Depression is the disease of the modern era. The lack of response to the available antidepressants, which were developed on the basis of the monoaminergic deficit hypothesis of depression, has ...encouraged scientists to think about new mechanisms explaining the pathogenesis of depression. In this context, the inflammatory theory has emerged to clarify many aspects of depression that the previous theories have failed to explain. Toll-like receptor-4 (TLR-4) has a regulatory role in the brain’s immune response to stress, and its activation is suggested to play a pivotal role in the pathophysiology of depression. In this study, we tested eritoran (ERI), a TLR-4 receptor-4 antagonist, as a potential antidepressant. We investigated the effect of long-term administration of ERI in three different doses on behavioral changes, hippocampal and prefrontal cortex (PFC) neurogenesis, and γ-aminobutyric acid (GABA)/glutamate balance in male Wistar rats exposed to chronic restraint stress (CRS). Long-term administration of ERI ameliorated CRS-induced depressive-like symptoms and hypothalamic–pituitary–adrenal axis hyperactivity alongside reducing levels of hippocampal and PFC inflammatory cytokines, restoring GABA and glutamate balance, and enhancing PFC and hippocampal neurogenesis, by increasing BDNF gene and protein expression in a dose-dependent manner. The results demonstrate an antidepressant-like activity of ERI in Wistar rats exposed to CRS, which may be largely mediated by its ability to reduce neuroinflammation, increase BDNF, and restore GABA/glutamate balance in prefrontal cortex and hippocampus. Nonetheless, further studies are needed to characterize the mechanism of the antidepressant effect of ERI.
The present study examined the effect of combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together. This combined exposure is thought ...to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of the tricyclic antidepressant imipramine and the anti-TNF-α pentoxyphylline were investigated.
Wistar rats were exposed to either repeated LPS (50μg/kg i.p.) over 2weeks, CMS protocol for 4weeks or LPS over 2weeks then 4weeks of CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes.
Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-α levels compared to those in the saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression showed significant increase in the LPS/CMS model compared to those in saline, LPS or CMS groups. The immunohistochemical findings scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-α gene expression changes induced by the LPS/CMS protocol.
This study gave a clue to the neurobiological processes underlying, at least, the subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways.
•Our results solidify the suggested link between depression and immune-inflammatory pathways.•The LPS/CMS model elaborated depressive-like symptoms.•Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression significantly increased in the LPS/CMS model.•Imipramine or pentoxifylline reversed behavioral, neurochemical and TNF-α gene expression changes induced by LPS/CMS protocol.
Breast cancer is the leading cause of cancer-related mortality. DNA methylations play important roles in cancer development and progression. Formal concept analysis was previously utilized for data ...mining hypermethylated and hypomethylated genes in breast cancer molecular subtypes in illumina methylation–based microarray database, to laboratory validate their outputs; HS3ST2 (heparan sulfate d-glucosaminyl 3-O-sulfonyl transferase-2) and MUC1 (mucin-1) were retrieved. Both play important roles in progression and invasion of breast cancer. The methylation status of both genes was laboratory validated using methylation-based polymerase chain reaction in breast cancer subtypes luminal A (early stages) and luminal B (late stages) in comparison with benign conditions and normal breast to conclude their roles in tumor invasion and to validate the newly developed algorithm (formal concept analysis). Significant cancer-specific hypermethylation of HS3ST2 was detected in luminal B (chi square = 30.6, p = 0.000), while significant cancer-specific hypomethylation of MUC1 was detected in luminal B (chi square = 30.5, p = 0.001) breast cancer. The median levels of the percentage of methylated allele of both genes were significantly discriminative between luminal A and luminal B subtypes and benign and healthy control groups. Detection of MUC1 and HS3ST2 promoter methylation status appears to be useful molecular markers for assessing the progressive state of the disease and could be helpful in discriminating breast cancer molecular subtypes. These results validate the methylation-based microarray analysis, thus trust their output in the future.
The objective of this study was to characterize the factors that influence the outcome of exposure to hepatitis C virus (HCV) genotype 4 (HCV-G4) and the course of recent infection.
In this ...longitudinal study, we prospectively assessed the clinical, genetic, virological, and immunological parameters and retrospectively determined single-nucleotide polymorphisms at interleukin-28B (IL-28B) rs12979860 in a well-characterized large cohort recently exposed to HCV-G4.
A total of 136 subjects with acute HCV (new viremia, seroconversion, and HCV-specific T-cell responses) were identified. Forty-eight subjects (35%) had spontaneous viral clearance and 88 subjects developed chronic HCV of which 42 subjects were treated with pegylated interferon monotherapy, with a sustained virologic response (SVR) rate of 88%. Twenty-six subjects developed HCV-specific T-cell immune responses without detectable viremia or seroconversion. IL-28B-CC (odds ratio (OR) 14.22; P<0.0001), multispecific T-cell responses (OR=11.66; P<0.0001), >300 IU/l alanine aminotransferase (ALT) decline within 4 weeks (OR=6.83; P<0.0001), jaundice (OR=3.54; P=0.001), female gender (OR=2.39; P=0.007), and >2.5 log10 HCV-RNA drop within 8 weeks (OR=2.48; P=0.016) were independently associated with spontaneous clearance. ALT normalization and undetectable HCV-RNA predicted SVR. Exposed apparently uninfected participants had a higher frequency of IL-28B-CC than patients with unresolved acute HCV (P<0.001). IL-28B-CC was associated with multispecific T-cell response (r(2)=0.0.835; P<0.001).
IL-28B-CC genotype, multispecific HCV T-cell responses, rapid decline in ALT, and viral load predict spontaneous clearance and response to acute HCV-G 4 therapy. IL-28B-CC genotype correlates with developing early multispecific T-cell responses. These findings have important implications for predicting the outcome of HCV exposure and acute infection and identifying patients likely to benefit from therapy.
Background: Ovarian cancer represents an important problem in gynecologic oncology. A growing tumor induces the host endothelial cells to proliferate and supply the requisite vascular support ...allowing tumor development. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) have been demonstrated to induce angiogenesis in epithelial tumors in vivo.
Patients and methods: This study included 24 tumors from patients with epithelial ovarian cancer in different stages, in addition to 20 tissue samples of benign ovarian lesions as a control group. VEGF has been measured in the cytosolic fractions using enzyme immunoassay and confirmed by Western blot analysis. Tissue IL-8 mRNA was assessed using reverse transcriptase polymerase chain reaction and immunohistochemistry for its protein.
Results: VEGF mean rank was significantly higher in ovarian cancer tumors compared to benign lesions (
P < 0.001). Moreover, it was increased with advanced stages (
P < 0.05) and in patients with poor survival (
P < 0.05). Eight samples were positive for IL-8 mRNA, seven of them were in malignant group, with highest frequency in stages III and IV of the disease (6/12, 50%). IL-8 correlated with poor survival of the patients (
P < 0.05). Log rank of Kaplan–Meier survival analysis was significant for FIGO stage, VEGF, and IL-8 (
P < 0.05).
Conclusion: These results indicate that VEGF and IL-8 are related to the malignant transformation process and can be considered as indicators of poor prognosis in epithelial ovarian cancer patients.
The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity ...among African individuals has been surveyed
. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.
Hepatitis C virus (HCV) is a major cause of chronic liver disease, end stage liver disease and liver cancer in Egypt. Genotype 4 is the prevalent genotype in Egypt and has recently spread to Southern ...Europe particularly France, Italy, Greece and Spain. Recently, new direct acting antivirals (DAAs) have caused a revolution in HCV therapy with response rates approaching 100%. Despite the diversity of DAAs, treatment of chronic hepatitis C genotype 4 has not yet been optimized. The aim of this study is to build a framework to predict the response of chronic HCV genotype 4 patients to various DAAs by applying Data Mining Techniques (DMT) on clinical information. The framework consists of three phases which are data preprocessing phase to prepare the data before applying the DMT; DM phase to apply DMT, evaluation phase to evaluate the performance and accuracy of the built prediction model using a data mining evaluation technique. The experimental results showed that the model obtained acceptable results.
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