The role of the Amyloid Precursor Protein mutations and PERK-dependent signaling pathways in the pathogenesis of Alzheimer’s disease

Alzheimer’s disease (AD) is a highly complex, progressive, age-related neurodegenerative human disease entity. The genetic basis of AD is strictly connected with occurrence of mutations in Amyloid Precursor (APP) gene on chromosome 21. Molecular mechanism that leads to AD development still remains unclear. Recent data reported that it is closely correlated with Endoplasmic Reticulum (ER) stress conditions, which subsequently activate Unfolded Protein Response (UPR) signaling pathways, via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a self-protective, adaptive response to adverse stress conditions. That results in the attenuation of global protein synthesis and, on the contrary, selective translation of Activating Transcriptor Factor 4 (ATF4) and secretase β. Interestingly, under prolonged, severe ER stress UPR may switch its signal into apoptotic cell death. That ensues by ATF4-CHOP-mediated activation of a range of pro-apoptotic genes and, on the other hand, downregulation of the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) genes. Current investigations suggest that inhibitions of PERK activity may contribute to the attenuation of the deposition of toxic senile plaques in the brain tissue and, as a result, prevent degeneration of neurons and decline in cognitive abilities

The Level of Isoprostanes as a Non-invasive Marker for in vivo Lipid Peroxidation in Secondary Progressive Multiple Sclerosis

This article is published with open access at Springerlink.comOxidative stress leads to lipid peroxidation and may contribute to the pathogenesis of lesions in multiple sclerosis (MS), an autoimmune disease characterized by inflammatory as well as degenerative phenomena. Isoprostanes are prostaglandin-like compounds which are formed by free radical catalysed peroxidation of arachidonic acid esterified in membrane phospholipids. They are a new class of sensitive specific markers for in vivo lipid peroxidation. In this study 26 patients (15 females and 11 males; mean age 48.2 ± 15.2 year; mean disease duration 10.0 ± 6.5 year) with secondary progressive MS (SPMS) and 12 healthy controls were enrolled. In patients with multiple sclerosis the lipid peroxidation as the level of urine isoprostanes and the level of thiobarbituric acid reactive species (TBARS) in plasma were estimated. Moreover, we estimated the total antioxidative status (TAS) in plasma. It was found that the urine isoprostanes level was over 6-fold elevated in patients with SPMS than in control (P\0.001). In SPMS patients TBARS level was also statistically higher than in controls (P\0.01).However, we did not observed any difference of TAS level in serum between SPMS patients and controls (P[0.05). In patients with SPMS the lipid peroxidation and oxidative stress measured as the increased level of isoprostanes was observed. Thus, we suggest that the level of isoprostanes may be used as non-invasive marker for a determination of oxidative stress what in turn, together with clinical symptoms, may determine an specific antioxidative therapy in SPMS patients

Single nucleotide polymorphisms of NR3C1 gene and recurrent depressive disorder in population of Poland

Depressive disorder is a disease characterized by disturbances in the hypothalamo–pituitary–adrenal axis. Abnormalities include the increased level of glucocorticoids (GC) and changes in sensitivity to these hormones. The changes are related to glucocorticoid receptors gene (NR3C1) variants. The NR3C1 gene is suggested to be a candidate gene affecting depressive disorder risk and management. The aim of this study was to investigate polymorphisms within the NR3C1 gene and their role in the susceptibility to recurrent depressive disorder (rDD). 181 depressive patients and 149 healthy ethnically matched controls were included in the study. Single nucleotide polymorphisms were assessed using polymerase chain reaction/restriction fragment length polymorphism method. Statistical significance between rDD patients and controls was observed for the allele and genotype frequencies at three loci: BclI, N363S, and ER22/23EK. The presence of C allele, CC, and GC genotype of BclI polymorphism, G allele and GA genotype for N363S and ER22/23EK variants respectively were associated with increased rDD risk. Two haplotypes indicated higher susceptibility for rDD, while haplotype GAG played a protective role with OR(dis) 0.29 [95 % confidence interval (CI) = 0.13–0.64]. Data generated from this study support the earlier results that genetic variants of the NR3C1 gene are associated with rDD and suggest further consideration on the possible involvement of these variants in etiology of the disease

Genetic polymorphisms in DNA base excision repair gene XRCC1 and the risk of squamous cell carcinoma of the head and neck

<p>Abstract</p> <p>Background</p> <p>The genes of base excision repair (BER) pathway have been extensively studied in the association with various human cancers. We performed a case-control study to test the association between two common single nucleotide polymorphisms (SNPs) of <it>XRCC1 </it>gene with human head and neck squamous cell carcinoma (HNSCC).</p> <p>Methods</p> <p>The genotype analysis of Arg194Trp and Arg399Gln gene polymorphisms for 92 HNSCC patients and 124 controls of cancer free subjects, in Polish population were performed using the PCR-based restriction fragment length polymorphism (PCR-RFLP) with endonuclease <it>Msp</it>I.</p> <p>Results</p> <p>No altered risk has been found individually for these SNPs, however haplotypes analysis showed high association with head and neck cancer. The highest frequency, according to wild-type of Arg194Arg and Arg399Arg genotypes, was identified for Arg194Trp-Arg399Arg haplotype (OR, 2.96; 95% CI, 1.01–8.80).</p> <p>Conclusion</p> <p>Finally, we identified the combined Arg194Trp-Arg399Arg genotype of base excision repair gene <it>XRCC1 </it>that was associated with HNSCC and may have an impact on identification of a high-risk cancer population.</p

New tetrahydroacridine hybrids with dichlorobenzoic acid moiety demonstrating multifunctional potential for the treatment of Alzheimers disease

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver-Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H)

The Level of Isoprostanes as a Non-invasive Marker for in vivo Lipid Peroxidation in Secondary Progressive Multiple Sclerosis

Oxidative stress leads to lipid peroxidation and may contribute to the pathogenesis of lesions in multiple sclerosis (MS), an autoimmune disease characterized by inflammatory as well as degenerative phenomena. Isoprostanes are prostaglandin-like compounds which are formed by free radical catalysed peroxidation of arachidonic acid esterified in membrane phospholipids. They are a new class of sensitive specific markers for in vivo lipid peroxidation. In this study 26 patients (15 females and 11 males; mean age 48.2 ± 15.2 year; mean disease duration 10.0 ± 6.5 year) with secondary progressive MS (SPMS) and 12 healthy controls were enrolled. In patients with multiple sclerosis the lipid peroxidation as the level of urine isoprostanes and the level of thiobarbituric acid reactive species (TBARS) in plasma were estimated. Moreover, we estimated the total antioxidative status (TAS) in plasma. It was found that the urine isoprostanes level was over 6-fold elevated in patients with SPMS than in control (P < 0.001). In SPMS patients TBARS level was also statistically higher than in controls (P < 0.01). However, we did not observed any difference of TAS level in serum between SPMS patients and controls (P > 0.05). In patients with SPMS the lipid peroxidation and oxidative stress measured as the increased level of isoprostanes was observed. Thus, we suggest that the level of isoprostanes may be used as non-invasive marker for a determination of oxidative stress what in turn, together with clinical symptoms, may determine an specific antioxidative therapy in SPMS patients

Angiogenesis Markers Quantification in Breast Cancer and Their Correlation with Clinicopathological Prognostic Variables

Tumoural angiogenesis is essential for the growth and spread of breast cancer cells. Therefore the aim of this study was to assess the diagnostic performance of angiogenesis markers in tumours and there reflecting levels in serum of breast cancer patients. Angiogenin, Ang2, fibroblast growth factor basic, intercellular adhesion molecule (ICAM)-1, keratinocyte growth factor (KGF), platelet-derived growth factor-BB, and VEGF-A were measured using a FASTQuant angiogenic growth factor multiplex protein assay. We observed that breast cancer tumours exhibited high levels of PDGF-BB, bFGF and VEGF, and extremely high levels of TIMP-1 and Ang-2, whereas in serum we found significantly higher levels of Ang-2, PDGF-BB, bFGF, ICAM-1 and VEGF in patients with breast cancer compared to the benign breast diseases patients. Moreover, some of these angiogenesis markers evaluated in tumour and serum of breast cancer patients exhibited association with standard clinical parameters, ER status as well as MVD of tumours. Angiogenesis markers play important roles in tumour growth, invasion and metastasis. Our results suggest that analysis of angiogenesis markers in tumour and serum of breast cancer patients using multiplex protein assay can improve diagnosis and prognosis in this diseases

Association of base excision repair pathway genes OGG1, XRCC1 and MUTYH polymorphisms and the level of 8-oxo-guanine with increased risk of colorectal cancer occurrence

Objectives Reduced efficiency of DNA repair systems has long been a suspected factor in increasing the risk of cancer. In this work authors investigate influence of selected polymorphisms of DNA repair genes (XRCC1, OGG1 and MUTYH) and level of oxidative damage (measured as level of 8-oxo-guanine, 8-oG) on modulation of the risk of colorectal cancer. Material and Methods In group of 324 patients with colorectal cancer the occurrence of polymorphic variants in Ser326Cys of OGG1, Arg399Gln of XRCC1 and Gln324His of MUTYH were studied with TaqMan technique. In addition level of 8-oG in isolated DNA was determined. Results Studied polymorphisms of OGG1, XRCC1 and MUTYH genes influence the risk of CRC: OGG1 Ser326Cys (OR = 1.259, 95% CI: 1.058–1.499, p = 0.007), XRCC1 Arg399Gln (OR = 2.481, 95% CI: 1.745–3.529, p < 0.0001) and MUTYH Gln324His (OR = 1.421, 95% CI: 1.017–1.984, p = 0.039) increase the risk. At the same time, studies examined level of 8-oG for each of the genotypes in both the patient and control group, and have shown that OGG1 Ser326Cys and XRCC1 Arg399Gln are associated with elevated 8-oG level, while MUTYH Gln324His is not, suggesting, that in case of OGG1 Ser326Cys and XRCC1 Arg399Gln CRC risk modulation is connected to mechanisms associated with 8-oG levels. Conclusions This work shows that patients with CRC not only have an increased level of 8-oG and that the studied polymorphisms modulate risk of cancer, but also indicate a relationship between these 2 phenomena, which may contribute to a better understanding of the mechanism of neoplastic process in case of reduced effectiveness of DNA repair mechanisms

miRNA-Dependent CD4+ T Cell Differentiation in the Pathogenesis of Multiple Sclerosis

Multiple sclerosis (MS) is characterized by multifocal lesions, chronic inflammatory condition, and degenerative processes within the central nervous system (CNS) leading to demyelination. The most important cells involved in its pathogenesis are those which are CD4+, particularly proinflammatory Th1/Th17 and regulatory Treg. Signal cascades associated with CD4+ differentiation are regulated by microRNAs (miRNAs): short, single-stranded RNAs, responsible for negative regulation of gene expression at the posttranscriptional level. Several miRNAs have been consistently reported as showing dysregulated expression in MS, and their expression patterns may be elevated or decreased, depending on the function of specific miRNA in the immune system. Studies in MS patients indicate that, among others, miR-141, miR-200a, miR-155, miR-223, and miR-326 are upregulated, while miR-15b, miR-20b, miR-26a, and miR-30a are downregulated. Dysregulation of these miRNAs may contribute to the imbalance between pro- and anti-inflammatory processes, since their targets are associated with the regulation of Th1/Th17 and Treg cell differentiation. Highly expressed miRNAs can in turn suppress translation of key Th1/Th17 differentiation inhibitors. miRNA dysregulation may result from the impact of various factors at each stage of their biogenesis. Immature miRNA undergoes multistage transcriptional and posttranscriptional modifications; therefore, any protein involved in the processing of miRNAs can potentially lead to disturbances in their expression. Epigenetic modifications that have a direct impact on miRNA gene transcription may also play an important role