Chia Seeds Oil Suppresses the Resistance of Hepatocellular Carcinoma Cells to Liposomal-doxorubicin and Upregulates the Tumor Suppressor miRNAs.

BACKGROUND: Chia seed is an oil seed with multiple biological activities. Doxorubicin is effective chemotherapy for liver cancer. Resistance and adverse effects are doxorubicin limitations. OBJECTIVE: This study aimed to investigate the effect of chia seeds oil (CSO) on the resistance of HepG2 cells to liposomal-doxorubicin (DOX). METHODS: The objective were investigated through measuring cytotoxicity, doxorubicin-metabolizing enzyme Cytochrome P450 3A4 (CYP-3A4), multidrug resistance-associated protein (MRP1), and the expression of multiple tumor suppressor microRNAs. RESULTS: The findings indicated that low concentration of CSO increased HepG2 cells' sensitivity to DOX, as concluded from its higher cytotoxicity. DOX-induced mRNAs of CYP-3A4 and MRP1 and their protein levels. CSO inhibited both in DOX-treated cells. CSO-induced tumor suppressor miRNAs. Doxorubicin inhibited miR-122 and let-7/b/e expression, while it led to overexpression of let- 7a. CSO/DOX upregulated let-7/b/e, miR-34a, and miR-122 (which inhibits MRP1) and downregulated let-7a, which may lead to increased apoptosis. CONCLUSION: CSO effectively re-sensitized HepG2 cells to liposomal-doxorubicin via inhibiting MRP1 and CYP-3A4, which may increase in vivo doxorubicin bioavailability and decrease its therapeutic dose to diminish its adverse effects.

The relationship between serum adiponectin and steatosis in patients with chronic hepatitis C genotype-4.

BACKGROUND: The mechanisms underlying steatosis during hepatitis C virus (HCV) infection are complex and multifactorial. The aim of our study was to assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus genotype 4 by investigating the role of adiponectin, leptin and insulin resistance. METHODS: Adiponectin and leptin levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 74 chronic patients with HCV genotype 4. RESULTS: Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of leptin, HOMA, alanine aminotransferase, gamma-glutamiltransferase and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Adiponectin levels showed significant inverse correlation between adiponectin and steatosis grade, BMI, HOMA and fibrosis stage. The multivariate analysis of factors showed that steatosis was significantly associated with low adiponectin concentration while leptin, insulin, HOMA, ALT, gamma-GT and cholesterol were positively associated with steatosis. CONCLUSIONS: This study stated that patients with HCV genotype-4 suffering from steatosis had a lower adiponectin level which is inversely correlated with insulin resistance. These data support a role for adiponectin in protecting against liver injury and also that hypoadiponectinaemia may contribute to the progression of hepatic steatosis. Further molecular and genetic studies with larger numbers of patients are required to confirm these results.

Host susceptibility to schistosomes: effect of host sera on cell proliferation of Schistosoma mansoni schistosomula.

To determine effects of the sera on cell proliferation, schistosomula of Schistosoma mansoni (20-days-old) were incubated in medium containing fetal calf serum plus hamster (highly susceptible host) portal or peripheral venous serum, or rat (poorly susceptible host) portal or peripheral venous serum in the presence of bromodeoxyuridine (BrdU). Compared with schistosomula cultured in presence of control medium containing fetal calf serum alone, BrdU labeling indices (BLIs) were increased by 39% in the presence of portal, but not in peripheral, serum of hamsters. In contrast, no significant differences were observed in the BLIs in rat portal, or peripheral, sera or in control media. In vivo BrdU labeling results revealed that there was no detectable cell proliferation in S. mansoni schistosomula (6 days old) in the lungs. However, cell proliferation was detected in schistosomula beginning at 17 days. The results indicated that portal venous serum from a highly susceptible host, but not from a poorly susceptible host, stimulated schistosome cell proliferation in vitro. The timing of the increase in cell proliferation in terms of development corresponded to liver portal-mesenteric localization of schistosomula. Together, the data support the conclusion that in susceptible hosts, portal serum may play a role in schistosome cell proliferation, possibly resulting in termination of schistosome migration. This may explain the colocalization of adults, and the known organ selectivity of disease.

MTP genetic variants associated with non-alcoholic fatty liver in metabolic syndrome patients.

This study was performed for investigation the relationship between variants of MTP gene polymorphism and the development of NAFLD in patients with and without MS. The study was included 174 NAFLD patients (106 with MS and 68 without MS), and 141 healthy control subjects. The 493 G/T polymorphism of MTP gene was evaluated by PCR-RFLP method. The frequency of MTP TT genotype and T allele were significantly higher in NAFLD patients when compared to healthy controls. Moreover, a significant association in MTP gene polymorphism was observed in NAFLD patients with MS compared to NAFLD patients without MS and controls. Our study suggested that MTP 493 G/T gene polymorphism may act as susceptibility biomarker for NAFLD and MS.

Evaluation of Biomarkers in Egyptian Patients with Different Grades of Nonalcoholic Fatty Liver Disease.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a silent disease; its spectrum includes simple steatosis, nonalcoholic steatohepatitis and fibrosis. Pro- and anti-inflammatory cytokines play roles in the pathogenesis of NAFLD and insulin resistance (IR). Moreover, plasma cell antigen-1 (PC-1) is related to IR and associated with NAFLD progression. Therefore, we aimed to detect biomarkers, ultrasonographic and anthropometric findings capable of differentiating NAFLD grades, since most previous investigators were concerned more with NAFLD patients without classifying them into grades. Methods: A total of 87 NAFLD patients (31 with grade 1 (mild NAFLD), 26 with grade 2 (moderate NAFLD) and 30 with grade 3 (severe NAFLD) were included in the study, in addition to 47 controls (grade 0). All subjects underwent ultrasonographic examination for NAFLD diagnosis. Serum interleukin-10 (IL-10), plasma interleukin-18 (IL-18) and plasma PC-1 levels were determined using enzyme-linked immunosorbent assay. Results: Homoeostasis model assessment (HOMA)-IR was higher in different NAFLD grades than in controls. Ultrasonographic and anthropometric findings and lipid profile indices (except for high-density lipoprotein cholesterol, which was decreased) were increased with NAFLD progression. Grade 3 patients showed significant increase in levels of IL-18 and significant decrease in IL-10 and PC-1 levels when compared to grade 1 patients. Conclusion: Anthropometric and ultrasonographic findings were valuable in differentiating NAFLD grades. IR is very important in NAFLD pathogenesis. IL-18, HOMA-index and PC-1 levels could be used to differentiate between NAFLD grades, together with other measurements.

Hepatobiliary Schistosomiasis.

Schistosomiasis is an ancient parasitic disease that has afflicted Egyptians since the time of the pharaohs. The disease is caused by lodged schistosome eggs in the host liver, evoking an immune response and leading in some patients to the development of hepatic granuloma and fibrosis. Here, we review the epidemiology, immunopathogenesis, and clinical profile of schistosomiasis. This information may aid in the development of more efficacious treatments and improved disease prognosis.

Acute and chronic saturated fatty acid treatment as a key instigator of the TLR-mediated inflammatory response in human adipose tissue, in vitro.

A post-prandial increase in saturated fatty acids (SFAs) and glucose (Glc) activates an inflammatory response, which may be prolonged following restoration of physiological SFAs and Glc levels--a finding referred to as 'metabolic memory'. This study examined chronic and oscillating SFAs and Glc on the inflammatory signalling pathway in human adipose tissue (AT) and adipocytes (Ads) and determined whether Ads are subject to "metabolic memory." Abdominal (Abd) subcutaneous (Sc) explants and Ads were treated with chronic low glucose (L-Glc): 5.6 mM and high glucose (H-Glc): 17.5 mM, with low (0.2 mM) and high (2 mM) SFA for 48 h. Abd Sc explants and Ads were also exposed to the aforementioned treatment regimen for 12-h periods, with alternating rest periods of 12 h in L-Glc. Chronic treatment with L-Glc and high SFAs, H-Glc and high SFAs up-regulated key factors of the nuclear factor-κB (NFκB) pathway in Abd Sc AT and Ads (TLR4, NFκB; P<.05), whilst down-regulating MyD88. Oscillating Glc and SFA concentrations increased TLR4, NFκB, IKKß (P<.05) in explants and Ads and up-regulated MyD88 expression (P<.05). Both tumor necrosis factor α and interleukin 6 (P<.05) secretion were markedly increased in chronically treated Abd Sc explants and Ads whilst, with oscillating treatments, a sustained inflammatory effect was noted in absence of treatment. Therefore, SFAs may act as key instigators of the inflammatory response in human AT via NFκB activation, which suggests that short-term exposure of cells to uncontrolled levels of SFAs and Glc leads to a longer-term inflammatory insult within the Ad, which may have important implications for patients with obesity and Type 2 diabetes.

Effects of PEG-interferon-alpha-2A on Schistosoma mansoni infection in mice.

In some regions of the world, co-existence of schistosomiasis and hepatitis C (HCV) infection is common. Because the morbidity in human schistosomiasis is primarily due to host cell-mediated immune response, it was of interest to determine the effects on Schistosoma mansoni infection of an immune stimulator used in the standard treatment of HCV infection. Schistosoma mansoni -infected mice were treated with PEG-interferon-alpha-2a (PEG-IFN-alpha) by subcutaneous injection. Groups 1, 2, and 3 received 0.2 microg, 0.6 microg, and 1 microg PEG-IFN-alpha/wk, respectively, while group 4 received saline. The total worm burden was lower in all treated groups, with a maximal reduction of 35% after 9 wk of treatment with 1 microg PEG-IFN-alpha. Interferon treatment also increased the proportion of single worms over pairs. Ova counts in intestine and liver, as well as the number of liver granulomas, were greatly decreased at all time points for all treated groups. PEG-IFN-alpha also had inhibitory effects on the size of granulomas after 4 wk of treatment. The results suggest that PEG-IFN-alpha may be worth investigating for the treatment of human schistosomiasis when standard oral agents cannot be used, or when rapid inhibition of granuloma formation may be a priority.

Elevated endotoxin levels in non-alcoholic fatty liver disease.

BACKGROUND: Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status. METHODS: Fasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8). RESULTS: Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively. CONCLUSIONS: Endotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.