Maciej Sobczyński

The influence of donepezil and EGb 761 on the innate immunity of human leukocytes: effect on the NF-κB system.

Ginkgo biloba special extract EGb 761 and donepezil are drugs used in Alzheimer therapy. The influence of donepezil and EGb 761 on two mechanisms of innate immunity, natural antiviral resistance of human leukocytes ex vivo and NF-κB activation, was studied. Correlation between the innate immunity of leukocytes and NF-κB activation was investigated. The effect of the two drugs on resistance of human leukocytes to vesicular stomatitis virus (VSV) infection was also assessed. Two groups of healthy blood donors (n=30) were distinguished: one with resistant leukocytes (n=15) and one (n=15) with leukocytes sensitive to VSV. The degree of natural resistance of human peripheral blood leukocytes (PBLs) was determined by studying the kinetics of VSV replication. NF-κB activation was assayed by immunocytochemical staining. Efficiency of donepezil and EGb 761 was determined by a special regression model. The toxicity of the preparations to PBLs and the cell lines L(929) and A(549) and their effect on the different viruses was established. Results showed that donepezil used in concentrations of 10-50 μg/ml and EGb761 of 25-100 μg/ml stimulated resistance of human leukocytes. At the same concentrations both preparations decreased activation of transcriptional factor NF-κB. Correlation between innate immunity of PBLs and NF-κB activation was observed. Comparison of the effects of these two drugs showed that EGb 761 is more effective in stimulating leukocyte resistance. Donepezil and EGb 761 regulated innate immunity of human leukocytes by stimulating resistance and modulating NF-κB activation. The natural drug was more efficient in stimulating innate antiviral immunity of human leukocytes.

ALCAM and CD6 — multiple sclerosis risk factors

ALCAM and CD6 may play an important role in the pathogenesis of multiple sclerosis (MS), since they are involved in the transmigration of leukocytes across the blood-brain barrier. In this study, we confirmed our previous findings about the association of the ALCAM gene with risk, development and progression of MS. Additionally, we showed that in the case of the CD6 gene (encoding receptor of ALCAM) not only polymorphisms but also mRNA expression level are associated with MS. Our analysis revealed that the risk of the disease for AA individuals in rs12360861 was almost 3.0-fold lower in comparison to GG individuals (OR=0.34; CI95%=0.12; 0.81). Moreover, we observed lower expression of CD6 mRNA in patients than in healthy individuals (T(2)2,74=6.678; p=0.002).

Polymorphisms in CD28, CTLA-4, CD80 and CD86 genes may influence the risk of multiple sclerosis and its age of onset

CD28/CTLA-4–CD80/CD86 molecules play an important role in the regulation of T cells activation. Defects in proteins involved in this pathway may lead to the development of autoimmune diseases in which T cells are involved. In this case–control study (336 multiple sclerosis (MS) patients and 322 controls) we investigated the possible association of eleven polymorphisms in CD28, CTLA-4, CD80 and CD86 genes with susceptibility to MS and/or its progression. We also took into account HLA-DRB1*15:01 status. Moreover, this study aimed to determine the possible gene-gene interactions between examined SNPs associated with the susceptibility to MS and its outcome. Our investigation revealed that in HLA-DRB1*15:01 negative individuals, G allele in rs231775A NGof CTLA-4 gene was associatedwith higher risk ofmultiple sclerosis. Additionally, the association of rs2715267T NGof CD86 gene withMS susceptibilitywas detected. In details, carriers of G allele at this polymorphic site possessed higher risk of MS in comparison to TT homozygotes. On the other hand, the lower risk of MS was observed in individuals carrying A allele at the rs1599795T N A polymorphic site of CD80. Furthermore, the analysis revealed an interaction between three polymorphisms: rs3116496T N C (CD28), rs6641T N G (CD80) and rs17281995G N C (CD86), associated with the age of MS onset.

Optimisation of Asymmetric Mutational Pressure and Selection Pressure Around the Universal Genetic Code

One of hypotheses explaining the origin of the genetic code assumes that its evolution has minimised the deleterious effects of mutations in coded proteins. To estimate the level of such optimization, we calculated optimal codes for genes located on differently replicating DNA strands separately assuming the rate of amino acid substitutions in proteins as a measure of codes susceptibility to errors. The optimal code for genes located on one DNA strand was simultaneously worse than the universal code for the genes located on the other strand. Furthermore, we generated 20 million random codes of which only 23 were better than the universal one for genes located on both strands simultaneously while about two orders of magnitude more codes were better for each of the two strands separately. The result indicates that the existing universal code, the mutational pressure, the codon and amino acid compositions are highly optimised for the both differently replicating DNA strands.

MS risk allele rs1883832T is associated with decreased mRNA expression of CD40

CD40-CD40L interactions mediate T-dependent B cell response and efficient T cell priming. Therefore, genes encoding these molecules are attractive candidates for studies on autoimmune diseases, such as multiple sclerosis (MS), in which activated T and B cells are involved. Thus, we analyzed CD40 and CD40L mRNA expression in whole blood samples from MS patients and controls. Additionally, we examined the effect of three SNPs of CD40 (rs1883832C>T, rs11569343C>G, and rs752118C>T) and two SNPs of CD40L (rs3092923T>C and rs3092952A>G) on their mRNA expression. Our results showed that the rs1883832C>T SNP affects CD40 gene expression. Our analysis revealed that individuals possessing CT and TT genotypes (predisposing to MS) had decreased level of CD40 mRNA in comparison to those with CC. Moreover, we demonstrated the potential role of impaired CD40-CD40L interaction in developing of multiple sclerosis.

Nitric oxide, IL-6 and IL-13 are increased in the exhaled breath condensates of children with allergic rhinitis.

To evaluate nitric oxide and interleukin (IL)‐6, IL‐8 and IL‐13 in the exhaled breath of children with allergic rhinitis (AR), before and after intranasal allergen exposure.

Frequency of human endogenous retroviral sequences (HERV) K113 and K115 in the Polish population, and their effect on HIV infection.

Background The human genome contains about 8% of endogenous retroviral sequences originated from germ cell infections by exogenous retroviruses during evolution. Most of those sequences are inactive because of accumulation of mutations but some of them are still capable to be transcribed and translated. The latter are insertionally polymorphic HERV-K113 and HERV-K115. It has been suggested that their presence and expression was connected with several human diseases. It is also believed that they could interfere with the replication cycle of exogenous retroviruses, including HIV. Results Prevalence of endogenous retroviral sequences HERV-K113 and HERV-K115 was determined in the Polish population. The frequencies were found as 11.8% for HERV-K113 and 7.92% for HERV-K115. To verify the hypothesis that the presence of these HERVs sequences could affect susceptibility to HIV infection, comparison of a control group (HIV-negative, not exposed to HIV; n = 303) with HIV-positive patients (n = 470) and exposed but uninfected (EU) individuals (n = 121) was performed. Prevalence of HERV-K113 and HERV-K115 in the EU group was 8.26% and 5.71%, respectively. In the HIV(+) group we detected HERV-K113 sequences in 12.98% of the individuals and HERV-K115 sequences in 7.23% of the individuals. There were no statistically significant differences between groups studied. Conclusion The frequency of HERV-K113 and HERV-K115 sequences in Poland were found to be higher than usually shown for European populations. No relation between presence of the HERVs and HIV infection was detected.

Association between periodontal health status and cognitive abilities. The role of cytokine profile and systemic inflammation.

Background: Contemporary neurobiology, periodontal medicine, and immunology are now focusing on the relationship between chronic periodontitis and systemic diseases, which also include Alzheimer’s disease (AD). However a causative relationship between dementia and periodontitis has yet to be confirmed. Objective: The aim of the study was to determine whether periodontal health status and cognitive abilities are correlated with the relative changes in systemic measures of pro- and anti-inflammatory cytokines as a reflection of systemic inflammation. We hypothesized that poor periodontal health status may be associated with cognitive impairment and dementia via the exacerbation of systemic inflammation. Methods: Based on the periodontal and psychiatric examinations and the cytokine levels produced by unstimulated and LPS-stimulated PBL isolated from 128 participants, we have examined if the coexisting of these two clinically described conditions may have influence on the systemic inflammation. Mini-Mental State Examination (MMSE) and Bleeding on Probing (BoP) test results were combined into the one mathematical function U, which determines the severity of specific condition, called Cognitive and periodontal impairment state. Similarly, the levels of cytokines were combined into the one mathematical function V, whose value determines the level of Inflammatory state. The correlation between U and V was determined. Results: These results confirm that the presence of cognitive decline and the additional source of pro-inflammatory mediators, like periodontal health problems, aggravate the systemic inflammation. Conclusion: It is most likely that the comorbidity of these two disorders may deepen the cognitive impairment, and neurodegenerative lesions and advance to dementia and AD.

Scaling Laws in City Growth: Setting Limitations with Self-Organizing Maps

Do scaling relations always provide the means to anticipate the relationships between the size of cities, costs of maintenance, and the socio-economic benefits resulting from their growth? Scaling laws are considered a universal principle that describes the development of complex systems such as cities. It seems that regardless of their location or history, the growth of cities is associated with the super-linear or sublinear scaling of features such as the amount of space required, infrastructure, or human activities. However, the results of our research, based on grouping by Self-Organizing Maps, reveal some limitations in the application of scaling laws: the trends of urban growth behave in a different manner when we consider both a large and diverse collection of cities and a subset of cities alike. This finding complements the existing body of knowledge on the growth of cities and allows for a more accurate prediction of their future.

Polymorphisms in genes of the BAFF/APRIL system may constitute risk factors of B-CLL – a preliminary study on a Polish population

The association of single-nucleotide polymorphisms (SNPs) of B-cell activating factor (BAFF)/a proliferation-inducing ligand (APRIL) system with B-cell chronic lymphocytic leukemia (B-CLL) have been suggested, therefore, we investigated 20 SNPs of BAFF, APRIL, BAFF-R, transmembrane activator and calcium modulator and cyclophilin-ligand interactor (TACI), B-cell maturation antigen (BCMA) genes and the risk and outcome of B-CLL in 187 patients and 296 healthy subjects as well as ligand-receptor gene × gene interactions. Although the obtained P-values for all 20 SNPs did not reach statistical significance for this study (α = 0.003), the high value of the global chi-squared statistic (χ(2) df = 38  = 52.65; P = 0.0586), and obtained values of odds ratio indicate that rs9514828 (BAFF), rs3803800 (APRIL) and rs4985726 (TACI) may be associated with the risk of B-CLL. We observed that the B-CLL patients with the genotype rs9514828CT/rs11570136AA were diagnosed with the disease 12 years later than the whole group of patients in this study.