Effect of some natural antioxidants on aflatoxin B1-induced hepatic toxicity

Aflatoxins are potent hepatotoxic and hepatocarcinogenic agents. This hepatotoxicity is thought to be mediated by their ability to generate reactive oxygen species and cause peroxidative damage. In the present investigation we assessed the ability of some natural antioxidants namely, vitamin E and Se, ß-carotene, silymarin and coenzyme Q10 on aflatoxin B1 (AFB1)-induced hepatotoxicity in a rat model. Alanine and aspartate aminotransferases and alkaline phosphatase (ALP) were found to be significantly increased in the serum of AFB1 administered (250 µg/kg body weight/day for 2 weeks) rats, suggesting hepatic damage. There was a marked increase in the lipid peroxide levels and a concomitant decrease in the hepatic reduced glutathione (GSH) and serum protein thiol (PrSHs) along with a nearly twofold increase in hepatic glutathione-S-transferase (GST) activity. The significant increase in GST may be attributed to its being a phase ?? enzyme that predominately participates in the detoxification of the ultimate electrophilic metabolite AFB1-8, 9 epoxide. On the other hand, no significant change was detected in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G-6-PDH), cytochrome creductase and levels of DNA and RNA in the hepatic tissue of AFB1 administered rats. Results also revealed that cotreatment with studied antioxidants offered substantial hepatoprotective effects in the AFB1 administered rats. Moreover, results revealed that vitamin E and selenium combination and ß-carotene are more efficient than coenzyme Q10 and silymarin in modulating the liver antioxidant enzymatic system

Zingiber officinale acts as a nutraceutical agent against liver fibrosis

<p>Abstract</p> <p>Background/objective</p> <p><it>Zingiber officinale </it>Roscoe (ginger) (<it>Zingiberaceae</it>) has been cultivated for thousands of years both as a spice and for medicinal purposes. Ginger rhizomes successive extracts (petroleum ether, chloroform and ethanol) were examined against liver fibrosis induced by carbon tetrachloride in rats.</p> <p>Results</p> <p>The evaluation was done through measuring antioxidant parameters; glutathione (GSH), total superoxide dismutase (SOD) and malondialdehyde (MDA). Liver marker enzymes; succinate and lactate dehydrogenases (SDH and LDH), glucose-6-phosphatase (G-6-Pase), acid phosphatase (AP), 5'- nucleotidase (5'NT) and liver function enzymes; aspartate and alanine aminotransferases (AST and ALT) as well as cholestatic markers; alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin were estimated. Liver histopathological analysis and collagen content were also evaluated. Treatments with the selected extracts significantly increased GSH, SOD, SDH, LDH, G-6-Pase, AP and 5'NT. However, MDA, AST, ALT ALP, GGT and total bilirubin were significantly decreased.</p> <p>Conclusions</p> <p>Extracts of ginger, particularly the ethanol one resulted in an attractive candidate for the treatment of liver fibrosis induced by CCl₄. Further studies are required in order to identify the molecules responsible of the pharmacological activity.</p

Association of CARD10 rs6000782 and TNF rs1799724 variants with paediatric-onset autoimmune hepatitis

Although the pathogenesis of paediatric-onset autoimmune hepatitis (pAIH) remains incompletely understood, genetic variants and environmental factors are known to be involved. Caspase recruitment domain family member 10 (CARD10) is a scaffold protein that participates in a complex pathway activating nuclear factor kappa-B (NFκB) and tumour necrosis factor alpha (TNF-α). This study aimed to investigate the association of CARD10 rs6000782 (g.37928186A > C) and TNF gene promoter rs1799724 (c.-1037C > T) variants with pAIH susceptibility in a cohort of Egyptian children. The research was also extended to assess the relationship of these variants with levels of NFκB-p65 and TNF-α. Fifty-six pAIH patients and 44 age- and sex-matched healthy controls were included. Variant genotyping was performed by polymerase chain reaction (PCR). Serum NFκB-p65 and TNF-α levels were measured using enzyme-linked immunosorbent assays (ELISAs). rs6000782 C and rs1799724 T alleles, separate or in combination, were significantly increased in pAIH patients compared to controls. Serum levels of NFκB-p65 and TNF-α were higher in pAIH differentiating both groups. Moreover, the recessive model of rs6000782 revealed a significant association with the levels of both NFκB-p65 and TNF-α. In conclusion, rs6000782 and rs1799724 variants are potential genetic risk factors for pAIH predisposition, with the former affecting NFκB-p65 and TNF-α levels. Overall, the inflammatory cascade was associated with the degree of liver cell destruction. Clinically, screening and genetic counselling are recommended for relatives of pAIH patients. Keywords: Hepatitis, Autoimmune, Variants, Paediatrics, Cytokines, Tumour necrosis facto

Modulation of Tamoxifen Cytotoxicity by Caffeic Acid Phenethyl Ester in MCF-7 Breast Cancer Cells

Although Tamoxifen (TAM) is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination

MicroRNAs as predictor markers for response to interferon treatment of chronic hepatitis C genotype-4 in Egyptian patients.

Hepatitis C virus genotype 4 (HCV-4) infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection. The aim of the present study was to assess serum miR-122, miR-221 and miR-21 expression profiles in HCV-4 patients prior to treatment with HCV-4 combination therapy (pegylated alpha interferon and ribavirin) and to determine whether the miRNAs were associated with the drug response.RNA was extracted from pretreatment serum samples, and miR-122, miR-221 and miR-21 levels were measured by quantitative PCR. The results were compared among patients with sustained virological responses (SVR) and non-responders (NR).The expression levels of miR-21 and miR-122 were significantly different between the SVR and NR groups. Receiver operator characteristic (ROC) analysis revealed that the sensitivity, specificity and positive predictive values of miR-21 were 82.2%, 77.3% and 88.1%, respectively, with a cut-off value of 1.7. The sensitivity, specificity and positive predictive values of miR-122 were 68.9%, 59.1% and 77.5%, respectively, with a cut-off value of 3.5.miR-21 and miR-122 might be useful predictors for SVR in HCV-4 patients prior to the administration of combination therapy. A higher predictive response power was obtained for miR-21 than for miR-122. These results should reduce ineffective treatments

Serum MicroRNAs as Potential Biomarkers for Early Diagnosis of Hepatitis C Virus-Related Hepatocellular Carcinoma in Egyptian Patients

<div><p>Circulating microRNAs are deregulated in liver fibrosis and hepatocellular carcinoma (HCC) and are candidate biomarkers. This study investigated the potential of serum microRNAs; miR-19a, miR-296, miR-130a, miR-195, miR-192, miR-34a, and miR-146a as early diagnostic biomarkers for hepatitis C virus (HCV)-related HCC. As how these microRNAs change during liver fibrosis progression is not clear, we explored their serum levels during fibrosis progression in HCV-associated chronic liver disease (CLD) and if they could serve as non-invasive biomarkers for fibrosis progression to HCC. 112 Egyptian HCV-HCC patients, 125 non-malignant HCV-CLD patients, and 42 healthy controls were included. CLD patients were subdivided according to Metavir fibrosis-scoring. Serum microRNAs were measured by qRT-PCR custom array. Serum microRNAs were deregulated in HCC versus controls, and except miR-130a, they were differentially expressed between HCC and CLD or late fibrosis (F3-F4) subgroup. Serum microRNAs were not significantly different between individual fibrosis-stages or between F1-F2 (early/moderate fibrosis) and F3-F4. Only miR-19a was significantly downregulated from liver fibrosis (F1-F3) to cirrhosis (F4) to HCC. Individual microRNAs discriminated HCC from controls, and except miR-130a, they distinguished HCC from CLD or F3-F4 patients by receiver-operating-characteristic analysis. Multivariate logistic analysis revealed a panel of four microRNAs (miR-19a, miR-195, miR-192, and miR-146a) with high diagnostic accuracy for HCC (AUC = 0.946). The microRNA panel also discriminated HCC from controls (AUC = 0.949), CLD (AUC = 0.945), and F3-F4 (AUC = 0.955). Studied microRNAs were positively correlated in HCC group. miR-19a and miR-34a were correlated with portal vein thrombosis and HCC staging scores, respectively. In conclusion, studied microRNAs, but not miR-130a, could serve as potential early biomarkers for HCC in high-risk groups, with miR-19a as a biomarker for liver fibrosis progression to cirrhosis to HCC. We identified a panel of four serum microRNAs with high accuracy in HCC diagnosis. Additional studies are required to confirm this panel and test its prognostic significance.</p></div

Differential expression of serum miRNA levels in HCC and CLD patients.

<p>The box represents the 25%-75% percentiles; the line inside the box represents the median and the upper and lower lines representing the 10%-90% percentiles of fold change in expression levels of studied miRNAs in serum of CLD (n = 125) and HCC patients (n = 112). Data were analyzed by Mann-Whitney <i>U</i>-test.</p

Signature of serum miRNAs relative expression during HCV-related liver disease progression.

<p>Panel (A) represents fold change of miRNA expression levels in early fibrosis (F1-F2, n = 75), late fibrosis (F3-F4, n = 50), and HCC (n = 112) groups. Comparison between F1-F2 vs F3-F4 or F3-F4 vs HCC was analyzed by Mann-Whitney <i>U</i>-test. Panel (B) represents detailed analysis of miRNA relative expression levels at different fibrosis stages (F1, n = 45, F2, n = 30, F3, n = 18, F4, n = 32) and HCC (n = 112). Comparison was done by Kruskal-Wallis test. Mann-Whitney <i>U</i>-test was used to compare F1-F3 vs F4 or F4 vs HCC. The box represents the 25%-75% percentiles; the line inside the box represents the median and the upper and lower lines representing the 10%-90% percentiles.</p

Diagnostic performance of the miRNA panel.

<p>AUCs of the miRNA panel (A) and miRNA panel in differentiating HCC from healthy controls (B), CLD (C), and F3-F4 patients (D).</p