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Aims: Wnt3a and Wnt5a are ligands orchestrating the canonical and non-canonical pathways, respectively, with involvement in hepatocellular carcinoma (HCC). Hesperidin (HP) is a natural product found in citrus fruits and reputed for its antitumor activity. The present study aims to investigate the potential hepatoprotective effect of HP against thioacetamide (TAA)-induced HCC focusing on its potential role on Wnt3a and Wnt5a signaling pathways., Main Methods: Forty rats were equally divided into groups; normal control, HP control (receiving HP, 150mg/kg/day), HCC (receiving TAA, 200mg/kg twice weekly for 14weeks) and HP-HCC (receiving HP and TAA). Gene expressions of Wnt3a, Wnt5a, β-catenin and Cyclin D1 were assessed by qPCR, while their protein levels, along with active caspase-3 level, were quantified by ELISA and immunohistochemistry. Liver functions, oxidative stress parameters and myeloperoxidase activity were measured. MTT assay of hepG2 cells treated with recombinant Wnt3a (10ng/ml) in presence or absence of HP (100μM) was performed., Key Findings: HCC group exhibited a significant increase in Wnt3a, β-catenin, Cyclin D1 and Wnt5a gene expressions, as well as, their protein levels. HP significantly prevented TAA-activated Wnt3a/β-catenin and Wnt5a pathways. Moreover, HP exerted hepatoprotective effect by significantly improving the oxidative imbalance, inflammation and liver function parameters, serum ALT, AST activities, and albumin level., Significance: Our study is the first to report the possible role of Wnt3a/β-catenin and Wnt5a pathways in TAA-induced early HCC model in rats. HP has a prophylactic effect against hepatocarcinogenesis via preventing the induction of both canonical and non-canonical Wnt pathways., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Receptor-interacting protein kinase-1 (RIPK1) is an important protein in hepatocellular carcinoma (HCC) pathogenesis. Hesperidin (Hes) is a natural product found in citrus species and is believed to have an anti-cancer effect. Aims: This research was planned to elucidate the protective influence of Hes on the RIPK1 pathway in thioacetamide (TAA)-induced HCC. Materials and methods: HCC was induced in male Sprague Dawley rats using TAA and Hes was administered orally. Liver function tests, oxidative stress status, and antioxidant markers were evaluated. Histopathological examination of hepatic tissues was carried out by staining with hematoxylin and eosin stains. The protein level of RIPK1 was quantified by ELISA. Results: Hes exerted a hepatoprotective effect by significantly improving liver functions and oxidative stress status. This was supported by the integrity preservation of the liver tissues, which was indicated by histopathological examination. Moreover, Hes significantly increased the hepatic RIPK1 protein level. Conclusion: These results reveal that, Hes protected against HCC by decreasing oxidative stress and upregulation of RIPK1 protein level. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the antitumor activity and possible molecular mechanism of Phenethyl isothiocyanate (PEITC) against Ehrlich ascites carcinoma in-vivo and in-vitro. In-vivo, ascetic fluid volume, body weight, serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined using Ehrlich ascites carcinoma (EAC) bearing mice. In-vitro, MTT assay was used. RT-PCR was used to investigate role of PEITC in apoptosis by analyzing the expression of Bax, caspase-9, and Bcl-2 genes. The effect of PEITC on caspase-9 enzyme activity was also tested. PEITC and/or Doxorubicin (Dox) treatment significantly suppressed EAC growth as compared to EAC/oil control mice. PEITC treatment showed a dose-dependent inhibition of EAC cells as indicated by MTT assay. We found that significant increase in MDA level and decrease in TAC caused by Dox treatment were significantly reduced by combination with PEITC treatment. Bax, caspase-9 genes' expression and caspase-9 enzymatic activity were significantly increased, while Bcl-2 gene expression was significantly decreased in PEITC treated mice. PEITC may act as a promising anticancer agent either alone or more effectively in combination with Dox through apoptotic cell death induction. [ABSTRACT FROM AUTHOR]

Background and rationale. Microtubule-associated protein light chain 3-II (LC3-II), and Sequestosome-1 (SQSTM1) are proteins that can be used as markers for autophagic pathway. Bcl-2 protein is reported to be inversely correlated with apoptosis. We aimed to investigate the effects of curcumin on liver inflammation and fibrosis up to the first dysplastic stage of Hepatocellular carcinoma (HCC) induced by Thioacetamide (TAA) in rats and to clarify the effects of curcumin on LC3-II, SQSTM1, and Bcl-2. Male Sprague-Dawley rats were randomized into four groups: Control group, TAA group, Curcumin low-dose group, and Curcumin highdose group. The last three groups received TAA 200 mg/kg i.p. twice weekly for 18 weeks. Oxidative stress markers as hepatic malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity were measured by colorimetric methods. Hepatic SQSTM1 concentration was measured by ELISA, and gene expression levels of Bcl-2, and LC3-II were measured by RT-PCR.We also investigated the in vitro effect of curcumin on HepG2 cells viability through MTT assay, and the involvement of autophagy in this effect. Results. Curcumin increased the survival percent in rats, decreased-fetoprotein (AFP) concentration, and serum aspartate aminotransferase (AST) activity, and increased serum albumin concentration. Curcumin also significantly reduced oxidative stress in liver, inhibited apoptosis, and induced autophagy. In vitro, curcumin (50 µM) decreased HepG2 cells viabilityand the concentration of SQSTM1. Conclusions. Curcumin leads to protection against TAA induced HCC up to the first dysplastic stage through activating autophagic pathway and inhibiting apoptosis. Also, the antioxidant activity of curcumin almost prevents liver fibrosis. [ABSTRACT FROM AUTHOR]

In Egypt, hepatocellular carcinoma (HCC) was predicted to continue to rise over the next few decades causing a national problem. Meanwhile, glypican-3 (GPC3), a highly expressed glypican, has emerged as a potential target for HCC immunotherapy. Therefore, we aimed to identify the impact of blocking GPC3 on liver damage in HCC as well as a possible mechanism. Fifty four HCC patients, 20 cirrhotic patients and 10 healthy subjects were recruited. Serum levels of GPC3, sulfatase-2 (SULF-2), heparan sulfate proteoglycan (HSPG), insulin-like growth factor-II (IGF-II) were measured by ELISA. In parallel, HCC was induced in 40 male Sprague-Dawley rats in presence/absence of antiGPC-3. Liver impairment was detected by investigating liver sections stained with hematoxylin/eosin and serum α-fetoprotein (AFP). Liver homogenates of GPC3, SULF-2, and HSPG were measured by ELISA. Gene expression of caspase-3 and IGF-II were assayed by RT-PCR. HCC patients showed significant elevated serum levels of GPC3, IGF-II and SULF-2 accompanied by decreased HSPG. However, treatment of HCC rats with antiGPC-3 significantly reduced serum AFP and showed nearly normal hepatocytes. In addition, antiGPC-3 significantly reduced elevated liver homogenates protein levels of GPC3 and SULF-2 and gene expression of IGF-II and caspase-3. antiGPC-3 restored the reduced hepatic HSPG. antiGPC-3 showed anti-tumor activity as well as hepatoprotective effects. antiGPC-3-chemoprotective effect can be explained by forced reduction of IGF-II expression, restoration of HSPGs, deactivation of SULF-2 and reduction of gene expression of caspase-3. Targeting GPC3 is a promising therapeutic approach for HCC. [ABSTRACT FROM AUTHOR]

Introduction: Anemia associated with chronic kidney disease is a serious complication necessitating expenditure of huge medical efforts and resources. This study investigates the role of alpha-lipoic acid (ALA) in end stage renal disease patients undergoing hemodialysis. By the virtue of its antioxidative effects, ALA is expected to act as an erythropoietin (EPO) adjuvant, and also has extended beneficial effects on endothelial dysfunction. Methods: Forty-four patients undergoing hemodialysis and receiving EPO were randomized into two groups: the first group received ALA 600 mg once daily for 3 months; while the other group represented the control group. Parameters measured at baseline and at end of study were hemoglobin, EPO doses, EPO resistance index (ERI), iron store indices, malondialdehyde, oxidized low-density lipoprotein (ox-LDL), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and asymmetric dimethylarginine (ADMA), as well as routine laboratory follow-up. Results: EPO doses and ERI were significantly decreased in the treatment group, while they did not change in the control group. Hemoglobin, iron store indices, malondialdehyde, oxidized ox-LDL, IL-6, TNF-α, and ADMA were similar in both treatment and control groups at baseline, and did not change by the end of study period. Likewise, routine laboratory measures were not affected by the treatment. Conclusion: ALA could be used in hemodialysis patients to reduce requirements for EPO. However, larger and longer term studies are required to clarify the exact role of ALA in hemodialysis as well as in pre-hemodialysis patients. [ABSTRACT FROM AUTHOR]

Cinnamaldehyde (CA) is a natural compound that has promising biological activity. The current study investigates the antitumor activity of CA in thioacetamide induced hepatocellular carcinoma (HCC) in rats through targeting the Wnt/β-catenin pathway and evaluates the capability of CA to relieve hepatocytes oxidative stress in the HCC-rat model. After 16 weeks of HCC induction by thioacetamide (TAA), rats were treated for 7 consecutive weeks with CA daily; i.p. injection, Alpha-fetoprotein (AFP) level, necroinflammatory score and fibrosis percentage were measured to assess HCC development. The Wnt/β-catenin pathway was evaluated by measuring the hepatic protein level of Wnt-3a, β-catenin, cyclin D, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF). Furthermore, hepatocytes' oxidative stress was assessed by measuring hepatic GSH and MDA contents. Results showed that CA was significantly inhibiting the Wnt/β-catenin pathway through the downregulation of hepatic Wnt-3a, β-catenin, cyclin D, MMP-9, and VEGF. Moreover, CA ameliorates hepatocytes' oxidative stress via lowering hepatic MDA content and rising hepatic GSH content. Thus, in conclusion, CA is a promising treatment for HCC. It not only has an effective antitumor activity but also ameliorates hepatocytes' oxidative stress. [ABSTRACT FROM AUTHOR]

Sitagliptin (STG) is a highly selective dipeptidyl peptidase-4 inhibitor recently used in the treatment of type 2 diabetes. The current study aimed to investigate the anti-neoplastic effect of STG alone and in combination with Doxorubicin (Dox), a known chemotherapeutic agent but with ominous side effects. After intramuscular inoculation of 2 × 106 Ehrlich tumor cells, Female Swiss mice were divided into tumor-bearing control, STG-treated, Dox-treated, and a combination of STG and Dox-treated groups. The results showed a significant reduction in the tumor growth of the treated animals in comparison with those of the positive control group with a more prominent effect in the co-treated group. Where, the anti-proliferative and apoptotic effect of STG, and its chemo-sensitizing ability, when used in combination with Dox, was mediated by modulation of oxidative stress (MDA and GSH), attenuation of tumor inflammation (IL-6 and IL-1β), and angiogenesis (VEGF), suppressing proliferation (β-catenin and cyclin-D1) and enhancement of apoptosis (survivin, p53, caspase 3). Thus, in conclusion, STG as adjunctive therapy for Dox could be a strategy for the treatment of breast cancer patients, by their ability in hindering cell proliferation and minimizing the associated oxidative and inflammatory adverse reactions. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. In an attempt to understand some potential mechanisms of persistence and oncogenicity of Hepatitis C virus (HCV)-related HCC, microfibrillar-associated protein 4 (MFAP4), fibrotic indices and oxidative status biomarkers were assessed in the sera of 50 patients with HCV-associated HCC, 25 patients with HCV-related liver cirrhosis and 15 healthy individuals. Serum oxidized Coenzyme Q10 (CoQ10) and malondialdehyde showed significant elevation in HCC patients compared to the control group (p < 0.001), as well as cirrhotic patients (p < 0.05 and p < 0.001, respectively), while serum glutathione content and superoxide dismutase activity were significantly decreased in HCC patients compared to the control group (p < 0.001). Serum MFAP4, aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4) and Forns index showed significant increase in HCC patients compared to the control group (p < 0.001), while only APRI and FIB-4 were significantly different between HCC and cirrhotic patients (p < 0.05), with a sensitivity of 86% and 92%, respectively, at cut off ≥0.7 for APRI and ≥1.57 for FIB-4. Therefore, increasing oxidative stress and fibrosis might mediate HCV induced cirrhosis and HCC. APRI and FIB-4 may be used as a simple non-expensive formula for the screening of HCC rather than MFAP4. [ABSTRACT FROM AUTHOR]

Aim Obesity based on insulin resistance is a state of chronic oxidative stress and inflammation that are highly regulated through nuclear factor Erythroid 2-related factor 2 (NrF2) pathway. Materials and methods 70 male Wistar rats were randomized into two models. The prophylactic model was 10 weeks and rats were grouped into: normal group, GL group (received glycyrrhizin 50 mg/kg/day orally along with normal pellet diet), HFD group and HFD + GL group (received glycyrrhizin along with HFD). The treatment model was 14 weeks and rats were grouped into: normal group, HFD group and HFD + GL group (received glycyrrhizin from the week 10). Key findings Glycyrrhizin decreased significantly rat weights and insulin resistance, normalized lipid profile and reduced significantly the adipocytes size in adipose tissue and lipid deposition in the liver tissue through histopathologic examination. Furthermore, glycyrrhizin ameliorated obesity-induced oxidative stress which indicated by significant decrease in liver malondialdehyde level (P < 0.001) and increase in the total antioxidant capacity (P < 0.001). Interestingly, molecular mechanism of glycyrrhizin was explored, that included significant reduction of liver gluconeogenic enzymes mRNA expression (P < 0.001), a significant increase of liver insulin receptor, NrF2 and homooxygenase-1 mRNA expressions (P < 0.001) and significant increase and nuclear translocation of NrF2 in liver tissue. Significance Glycyrrhizin ameliorates HFD-induced obesity in rats that may be attributed to its ability to increase insulin receptor expression and to activate NrF2 and subsequent homooxygenase-1 pathway. Thus, this work represents a safe natural compound (glycyrrhizin) that has a great role either as prophylaxis or treatment for insulin resistance related to obesity. [ABSTRACT FROM AUTHOR]

Aims Hyperglycemia leads to elevation of oxidative stress and proinflammatory cytokines which are the main causes of diabetic nephropathy (DN). NLRP3 inflammasome and thioredoxin-interacting protein (TXNIP) are recently assumed to participate in the development of DN. We aimed to investigate the effects of Cepharanthine (CEP), Piperine (Pip) and their combination in streptozotocin (STZ)-induced DN focusing on their role to modulate NLRP3 and TXNIP induced inflammation. Main methods Diabetic rats were treated with intraperitoneal (i.p.) injection of CEP (10 mg/kg/day), Pip (30 mg/kg/day) or their combination for 8 weeks. Nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) were assessed by ELISA technique. TXNIP and NLRP3 genes expressions were evaluated by real time-PCR. Key findings Diabetic rats showed significant increase in renal TXNIP and NLRP3 expression. CEP, Pip or their combination significantly decreased TXNIP and NLRP3 expression in diabetic kidneys. Hyperglycemia induced NF-κB activation leading to increased IL-1β and TNF-α levels. CEP, Pip or their combination showed significant inhibition of NF-κB together with decreased IL-1β and TNF-α levels in diabetic rats. Also, diabetic rats showed significant decrease in creatinine clearance and increase in blood glucose, serum creatinine, blood urea nitrogen, malondialdehyde, proteinuria, and kidney weight to body Weight ratio. All of these changes were reversed by CEP, Pip or their combination. Significance The antioxidant and anti-inflammatory effects of CEP and Pip which were accompanied by inhibition of NF-κB and NLRP3 activation might be helpful mechanisms to halt the progression of DN. [ABSTRACT FROM AUTHOR]