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Silibinin (SBN), a sirtuin 1 (SIRT1) activator, has been evaluated for its anti-inflammatory activity in many inflammatory diseases. However, its role in diabetes-induced peripheral neuropathy (DPN) remains unknown. The SIRT1 activation convalesces nerve functions by improving mitochondrial biogenesis and mitophagy. DPN was induced by streptozotocin (STZ) at a dose of 55 mg/kg, i.p. in the male SD rats whereas neurotoxicity was induced in Neuro2A cells by 30 mM (high glucose) glucose. Neurobehavioural (nerve conduction velocity and nerve blood flow) western blot, immunohistochemistry, and immunocytochemistry were performed to evaluate the protein expression and their cellular localisation. Two-week SBN treatment improved neurobehavioural symptoms, SIRT1, PGC-1α, and TFAM expression in the sciatic nerve and HG insulted N2A cells. It has also maintained the mitophagy by up-regulating PARL, PINK1, PGAM5, LC3 level and provided antioxidant defence by upregulating Nrf2. SBN has shown neuroprotective potential in DPN through SIRT1 activation and antioxidant mechanism. [ABSTRACT FROM AUTHOR]

Nanoparticles capped with natural products can be a cost-effective alternative to treat drug-resistant nosocomial infections. Therefore, silibinin-loaded chitosan-capped silver nanoparticles (S-C@AgNPs) were synthesized to evaluate their antimicrobial and anti-inflammatory potential. The S-C@AgNPs plasmon peak was found at 430 nm and had a particle size distribution of about 130 nm with an average hydrodynamic diameter of 101.37 nm. The Scanning Electron Microscopy images showed the presence of sphere-shaped homogeneous nanoparticles. The Fourier Transform Infrared Spectroscopy analysis confirmed the loading of silibinin and chitosan on the AgNPs surface. The minimum inhibitory concentration of the S-C@AgNPs was reported between 3.12 μg/ml to 12.5 μg/ml and a minimum bactericidal concentration between 6.25 μg/ml to 25 μg/ml against drug-resistant nosocomial pathogens. Moreover, concentration-dependent significant inhibition of the biofilm formation was reported against P. aeruginosa (70.21%) and K. pneumoniae (71.02%) at 30 μg/ml, and the highest destruction of preformed biofilm was observed at 100 μg/ml against P. aeruginosa (89.74%) and K. pneumoniae (77.65%) as compared to individual bacterial control. Additionally, the fluorescence live/dead assay for bacterial biofilm confirmed that 100 µg/ml effectively inhibits the biofilm formed by these pathogens. S-C@AgNPs also showed anti-inflammatory activity, which is evident by the significant decrease in the proinflammatory cytokines and chemokines level in THP1 cells treated with LPS. This study concluded that S-C@AgNPs have potent antimicrobial, antibiofilm, and anti-inflammatory properties and could be a potential option for treating drug resistant nosocomial infections. [ABSTRACT FROM AUTHOR]

Belonging to the class II drugs according to the biopharmaceutics classification system, silibinin (SLB) benefits from high permeability but suffers poor solubility that negatively affects the development of any delivery system. This research aimed to improve SLB solubility by combined use of co-solvency and complexation phenomena. Solubility studies were performed using the phase solubility analysis according to the shake-flask method in the presence of ethanol and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as a co-solvent and inclusion complexing agent, respectively. SLB release studies from chitosan nanoparticles were carried out in double-wall, diffusion cells using the optimized drug release medium. SLB solubility was mathematically optimized constraining to using the lowest concentrations of ethanol and HP-β-CD. SLB solubility increased linearly with the increase of HP-β-CD concentration. The solubility in PBS-ethanol mixtures followed a log-linear model. SLB solubility in the presence of the ethanol co-solvent and HP-β-CD complexing agent was optimized by adopting a genetic algorithm suggesting the phosphate buffer saline solution supplemented by 6%v/v ethanol and 8 mM HP-β-CD as an optimized medium. The optimized solution was examined to study SLB release from chitosan nanoparticles (4.5 ± 0.2% drug loading) at 37 °C under static conditions. The sigmoidal release profile of SLB from the particles indicated a combination of erosion and diffusion mechanisms governing drug release from the nanoparticles. SLB solubility in a buffered solution supplemented by ethanol co-solvent and HP-β-CD complexing agent is a function of free drug present in the semi-aqueous media, the drug-ligand binary complex, and the drug/ligand/co-solvent ternary complex. [ABSTRACT FROM AUTHOR]

We investigated possible protective effects of chlorogenic acid (CGA) against cyclophosphamide (CP) induced hepatic injury in mice. We measured aminotransferase alanine transaminase (ALT) and aspartate transaminase (AST) levels in the serum. We assayed catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in hepatic tissue. We assessed expression of nuclear transcription factor 2 (Nrf2) and Kelch sample related protein-1 (keap1) proteins in hepatic tissues using immunohistochemistry. The relative mRNA expression levels of heme oxygenase-1 (HO-1), NADH quinone oxidoreductase 1 (NQO1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Hematoxylin & eosin staining was used to assess liver histopathology. We found that administration of CGA prior to induction of injury by CP decreased serum ALT, AST and MDA expressions in hepatic tissue, while CAT, SOD, GSH and GSH-Px concentrations were increased. We found that hepatocytes of animals administered CGA gradually returned to normal morphology. CGA increased the protein expression of Nrf2 in murine hepatic tissue. Administration of CGA up-regulated mRNA expression levels of HO-1, NQO1, TNF-α and IL-6 in hepatic tissue. CGA exhibited a marked protective effect on CP induced liver injury in mice. [ABSTRACT FROM AUTHOR]

Polycyclic Aromatic Hydrocarbons present in Diesel exhaust particle (DEP) has been established in different studies to cause deleterious toxic effects by inducing oxidative and pro-inflammatory effects. Diabetes is among the world's top diseases. Silibinin (SIL) is a plant bioflavolignan with numerous health benefits. This study examined the effects of SIL on the oxidative and inflammatory status in the heart and aorta of type-2-diabetic (T2D) Wistar rats exposed to DEP. Type 2 diabetes was induced using streptozocin 45 mg/kg b.w of Wistar rats, which were later exposed to DEP (0.4 and 0.5 mg/kg) and post-treated with SIL. Another group of nondiabetic rats were administered DEP and later post-treated with 40 mg/kg SIL and the results were compared to the diabetic group. The results showed that DEP caused a significant (p < 0.001) increase in malondialdehyde and conjugated diene levels in the heart and aorta of T2D rats but was significantly (p < 0.001) attenuated by SIL. DEP induced interleukin 1 beta IL-1β, forkhead box protein 1 (FOXO1), heme-oxygenase HO-1, and decreased interleukin 10 (IL-10) gene expression, all of these were reversed in the presence of SIL. The expression of PI3K-AKT-GLUT4 (phosphatidylinositol-3-kinase, protein kinase B, glucose transporter 4) was significantly reduced by DEP in both tissues of T2D rats while SIL ameliorates against these effects. This indicates the potential of SIL to protect against DEP-induced cardiotoxicity in T2D subjects. [ABSTRACT FROM AUTHOR]

We investigated whether silibinin, a flavonoid, might be useful for treating diabetes mellitus by treating five groups of rat RINm5F β-insulinemia cells as follows: control streptozotocin (STZ) group administered citrate buffer and dimethyl sulfoxide; STZ group administered 20 mM STZ; silibinin group administered 50 µM silibinin; pre-silibinin group administered 50 µM silibinin 5 h before administering 20 mM STZ; simultaneous group administered 50 µM silibinin at the same time as 20 mM STZ. For all groups, MTT assay and flow cytometry were used to evaluate cell viability and necrosis, respectively. Glucose-stimulated insulin secretion (GSIS) and insulin cell content were determined using enzyme-linked immunosorbent assay. Also, expression of genes, pancreatic and duodenal homeobox 1 (pdx1), neuronal differentiation 1 (neurod1), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (mafa), glucose transporter 2 (glut2)) was determined using the real-time polymerase chain reaction. We found that silibinin improved the viability of RINm5F cells and increased GSIS and cellular insulin under glucotoxic conditions. Silibinin increased the expression of neurod1, mafa and glut2, but reduced pdx1 expression. Our findings suggest that silibinin might increase glucose sensitivity and insulin synthesis under glucotoxic conditions, which could be useful for diabetes treatment. [ABSTRACT FROM AUTHOR]

A study of the vibrational and structural properties of the herbal plant bioactive compound (Silibinin) polyphenolic flavonolignan (molecular formula C 25 H 22 O 10) is reported. Silibinin is a flavonolignan mixture extracted from milk thistle that has been used to treat acute and chronicliver disorders caused by toxins, alcohol and hepatitis, as well as gall bladder disorders, due to it a hepatoprotective properties. DFT has also been used to investigate the correlation of experimental and theoretical data on structural and vibrational studies. This method employs the HF and DFT basis sets B3LYP/6-311G++ (d,p). The calculated and experimental spectroscopic data were found to be in good agreement. Mulliken population analysis of atomic charges, an electric dipole moment, anatural bond orbital analysis, and thermodynamic properties were carried out. The various ligands derived from the title molecule are used in cervical cancer protein docking. [ABSTRACT FROM AUTHOR]

Silibinin is a natural flavonoid with anti-diabetic activity. Glucagon-like peptide−1 (GLP−1), an intestinal hormone mainly secreted from L cells, which regulates insulin production and sensitivity, appears to be a potential therapeutic strategy for T2DM. The current study aims to determine the protective effect of silibinin against palmitic acid (PA)-induced damage in GLUTag cells. The results revealed that PA triggered endoplasmic reticulum (ER) stress and apoptosis in GLUTag cells, while silibinin attenuated PA-induced lipotoxicity. Based on the estrogen-like effects of silibinin and the role of estrogen receptors in regulating glycolipid metabolism, the involvement of estrogen receptors in the protective effects of silibinin in GLUTag cells was further investigated. The results showed that estrogen receptor α- and β-specific inhibitors reversed the inhibitory impact of silibinin on ER stress. Our study demonstrated that silibinin protects GLUTag cells from PA-induced injury by decreasing ER stress under the regulation of estrogen receptors α and β. [ABSTRACT FROM AUTHOR]

Silymarin is an herbal remedy, commonly called milk thistle, or St. Mary's Thistle, and has been used for over 2000 years. It has been available as a capsule of the plant extract in Europe since 1974 to treat hepatic disorders. To date toxicologists have relied on animal studies, human case series, or retrospective reviews to decide on its use. In the U.S. the ability to use IV silibinin, its pharmacologically active purified flavonolignan, is hindered by its lack of availability as a Food and Drug Administration approved pharmaceutical preparation. This commentary reviews the in vitro studies, animal studies, and human retrospective analyses which form the basis for its clinical use. Despite the numerous publications, summarized in this issue in a systematic review, the mortality rate from Amanita mushroom ingestion remains stubbornly the same over four decades of use, and hovers around 10%. Although in the retrospective systematic review the use of silibinin, or penicillin, compared to routine care is statistically significantly superior when the primary outcome is fatality. Despite this there is no quality randomized trial to definitively demonstrate its utility. While, intravenous silibinin has a low toxicity, unanswered is whether it is useful in protecting the liver in cases of amanitin-containing mushrooms toxicity, and whether earlier administration would likely improve outcomes. [ABSTRACT FROM AUTHOR]

Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified. We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity. We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14–13.04]) and 89% (OR 5.24 [2.87–9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality. Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes. [ABSTRACT FROM AUTHOR]

Aim: In the current study, efforts are being made to prepare Inhalable Silibinin loaded solid lipid nanoparticles (SLNs) with narrow size distribution with improved bioavailability. Methods: SLNs were formulated by high shear homogenisation method SLNs were characterised, including Differential Scanning Calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), particle size analysis, entrapment efficiency with Aerodynamic behaviour. The MTT assay was performed against A549 cell line, to measure their anticancer cell activity with In vivo study. Results: Optimized formulation exhibited spherical surface with a mean particle size of 221 ± 1.251 nm, PI of 0.121 ± 0.081, zeta potential of -4.12 ± 0.744. Aerodynamic behaviour such as Mass median aerodynamic diameter (MMAD) and Geometric size distribution (GSD) were found to be 5.487 ± 0.072 and 2.321 ± 0.141 respectively proved formulation is suitable for inhalation. In vitro cellular efficacy against A549 cells, revealed that the optimised formulations were more effective and potent. Conclusion: The Inhalable SLNs approach was successfully engineered and administered to the lungs safely without causing any problems. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the supernatant from monocytes of preeclamptic and normotensive pregnant women, cultured in vitro with silibinin, can modulate oxidative stress in HUVEC. Methods: Concentrations of IL-1β, IL-10, and TNF-α in monocyte culture supernatants were determined by ELISA. HUVEC and their supernatant cultures were employed for determination of NO, nitrite and nitrate, lipid peroxidation, and hemeoxygenase-1 (HO-1). Results: HUVEC treatment with supernatant of preeclamptic monocytes cultured with silibinin produced increased levels of nitrite, reduced lipid peroxidation, and increased HO-1. Conclusion: Supernatant of monocytes from preeclamptic women induce oxidative stress in HUVEC which can be reduced by silibinin treatment. Abbreviations: DAF-FMTM, Diaminofluorescein-FM; EDTA, Ethylenediaminetetraacetic acid; HO-1, heme oxygenase-1; HPLC, high-performance liquid chromatography; HUVEC, human umbilical vein endothelial cell; MDA, malondialdehyde; NO, nitric oxide; NT, normotensive; PE, preeclampsia; ROS, reactive oxygen species; Sb, silibinin. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop silibinin-loaded hydrogel for skin protection against UVB damage. Physical grafting was used to prepare hydrogel based on chitosan–fucoidan. Then, hydrogel properties, such as swelling, drug release rates, morphology, and structure, were evaluated to determine the optimum hydrogel for in vivo studies. In in vivo experiments, the silibinin permeability parameters were investigated through normal and UV-irradiated skin, anti-inflammatory property, and antioxidant effects after application of optimum hydrogel. The silibinin completely dispersed in the hydrogel, and FT-IR results showed that silibinin reacted with the chitosan and fucoidan and demonstrated a slow release pattern. The 50% and less than 70% of the drug-loaded on hydrogel were passed through normal and irradiated skin after 48 h, respectively. In vivo studies showed the effectiveness of optimized hydrogel in preventing the production of oxidative species and H2O2 after UVB radiation. Histological studies have shown that silibinin-loaded optimized hydrogel can prevent the hyperkeratosis, acanthosis, and infiltration of neutrophils into the dermis by UVB. Optimized hydrogel effectively reduced the inflammation mediators interleukin-22 and TNF-α, which signify tissue destruction. Therefore, silibinin-loaded hydrogel can be introduced as an effective sun-protective product. [ABSTRACT FROM AUTHOR]

Daily exposure to ultraviolet (UV) light induces inflammation and tumorigenesis in the skin. Silibinin and ellagic acid are natural products that exhibit anti-inflammatory and anti-tumorigenic properties. Insulin receptor substrate protein 1 (IRS1) is important for skin homeostasis and physiology, but its activity following UV radiation remains unclear. We investigated the effects of ellagic acid and silibinin on IRS1 expression in ultraviolet A (UVA) and ultraviolet B (UVB) irradiated rat skin. Forty-two female Wistar rats were divided randomly into six groups of seven animals. The dorsal skin of rats was exposed to UVA + UVB, then treated with ellagic acid and silibinin by gavage. IRS1 expression in skin tissues was determined by western blot analysis. IRS1 expression increased significantly following treatment with ellagic acid and silibinin in UVA + UVB irradiated skin compared to the UVA + UVB only group. After UVA + UVB treatment, ellagic acid effected greater induction of IRS1 expression than silibinin. Our findings suggest that the photoprotective roles of ellagic acid and silibinin may be due to induction of IRS1 expression in UVA + UVB treated rat skin. [ABSTRACT FROM AUTHOR]

Biological and chemical agents cause dangerous effects on human health via different exposing ways. Recently, herbal medicine is considered as a biological and safe treatment for toxicities. Silybum marianum (milk thistle), belongs to the Asteraceae family, possesses different effects such as hepatoprotective, cardioprotective, neuroprotective, anti-inflammatory and anti-carcinogenic activities. Several studies have demonstrated that this plant has protective properties against toxic agents. Herein, the protective effects of S. marianum and its main component, silymarin, which is the mixture of flavonolignans including silibinin, silydianin and silychristin acts against different biological (mycotoxins, snake venoms, and bacterial toxins) and chemical (metals, fluoride, pesticides, cardiotoxic, neurotoxic, hepatotoxic, and nephrotoxic agents) poisons have been summarized. This review reveals that main protective effects of milk thistle and its components are attributed to radical scavenging, anti-oxidative, chelating, anti-apoptotic properties, and regulating the inflammatory responses. [ABSTRACT FROM AUTHOR]

A new tetracyclic saponin, 17(R),20(R)-3β,6α,16β-trihydroxycycloartanyl- 23-carboxylic acid 16-lactone 3-O-β-D-glucopyranoside (1) together with one known flavonoid, camelliaside A (2) were isolated from the aerial parts of Astragalus glycyphyllos L. Their structures were determined by chemical, HRESIMS and NMR methods. On 6-hydroxydopamine in vitro model on isolated rat brain synaptosomes, compounds 1-2 had statistically significant neuroprotective activity similar to that of Silibinin, tested at 100 lM. Saponin 1 possessed the most prominent neuroprotective and antioxidant effects in this in vitro model. On human recombinant monoamine oxidase type B enzyme compound 1 displayed strong inhibiting activity, compared to Selegiline (1 lM). It could be concluded that the new epoxycycloartane saponin 1 could be a promising leading structure in respect of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the protective effects of silibinin on blue light-emitting diode (LED)-induced retinal ganglion cells (RGCs) damage. Methods: Silibinin was applied in RGCs damage in vitro model to test its protective effects. Cell viability was assessed with the MTT method and cell apoptosis was evaluated by TUNEL and Annexin V/propidium iodide staining. The expressions of apoptosis related proteins and influenced signalling pathways were measured using western blotting and immunohistochemistry. Inflammatory factors induced by RGC damage were detected using ELISA method. Results: It was found that silibinin in 50 and 100 μM treatment showed a significant protective effect in RGCs under blue light damage. Apoptosis assay showed that silibinin treatment could significantly improve the apoptotic status of RGCs. When the potentially affected signal pathway was considered, blue light would down-regulate the expression of MEK1/ERK/CREB. The levels of inflammatory factors (TNF-α, IL-1β, IL-6 and IL-10) were significantly regulated by silibinin treatment. Conclusions: Silibinin pretreatment would demonstrate protective effect against blue light induced acute RGCs damage. Silibinin treatment has a direct suppression of apoptosis and inflammation through the activation of MEK/ERK/CREB pathway in vitro. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) molecules have multiple functions; prevention of cytotoxicity, provision of mechanical support, cell adhesive substrates and structural integrity in addition to mediation of cellular signaling. In this study, we report that the proliferation of INS-1 cells cultured on collagen I-coated dishes is enhanced, but it is inhibited on collagen V-coated dishes. Inhibitory proliferation on collagen V-coated is not due to apoptosis induction. Silibinin decreases hepatic glucose production and protects pancreatic β-cells, as a potential medicine for type II diabetes. Silibinin up-regulates the proliferation of cells cultured on both collagen I- and V-coated dishes. Collagen-coating regulates gene expression of collagen in a collagen type-related manner. Silibinin increases mRNA expression of collagen I in the cells on collagen I- and V-coated dishes; however, silibinin decreases collagen V mRNA expression on collagen I- and V-coated dishes. Collagen I-coating significantly enhances nuclear translocation of β-catenin, while collagen V-coating reduces it. Differential effects of silibinin on collagen I mRNA and collagen V mRNA can be accounted for by the finding that silibinin enhances nuclear translocation of β-catenin on both collagen I- and V-coated dishes, since phenomenologically nuclear translocation of β-catenin enhances collagen I mRNA but represses collagen V mRNA. These results demonstrate that nuclear translocation of β-catenin up-regulates proliferation and collagen I gene expression, whereas it down-regulates collagen V gene expression of INS-1 cells. Differential gene expressions of collagen I and V by nuclear β-catenin could be important for understanding fibrosis where collagen I and V may have differential effects. [ABSTRACT FROM AUTHOR]

The antitumor effects of silibinin are of increasing interest, though its mechanism is not yet clear. The goal of this study was to clarify the mechanism of silibinin-induced cell death in the A431 human epidermoid carcinoma cell line. We used a cell viability assay, flow cytometry, nitric oxide (NO) assay, and western blotting to examine relationships between silibinin, NO generation and apoptosis in A431 cells. Silibinin inhibited A431 cell growth in a dose-dependent manner, inducing mitochondrial damage, and apoptosis at a high dose. At the same time, high dose silibinin increased NO levels in A431 cells and the endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methylester (L-NAME) attenuated silibinin-induced cell growth inhibition. By western blotting, silibinin caused increased eNOS phosphorylation in the mitochondria. The AMP-activated protein kinase inhibitor compound C significantly decreased p-eNOS expression, while blocking eNOS did not affect p-AMPK levels, suggested that AMPK acted upstream of eNOS. This study showed that silibinin increased NO levels in A431 cells by activating the AMPK–eNOS pathway, leading to mitochondrial dysfunction and apoptosis. In this mechanism of action, mitochondrial eNOS played an important role. The results provided new understanding of the functions of intracellular NO. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the hepatoprotective effect of Silibinin (SLB) to ischemia-reperfusion (I/R) rat model, by evaluating the histological expression of the tissue markers Fas/FasL, HMGB-1 and CD45, and SLB pharmacokinetics. Methods: Seventy-three Wistar-type male rats were randomized in 11 groups: Sham control group (open-close laparotomy); four I/R control groups (laparotomy, 45 min vascular occlusion, reperfusion, euthanasia after 60, 120, 180, and 240 min); four SLB (Si) groups (laparotomy, 45 min vascular occlusion, IV administration of SLB, reperfusion, euthanasia after 60, 120, 180, and 240 min); two SLB pharmacokinetics (PK) groups (IV administration of SLB, euthanasia after 45 and 240 min). Results: Fas/FasL increased with reperfusion time in I/R control groups and decreased in the Si groups, reaching, respectively, the highest and lowest values at 240 min of reperfusion (p <.0001). HMGB1 and CD45 increased with time in the I/R control groups up to 240 min and decreased in the Si groups, approaching zero expression after 180 and 60 min, respectively. Pharmacokinetic data showed higher liver accumulation and slower plasma elimination of SLB in ischemic animals. Conclusions: The hepatoprotective effect of SLB was demonstrated through the reduction of the expression of Fas/FasL, HMGB-1 and CD45 in liver tissue under I/R conditions, and in the pharmacokinetic study. The results document the efficacy of silibinin in the protection of the liver, and are particularly encouraging for its use in hepatic surgery. [ABSTRACT FROM AUTHOR]

Background: Ovarian carcinoma is the most lethal cancer among all gynaecological malignancies. One of the most chemotherapy drugs used for ovarian cancer is paclitaxel which induces apoptosis. Paclitaxel has been used for many years. Similar to the most cancers this responds to chemotherapy initially but in a long run, drug resistance happens which fails the treatment procedure. Combination of chemotherapy drugs has been suggested to deal with this issue. Silibinin, a plant extraction, has been used from ancient time in traditional medicine and identified to have powerful antioxidant activity. Aim: The aim of this study was to examine the effect of paclitaxel and silibinin combination on SKOV-3 cancer cell line. Materials and methods: The human epithelial ovarian cancer cell line, SKOV-3, was cultured and treated with paclitaxel, silibinin and paclitaxel plus silibinin for 48 hours. MTT assay was carried out to determine cell viability. For apoptotic process, we used real-time PCR to study P53 and P21 genes expression after drug treatment and network analysis was performed using Pathway Studio web tool (Elsevier). Results: Cell growth was inhibited considerably (p < .05) by combination of paclitaxel and silibinin after 48 hours of treatment. Also silibinin and paclitaxel combination induced apoptosis in SKOV-3 cells. Expression analysis by real-time PCR showed the significant up-regulation of two tumour suppressor genes, P53 and P21 in response to combination of silibinin and paclitaxel. In addition, computational network analysis demonstrated the crosstalk between paclitaxel, silibinin and ovarian cancer. Conclusions: Our results showed that combination of chemotherapy drugs of silibinin and paclitaxel can be more efficient in treatment of ovarian cancer cells. [ABSTRACT FROM AUTHOR]

Aim of the study: Astrogliosis is a key contributor for many neurological disorders involving apoptosis, neuroinflammation and subsequent neuronal death. Silibinin, a polyphenol isolated from milk thistle (Silybum marianum), has been shown to suppress the astrocyte activation in various neurodegenerative disorders and also exhibit a neuroprotective role in neuroinflammation-driven oxidative damage. The present study was designed with an aim to investigate the neuroprotective effects of Silibinin against LPS induced oxido-inflammatory cascade and astrocyte activation. Materials and methods: We have used in-silico molecular modelling techniques to study the interaction and binding affinity of silibinin with chemokine receptors associated with neuroinflammation. We have also tested silibinin against LPS induced oxido-inflammatory cascade and astrocyte activation in C6 glia cell lines. Results: In the present study, we found that treatment with silibinin significantly attenuates LPS-oxidative-nitrosative stress in C6 astrocytoma cells. We also observed the significant inhibition of induced astrocyte activity after treatment with silibinin. Moreover, molecular modelling studies have proposed a binding pose of silibinin with binding sites of p38 MAPK, CX3CR1 and P2X4 which is an important downstream cascade involved in glia cell activation and neuroinflammation. Conclusions: Overall, the findings from the current study suggests that silibinin exhibits neuroprotective activity by attenuating oxidative damage and astrocytes activation. [ABSTRACT FROM AUTHOR]

Background: Remote kidney damage is a sequel of hepatic ischemia-reperfusion (I/R) injury. Silibinin is the main ingredient of the milk thistle plant seed extract with known antioxidant and hepatoprotective activity. Our study investigates the nephroprotective potential of intravenously administered silibinin, as a lyophilized SLB-hydoxypropyl-beta-cyclodextrin product, in hepatic I/R injury. Material and methods: 63 Wistar rats were divided into three groups: Sham (virtual intervention); Control (45 min ischemia and reperfusion); and Silibinin (200 μL intravenous silibinin administration after 45 min of ischemia). Kidney tissues were collected to determine TNF-α, M30 and histopathological changes at predetermined time intervals. Results: Comparing Sham vs. Control groups, proved that hepatic I/R injury increased renal TNF-α and M30 expression. Deterioration was observed in hyperemia/filtration of renal parenchyma and tubules, cortical filtration, tubular necrosis and edema (tissue swelling index). Intravenous silibinin administration and comparison of the Control vs. Silibinin groups showed a statistically significant decrease in TNF-α levels at 240 min following I/R (p < 0.0001), and in M30 at 180 min (p = 0.03) and 240 min (p < 0.0001). Renal parameters have significantly decreased in: hyperemia/filtration of renal parenchyma at 120 min (p = 0.003), 180 min (p = 0.0001) and 240 min (p = 0.0002); hyperemia/filtration of renal tubules at 120 min (p = 0.02), 180 min (p = 0.0001) and 240 min (p = 0.0005); cortical filtration (240 min - p = 0.005); tubular necrosis (240 min - p = 0.021); and edema (240 min - p = 0.001). Conclusion: Our study confirms that hepatic I/R injury causes remote renal damage while the intravenous administration of silibinin leads to statistically significant nephroprotective action. [ABSTRACT FROM AUTHOR]

Silibinin-loaded soy flour-zinc oxide nanoparticle (ZnO) nanoparticles were prepared and characterized by different techniques. The average particle size and zeta potential value of the nanoparticles were found in the range 10-15 nm and −29.88 to −40.85 mV, respectively. The effects of ZnO nanoparticle, surfactant, and cross-linker were evaluated with regard to swelling, encapsulation efficiency, and drug release in different pH medium. Both swelling degree (%) and cumulative release (%) were better in pH 7.4 and maximum cumulative release (%) was 50%. Cytotoxicity study was performed by MTT assay using normal human blood and MDA-MB-435S cancer cell lines. [ABSTRACT FROM AUTHOR]

Introduction: Guizhou Province in China has an abundant resource of wild mushrooms, including numerous poisonous species which contain various toxins. The mortality rate from wild mushroom poisoning has been high in this area in recent years. Galerina sulciceps is a dangerously toxic mushroom which can be fatal if ingested. Methods: we report on an epidemiological investigation of G. sulciceps poisoning which occurred in Duyun City of Guizhou Province. The characteristics of this species, its toxicity, observed clinical features, laboratory data, treatment modality, and prognosis were investigated in order to provide a reference point for the prevention and treatment of this kind of mushroom poisoning. Results: Thirteen employees showed toxic symptoms after ingesting wild mushrooms the previous day in a company canteen. Clinical manifestation varied from gastroenteritis to hepatic and renal dysfunction. Most of the 13 patients presented with nausea, vomiting, abdominal pain, diarrhea, and elevated levels of biochemical indices of hepatic and renal function, during which transaminase concentration peaked within 48-72 h. At 48 hours post-ingestion, all patients had hemodialysis, in addition to supportive care for hepatic and renal injury with oral Silibinin and Shenshuaining. All acute renal injury had resolved by day 10, and liver transaminases had trended toward normal in all patients and they were discharged. At follow-up in 30 days, both liver and renal function had completely recovered in all. Conclusion: This poisoning occurs as a result of unintentional consumption of G. sulciceps, which is relatively rare in mushroom poisonings. All patients recovered fully after timely diagnosis and treatment. To prevent wild mushroom poisoning, the best preventive measure is to educate the public not to gather and eat any unidentified wild mushrooms. [ABSTRACT FROM AUTHOR]

Silibinin is a natural flavonoid with a strong antioxidant property and weak cytotoxic activity. It has demonstrated anti-tumoural activity against many types of malignancies; however, due to its hydrophobic structure, it has poor water solubility, bioavailability and permeability across intestinal epithelial cells. To improve the effect of silibinin, we have vehiculated silibinin by a highly stable niosomal nanostructure based on a Span 60/cholesterol (CH)/N-trimethyl chitosan (TMC) system in order to study its potential application for the delivery of silibinin in T47D cultured under three-dimensional (3D) and two-dimensional (2D) conditions. To study the effect of nanodrug on miRNAs expression, we evaluated quantitative expression of miRNA-21 and miRNA-15a as well as miR-141 and miR-200c which act as oncogene and tumour suppressors by real-time PCR. Results demonstrated that the mechanism of nanodrug action as well as the response of tumour cells differed in 3D culture as compared to 2D. Delivery of silibinin-loaded niosomes coated with TMC was found to be more effective in inhibiting the growth of tumour cells and inducing apoptosis than free silibinin administration. In silibinin‐treated cells, death occurred in a dose- and time- dependent manner by induction of apoptosis and alteration of the cell cycle. Real-time PCR analysis revealed a decrease in miR-21, miR-15a and miR-141while increase in miR-200c expression levels was observed in silibinin-treated cells relative to the levels in the untreated cells. The results show that nanodrug delivery was more effective than free silibinin administration in changing the level of miRNAs expression in cancer cells. Therefore, niosomal nanostructure with TMC could be a suitable vehicle for hydrophobic compounds, such as silibinin, by improving their action in cancer therapy. [ABSTRACT FROM AUTHOR]

Nanoparticle-based targeted drug delivery has the potential for rendering silibinin specifically at the favorite site using an external magnetic field. Also, it can circumvent the pitfalls of poor solubility. For this purpose, silibinin-loaded magnetic nanoparticles are fabricated, characterized and evaluated cytotoxicity and hTERT gene expression in A549 lung cancer cell line. silibinin-loaded PLGA-PEG-Fe3O4had dose- and time-dependent cytotoxicity than pure silibinin. Additionally, hTERT expression is more efficiently reduced with increasing concentrations of nanosilibinin than pure silibinin. The present study indicates that PLGA-PEG-Fe3O4nanoparticles, as an effective targeted carrier, can make a promising horizon in targeted lung cancer therapy. [ABSTRACT FROM PUBLISHER]

Context:Multiple drug resistance is the major obstacle to conventional chemotherapy. Silibinin, a nontoxic naturally occurring compound, has anticancer activity and can increase the cytotoxic effects of chemotherapy in various cancer models. Objective:To evaluate the effects of silibinin on enhancing the sensitivity of chemo-resistant human breast cell lines to doxorubicin (DOX) and paclitaxel (PAC). Materials and methods:The cells were treated with silibinin (at 50 to 600 μM concentrations) and/or chemo drugs for 24 and 48 h, then cell viability and changes in oncogenic proteins were determined by MTT assay and Western blotting/RT-PCR, respectively. Flow cytometry was used to study apoptosis in the cells receiving different treatments. The antitumorigenic effects of silibinin (at 200 to 400 μM concentration) were evaluated by mammosphere assay. Results:Silibinin exerted significant growth inhibitory effects with IC50ranging from 200 to 570 μM in different cell lines. Treatment of DOX-resistant MDA-MB-435 cells with silibinin at 200 μM reduced DOX IC50from 71 to 10 μg/mL and significantly suppressed the key oncogenic pathways including STAT3, AKT, and ERK in these cells. Interestingly treatment of DOX-resistant MDA-MB-435 cells with silibinin at 400 μM concentration for 48 h induced a 50% decrease in the numbers of colonies as compared with DMSO-treated cells. Treatment of PAC-resistant MCF-7 cells with silibinin at 400 μM concentration generated synergistic effects when it was used in combination with PAC at 250 nM concentration (CI = 0.81). Conclusion:Silibinin sensitizes chemo-resistant cells to chemotherapeutic agents and can be useful in treating breast cancers. [ABSTRACT FROM PUBLISHER]

Lung cancer is an invasive and progressive, fatal disease with few treatment choices and poor overall survival rates in nonsurgical stages. Leptin (LEP), an adipocyte derivative cytokine, participates in carcinogenesis. Increased amounts of systemic and pulmonary LEP indicate lung cancer. Curcumin (CUR) and silibinin (SIL) are herbal compounds which have many anticancer properties, but they have hydrophobic structures and low solubility in water. In this study, evaluated CUR–SIL dual drug-loaded poly (ɛ-caprolactone) [PCL]–co-poly ethylene glycol (PEG) magnetic nanoparticles (MNPs) were used to determine the inhibitory effect on LEP gene expression. The physicochemical properties of free and CUR–SIL-loaded PCL–PEG were fully characterized. The cytotoxic effect of CUR–SIL-loaded PCL–PEG magnetic nanoparticles was determined by MTT assay. Afterward, the inhibition of LEP gene expression was specified through real-time PCR. Results indicated that CUR–SIL cytotoxicity is time- and dose-dependent. CUR–SIL loaded MNPs showed the IC50 limit in lower concentrations in comparison to net CUR–SIL. CUR–SIL loaded MNPs reduced LEP expression more than net CUR–SIL. These results revealed the possibilities of CUR–SIL-loaded MNPs as a natural and effective antitumor drug delivery system to fight lung tumors. [ABSTRACT FROM PUBLISHER]

Introduction: Silibinin is mixture of flavonolignans extracted from milk thistle and often has been used in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol and hepatitis and gall bladder disorders for its antioxidant and hepatoprotective properties. Areas covered: However, increasing evidence suggest that silibinin is not solely limited in the treatment of these diseases. Further research suggests that silymarin may function diversely and may serve as a novel therapy for cancer therapy, such as lung cancer, prostatic cancer, colon cancer, breast cancer, bladder cancer and hepatocellular carcinoma by regulating cancer cells growth, proliferation, apoptosis, angiogenesis and many other mechanism. Expert commentary: In this review, in order to provide potential new treatment for these cancer, we summarize the recent anti-cancer findings of silibinin in these cancer and clarify the mechanisms of this effect. [ABSTRACT FROM AUTHOR]

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), an oncogenic fusion protein carrying constitutively active tyrosine kinase, is known to be central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK+ALCL). Here, it is reported that silibinin, a non-toxic naturally-occurring compound, potently suppressed NPM-ALK and effectively inhibited the growth and soft agar colony formation of ALK+ALCL cells. By western blots, it was found that silibinin efficiently suppressed the phosphorylation/activation of NPM-ALK and its key substrates/downstream mediators (including STAT3, MEK/ERK and Akt) in a time- and dose-dependent manner. Correlating with these observations, silibinin suppressed the expression of Bcl-2, survivin and JunB, all of which are found to be upregulated by NPM-ALK and pathogenetically important in ALK+ALCL. Lastly, silibinin augmented the chemosensitivity of ALK+ALCL cells to doxorubicin, particularly the small cell sub-set expressing the transcriptional activity of Sox2, an embryonic stem cell marker. To conclude, the findings suggest that silibinin might be useful in treating ALK+ALCL. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate beneficial effects of erdosteine in the alpha amanitine-induced hepatotoxicity in mice. Three hours after giving alpha amanitin (0.5 mg/kg, i.p.) to the mice, they were administered silibinin (50 mg/kg/d, i.p.) or erdosteine (100 mg/kg/d, oral) therapies once a day for 3 d. A histopathological examination of their liver tissues was carried out 24 h after the last treatment; transaminase levels, blood urea nitrogen, urea, and creatinine were analyzed in serum. Erdosteine showed a beneficial effect by significantly improving the functional parameters particularly in alpha amanitin-induced hepatotoxicity and partially in renal toxicity. In the histopathological evaluation, the toxicity that was generated with alpha amanitin was significantly reduced by erdosteine, showing a possible hepatoprotective effect. [ABSTRACT FROM AUTHOR]

1. The present study was to investigate the effects of giving N-acetylcysteine (NAC) alone and in combination with either glycyrrhizin (GL), silibinin (SIB) or spironolactone (SL) on the plasma pharmacokinetic (PK) profiles, hepatic exposure, biliary excretion and urinary excretion of acetaminophen (APAP) and its major metabolite, acetaminophen glucuronide (AG). 2. Groups of rats ( n = 5) were pretreated with oral doses of either NAC, NAC + GL, NAC + SIB or NAC + SL on five occasions every 12 h. At 1 h, after the last dose, they received APAP (200 mg/kg) by intraperitoneal injection. Blood, bile, liver and urine samples were collected at various times after APAP injection and analyzed for APAP and AG by HPLC. NAC alone and NAC + SIB did not significantly change the PK profiles of APAP and AG. In contrast, NAC + GL decreased the biliary excretion of APAP and AG leading to accumulation of APAP in the liver and systemic circulation whereas NAC + SL [multidrug resistance associated 2 (Mrp2) inducer] increased the biliary excretion of AG and decreased the hepatic exposure to APAP and AG. 3. Our results suggest that Mrp2 inhibitor GL should be discouraged with NAC to treat APAP hepatotoxicity. Such PK drug-drug interactions should be considered in the treatment of APAP-induced liver injury. [ABSTRACT FROM AUTHOR]

Amiodarone (AMD) is a hepatotoxic drug that has been widely used as a class III antiarrhythmic drug. Because, to date, only a few kinds of protectants are able to reduce AMD hepatotoxicity, this article utilized gel-entrapped rat hepatocytes to screen effective protectants from a series of herbal compounds for their effects against AMD-induced toxicity. Herbal compounds, including matrine, silibinin, glycyrrhizic acid, schisandrin B, epigallocatechin gallate and anisodamine, were cotreated with AMD to assess their protective effect, whereas vitamin E, which has been shown to be protective in rats, was selected as a control. It was found that vitamin E, as with its function in rats, provided the best protection in gel-entrapped rat hepatocytes, whereas silibinin, a major component of silymarin, could largely reduce AMD-induced hepatotoxicity, performing a similar function as silymarin in rats. The results illustrated that gel-entrapped hepatocytes may reflect the protective effects of drugs and serve as a reliable model for screening hepatoprotectants. Moreover, matrine, a widely used monomer of the traditional Chinese medicine, Sophora flavescens, for treatment of arrhythmia, was evidenced to show some effective protections against AMD hepatotoxicity. Taken together, gel-entrapped rat hepatocytes may provide a platform for screening effective candidates from the herbal component library. [ABSTRACT FROM AUTHOR]

Silibinin is a polyphenolic plant flavonoid with anti-inflammatory properties. The present study investigated the effect of silibinin on oxidative metabolism and cytokine production - tumor necrosis factor-alpha (TNF-α), interleukin (IL)12, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-10, and transforming growth factor beta (TGF-β1) - by peripheral blood monocytes (PBM) from preeclamptic pregnant women. It is a case-controlled study involving women with preeclampsia (PE, n = 30) compared with normotensive pregnant (NT, n = 30) and with non-pregnant (NP, n = 30) women. Monocytes were obtained and cultured with or without silibinin (5 μM or 50 μM) for 18 h. Superoxide anion (O2−) and hydrogen peroxide (H2O2) release were determined by specific assays, and cytokine levels were determined by immunoenzymatic assays (ELISA). Monocytes from preeclamptic women cultured without stimulus released higher levels of O22, H2O2 and TNF-α, and lower levels of IL-10 and TGF-β1 than did monocytes from NT and NP women. Treatment in vitro with silibinin significantly inhibited spontaneous O2− and H2O2 release and TNF-α production by monocytes from preeclamptic women. The main effect of silibinin was obtained at 50 μM concentration. Thus, silibinin exerts anti-oxidative and anti-inflammatory effects on monocytes from preeclamptic pregnant women by inhibiting the in vitro endogenous release of reactive oxygen species and TNF-α production. [ABSTRACT FROM AUTHOR]

Apoptosis in murine dermal cells is retarded by ultraviolet B (UVB) irradiation-induced autophagic intervention while simultaneously epidermal cells commit apoptosis, during which inflammatory cytokines released from the lost epidermal cells promote immune responses of dermal inflammatory cells, forming morphological symptoms of acute cutaneous diseases. Autophagy is involved in prevention or provocation of apoptosis of dermal or epidermal cells of UVB-irradiated mice via modulation of intracellular metabolism, intervening the balance between cell death and survival in dermis and epidermis. p53 expressed in immune system affects autophagy function through activating or inactivating genes encoding apoptotic factors and inflammatory cytokines. Silibinin protects dermal and epidermal cells of UVB irradiated skin against abnormally autophagy-mediated apoptosis adjustments. In this study, how UVB irradiation intervenes autophagy in dermal and epidermal cells as well as how silibinin protects UVB irradiated skin through physiological recovering of autophagy function in dermis and epidermis are focused and elucidated preliminarily. Silibinin treatment (50 mg/kg/day for 4 days) reversed dermal and epidermal autophagy levels from UVB irradiation-induced improper autophagy intervention, repaired the balance between cell survival and death in dermis and epidermis, and protected skin against damage through mediation of p53 activation in dermal and epidermal cells. [ABSTRACT FROM PUBLISHER]

Silibinin, a major active constituent of silymarin, is clinically used as a hepatoprotectant, and in recent years, it has been used for the treatment of cancer in China. Because the mechanism of silibinin action on cancer cells was still unclear, we investigated the contribution of silibinin to the induction of apoptosis and autophagy via generation of reactive oxygen species (ROS) and nitric oxide (•NO) in human epidermoid carcinoma A431 cells. Silibinin inhibited the cell growth in a dose-and time-dependent manner. Obvious autophagy was observed after treatment with different doses of silibinin. At a high dose (400 μM), silibinin induced apoptosis through both the intrinsic and extrinsic apoptotic pathways. Loss of mitochondrial membrane potential by silibinin led to mitochondrial dysfunction and decreased ROS levels, suggesting that silibinin might act as an antioxidant in this process. Furthermore, silibinin induced •NO generation in a time-and dose-dependent manner. The •NO scavenger PTIO could effectively clear •NO and exerted a minor cell protection effect through partial inhibition of silibinin-induced apoptosis and autophagy. [ABSTRACT FROM AUTHOR]

Silibinin is an active constituent extracted from the blessed milk thistle ( Silybum marianum). In a previous study, we demonstrated that silibinin treatment induced the generation of reactive nitrogen species (RNS), which were associated with reactive oxygen species (ROS), and caused apoptosis and autophagy in HeLa cells. Another study reported that silibinin treatment attenuated the apoptotic effect of sodium nitroprusside (SNP) by generating ROS in rat pheochromocytoma PC12 cells [1]. To clarify the relationship between RNS and nitric oxide (NO) in HeLa cells, we chose SNP as a NO donor to inhibit the cell viability. We found that silibinin treatment did not reduce the cytotoxicity of NO by reducing the ROS-induced RNS levels; conversely, silibinin treatment enhanced the cytotoxicity of NO. Pre-treatment with the NO scavenger PTIO preserved the viability of SNP- or silibinin-treated cells. Buthionine sulfoximine (BSO) treatment was also used to deplete the level of glutathione (GSH) and subsequently enhance the cytotoxicity of NO. Pre-treatment with BSO enhanced the SNP-induced reduction of cell viability but had no such effects in the silibinin-treated cells. These results led us to investigate whether silibinin treatment could induce the depletion of GSH. JNK and p53 have been shown to mediate the depletion of GSH [2,3], and we previously demonstrated the existence of a ROS-JNK-p53 cycle in silibinin-treated HeLa cells [4]. Thus, we speculated that p53 also plays a crucial role in the silibinin-induced GSH depletion. To elucidate the role of p53 in this process, A431 cells were used because they are naturally devoid of a functional p53 (p53His273 mutation). To our surprise, silibinin treatment did not lower the GSH level in A431 cells but rather elevated the GSH level. Unlike the ROS level, the NO level was still up-regulated by silibinin treatment in A431 cells. Cumulatively, these findings support the idea that the silibinin-induced GSH depletion, which is mediated by p53, enhances the cytotoxicity of NO in HeLa cells. [ABSTRACT FROM AUTHOR]

Skin inflammation induced by ultraviolet B (UVB) radiation is characterized by migration and chemotaxis of inflammatory cells, epidermic thickening and erythema. Apoptosis and autophagy of epidermal and dermal cells are involved in its development through the adjustment of balance between cell survival and death. In this study, the role of balance between cell survival and apoptosis in dermis and epidermis in UVB-induced skin inflammation and the effect of autophagy on the balance were elucidated, and the protective mechanism of silibinin was investigated through the examination of the influence of autophagy activation or inhibition on erythema, migration, and chemotaxis of inflammatory cells as well as apoptosis adjustments. In UVB-irradiated controls, dermal apoptosis was retarded and the survival of inflammatory cells was promoted through the up-regulation of dermal autophagic level; epidermal apoptosis was increased through the down-regulation of epidermal autophagic level, causing migration and chemotaxis of neutrophils and mast cells as well as skin erythema. In silibinin-treated group (50 mg/kg/day for 4 days), dermal apoptosis was increased through inhibiting dermal autophagy; improper adjustment of epidermal apoptosis was attenuated through promoting epidermal autophagy, presenting dual effects on the balance between autophagy and apoptosis of epidermal and dermal cells and the protection. [ABSTRACT FROM PUBLISHER]

Arsenic (As) compounds are reported as environmental toxicants and human carcinogens. Exposure to arsenic imposes a big health issue worldwide. Silibinin (SB) is a major flavonolignan compound of silimarin and is found in milk thistle of Silybum marianum. It has been reported that silibinin has antioxidant efficacy as metal chelators due to the orientation of its functional groups. However, it has not yet been explored in experimental animals. In view of this fact, the purpose of this study was to delineate the ameliorative role of silibinin against arsenic-induced hepatotoxicity in rats. Rats were orally treated with arsenic alone (5 mg/kg body weight (bw)/day) plus silibinin (75 mg/kg bw/day) for 4weeks. Hepatotoxicity was evaluated by the increased activities of serum hepatospecific enzymes namely aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase and total bilirubin along with increased elevation of lipid peroxidative markers, thiobarbituric acid reactive substances, lipid hydroperoxides, protein carbonyl content and conjugated dienes. The toxic effect of arsenic was also indicated by significantly decreased activities of membrane bound ATPases, enzymatic antioxidants like superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase along with nonenzymatic antioxidants like reduced glutathione, total sulfhydryl groups, vitamins C and E. Administration of silibinin exhibited a significant reversal of arsenic-induced toxicity in hepatic tissue. All these changes were supported by reduction of DNA damage in hepatocytes and histopathological observations of the liver. These results suggest that silibinin has a potential protective effect over arsenic-induced hepatotoxicity in rat. [ABSTRACT FROM AUTHOR]

Improper adjustments of autophagy and silent information regulator 1 (Sirt-1) expression were reported to be closely associated with metabolic disorders. In this study, we examined the roles of Sirt-1 and autophagy in streptozotocin-induced diabetes mellitus, assessed the relationship between autophagy and Sirt-1, and investigated the protective mechanism of silibinin. Diabetes was induced in 6-week-old mice by intravenous injection of streptozotocin (150 mg/kg/day, for 2 weeks). In the treatment groups, silibinin (50 mg/kg/day, intramuscular injection, for 8 weeks) or inhibitors (50 mg/kg/day, subcutaneous injection, for 8 weeks) were given. Diabetic control animals received vehicle for the same time. Compared with diabetic controls, silibinin or autophagy inhibitor, 3-methyladenine, treated mice showed decreased levels of glycosylated hemoglobin A1C (P < 0.01), serum triglyceride (P < 0.01), cholesterol (P < 0.01), blood glucose (P < 0.05), autophagy (P < 0.05), and apoptosis ratio (P < 0.05) of pancreatic β-cells. Systemic administration of silibinin reversed streptozotocin-induced downregulation of Sirt-1 expression. Sirt-1 may play a role in regulating the physiological level of autophagy and is associated with loss of pancreatic β-cells and metabolic biochemical disorders. Through promoting Sirt-1 expression and recovering autophagy physiologically, silibinin may reverse hyperglycemia and repair damaged pancreatic β-cells. [ABSTRACT FROM PUBLISHER]

Context: Amla [ Emblica officinalis Gaertn. (Euphorbiaceae)], a major constituent of several herbal formulations, is a well-known hepatoprotectant. Despite its extensive use, mechanistic understanding of its antioxidant action is rather limited. Objective: In the current study, we investigated the effects of E. officinalis extracts (from dried fruits) on cellular oxidative state using a hepatocyte cell line (HepG2). We hypothesize that E. officinalis aqueous extracts have potency to modulate basal oxidative markers and enhance endogenous antioxidant defenses. Materials and methods: Cells were incubated with aqueous extracts of E. officinalis (1-100 μg/ml) for varied time points (4-24 h) and biochemical markers of oxidative stress were determined in cell lysate. Discussion: Aqueous extracts of E. officinalis at 100 μg/ml can significantly modulate the basal levels of oxidative markers and enhance antioxidant defenses of the cells. Conclusions: Our findings clearly indicate the propensity of E. officinalis aqueous extracts to improve endogenous antioxidant defenses in HepG2 cells. Although further studies are required to assess their efficacy under experimentally induced oxidative, our data suggest that the hepatoprotective effects of E. officinalis reported earlier may be largely due to its potential to enhance the antioxidant defenses in vivo. Results: Because E. officinalis up to 100 μg/ml concentrations had no effect on cell viability; it was considered noncytotoxic. Incubation with E. officinalis for 24 h resulted in significant diminution in the levels of lipid hydroperoxide (18-42%) and reactive oxygen species (11-29%). Furthermore; E. officinalis increased the levels of glutathione (GSH; 18-32%); antioxidant capacity (19-31%); and activities of antioxidant enzymes (superoxide dismutase; 25-41%; catalase; 39-50%; GSH peroxidase; 20-35%; GSH reductase; 26-35%; and GSH S-transferase; 12-30%). [ABSTRACT FROM AUTHOR]

Context: Ursolic acid is a pentacyclic triterpenoid which has hepatoprotective and antihepatotoxic activities. Objective: This study investigated whether ursolic acid is able to stimulate liver regeneration in partially hepatectomized mice. Materials and methods: Ursolic acid or the vehicle solution was orally administered to the experimental, sham-operated and vehicle-treated group mice for 7 days, positive control animal (mice) was treated with recombinant human hepatocyte growth factor (rhHGF), and then the 70% liver partial hepatectomy was performed. The liver mass recovery rate was estimated by measuring the ratios of mice liver weight to body weight. The liver cells undergoing DNA synthesis were identified by immunohistochemistry analysis using monoclonal anti-BrdU antibodies. The expression levels of cyclin D1, cyclin E and C/EBP proteins (C/EBPα and C/EBPβ) were detected by the Western blotting technique. Results: Our results showed administration of ursolic acid significantly increased the ratio of the liver to body weight and BrdU labeling index at 36 and 48 h after partial hepatectomy, and the potency of UA is similar to rhHGF treated positive control mice. In addition, ursolic acid treatment significantly increased cyclin D1, cyclin E and C/EBPβ protein expression levels at 36 h after liver PHx compared with the vehicle-treated control mice. Discussion and conclusion: All these results suggest that ursolic acid stimulates liver proliferation after partial hepatectomy, and this effect may be associated with the stimulation of C/EBPβ expression. [ABSTRACT FROM AUTHOR]

Silibinin is an active constituent extracted from blessed milk thistle ( Silybum marianum). Our previous study demonstrated that silibinin induced autophagy and apoptosis via reactive oxygen species (ROS) generation in HeLa cells. In this study, we investigated whether the autophagy- and apoptosis-associated molecules also involved in ROS generation. Silibinin promoted the expression phosphorylated-p53 (p-p53) in a dose-dependent manner. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced ROS production and reversed silibinin's growth-inhibitory effect. The ROS scavenger N-acetyl cysteine (NAC) attenuated silibinin-induced up-regulation of p-p53 expression, suggesting that p53 might be regulated by ROS and forms a positive feedback loop with ROS. On the other hand, silibinin dose-dependently promoted the expression of phosphorylated-c-Jun N-terminal kinase (p-JNK). Inhibition of JNK by SP600125 decreased ROS generation. NAC down-regulated the expression of p-JNK, indicating that JNK could be activated by ROS. Activation of p53 was suppressed by SP600125 and expression of p-JNK was inhibited by PFT-α, therefore silibinin might activate a ROS-JNK-p53 cycle to induce cell death. Silibinin up-regulated the PUMA and Bax expressions and down-regulated the mitochondrial membrane potential (MMP) level. PFT-α reduced the expression of PUMA and Bax. These results showed that p53 could interfere with mitochondrial functions such as MMP via PUMA pathways, thus resulting in ROS generation. In order to elucidate the functions of p53 in silibinin induced ROS generation, we have chosen the A431 cells (human epithelial carcinoma) because they lack p53 activity (p53His273 mutation). Interestingly, silibinin did not up-regulate the ROS level in A431 cells but lower the ROS level. PFT-α had no influence on ROS level in A431 cells. p53 activation plays a crucial role in silibinin induced ROS generation. [ABSTRACT FROM AUTHOR]

Silibinin, as the major active constituent of silymarin, has its various biological effects. Here, we investigated the inhibitory effects of silibinin on HeLa cell growth in relation to autophagy and apoptosis induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. Silibinin dose and time-dependently decreased cell growth cultured in medium containing 10% fetal bovine serum or in serum free media (SFM) with an IC50 of approximately 80-100 and 40-60 μM at 24 h, respectively. Silibinin induced autophagy at 12 h, confirmed by monodansylcadervarine (MDC) staining and up-regulation of beclin-1, and induced apoptosis at 24 h, detected by observation of apoptotic bodies and activation of caspase-3. 3-methyladenine (3-MA) inhibited silibinin-induced autophagy and attenuated the silibinin's inhibitory effect on cell viability, suggesting that autophagy enhanced silibinin-induced cell death. Silibinin increased ROS levels at 12 h, and ROS scavenger, N-acetylcysteine (NAC), significantly reversed the cytotoxicity of silibinin through inhibiting both autophagy and apoptosis. Specific antioxidants were applied and results indicated that hydroxyl radical (·OH) was the major ROS induced by silibinin, and OH scavenger glutathione (GSH) inhibited apoptosis and autophagy. Silibinin also generated RNS production in the cells at 12 h. High concentration of N omega-nitro-l-arginine methyl ester (L-NAME) as nitric oxide synthase (NOS) inhibitor attenuated the cytotoxicity of silibinin by decreasing ROS levels, leading to down-regulation of apoptosis. Silibinin also could interrupt the respiring functions of mitochondria, leading to ROS production and oxidative damage. [ABSTRACT FROM AUTHOR]

Silibinin mostly has been used as hepatoprotectants, but it has other interesting activities, e.g. anti-cancer, cardial protective and brain-protective activities. A previous study demonstrated that silibinin protected amyloid ββ (Aββ)-induced mouse cognitive disorder by behavioural pharmacological observation. This study assessed the effect of silibinin on sodium nitroprusside (SNP)-treated rat pheochromocytoma PC12 cells. Subsequent morphologic observation, flow cytometric analysis and Western blot analysis indicated that treatment with SNP significantly induced apoptosis in PC12 cells. However, silibinin eliminated the apoptotic effect by reactive oxygen species (ROS) generation, especially hydroxyl free radical. Silibinin-induced autophagy through ROS generation when exerting a protective effect and silibinin-induced autophagy also enhanced the ROS generation since 3-methyladenine (3-MA), a specific autophagy inhibitor, decreased the ROS generation and rapamycin, an autophagy inducer, enhanced the ROS generation. Therefore, there exists a positive feedback loop between autophagy and ROS generation. Autophagy prevented SNP-induced apoptosis, since the addition of 3-MA significantly eliminated the protective effect of silibinin. This protective effect was attributed to the generation of ROS and its two downstream Ras/PI3K/NF-κκB and Ras/Raf/MEK/ERK pathways. Both prevented PC12 cells from apoptosis. The PI3K/NF-κκB pathway induced autophagy to protect PC12 cells, but the Raf/MEK/ERK pathway directly protected PC12 cells bypassing the autophagic effect. [ABSTRACT FROM AUTHOR]