RESUMO
Triazole fungicides, such as difenoconazole (DFZ), are frequently used to control fungus in crops that pollute water. The common carp (Cyprinus carpio) (hereafter referred to as "carp") is an excellent bio-indicator of water quality. The seeds of the silymarin plant contain a flavonolignan called silybin (SYB), which is used to treat liver disease. To explore SYB's involvement in DFZ-triggered kidney damage in carps, an H&E assay was conducted, and ROS level was also examined. The results demonstrated that SYB alleviated DFZ-induced destruction of kidney tissue structure in carps, as well as alleviating the elevation of kidney ROS level in carps. RT-qPCR and Western blot were used to detect inflammation-, oxidative stress- and apoptosis-related factors at mRNA level and protein level. The experimental findings indicated that relative to the DFZ group, SYB + DFZ co-treatment reduced inflammation-related mRNA level of il-6, il-1ß and tnf-α, elevated mRNA level of il-10. It also reduced protein expression levels of NF-κB and iNOS. In addition, SYB + DFZ co-treatment reduced DFZ-induced increase in the oxidative stress-related mRNA indicators sod and cat, and decreased the protein expression levels of Nrf2 and NQO1. SYB reduced the DFZ-induced increase in pro-apoptotic gene Bax mRNA and protein expression levels and the DFZ-induced decrease in anti-apoptotic gene Bcl-2 mRNA and protein expression levels. In summary, SYB potentially mitigates DFZ-induced kidney damage in carp by addressing inflammation, oxidative stress, and apoptosis. Our results establish a theoretical foundation for the clinical advancement of freshwater carp feeds.
Assuntos
Apoptose , Carpas , Inflamação , Estresse Oxidativo , Silibina , Triazóis , Animais , Carpas/imunologia , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Triazóis/farmacologia , Inflamação/veterinária , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Silibina/farmacologia , Silibina/administração & dosagem , Fungicidas Industriais/farmacologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/induzido quimicamente , Dioxolanos/farmacologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefropatias/veterinária , Nefropatias/induzido quimicamente , Nefropatias/imunologia , Nefropatias/tratamento farmacológicoRESUMO
Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aß1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aß1-42 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 Aß1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aß1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aß1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aß1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores , Fragmentos de Peptídeos , Silibina , Animais , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Camundongos , Silibina/farmacologia , Silibina/administração & dosagem , Fragmentos de Peptídeos/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Tamanho da Partícula , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Modelos Animais de Doenças , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Acetilcolinesterase/metabolismoRESUMO
Chemotherapeutic agents often lack specificity, intratumoral accumulation, and face drug resistance. Targeted drug delivery systems based on nanoparticles (NPs) mitigate these issues. Poly (lactic-co-glycolic acid) (PLGA) is a well-studied polymer, commonly modified with aptamers (Apts) for cancer diagnosis and therapy. In this study, silybin (SBN), a natural agent with established anticancer properties, was encapsulated into PLGA NPs to control delivery and improve its poor solubility. The field-emission scanning electron microscopy (FE-SEM) showed spherical and uniform morphology of optimum SBN-PLGA NPs with 138.57±1.30nm diameter, 0.202±0.004 polydispersity index (PDI), -16.93±0.45mV zeta potential (ZP), and 70.19±1.63% entrapment efficiency (EE). The results of attenuated total reflectance-Fourier transform infrared (ATR-FTIR) showed no chemical interaction between formulation components, and differential scanning calorimetry (DSC) thermograms confirmed efficient SBN entrapment in the carrier. Then, the optimum formulation was functionalized with 5TR1 Apt for active targeted delivery of SBN to colorectal cancer (CRC) cells in vitro. The SBN-PLGA-5TR1 nanocomplex released SBN at a sustained and constant rate (zero-order kinetic), favoring passive delivery to acidic CRC environments. The MTT assay demonstrated the highest cytotoxicity of the SBN-PLGA-5TR1 nanocomplex in C26 and HT29 cells and no significant cytotoxicity in normal cells. Apoptosis analysis supported these results, showing early apoptosis induction with SBN-PLGA-5TR1 nanocomplex which indicated this agent could cause programmed death more than necrosis. This study presents the first targeted delivery of SBN to cancer cells using Apts. The SBN-PLGA-5TR1 nanocomplex effectively targeted and suppressed CRC cell proliferation, providing valuable insights into CRC treatment without harmful effects on healthy tissues.
Assuntos
Neoplasias Colorretais , Sistemas de Liberação de Medicamentos , Ácido Láctico , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Silibina , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Silibina/administração & dosagem , Silibina/farmacologia , Silibina/química , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Nanopartículas/química , Ácido Láctico/química , Sistemas de Liberação de Medicamentos/métodos , Silimarina/química , Silimarina/administração & dosagem , Silimarina/farmacologia , Portadores de Fármacos/química , Linhagem Celular Tumoral , Ácido Poliglicólico/química , Tamanho da Partícula , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/química , Solubilidade , Células HT29 , Liberação Controlada de Fármacos , Varredura Diferencial de Calorimetria/métodosRESUMO
OBJECTIVES: Milk thistle has long been used in the treatment of liver and biliary disorders. In the present study, to make a long-acting delivery system for silibinin (SBN, a major active constituent of milk thistle seeds with antioxidant and hepatoprotective function), mesoporous silica composite nanoparticles (NC) were synthesized and coated with RBC membrane. METHODS: A modified Stöber method was used for NC synthesis, which was then characterized using FE-SEM, DLS, TEM, FTIR, and EDAX techniques. A suitable lysis buffer was used to prepare RBC-ghost, and sonication was used to coat SBN-loaded NC (SBN-NC). The RBC-ghost coated SBN-NC (SBN-NC-RBCG) was evaluated by SDS-PAGE, Bradford, TEM, EDAX, and DLS methods. SBN release was then compared for the SBN-NC and SBN-NC-RBCG samples. KEY FINDINGS: the RBC membrane proteins were recovered from the coating of SBN-NC-RBCG, and SBN release was sustained over 24 h when compared with the SBN-NC. CONCLUSIONS: Overall, through prolonging circulation in the bloodstream and evading the immune system, the developed system can improve SBN bioavailability in liver inflammation and fibrosis conditions that need further research.
Assuntos
Preparações de Ação Retardada , Membrana Eritrocítica , Nanopartículas , Dióxido de Silício , Silibina , Silibina/farmacologia , Silibina/administração & dosagem , Silibina/química , Dióxido de Silício/química , Membrana Eritrocítica/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/administração & dosagem , Liberação Controlada de Fármacos , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Portadores de Fármacos/química , Silimarina/administração & dosagem , Silimarina/farmacologia , Silimarina/química , Silimarina/farmacocinética , Porosidade , Fígado/metabolismo , Fígado/efeitos dos fármacos , Silybum marianum/química , HumanosRESUMO
OBJECTIVE: 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. METHODS: Solubility studies were performed using the phase solubility analysis according to the shake-flask method in the presence of ethanol and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-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. RESULTS: SLB solubility was mathematically optimized constraining to using the lowest concentrations of ethanol and HP-ß-CD. SLB solubility increased linearly with the increase of HP-ß-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-ß-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-ß-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. CONCLUSION: SLB solubility in a buffered solution supplemented by ethanol co-solvent and HP-ß-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.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina , Quitosana , Liberação Controlada de Fármacos , Nanopartículas , Silibina , Solubilidade , Solventes , Silibina/química , Silibina/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/química , Quitosana/química , Nanopartículas/química , Solventes/química , Etanol/química , Silimarina/química , Silimarina/administração & dosagem , Química Farmacêutica/métodos , Portadores de Fármacos/químicaRESUMO
BACKGROUND: The purpose of this study was to investigate the protective effect of Silibinin-loaded polymeric micelles from human hair against UV-B radiation. METHODS: Eight formulations with different concentrations of Silibinin, Pluronic F-127, and Labrasol-Labrafil were made by a solvent evaporation method, and the selected formulation was chosen by examining their properties like particle size and loading efficiency. Six groups of human hair, including a group that received the selected formulation, were exposed to UV-B radiation and by calculating its factors such as peak-to-valley roughness, RMS roughness, FTIR, and the amount of protein loss, the protective effect of the selected formulation was judged. RESULTS: According to the results, the loading efficiency and particle size of the selected formulation were 45.34% and 43.19 nm. The Silibinin release profile had two parts, fast and slow, which were suitable for creating a drug depot on hair. Its zeta potential also confirmed the minimum electrostatic interference between the formulation and hair surface. The zeta potential of selected formulation was -5.9 mv. Examination of AFM images showed that the selected formulation was able to prevent the increase in peak-to-valley roughness and RMS roughness caused by UV-B radiation. RMS roughness after 600 h of UV radiation in Groups 5 and 6 was significantly lower than the negative control group and the amount of this factor did not differ significantly between 0 and 600, so it can be concluded that the selected formulation containing Silibinin and the positive control group was able to prevent the increase of RMS roughness and hair destruction. In other hands, the two positive control groups and the selected formulation containing Silibinin were able to effectively reduce hair protein loss. CONCLUSION: Silibinin-loaded polymeric micelles were able to effectively protect hair from structural and chemical changes caused by UV-B radiation.
Assuntos
Cabelo , Micelas , Tamanho da Partícula , Silibina , Raios Ultravioleta , Humanos , Raios Ultravioleta/efeitos adversos , Silibina/farmacologia , Silibina/administração & dosagem , Silibina/química , Cabelo/efeitos dos fármacos , Cabelo/efeitos da radiação , Silimarina/farmacologia , Silimarina/administração & dosagem , Silimarina/química , Polímeros/química , Liberação Controlada de Fármacos/efeitos da radiação , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/efeitos da radiaçãoRESUMO
BACKGROUND: Silibinin is a polyphenolic compound that could modulate estrogen receptor activation. Vascular dysfunction is considered a key initiator in atherosclerosis and may occur in the postmenopausal period. This manuscript compares estrogen and silibinin's impacts on factors that change endothelial function in ovariectomized (OVX) rats. METHODS: 32 female Wistar rats were subdivided into control; OVX; OVX + estrogen (1 mg/kg/day); and OVX + silibinin (50 mg/kg/day) groups. After the experimental period, lipid profile, atherogenic indices, and histopathology of endothelium were monitored. The vascular oxidative stress, adhesion molecules, inflammatory cytokine levels, nitric oxide (NO), angiotensin-II (Ang-II), and endothelin-1 (ET-1) were also analyzed. RESULTS: Silibinin treatment, similar to estrogen, significantly normalized the adverse changes of OVX on vascular function, including improved lipid profile and oxidative stress, increased endothelial nitric oxide synthase (eNOS) expression, diminished inflammatory status, and reduced adhesion molecule levels, ET-1 and Ang-II substances. Our findings also revealed that the administration with estrogen or silibinin resulted in a normal endothelium layer in the aorta tissues of OVX rats. CONCLUSION: Estrogen and silibinin have similar effects in improving vascular function. These treatments' protective impacts on vasculature indicate their potential benefits on the cardiovascular system in the postmenopausal period.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Estrogênios/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Ovariectomia/efeitos adversos , Silibina/administração & dosagem , Animais , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pós-Menopausa , Ratos , Ratos Wistar , Silibina/farmacologiaRESUMO
BACKGROUND: Silibinin, the principal flavonoid derived from milk thistle seeds, has been demonstrated to have strong inhibitory effects against human malignancies. The inhibitory function of silibinin on ovarian cancer, however, is not fully identified. In this essay, both in vivo and in vitro investigations were conducted to survey the silibinin's blocking effects on ovarian cancer. METHODS: The impacts of silibinin on two ovarian cancer cell lines, SKOV-3 and A2870, were determined by evaluating cell viability, migration, invasion, and apoptosis. Q-RT-PCR and western blotting techniques were carried out to explore the protein levels of signaling pathway markers. A mouse xenograft model was utilized to determine the silibinin efficacy in inhibiting tumor growth. RESULTS: After cell treatment with silibinin, cell viability, migration, and invasion were appreciably inhibited in cancer cell lines, but cell apoptosis was promoted. Also, silibinin reversed the epithelial-mesenchymal transition (EMT) mechanism by inducing E-cadherin expression and reducing N-cadherin and vimentin expression, suppressing the levels of regulators related to EMT such as Snail, Slug, and ZEB1 transcription factors, and also decreasing PI3K/AKT, Smad2/3, and ß-catenin intermediate molecules in vitro. Silibinin effectively ameliorated tumor growth in vivo. CONCLUSION: silibinin could be considered a potent agent against ovarian cancer based on the results.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Silibina/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Silibina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Chemotherapeutic combinational approaches would be more efficient in decreasing toxicity of drug, preventing tumor progression in relation to either drug alone. Hence, the aim of this study is to constract magnetic PLGA/PEG nanoparticles (NPs) co-loaded with Metformin (Met) and Silibinin (Sil) to investigate their cytotoxicity as well as their impact on mRNA expression levels of leptin and leptin receptor genes in A549 lung cancer cells. MATERIALS AND METHODS: The synthesized NPs were characterized by FTIR, FE-SEM, and VSM and then, MTT assay was utilized to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Moreover, the mRNA levels of leptin and its receptor genes expression were studied by quantitative real-time PCR. By co-encapsulation of Met and Sil into PLGA/PEG/ Fe3O4, cytotoxic efficiency of the compounds considerably augmented for all concentrations. RESULTS: Cytotoxicity assay displayed that combination of Met and Sil had a synergistic concentration-dependent effect on A549 lung cancer cells. Moreover, qPCR data revealed that the expression levels of the leptin and leptin receptor was considerably reduced with increasing concentrations of drug-encapsulated magnetic NPs, especially Met/Sil-encapsulated PLGA/PEG/ Fe3O4 NPs. CONCLUSION: Present preliminary study shows that co-incorporating Met, Sil, Fe3O4 into PLGA/PEG NPs might provide a more promising and safe treatment strategy for lung cancer.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Metformina/administração & dosagem , Silibina/administração & dosagem , Células A549 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leptina/metabolismo , Neoplasias Pulmonares/genética , Fenômenos Magnéticos , Sistemas de Liberação de Fármacos por Nanopartículas/administração & dosagem , Polietilenoglicóis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Receptores para Leptina/metabolismoRESUMO
The present work was designed to assess the efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally induced renal carcinogenesis in male Wistar rats and their roles in regulating oxidative stress, inflammation, apoptosis, and carcinogenesis. The diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4)-administered rats were orally treated with STE (200 mg/kg b.w.), Sm (150 mg/kg b.w.), and Sb (5 mg/kg b.w.) every other day either from the 1st week or from the 16th week of carcinogen administration to the end of 25th week. The treatments with STE, Sm, and Sb attenuated markers of toxicity in serum, decreased kidney lipid peroxidation (LPO), and significantly reinforced the renal antioxidant armory. The biochemical results were further confirmed by the histopathological alterations. The treatments also led to suppression of proinflammatory mediators such as NF-κß, p65, Iκßα, and IL-6 in association with inhibition of the PI3K/Akt pathway. Furthermore, they activated the expressions of PPARs, Nrf2, and IL-4 in addition to downregulation of apoptotic proteins p53 and caspase-3 and upregulation of antiapoptotic mediator Bcl-2. The obtained data supply potent proof for the efficacy of STE, Sm, and Sb to counteract renal carcinogenesis via alteration of varied molecular pathways.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silibina/administração & dosagem , Silybum marianum/química , Silimarina/administração & dosagem , Animais , Carcinogênese/induzido quimicamente , Modelos Animais de Doenças , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/prevenção & controle , Masculino , Ratos , Ratos WistarRESUMO
Besides motor disorder, cognitive dysfunction is also common in Parkinson's disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD.
Assuntos
Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Silibina/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Memantina/uso terapêutico , Camundongos Endogâmicos C57BL , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/patologia , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Silibina/administração & dosagem , alfa-Sinucleína/metabolismoRESUMO
Components of the extracellular matrix (ECM) are overexpressed in fibrotic liver. Collagen is the main component of the liver fibrosis stroma. Here we demonstrate that chondroitin sulfate coated multilayered 50-nm nanoparticles encapsulating collagenase and silibinin (COL + SLB-MLPs) break down the dense collagen stroma, while silibinin inhibits activated hepatic stellate cells. The nanoparticles were taken up to a much greater extent by hepatic stellate cells than by normal hepatocytes, and they down-regulated production of type I collagen. In addition, chondroitin sulfate protected the collagenase from premature deactivation. COL + SLB-MLPs were delivered to the cirrhotic liver, and the collagenase and silibinin synergistically inhibited fibrosis in mice. Immunofluorescence staining of liver tissues revealed that CD44, mediated by chondroitin sulfate, delivered the nanoparticles to hepatic stellate cells. This strategy holds promise for degrading extracellular stroma and thereby facilitating drug penetration into fibrotic liver and related diseases such as liver cirrhosis and liver cancer.
Assuntos
Sulfatos de Condroitina/química , Sulfatos de Condroitina/metabolismo , Colagenases/química , Colagenases/farmacologia , Cirrose Hepática/tratamento farmacológico , Nanopartículas/química , Silibina/química , Silibina/farmacologia , Animais , Cápsulas/química , Linhagem Celular , Sulfatos de Condroitina/administração & dosagem , Colagenases/administração & dosagem , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/patologia , Camundongos , Nanopartículas/uso terapêutico , Silibina/administração & dosagemRESUMO
OBJECTIVES: We investigated the positive effect of silibinin after IV administration as silibinin-hydroxypropyl-ß-cyclodextrin lyophilized product, by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases-2. METHODS: 63 Wistar rats of age 13.24±4.40 weeks underwent ischemia/reperfusion (I/R) injury of the liver. The animals were randomized into three groups: Sham (S; n = 7); Control (C; n-28); silibinin (Si; n-28). The C and Si groups underwent 45 min ischemia. Si received silibinin-hydroxypropyl-ß-cyclodextrin intravenously immediately before reperfusion at a dose of 5 mg/kg. Both groups were further divided into 4 subgroups, based on euthanasia time (i.e., 60, 120, 180 and 240 min). KEY FINDINGS: qRT-PCR results confirmed the statistically significant reduction of the expression of the pro-inflammatory factors at 240 min after I/R injury (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases (matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) and the increase of tissue inhibitor of matrix metalloproteinases-2 in liver tissue in the Si group. Moreover, results of immunohistochemistry levels confirmed that at 240 min pro-inflammatory factors (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases ( matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) had a statistically significantly lower expression in the Si group while tissue inhibitor of matrix metalloproteinases-2 had a higher expression. CONCLUSIONS: Silibinin may have a beneficial effect on the protection of the liver.
Assuntos
Isquemia/metabolismo , Hepatopatias/metabolismo , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/metabolismo , Silibina/química , Silimarina/química , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quimiocina CCL2/metabolismo , Liofilização , Inflamação/metabolismo , Isquemia/tratamento farmacológico , Isquemia/patologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/tratamento farmacológico , Hepatopatias/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Distribuição Aleatória , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Silibina/administração & dosagem , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIMS: Silibinin offers potential anticancer effect with less aqueous solubility and high permeability. The present study aimed to develop biocompatible magnetic-core-based nanopolymeric carriers of poly (D, l-lactide-co-glycolic) acid (PLGA) encapsulated silibinin for the sustained release action on renal cancerous cell. MAIN METHODS: The synthesized iron oxide nanoparticles were prepared by precipitation method via encapsulation of silibinin in PLGA network using double emulsion method. The nanoparticle formulations were characterized for morphological, physicochemical properties (HRTEM, FTIR, Raman Spectroscopy and VSM), in vitro drug release and cytotoxicity study on kidney cancer cells (A-498). The safety of magnetic-core-based silibinin nanopolymeric carriers was conducted by i.v. administration at a dose of 50 mg/kg in mice. KEY FINDINGS: The mean particle size, zeta potential and % encapsulation efficiency of magnetic-core-based silibinin nanopolymeric carriers were found to be 285.9 ± 0.28 nm, -14.71 ± 0.15 mV and 84.76 ± 1.29%, respectively. The saturation magnetization of magnetic core and optimized nanoparticles were reported as 36.35 emu/g and 12.78 emu/g, respectively. HRTEM analyses revealed the spherical shapes of the particles with uniform size distribution. The in vitro release profile of silibinin from the nanoparticles exhibited a sustained delivery for 15 days and displayed better cytotoxicity against human kidney cancer cells (A-498) than silibinin. In vivo study showed the safety of magnetic-core-based silibinin nanopolymeric carriers in mice. SIGNIFICANCE: The magnetic-core-based silibinin nanopolymeric carriers will act as a potential carrier for targeted transportation of actives in cancer therapy.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Portadores de Fármacos , Neoplasias Renais/tratamento farmacológico , Nanopartículas de Magnetita , Silibina/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos adversos , Humanos , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/efeitos adversos , Silibina/administração & dosagem , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral RamanRESUMO
The coexistence of HBV infection and hepatic steatosis is a novel characteristic of liver disease. Silibinin capsules (SC) is a silybin-phospholipid complex containing silybin as the bioactive component, which exerts a remarkable biological effect on various liver diseases, including nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to investigate (1) the prevalence of hepatic steatosis in the general population and patients with chronic hepatitis B (CHB) and (2) to evaluate the effect of SC combined with therapeutic lifestyle changes (TLC) compared with TLC alone on hepatic steatosis in patients with CHB. A total of 16,451 individuals underwent transient elastography (TE) with the control attenuation parameter (CAP) measurement, among which the prevalence of hepatic steatosis was 31.1% in patients with CHB and 42.2% in the general population. The prevalence of hepatic steatosis differed between patients with CHB and the general population at an age of 40 years or older but was similar in individuals aged 39 years or younger (p < 0.05). Furthermore, in patients with CHB presenting hepatic steatosis, the post-6-month relative reduction in CAP in the SC combined with TLC group (p = 0.001) was significantly greater than in the TLC alone group (p = 0.183). The CAP distribution of different steatosis grades (S1, S2, and S3) in the SC combined with TLC group was decreased and S0 (CAP < 248 dB/m) increased significantly, but not significant in the TLC group. Thus, SC combined with TLC may effectively improve hepatic steatosis in patients with CHB.
Assuntos
Cápsulas/administração & dosagem , Fígado Gorduroso/terapia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/complicações , Estilo de Vida , Índice de Gravidade de Doença , Silibina/administração & dosagem , Adulto , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Substâncias Protetoras/administração & dosagem , Curva ROC , Estudos RetrospectivosRESUMO
PURPOSE: The objective of this study was to develop silibinin-loaded hydrogel for skin protection against UVB damage. METHOD: 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. RESULTS: 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. CONCLUSION: 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.
Assuntos
Quitosana/química , Polissacarídeos/química , Silibina/administração & dosagem , Raios Ultravioleta/efeitos adversos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Preparações de Ação Retardada , Feminino , Hidrogéis , Peróxido de Hidrogênio/metabolismo , Inflamação/prevenção & controle , Camundongos , Camundongos Pelados , Silibina/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiaçãoRESUMO
BACKGROUND/AIM: Advanced ovarian clear-cell carcinoma (CCC) fails to respond to standard chemotherapy, and has a poor prognosis. Since hypoxia-inducible factor-1 (HIF-1) stimulates various genes involved in cancer, we aimed to examine the efficacy of silibinin, an active component of milk thistle belonging to Asteraceae, in suppressing HIF-1 activity, and elucidate the underlying mechanism in human CCC cell lines. MATERIALS AND METHODS: Human ovarian CCC cell lines HAC-2, OVISE, and RMG-1 were treated with 500 µM silibinin for 4 h under normoxic and hypoxic conditions. Using DNA microarray, we analysed genes whose expression modulated more than 2-fold in response to hypoxia, whereas HIF-1α expression was measured using ELISA. RESULTS: Silibinin treatment decreased HIF-1α protein in all cell lines, and eIF4E2 and RPS6 mRNA in HAC-2 and RMG-1 cells. CONCLUSION: Silibinin suppressed HIF-1α protein under hypoxic conditions in CCC cell lines and could be a potential anti-cancer drug.
Assuntos
Adenocarcinoma de Células Claras/metabolismo , Antineoplásicos Fitogênicos/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Ovarianas/metabolismo , Silibina/administração & dosagem , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Biomarcadores , Hipóxia Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: We investigated the protective effect of silibinin on rat liver and kidney after hepatic inschemia/reperfusion (I/R) injury. METHODS AND MATERIALS: Sixty three male Wistar-type rats (median age 13 weeks; average weight 314 g) were subjected to I/R injury of the liver. They were randomly divided into three groups: Sham (n = 7), Control (C, n = 28) and Silibinin (Si, n = 28). The last group received intravenously silibinin. The C and Si groups were each subdivided in four subgroups according to euthanasia times (i.e., 60, 120, 180, 240 min). We assessed expression of caspase-3 and TUNEL assay, and biochemical and histological parameters. RESULTS: At 240 min, expression of caspase-3 and TUNEL assay were statistically significantly lower in the Si compared to the C group for both liver and kidney. SGOT and SGPT were also statistically significantly lower in the Si than in the C group at all time points. Histological parameters of the liver were also improved in the Si group. CONCLUSION: Silibinin was found to exhibit a protective effect on liver and kidney after hepatic I/R injury. The present results are encouraging for further studies and future clinical application.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Silibina/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/química , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Humanos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Silibina/químicaRESUMO
OBJECTIVE: Psoriasis is an inflamed skin disorder associated with the activation of phosphorylation signals in keratinocytes, which leads to proliferation. Phosphorylation signal inhibitors, such as silibinin can inhibit cell proliferation. Unlike current psoriasis treatment approaches that are associated with dangerous side effects; natural components can introduce new trends in psoriasis treatment. The major problem in the topical treatment of psoriasis is drug localization through the psoriasis lesions. METHODS: In this study, silibinin-loaded polymeric micelles prepared and characterized for drug loading and release and ex vivo permeation through psoriatic and normal mice skin. The optimized batch was used for the treatment of psoriasis lesions in the mice model. RESULTS: The optimized batch demonstrated mean particle size 18.3 ± 2.1 nm, entrapment efficiency 75.8 ± 5.8%, and prolonged silibinin release. % Silibinin permeated through psoriatic skin after 48 treated by polymeric micelle and aqueous control was 80.35, and 92.6, respectively. Polymeric micelles increased silibinin localization in the psoriatic skin in comparison with control. In psoriatic skin after 7- 10 days treatment by silibinin- loaded polymeric micelle, there was no evidence of psoriasis and the histological evaluation showed no sign of psoriasis. Silibinin-loaded polymeric micelles reduced Psoriasis area index by more than 78% after 14 days. CONCLUSION: It seems that polymeric micelles increased the effectiveness of silibinin by drug localization into the psoriatic plaque. Topical STAT- 3inhibitors can be introduced as a new strategy in psoriasis treatment.
Assuntos
Portadores de Fármacos/química , Psoríase/tratamento farmacológico , Silibina/administração & dosagem , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Imiquimode/administração & dosagem , Imiquimode/imunologia , Camundongos , Micelas , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Psoríase/imunologia , Psoríase/patologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Silibina/farmacocinética , Pele/imunologia , Pele/metabolismo , Pele/patologia , Absorção CutâneaRESUMO
In this study, we investigated the effect of silybin on the pharmacokinetics of brexpiprazole and the underlying mechanism in rats. Two groups of animals received silybin at different doses (50 mg/kg, 25 mg/kg) for 2 weeks, while another group was given vehicle alone. After that, rats were intragastrically administrated with 2 mg/kg brexpiprazole. Then, the tail blood and liver tissues were collected from each rat at different time points. Brexpiprazole in serum was determined by an established UPLC-MS/MS assay. Finally, pharmacokinetic parameters of animals in each group were figured out. The results show that silybin remarkably changed the pharmacokinetic properties of brexpiprazole, especially at the highest dose. AUC and Cmax in the combination group with 50 mg/kg silybin were enhanced approximately 4 times as much as after a single dose of brexpiprazole, p < 0.05. Meanwhile, total liver protein of each sample was extracted, and was subjected to immunoblotting assay for probing CYP3A4 and CYP2D6. Therein CYP3A4 was significantly downregulated compared to the control group. Overall, silybin can increase blood concentration of brexpiprazole in rat by downregulating its main metabolic enzyme CYP3A4. Therefore, the maintenance dose of brexpiprazole should be decreased while co-treating with silybin.