IL-28ß gene polymorphism determines virological response to PEGylated interferon therapy in hepatitis C virus genotype 4 Egyptian patients.

BACKGROUND: PEGylated interferon (PEG-IFN) in combination with ribavirin is the gold standard for chronic hepatitis C virus (HCV). The majority of patients received PEG-IFN/ribavirin achieve a sustained viral response (SVR), but few cases failed to respond. It was evident that host genetic factors determine the treatment-induced viral clearance as well as spontaneous response. In the current study, the rs12979860 polymorphism of IL28ß gene was analyzed and its association with the virological response to PEG-IFN treatment was determined. METHODS: One hundred and fifty Egyptian patients with HCV genotype 4 treated with PEG-IFN/ribavirin were assessed at 12 and 24 weeks of therapy, the rs12979860 genotype was determined using TaqMan-based quantitative polymerase chain reaction. RESULTS: Although the CC genotype was the most frequent (58%), the higher SVR was achieved for patients with favorable CC genotype (93%) in contrast to CT and TT genotypes. CONCLUSION: we conclude that IL28B polymorphism is highly associated with SVR to therapy in the Egyptian population infected with HCV genotype 4 and patients who carry CC genotype have a higher chance of SVR.

Flaxseed suppressed prostatic epithelial proliferation in a rat model of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH), a disease occurring frequently among elderly males, is a slow progressive enlargement of the fibromuscular and epithelial structures of the prostate gland. Dietary factors may influence the prostate and exert an influence on prostatic growth and disease. The current study was undertaken to investigate the protective effect of dietary flaxseed supplementation against testosterone-induced prostatic hyperplasia in male rats. Forty male Wistar rats were divided into 5 groups: (1) untreated control; (2) treatment with testosterone propionate (TP) to induce prostate enlargement; (3) TP-treated group fed a diet containing 5% milled flaxseed; (4) TP-treated group fed a diet containing 10% milled flaxseed; and (5) TP-treated group fed a diet containing 20 ppm finasteride. Treatment with TP significantly increased the absolute and relative weights of different prostatic lobes, serum testosterone (T), and testosterone/estradiol ratio, as well as prostatic vascular endothelial growth factor (VEGF) expression, RNA synthesis per cell, and epithelial cell proliferation, detected as Ki67 labeling. Histopathological examination did not reveal marked differences in acinar morphology in ventral prostate, whereas morphometric analysis showed significantly increased epithelial cell height. Co-administration of flaxseed or finasteride with TP significantly reduced prostatic VEFG, epithelial cell proliferation, and RNA/DNA ratio, along with a significant increase in serum T and testosterone/estradiol ratio compared with TP-only-treated rats. Our results indicate that flaxseed, similar to the 5α-reductase inhibitor finasteride, blocked TP-induced prostate enlargement in a rat model of BPH, likely through suppression of prostatic VEFG and cellular proliferation.

Sensitivity and specificity of microRNA-204, CA125, and CA19.9 as biomarkers for diagnosis of ovarian cancer.

BACKGROUND: Ovarian cancer is usually detected at later stages and no effective screening approach, has been identified. Therefore, sensitive and specific biomarkers for detecting ovarian cancer are urgently needed. OBJECTIVE: This study aimed to investigate the efficacy of six biomarkers for the early clinical diagnosis of ovarian cancer. SUBJECTS & METHODS: The study included 120 patients (benign ovarian tumors and early and late ovarian carcinoma) and 30 control healthy volunteers. MiRNA-204, CA125, CA19.9, hepcidin, microfibril-associated glycoprotein 2, and ferroportin levels were determined in all patients and control volunteers. RESULTS: The combined area under the receiver operating characteristic curves for miRNA-204, CA125, and CA19.9 were 0.938, 1.000, and 0.998 for benign tumors and early and late ovarian carcinomas, respectively. The sensitivities of miRNA-204, CA125, and CA19.9 were 98.04%, 100.00%, and 96.19% and the specificities were 58.33%, 62.50%, and 57.78%, respectively. CONCLUSION: The positive predictivity of miRNA-204, CA125, and CA19.9 for ovarian cancer is high (59.57%, 58.24%, and 61.67%, respectively). Thus, the combination of these three biomarkers is a good diagnostic tool for ovarian cancer.

Novel quercetin encapsulated chitosan functionalized copper oxide nanoparticles as anti-breast cancer agent via regulating p53 in rat model.

This study was designed to present a new quercetin encapsulated chitosan functionalized copper oxide nanoparticle (CuO-ChNPs-Q) and assessed its anti-breast cancer activity both in vitro and in vivo. The CuO-ChNPs-Q may act as anti-proliferating agent against DMBA-induced mammary carcinoma in female rats. The CuONPs was functionalized with chitosan then quercetin was conjugated with them producing CuO-ChNPs-Q, then characterized. The in vitro anti-proliferating activity of the CuO-ChNPs-Q was evaluated against three human cell line. Then, the anti-breast cancer effect of the CuO-ChNPs-Q was assessed against DMBA-induction compared to both CuONPs and Q in female rat model. The in vitro results proved the potent anticancer activity of the CuO-ChNPs-Q compared to CuONPs and quercetin. The in vivo data showed significant reduction in breast tumors of DMBA-induced rats treated with CuO-ChNPs-Q compared to CuONPs and Q. The CuO-ChNPs-Q treatment had induced apoptosis via increased p53 gene, arrested the cell-cycle, and increased both cytochrome c and caspase-3 levels leading to mammary carcinoma cell death. Also, the CuO-ChNPs-Q treatment had suppressed the PCNA gene which decreased the proliferation of the mammary carcinoma cells. In conclusion, the CuO-ChNPs-Q might be a promising chemotherapeutic agent for treatment of breast cancer with a minimal toxicity on vital organs.

Assessment of the association of serum progranulin with autophagy in diabetic patients.

INTRODUCTION: Progranulin (PGRN) has newly arisen as an important regulatory protein of glucose metabolism and insulin sensitivity. Progranulin expression is interrelated with lysosomal function strongly linked to autophagy pathway. We aimed to evaluate the correlation between PGRN protein and microtubule-associated protein light chain 3B (LC3B) expression level in diabetic patients. MATERIAL AND METHODS: Blood samples of 70 type 2 diabetic Egyptian patients were provided for analysis of concentrations of serum progranulin and interleukin 6 (IL-6) using ELISA, and quantifying expression of LC3B RNA level using qPCR. A group of 20 healthy volunteers were also enrolled. RESULTS: Serum levels of PGRN and IL-6 as well as LC3B gene expression levels were markedly higher in type 2 diabetic patients. Additionally, our study revealed a cut-off value of 18.14 ng/mL for progranulin serum level and 3.23 for LC3B expression level, with sensitivities of 83.6% and 75.4% and specificities of 83.8% and 58.3%, respectively. Circulating PGRN levels are positively correlated with body mass index (BMI), glucose concentration, and IL-6. CONCLUSION: Our results support the hypothesis that progranulin is introduced as a novel marker of chronic inflammatory response in type 2 diabetes that aggravates insulin resistance via activated autophagy, indicating the importance of this novel adipokine in the regulation of glucose metabolism and as a promising therapeutic target in the treatment of diabetes. KEY WORDS: diabetes; progranulin; autophagy; microtubule-associated proteins light chain 3B; interleukin 6.

Upregulation of long noncoding RNA Lnc-IRF2-3 and Lnc-ZNF667-AS1 is associated with poor survival in B-chronic lymphocytic leukemia.

BACKGROUND: Lnc-IRF2-3 and Lnc-ZNF667-AS1 were recently studied as a positive biomarker for many tumor cells. However, experimental studies found that they are associated with worse outcomes in B-CLL. METHODS: A prospective case study was conducted on 135 B-CLL patients that were compared to thirty healthy controls. The patients were followed up for 40 months and quantitative measurements of Lnc-IRF2-3 and Lnc-ZNF667-AS1 were measured and compared between the two groups as well as high-risk and low low-risk B-CLL. RESULTS: Lnc-IRF2-3 and Lnc-ZNF667-AS1 had a high specificity (94% and 85%) and sensitivity (85%, 87%), respectively, to differentiate B-CLL from healthy controls. Furthermore, they showed high expression levels in high-risk CLL groups. For survival analysis, there was a negative correlation between overall survival (OS) and progression-free survival (PFS) and both biomarkers. However, it was not evident in multivariate Cox regression analysis; in patients with Lnc-IRF2-3 expression level, >67 had a significant decrease in OS and PFS. However, there is no significant effect for high expression levels of Lnc-ZNF667-AS1 on OS (P = .16) or PFS (P = .48). CONCLUSION: The Lnc-IRF2-3 and Lnc-ZNF667-AS1 are promising prognostic biomarkers in B-CLL.

Pterocarpus santalinus ameliorates streptozotocin-induced diabetes mellitus via anti-inflammatory pathways and enhancement of insulin function.

OBJECTIVES: Morbidity and mortality due to diabetes mellitus (DM) result in exorbitant psycho-economical costs, so there is a strong need to create new strategies and drugs for controlling DM. The aim of the current study was to investigate the anti-diabetic effect of the aqueous extract of Pterocarpus santalinus on streptozotocin (STZ)-induced DM as compared to glustin. MATERIALS AND METHODS: Thirty male rats were divided into five groups of six rats each as follows: control; the second group, received the aqueous plant extract (250 mg/kg) orally and daily for three weeks; the third group, was intraperitoneally injected with a single dose of 65 mg/kg of STZ and sacrificed after four weeks; the fourth and fifth groups, were injected with STZ, then after one week these were treated orally with either plant extract or with 3 mg/kg of glustin for three weeks, then sacrificed. RESULTS: HPLC analysis of the plant aqueous extract showed that it contains many polyphenols and flavonoids. Treatment with STZ resulted in significant reductions in body weight, insulin level, and the expression of Fetuin-A and IRS-1. It also caused significant elevations in glucose, HOMA-IR, glycated hemoglobin, urea, and the expression of JNK and SIRT-1. STZ also caused an extensive ß-cell degranulation and decreased cellular density. The aqueous extract of red sandalwood was able to abrogate the deleterious effects caused by STZ and improved the histological architecture of pancreas. CONCLUSION: The aqueous extract of P. santalinus ameliorates diabetes mellitus via anti-inflammatory pathways and enhancement of insulin function.

Synergistic Effect of α-Solanine and Cisplatin Induces Apoptosis and Enhances Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells.

AIM: The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated. METHODS: HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement. RESULTS: α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression. CONCLUSION: Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma.

An unconventional RNA-based thermosensor within the 5' UTR of Staphylococcus aureus cidA.

Staphylococcus aureus is a Gram-positive bacterial pathogen of global concern and a leading cause of bacterial infections worldwide. Asymptomatic carriage of S. aureus on the skin and in the anterior nares is common and recognized as a predisposing factor to invasive infection. Transition of S. aureus from the carriage state to that of invasive infection is often accompanied by a temperature upshift from approximately 33°C to 37°C. Such a temperature shift is known in other pathogens to influence gene expression, often resulting in increased production of factors that promote survival or virulence within the host. One mechanism by which bacteria modulate gene expression in response to temperature is by the regulatory activity of RNA-based thermosensors, cis-acting riboregulators that control translation efficiency. This study was designed to identify and characterize RNA-based thermosensors in S. aureus. Initially predicted by in silico analyses of the S. aureus USA300 genome, reporter-based gene expression analyses and site-specific mutagenesis were performed to demonstrate the presence of a functional thermosensor within the 5' UTR of cidA, a gene implicated in biofilm formation and survival of the pathogen. The nucleic sequence composing the identified thermosensor are sufficient to confer temperature-dependent post-transcriptional regulation, and activity is predictably altered by the introduction of site-specific mutations designed to stabilize or destabilize the structure within the identified thermosensor. The identified regulator is functional in both the native bacterial host S. aureus and in the distally related species Escherichia coli, suggesting that its regulatory activity is independent of host-specific factors. Interestingly, unlike the majority of bacterial RNA-based thermosensors characterized to date, the cidA thermosensor facilitates increased target gene expression at lower temperatures. In addition to the characterization of the first RNA-based thermosensor in the significant pathogen S. aureus, it highlights the diversity of function within this important class of ribo-regulators.

Umbelliferone and daphnetin ameliorate carbon tetrachloride-induced hepatotoxicity in rats via nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1 expression.

Among various phytochemicals, coumarins comprise a very large class of plant phenolic compounds that have good nutritive value, in addition to their antioxidant effects. The purpose of the present study was to investigate the protective effects of two coumarin derivatives, umbelliferone and daphnetin, against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats and elucidate the underlying mechanism. Treatment of rats with either umbelliferone or daphnetin significantly improved the CCl4-induced biochemical alterations. In addition, both compounds alleviated the induced-lipid peroxidation and boosted the antioxidant defense system. Moreover, the investigated compounds attenuated CCl4-induced histopathological alterations of the liver. Finally, umbelliferone and daphnetin induced the nuclear translocation of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective heme oxygenase-1 (HO-1). These results suggest that umbelliferone and daphnetin ameliorate oxidative stress-related hepatotoxicity via their ability to augment cellular antioxidant defenses by activating Nrf2-mediated HO-1 expression.