silibinin
در نشریات گروه پزشکی-
مجله علمی دانشگاه علوم پزشکی کردستان، سال بیست و نهم شماره 6 (پیاپی 135، بهمن و اسفند 1403)، صص 1 -12زمینه و هدف
سرطان کولورکتال یکی از سرطان های رایج در دنیا است که سالانه باعث مرگ ومیر زیادی در جهان می شود. داروی 5-فلوئورواوراسیل به عنوان خط اول درمان در این نوع سرطان است. مقاومت به این دارو و عوارض جانبی متعددش از نقاط ضعف این دارو به حساب می آید. سیلیبینین جزء فعال زیستی اصلی سیلیمارین است و از گیاه خار مریم استخراج می شود، مخلوطی از پلی فلاونوئیدها است و به طور سنتی به عنوان یک عامل ضد کبدی استفاده می شود. در سال های اخیر اثرات ضد توموری سیلیبینین در رده های مختلف سلول های سرطانی گزارش شده است. مطالعه حاضر با هدف بررسی اثرات سیتوتوکسیک سیلیبینین در ترکیب با 5-فلوئورواوراسیل بر روی زنده ماندن سلولی و بیان P53 در رده سلولی سرطان کولورکتال HT29 انجام شد.
مواد و روش هابقای سلولی سلول های HT29 با روش MTT پس از 48 ساعت تیمار با غلظت های مختلف سیلیبینین و 5-فلوئورواوراسیل به تنهایی و به صورت ترکیبی ارزیابی شد. میزان بیان پروتئین P53 با روش وسترن بلات اندازه گیری شد.
نتایجسیلیبینین و 5-فلوئورواوراسیل به صورت وابسته به دوز توانستند بقای سلولی HT29 را به طور معنی داری مهار کنند. استفاده هم زمان از تیمار سیلیبینین و 5-فلوئورواوراسیل نشان داد که سیلیبینین اثرات سیتوتوکسیک 5-فلوئورواوراسیل را تقویت می کند. همچنین سیلیبینین در غلظت100 میکرو گرم بر میلی لیتر، باعث تشدید در اثرات غلظت 100 میکرومولار 5-فلوئورواوراسیل بر روی میزان بیان پروتئین P53 شد.
نتیجه گیریاین مطالعه نشان داد که ترکیب سیلیبینین - 5-فلوئورواوراسیل ممکن است کاندیدای ارزشمند برای بیماران مبتلا به سرطان کولورکتال باشد؛ البته برای نتیجه گیری قطعی مطالعات بیشتری لازم است.
کلید واژگان: سرطان کولورکتال، سیلیبینین، 5-فلوئورواوراسیل، پروتئین P53، رده سلولی HT2Background and AimColorectal cancer is one of the most common types of cancer in the world, causing many deaths worldwide each year. 5-Fluorouracil is the first choice for the treatment of this type of cancer. Drug resistance and its many side effects are among the weaknesses of this drug. Silibinin, the main bioactive component of silymarin, is originally extracted from Silybum marianum, which is commonly used as an anti-hepatic agent. In recent years, the anticancer effect of silibinin has been observed on different cancer cells. This study aimed to investigate the combined cytotoxic effects of silibinin and 5-fluorouracil on cell viability and p53 expression in the colon cancer HT29 cell line.
Material and MethodsSurvival of HT29 cells was evaluated by the MTT method after 48 hours of treatment with different concentrations of silibinin and 5 fluorouracil alone and in combination. The expression level of the P53 protein was measured by Western blot method.
ResultsSilibinin and 5-fluorouracil significantly inhibited HT29 cell survival in a dose-dependent manner. The simultaneous use of silibinin and 5-fluorouracil showed that silibinin enhances the cytotoxic effects of 5-fluorouracil. In addition, 100 μg/ml silibinin enhanced the impact of 100 μM 5-fluorouracil on P53 protein expression.
ConclusionThis study suggested that silibinin-5-fluorouracil combination may be a valuable candidate for colon cancer patients. Of course, further studies are needed to reach definitive conclusion.
Keywords: Colorectal Cancer, Silibinin, 5-Fluorouracil, P53 Protein, HT29 Cell Line -
Objectives
Liver ischemia-reperfusion (I/R) is the director’s origin of damages in various clinical situations, especially surgery and transplantation. Inflammatory damages are critical because of the chronicity of I/R injuries (I/RI). The hepatoprotective and antiinflammatory properties of silibinin have been reported in different studies. This study aimed to investigate the effect of Silibinin on the expression of the pannexin-1 (Panx1) gene during hepatic I/R.
Materials and MethodsIn this case-control animal study, a total of 32 male Wistar rats (n=8 in each) were surveyed. The animals were randomly assigned into four equal groups as follows: Group 1 (Control): the rats underwent a midline laparotomy with normal saline injection; Group 2 (SILI): the rats received Silibinin (50 mg/kg) after laparotomy; Group 3 (I/R): the rats underwent I/R surgery and received normal saline; and Group 4 (I/R+SILI): the rats received silibinin before ischemia and directly following reperfusion. Blood and liver tissue samples were taken after three hours of reperfusion aftermath 1-hour ischemia to evaluate histological changes, gene expression, and serum markers of hepatic injury.
ResultsWhile the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the I/R group significantly increased compared to the control group (P<0.001), they significantly decreased in the SILI+I/R group (P<0.001). Silibinin ameliorated inflammatory impairments of liver tissue, such as neutrophil and macrophage infiltration and activation, hepatocyte degeneration and vacuolation, hepatic vascular endothelial damage, and sinusoid proliferation in the I/R group. The expression of the Panx1 mRNA during I/R significantly increased compared to the control group (P<0.001), but silibinin reduced the expression (P<0.001).
ConclusionsWe witnessed that silibinin reduced liver tissue damages during hepatic I/R. Correcting the expression of the Panx1 gene during I/R is probably one of the mechanisms of anti-inflammatory effects of silibinin.
Keywords: Ischemia, Pannexin-1, Reperfusion, Silibinin -
International Journal of Hematology-Oncology and Stem Cell Research, Volume:18 Issue: 2, Apr 2024, PP 174 -182Background
Triple-negative breast cancer (TNBC) with a poor prognosis and survival is the most invasive subtype of breast cancer. Usually, TNBC requires a chemotherapy regimen at all stages, but chemotherapy drugs have shown many side effects. We assumed that combination therapy of vinblastine and silibinin might reduce the vinblastine toxicity and dose of vinblastine.
Materials and MethodsThe MDA-MB-231 were cells subjected to MTT assay for IC50 determination and combination effects, which were measured based on Chou-Talalay's method. The type of cell death was determined by using a Flow-cytometric assay. Cell death pathway markers, including Bcl-2, Bax, and caspase-3 were analyzed by western blot and Real-Time PCR.
ResultsThe treatment of MDA-MB-231 cells exhibited IC50 and synergism at the combination of 30 µM of silibinin and 4 µm of vinblastine in cell viability assay (CI=0.69). YO-PRO-1/PI double staining results showed a significant induction of apoptosis when MDA-MB-231 cells were treated with a silibinin and vinblastine combination (p<0.01). Protein levels of Bax and cleaved caspase-3 were significantly upregulated, and Bcl-2 downregulated significantly. Significant upregulation of Bax (2.96-fold) and caspase-3 (3.46-fold) while Bcl-2 was downregulated by 2-fold.
ConclusionFindings established a preclinical rationale for the combination of silibinin and vinblastine. This combination produces synergistic effects in MDA-MB-231 cells by altering pro- and anti-apoptotic genes, which may reduce the toxicity and side effects of vinblastine.
Keywords: Vinblastine, Silibinin, Drug combination, Triple negative breast cancer (TNBC), Apoptosis -
Objective
Silibinin has exhibited antitumor activities. However, there are few reports about the immunomodulatory properties of silibinin on T lymphocyte function in the tumor microenvironment. Here, we determined the effects of silibinin on T cells of peripheral blood mononuclear cells (PBMCs), cultivated alone or with a human cell line of glioblastoma (U-87 MG).
Materials and MethodsThe proliferation of T lymphocytes was assessed by MTT test in the presence of silibinin (15 and 45 µM). Also, total antioxidant capacity (TAC), the activity of superoxide dismutase-3 (SOD3), and the levels of two cytokines interferon gamma (IFN-γ) and tumor growth beta (TGF-β) were compared between treated and untreated PBMCs alone or co-cultured with U-87 cells.
ResultsAccording to our results, silibinin raised the TAC levels and SOD3 activity in the PBMCs and in the co-culture condition. Moreover, silibinin-treated PBMCs showed higher IFN-γ levels and lower TGF-β levels. Interestingly, silibinin protected PBMCs against the U-87-induced suppression.
ConclusionAltogether, these results proposed the immunomodulatory potential of silibinin on T cells of PBMCs, as well as its partially protective effects on PBMCs against the suppression induced by U-87 MG cells.
Keywords: Silibinin, Glioblastoma, IFN-γ, TGF-β, Peripheral blood mononuclear cells (PBMCs) -
According to availability of natural products, lower cost and less toxic effects compared to synthetic drugs make them an easy and excellent choice in the treatment of diseases. Silymarin “milk thistle” has been used for many years. Silymarin has antioxidant, anti-lipid peroxidation, anti-fibrotic, anti-inflammatory, and immunomodulatory properties. These effects are due to the addition of endogenous antioxidant enzymes, inhibition of neutrophil infiltration, and a reduction in serum malondialdehyde as an end product of myocardial lipid peroxide. The antioxidant and anti-inflammatory properties of silymarin may also have a protective role against carcinogens. Studies have shown that Silymaran can have protective effects against hepatotoxicity, nephrotoxicity and cardiotoxicity caused by chemical agents. A notable feature is the prowess of silymarin in shielding against reperfusion injury and inflammation, sustained by its unwavering support of anti-inflammatory and antioxidant functions .This review provides a comprehensive survey of the potentials of silymarin in cardio-protection, nephroprotection, and hepatoprotection.
Keywords: Silymarin, Silibinin, Cardiovascular Diseases, Cardiotoxicity, Nephrotoxicity, Hepatotoxicity -
Background
Silibinin, an herbal polyphenolic flavonolignan, has antioxidant and anticancer properties.
ObjectivesThis study aimed to evaluate some cellular and molecular effects of silibinin on the human ovarian cancer SKOV-3 cell line.
MethodsFor cytotoxicity investigations of silibinin, MTT assay was used at 24, 48, and 72 hours. Apoptosis and cell cycle were studied by flow cytometry. The effect of silibinin on mRNA expression of B-cell lymphoma 2 (Bcl-2), cyclin E, and S-phase kinase-associated protein 2 (SKP2) was determined by Quantitative reverse transcription polymerase chain reaction (QRT-PCR).
ResultsSilibinin administration in lower concentrations (12.5 and 25 µg/mL) did not lead to significant (P < 0.05) changes in cell viability and even slightly increased cell growth after 72 hours. However, silibinin in higher concentrations (≥ 50µg/mL) inhibited SKOV-3 cell proliferation in a dose- and time-dependent manner. The mode of cell growth inhibition was apoptosis induction and G2/M cell cycle arrest. Silibinin caused down-regulation of the anti-apoptotic gene, namely Bcl-2. Additionally, silibinin resulted in down-regulation of the major genes in the cell cycle, including cyclin E and SKP2.
ConclusionsOverall, this study confirmed the ability of silibinin to suppress ovarian cancer progression through the induction of apoptosis and inhibition of G2/M phase transition. Silibinin may be considered an efficient and safe herbal medication for ovarian cancer.
Keywords: Silibinin, SKOV-3, Apoptosis, Cell Cycle, Bcl-2, Cyclin E, SKP2 -
Objective
Almost all diseases of the nervous system are related to neuroinflammation, oxidative stress, neuronal death, glia activation, and increased pro-inflammatory cytokines. Cognitive disorders are one of the common complications of nervous system diseases. The role of some plant compounds in reducing or preventing cognitive disorders has been determined. Silibinin is a plant bioflavonoid and exhibits various effects on cognitive functions. This article discusses the different mechanisms of the effect of silibinin on cognitive disorders in experimental studies.
Materials and MethodsDatabases, including ISI, , Google Scholar, Scopus, Medline and PubMed, were investigated from 2000 to 2021, using related keywords to find required articles.
ResultsSilibinin can improve cognitive disorders by different pathways such as reducing neuroinflammation and oxidative stress, activation of reactive oxygen species- Brain-derived neurotrophic factor- Tropomyosin receptor kinase B (ROS–BDNF–TrkB) pathway in the hippocampus, an increase of dendritic spines in the brain, inhibition of hyperphosphorylation of tau protein and increasing the expression of insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R), inhibiting inflammatory responses and oxidative stress in the hippocampus and amygdala, and decrease of Homovanillic acid/Dopamine (HVA/DA) ratio and 3,4-Dihydroxyphenylacetic acid + Homovanillic acid/Dopamine (DOPAC+ HVA/DA) ratio in the prefrontal cortex and 5-hydroxyindoleacetic acid/5-hydroxytryptamine (5-HIAA/5-HT) ratio in the hippocampus.
ConclusionThese results suggest that silibinin can be considered a therapeutic agent for the symptom reduction of cognitive disorders, and it acts by affecting various mechanisms such as inflammation, programmed cell death, and oxidative stress.
Keywords: Silibinin, Cognitive disorders, Neuroinflammation, Oxidative stress -
زمینه و هدف
سیلیبینین به عنوان یک آنتی اکسیدان قوی برای پیشگیری و درمان اختلالات التهابی پوست استفاده می شود. هدف از این پژوهش ساخت فرمولاسیون لیپوزومال سیلیبینین جهت افزایش زیست فراهمی و حلالیت این ماده در آب و همچنین کنترل کنتیک رهایش آن با هدف بهبود روند درمان آسیب های پوستی می باشد.
روش بررسیلیپوزوم حاوی سیلیبینین به روش فیلم نازک تهیه گردید. میزان بارگذاری و کنتیک رهایش دارو با استفاده از خوانش جذب دارو در طول موج مناسب مورد بررسی قرار گرفت. اندازه ذرات و بار سطحی (پتانسیل زتا) نانوسامانه ها با استفاده از تکنیک پراکندگی نور پویا (DLS) تعیین گردید. مورفولوژی نانوذرات لیپیدی با استفاده از میکروسکوپ الکترونی روبشی (SEM) مشخص گردید. سمیت سلولی با روش MTT بر روی سلول های فیبرولاست پوستی انسان بررسی گردید. نتایج بدست آمده با استفاده از نرم افزار SPSS نسخه 18 و آزمون آنالیز واریانس یک طرفه (ANOVA) تجزیه و تحلیل شد.
یافته هااندازه ذرات و پتانسیل زتای نانوذرات لیپوزومال حاوی سیلیبینین در فرمولاسیون بهینه به ترتیب9/07±112 نانومتر و 2/2± 14/5- میلی ولت بود. میزان انکپسوله شده سیلیبینین در لیپوزوم 5/3±84 % و میزان رهایش جمعی دارو در دمای 37 درجه سانتی گراد در مدت زمان 48 ساعت 4/98± 67/3% بود. همچنین نتایج ارزیابی سمیت سلولی نشان داد که هم سیلیبینین به تنهایی و هم لیپوزوم های حاوی سیلیبینین بر روی سلول های سالم فیبروبلاست انسانی اثرات سمی نداشته اند. علاوه بر آن، سیلیبینین در حالت انکپسوله نسبت به حالت آزاد در افزایش رشد سلول های سالم فیبروبلاستی تاثیر گذار بوده است.
نتیجه گیرینتایج بدست آمده نشان می دهد فرمولاسیون نانولیپوزومال سیلیبیین می تواند به عنوان یک نانوداروی حاوی ماده موثره گیاهی برای تسریع بهبود زخم های پوستی به کار روند.
کلید واژگان: دارورسانی پوستی، سیلیبینین، لیپوزوم، ترمیم زخمBackground and ObjectivesThis study aimed to develop a liposomal silibinin formulation that would reduce healing time and improve wound healing.
MethodsA thin film method was used to prepare liposomal silibinin. They were characterized for their size, ζ-potential, drug encapsulation efficiency, and silibinin release kinetics in vitro. By using a scanning electron microscope, lipid nanoparticle morphology was determined. A MTT assay was then used to determine the cytotoxicity of liposomal silibinin for human skin fibroblasts. SPSS version 18 software was used to analyze the results using one-way analysis of variance (ANOVA).
ResultsThe optimized liposomal silibinin with a size of 112 ± 9.07 nm, and ζ-potential value of -14.5 ± 2.2 mV exhibited a high silibinin encapsulation efficiency (84± 5.3%). Results of the MTT assay indicated that the liposomal silibinin formulation does not have cytotoxicity besides they promote the growth of fibroblast cells.
ConclusionLiposomal silibinin promotes the therapeutic effect of silibinin for wound healing.
Keywords: Liposome, Silibinin, Topical drug delivery, Wound healing -
Objective(s)Alzheimer’s disease (AD), the most common cause of dementia, is one of the leading causes of morbidity and death in the world. Currently, treatment mostly used to slow down the disease progression. Herbal remedies are considered by many in the community as a natural and safe treatment with fewer side effects. Silibinin, the active ingredient of Silybum marionum, has anti-oxidant, neurotrophic and neuroprotective characteristics. Therefore, here, the effect of different doses of Silibinin extract on oxidative stress and expression of neurotrophic factors was investigated.Materials and MethodsForty eight male Wistar rats were randomly divided into sham, lesion; Aβ1-40 injection, lesion-treatment; Aβ1-40 injection followed by different doses of silibinin (50, 100, 200 mg / kg) through gavage and lesion-vehicle group; Aβ1-40 injection + vehicle of silibinin. Morris water Maze (MWM) was done 28 days after the last treatment. Hippocampal tissue was removed for biochemical analysis. Production of nitric oxide (NO) and reactive oxygen species (ROS), expression of BDNF/VEGF and cell viability were measured using Griess, fluorimetry, Western blotting and MTT techniques.ResultsDifferent concentrations of silibinin improved behavioral performance in animals. Higher doses of Silibinin could improve memory and learning function through MWM. Also, increasing the concentration of silibinin resulted in decreased ROS and NO production in a dose-dependent manner.ConclusionConsequently, silibinin may act as a potential candidate for alleviating symptoms of AD.Keywords: Alzheimer’s disease, amyloid, BDNF, Oxidative stress, Silibinin, VEGF
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Background
Colorectal Cancer (CRC) is the most common malignant gastrointestinal cancer. Cancer stem cells (CSCs) are the major cause of cancer recurrenceand cancer drug resistance. Silibinin, as an herbal compound, has anticancer properties.
ObjectivesThe present study aimed to evaluate the antiproliferative effects of silibinin on HT29 stem-like cells (spheroids).
MethodsIn this study, antiproliferative and apoptotic properties of Silibinin encapsulated in Polymersome Nanoparticles (SPNs) were evaluated by MTT assay, propidium iodide(PI)/AnnexinV assay, cell cycle analysis, and DAPI (4',6-diamidino-2-phenylindole) staining. The expression of some miRNAs and their potential targets was evaluated by real-time reverse transcription-polymerase chain reaction (qRT-PCR).
ResultsIC50 of SPNs was determined at 28.13±0.78μg/ml after 24 h. SPNs (28μg/ml) induced apoptosis by 32.36% in HT29 cells after 24 h. DAPI staining indicated a decrease instained nuclei after SPNs induction.SPNs treatment increased the expression of miR-34a, as well as P53, BAX, CASP9, CASP3, and CASP8. The downregulation of miR-221 and miR-222 was observed in SPNs treated cells. Moreover, SPNs decrease the expression level of CD markers inHT29 spheroids (cancer stem cells) compared to untreated spheroids.Spheroids were completely destroyed after 72 h treatment with SPNs (28μg/ml).
ConclusionAs evidenced by the obtained results, SPNs can be used as an effective anticancer agent in multi-layer (cancer stem cells) and mono-layer cancerous cells with the upregulation of tumor suppressive miRs and genes, as well as downregulation of oncomiRs and oncogenes.
Keywords: Cancer stem cells, miR-34a, miR-221, 222, Silibinin, SPNs -
Introduction
Silibinin is a natural flavonoid compound known to induce apoptosis in cancer cells. Despite silibinin's safety and efficacy as an anticancer drug, its effects on inducing immunogenic cell death (ICD) are largely unknown. Herein, we have evaluated the stimulating effects of silibinin on ICD in cancer cells treated with silibinin alone or in combination with chemotherapy.
MethodsThe anticancer effect of silibinin, alone or in combination with doxorubicin or oxaliplatin (OXP), was assessed using the MTT assay. Compusyn software was used to analyze the combination therapy data. Western blotting was conducted to examine the level of STAT3 activity. Flow cytometry was used to analyze calreticulin (CRT) and apoptosis. The heat shock protein (HSP70), high mobility group box protein1 (HMGB1), and IL-12 levels were assessed by ELISA.
ResultsCompared to the negative control groups, silibinin induced ICD in CT26 and B16F10 cells and significantly enhanced the induction of this type of cell death by doxorubicin, and these changes were allied with substantial increases in the level of damage-associated molecular patterns (DAMPs) including CRT, HSP70, and HMGB1. Furthermore, conditioned media from cancer cells exposed to silibinin and doxorubicin was found to stimulate IL-12 secretion in dendritic cells (DCs), suggesting the link of this treatment with the induction of Th1 response. Silibinin did not augment the ICD response induced by OXP.
ConclusionOur findings showed that silibinin can induce ICD and it potentiates the induction of this type of cell death induced by chemotherapy in cancer cells.
Keywords: Immunotherapy, Combination therapy, DAMPs, Silibinin, Th1 response -
Background
This study aimed to investigate the radioprotective effect of liposomal silibinin (Lip-SIL) on human lymphocytes in the treatment of non-small lung cancer cells using a combined method of cell viability assay and cytokinesis-block micronucleus assay for a better evaluation of whether one active compound is suitable to be used as a radioprotector in radiotherapy or not.
Materials and MethodsFirstly, Lip-SIL was prepared by the lipid film hydration method combined with sonication. Secondly, penetration of Lip-SIL into cells was observed by fluorescence microscopy. Finally, the potential application of Lip-SIL as a radioprotector of human lymphocytes in the treatment of non-small cell lung cancer was evaluated using the above combined method with A549 cell line as a model.
ResultsThe successfully prepared Lip-SIL had a spherical shape and good physical characteristics (particle size of approximately 83.9 nm, zeta potential of -20.6 mV, encapsulation efficiency of 28.8 % and payload of 5.1 %). At a SIL concentration of 10 µg/mL, Lip-SIL exhibited the highest radioprotection for lymphocytes, but showed no radioprotection or even increased genotoxicity in human lung cancer A549 cells.
ConclusionLip-SIL is a potential protector of human lymphocytes during radiotherapy in the treatment of non-small lung cancer. Moreover, the results of this study also imply that the radioprotection ability of bioactive compounds for normal cells is not only based on their scavenging activity on reactive oxygen species (ROS) but also on their mechanisms of intracellular activations.
Keywords: Liposomes, lung cancer, radioprotection, radiotherapy, silibinin -
Objective (s)
Signal transduction of mitogen-activated protein kinases (MAPKs) is activated during ischemia. In this study, c-Jun N-terminal Kinase (JNK) and p38 MAPK (p38) gene and protein expression were evaluated as two members of the MAPK family during liver ischemia-reperfusion in rats.
Materials and MethodsThirty-two male Wistar rats were divided into four groups of eight: Vehicle, ischemia-reperfusion (IR), ischemia-reperfusion+silibinin (IR+SILI), and SILI. The IR and IR+SILI groups differed from the other two groups in that they underwent one hour of ischemia followed by three hr of reperfusion. The Vehicle and IR groups received normal saline while the SILI and IR+SILI groups were treated with silibinin (50 mg/kg). At the end of the reperfusion time, blood and ischemic liver tissue were collected for further experiments.
ResultsThe expression of JNK and p38 gene, the amount of serum hepatic injury indices, and malondialdehyde (MDA) in the IR group increased significantly compared with the vehicle group. The JNK and p38 gene expression decreased significantly in the IR + SILI group compared with the IR group. Glutathione peroxidase (GPx) and total antioxidant capacity (TAC) levels decreased in the IR group while increasing in the IR+SILI group. Histological examination showed that silibinin significantly reduced the severity of hepatocyte degradation. Western blot results were completely consistent with real-time PCR results.
ConclusionThe possible pathways of the protective effect of silibinin against hepatic ischemia damages is to reduce the expression of the p38 and JNK gene and protein.
Keywords: Ischemia, JNK, p38, Reperfusion, Silibinin -
Biolmpacts, Volume:12 Issue: 5, Sep 2022, PP 415 -429Introduction
Malignant breast cancer (BC) frequently contains a rare population of cells called cancer stem cells which underlie tumor relapse and metastasis, and targeting these cells may improve treatment options and outcomes for patients with BC. The aim of the present study was to determine the effect of silibinin on the self-renewal capacity, tumorgenicity, and metastatic potential of mammospheres.
MethodsThe effect of silibinin on viability and proliferation of MCF-7, MDA-MB-231 mammospheres, and MDA-MB-468 cell aggregation was determined after 72-120 hours of treatment. Colony and sphere formation ability, and the expression of stemness, differentiation, and epithelial-mesenchymal-transition (EMT)-associated genes were assessed by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in mammospheres treated with an IC50 dose of silibinin. Additionally, the antitumor capacity of silibinin was assessed in vivo, in mice.
ResultsThe results of the present study showed that silibinin decreased the viability of all mammospheres derived from MCF-7, MDA-MB-231, and MDA-MB-468 cell aggregation in a dose-dependent manner. Colony and sphere-forming ability, as well as the expression of genes associated with EMT were reduced in mammospheres treated with silibinin. Additionally, the expression of genes associated with stemness and metastasis was also decreased and the expression of genes associated with differentiation were increased. Intra-tumoral injection of 2 mg/kg silibinin decreased tumor volumes in mice by 2.8 fold.
ConclusionThe present study demonstrated that silibinin may have exerted its anti-tumor effects in BC by targeting the BC stem cells, reducing the tumorgenicity and metastasis. Therefore, silibinin may be a potential adjuvant for treatment of BC.
Keywords: Breast cancer stem cells, Silibinin, Mammospheres, Epithelial to mesenchymal transition -
مقدمه
فیبروز کبدی، یک بیماری مزمن است که در اثر عفونت های ویروسی (مانند ویروس هپاتیت B و C)، سوء مصرف الکل و اختلالات متابولیکی و ژنتیکی ایجاد می شود و منجر به تجمع بیش از حد پروتیین های ماتریکس خارج سلولی از جمله کلاژن می شود. پیشرفت فیبروز کبدی می تواند باعث سیروز و سرطان کبد شود. در این مطالعه به بررسی نقش سیلیبینین در جلوگیری از پیشرفت بیماری فیبروز کبدی پرداخته شده است.
روش هاسلول های LX2 در محیط کشت DMEM همراه با 10 درصد از (Fetal bovine serum) FBS کشت داده شدند. در مرحله ی اول، تیمار سلول ها با TGF-β با غلظتng/ml 2 (گروه فیبروتیک) به منظور آسیب سلولی و ایجاد شرایط فیبروتیک به مدت 24 ساعت انجام شد. سپس با غلظت های 10، 20، 40، 60 و 80 میکرومولار از سیلیبینین (گروه های درمان) به مدت 24 ساعت، تیمار شدند و میزان بیان mRNA ژن های αSMA، collagen1α، NOX1 و NOX2 و میزان تولید (Reactive oxygen species) ROS درون سلولی مورد سنجش قرار گرفت.
یافته هانتایج نشان داد که میزان بیان mRNA ژن هایαSMA ، collagen1α، NOX1 و NOX2 در غلظت های 60 و 80 میکرومولار سیلیبینین نسبت به گروه فیبروتیک به صورت معنی داری کاهش یافت. همچنین میزان تولید ROS درون سلولی در غلظت های 60 و80 میکرومولار از سیلیبینین نسب به گروه فیبروتیک کاهش معنی داری پیدا کرد (0/05 > P).
نتیجه گیریبر اساس مطالعه ی ما، سیلیبینین با کاهش بیان ژن های درگیر در پیشرفت فیبروز کبدی، باعث مهار فعال شدن (HSCs) Hepatic stellate cells و کاهش آسیب کبدی ناشی از تولید فراوان کلاژن و گونه های فعال اکسیژن در شرایط آزمایشگاهی شد. این نتایج شواهدی را نشان می دهد که سیلیبینین ممکن است یک عامل جذاب برای درمان فیبروز کبد باشد.
کلید واژگان: فیبروزکبدی، سیلیبینین، گونه های فعال اکسیژن، Transforming growth factor betaBackgroundLiver fibrosis is a chronic disease caused by viral infections (such as hepatitis B and C viruses), alcohol abuse, and metabolic and genetic disorders that leads to excessive accumulation of extracellular matrix proteins, including collagen. The progression of liver fibrosis can leads to cirrhosis and liver cancer. In this study, the role of silibinin in the prevention of liver fibrosis progression was investigated.
MethodsLX2 cells were cultured in DMEM medium with 10% Fetal Bovine Serum (FBS). In the first stage, cells were treated with TGF-β at a concentration of 2 ng / ml (fibrotic group) for cell damage and fibrotic conditions for 24 hours, then at concentrations of 10, 20, 40, 60 and 80 μM of silibinin (The treatment groups) were treated for 24 hours and the mRNA expression of αSMA, collagen1α, NOX1 and NOX2 genes and the rate of intracellular reactive oxygen species (ROS) production were measured.
FindingsThe results showed that the mRNA expression of αSMA, collagen1α, NOX1 and NOX2 genes at concentrations of 60 and 80 μM silibinin was significantly reduced compared to the TGF-β group. Also, the rate of intracellular ROS production at 60 and 80 μM concentrations of silibinin was significantly reduced compared to the TGF-β group (P < 0.05).
ConclusionAccording to our study, silibinin inhibits the activation of Hepatic stellate cells (HSCs) by reducing the expression of genes involved in the progression of hepatic fibrosis and reduces liver damage caused by excessive production of collagen and reactive oxygen species in vitro. The findings from this study indicate that silybinin may be a potential therapeutic agent in the treatment of liver fibrosis.
Keywords: Liver fibrosis, Silibinin, Reactive oxygen species, Transforming growth factor beta -
Introduction
Ovarian cancer is one of the deadliest genital cancers among females and mainly originates from epithelial cells. The cancer generally remains asymptomatic until metastasis. Silibinin, a derivative of Silybum marianum, is a flavonoid with anticancer effects against many tumor cells. The sortilin1 (SORT1) gene has been shown to be overexpressed in ovarian tumors. Here, we investigated the effects of silibinin on SORT1 gene expression and the viability of ovarian A2780s cancer cell line.
MethodsThe A2780s ovarian cancer cell line was treated with silibinin at the concentrations of 50, 100, and 200 μM for 24 hours, and IC50 (half-maximal inhibitory concentration) was determined. Then the viability percentage of the cells treated with 100 μM silibinin was determined at 24, 48, and 72 hours. After 24 and 48 hours exposure to 100 μM silibinin, RNA was extracted, followed by cDNA synthesis and SORT1 gene expression analysis using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the reference gene by real-time Polymerase chain reaction (PCR).
ResultsSilibinin in a dose- and time-dependent manner reduced the viability of ovarian cancer cells (P < 0.05), accompanied by a reduction in SORT1 gene expression.
ConclusionThe present study showed that silibinin had toxic effects against the A2780s ovarian cancer cell line, suggesting this compound as a potential anticancer agent.
Keywords: Ovarian cancer, A2780s, Silibinin, SORT1 -
زمینه و هدف
فیبروبلاست ها در تمام دوران زندگی قدرت ترمیم را حفظ می کنند، در تولید عوامل رشد دخالت دارند و در بین سلول های بافت همبند، ظرفیت تمایز به دیگر اعضا خانواده را دارا می باشند. فاکتور رشد شبه انسولین-1 (IGF-1)[1] در تمایز و رشد رده های سلولی مختلف، نقش مهمی دارد. سیلی بینین، فعال ترین ترکیب دانه های گیاه خار مریم است که تاثیر آن بر سلول سرطانی مطالعه شده است. در این مطالعه تاثیر سیلی بینین بر بقای سلولی و بیان ژن IGF-1 در سلول های فیبروبلاست ختنه گاه انسانی (HFF) بررسی شد.
روش کارمیزان سمیت محلول سیلی بینین در غلظت های 10، 20، 40 و 60 میکرومولار با آزمون MTT بر سلول های فیبروبلاست انسانی پس از 24 و 48 ساعت و ارزیابی میزان بیان ژن IGF-1، با آزمون Real time -PCR انجام گردید.
یافته هانیمار سیلی بینین پس از 24 ساعت در مقایسه با کنترل دارای تاثیرات سمی بر فیبروبلاست ها بود. اما پس از 48 ساعت، تفاوت نسبت به کنترل معنادار نبود. پس از 24 ساعت تیمار، در غلظت های 20 تا60 میکرومولار سیلی بینین، به طور معناداری بیان ژن IGF-1 سلول های فیبروبلاست نسبت به گروه کنترل افزایش داشت.
نتیجه گیریسیلی بینین احتمالا به صورت وابسته به غلظت باعث القای بیان ژن IGF-1 پس از تیمار 24 ساعته در سلول های فیبروبلاست می شود. در بررسی سمیت سلولی در غلظت 60 میکرومولار بیشترین مرگ سلولی بعد از 24 ساعت مشاهده شد؛ از این رو برای معرفی سیلی بینین به عنوان محرک تکثیر فیبروبلاست ها نیاز به انجام مطالعات گسترده تر می باشد.
کلید واژگان: سیلی بینین، فیبروبلاست انسانی، فاکتور رشد شبه انسولین-1IntroductionFibroblasts are involved in production of growth factors which are effective on cells’ growth and differentiation. They are the most adaptable cells in connective tissue with significant capacity for differentiation to the other cell group. Insulin-like growth factor-1 (IGF-1) plays an important role in differentiation and growth of different cell lines. Silibinin is extracted from seeds of Silybum marianum, which it's effects in cancer cell lines, have been studied in limited studies. In this study we evaluated the silibinin effect on viability and IGF-1 gene expression in human foreskin fibroblast (HFF).
Materials and MethodsThe cytotoxic effect of 10, 20, 40 & 60 µM solution of silibinin was evaluated on HFF cells using MTT assay, after 24 & 48 hours. Then, the expression of IGF-1 gene was evaluated by means of real time-PCR.
ResultsSilibinin had toxic effect on HFF cells in dose-dependent manner after 24 hours of incubation in comparison with control group but no significant difference observed after 48 hours. Besides, after 24 hours of incubation, silibinin with a concentration of 20-40-60 µM significantly increased the IGF-1 gene expression in fibroblast cells in comparison with control group.
ConclusionBased on the results, silibinin significantly induces IGF-1 gene expression in dose dependent manner after 24 hours incubation with HFF cells. However, in cytotoxicity assay, concentration of 60 µM caused the highest rate of cell death after 24 hours. So, before introduction of this compound as a fibroblasts proliferation stimulant, more extensive studies are needed.
Keywords: Silibinin, human fibroblast, insulin like growth factor-1 -
Objective(s)Recently, there is a significant focus on combination chemotherapy for cancer using a cytotoxic drug and a phytochemical compound. We investigated the effect of silibinin on etoposide-induced apoptosis in MCF-7 and MDA-MB-231 breast carcinoma cell lines.Materials and MethodsThe cytotoxic effects of silibinin and etoposide were determined using MTT assay after 24 and 48 hr incubation with these drugs individually and combined. The mRNA expression of Bax and Bcl2, and protein levels of P53, phosphorylated p53 (P-P53), and P21 were determined using real-time PCR and western blot analysis, respectively. The caspase 9 activity was measured using an ELISA kit.ResultsSilibinin and etoposide alone and combined significantly inhibit cell growth in a dose and time-dependent manner in both cell lines. The strongest synergistic effects in terms of MCF-7 cell growth inhibition [combination index (CI) = 0.066] were evident. The silibinin-etoposide combinations cause a much powerful apoptotic death (47% and 40%) compared with each compound individually in MCF-7 and MDA-MB 231 cells, respectively. Additionally, the silibinin-etoposide combinations significantly increased the expression of P53, P-P53, and P21 in MCF-7 cells. Neither silibinin nor etoposide individually increased the level of P53 and P-P53 in MDA-MB-231 cells, but both of them individually and combined increased the level of P21.ConclusionSince the silibinin-etoposide combination induces apoptosis in both cell lines with and without expression of p53, thus, it is suggested that this combination may be a successful therapeutic strategy for breast cancer regardless of P53 status.Keywords: Apoptosis, Breast Cancer, Drug synergism, Etoposide, MCF-7 cells, Silibinin
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Gastroenterology and Hepatology From Bed to Bench Journal, Volume:14 Issue: 3, Summer 2021, PP 267 -275Aim
This research examined silibinin's anti-inflammatory outcomes on the NOD-like receptor protein-3 (NLRP3) and NF-κB gene expression, which plays a notable role in inciting inflammatory pathways.
BackgroundHepatic ischemia-reperfusion (I/R) is a common phenomenon in many clinical cases, including liver surgery and transplantation. Inflammatory mediators are vital contributors to the expansion of hepatic damage after I/R injury (I/RI), and therefore, targeting inflammation is a considerable candidate for the management of hepatic I/RI and its complications.
MethodsThirty-two male Wistar rats were divided equally into four groups: 1) Control (Vehicle) group, in which rats underwent laparotomy and received normal saline; 2) SILI group, in which rats underwent laparotomy, and 30 mg/kg silibinin was injected intraperitoneal (IP); 3) I/R group, in which rats underwent I/R and received normal saline; and 4) I/R + SILI group, who encountered I/R after laparotomy and received silibinin. After one hour of ischemia and three hours of reperfusion, blood and liver tissue samples were assembled for future biochemical, histological, and gene expression studies.
ResultsIn vivo analysis attested that serum AST and ALT activities were significantly lessened by silibinin in the SILI + I/R group (p <0.001). Silibinin ameliorated inflammatory liver tissue injuries, including neutrophil and macrophage infiltration, hepatocyte degeneration, cytoplasmic vacuolation, vascular endothelial damages, and sinusoid dilation observed in the I/R group. During I/R, NLRP3 and NF-κB gene expression showed a significant increment compared to the control group (p <0.001), which could be alleviated by silibinin (p <0.01).
ConclusionThe results evidence that adjusting the expression of NLRP3 and NF-κB genes during I/R is probably one of the mechanisms of the anti-inflammatory effects of silibinin.
Keywords: Ischemia, NF-Κb, NLRP3, Reperfusion, Silibinin -
Introduction
Silibinin (silibinin A) is the most active silymarin component, which acts both as a hepatoprotective [1] and an antiviral agent. The present study investigated the silibinin effect on IFN-related innate immune genes in PBMCs from HCV-infected patients.
Method22 chronic HCV patients, including 10 IFN responders and 12 non-responders, were included. Their isolated PBMCs were treated for 6 hours in the presence of silibinin, IFN-α, or their combination. The transcription level of TLR7, ISG15, and SOCS1 genes was compared using real-time PCR.
ResultOur result showed that IFN-α induced a significant up-regulation of TLR7 and ISG15 in PBMCs of both responder and non-responder groups. Nevertheless, the SOCS1 gene was not significantly changed in the non-responder group (P=0.32). The combination of IFNα- and silibinin showed a similar pattern to IFN-α alone. By itself, silibinin did not leave a significant change on the expression level of the studied genes.
ConclusionThe results indicated that silibinin did not enhance or suppress the expression level of TLR7, ISG15, and SOCS1 genes. Therefore, it has been suggested that its anti-inflammatory role might be devoid of IFN pathways.
Keywords: HCV, Silibinin, Interferon, ISG15, SOCS1
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