixture of flavonolignans. Many polysaccharides, polyphenols, and terpenoids have a detoxifying effect. Overall, scientific data on medicinal plants used in phytotherapeutic practice worldwide provides an understanding and awareness of their efficacy in detoxification.
Background:
Silymarin is an antioxidant without side effects even at relatively high physiological dosage. Therefore, it is safely used as a herbal medicine for treating different diseases.
Aim of work:
The purpose of this study was to examine the toxicity of cadmium (Cd) in pregnant rats and their fetuses and the ameliorative effects of silymarin (SL) against this toxicity.
Materials & methods:
A total of 24 pregnant rats allocated into four equal groups. Control, silymarin (200 mg/kg), Cd (5 mg/kg), and a combination of Cd and silymarin concurrent from 6 to 20th gestational day. Number of corpora lutea, dams', gravid uteri, placental weights, and likewise fetal body weights and lengths were analyzed as physical parameters. Serum levels of aspartate transaminase, alanine transaminase, creatinine, urea, uric acid, and maternal and fetal liver tissues for malondialdehyde, superoxide dismutase, catalase and glutathione activity were studied. The histology of hepatic and renal tissues for both mothers and fetuses was examined. Data were statistically analyzed by analysis of variance test and Duncan's multiple range test was used to compare group means.
Results:
The findings evidenced that Cd causes teratogenic abnormalities and histopathological variation in hepatic and renal tissues of both mothers and fetuses. Cd triggers oxidative stress and disrupts liver and kidney function. In Cd + silymarin treated rats exhibited improvement in the pregnancy outcomes, reduced histopathological changes, oxidative stress as well as liver and kidney enzymes.
Conclusion:
We deduced that using of silymarin during gestation is effective and ameliorate the toxic maternal complications caused by cadmium.
In the present experiment, Indole-3-acetic acid (IAA)-mediated alleviation of lead (Pb) stress was investigated by analyzing the morphological, biochemical aspects and lead (Pb) metal uptake in Silybum marianum under Pb stress. Pb was applied in the form of lead acetate at concentration of 0.5 mM in the soil and IAA at 25, 50 and 100 ppm concentration. Pb stress significantly declined the S. marianum growth and biochemical aspects while application of IAA reversed this effect under Pb toxicity. IAA application also reduced the Pb uptake in which minimum Pb uptake of 12.10 µg g−1 was at 50 ppm under Pb stress after 60 DAS. It was concluded from the study that Pb stress can be mitigated successfully by the exogenous application of plant growth regulator, i.e., IAA.
Silybum Marianum (SM) belongs to the family Asteraceae, which holds therapeutic significance in medicinal chemistry. Phytochemistry analysis revealed an abundance of active constituents, particularly silymarin, composed of polyphenols and flavonolignans. Silymarin is majorly found in leaves, seeds, and fruits and is comprised of seven flavonolignans. Silymarin derivatives, specifically silybin, were reported for their medicinal properties. This review summarizes the studies conducted to evaluate SM's pharmacological properties and proposed mechanisms. SM exhibited anticancer properties due to being capable of modifying the induction of apoptosis, inhibiting the STAT3 pathway, decreasing the transcription of various growth factors, impeding the growth of 4T1 cells and inducing cell cycle arrest in various types of cancers, i.e., skin cancer, liver cancer, breast cancer, ovarian cancer etc. Silymarin and its derivatives protect the liver and ameliorate various immune-mediated and autoimmune hepatic diseases. Moreover, antimicrobial, antidiabetic, cardioprotective, nephroprotective, and neuroprotective activities were also reported. Based on testified in vitro and in vivo studies, SM can serve as an alternative to cure various pathological ailments.
The anticancer potential of silymarin is well known, including its anti-inflammatory as well as antiproliferative effect mediated by influencing the cell cycle, suppression of apoptosis, and inhibition of cell-survival kinases. However, less is known about silybin, the main component of the silymarin complex, where studies indicate its dual effect on the proliferation and immune response of various cell types in a dose-dependent manner. Moreover, there is a lack of studies comparing the effect of silybin on the same type of healthy and tumor cells, especially intestinal ones. Therefore, our study aimed to investigate the concentration-dependent effect of silybin on the normal intestinal porcine epithelial cell line-1 (IPEC-1) and the human epithelial colorectal adenocarcinoma cell line (CaCo-2). The metabolic viability, cell cycle, mitochondrial membrane potential, apoptosis, and the relative gene expression for pro- and anti-inflammatory cytokines were monitored in cells treated with silybin. Silybin stimulates metabolic viability as well as proliferation in IPEC-1 cells, protects the mitochondrial membrane, and thus exerts a cytoprotective effect, and has only a minimal effect on the gene expression of pro-inflammatory cytokines but significantly increases the expression of anti-inflammatory TGF-β. In contrast, it inhibits metabolic viability in tumor intestinal CaCo-2 cells, has an antiproliferative effect accompanied by increased apoptosis, and significantly reduces the expression of genes for pro-inflammatory interleukins as well as TGF-β. The antiproliferative and anti-inflammatory effect of silybin on tumor intestinal cells without a negative effect on healthy cells is a prerequisite for its potential use in the adjuvant therapy of colon cancer; however, further studies are necessary.
The reproductive system is extremely vulnerable to chemotherapy drugs, ionizing radiation, toxic heavy metals, chemicals, and so on. These harmful stimuli are able to induce oxidative damage, apoptosis, inflammation, and other mechanisms in the reproductive organs, leading to different adverse reproductive effects. It was shown that using medicinal plants (medicinal herbs) can be an effective medication for the prevention and treatment of multiple health conditions. Silymarin is a medicinal herb extract, obtained from the seeds of Silybum marianum. This herbal agent is a nontoxic agent even at relatively high physiological dose values, which suggests that it is safe for use in the treatment of different diseases. The hepato-, neuro-, cardio-and nephro-protective effects of silymarin have been assessed previously. The protective activities of silymarin can point to anti-oxidant, anti-apoptotic, anti-inflammatory, anti-fibrotic, immunomodulatory, and membrane-stabilizing properties. In this review, we aim to summarize current studies on the protective potentials of silymarin against reproductive toxicity. The molecular mechanisms of silymarin protection against cellular toxicity are also studied. Moreover, the findings obtained from improved formulations and delivery systems of silymarin have been addressed.
Herb medicine has a long history of application and is still used worldwide. With the development of complementary and alternative medicine, the interaction between herb and drugs has attracted more and more attention. Herb-drug interactions (HDI) could cause decreased efficiency, increased toxicity, and affect the drug absorption and disposition processes due to the interference of their pharmacological or pharmacokinetic effects. Hence, the mechanisms and results of herb-pharmacokinetic interactions should be comprehensively summarized. Here, we have summarized the mechanisms of HDI and pharmacokinetic interactions in the last ten years based on searching on PubMed, Science Direct, and Web of Science with different keywords. Besides, the pharmacokinetic interactions were related to nine commonly used herbs and drugs, including Ginseng, Salvia miltiorrhiza, Ginkgo biloba, Garlic, Coptis chinensis, St. John's wort, Ginger, Licorice, Silythistle and Fructus Schisandrae. This review provides an overview of HDI to provide a reference for the rational and safe clinical use of herbs and drugs.
The metabolic syndrome as a consequence of the obesity pandemic resulted in a substantial increase in the prevalence of metabolic-associated fatty live disease (MAFLD) and type 2 diabetes mellitus (T2DM). Because of the similarity in pathobiology shared between T2DM and MAFLD, both disorders coexist in many patients and may potentiate the disease-related outcomes with rapid progression and increased complications of the individual diseases. In fact, awareness about this coexistence and the risk of complications are often overlooked by both hepatologists and diabetologists. Management of these individual disorders in a patient should be addressed wholistically using an appropriate multidisciplinary team approach involving both the specialists and, when necessary, liaising with dieticians and surgeons. This comprehensive review is to compile the current evidence from a diabetologist's perspective on MAFLD and T2DM and to suggest optimal management strategies.
The current study aimed to know the extent of the effect of silymarin and its usefulness on the productive performance and some characteristics of the carcass of broilers which consuming diets containing aflatoxins which counteract the effects of negative toxins, which is One hundred and forty-four male broiler chicks, type (ROSS 308), one day old, of similar weights (40 + 5g), were distributed into four groups of equal number by 36 birds per group, which in turn was divided into three replicates by 12 birds for each duplicate. In the following figure, the first group (the control group), the second group (the standard diet plus aflatoxin in an amount of 500 micrograms/ kg of feed), the third group (the standard diet plus aflatoxin in an amount of 500 micrograms/ kg of feed in addition to 0.5 ml of silymarin per 1 liter of drinking water), the fourth group (the standard ration plus aflatoxin in an amount of 500 micrograms / kg of feed in addition to 1 milliliter of silymarin per 1 liter of drinking water). Ground culture was used on a deep litter, the experiment lasted for (35 days). During the trial period, the characteristics of the production performance for a period of five weeks were calculated, which are body weight, amount of feed consumed, weight gain rate, and feed conversion ratio. The results showed a mathematical and significant improvement in favor of the fourth group compared to the rest of the groups. On the last day of the experiment, five chicks were slaughtered from each replicate. The carcass characteristics were measured and the proportions of the following organs were studied: the pancreas, the gizzard, the liver, the spleen, the heart, and the stomach. The results showed that there were no significant differences between the four groups in most of the carcass characteristics, despite some slight improvement in some of the carcass characteristics. It is concluded from this study that adding silymarin to drinking water for groups of male broilers consuming aflatoxin may improve some of their productive characteristics.
Silybum marianum (L.) Gaertn. (family: Asteraceae), commonly known as milk thistle, has been widely used from ancient period of times for the treatment of various ailments related to liver, kidneys, gallbladder, etc. It is an extensively used and studied herb for the treatment of hepatobiliary diseases. Silymarin is the major active fraction of seeds/fruits and is a mixture of taxifolin and several flavonolignans such as silibinin A (silybin A), silibinin B (silybin B), isosilibinin A (isosilybin A), isosilibinin B (isosilybin B), silychristin, isosilychristin, and silydianin. Silibinin (a mixture of diastereoisomers silibinin A and B) is the major component of silymarin and possesses the greatest degree of biological activity. Various pharmacological activities such as antioxidant, hepatoprotective, renoprotective, neuroprotective, anti-inflammatory, anticancer, cardioprotective, and antidiabetic activities have been reported from milk thistle. Several clinical trials have been performed to evaluate the safety and efficacy profile of this plant. However, these researches/clinical trials are inadequate, so well-designed clinical studies should be conducted and an extensive research on pharmacokinetics profile should be carried out to launch S. marianum as a clinically proven drug for different health disorders in the market.KeywordsSilymarinMilk thistleHepatoprotectiveSilibinin
In the study the cold-pressed, natural (unfiltered, unrefined) vegetable oils: hemp and milk thistle seed oils were tested for their chemical composition and antioxidant properties. The physico-chemical parameters, content of saturated and unsaturated fatty acids were determined. Solid phase extraction and simple extraction with the use of methanol, ethanol, 80% methanol, 80% ethanol were used to obtain the extracts for the analysis of antioxidant activity and phenolic compounds in oils. The composition of phenolic compounds was studied by means of high-performance liquid chromatography (HPLC–DAD) and spectrophotometric test with the Folin-Ciocalteu reagent. The antioxidant property of extracts was established by means of the following methods: with the DPPH• (2,2-diphenyl-1-picrylhydrazyl) radical, ABTS•+ (2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical, FRAP (ferric ion reducing antioxidant parameter) and CUPRAC (cupric-reducing antioxidant capacity). Moreover the influence of chlorogenic acid on the inhibition of lipid peroxidation process in the hemp and milk thistle seed oils was also investigated. The tested oils showed different antioxidant properties which was related to the their different chemical composition. The main phenolic compounds present in hemp seed oil were vanillic, ferulic and p-coumaric acids, (-)epicatechin, catechin, kaempferol and procyanidin B2, whereas in milk thistle seed oil—catechins, procyanidin B2, procyanidin C1, p-coumaric acid, phloridzin, quercetin, protocatechuic acid, kaempferol, and syringic acid. The methanolic extracts of hemp and milk thistle seed oils showed the highest antiradical activity, whereas the ethanolic extracts revealed the best reducing properties. The obtained antioxidant parameters for hemp seed oil were: the IC50 = 3.433 ± 0.017 v/v (DPPH test), the percent of ABTS•+ inhibition = 93.301 ± 1.099%, FRAP value = 1063.883 ± 39.225 µmol Fe²⁺, CUPRAC value = 420.471 ± 1.765 µmol of Trolox. Whereas the antioxidant parameters for milk thistle seed oil were: the IC50 = 5.280 ± 0.584 v/v (DPPH test), 79.59 ± 3.763% (ABTS test), 2891.08 ± 270.044 µmol Fe²⁺ (FRAP test), 255.48 ± 26.169 µmol of Trolox (CUPRAC assay). Chlorogenic acid effectively inhibited the lipid peroxidation process in hemp and milk thistle seed oils.
It is well known that the excessive accumulation of lipid in hepatocytes is one of the important causes of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to explore the effects of isosilybin on lipid metabolism in free fatty acids (FFAs) or TO901317-induced HepG2 cells. Cells were treated with FFAs (oleic acid: palmitic acid, 2:1) or TO901317 to induce steatosis in vitro. Intracellular triglyceride (TG) content was quantified using commercial assay kits. The mRNA and protein expression of genes involved in fatty acid uptake, synthesis and oxidation were analyzed by RT-qPCR and western blotting. Selected biological pathways regulated by isosilybin treatment were determined by GO and KEGG analysis. The results showed that isosilybin significantly reduced TG levels in FFAs- and TO901317-induced HepG2 cells. Further studies showed that isosilybin treatment decreased the mRNA and protein expression of lipid synthesis genes Srebp-1c, Pnpla3, Acc and Fas, as well as the mRNA expression of fatty acid uptake gene CD36, whereas increased the mRNA levels of lipid oxidation genes Pparα, Acox1 and Cpt1α, as well as the mRNA expression of lipid export gene Mttp, in FFAs-induced HepG2 cells. Moreover, TO901317 was employed to induce endogenous lipid synthesis and steatosis, and the expression of Srebp-1c and its target genes in TO901317-induced hepatocytes was basically similar to that in FFAs-induced hepatocytes following isosilybin treatment. We also observed the increased level of phosphorylated AMP kinase (AMPK) after isosilybin treatment, while this effect was reversed after further treatment with AMPK inhibitor, compound C. The results of GO and KEGG analysis indicated that the pathways of fatty acid and TG metabolism were regulated by isosilybin. Interestingly, we found that treatment with the diastereoisomer A of isosilybin increased TG level, while exposure to the diastereoisomer B of isosilybin decreased TG level in FFAs-induced HepG2 cells. The above results suggest that isosilybin can inhibit lipid synthesis and activate lipid oxidation through AMPK signaling pathway, thereby improving steatosis of hepatocytes, and isosilybin B is the basis of its active substance.
Dietary supplements containing plant extracts are often marketed as having antioxidant properties. Using complex lipid mixtures derived from cellular tissue, we perform a targeted lipidomic assessment of the antioxidant activity of five plant extract supplements. Formulations derived from grape seed, milk thistle, pine bark, turmeric and hawthorn extract were evaluated. Overall, we find evidence to suggest that all supplements suppressed in vitro lipid oxidation to some degree. Suppression of oxidation was most effective in the dominant lipid classes, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), which contain significant numbers of polyunsaturated lipids. Under the conditions of study, grape seed extract supplement was the most effective antioxidant showing statistically significant suppression of lipid oxidation in 11 of the 15 lipid classes quantified. Lipid compositional changes and metrics such as the PC: PE ratio and the double bond index were determined to provide an insight into the effect of oxidative stress and antioxidants on collective membrane properties. Finally, the likely stress that in vivo lipid oxidation could cause to cells, and the mitigating effects of supplements in this context, is also discussed.
We report a living cell-target responsive accessibility profiling (LC-TRAP) approach to identify the targetome of silibinin (SIL), a well-established hepatoprotective natural product (NP), in HepG2 cells. Proteins showing accessibility changes, probed by covalent lysine labeling reagents and leveraged by multiplexed quantitative proteomics, following the administration of SIL to the living cells were assigned as potential targets. Among the assigned targetome, ACSL4, an enzyme essential for ferroptosis induction, might be involved in the hepatoprotective effects of SIL and hence was intensively validated. We first demonstrated that SIL protected HepG2 cells from ferroptosis dependent on ACSL4. Then, we used biophysical assays and a SIL-derivatized chemical probe to corroborate that SIL can bind to ACSL4. The ensuing enzymatic assays showed that SIL inhibited ACSL4 enzymatic activity, thereby mitigating the ACSL4-mediated ferroptosis. As such, we revealed that ACSL4 inhibition, using SIL as a model compound, represents a promising hepatoprotective strategy. Further, since TRAP probes the accessibility changes of reactive proteinaceous lysines, it can pinpoint the proximal regions where the ligand engagement may occur. Thus, the LC-TRAP analysis of SIL, the newly discovered ligand of ACSL4, and arachidonic acid (AA), the substrate, intriguingly showed that SIL and AA both affected the conformation of the K536-proximal region of ACSL4, albeit through distinct binding patterns. Collectively, we describe a straightforward LC-TRAP workflow that does not involve ligand-derived probe synthesis and is widely applicable to target discovery of NPs.
Oral cancer is a disease with high incidence and mortality worldwide, and its treatment still needs to be improved. The search for new therapies using natural products is strongly supported, given the wide chemical range of these compounds. In addition, phytochemicals can exert antitumor activities by several mechanisms of action, including the modulation of non-coding RNAs. Thus, in this review, we discussed the role of non-coding RNAs, including circular RNAs, microRNAs, and long non-coding RNAs, in oral cancer and presented their potential as treatment targets using natural products. Some natural products capable of being used to treat oral cancer have been suggested.
Silybum marianum, commonly known as Milk Thistle and one of the important members of the Asteraceae family, is the focus of research due to both its wide range of medicinal effects and its use as vegetables. Having a history of over 2000 years, S. marianum has been used by different civilizations and cultures against various diseases. Traditionally, it comes to the fore with its use to treat liver diseases of different etiologies. Although there are some negative results for its efficacy against liver diseases, it is commercially sold under names such as Legalon®, Livergol®, Silipide®, and Siliphos® due to its hepatoprotective effect. Although several studies of the plant on various types of cancer and diabetes continue, its antioxidant, anti-inflammatory, immunomodulatory, and antidot against Amanita poising effects have been revealed by studies. Most of the biological effects of S. marianum are attributed to silymarin, which is a flavonolignan mixture such as silybinin A, isosilybinin A and B, silychristin, and silydianin in its structure. In clinical studies, no serious side effects were observed except for gastrointestinal disorders, diarrhea, vomiting, and allergic reactions, and it was revealed that the plant is safe and tolerable. since S. marianum has traditionally a wide range of uses, clinical studies can be performed on the plant other than its widely known uses.Keywords
Silybum marianum
Milk ThistleHepatoprotectiveBiological effectsClinical trials
Background:
Silymarin (SIL) is an active extraction of the silybum marianum, milk thistle, which is an ancient medicinal plant for treatment of various liver diseases for centuries. This study is to assess the therapeutic effect of SIL in the treatment of nonalcoholic fatty liver disease through meta-analysis.
Methods:
Published randomized controlled trials (RCTs) were included from electronic databases (PubMed, Embase, Cochrane library, Web of Science, and so forth). Cochrane handbook was applied to evaluate the methodological quality. All statistical analyses were directed by Revman 5.3 software, and statistical significance was defined as P < .05.
Results:
Eight RCTs involved 587 patients were included in this study. The results showed that SIL reduced the AST and ALT levels more significantly than the control group (AST UI/L: MD = -6.57; 95% CI, -10.03 to -3.12; P = .0002; ALT UI/L: MD = -9.16; 95% CI, -16.24 to -2.08; P = .01). Compared with other interventions, there were significant differences decreasing AST and ALT levels when SIL was used alone (AST UI/L: MD = -5.44; 95% CI, -8.80 to -2.08; P = .002; ALT UI/L: MD = -5.08; 95% CI, -7.85 to -2.32; P = .0003).
Conclusion:
SIL has positive efficacy to reduce transaminases levels in NAFLD patients. SIL can be an encouraging and considerable phytotherapy for NAFLD patients.
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.
Objective
To describe and analyze the clinical characteristics and outcome of amatoxin poisoning cases.
Methods
We performed a retrospective cohort study of amatoxin poisoning cases from Ramathibodi Poison Center Toxic Exposure Surveillance System, from May 2013 to August 2015.
Results
There were 30 consultations with a total of 55 poisoning cases. Most cases were male and from the north-east region. Hepatitis, acute kidney injury, jaundice, and coagulopathy accounted for 74%, 46.3%, 44.7%, and 52.8% of the cases, respectively. Almost all of the patients were admitted to the hospital, and the median duration of hospital stay was found to be 4 days. Mortality rate was found to be 27.3%. Most patients (73%) received the treatment including multiple-dose activated charcoal (67.5%), intravenous N-acetylcysteine (87.5%), and benzylpenicillin (45%). In 60% of the cases, the treatment was initiated within 24 h after eating mushrooms. Exchange transfusion and liver transplantation were performed in one severe case. However, this patient died eventually. Because intravenous silybinin is not available in Thailand during the study period, 8 patients received oral silymarin instead. All 8 patients had hepatitis and were treated with high dosage of oral silymarin (5 patients with 4.48 g/day, 2 patients with 1.68 g/day, and 1 patient with 1.4 g/day) for a couple of days. One of these patients died as she received treatment very late; she was treated with silymarin at 1.68 g/day dosage. Thus, the fatality in oral silymarin treatment group was 12.5%. We performed the analysis between the dead and survival groups. We found that in hepatitis, initial and maximum serum aspartate transaminase, initial and maximum serum alanine transaminase, and acute kidney injury were significantly different between the two groups.
Conclusion
Amanita mushroom poisoning caused high fatalities. Serum transaminase and creatinine were the factors associated with death. Treatment with oral high dose silymarin should be investigated further as one of the principal therapies in amatoxin poisoning.
Silymarin is a collection of compounds extracted from the medicinal herb milk thistle, among which silybin is the major flavonolignan. However, the biosynthesis pathway of silybin remains unclear. In this study, biomimetic reactions demonstrated that silybin can be synthesized from coniferyl alcohol and taxifolin by the action of peroxidase. The concentration profiles of silybin and its precursors and RNA-Seq analysis of gene expression revealed that the amount of taxifolin and the activity of peroxidase serve as the limiting factors in silybin biosynthesis. Hierarchical clustering of the expression profile of genes of the flavonoid biosynthesis pathway distinguished flowers from other organs. RNA-Seq revealed five candidates for the peroxidase involved in silybin production, among which APX1 (ascorbate peroxidase1) showed a distinct peroxidase activity and the capacity to synthesize silybin. The spatial organization of silybin biosynthesis in milk thistle was elucidated, which could help our understanding of the biosynthesis of silybin and other flavonolignans.
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, characterized by liver fatty acid accumulation and fibrosis, not due to the excessive alcohol consumption. Notably, nutritional habits have been reported to be implicated in the onset and severity of the hepatic damage, while the Mediterranean diet has shown beneficial effects on NAFLD. Free radicals and oxidative stress were suggested to be involved in the pathogenesis and progression of NAFLD and several data highlighted the efficacy of the antioxidant supplementation in its treatment. The aim of this study was to compare the effects of the Mediterranean diet, with or without an antioxidant complex supplement, in overweight patients suffering from NAFLD. In this prospective study, fifty Caucasian overweight patients were randomized into three groups (group A, B and C). A personalized moderately hypocaloric Mediterranean diet was prescribed to all patients included in A and B groups. In addition to diet, group B was administered antioxidant supplementation, daily and for the period of 6 months. Group C did not have any type of treatment. The study proved that the Mediterranean diet alone or in association with the antioxidant complex improved anthropometric parameters, lipid profile, and reduced hepatic fat accumulation and liver stiffness. However, group B patients, in which diet was associated with antioxidant intake, showed not only a significant improvement in insulin sensitivity but also a more consistent reduction of anthropometric parameters when compared with group A patients. Taken together, these results support the benefit of antioxidant supplementation in overweight patients with NAFLD.
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.
AIM
To evaluate the effect of silymarin on the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (γGT) in patients with liver diseases.
METHODS
A systematic review with meta-analysis of ramdomized and controlled clinical trials was performed, evaluating the effects of sylimarin in patients with hepatic diseases, published by January 31, 2016. Clinical trials were sought on the basis of The Cochrane Central Register of Controlled Trials in the Cochrane Library, PubMed/Medline, Scopus, Web of Science, Lilacs and Clinical Trials. The trials with adult and elderly patients of both sexes, with Liver Diseases who took oral silymarin supplementation, as extract or isolated, as well as Silymarin combined with other nutrients, were included. The trials should provide information about the intervention, such as dosages and detailing of the product used, besides the mean and standard deviation of serum levels of ALT, AST and γGT of the baseline and at the end of the intervention.
RESULTS
An amount of 10904 publications were identified. From those, only 17 were included in the systematic review and 6 in the meta-analysis, according to the used selection criteria. In this meta-analysis, the results indicated a reduction of 0.26 IU/mL (95%CI: -0.46-0.07, P = 0.007) at the level of ALT and 0.53 IU/mL (95%CI: -0.74-0.32, P = 0.000) at the serum levels of AST after using the silymarin, both, statistically significant, but with no clinical relevance. There was no significant change in the γGT levels. Subgroup analyzes were also performed for the biochemical markers in relation to the type of intervention, whether silymarin isolated or associated with other nutrients and the time of intervention (whether ≥ 6 mo or < 6 mo). Significant differences were not found. The evaluated studies presented a high degree of heterogeneity and low methodological quality in the carried out analysis.
CONCLUSION
Silymarin minimally reduced, but without clinical relevance, the serum levels of ALT and AST. It is necessary to carry out studies with more appropriate methodological designs.
Cancer is a serious health problem and the second leading cause of death around the globe. Present review is an attempt to provide utmost information based on ethno-pharmacological and toxicological aspects of anti-cancer plants of the world. A total of 276 articles published in English journals and containing maximum ethnomedicinal information were reviewed using several data sources such as; Google scholar, Web of Science, Scopus, PubMed and floras of different countries. A total of 199 anti-cancer plants were recorded in present review and results indicated that traditional medicines are mostly being use in developing countries for cancer treatment. Traditionally and scientifically skin and breast cancer types gained more focus. Seventy plants were reportedly analyzed for in-vitro activities while 32 plants were having in-vivo reports. Twenty nine pure compounds (mostly phenolic) were reportedly isolated from anti-cancer plants and tested against different cancer cell lines. Inspite having better efficiency of ethnomedicines as compared to synthetic drugs, several plants have also shown toxic effects on living system. Therefore, we invite researchers attention to carry out detailed ethno-pharmacological and toxicological studies on un-explored anti-cancer plants in order to provide reliable knowledge to the patients and develop novel anti-cancer drugs.
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.
Alcohol represents the oldest substance of abuse known and Alcoholic Liver Disease (ALD) is the most common cause of chronic liver disease worldwide. The ALD includes a wide spectrum of injury and may lead progressively from simple steatosis to frank cirrhosis. The ALD diagnosis may be hard and it is mainly defined by the history of chronic alcohol intake, physical and laboratory abnormalities suggestive of liver disease. Abstinence is the cornerstone of ALD therapy. Although the burden on health of ALD is not negligible, in the last decades few therapeutic advances have been made. Because of the complex pathogenetic mechanisms, the therapy of ALD and especially of severe Alcoholic Hepatitis (AH), represents a thorny problem in the clinical practice. In severe forms of acute AH, some specific drug treatments, including glucorticoids or pentoxifylline, have been defined and are, at the moment, recommended by international guidelines. On the contrary, specific long-term treatments of ALD, aimed at stopping the progression of fibrosis, are not yet approved.
Silymarin is a flavonoid extracted from the milk thistle Silybum marianum. It has been reported to prevent liver injuries induced by various chemicals or toxins. Our recent study suggested that silymarin induces hepatic synthesis of glutathione by increasing cysteine availability, which may consequently contribute to increased antioxidant capacity of the liver. In the present study, we investigated the effects of silymarin on acute liver injury induced by restraint stress. Silymarin (100 mg/kg) was orally administered to BALB/c mice every 12 h (3 times in total). After the last dose, mice were subjected to restraint stress for 6 h, and serum levels of aspartate and alanine aminotransferases, and hepatic levels of lipid peroxidation were determined. Hepatic levels of sulfur-containing metabolites such as methionine, S-adenosylmethionine, cysteine, and glutathione were also measured. The level of pro-inflammatory mediators in both liver and serum was determined. To study the mechanism of the effects of silymarin, we assessed Jun N-terminal kinase (JNK) activation and apoptotic signaling. Restraint stress induced severe oxidative stress and increased mRNA levels of pro-inflammatory mediators; both effects of restraint stress were significantly inhibited by silymarin. Moreover, administration of silymarin significantly prevented acute liver injury induced by restraint stress by blocking JNK activation and subsequently apoptotic signaling. In conclusion, these results suggest that the inhibition of restraint stress-induced liver injury by silymarin is due at least in part to its anti-oxidant activity and its ability to suppress the inflammatory response.
The aim of this investigation was to develop a procedure to improve the dissolution and bioavailability of silymarin (SM) by using bile salt-containing liposomes that were prepared by supercritical fluid technology (ie, solution-enhanced dispersion by supercritical fluids [SEDS]). The process for the preparation of SM-loaded liposomes containing a bile salt (SM-Lip-SEDS) was optimized using a central composite design of response surface methodology with the ratio of SM to phospholipids (w/w), flow rate of solution (mL/min), and pressure (MPa) as independent variables. Particle size, entrapment efficiency (EE), and drug loading (DL) were dependent variables for optimization of the process and formulation variables. The particle size, zeta potential, EE, and DL of the optimized SM-Lip-SEDS were 160.5 nm, -62.3 mV, 91.4%, and 4.73%, respectively. Two other methods to produce SM liposomes were compared to the SEDS method. The liposomes obtained by the SEDS method exhibited the highest EE and DL, smallest particle size, and best stability compared to liposomes produced by the thin-film dispersion and reversed-phase evaporation methods. Compared to the SM powder, SM-Lip-SEDS showed increased in vitro drug release. The in vivo AUC0-t of SM-Lip-SEDS was 4.8-fold higher than that of the SM powder. These results illustrate that liposomes containing a bile salt can be used to enhance the oral bioavailability of SM and that supercritical fluid technology is suitable for the preparation of liposomes.
Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert anti-fibrogenic and anti-tumoral effects in animal models, which appear relevant from a clinical point of view due to the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in pre-clinical models of NAFLD and in pilot clinical studies, and thus need clinical evaluation. In this review we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications. This article is protected by copyright. All rights reserved.
Background:
Hepatitis is a common adverse effect of antituberculosis drugs. Silymarin prevented drug-induced hepatoxicity in animals with anti-oxidative mechanisms but its effect in human has been unknown. We aimed to evaluate the efficacy of silymarin for preventing antituberculosis-drug induced liver injury (antiTB-DILI) in patients with tuberculosis.
Methods:
A double-blind randomized placebo-controlled trial was performed. Tuberculosis patients were randomly allocated to receive placebo or silymarin. The outcomes of interests were antiTB-DILI and the maximum liver enzymes at week 4. Antioxidative enzymes (i.e., superoxide dismutase (SOD), glutathione and malondialdehyde assays) were assessed. The risks of antiTB-DILI between the two groups were compared. A number need to treat was estimated.
Results:
A total of 55 out of 70 expected numbers of patients were enrolled. There were 1/27 (3.7 %) and 9/28 (32.1 %) patients who developed antiTB-DILI in the silymarin and the placebo groups. Risk reduction was 0.28 (0.10, 0.47), i.e., receiving silymarin was 28 % at lower risk for antiTB-DILI than placebo. This led to prevention of 28 patients from being antiTB-DILI among 100 treated patients. Median (IQR) of ALT levels at week 4 in the placebo and the silymarin group were 35.0 (15, 415) IU/L and 31.5 (20, 184) IU/L (p = 0.455). The decline of SOD level at week 4 in the silymarin group was less than the placebo group (p < 0.027).
Conclusions:
Silymarin reduced the incidence of antiTB-DILI. The benefit of silymarin may be explained from superoxide dismutase restoration. Larger clinical trials are required to confirm the result of our small study [Clinicaltrials.Gov Identifier Nct01800487].
Hepatoprotectants are routinely prescribed in China to prevent anti-tuberculosis drug-induced liver injury (ATLI). However, their biological mechanisms have not yet been clearly demonstrated. This study aims to evaluate the preventive effects of Silybum Marianum against drug-induced liver injury among tuberculosis patients and to provide clinical guidelines for tuberculosis management in China.
A randomized controlled trial was performed in Jiangsu, China. Tuberculosis patients were randomly allocated to the experimental group (anti-tuberculosis therapy plus Silybum Marianum capsule) or the control group (anti-tuberculosis therapy plus vitamin C tablet). The primary outcomes were the occurrence of probable and possible ATLI, the peak AST/ALT ratio and the maximum altered ALP or GGT.
The final analysis comprised 183 cases in the experiment group and 187 cases in the control group. The risk of developing probable ATLI was not significantly different between the two groups. During the follow-up period, 43.72% of cases in the experiment group and 35.83% of cases in the control group were determined to have possible ATLI (RR = 1.23, 95% CI: 0.94-1.54). When using a more strict definition of possible ATLI, the adjusted RR (95% CI) was 1.76 (1.14-2.56). The risks of adverse drug reactions, prolonged treatment length, taking second-line tuberculosis drugs and the clearance of tuberculosis bacteria were similar between the two groups.
No significant preventive effect of silymarin was found for either lowering the risk of liver injury or boosting the positive outcomes. Worse, we even found a potential risk of liver damage caused by the hepatoprotectant. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000‐year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti‐inflammatory, immunomodulating, antifibrotic, antioxidant, and liver‐regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug‐induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well‐designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.
The estimated prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide is approximately 25%. However, the real prevalence of NAFLD and the associated disorders is unknown mainly because reliable and applicable diagnostic tests are lacking. This is further complicated by the lack of consensus on the terminology of different entities such as NAFLD or nonalcoholic steatohepatitis (NASH). Although assessing fatty infiltration in the liver is simple by ultrasound, the gold standard for the assessment of fibrosis, the only marker of progression towards more severe liver disease is still liver biopsy. Although other non-invasive tests have been proposed, they must still be validated in large series. Because NAFL/NAFLD/NASH and related metabolic diseases represent an economic burden, finding an inexpensive method to diagnose and stage fatty liver is a priority. A translational approach with the use of cell and/or animal models could help to reach this goal.
Purpose:
The purpose of this study was to compare the bioavailability between 2 milk thistle-containing dietary supplements, Product B and IsaGenesis, in healthy volunteers.
Methods:
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.
Findings:
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.
Implications:
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.
This study aimed to determine the potential iron-chelating effects of silymarin in patients with β-thalassemia major receiving standard iron-chelation therapy. We evaluated whether addition of silymarin to standard iron-chelation therapy could improve iron burden markers and liver and cardiac function in these patients, via a placebo-controlled, crossover clinical study. Silymarin (140 mg) or placebo were administered thrice daily to all patients (n = 82) for 12 weeks, and after a 2-week washout period, patients were crossed over to the other groups. Silymarin efficacy was assessed by measuring serum iron level, ferritin level, total iron-binding capacity and liver and cardiac function on magnetic resonance imaging. Silymarin treatment resulted in a negative change in the serum iron and ferritin levels and a positive change in the total iron-binding capacity levels (treatment effect, p < .001, p = .06, and p = .05, respectively). Silymarin treatment led to positive changes in cardiac and liver function in both treatment sequences of study; however, this was not statistically significant. There was a negative change in liver iron concentration in both treatment sequences (treatment effect, p = .02). In conclusion, combined iron-chelation and silymarin therapy was effective for improving the iron-burden status in patients with β-thalassemia major.
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.
Silybin is one of the effective, traditional Chinese medicines used as a hepatoprotective agent in nonalcoholic fatty liver disease (NAFLD) therapy worldwide, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been recognized as an important factor involved in NAFLD development. However, little is known about the mechanisms of silybin in the regulation of high-fat diet (HFD)-induced liver inflammation. In our study, we found that silybin inhibited endoplasmic reticulum stress and NLRP3 inflammasome activation in the livers of HFD-fed mice and in cultured hepatocytes. Phosphorylation of inositol-requiring enzyme (IRE)1α and eIF2α, expression of thioredoxin-interacting protein and cleaved caspase-1, and release of IL-1β were reduced by silybin. In addition, silybin inhibited the approach of calreticulin and translocase of outer membrane 20 (Tom20), prevented assembly of the NLRP3 inflammasome complex, and suppressed the accumulation of acetylated α-tubulin in the perinuclear region. Both MEC-17 and sirtuin 2 (SIRT2) were influenced by palmitate and silybin, whereas histone deacetylase 6 was not affected. In addition, supplementing NAD(+) directly or increasing NAD(+) concentration with silybin could maintain the activity of SIRT2. The anti-inflammatory effect of silybin was blocked by SIRT2 silencing or by the SIRT2 inhibitor AGK2, as evidenced by NLRP3/ASC colocalization, AC-α-tubulin expression, and IL-1β release. These findings indicate that the NAD(+)/SIRT2 pathway is an important mediator through which silybin prevents NLRP3 inflammasome activation during NAFLD.-Zhang, B., Xu, D., She, L., Wang, Z., Yang, N., Sun, R., Zhang, Y., Yan, C., Wei, Q., Aa, J., Liu, B., Wang, G., Xie, Y. Silybin inhibits NLRP3 inflammasome assembly through the NAD(+)/SIRT2 pathway in mice with nonalcoholic fatty liver disease.
The extract from milk thistle (Silybum marianum (L.) Gaertn. (Asteraceae)), known as silymarin, contains a variety of flavonolignans and displays antioxidant, anti-inflammatory, immunomodulatory and hepatoprotective properties. As silybin is the main component of silymarin, the literature mainly focuses on this compound, ignoring all other components. This leads to problems in reproducibility of scientific results, as the exact composition of silymarin is often unknown and can vary to a certain degree depending on the processing, chemo-variety of the plant used and climatic conditions during the plant growth. There are studies dealing with the analytical separation and quantification of silymarin components as well as studies focused on silymarin content in clinically used drugs, in various plant parts, seasons, geographic locations etc. However, no comparison of detail flavonolignan profiles in various silymarin preparations is available to date. Also, as a result of the focus on the flavonolignans; the oil fraction, which contains linoleic, oleic and palmitic acids, sterols, tocopherol (vitamin E) and phospholipids, has been neglected. Due to all these factors, the whole plant is used e.g. as animal feed, the leaves can be eaten in salads and seed oil, besides culinary uses, can be also utilized for biodiesel or polymer production. Various HPLC separation techniques for the determination of the content of the flavonolignans have been vastly summarized in the present review.
Silymarin is a flavonoid complex extracted from the Silybum marianum plant. It acts as a strong antioxidant and free radical scavenger by different mechanisms. But in addition to antioxidant effects, silymarin/silybin reveals immunomodulatory affects with both immunostimulatory and immunosuppression activities. Different studies have shown that silymarin has the anti-inflammatory effect through the suppression of NF-κB signaling pathway and TNF-α activation. It also has different immunomodulatory activities in a dose and time-dependent manner. As an immunomodulator agent, silymarin inhibits T-lymphocyte function at low doses while stimulates inflammatory processes at high doses. Studies have shown that silymarin has attenuated autoimmune, allergic, preeclampsia, cancer, and immune-mediated liver diseases and also has suppressed oxidative and nitrosative immunotoxicity. Silymarin also has indicated dual effects on proliferation and apoptosis of different cells. In conclusion, based on the current review, silymarin has a broad spectrum of immunomodulatory functions under different conditions. Recognizing the exact mechanisms of silymarin on cellular and molecular pathways would be very valuable for treatment of immune-mediated diseases. Also further studies are needed to assess the utility of silymarin in protection against autoimmune, cancer, allergic and other diseases in human subjects.
Linked articles:
This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin, silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but the effect of the individual flavonolignans on this enzyme has not been studied. To investigate the effects of milk thistle extract and its main flavonolignans (silybin A, silybin B, isosilybin A and isosilybin B) on CYP2C8 activity at relevant concentrations, the effect of milk thistle extract and the flavonolignans on CYP2C8 enzyme activity was studied in vitro using human liver microsomes (HLM) incorporating an enzyme-selective substrate for CYP2C8, amodiaquine. Metabolite formation was analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). The concentration causing 50% inhibition of enzyme activity (IC50) was used to express the degree of inhibition. Isosilibinin, a mixture of the diastereoisomers isosilybin A and isosilybin B, was found to be the most potent inhibitor, followed by isosilybin B with IC50 values (mean ± SE) of 1.64 ± 0.66 μg/mL and 2.67 ± 1.18 μg/mL, respectively. The rank order of observed inhibitory potency after isosilibinin was silibinin > isosilybin A > silybin A > milk thistle extract > and silybin B. These in vitro results suggest a potentially significant inhibitory effect of isosilibinin and isosilybin B on CYP2C8 activity. However, the observed IC50 values are unlikely to be achieved in humans supplemented with orally administered milk thistle extracts due to the poor bioavailability of flavonolignans documented with most commercially available formulations.
Background & aims:
Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum; it has shown anti-oxidant, anti-inflammatory and anti-fibrotic effects, and may be useful in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to study the efficacy of silymarin in patients with non-alcoholic steatohepatitis (NASH)-the more severe form of NAFLD.
Methods:
We performed a randomized, double-blind, placebo-controlled trial of consecutive adults with biopsy-proven NASH and a NAFLD activity score (NAS) of 4 or more at a tertiary care hospital in Kuala Lumpur, Malaysia, from November 2012 through August 2014. Patients were randomly assigned to groups given silymarin (700 mg; n=49 patients) or placebo (n=50 patients) 3 times daily for 48 weeks. After this 48-week period, liver biopsies were repeated. The primary efficacy outcome was a decrease of 30% or more in NAS; findings from 48-week liver biopsies were compared with those from the baseline biopsy. Secondary outcomes included changes in steatosis, lobular inflammation, hepatocyte ballooning, NAS and fibrosis score, and anthropometric measurements, as well as glycaemic, lipid, and liver profiles and liver stiffness measurements.
Results:
The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups (32.7% in the silymarin group vs 26.0% in the placebo group; P=.467). A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology (reductions of 1 point or more), (22.4%) than the placebo group (6.0%) (P=.023), and based on liver stiffness measurements (decrease of 30% or more) (24.2%) than the placebo group (2.3%) (P=.002). The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index (reduction of 0.14, P=.011 compared with baseline), fibrosis-4 score (reduction of 0.20, P=.041 compared with baseline), and NAFLD fibrosis score (reduction of 0.30, P<.001 compared with baseline); these changes were not observed in the placebo group (reduction of 0.07, P=.154; increase of 0.18, P=.389; and reduction of 0.05, P=0.845, respectively). There was no significant difference between groups in number of adverse events; adverse events that occurred were not attributed to silymarin.
Conclusion:
In a randomized trial of 99 patients, we found that silymarin (700 mg, given 3 times daily for 48 weeks) did not reduce NAS scores by 30% or more in a significantly larger proportion of patients with NASH than placebo. Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial. It appears to be safe and well-tolerated. ClinicalTrials.gov no: NCT02006498.
