Administration of silymarin in NAFLD/NASH: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide and poses serious harm to human health. There is growing evidence suggesting that the administration of specific supplements or nutrients may slow NAFLD progression. Silymarin is a hepatoprotective extract of milk thistle, but its efficacy in NAFLD remains unclear. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrails.gov, and China National Knowledge Infrastructure and were screened according to the eligibility criteria. Data were analyzed using Revman 5.3. Continuous values and dichotomous values were pooled using the standard mean difference (SMD) and odds ratio (OR). Heterogeneity was evaluated using the Cochran's Q test (I2 statistic). A P<0.05 was considered statistically significant. RESULTS: A total of 26 randomized controlled trials involving 2,375 patients were included in this study. Administration of silymarin significantly reduced the levels of TC (SMD[95%CI]=-0.85[-1.23, -0.47]), TG (SMD[95%CI]=-0.62[-1.14, -0.10]), LDL-C (SMD[95%CI]=-0.81[-1.31, -0.31]), FI (SMD[95%CI]=-0.59[-0.91, -0.28]) and HOMA-IR (SMD[95%CI]=-0.37[-0.77, 0.04]), and increased the level of HDL-C (SMD[95%CI]=0.46[0.03, 0.89]). In addition, silymarin attenuated liver injury as indicated by the decreased levels of ALT (SMD[95%CI]=-12.39[-19.69, -5.08]) and AST (SMD[95% CI]=-10.97[-15.51, -6.43]). The levels of fatty liver index (SMD[95%CI]=-6.64[-10.59, -2.69]) and fatty liver score (SMD[95%CI]=-0.51[-0.69, -0.33]) were also decreased. Liver histology of the intervention group revealed significantly improved hepatic steatosis (OR[95%CI]=3.25[1.80, 5.87]). CONCLUSIONS: Silymarin can regulate energy metabolism, attenuate liver damage, and improve liver histology in NAFLD patients. However, the effects of silymarin will need to be confirmed by further research.

Silymarin enriched gelatin methacrylamide bioink imparts hepatoprotectivity to 3D bioprinted liver construct against carbon tetrachloride induced toxicity.

Three-dimensional liver bioprinting is an emerging technology in the field of regenerative medicine that aids in the creation of functional tissue constructs that can be used as transplantable organ substitutes. During transplantation, the bioprinted donor liver must be protected from the oxidative stress environment created by various factors during the transplantation procedure, as well as from drug-induced damage from medications taken as part of the post-surgery medication regimen following the procedure. In this study, Silymarin, a flavonoid with the hepatoprotective properties were introduced into the GelMA bioink formulation to protect the bioprinted liver against hepatotoxicity. The concentration of silymarin to be added in GelMA was optimised, bioink properties were evaluated, and HepG2 cells were used to bioprint liver tissue. Carbon tetrachloride (CCl4) was used to induce hepatotoxicity in bioprinted liver, and the effect of this chemical on the metabolic activities of HepG2 cells was studied. The results showed that Silymarin helps with albumin synthesis and shields liver tissue from the damaging effects of CCl4. According to gene expression analysis, CCl4 treatment increased TNF-α and the antioxidant enzyme SOD expression in HepG2 cells while the presence of silymarin protected the bioprinted construct from CCl4-induced damage. Thus, the outcomes demonstrate that the addition of silymarin in GelMA formulation protects liver function in toxic environments.

Silymarin (Milk Thistle) Treatment of Adults With Gambling Disorder: A Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Data on the pharmacological treatment of gambling disorder are limited. Silymarin (derived from milk thistle) has antioxidant properties. The goal of the current study was to determine the efficacy and tolerability of silymarin in adults with gambling disorder. METHODS: Forty-three individuals (18 [41.9%] women; mean age=49.61 [±13.1] years) with gambling disorder entered an 8-week, double-blind, placebo-controlled study. Dosing of silymarin ranged from 150 to 300 mg twice a day. The primary outcome measure was the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS). Secondary outcome measures comprised the Gambling Symptom Assessment Scale and measures of depression and anxiety. Outcomes were examined using mixed-effect models. RESULTS: Silymarin did not statistically differentiate from the placebo on any of the outcome measures of interest, in terms of treatment group×time interactions. There was a robust response in the placebo group (57% reduction on the PG-YBOCS), and on average there was a 56% reduction in YBOCS score for the milk thistle. CONCLUSIONS: The findings of this study do not support the use of silymarin/milk thistle in the treatment of gambling disorder but highlight the large placebo response seen in gambling disorder. Treatment interventions for gambling disorder need to better understand and address the placebo response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02337634.

A combination of silymarin and garlic extract enhances thyroid hormone activation and body metabolism in orally intoxicated male rats with atrazine: Impact on hepatic iodothyronine deiodinase type 1.

Atrazine is a widely applied herbicide to improve crop yield and maintain general health. It has been reported to impair thyroid function and architecture in experimental animals. Alterations in thyroid hormones disrupt normal body function and metabolism. Silymarin, a hepatoprotective flavonolignan, was found to improve thyroid function and body metabolism. Additionally, garlic displays several protective effects on body organs. Therefore, this study explored the prophylactic impact of natural compounds comprising silymarin and garlic extract on disrupted thyroid function, hepatic iodothyronine deiodinase type 1, and metabolic parameters in atrazine-intoxicated male rats. We found that daily pre- and co-treatment of atrazine-intoxicated male rats with silymarin (100 mg/kg, p.o) and/or garlic extract (10 mg/kg, p.o) significantly improved thyroid activation and hepatic functionality as evidenced by the re-establishment of T3, T3/T4, and TSH values as well as ALT and AST activities. Interestingly, individual or concurrent supplementation of the atrazine group with silymarin and garlic extract prevented the down-regulation in hepatic iodothyronine deiodinase type 1. These effects were coupled with the repletion of serum and hepatic antioxidants and the amelioration of lipid peroxidation. In addition, current natural products markedly alleviated weight gain, dyslipidemia, hyperglycemia, glucose intolerance, and insulin resistance. Notably, a cocktail of silymarin and garlic extract exerted superior protection against atrazine-triggered deterioration of thyroid, hepatic, and metabolic functioning to individual treatments. Present findings pinpoint the prophylactic and synergistic influence of silymarin and garlic extract combinatorial regimen on thyroid activation and body metabolism via enhancing antioxidant potential, maintaining hepatic function, and iodothyronine deiodinase type 1.

Effects of silymarin supplementation on liver and kidney functions: A systematic review and dose-response meta-analysis.

It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate aminotransferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignificant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Sub-group analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxidative stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.

Silibinin is a suppressor of the metastasis-promoting transcription factor ID3.

BACKGROUND: ID3 (inhibitor of DNA binding/differentiation-3) is a transcription factor that enables metastasis by promoting stem cell-like properties in endothelial and tumor cells. The milk thistle flavonolignan silibinin is a phytochemical with anti-metastatic potential through largely unknown mechanisms. HYPOTHESIS/PURPOSE: We have mechanistically investigated the ability of silibinin to inhibit the aberrant activation of ID3 in brain endothelium and non-small cell lung cancer (NSCLC) models. METHODS: Bioinformatic analyses were performed to investigate the co-expression correlation between ID3 and bone morphogenic protein (BMP) ligands/BMP receptors (BMPRs) genes in NSCLC patient datasets. ID3 expression was assessed by immunoblotting and qRT-PCR. Luciferase reporter assays were used to evaluate the gene sequences targeted by silibinin to regulate ID3 transcription. In silico computational modeling and LanthaScreen TR-FRET kinase assays were used to characterize and validate the BMPR inhibitory activity of silibinin. Tumor tissues from NSCLC xenograft models treated with oral silibinin were used to evaluate the in vivo anti-ID3 effects of silibinin. RESULTS: Analysis of lung cancer patient datasets revealed a top-ranked positive association of ID3 with the BMP9 endothelial receptor ACVRL1/ALK1 and the BMP ligand BMP6. Silibinin treatment blocked the BMP9-induced activation of the ALK1-phospho-SMAD1/5-ID3 axis in brain endothelial cells. Constitutive, acquired, and adaptive expression of ID3 in NSCLC cells were all significantly downregulated in response to silibinin. Silibinin blocked ID3 transcription via BMP-responsive elements in ID3 gene enhancers. Silibinin inhibited the kinase activities of BMPRs in the micromolar range, with the lower IC50 values occurring against ACVRL1/ALK1 and BMPR2. In an in vivo NSCLC xenograft model, tumoral overexpression of ID3 was completely suppressed by systematically achievable oral doses of silibinin. CONCLUSIONS: ID3 is a largely undruggable metastasis-promoting transcription factor. Silibinin is a novel suppressor of ID3 that may be explored as a novel therapeutic approach to interfere with the metastatic dissemination capacity of NSCLC.

Innovative prophylactic and therapeutic approaches in liver cirrhosis.

Liver cirrhosis is the consequence of chronicisation and of the evolution of untreated liver diseases. The complexity of the disease and the complications it can cause have been and are still intensively researched, aiming to discover new therapies or improve existing ones for the effective management of liver cirrhosis. Currently, the treatment used is directed against the cause that caused the disease, if it is known; in advanced cases, liver transplantation is the only valid therapeutic option. Hepatoprotectors that are currently on the market are numerous, having as common properties the antioxidant, anti-inflammatory, stabilizing properties of the hepatocytic membrane; A few examples: the ethanolic extract of Curcuma longa, the extract from the plant called Sophora flavescens, the extract of Glycyrrhiza glabra, silymarin (extracted from Sylibum marianum), the extract of Ganoderma lucidum, etc. Liver cirrhosis is accompanied by generalized hypovitaminosis, so supplementing the diet with hydro- and liposoluble vitamins is mandatory. Protein-caloric malnutrition can be prevented by a hyperprotein diet, especially beneficial being the supplementation with branched-chain amino acids, which are also applicable in the prophylaxis and treatment of hepatic encephalopathy. Nanoparticles are a state-of-the-art therapeutic option, proving increased bioavailability, for example polydopamine nanoparticles loaded with l-arginine have been tested as therapy in liver cirrhosis. Among the innovative treatment directions in liver cirrhosis are hybrid products (e.g. hybrid polymer nanoparticles loaded with caffeic acid), cell cultures and artificial or bioartificial liver support.

The effects of silymarin consumption on inflammation and oxidative stress in adults: a systematic review and meta-analysis.

BACKGROUND: Owing to the rich phytochemical content of Silymarin, it may effectively manage inflammation and oxidative stress. We, therefore, aimed to examine the existing evidence on the effect of Silymarin consumption on inflammation and oxidative stress factors by conducting a systematic review and meta-analysis of randomized controlled trials. METHODS: A systematic literature search up to September 2023 was completed in PubMed/Medline, Scopus, and Web of Science, to identify eligible RCTs. Heterogeneity tests of the selected trials were performed using the I2 statistic. Random effects models were assessed based on the heterogeneity tests, and pooled data were determined as weighted mean differences with a 95% confidence interval. RESULTS: Fifteen RCTs were included in this meta-analysis. Our findings showed that Silymarin consumption significantly decreased CRP (WMD, - 0.50 mg/L; 95% CI, (- 0.95 to - 0.04); p = 0.03), MDA (WMD, - 1.19 nmol/mL; 95% CI, (- 1.99 to - 0.38); p = 0.004), and IL-6 (WMD, - 0.44 pg/ml; 95% CI, (- 0.75 to - 0.12); p = 0.006). Silymarin consumption had no significant effects on IL-10, TAC, and GSH. A significant non-linear relationship was observed between the duration of the intervention and MDA changes. CONCLUSIONS: Silymarin can help reduce inflammation in patients with diabetes and thalassemia by reducing MDA as an oxidative stress marker and CRP and IL-6 as inflammatory markers.

Thermoresponsive in situ forming and self-healing double-network hydrogels as injectable dressings for silymarin/levofloxacin delivery for treatment of third-degree burn wounds.

Our study aimed to introduce a novel double-cross-linked and thermoresponsive hydrogel with remarkable potential for accelerating third-degree burn wound healing. Burn injuries are recognized as challenging, critical wounds. Especially in third-degree burns, treatment is demanding due to extended wounds, irregular shapes, significant exudation, and intense pain during dressing changes. In this work, hydrogels made of zwitterionic chitosan and dialdehyde starch (ZCS and ZDAS) were created to deliver silymarine (SM) and levofloxacin (LEV). The hydrogels were effortlessly produced using dynamic Schiff base linkages and ionic interactions between ZCS and ZDAS at appropriate times. The pore uniformity, gel fraction, and commendable swelling properties can imply a suitable degree of Schiff base cross-link. The hydrogel demonstrated outstanding shape retention, and significant self-healing and flexibility abilities, enabling it to uphold its form even during bodily movements. After injecting biocompatible hydrogel on the wound, a notable acceleration in wound closure was observed on day 21 (98.1 ± 1.10 %) compared to the control group (75.1 ± 6.13 %), and histopathological analysis revealed a reduction of inflammation that can be linked to remarkable antioxidant and antibiotic properties. The results demonstrate the hydrogel's efficacy in promoting burn wound healing, making it a promising candidate for medical applications.

Antiproliferative and Antitelomerase Effects of Silymarin on Human Colorectal and Hepatocellular Carcinoma Cells.

Silymarin, a widely-used hepatoprotective agent, has shown antitumor properties in both in vitro and animal studies. Currently, there is limited knowledge regarding silymarin's antitelomerase effects on human colorectal cancer and hepatocyte carcinoma cells. In this study, we investigated the antiproliferative and antitelomerase effects of silymarin on four human colorectal cancer and HepG2 hepatocyte carcinoma cell lines. The cell viability and telomerase activity were assessed using MTT and the telomerase repeat amplification protocol assay, respectively. We also investigated the effects of silymarin on the expression of human telomerase reverse transcriptase and its promoter methylation in HepG2 cells by real-time RT-PCR and methylation-specific PCR, respectively. Silymarin treatment inhibited cell proliferation and telomerase activity in all cancer cells. After 24 h of treatment, silymarin exhibited IC50 values ranging from 19 - 56.3 µg/mL against these cancer cells. A 30-min treatment with silymarin at the IC50 concentration effectively inhibited telomerase activity in cell-free extracts of both colorectal cancer and hepatocyte carcinoma cells. Treatment of HepG2 cells with 10 and 30 µg/mL of silymarin for 48 h resulted in a decrease in human telomerase reverse transcriptase expression to 75 and 35% of the level observed in the untreated control (p < 0.01), respectively. Treatment with silymarin (10, 30, and 60 µg/mL) for 48 h did not affect human telomerase reverse transcriptase promoter methylation in HepG2 cells. In conclusion, our findings suggest that silymarin inhibits cancer cell growth by directly inhibiting telomerase activity and downregulating its human telomerase reverse transcriptase catalytic subunit. However, silymarin did not affect human telomerase reverse transcriptase promoter methylation at the concentrations of 10 - 60 µg/mL used in this study.

Co-treatment of silymarin and cisplatin inhibited cell proliferation, induced apoptosis in ovarian cancer.

BACKGROUND: Ovarian cancer is one of the most lethal gynecological cancers among women worldwide. Cisplatin (Cis) is an effective chemotherapeutic agent used to treat several types of cancer. Silymarin (SLM) is an extract of medicinal plant Silybum marianum (milk thistle) with anti-inflammatory, anti-angiogenesis, antioxidant, and anticancer properties used alone or in combination with other drugs. OBJECTIVE: This study aimed to explore the effects of co-treatment with SLM and Cis on A2780 human ovarian cancer cell lines. METHODS: In this study, A2780 cells were treated with various concentrations of SLM and Cis, separately and in combination. Cell cytotoxicity, scratch, clonogenic, and flow-cytometry assays were accomplished to estimate cell viability, migration, colony formation, and apoptosis, respectively. Real-time PCR was utilized to determine the expression levels of miR-155 and miR-27a. RESULTS: SLM significantly reduced the proliferation of A2780 cells in a concentration- and time-dependent manner. Combination treatment with SLM and Cis was more potent than either single treatment in reducing viability, suppressing migration, inhibiting colony formation, and promoting the induction of apoptosis. Additionally, gene expression analysis revealed a significant decline in the expression levels of miR-155 and miR-27a in response to all separate and combined treatments, and co-treatment was more effective than individual treatments in altering miRNAs expression. CONCLUSION: Based on our findings, SLM boosts the anticancer activity of Cis and mitigates its side effects. Thus, the co-treatment of SLM and Cis can be proposed as a promising therapeutic strategy for further investigation.

Fermented formulation of Silybum marianum seeds: Optimization, heavy metal analysis, and hepatoprotective assessment.

BACKGROUND: Fermented formulations are extensively used in Ayurveda due to several benefits like improved palatability, bioavailability, pharmacological potential, and shelf life. These formulations can also quench the heavy metals from the plant material and thus reduce the toxicity. Seeds of Silybum marianum (L.) Gaertn. are widely used for the management of many liver diseases. STUDY DESIGN AND METHODS: In the present study, we developed a novel fermented formulation of S. marianum seeds and evaluated parameters like safety (heavy metal analysis) and effectiveness (hepatoprotective). As the developed formulation's validation is crucial, the critical process variables (time, pH, and sugar concentration) are optimized for alcohol and silybin content using the Box-Behnken design (BBD). RESULTS: The response surface methodology coupled with BBD predicted the optimized conditions (fermentation time (28 days), pH 5.6, and sugar concentration (22.04%)) for the development of a fermented formulation of the selected herb. Moreover, the alcohol content (6.5 ± 0.9%) and silybin concentration (26.1 ± 2.1%) were confirmed in optimized formulation by GC-MS and HPTLC analysis. The optimized formulation was also analyzed for heavy metals (Pb, As, Hg, and Cd); their concentration is significantly less than the decoction of herbs. Further, the comparative evaluation of the developed formulation with the marketed formulation also confirmed that the fermented formulation's silybin concentration and percentage release were significantly enhanced. In addition, the developed fermented formulation's percentage recovery of HepG2 cell lines after treatment with CCl4 was significantly improved compared with the marketed formulation. CONCLUSION: It can be summarized that the developed fermented formulation improves safety and effectiveness compared to other market formulations. Finally, it can be concluded that the developed fermented formulation could be further explored as a better alternative for developing Silybum marianum preparation.

Topical Silymarin Cream as a Novel Therapy Versus Salicylic Acid Peels in Acne Vulgaris: A Split-Face Clinical Trial.

BACKGROUND: Acne vulgaris is a common dermatological condition that greatly impacts patients' self-confidence. Ongoing research is conducted to explore new treatment modalities. Silymarin owns special characteristics that qualify it as a possible treatment for acne vulgaris. OBJECTIVE: We evaluated the efficacy and safety of silymarin cream as a new therapeutic option against salicylic acid peels in the treatment of mild to moderate acne vulgaris. METHODS: A split-face, comparative, Quasi-experimental clinical trial included 30 patients with acne vulgaris. Salicylic acid 30% peels were applied as an office procedure to one half of the face every 2 weeks for 3 months. Topical silymarin 1.4% cream was prescribed as a home treatment, twice daily, to the other half of the face for 3 months. The results were evaluated using the Global Acne Grading System (GAGS), photographic evaluation, and patient self-assessment scale. The adverse effects during treatment were recorded. The sample size was calculated by Stata/IC 16.1. RESULTS: After treatment, a significant reduction of GAGS was noted on both sides of the face, with an insignificant difference between both treatments. The comparative photographic evaluation and patient self-assessment scale were also insignificant. Hyperpigmentation was recorded in 2 cases on the salicylic acid-treated side. No side effects for silymarin cream were observed. CONCLUSION: Topical silymarin cream 1.4% showed comparable results to Salicylic acid 30% peels. It can be considered a promising safe treatment modality for mild to moderate acne vulgaris.

Evaluation of the effect of herbal agents as management of radiodermatitis in breast cancer patients: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of herbal agents in the prevention and therapy of radiodermatitis in breast cancer patients. METHODS: Randomized controlled trials were searched from databases such as PubMed, Web of Science, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure (CNKI) to assess the effectiveness of herbal agents compared to a standard medication or placebo in prevention or treatment of radiodermatitis in breast cancer. RESULTS: Data from 16 studies involving 1994 patients were included. This meta-analysis included 10 clinical trials of 562 breast cancer patients treated with calendula, silymarin, or aloe vera for the prevention of radiodermatitis. Silymarin showed positive effects in ameliorating the damage of radiodermatitis, whereas the efficacy of calendula and aloe vera in the treatment of radiodermatitis lacks sufficient evidence. CONCLUSIONS: Herbal medicine may show therapeutic effects on radiodermatitis in breast cancer, but more comprehensive investigations and clinical trials are required in the future.

Pharmacokinetics, dynamics, toxicology and molecular docking of bioactive alkaloid vasicine from Adhatoda vasica: a promising toxin binder against aflatoxin B1 and ochratoxin A.

Vasicine from Adhatoda vasica was investigated in the management of aflatoxicosis and ochratoxicosis by in silico molecular docking approach. The computational analysis was carried out using Discovery Studio Autodock 4.5 tool. Absorption, distribution, metabolism, and excretion (ADME), pharmacodynamics and toxicity studies were also carried out using Swiss ADME and PASS online server, respectively. The standard drug compound used was silymarin and the structure were retrieved from the protein data bank for both the test compound vasicine and the standard drug. Vasicine interacted with aflatoxin B1 at 10 different poses and the maximum dock score was found to be 83.04 and the binding energy was -37.54 kcal/mol. Silymarin interacted with aflatoxin B1 at 10 different poses and the maximum dock score was found to be 143.578 and the binding energy was -67.32 kcal/mol. Vasicine interacted with ochratoxin A at 10 different poses and the maximum dock score was found to be 73.75 and the binding energy was -56.20 kcal/mol. Silymarin interacted with ochratoxin A at 10 different poses and the maximum dock score was found to be 89.23 and the binding energy was -98.86 kcal/mol. The compounds possess good gastro intestinal absorption with antioxidant property and exhibits minimum adverse effects. The obtained results support the toxin mitigating potential of the test compound with minimum adverse effects and hence vasicine can be regarded as a potential toxin binder of aflatoxin B1 and ochratoxin A, wherein it can be implemented for alleviating aflatoxicosis and ochratoxicosis.

Structure-activity relationship and docking analysis of nature flavonoids as inhibitors of human and rat gonadal 3ß-hydroxysteroid dehydrogenases for therapeutic purposes.

The potential inhibitory effects of flavonoids on gonadal steroid biosynthesis have gained attention due to their widespread presence in natural plant sources. Specifically, our study focused on evaluating the inhibitory efficacy of these compounds on human 3ß-hydroxysteroid dehydrogenase 2 (h3ß-HSD2) and rat homolog r3ß-HSD1, enzymes responsible for the conversion of pregnenolone to progesterone. Through our investigations, we observed that the potency of flavonoids was silymarin (IC50, 1.31 µM) > luteolin (4.63 µM) > tectorigenin > (5.86 µM), and rutin (44.12 µM) in inhibiting human KGN cell microsomal h3ß-HSD2. Similarly, the potency of flavonoids was silymarin (9.50 µM) > luteolin (11.49 µM) > tectorigenin (14.06 µM), and rutin (145.71 µM) in inhibiting rat testicular r3ß-HSD1. Silymarin, luteolin, and tectorigenin acted as mixed inhibitors of both human and rat 3ß-HSDs. Luteolin and tectorigenin were able to penetrate human KGN cells to inhibit progesterone secretion. Furthermore, docking analysis and structure-activity relationship analysis highlighted the importance of hydrogen bond formation for the inhibitory efficacy of these compounds against h3ß-HSD2 and r3ß-HSD1. Overall, this study demonstrates that silymarin exhibits the most potent inhibition of human and rat gonadal 3ß-HSDs, and significant SAR differences exist among the tested compounds.

Application of SNAP-tag-EGFR cell membrane chromatography model in screening antitumor active components of Silybum marianum (L.) Gaertn.

The SNAP-tag-epidermal growth factor receptor (SNAP-tag-EGFR) cell membrane chromatography (CMC) model is a powerful tool for investigating ligand-receptor interactions and screening active ingredients in traditional Chinese medicine. Most tyrosine kinase inhibitors (TKIs) target epidermal growth factor receptors. However, TKIs associated with significant side effects and drug resistance must be addressed immediately. Therefore, there is an urgent need to develop new TKIs with high efficiency and low toxicity. Because of its low toxicity and side effects, traditional Chinese medicine has been widely employed to treat various diseases, including cancer. Hence, this study aimed to use the SNAP-tag-EGFR/CMC-high-performance liquid chromatography-mass spectrometry (HPLC-MS) two-dimensional system model as the research tool to screen and identify potential EGFR antagonists from the Chinese medicine Silybum marianum (L.) Gaertn. The applicability of the system was verified using the positive control drug osimertinib. Four potential EGFR antagonists were screened from the Chinese medicine Silybum marianum (L.) Gaertn.. They were identified as silydianin, silychristin, silybin, and isosilybin. Additionally, their pharmacological activity was preliminarily verified using a CCK-8 assay. The kinetic parameters of the four active ingredients interacting with EGFR and their binding modes with EGFR were analyzed using nonlinear chromatography (NLC) and molecular docking. This study identified silydianin, silychristin, silybin, and isosilybin from Silybum marianum (L.) Gaertn. and verified their potential antitumor effects on EGFR.

Cakes fortified with papaya seeds effectively protects against CCl4-induced immunotoxicity.

Maintaining a robust immune system and safeguarding the liver from toxins are crucial for overall health. The study aimed to investigate the immunostimulant effects of papaya seed-enriched cakes (CPS) in countering carbon tetrachloride (CCl4)-induced immunocytotoxicity in rats (n = 48). The rats were divided into six groups (8 each): a control group (Group 1), rats fed cakes containing 15% papaya seeds (Group 2 - CPS), rats exposed only to CCl4 (Group 3 - CCl4), rats injected with CCl4 and administered silymarin (Group 4 - CCl4 + S), rats receiving both CCl4 and cakes with papaya seeds (Group 5 - CCl4 + CPS), and rats receiving both CCl4 and silymarin with papaya seed-enriched cakes (Group 6 - CCl4 + CPS + S). HPLC analysis of papaya seeds revealed the presence of ten polyphenol compounds, with quercetin, apigenin, and catechin identified as major flavonoids, along with pyrogallol, ellagic, and gallic acid as predominant phenolic acids. These compounds displayed potent antioxidant activity, attributed to the seeds' high total phenolic and flavonoid content. The administration of CCl4 significantly affected hematological parameters, liver enzymes, hepatic oxidative stress, levels of TNF-α, IL-6, IgG, as well as IgM. However, rats fed with CPS exhibited mitigation of CCl4-induced toxic effects on hematological parameters and hepatotoxicity. CPS consumption enhanced the antioxidant system, improved inflammatory markers, and immune parameters, restoring them to normal levels. Histopathological analysis confirmed CPS's ability to reduce CCl4-induced hepatocellular necrosis. Immunohistochemical assessment further revealed reduced immunoreactivity against cleaved caspase-3 expression and increased COX2 immunoreactivity, indicating hepatocellular regeneration in CPS. The combination of CPS and silymarin demonstrated even more notable improvements, suggesting augmented protective impacts against CCl4-induced immunosuppression and hepatotoxicity. In conclusion, CPS exhibited antioxidant properties and effectively protected against CCl4-induced immunotoxicity and hepatotoxicity, with additional benefits observed when combined with silymarin. These findings emphasize the potential health advantages of incorporating papaya seeds into food products, promoting immune system health, and safeguarding against liver damage induced by hazardous agents like CCl4.

Methanol Extracts from Cirsium japonicum DC. var. australe Kitam. and Their Active Components Reduce Intracellular Oxidative Stress in Caenorhabditis elegans.

Cirsium japonicum DC. var. australe Kitam. has been used as an herbal remedy and often involves using the whole plant or roots. However, the bioactivities of different parts of the plant have been far less explored. This study aimed to evaluate the antioxidative ability of methanol extracts from the flowers, leaves, stems, and roots of the Cirsium plant and their possible active components against juglone-induced oxidative stress in the nematode Caenorhabditis elegans. The results showed that the highest dry weight (12.3 g per plant) was observed in leaves, which was followed by stems (8.0 g). The methanol extract yields from the flowers, leaves, and roots were all similar (13.0-13.8%), while the yield from stems was the lowest (8.6%). The analysis of the silymarin contents in the extracts indicated that the flowers, leaves, stems, and roots contained silychristin and taxifolin; however, silydianin was only found in the leaves, stems, and roots. The flower, leaf, and stem extracts, at a concentration of 10 mg/L, significantly reduced juglone-induced oxidative stress in C. elegans, which was potentially due to the presence of silychristin and taxifolin. Overall, C. japonicum DC. var. australe Kitam. contains a significant amount of silymarin and exhibits in vivo antioxidative activity, suggesting that the prospects for the plant in terms of health supplements or as a source of silymarin are promising.

The deleterious effects of cadmium on oxidative stress markers, drug-metabolizing, and antioxidant enzyme activities: Role of Silymarin and Garlic as Antioxidants.

Exposure to cadmium has been related to liver and kidney diseases such as polycystic and nephrotic syndrome. It is still unclear how cadmium contributes to these diseases. It is believed that the induction of oxidative stress resulting from the inhibition of antioxidant enzyme activities and changes in drug-metabolizing enzymes in the liver could explain the role of cadmium in the development of different diseases in the kidney and probably other organs. Changes in oxidative stress markers, antioxidant enzymes, and drug-metabolizing enzyme activities were assessed in the liver of male rats exposed to cadmium chloride. Additionally, the protective effects of silymarin and garlic extract against cadmium toxicosis were evaluated. Rats were randomly divided into eight groups as follows, groups 1, 2, 3, 4, and 5, received orally saline, CdCl2 (1 mg/kg), garlic extract [800 mg/kg], silymarin (25 mg/kg) and silymarin plus garlic extract respectively for 28 consecutive days. Rats in groups 6, 7, and 8 were pretreated with the same doses of garlic, silymarin, and garlic plus silymarin, respectively for two hours before cadmium administration. The Western immunoblotting technique was used to investigate the protein expression of cytochrome P450 isozymes. Spectrophotometric methods were used to assess the activity of both antioxidant- and drug-metabolizing enzymes. Free radical levels [measured as thiobarbituric acid reactive substances (TBARS)], catalase, superoxide dismutase, and glutathione peroxidase activities increased whereas the levels of glutathione and the activities of glutathione S-transferase, glutathione reductase, and glutamyl transferase, cytochrome P450, aryl hydrocarbon dehydrogenase (AHH), dimethylnitrosamine-N-demethylase I (DMN-dI), 7-ethoxycoumarine-O-deethylase (ECOD), cytochrome b5 and NADPH-Cytochrome-c-reductase enzyme activities decreased after cadmium treatment. Furthermore, Western immunoblotting data revealed that glutathione peroxidase protein expression increased following cadmium exposure, but cytochrome P450 2E1 and 3A4 expressions were downregulated. However, pretreatment of rats with silymarin or garlic extract or both before cadmium administration was found to restore the protein expression of cytochrome P450 2E1 and 3A4, the level of free radicals, antioxidant enzymes, drug-metabolizing enzyme activities to their normal levels. Similarly, histological studies revealed that silymarin and/or garlic extract reduced the liver damage caused by cadmium. Silymarin and/or garlic extract reduced the adverse effects of cadmium on the activity of both drug-metabolizing and antioxidant enzymes activity. These antioxidants could be provided to those who work in cadmium-based sectors to help them cope with the adverse effects of cadmium on their kidneys. In addition, Inhibiting drug-metabolizing enzyme activity should be considered when administering therapeutic medications to persons exposed to cadmium because most therapeutic drugs and many endogenous substances are largely metabolized by these enzymes.