Search Results (93)

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), remains a therapeutic challenge due to its aggressive nature, limited treatment options, and high recurrence rates. Current therapies, including chemotherapy and immune checkpoint inhibitors, face resistance driven by tumor heterogeneity, immunosuppressive signaling, and dysregulated redox pathways. This review explores silibinin’s potential to modulate the tumor immune microenvironment (TIME) and overcome therapeutic resistance in TNBC. Silibinin exerts multifaceted anticancer effects by suppressing PD-L1 expression through the inhibition of JAK/STAT3 signaling and MUC1-C interaction, attenuating NF-κB-driven inflammation, and downregulating CCL2-mediated recruitment of tumor-associated macrophages (TAMs). Additionally, silibinin disrupts redox adaptation by targeting the Nrf2-EGFR-MYC-TXNIP axis, enhancing oxidative stress and chemosensitivity. Preclinical studies highlight its ability to inhibit epithelial–mesenchymal transition (EMT), reduce cancer stem cell (CSC) populations, and synergize with existing therapies like PD-1 inhibitors. Despite its low bioavailability, advanced formulations such as liposomes and nanoparticles show promise in improving delivery and efficacy. By reshaping TIME through dual antioxidant and immunomodulatory mechanisms, silibinin emerges as a viable adjunct therapy to reverse immunosuppression and chemoresistance in TNBC. Full article

Chronic oxidative distress results in cellular damage, necessitating adaptive mechanisms for redox balance. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is pivotal in the regulation of key antioxidant and cytoprotective genes. Under normal conditions, Nrf2 undergoes rapid degradation through polyubiquitination. However, it can be activated during oxidative eustress and distress via modifications of its inhibitor Kelch-like ECH-associated protein 1 (KEAP1). Activation of the Nrf2-Keap1 signaling pathway may decelerate aging-related muscle degeneration, such as sarcopenia and cachexia. In this study, we investigated the efficacy of two muscle-active endogenous factors, creatine and L-β-aminoisobutyric acid (L-BAIBA), as well as two natural phytochemicals, luteolin and silibinin, to induce Nrf2 in the murine myoblast cell line C2C12. Our results revealed that only luteolin significantly enhances Nrf2 activity in both proliferating and differentiated C2C12 cells, leading to increased expression of Nrf2 target genes in proliferating C2C12 cells. In contrast, the other three compounds had either no or only minor effects on Nrf2 activity or target gene expression. Our results underscore the distinct responses of C2C12 cells to different Nrf2 activators, emphasizing the significance of cellular context in their biological effects and highlight luteolin as a potential future treatment option to counteract muscle wasting associated with sarcopenia and cachexia. Full article

Background: Dengue virus (DENV) is the fatal pathogenic arthropod-borne virus (arboviruses) that belongs to the Flaviviridae family, which transmits to humans through mosquito bites from infected Aedes aegypti and Aedes albopictus mosquitoes or maternal-fetal transmission. Despite antigenic differences, the four serotypes of DENV (DENV-1 to DENV-4) share 65–78% of their genome. Non-structural (NS) proteins amongst serotypes show analogous functions. Among NS proteins, NS3 and NS5 are frequently used as targets for antiviral drugs due to their multifunctional roles. Methods: To identify potential inhibitors of DENV, we created a phytochemical library of 898 compounds derived from 17 medicinal plants recognized for their medicinal and antiviral properties. The phytochemicals library has been docked against the target proteins. Phytochemicals with a docking score greater than −8.0 kcal/mol were selected for further evaluation using a machine learning approach. Further, molecular dynamics (MD) simulations were conducted to evaluate the root mean square deviation, root mean square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond count of the compounds. Results: From the docking results, Silibinin, Rubiadin, and Ellagic acid showed binding affinities of −8.5, −8.3, and −8.2 kcal/mol, respectively, for NS3, and NSC 640467, Bisandrographolide A, and Andrographidin A showed binding affinities of −9.3, −10.1, and −9.3 kcal/mol, respectively, for NS5 target proteins. These compounds exhibited strong interactions with target proteins. MD simulation results confirmed the stable formation of protein–ligand complexes. Further, absorption, distribution, metabolism, excretion, and toxicity (ADMET) and bioactivity predictions confirmed their pharmacological safety. Conclusions: Despite global public health concerns, DENV still lacks specific drug treatments. Our identified new drug candidates might help for developing effective antiviral inhibitors against the DENV. However, further confirmation is needed through in vivo and in vitro research. Full article

Background: Silibinin (SLB), a flavonoid derived from milk thistle, exhibits promising therapeutic properties but faces significant clinical limitations due to poor solubility and bioavailability. Objectives: This study focuses on the development and characterization of SLB-loaded nanoemulsions designed for mucosal delivery. Methods: Nanoemulsions were prepared using the spontaneous emulsification method, guided by pseudoternary phase diagrams to determine selected component ratios. Comprehensive characterization included particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, rheological properties, and surface tension. Mucoadhesive properties were evaluated using quartz crystal microbalance with dissipation (QCM-D) to quantify interactions with mucin layers. Results: The combination of Capryol 90, Tween 80, and Transcutol in selected proportions yielded nanoemulsions with excellent stability and solubilization capacity, enhancing the solubility of silibinin by 625 times compared to its intrinsic solubility in water. The ternary phase diagram indicated that achieving nanoemulsions with particle sizes between 100 and 300 nm required higher concentrations of surfactants (60%), relative to oil (20%) and water (20%), with formulations predominantly composed of Smix (surfactant and cosurfactant mixture in a 1:1 ratio). Rheological analysis revealed Newtonian behavior, characterized by constant viscosity across varying shear rates and a linear torque response, ensuring ease of application and mechanical stability. QCM-D analysis confirmed strong mucoadhesive interactions, with significant frequency and dissipation shifts, indicative of prolonged retention and enhanced mucosal drug delivery. Furthermore, contact angle measurements showed a marked reduction in surface tension upon interaction with mucin, with the SLB-loaded nanoemulsion demonstrating superior wettability and strong mucoadhesive potential. Conclusions: These findings underscore the suitability of SLB-loaded nanoemulsions as a robust platform for effective mucosal drug delivery, addressing solubility and bioavailability challenges while enabling prolonged retention and controlled therapeutic release. Full article

Background: Insufficient treatment options are available for metabolic dysfunction-associated steatotic liver disease (MASLD). Flavonoids and topiramate have been studied for weight loss but need investigation into their effects on liver metabolism. This study’s aim was to examine the effects of flavonoids or topiramate on glucose metabolic carbon flux in a cell culture model of steatosis. Methods: Steatosis was induced in HepG2 cells through exposure to oleic acid (OA, 0.5 mml/L) conjugated to bovine serum albumin (2:1). Additionally, 50% U¹³C-glucose was supplied in the medium as a stable isotope tracer. Cells were treated with DMSO, 10 μM of naringenin, morin, silibinin, or topiramate (44 μM) for 72 h. A non-steatotic, untreated HepG2 cell control was included. Cell extracts were analyzed by gas chromatography/mass spectrometry and mass isotopomer distribution analysis for glycogen synthesis, de novo fatty acid synthesis, tricarboxylic acid (TCA) cycle activity, and ribose synthesis. Groups were compared by ANOVA with Tukey’s pair-wise testing. Results: Compared to untreated HepG2 controls, OA-exposed steatotic cells exhibited increased lipid accumulation by ORO staining (1.6-fold), enhanced palmitate de novo synthesis, reduced pyruvate carboxylase/pyruvate dehydrogenase (PC/PDH) ratio, and reduced ribose synthesis. Treatment with topiramate or silibinin ameliorated the lipid accumulation (1.3-fold) and mitigated enhancement of de novo synthesis. Morin-treated cells exhibited enhanced de novo synthesis but suppressed ribose synthesis. Conclusions: Potential mechanisms of reduced lipid accumulation by topiramate and silibinin may include suppression of palmitate de novo synthesis and a relative decrease in carbon flux through the PDH pathway. Further studies are needed on potential utility in MASLD based on their specific metabolic effects. Full article

Aging is an inevitable physiological process, but delaying aging has always been an enduring human pursuit. Silibinin (SIL), derived from the seeds of the milk thistle plant, exhibits a broad spectrum of pharmacological properties, including anti-tumor effects, liver protection, inhibition of apoptosis, and alleviation of inflammation. However, whether it has anti-aging effects remains unclear. The SIL dietary supplement to Drosophila melanogaster prolonged lifespan, improved climbing ability, ameliorated age-associated intestinal barrier disruption, enhanced the resistance to oxidative stress, and increased the enzyme activities of superoxide dismutase (SOD) and catalase (CAT). Furthermore, RNA-seq results showed that SIL addition significantly upregulated 74 genes and downregulated 50 genes compared with the control. KEGG (Kyoto Encyclopedia of genes and genomes) analysis demonstrated that these differentially expressed genes were primarily involved in the Toll signaling pathway and endoplasmic reticulum proteins processing, six among which, including IM2, IM3, Drsl3, CG7556, GCS1, and TRAM, were particularly involved in the regulation by SIL supplementation. The results indicate that SIL exhibits anti-aging effects by enhancing antioxidant capacity and regulating aging-related signaling pathways. Therefore, SIL shows a potential application in anti-aging dietary regimens. Full article

Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of Cichorium glandulosum (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Methods: Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including HMOX1, RSAD2, BCL6, CDKN1A, THBD, SLC2A4, and TGFβ3, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. Conclusions: CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE’s potential as a promising therapeutic candidate for ALD treatment. Full article

Amanita phalloides is well-established as one of the most poisonous mushrooms; toxicity from ingestion was reported as early as the first century. Although native to Europe, this ectomycorrhizal fungus has been widely spread and is responsible for liver toxicity in many parts of the world. Toxicity is characterized by delayed gastrointestinal symptoms mimicking acute gastroenteritis followed by severe hepatotoxicity and liver failure with consequent multi-organ failure. The primary mechanism of liver toxicity is considered to be the inhibition of RNA polymerase II with consequent hepatocyte apoptosis. Treatment measures include supportive measures such as rehydration and correction of electrolytes on initial presentation, activated charcoal and lavage to decrease absorption, extracorporeal purification methods such as plasmapheresis, fractionated plasma separation and adsorption, and molecular adsorbent recirculating system, as well as drug therapies including antibiotics, N-acetylcysteine, and silibinin. Liver transplantation is required in those with acute liver failure and poor prognostic features. Here, we reviewed the basic biology, pathophysiology, and molecular mechanisms of Amanita phalloides liver toxicity, as well as available treatments. Full article

Thistle (Onopordum acanthium) has been traditionally employed for liver protection. However, we recently identified silibinin, the main bioactive compound of thistle extract, as an in vitro pancreatic lipase inhibitor, which suggested a potential role as an anti-obesity agent. This study aimed to assess, in vivo, the efficacy, safety, and effects of silibinin on human lipase. As a secondary objective, we evaluated potential changes in gut microbiota after silibinin treatment. A randomized trial comparing 150 mg/silibinin, 300 mg/silibinin, and a thistle extract (equivalent to 150 mg/silibinin) with placebo and orlistat/120 mg was conducted. Fecal fat excretion, clinical parameters, and microbiota changes were analyzed. Orlistat showed the highest fecal fat excretion, although thistle extract had similar results (p = 0.582). The 150 mg/silibinin group reported the fewest adverse effects. Both silibinin and orlistat reduced plasma triglycerides (p = 0.016) and waist circumference (p = 0.001). Specific microbiota changes, such as increases in Mycobacteriaceae and Veillonellaceae, were associated with higher fat excretion. Although the present work was conducted in the short term and in people of normal weight, our results suggest that silibinin may be safe and effective for obesity, with minimal adverse effects and no significant changes in microbiota diversity. Further studies are needed to explore its microbiota-related benefits. Full article

Elaeagnus angustifolia L. can attract adult Asian longhorned beetle (ALB), Anoplophora glabripennis (Motschulsky), and kill their offspring by gum secretion in oviposition scars. This plant has the potential to be used as a dead-end trap tree for ALB management. However, there is a limited understanding of the attraction ability and biochemical defense response of E. angustifolia to ALB. In this study, we conducted host selection experiments with ALB and then performed physiological and biochemical assays on twigs from different tree species before and after ALB feeding. We analyzed the differential metabolites using the liquid chromatograph–mass spectrometer method. The results showed that ALB’s feeding preference was E. angustifolia > P.× xiaohei var. gansuensis > P. alba var. pyramidalis. After ALB feeding, the content of soluble sugars, soluble proteins, flavonoids, and tannins decreased significantly in all species. In three comparison groups, a total of 492 differential metabolites were identified (E. angustifolia:195, P.× xiaohei var. gansuensis:255, P. alba var. pyramidalis:244). Differential metabolites were divided into overlapping and specific metabolites for analysis. The overlapping differential metabolites 7-isojasmonic acid, zerumbone, and salicin in the twigs of three tree species showed upregulation after ALB feeding. The specific metabolites silibinin, catechin, and geniposide, in E. angustifolia, significantly increased after being damaged. Differential metabolites enriched in KEGG pathways indicated that ALB feeding activated tyrosine metabolism and the biosynthesis of phenylpropanoids in three tree species, with a particularly high enrichment of differential metabolites in the flavonoid biosynthesis pathway in E. angustifolia. This study provides the metabolic defense strategies of different tree species against ALB feeding and proposes candidate metabolites that can serve as metabolic biomarkers, potentially offering valuable insights into using E. angustifolia as a control measure against ALB. Full article

Background/Objectives: The aims of the presented study were the development of four types of silibinin-loaded liposomes (multilamellar liposomes—MLVs, sonicated small unilamellar liposomes—SUVs, UV-irradiated liposomes, and lyophilized liposomes) and their physicochemical characterization and biological potential related to skin health benefits. Methods: The characterization was performed via the determination of the encapsulation efficiency (EE), particle size, polydispersity index, zeta potential, conductivity, mobility, storage stability, density, surface tension, viscosity, FT-IR, and Raman spectra. In addition, cytotoxicity on the keratinocytes and antioxidant and anti-inflammatory potential were also determined. Results: UV irradiation significantly changed the rheological and chemical properties of the liposomes and increased their cytotoxic effect. The lyophilization of the liposomes caused significant changes in their EE and physical characteristics, decreased their ABTS and DPPH radical scavenging potential, and increased their potential to reduce the expression of interleukin 1 beta (IL-1β) in cells treated with bacterial lipopolysaccharide. Sonication significantly changed the EE and physical and rheological properties of the liposomes, and slightly increased their cytotoxicity and reduction effect on IL-1β, while the anti-ABTS and anti-DPPH capacity of the liposomes significantly increased. All developed liposomes showed an increasing trend in particle size and a decreasing trend in zeta potential (absolute values) during storage. Conclusions: Silibinin-loaded liposomes (MLVs and lyophilized) showed promising antioxidant activity (toward reactive oxygen species generated in cells) and anti-inflammatory effects (reducing macrophage inhibitory factor expression) on keratinocytes and did not lead to a change in their viability. Future perspectives will focus on wound healing, anti-aging, and other potential of developed liposomes with silibinin in sophisticated cell-based models of skin diseases, wounds, and aging. Full article

To protect ruminants from the harmful effects of mycotoxins, anti-mycotoxin agents can be added to the dietary ration, thus guaranteeing animal health and production. Therefore, the objective of this study was to evaluate the in vitro ruminal initial sequestration (weak binding) and subsequent desorption (strong binding) of an anti-mycotoxin agent based on a mixture of adsorbing material, turmeric and milk thistle extracts and yeast-based components to adsorb or bio-convert aflatoxins (AF), fumonisins B1 and B2 (FB), trichothecene deoxynivalenol (DON), T-2 and HT-2 toxins, and zearalenone (ZEN). Two doses were tested: Dose 1 simulated 30 mg/cow/d, while Dose 2 simulated 90 mg/cow/d of the anti-mycotoxin agent. Each treatment involved three analytical replicates at each of three incubation times (1, 4, and 24 h post-incubation), with two independent experimental runs providing experimental replicates. Analytical methods, including UHPLC-HRMS and multivariate analyses, were used to both quantify mycotoxin concentrations and reveal dose-dependent reductions, with statistical validations indicating significant changes in mycotoxin levels across both dose and time. The results indicated that the anti-mycotoxin agent was able to highly bind AFB1, T2, and HT-2 toxins since its concentration was always under the limit of detection (<1 ppb). Regarding ZEN (weak binding mean: 94.6%; strong binding mean: 62.4%) and FBs (weak binding mean: 58.7%; strong binding mean: 32.3%), orthogonal contrasts indicated that the anti-mycotoxin agent was able to effectively bind these toxins using Dose 1 (p < 0.05). This finding suggests that Dose 1 may be sufficient to achieve the targeted effect and that a further increase does not significantly improve the outcome. Regarding DON, a strong linear relationship was observed between dose and adsorption. However, the complex interactions between the mycotoxin, the ruminal environment, and the anti-mycotoxin agent made it difficult to establish a clear dose–effect relationship (p > 0.10). UHPLC-HRMS analysis identified over 1500 mass features in rumen samples, which were further analyzed to assess the effects of the anti-mycotoxin agent. Hierarchical clustering analysis (HCA) revealed significant changes in the untargeted metabolomic profiles of samples treated with mycotoxins compared to control samples, particularly after 24 h with the anti-mycotoxin treatments. Clear differences were noted between strong binding and weak binding samples. Further analysis using orthogonal partial least squares discriminant analysis (OPLS-DA) highlighted distinct metabolomic profiles, with stronger predictive ability in the strong binding group (Q² cumulative value of 0.57) compared to the weak binding group (0.30). The analysis identified 44 discriminant compounds in the strong binding model and 16 in the weak binding model. Seven compounds were common to both groups, while silibinin, known for its antioxidant and anti-inflammatory properties, was found among the unique compounds in the weak binding group. Overall, the findings suggest that both doses of the anti-mycotoxin agent significantly influenced the chemical profiles in the rumen, particularly enhancing the binding of mycotoxins, thereby supporting the role of phytogenic extracts in mitigating mycotoxin effects. Full article

Despite its potential against several carcinomas, the pharmacological efficacy of silibinin (SLB) is hampered by poor solubility, absorption, and oral bioavailability. To face these issues, we developed polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) coated with hydrophilic polyethene oxide (PEO) for controlled and targeted SLB delivery. NPs were produced at two different SLB loadings and presented a spherical shape with smooth surfaces and stable size in water and cell culture medium. The encapsulation efficiencies were found to be >84%, and thermal analysis revealed that the SLB was present in an amorphous state within the NPs. In vitro SLB release experiments revealed that at the lowest SLB loading, desorption of the active molecule from the surface or nanoporosities of the NPs mainly dictates release. In contrast, at the highest SLB loading, diffusion primarily regulates release, with negligible contributions from other mechanisms. Cell experiments showed that, compared with the free drug, SLB loaded in the produced NPs significantly increased the bioactivity against H1299, H1975, and H358 cells. Full article

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and it is highly aggressive and heterogeneous. Targeted therapy is still the main treatment method used in clinic due to its lower risk of side effects and personalized medication. Excessive activation of PI3Kδ in DLBCL leads to abnormal activation of the PI3K/Akt pathway, promoting the occurrence and development of DLBCL. The side effects of existing PI3Kδ inhibitors limit their clinical application. The discovery of PI3Kδ inhibitors with novel structures and minimal side effects is urgently needed. This study constructed a PI3Kδ inhibitor screening model to screen natural product libraries. Revealing the mechanism of natural product therapy for DLBCL through network pharmacology, kinase assays, and molecular dynamics. The results of molecular docking indicated that Silibinin had a high docking score and a good binding mode with PI3Kδ. The results of network pharmacology indicated that Silibinin could exert therapeutic effects on DLBCL by inhibiting PI3Kδ activity and affecting the PI3K/Akt pathway. The kinase assays indicated that Silibinin concentration dependently inhibited the activity of PI3Kδ. The results of molecular dynamics indicated that Silibinin could stably bind to PI3Kδ. Silibinin was a structurally novel 3,5,7-trihydroxychroman-4-one PI3Kδ inhibitor, providing valuable information for the subsequent discovery of PI3Kδ inhibitors. Full article

Background: Bones are biological reservoirs for minerals and cells, offering protection to the other organs and contributing to the structural form of the body. Osteoporosis is a prevalent bone condition that significantly impacts people’s quality of life. Treatments utilizing natural products and medicinal plants have gained important attention in the management of osteoporosis and its associated implications, such as osteoporotic fractures. Even though thousands of plants grow in the Mediterranean region, the use of medicinal plants as an alternative therapy for osteoporosis is still limited. Methods: This article provides a comprehensive overview of seven Mediterranean medicinal plants that are used in osteoporosis and osteoporotic fractures in in vitro, in vivo, and clinical trials. The mechanism of action of the medicinal plants and their bioactive compounds against diseases are also briefly discussed. Results: The findings clearly indicate the ability of the seven medicinal plants (Ammi majus, Brassica oleracea, Ceratonia siliqua L., Foeniculum vulgare, Glycyrrhiza glabra, Salvia officinalis, and Silybum marianum) as anti-osteoporosis agents. Xanthotoxin, polyphenols, liquiritin, formononetin, silymarin, and silibinin/silybin were the main bioactive compounds that contributed to the action against osteoporosis and osteoporotic fractures. Conclusions: In this review, the Mediterranean medicinal plants prove their ability as an alternative agent for osteoporosis and osteoporotic fractures instead of conventional synthetic therapies. Thus, this can encourage researchers to delve deeper into this field and develop medicinal-plant-based drugs. Full article