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Representative AgNOR staining in liver of control and experimental group of animals at 940 of original magnification. Plates a– e represent the liver sections of groups 1–5 of experimental animals, respectively. Plate f shows the bar graph representing the number of AgNORs/nuclei in ten different fields in control and experimental groups. Results are expressed as mean ± SD (n = 6). P \ 0.05 compared with agroup1, bgroup2, cgroup4, dgroup5. Arrow shows nuclei with increased AgNORs
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Hepatocellular carcinoma (HCC) incidence rates are increasing in many parts of the world. HCC's limited treatment remedies and the poor prognosis emphasize the importance in developing an effective chemoprevention for this disease. Here, we investigated the molecular mechanisms involved in the chemoprevention of silymarin in N-nitrosodiethylamine (...
Citations
... The present study results revealed a strong positive reaction to Bax immunostaining and a faint cytoplasmic reaction to Bcl-2 antibodies in the cytoplasm of liver cells which indicates the hepatocyte apoptosis in the rat model is in line with the previously reported in different studies. A previous study used a rat model of HCC induced by DENA recorded increased cytoplasmic staining for Bcl-2 with subsequently decreased cytoplasmic staining for Bax [34], and recently, CCl4 administration was recorded to cause upregulation of pro-apoptotic protein Bax and downregulation of antiapoptotic protein Bcl-2 [26]. It was postulated later that the mitochondrial signaling pathway might be involved in CCl4-induced hepatocyte apoptosis through upregulating Bax and downregulating Bcl2 [35]. ...
... Терапевтическая активность силибинина в отношении печени объясняется стимуляцией регенерации гепатоцитов [6,7]. Антиоксидантные и гепатопротекторные свойства силибинина хорошо изучены in vitro [8][9][10]. Силибинин стабилизирует клеточные мембраны, выводит различные токсины, такие как тиоацетамид, диэтилнитрозамин, ацетаминофен и бромбензол [11]. ...
The aim of this work was to determine in vitro the effect of different classes of excipients on the solubility and membrane permeability of silibinin. Silibinin is a medicinal compound of natural origin with a wide spectrum of therapeutic activity. It is used in the treatment of cardiovas-cular diseases and a number of cancers. Despite the promising use of silibinin, it has low bioavail-ability due to the poor aqueous solubility. In this regard, the ways to increase the solubility of silibinin were examined in this work. The solubility of silibinin was determined in the presence of solubilizers of various nature (polyvinylpyrrolidone, hydroxypropyl-β-cyclodextrin, Pluronic F127 and sodium dodecyl sulfate). It was found that Pluronic F127 and hydroxypropyl-β-cyclodextrin are the most effective solubilizers. The insertion of silibinin into Pluronic micelles and into the macrocyclic cavity of cyclodextrin improves the aqueous drug solubility. The grinding was used to obtain solid dispersions of silibinin with hydroxypropyl-β-cyclodextrin with improved solubility. Using a Franz diffusion cell, the coefficients of membrane permeability of silibinin through the cellulose membrane were determined. It was found that the membrane permeability of silibinin decreases in the presence of solubilizers. This may be due to interactions occurring in solution between the molecules of the drug and the solubilizer. A slightly more pronounced decrease in the permeability coefficients for micellar systems with Pluronic and sodium dodecyl sulfate is also due to an increase in the viscosity of solutions. Cyclodextrins and nonionic surfactants exhibit the most pronounced solubilizing effect with respect to silibinin, due to the formation of water-soluble in-clusion complexes and the penetration of the drug compound into surfactant micelles, respectively.
... Therefore, the CT scan was repeated on 12 January 2016, and it showed only chronic hepatitis/COL. After that, AFP levels continue to raise progressively and eventually reached the previous highest level at 25 April 2016, and so, the TACE was done as the second time on 1 May 2016. ...
... In vivo studies showed that silymarin could suppress the N-nitrosodiethylamine (NDEA) induced hepatocarcinogenesis in rats by modulating the antioxidant defence status of those animals [24]. Also, silymarin administration can decrease cell proliferation, increase apoptosis and activate the detoxification system in NDEAinduced HCC in rats [25]. ...
... In an in vivo study, treatment with silybin-vitamin E-phospholipids complex for 12 weeks was able to reduce liver fibrosis in 35 patients who underwent liver biopsies (Loguercio et al., 2012). In an N-nitrosodiethylamine (NDEA)-induced rat model of HCC, studies show that the treatment with silymarin was able to efficaciously modulate different molecular patterns in an anticarcinogenic sense and reduce mitochondrial membrane potential probably associated with cytochrome c release in cytoplasm (Gopalakrishnan et al., 2013). ...
Theorical framework: Hepatocellular carcinoma is a unique cancer that typically arises in the setting of chronic liver disease at a rate dependent upon the complex interplay between the host, disease, and environmental factors. Unfortunately, with contemporary management, patients with advanced hepatocellular carcinoma have few treatment options, and the prognosis is poor. Objective: Evaluate the role of antioxidants in the treatment of hepatocellular carcinoma. Methodology: It is an integrative review, with a qualitative approach. Based on research on ScienceDirect and PubMed databases, 12 articles were selected that were consistent with the theme and the inclusion and exclusion criteria, through the association of descriptors and keywords. Results: Studies in vivo demonstrated a positive correlation of antioxidants in the treatment of hepatocellular carcinoma. The antioxidants were able to promote inhibition of development tumor through promotes decrease of proinflammatory cytokines IL-1 and IL-6 and changes the ratios of Bax/Bcl2 that supports apoptosis. In oxidative stress, may be able to direct free radical scavenging activity. Among the main antioxidants with advanced preclinical evidence in the treatment of hepatocellular carcinoma is curcumin with tests in humans, and gallic acid, quercetin and resveratrol with several tests in vitro and in vivo. Conclusion: This study highlights that antioxidants can be a promising therapy in the treatment of hepatocellular carcinoma.
... In the studies of experimentally induced HCC (Gopalakrishnan et al. 2013), it was demonstrated that treatment of Silymarin significantly reduced the expression of PCNA and showed antiproliferative effect by immunohistochemically. In this study, contrast to the literature data (Gopalakrishnan et al. 2013), we observed that the treatment of Silymarin resulted in a decrease in PCNA positive cell number. ...
... In the studies of experimentally induced HCC (Gopalakrishnan et al. 2013), it was demonstrated that treatment of Silymarin significantly reduced the expression of PCNA and showed antiproliferative effect by immunohistochemically. In this study, contrast to the literature data (Gopalakrishnan et al. 2013), we observed that the treatment of Silymarin resulted in a decrease in PCNA positive cell number. However, there was no statistically dramatic difference between DEN and DEN + Silymarin groups. ...
The aim of this study was to evaluate the anticancerogenic effect of Silimarin by
immunohistochemical methods on Diethylnitrosamine (DEN) induced Hepatocellular
carcinoma (HCC) model in Wistar rats. Fifty male Wistar-Albino rats aging 2 months were
randomly divided into 5 equal groups. The Control group rats were given pellet feed and
drinking water for 20 weeks. The Sham group rats were injected intraperitoneally Propylene glycol dissolved in %0.9 NaCl three times for 20 weeks. The Silymarin group rats were injected intraperitoneally 100 mg/kg Silymarin three times a week for 20 weeks. The DEN group rats were injected intraperitoneally 50 mg/kg DEN once a week for 20 weeks. The DEN + Silymarin group rats were injected 50 mg/kg DEN once a week for 20 weeks. Silymarin at a dose of 100 mg/kg was injected intraperitoneally for 21 weeks, three times a week, starting 1 week before DEN administration. At the end of 21 weeks, macroscopically multifocal nodular structures were detected in the DEN and DEN + Silymarin group. A mix pattern of trabecular and acinar structures of HCC was observed in DEN and DEN + Silymarin groups. Besides; No statistically significant results were found between DEN and DEN + Silymarin
groups in terms of iNOS, Nitrotyrosine, PCNA, GSTPi, MMP-9, HPIP and TUNEL staining
(P > 0.05). In line with the results of our study, we determined that Silymarin did not show the
expected anticarcinogenic effect
... Resistance to apoptosis contributes to cancer development resistance to antineoplastic drugs (68). In our study, the DMBA-induced liver carcinogenesis produced a down-regulation of Caspase-3 expression and upregulation of Bcl-2 gene expression to avoid apoptosis and these results are agreed with the results of Gopalakrishnan et al. (69). Karabulut et al. (70) found a decrease in Caspase-3 and Bax expressions in liver tissue of DMBA-administrated group which indicate liver degeneration, and carcinogenesis. ...
Phytochemicals appeared as a rich source of efficient and safe agents against many diseases like cancer. Various herbal sources are rich in oleanolic acid (OA). The scope of this study was to assess the biochemical and molecular mechanisms implicated in the ameliorative potency of OA against DMBA-induced liver carcinogenesis. Forty-eight male albino mice were assigned randomly to five groups (eight mice each) as follows: control healthy group, olive oil group, OA group, DMBA group, and DMBA with OA. Apoptosis, autophagy, inflammation, proliferation, and angiogenesis were investigated in the tissue samples. Histopathological examination was carried out as well as liver enzymes activity and other hepatic antioxidant and inflammatory biomarkers. The treatment with OA effectively suppressed the DMBA-initiated liver carcinogenesis via modulation of antioxidant status, induction of apoptosis and autophagy through modulating the expression of Caspase-3, Bcl-2 and Beclin-1, inhibiting angiogenesis (VEGF), proliferation (PCNA), and improved liver function and histological picture with a reduction in AFP level. Additionally, OA applies its antitumor effects by inhibition of proinflammatory transcription factor NF-κB and inflammatory markers (TNF-α and Cox-2) associated with DMBA administration. The present study shows that OA treatment efficiently suppressed the DMBA-initiated liver carcinogenesis through induction of mitochondrial-mediated apoptosis and autophagy and modulating inflammation.
... Silymarin is a well-known hepatoprotective agent (Salam et al. 2010;Jain et al. 2011) which has been reported to possess both anti-inflammatory (Mayer et al. 2005;Féher and Lengyel 2012) and antiapoptotic effects (Gopalakrishnan et al. 2013;Federico et al. 2017). In the current study, silymarin was used as a reference standard hepatoprotective agent since each of its reported effects has been indicated in this study in the serum, liver, and brain of TAA-challenged rats. ...
Brain affection is a common symptom of liver insufficiency. This study aimed to evaluate the role of low-dose γ irradiation (LDR) as a potential therapeutic agent in thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats. Effects of local and whole-body irradiation (0.5 Gy) on rat brain/liver were evaluated following the induction of HE by TAA (200 mg/kg/day/for 3 successive days). Serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) and ammonia level were assessed. The effect of HE on brain was evaluated through the determination of brain contents of malondialdehyde (MDA), reduced glutathione (GSH), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) and glutathione peroxidase (GPx) activity. Moreover, apoptotic and inflammatory changes in brain and liver tissues were assessed together with alpha-smooth muscle actin (α-SMA); fibrosis marker. Results showed correction of the biochemical parameters which was supported by the results of the immunohistochemical examinations. LDR is a promising hepato- and neurotherapy against HE.
... Silymarin is a well-known hepatoprotective, anticarcinogenic, and anti-inflammatory agent [4]. It is a potent antioxidant which stabilizes cell membranes, detoxifies harmful entities [4,5] such as thioacetamide [6], diethylnitrosamine [7], carbon tetrachloride, acetaminophen and bromobenzene [8], and regenerates damaged hepatocytes [9]; thus, it has a significant role in the supportive treatment of hepatic illnesses and adversities [10]. Silymarin enhances the survival percentage of cirrhotic patients [11,12]. ...
The aim of this work was to develop, optimize and characterize a silymarin-laden polyvinylpyrrolidone (PVP)-polyethylene glycol (PEG) polymeric composite to resolve low aqueous solubility and dissolution rate problem of the drug. A number of silymarin-laden polymeric formulations were fabricated with different quantities of PVP K-30 and PEG 6000 by the solvent-evaporation method. The effect of PVP K-30 and PEG 6000 on the aqueous solubility and dissolution rate was investigated. The optimized formulation and its constituents were characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) techniques. Both the PEG 6000 and PVP K-30 positively affected the aqueous solubility and dissolution rate of the drug. In particular, a formulation consisting of silymarin, PVP K-30 and PEG 6000 (0.25/1.5/1.5, w/w/w) furnished the highest solubility (24.39±2.95 mg/mL) and an excellent dissolution profile (~100% in 40 min). The solubility enhancement with this formulation was ~1150-fold as compared to plain silymarin powder. Moreover, all the constituents existed in the amorphous state in this silymarin-laden PVP-PEG polymeric composite. Accordingly, this formulation might be a promising tool to administer silymarin with an enhanced effect via the oral route.
... In the past few decades, dietary studies have shown that regular consumption of fruits and vegetables reduces the risk of chronic diseases such as heart disease and cancer [5] [6] [7]. Colored fruits and vegetable foods contain abundant anthocyanins, including cyanidin-3-glucoside (C3G), pelargonidin-3-glucoside (P3G), malvidin-3-glucoside (M3G), peonidin-3-glucoside, petunidin-3-glucoside, and delphinidin-3-galacside, etc. [8] [9]. Epidemiological and laboratory data have shown that anthocyanins have many biological activities, such as inhibition of the growth of cancerous cells, improving immune responses [7] [10], reducing cardiovascular diseases [11], and promoting anti-obesity effects [12]. ...
... Furthermore, biotransformation of NDEA mediated by NADPH reductase causes the production of reactive oxygen species (ROS), thus leading to oxidative stress [56]. In rodents, NDEA primarily induces the formation of liver tumors and it has been used as a model hepatic carcinogen in experimental studies of carcinogenesis and chemoprevention [57]. In this investigation, NDEA administration evoked significant increase (p < .05) in serum AST (95.5%), ...
Bile salts containing vesicles (bilosomes) represent a portentous vesicular carrier that showed prosperous results in delivering active moieties in the gastrointestinal tract (GIT). In this study, bilosomes were exploited to deliver sulphated polysaccharide-protein complexes of Enteromorpha intestinalis (EHEM) and enhance its activity against hepatocellular carcinoma as well as resist harsh GIT conditions. Bilosomes were prepared using the sodium salt of three different bile acids (cholic, deoxycholic, taurodeoxycholic) and two different non-ionic surfactants (Span 40 and 65). The effects of experimental variables were thoroughly studied to obtain an optimum formulation loading EHEM. The selected formulation (EH-Bilo-2) prepared with sodium cholate and Span 65 displayed nano-sized (181.1±16.80 nm) spherical vesicles with reasonable entrapment efficiency (71.60 ± 0.25%) and controlled release properties; and thus was investigated as anti-hepatocarcinogenic candidate for in vivo studies. Treatment of hepatocellular carcinoma (HCC) bearing rats with EH-Bilo-2 experienced significant decrease in serum α-fetoprotein, endoglin, lipocalin-2 and heat shock protein 70 levels versus the untreated counterparts. Furthermore, the photomicrographs of their liver tissue sections showed focal area of degenerated pleomorphic hepatocytes with fine fibrosis originating from the portal area. Thus, the optimized bilosomal formulation is a promising delegate for tackling hepatocellular carcinoma owing to its powerful anti-cancer and anti-angiogenic activity.
