The bacterial cell division protein FtsZ has been considered a potential therapeutic target due to its rapid treadmilling that induces cellular wall construction in bacteria. The current study discovered a novel antimicrobial compound, silibinin, a natural flavonolignan and its impact on the recombinant S. aureus FtsZ (SaFtsZ). Silibinin inhibited S. aureus Newman growth in a dose-dependent manner. The IC50 and MIC values for silibinin were 75 μM and 200 μM, respectively. It had no cytotoxicity against HEK293 cells in vitro. Silibinin also enlarged the bacterial cell morphology by ∼40 folds and showed antibiofilm property. It perturbed the S. aureus membrane potential both at IC50 conc. and at MIC conc. Further, it inhibited both the polymerization and GTPase activity of SaFtsZ. It did not inhibit tubulin assembly, a eukaryotic FtsZ homolog. A fluorescence quenching study yielded the Kd value for SaFtsZ-Silibinin interaction and binding stoichiometry 0.857 ± 0.188 μM and 1:1, respectively. Both in silico study and competition assay indicated that silibinin binds at the GTP binding site on SaFtsZ. The Ki value for the silibinin-mediated inhibition of SaFtsZ was 8.8 μM. Therefore, these findings have comprehensively shown the antimicrobial behavior of silibinin on S. aureus Newman cells targeting SaFtsZ.

OBJECTIVE: Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury.
METHODS: Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts.
RESULTS: Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils.
CONCLUSIONS: These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants.

Silymarin, a bioflavonoid derived from the Silybum marianum plant, was discovered in 1960. It contains C25 and has been extensively used as a therapeutic agent against liver-related diseases caused by alcohol addiction, acute viral hepatitis, and toxins-inducing liver failure. Its efficacy stems from its role as a potent anti-oxidant and scavenger of free radicals, employed through various mechanisms. Additionally, silymarin or silybin possesses immunomodulatory characteristics, impacting immune-enhancing and immune-suppressive functions. Recently, silymarin has been recognized as a potential neuroprotective therapy for various neurological conditions, including Parkinson\'s and Alzheimer\'s diseases, along with conditions related to cerebral ischemia. Its hepatoprotective qualities, primarily due to its anti-oxidant and tissue-regenerating properties, are well-established. Silymarin also enhances health by modifying processes such as inflammation, β-amyloid accumulation, cellular estrogenic receptor mediation, and apoptotic machinery. While believed to reduce oxidative stress and support neuroprotective mechanisms, these effects represent just one aspect of the compound\'s multifaceted protective action. This review article further delves into the possibilities of potential therapeutic advancement of silymarin and silibinin for the management of neurodegenerative disorders via mechanics modules.

As a toxic heavy metal, lead (Pb) is well known for impairment of renal function due to oxidative injuries. In contrast, the antioxidant activity of silibinin has been approved. Given the role of silibinin antioxidant activity, the present study investigated the effectiveness of silibinin-loaded nanostructured lipid carriers (Sili-NLCs) against Pb-induced acute nephrotoxicity in rats. The emulsification-solvent evaporation method was applied to prepare Sili-NLCs. Sixty male Wistar rats were divided into ten separate groups. Pb (20 mg/kg/day, i.p.) was applied to induce nephrotoxicity and in the treatment groups animals received the same concentration of silibinin and Sili-NLCs (25, 50, and 100 mg/kg/day, p.o.) for five days. After sacrificing rats, kidney tissue samples were collected to assess the oxidative stress parameters, including lipid peroxidation (LPO), nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity. Also, histopathological examination using Hematoxylin-Eosin (H&E) was studied. Not only did Pb injection significantly increase the renal levels of LPO and NO, but also decreased the levels of antioxidant enzyme activity. On the other hand, Sili-NLCs were more effective than silibinin in decreasing renal oxidative damage by increasing the antioxidant defense system. Moreover, the histopathological examination correlated well with biochemical findings. Our data suggested that Sili-NLCs are potentially superior to pure silibinin for attenuating Pb-induced acute nephrotoxicity.

BACKGROUND: Lung cancer incidence is steadily on the rise, posing a growing threat to human health. The search for therapeutic drugs from natural active substance and elucidating their mechanism have been the focus of anti-tumor research.
OBJECTIVE: In our work, Silibinin (SiL) was chosen as a possible substance that could inhibit lung cancer. and its effects on inducing tumor cell death have been studied.
METHODS: CCK-8 analysis and morphological observation were used to assess the cytotoxic impacts of SiL on lung cancer cells in vitro. The alterations in mitochondrial membrane potential (MMP) and apoptosis rate of cells were detected by flow cytometry. The level of lactate dehydrogenase (LDH) release out of cells was measured. The expression changes of apoptosis or necroptosis-related proteins were detected using western blotting. Protein interactions among RIPK1, RIPK3 and MLKL were analyzed using the co-immunoprecipitation technique. In vivo, SiL was evaluated for its antitumor effects using LLC tumor-bearing mice with mouse lung cancer.
RESULTS: With an increased dose of SiL, the proliferation ability of A549 cells was considerably inhibited, and the accompanying cell morphology changed. The results of flow cytometry showed that after SiL treatment, MMP levels decreased, and the proportion of cells undergoing apoptosis increased. The proteins associated with apoptosis were upregulated and activated. The amount of LDH released from the cells increased following SiL treatment, accompanied by augmented expression and phosphorylation levels of necroptosis-related proteins. The co-IP assay further confirmed necrosome formation induced by SiL. Furthermore, Necrosulfonamide (an MLKL inhibitor) increased the apoptotic rate of SiL-treated cells and aggravated the cytotoxic effect of SiL, indicating that necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL on A549 cells. In LLC-bearing mice, gastric administration of SiL significantly inhibited tumor growth.
CONCLUSIONS: This study helped clarify the anti-tumor mechanism of SiL against lung cancer, elucidating its role in dual induction of apoptosis and necroptosis. In particular, necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL. Our work provided an experimental basis for the research on cell death induced by SiL and revealed its possible applications for improving the management of lung cancer.

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OBJECTIVE: Colorectal cancer is a significant global health concern with high mortality rates. Silibinin is a compound derived from milk thistle with anticancer properties and may be a potential treatment option for colorectal cancer. Its poor solubility limits its clinical application, but various strategies, such as nanoparticle encapsulation, have shown promise. In this study, a PEGylated niosomal drug delivery system was used to enhance the solubility of silibinin, and its anti-proliferative effects were evaluated against human colorectal cancer cell lines.
METHODS: The silibinin-loaded PEGylated niosomal nanoparticles (NIO-SIL) were fabricated using the thin-film hydration method and characterized with dialysis bag, AFM, SEM, DLS, and FTIR systems. Finally, the cancerous cells and human normal cells were treated with NIO-SIL and pure silibinin. The proliferation, apoptosis, and cell cycle of these cells were evaluated. Subsequently, the expression of Bax, Bcl-2, p53, and cyclin D1 genes was measured using real-time PCR.
RESULTS: The drug release profile, size, morphology, and chemical interactions of the synthesized PEGylated niosomal nanoparticles were suitable for use as a drug delivery system. Both pure silibinin and NIO-SIL could reduce the proliferation of cancerous cells, induce apoptosis, and cause cell cycle arrest, with no significant negative effects reported on human normal cells. Both pure silibinin and NIO-SIL reduced the expression of the Bcl-2 and cyclin D1 genes while increasing the expression of Bax and p53. (p-value < 0.05 *).
CONCLUSIONS: The outcomes of this study indicate the high potential of PEGylated niosomal nanoparticles for encapsulation and delivery of silibinin to cancer cells, with no negative effects on normal cells.

UNASSIGNED: Silibinin has exhibited antitumor activities. However, there are few reports about the immunomodulatory properties of silibinin on T lymphocyte function in the tumor microenvironment. Here, we determined the effects of silibinin on T cells of peripheral blood mononuclear cells (PBMCs), cultivated alone or with a human cell line of glioblastoma (U-87 MG).
UNASSIGNED: The proliferation of T lymphocytes was assessed by MTT test in the presence of silibinin (15 and 45 µM). Also, total antioxidant capacity (TAC), the activity of superoxide dismutase-3 (SOD3), and the levels of two cytokines interferon gamma (IFN-γ) and tumor growth beta (TGF-β) were compared between treated and untreated PBMCs alone or co-cultured with U-87 cells.
UNASSIGNED: According to our results, silibinin raised the TAC levels and SOD3 activity in the PBMCs and in the co-culture condition. Moreover, silibinin-treated PBMCs showed higher IFN-γ levels and lower TGF-β levels. Interestingly, silibinin protected PBMCs against the U-87-induced suppression.
UNASSIGNED: Altogether, these results proposed the immunomodulatory potential of silibinin on T cells of PBMCs, as well as its partially protective effects on PBMCs against the suppression induced by U-87 MG cells.

In this study, we delved into the intricate world of autism spectrum disorder (ASD) and its connection to the disturbance in the Wnt signaling pathway and immunological abnormalities. Our aim was to evaluate the impact of silibinin, a remarkable modulator of both the Wnt signaling pathway and the immune system, on the neurobehavioral and molecular patterns observed in a zebrafish model of ASD induced by valproic acid (VPA). Because silibinin is a hydrophobic molecule and highly insoluble in water, it was used in the form of silibinin nanoparticles (nanosilibinin, NS). After assessing survival, hatching rate, and morphology of zebrafish larvae exposed to different concentrations of NS, the appropriate concentrations were chosen. Then, zebrafish embryos were exposed to VPA (1 μM) and NS (100 and 200 μM) at the same time for 120 h. Next, anxiety and inattentive behaviors and the expression of CHD8, CTNNB, GSK3beta, LRP6, TNFalpha, IL1beta, and BDNF genes were assessed 7 days post fertilization. The results indicated that higher concentrations of NS had adverse effects on survival, hatching, and morphological development. The concentrations of 100 and 200 μM of NS could ameliorate the anxiety-like behavior and learning deficit and decrease ASD-related cytokines (IL1beta and TNFalpha) in VPA-treated larvae. In addition, only 100 μM of NS prevented raising the gene expression of Wnt signaling-related factors (CHD8, CTNNB, GSK3beta, and LRP6). In conclusion, NS treatment for the first 120 h showed therapeutic effect on an autism-like phenotype probably via reducing the expression of pro-inflammatory cytokines genes and changing the expression of Wnt signaling components genes.

Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aβ1-42 intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aβ1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aβ1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aβ1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aβ1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer\'s disease.

Colon cancer (CC) is one of the most prevalent cancers in the world, and chemotherapy is widely applied to combat it. However, chemotherapy drugs have severe side effects and emergence of multi drug resistance (MDR) is common. This bottleneck can be overcome by niosome nanocarriers that minimize drug dose/toxicity meanwhile allow co-loading of incompatible drugs for combination therapy. In this research, silibinin (Sil) as a hydrophobic drug was loaded into the lipophilic part, and methotrexate (MTX) into the hydrophilic part of niosome by the thin film hydration (TFH) method to form Nio@MS NPs for CT26 colon cancer therapyin vitro. Our results indicated synthesis of ideal niosome nanoparticles (NPs) with spherical morphology, size of ∼100 nm, and a zeta potential of -10 mV. The IC50value for Nio@MS was determined ∼2.6 µg ml-1, which was significantly lower than MTX-Sil (∼6.86 µg ml-1), Sil (18.46 µg ml-1), and MTX (9.8 µg ml-1). Further, Nio@MS significantly reduced cell adhesion density, promoted apoptosis and increased gene expression level of caspase 3 and BAX while promoted significant downregulation of BCL2. In conclusion, the design and application of niosome to co-administer Sil and MTX can increase the drugs cytotoxicity, reduce their dose and improve anti-cancer potential by combating MDR.