Discovery of alkenylboronic acids as neuroprotective agents affecting multiple biological targets involved in Alzheimer’s disease

Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.     

Levodopa influences the regularity of the ankle joint kinematics in individuals with Parkinson’s disease

The aim of the investigation was to explore the influence of levodopa therapy on the regularity of the structural variations present in the lower extremity joints of individuals with Parkinson’s disease (PD). Ten participants with PD walked on a treadmill during the states of “off” and “on” levodopa. Approximate entropy was used to quantify the regularity of the structural variations present in the joint kinematics. Additionally, a pseudo-periodic surrogation analysis was used to evaluate if changes in the regularity of the joint’s movement were associated with a noisy or deterministic motor process. This investigation provided two key findings. The first was that the structural variations present in ankle joint were more regular with levodopa therapy. The second was that changes in the structural variations were related to a deterministic motor process. This indicated that the variations present in the walking patterns of individuals with PD most likely arose from higher-order neural couplings rather than noise in the motor process. Monitoring the regularity of the structural variations present in gait may help improve the management of PD.     

Clock gene PERIOD3 polymorphism is associated with susceptibility to Graves’ disease but not to Hashimoto’s thyroiditis

ABSTRACT

Circadian disruption has been linked with immune-related morbidities including autoimmune diseases. PERIOD3 (PER3) clock gene is a key player in the mammalian circadian system. This study evaluated the possible association of PER3 rs2797685 (G/A) polymorphism and susceptibility of autoimmune thyroid diseases (AITD) and assessed if this SNP contributes to disease characteristics and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The PER3 rs2797685 (G/A) polymorphism was assessed in 125 patients with AITD [Graves’ disease (GD), 69; Hashimoto’s thyroiditis (HT), 56] and 115 unrelated healthy controls. Subjects carrying at least one variant allele of PER3 rs2797685 (GA+AA) had increased risk for GD (OR 1.9, 95% CI 1–3.61, p= .05). There were no differences in the frequencies of genotypes and alleles of the PER3 rs2797685 polymorphism between HT patients and control subjects. No association was observed between genotypes of the studied SNP and any of the disease characteristics in GD and HT patients. The GA+AA genotype of PER3 rs2797685 was associated with lower levels of IL-6 in patients with Graves’ disease. There were no differences between genotypes of the studied SNP regarding TNF-α levels in GD, HT or control groups. In conclusion, this study provides the first evidence for a genetic association between GD and the PER3 gene, highlighting the possible relevance of polymorphisms in clock genes in the etiopathogenesis of AITD. However, functional studies to identify the underlying molecular mechanisms of this association are needed to translate these findings to clinical applications.     

Complexity of resting-state EEG activity in the patients with early-stage Parkinson’s disease

To investigate the abnormal brain activities in the early stage of Parkinson’s disease (PD), the electroencephalogram (EEG) signals were recorded with 20 channels from non-dementia PD patients (18 patients, 8 females) and age matched healthy controls (18 subjects, 8 females) during the resting state. Two methods based on the ordinal patterns of the recorded series, i.e., permutation entropy (PE) and order index (OI), were introduced to characterize the complexity of the cortical activities for two groups. It was observed that the resting-state EEG of PD patients showed lower PE and higher OI than healthy controls, which indicated that the early-stage PD caused the reduced complexity of EEG. We further applied two methods to determine the complexity of EEG rhythms in five sub-bands. The results showed that the gamma, beta and alpha rhythms of PD patients were characterized by lower PE and higher OI, i.e., reduced complexity, than healthy subjects. No significant differences were observed in theta or delta rhythms between two groups. The findings suggested that PE and OI were promising methods to detect the abnormal changes in the dynamics of EEG signals associated with early-stage PD. Further, such changes in EEG complexity may be the early markers of the cortical or subcortical dysfunction caused by PD.     

DNM3OS regulates GAPDH expression and influences the molecular pathogenesis of Huntington’s disease

Emerging studies have suggested that dysregulated long non-coding RNAs (lncRNAs) are associated with the pathogenesis of neurodegenerative diseases (NDD) including Huntington's disease (HD); however, the pathophysiological mechanism by which lncRNA dysregulation participates in HD remains to be elucidated. Here, we aim to analyse the expression of lncRNA-DNM3OS and identify the possible DNM3OS/miR-196b-5p/GAPDH pathway. PC12 cells induced by rat pheochromocytoma expressing HD gene exon 1 fragment with either 23 or 74 polyglutamine repeats fused to the green fluorescent protein (GFP) were cultured. Our results show that GAPDH and DNM3OS were upregulated in HD PC12 cells, downregulation of which lead to inhibition of aggregate formation accompanied by a decreased apoptosis rate and increased relative ROS levels and cell viability. Moreover, upregulated DNM3OS decreased the expression of miR-196b-5p by sponging, and GAPDH was a direct target of miR-196b-5p, playing an important pathogenic role in the formation of aggregates in the HD cell model. Our study uncovers a novel DNM3OS/miR-196b-5p/GAPDH pathway involved in the molecular pathogenesis of HD, which may offer a potential therapeutic strategy for HD.     

Crohn’s disease of the colon: ultrastructural changes in submuscular interstitial cells of Cajal

Interstitial cells of Cajal (ICC) at the submuscular border of the human colon (ICC-SMP) are the proposed pacemaker cells of the musculature. In patients with Crohn’s disease (CD) of the colon, ICC-SMP showed characteristic cytological changes from controls. The changes comprised secondary lysosomes in connection with lipid droplets and cytoplasmic vacuoles or multiple empty, confluent and often outbulging vacuoles merging with cisterns of granular endoplasmic reticulum and clusters of glycogen granules. These changes were most pronounced in patients with macroscopical mucosal inflammation but were also demonstrable in uninvolved colonic segments. Relationships of ICC to other cells were undisturbed. The changes were selective to ICC-SMP, as glial cells, muscle cells and fibroblast-like cells at the submuscular border showed no cytological alterations compared with controls. Varicosities of the submuscular plexus were often empty and dilated. Fibroblast-like cells selectively encased macrophages and mast cells. The cytological changes in ICC-SMP in CD are thus similar to changes seen in ulcerative colitis and may be of pathophysiological significance with regard to the motility and sensory disturbances seen in patients with CD.     

A comparative analysis of the molecular genetic processes in the pathogenesis of psoriasis and Crohn’s disease

Molecular Biology - A comparative bioinformatics analysis of the molecular genetic processes in the pathogenesis of multifactorial diseases—psoriasis and Crohn’s disease—was...     

LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn’s disease

Background

Long non-coding RNAs (lncRNAs) have different functions in cells. They work as signals, decoys, guides, and scaffolds. Altered lncRNA levels can affect the expression of gene products. There are seldom studies on the role of lncRNAs in inflammatory bowel disease (IBD).

Results

Quantitative RT-PCR showed that {"type":"entrez-nucleotide","attrs":{"text":"DQ786243","term_id":"110631570","term_text":"DQ786243"}}DQ786243 was significantly overexpressed in clinical active CD patients compared with clinical inactive CD patients (P = 0.0118) or healthy controls (P = 0.002). CREB was also more highly expressed in active CD than in inactive CD (P = 0.0034) or controls (P = 0.0241). Foxp3 was interestingly lower in inactive CD than in active CD (P = 0.0317) or controls (P = 0.0103), but there were no apparent differences between active CD and controls. CRP was well correlated with {"type":"entrez-nucleotide","attrs":{"text":"DQ786243","term_id":"110631570","term_text":"DQ786243"}}DQ786243 (r = 0.489, P = 0.034), CREB (r = 0.500, P = 0.029) and Foxp3 (r = 0.546, P = 0.016). At 48 hours after {"type":"entrez-nucleotide","attrs":{"text":"DQ786243","term_id":"110631570","term_text":"DQ786243"}}DQ786243 transfection, qRT-PCR showed both CREB (P = 0.017) and Foxp3 (P = 0.046) had an increased mRNA expression in Jurkat cells. Western blot showed the same pattern. After {"type":"entrez-nucleotide","attrs":{"text":"DQ786243","term_id":"110631570","term_text":"DQ786243"}}DQ786243 transfection, CREB phosphorylation ratio (p-CREB/t-CREB) was increased (P = 0.0043).

Conclusion

{"type":"entrez-nucleotide","attrs":{"text":"DQ786243","term_id":"110631570","term_text":"DQ786243"}}DQ786243 can be related with severity of CD. It can affect the expression of CREB and Foxp3 through which regulates the function of Treg. CREB itself seems not the mediator of {"type":"entrez-nucleotide","attrs":{"text":"DQ786243","term_id":"110631570","term_text":"DQ786243"}}DQ786243 to up-regulate Foxp3. The phosphorylation of CREB might play a more important role in the process.     

Immediate response to translocation without acclimation from captivity to the wild in Hermann’s tortoise

Survival, reproductive and recruitment rates, along with health status, of translocated and resident individuals should be evaluated. However, gathering this information poses logistical constraints and requires long-term studies. Considering the urgent nature of many species’ situations where translocation would be appropriate, fast-assessment techniques should be tested. We assessed the immediate response to translocation of Hermann’s tortoises (Testudo hermanni hermanni) directly from captivity to the wild. Individuals were maintained in captivity 2 to 8 years before being released in spring 2013 into a natural population impacted by fire. During the critical 3 months post-release period, we radio-tracked translocated individuals (N?=?12) and resident tortoises in spring 2013 (N?=?14), plus another batch of resident tortoises in spring 2012 (N?=?9). Movements, behaviours, body condition and body temperature were regularly recorded. All translocated tortoises acclimated well to their novel environment. We found no differences in movement, thermoregulation and body condition between translocated and resident tortoises. Body condition of all tortoises increased rapidly in spring. We found no sign of perturbation in resident tortoises. Contrarily, resident males mated with translocated females. Translocations should be further tested on larger spatial and time scales to improve population restoration programmes, especially in threatened species with limited dispersal ability.     

Growth peculiarities of commensal Escherichia coli isolates from the gut microflora in Crohn’s disease patients

Verhulst’s logistic differential equation, popular in mathematical ecology, is used in modeling of population growth, neural networks, statistics, reaction models, Fermi distribution, modeling of tumor growth, etc. We used this function to characterize growth of commensal Escherichia coli isolates from gut microflora in Crohn’s disease patients. The results of our investigations show differences in growth parameters of commensal E. coli, isolated from the gut microflora in Crohn’s disease patients and healthy volunteers; it is most likely explained by the influence of chronic inflammatory processes on growth and reproduction of these bacteria. It has been established that the used mathematical model well characterizes growth of patients’ gut E. coli isolates, and it can be important for the expedient probiotics’ application during the disease.     

HLA-DRB1 * 03, but not the TNFA -308 promoter gene polymorphism, confers protection against fistulising Crohn’s disease

 Crohn’s disease (CD) appears in forms so diverse that it has been hypothesized CD might be a syndrome, with different pathogenic mechanisms leading to the various clinical phenotypes. This may plausibly explain the conflicting and inconclusive results with regard to HLA associations in unselected groups of patients. The power of these association studies may increase when disease heterogeneity is taken into account. As fistulising CD has been proposed as a separate subgroup of patients with CD, we studied the carrier frequencies (CF) of the DRB1 alleles in 35 unrelated Caucasian Dutch CD patients with proven peri-anal fistulas. A striking decrease in the frequency of the DRB1 ^* 03 allele was found in those patients with peri-anal fistulas when compared with a panel of 2400 healthy controls (HC) (3% vs 25%; P = 0.005; Odds Ratio [OR] = 0.09). The DRB1 ^* 03 allele is in strong linkage disequilibrium with a polymorphism at position –308 in the promoter region of the gene encoding TNFα (TNFA-308 ^* 2). We investigated whether this allele frequency was decreased as well. Surprisingly, the CF of TNFA-308 ^* 2 was 29%, not different from the CF of 98 HC (34%; P = 0.7; OR = 0.8). This study is the first showing a significant negative association between DRB1 ^* 03 and a particular subgroup of CD patients. Thus, patient selection may largely determine the outcome of genetic association studies in CD, as we previously observed no association with this allele in an unselected population of CD patients. As DRB1 ^* 03 frequency, but not the closely linked TNFA-308 ^* 2, was decreased, this suggests recombination between the DRB1 and TNFA loci in this group of patients, and may help to define the biological basis of fistula formation. Received: 29 September 1997 / Revised: 3 December 1997     

Imbalanced estrogen metabolism in the brain: possible relevance to the etiology of Parkinson’s disease

Damage to DNA by dopamine quinone and/or catechol estrogen quinones may play a significant role in the initiation of Parkinson’s disease (PD). Depurinating estrogen–DNA adducts are shed from cells and excreted in urine. The aim of this study was to discover whether higher levels of estrogen–DNA adducts are associated with PD. Forty estrogen metabolites, conjugates, and DNA adducts were analyzed in urine samples from 20 PD cases and 40 matched controls by using ultra performance liquid chromatography/tandem mass spectrometry. The levels of adducts in cases versus controls (P?<?0.005) suggest that unbalanced estrogen metabolism could play a causal role in the initiation of PD.     

Analysis of the rs12720208 single-nucleotide polymorphism of the FGF20 gene in Russian patients with sporadic Parkinson’s disease

Parkinson??s disease (PD) is a multifactorial neurodegenerative disease whose pathogenesis involves a number of genes and environmental factors. The FGF20 gene encoding the fibroblast growth factor and paying an important role neuron proliferation and survival is one of candidate genes of PD. There is evidence that this gene is also involved in the control of ??-synuclein (SNCA) gene expression. The rs12720208 single-nucleotide polymorphism (SNP) in the FGF20 gene has been found to be associated with PD; it has been located to the 3??-UTR binding site for microRNA-433, which is involved in the control of FGF20 expression. Therefore, the frequency distribution of rs12720208 genotypes in the FGF20 gene has been analyzed in a sample of patients with sporadic PD and a control sample of the Russian population. The results have not shown any effect of rs12720208 in the FGF20 gene on the risk of PD in patients residing in Russia (OR = 0.95, the 95% confidence interval (CI) is 0.55?C1.63, p = 0.9).     

Short term response is predictive of long term response to acetylcholinesterase inhibitors in Alzheimer’s disease: A starting point to explore Bayesian approximation in clinical practice

This study was aimed at identifying, in 203 patients with Alzheimer''s disease followed during long-term treatment with Acetylcholinesterase inhibitors (ChEIs), the predictive factors of the clinical response among cognition (MMSE), functioning (BADL and IADL) measures and age and gender at the baseline (T0). The ANCOVA test showed a significant association between MMSE scores at time T0 and T3, and the variation T9 to T0, T15 to T0 and T21 to T0 of the MMSE scores, using also gender, age and drug as covariates. The significance was higher for the patients affected by mild dementia. Regarding functional activities, a significant relationship was detected, by the ANCOVA test, only between the scores at T3 and the variation T15 to T0 for BADL, and the variation T9 to T0, T15 to T0 for IADL, respectively. Our results confirm, in a real world setting, that ChEIs provide long-term cognitive benefit, which is correlated to, and predictable by, the short-term response (within the third month) as well as the cognitive status (evaluated by means of the MMSE) at the beginning of the treatment. These factors should be the basis of any cost/effectiveness algorithm in health economic decision models.     

Design and characterization of bivalent compounds as potential neuroprotectants for Alzheimer’s disease: Impact of the spacer on biological activity

In our continuing efforts to develop bivalent compounds as potential neuroprotectants for Alzheimer’s disease, a series of bivalent compounds that contain cholesterylamine and an extended spacer were synthesized and biologically characterized. Our results demonstrated that incorporation of a piperazine ring into the spacer composition significantly improved the protective potency in MC65 cell models. Our results also suggested that the optimal spacer length for such bivalent compounds ranges from 17 to 21 atoms, and further spacer extension beyond 21 atoms results no further optimization. Notably, incorporation of a piperazine ring into the spacer diminished the biometal chelating capacity for these bivalent compounds, thus suggesting structural flexibility of these compounds in interactions with metals. Collectively, the results provided valuable guidance to develop new bivalent compounds as neuroprotectants for Alzheimer’s disease.