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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]

Obesity is a chronic inflammatory disease that represents a risk factor for number of diseases including diabetes, steatohepatitis, and cancer. Using safe natural compounds to ameliorate obesity and its related metabolic syndrome is an interesting spot for research. We investigated the regulatory role and the underlying mechanism of black seed oil (BSO) on high-fat diet (HFD)-induced obesity in rats. The study included two models: the first one aimed to study the prophylactic effect of BSO (BSO administration for 10 weeks along with HFD) while the second one aimed to study the treatment role of BSO (BSO administration starting from the 10th week for 4 weeks along with HFD). BSO significantly decreased insulin resistance and body weight characteristics in both models. It also normalized lipid profile. Moreover, histopathological examination confirmed these results as BSO significantly decreased adipocyte size and hepatic lipid deposition. Besides, BSO alleviated HFD-induced oxidative stress as indicated by significant increase in the total antioxidant capacity and significant decrease in liver malondialdehyde. Moreover, BSO decreased significantly liver gluconeogenic enzymes mRNA expressions (phosphoenolpyruvate carboxykinase and glucose-6- phosphatase) and increased significantly heme oxygenase-1 (HO-1), nuclear factor erythroid-2- related factor-2 (Nrf2) and insulin receptor mRNA expressions. In conclusion, BSO represents a natural therapy that has the ability to prevent and treat HFD-induced obesity in rats that may be mediated through Nrf2/HO-1 pathway's activation and insulin receptor expression's increase. To our best knowledge, this study represents a novel study that investigates the regulatory role of BSO on Nrf2 pathway in preventing and treating HFD-induced obesity. Practical applications: Black seed oil is a natural available safe supplement, thus it can be used for prevention from obesity and even treatment of obesity and obesity related complications. Introducing of black seed oil in the treatment regimen of obese patients may be promising. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a highly fatal tumor which represents a major health problem worldwide. Due to asymptomatic nature of HCC, most patients present with the progressive stage of disease, so, unfortunately, there are no effective therapies. Existing techniques for HCC surveillance and diagnosis lack the required accuracy. Therefore, searching for new diagnostic and/or therapeutic tools could improve patient survival. This study aimed to estimate the diagnostic role of Dickkopf-1 (DKK1) and amphiregulin (AREG) and to find out their correlation with different clinicopathological parameters in HCC patients. Materials and Methods: Serum levels of DKK1 and AREG in 55 HCC patients, 20 cirrhotic patients, and 15 healthy subjects as control group were measured using the ELISA technique. Results: Both of DKK1 and AREG showed a significant increase in the HCC group compared to cirrhotic and healthy groups. DKK1 at a cutoff point of 8.92 ng/ml showed that the area under the curve (AUC) was 0.826 with 87.3% sensitivity and 82.9% specificity. DKK1 showed a significant correlation with tumor size, liver dysfunction, and poor performance status in HCC patients. AREG at a cutoff point of 8.74 pg/ml showed a sensitivity of 74.5% but low specificity (47.1%). AREG showed a significant correlation with portal vein thrombosis and tumor metastasis in HCC patients. Conclusion: Serum DKK1 could be a diagnostic biomarker for HCC. Both of DKK1 and AREG may play significant roles in tumor progression and may offer promising therapeutic targets in HCC patients. [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]

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]

Elevated serum levels of cystatin C are found to be related to poor outcome and metastatic potential of some malignant disorders. To evaluate the clinical prominence of serum cystatin C in diffuse large B-cell lymphoma (DLBCL), blood samples were obtained from 58 patients at the time of diagnosis and paired blood samples were obtained from 22 patients at the time of remission. Also, serum cystatin C level was measured in matched healthy controls. Serum cystatin C levels were significantly more elevated in DLBCL patients than in controls (p < 0.0001). Furthermore, paired-sample analysis revealed that pretreatment cystatin C levels were reduced significantly in patients who achieved remission after therapy (p = 0.016). High serum cystatin C levels were correlated with age over 60 years (p = 0.049), extra-nodal involvement (p = 0.005) and with high serum lactate dehydrogenase (LDH) (p < 0.013). Elevated serum cystatin C levels were associated with extra-nodal involvement and they were significantly reduced to normal range after the remission. However, Kaplan-Meier curves revealed no survival difference in the pretreatment serum cystatin C levels. Therefore, serum cystatin C may be a novel biomarker that reflects tumor burden in DLBCL but bears no prognostic significance regarding survival. [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]

Syndecan-1 is a trans-membrane heparan sulfate proteoglycan that localizes in epithelial cells and has been shown to be present in normal hepatocytes. It is thought to be involved in processes such as cell growth, differentiation and adhesion. However, the clinical data regarding syndecan-1 in patients with hepatocellular carcinoma (HCC) are scarce and controversial. Therefore, we need to evaluate the effects of HCC on the serum levels of syndecan-1. Thus, 40 patients with HCC and 31 patients with liver cirrhosis were physically examined. Blood samples were taken for measurements of routine markers (sGPT, sGOT, bilirubin, albumin, and a-fetoprotein), as well as serum levels of interleukin (IL)-6 and syndecan-1. Patients with liver cirrhosis showed significant increase in serum IL-6 as compared with HCC patients and the control subjects. Serum level of syndecan-1 was significantly increased in HCC patients as compared with the cirrhotic and control groups. In addition, significant positive correlations between syndecan-1 and serum levels of ALT, AST in HCC patients were found. Moreover, syndecan-1 increased significantly with increasing stage of Barcelona-Clinic Liver Cancer Group diagnostic and treatment strategy. In conclusion, the development of HCC is accompanied by a significant elevation in serum syndecan-1 levels. The increase in serum syndecan-1 may be linked with progression of HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers, associated with a high rate of mortality. A disturbance between cell proliferation and cell death is one of the cancer hallmarks including HCC. Cell proliferation is mainly controlled by the cell cycle. The arrest of the cell cycle is one of the important targets of anticancer agents., Objectives: The present study tries to clarify the exact role of some natural products such as daidzein (DAZ) and alcoholic chicory leaf extract (CE), as possible regulators of cell cycle and apoptosis., Methods: HCC in rats was induced using diethylnitrosamine (DENA). Ninety rats were allocated and divided equally into nine groups, treated with CE, DAZ, a combination of both, and sorafenib with non-treated control groups., Results: Treatment with CE, DAZ, and their combination significantly downregulated hepatic tissue expression of cyclin D1/CDK4 axis as well as cyclin A/CDK2 axis. The suggested therapeutic protocol inhibited the proliferation and dampened Bcl-2 expression. Furthermore, the efficiency of combining CE and DAZ demonstrated a potency comparable to sorafenib in terms of cyclin D/CDK4 axis expression, as well as; this combination protocol was more potent in revealing a potentiated inhibitory effect on cyclin A and Ki-67 expression., Conclusion: Treatment with DAZ or CE alone, or in combination, could possess an inhibitory effect on hepatocarcinogenesis via cell cycle arrest, inhibition of proliferation through suppression of Ki-67 expression, and apoptosis induction, mediated by downregulation of Bcl-2., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer-related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance., Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway., Methods: HCC was induced in rats using a single dose of diethylnitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of the 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after the last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki-67 was assessed immunohistochemically., Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib., Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via the intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hepatocellular carcinoma (HCC) is a main cause of cancer death all over the world. Treatment and outcome of HCC based on its early diagnosis. This study was conducted to estimate the role of talin-1 and midkine in combination with total antioxidant capacity (TAC) as tumor markers in HCC patients. Methods: Serum levels of talin-1 and midkine were measured in 90 Egyptian subjects including 44 patients with HCC, 31patients with cirrhosis and 15 healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. While a colorimetric method was used for measurement of TAC. Results: Serum talin-1 in HCC patients was significantly lower than that in patients with cirrhosis (P<0.001) and normal control (P<0.001). In addition, increased invasion and metastasis correlated with reduced talin-1 level. Serum midkine in HCC patients was significantly higher compared to cirrhotic patients (P<0.001) and normal control (P<0.001). Midkine at a cut off value of 1683 pg/ml showed a sensitivity of (81.82%) and specificity of (83.87%). While alpha-fetoprotein (AFP) at a cut off value of 200 ng/ml had a sensitivity of (52.27%), while specificity was (96.77%). Midkine was positive in 80.9% of HCC patients with negative AFP. Serum TAC was significantly decreased in HCC patients when compared with control group (P<0.001). Conclusion: Talin-1 may be implicated in the carcinogenesis and metastasis of HCC and can be used as a useful tumor marker for HCC. Midkine may be a potential diagnostic marker for HCC and may be used in addition to AFP to increase the sensitivity of HCC detection., (Creative Commons Attribution License)

Advanced glycation end products (AGEs) are complex, heterogenous molecules generated by glycation and oxidation of proteins in vivo, which are thought to markedly increase in diabetic patients. One of the recently identified AGEs is carboxy methyl lysine (CML), which is the main ligand of receptors for advanced glycation end products (RAGE). The present study aimed to assess the effect of obesity on such pathways in presence and absence of Type 2 diabetes mellitus. CML, soluble receptors for advanced glycation end products (sRAGE), HbA1C, lipid profile, liver function tests and kidney function tests were determined in 29 diabetic obese, 29 diabetic non-obese, 15 non-diabetic obese and 15 non-diabetic non-obese subjects. The study compared obese and non-obese subjects in presence and absence of type 2 diabetes. The results showed a significant increase in CML and a significant decrease in sRAGE in each of the diabetic obese group when compared with the diabetic non-obese group and the non-diabetic obese group when compared with the non-diabetic non-obese group. A significant positive correlation was found between CML and markers of obesity (body mass index and waist/hip ratio). These results suggest that obesity can increase CML independent of diabetes and support the reports that CML could be generated from both sugars and lipids. The present study suggests that treatment using glycation inhibitors like aminoguanidine or recombinant sRAGE will not only retard the diabetic complications, but may also have a prophylactic effect.