ABSTRACT
In complex etiopathogenesis of diabetic peripheral neuropathy (DPN), hemostatic dysfunction and subclinical inflammation play a possible role. Fibrinogen is involved in both the hemostatic and inflammatory pathways, so we hypothesize that fibrinogen gene polymorphisms might be associated with DPN. A total of 127 young patients with type 1 diabetes (T1D) (average age, 18.5 ± 4.65 years; average diabetes duration, 14.5 ± 2.26 years) and 90 healthy controls were enrolled into the study. Basic biochemical and coagulation parameters were measured and gene polymorphisms of fibrinogen alpha (rs6050) and beta (rs1800790) were established. DPN was diagnosed in 38 diabetic patients by neurological examination. AA genotype and A allele of rs1800790 polymorphism of fibrinogen beta were associated with increased risk of DPN (odds ratio [OR] 4.537, 95% confidence interval [95CI] 1.14-19.94, p = 0.019 and OR 1.958, 95CI 1.038-3.675, p = 0.029, respectively). No association was found between DPN and rs6050 gene polymorphisms. Plasma fibrinogen concentration significantly correlated with HbA1c (Spearman's correlation coefficient [r] = 0.54) and HDL cholesterol (r = - 0.67). A allele and AA genotype of rs1800790 seem to be associated with DPN in young patients with T1D. Further studies are appropriate to elucidate the role of fibrinogen gene polymorphisms in the complex etiology of DPN.
Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Diabetic Neuropathies/etiology , Diabetic Neuropathies/genetics , Fibrinogen/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Alleles , Case-Control Studies , Child , Cross-Sectional Studies , Diabetes Mellitus, Type 1/epidemiology , Diabetic Neuropathies/epidemiology , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Risk Factors , Slovakia/epidemiology , Young AdultABSTRACT
A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid ß (Aß) aggregation and mitochondrial enzyme ABAD, whose interaction with Aß leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aß aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
