In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer's disease (AD). Because of the ...important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (
< 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13-21.34) compared with individuals with MCI (0.68; 0.02-19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (
< 0.001) and Clock Drawing test (
< 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body's attempt to counteract the early and middle stages of neurodegeneration.
Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting the elderly. The most common ...forms are Alzheimer’s disease, vascular dementia, and other (frontotemporal, Lewy body disease) dementias. The etiology of these multifactorial disorders involves complex interactions of various environmental and (epi)genetic factors and requires multiple forms of pharmacological intervention, including anti-dementia drugs for cognitive impairment, antidepressants, antipsychotics, anxiolytics and sedatives for behavioral and psychological symptoms of dementia, and other drugs for comorbid disorders. The pharmacotherapy of dementia patients has been characterized by a significant interindividual variability in drug response and the development of adverse drug effects. The therapeutic response to currently available drugs is partially effective in only some individuals, with side effects, drug interactions, intolerance, and non-compliance occurring in the majority of dementia patients. Therefore, understanding the genetic basis of a patient’s response to pharmacotherapy might help clinicians select the most effective treatment for dementia while minimizing the likelihood of adverse reactions and drug interactions. Recent advances in pharmacogenomics may contribute to the individualization and optimization of dementia pharmacotherapy by increasing its efficacy and safety via a prediction of clinical outcomes. Thus, it can significantly improve the quality of life in dementia patients.
Due to the increasing number of progressive dementias in the population, numerous studies are being conducted that seek to determine risk factors, biomarkers and pathological mechanisms that could ...help to differentiate between normal symptoms of aging, mild cognitive impairment (MCI) and dementia. The aim of this study was to investigate the possible association of levels of
and
gene expression and methylation in peripheral blood cells with the development of Alzheimer's disease (AD). Our results revealed higher expression levels of
(
< 0.001) in MCI subjects compared to individuals diagnosed with AD. However, no difference in
gene expression (
= 0.366) was detected. DNA methylation of the CpG islands and other sequences with potential effects on gene expression regulation revealed just one region (BDNF_9) in the
gene (
= 0.078) with marginally lower levels of methylation in the AD compared to MCI subjects. Here, we show that the level of
expression in the periphery is decreased in subjects with AD compared to individuals with MCI. The combined results from the gene expression analysis and DNA methylation analysis point to the potential of BDNF as a marker that could help distinguish between MCI and AD patients.
Some of the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's disease, are proteinopathies characterized by the accumulation of specific protein aggregates in the ...brain. Such misfolded protein aggregates can trigger modulation of the innate and adaptive immune systems and subsequently lead to chronic neuroinflammation that drives the onset and progression of neurodegenerative diseases. Since there is still no effective disease-modifying treatment, new therapeutic targets for neurodegenerative proteinopathies have been sought. The endocannabinoid system, and in particular the cannabinoid CB2 receptors, have been extensively studied, due to their important role in neuroinflammation, especially in microglial cells. Several studies have shown promising effects of CB2 receptor activation on reducing protein aggregation-based pathology as well as on attenuating inflammation and several dementia-related symptoms. In this review, we discuss the available data on the role of CB2 receptors in neuroinflammation and the potential benefits and limitations of specific agonists of these receptors in the therapy of neurodegenerative proteinopathies.
Along with the typical biochemical alterations that occur during pregnancy, certain metabolic changes might be associated with the development of several psychiatric disorders, including postpartum ...depression (PPD), which is the most common type of psychiatric disorder during pregnancy or first postpartum year, and it develops in about 15% of women. Metabolomics is a rapidly developing discipline that deals with the metabolites as the final products of all genetically controlled biochemical pathways, highly influenced by external and internal changes. The aim of this paper was to review the published studies whose results suggest or deny a possible association between the fine regulation of the metabolome and PPD, enabling conclusions about whether metabolomics could be a useful tool in defining the biochemical pathways directly involved in the etiology, diagnosis and course of PPD. Beside numerous hormonal changes, a lot of different metabolic pathways have been discovered to be affected in women with PPD or associated with its development, including alterations in the energy metabolism, tryptophan and amino acid metabolism, steroid metabolism, purine cycle, as well as neurotransmitter metabolism. Additionally, metabolomics helped in defining the association between PPD and the exposure to various endocrine disrupting metabolites during pregnancy. Finally, metabolome reflects different PPD therapies and exposure of fetus or breastfed infants to pharmacotherapy prescribed to a mother suffering from PPD. This review can help in creating the picture about metabolomics' broad application in PPD studies, but it also implies that its potential is still not completely used.
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•Pregnancy associated hormonal changes lead to postpartum depression.•Altered energy and amino acid metabolisms are associated with postpartum depression.•Purine cycle and neurotransmitter metabolism are disrupted in postpartum depression.•Exposure to xenobiotics during pregnancy might contribute to postpartum depression.•Metabolomes of mother and child can reflect mother's antidepressant therapy.
Alzheimer's disease (AD) is often not recognized or is diagnosed very late, which significantly reduces the effectiveness of available pharmacological treatments. Metabolomic analyzes have great ...potential for improving existing knowledge about the pathogenesis and etiology of AD and represent a novel approach towards discovering biomarkers that could be used for diagnosis, prognosis, and therapy monitoring. In this study, we applied the untargeted metabolomic approach to investigate the changes in biochemical pathways related to AD pathology. We used gas chromatography and liquid chromatography coupled to mass spectrometry (GC–MS and LC-MS, respectively) to identify metabolites whose levels have changed in subjects with AD diagnosis (N = 40) compared to healthy controls (N = 40) and individuals with mild cognitive impairment (MCI, N = 40). The GC–MS identified significant differences between groups in levels of metabolites belonging to the classes of benzene and substituted derivatives, carboxylic acids and derivatives, fatty acyls, hydroxy acids and derivatives, keto acids and derivatives, and organooxygen compounds. Most of the compounds identified by the LC-MS were various fatty acyls, glycerolipids and glycerophospholipids. All of these compounds were decreased in AD patients and in subjects with MCI compared to healthy controls. The results of the study indicate disturbed metabolism of lipids and amino acids and an imbalance of metabolites involved in energy metabolism in individuals diagnosed with AD, compared to healthy controls and MCI subjects.
•Decreased levels of benzoic and hippuric acid in MCI subjects.•Lower levels of various amino acids and their derivatives in AD patients.•Lower levels of glyceric acid, fructose and glucosaminic acid in patients with AD.•Fatty acyls, glycerolipids and glycerophospholipids decreased in AD and MCI subjects.•Decreased dehydroepiandrosterone sulfate abundance in AD and MCI subjects.
Recycling of concrete waste to produce recycled concrete aggregates (RCA) and its use in the production of structural concrete is the way towards reducing the depletion of natural mineral resources ...and the amount of construction and demolition waste being land-filled. The goal of this study was to determine the optimal choice of aggregate type and transport scenario in concrete production, employing a multicriteria optimization method taking into account technical, economical and environmental limits and constraints. Several concrete types with different type of used aggregate (river aggregate, crushed stone and recycled concrete aggregate) and different transport scenarios were analyzed. The environmental system evaluation criteria were chosen according to the Life Cycle Assessment methodology and the economical system evaluation criteria were determined in accordance with the current state of the ready-mixed concrete market in Serbia. The normative multicriteria optimization method (VIKOR method) was employed to determine the optimal solution. Analysis was performed for different decision making scenarios that gave emphasis to different criteria. Results have shown that concrete with a 50% replacement ratio of coarse aggregate with RCA can be presented as an optimal solution. Since natural aggregate concrete made with river aggregate was shown to have the lowest price, a further analysis was conducted to determine what economical measures should be undertaken in order to achieve cost equality of recycled and natural aggregate concrete. The analysis identified taxes on river aggregate, taxes on land-filling and subsidies for using RCA as viable measures.
•Four concrete types differentiated by type of aggregate and transport scenario.•Optimization according to environmental and economical criteria.•Three different rankings of criteria relative importance.•Optimal solution recycled aggregate concrete with 50% replacement of coarse fraction.•Determining economical measures for viability of recycled aggregate concrete use.
Viscoelastic hydrogels are gaining interest as they possess necessary requirements for bioprinting and injectability. By means of reversible, dynamic covalent bonds, it is possible to achieve ...features that recapitulate the dynamic character of the extracellular matrix. Dually cross-linked and double-network (DN) hydrogels seem to be ideal for the design of novel biomaterials and bioinks, as a wide range of properties required for mimicking advanced and complex tissues can be achieved. In this study, we investigated the fabrication of chondroitin sulfate/hyaluronic acid (CS/HA)-based DN hydrogels, in which two networks are interpenetrated and cross-linked with the dynamic covalent bonds of very different lifetimes. Namely, Diels–Alder adducts (between methylfuran and maleimide) and hydrazone bonds (between aldehyde and hydrazide) were chosen as cross-links, leading to viscoelastic hydrogels. Furthermore, we show that viscoelasticity and the dynamic character of the resulting hydrogels could be tuned by changing the composition, that is, the ratio between the two types of cross-links. Also, due to a very dynamic nature and short lifetime of hydrazone cross-links (∼800 s), the DN hydrogel is easily processable (e.g., injectable) in the first stages of gelation, allowing the material to be used in extrusion-based 3D printing. The more long-lasting and robust Diels–Alder cross-links are responsible for giving the network enhanced mechanical strength and structural stability. Being highly charged and hydrophilic, the cross-linked CS and HA enable a high swelling capacity (maximum swelling ratio ranging from 6 to 12), which upon confinement results in osmotically stiffened constructs, able to mimic the mechanical properties of cartilage tissue, with the equilibrium moduli ranging from 0.3 to 0.5 MPa. Moreover, the mesenchymal stromal cells were viable in the presence of the hydrogels, and the effect of the degradation products on the macrophages suggests their safe use for further translational applications. The DN hydrogels with dynamic covalent cross-links hold great potential for the development of novel smart and tunable viscoelastic materials to be used as biomaterial inks or bioinks in bioprinting and regenerative medicine.
Three new silver(I) complexes Ag(NO
)(tia)(H
O)
(
), Ag(CF
SO
)(1,8-naph)
(
) and Ag
(1,8-naph)
(H
O)
(PF
)
(
), where tia is thianthrene and 1,8-naph is 1,8-naphthyridine, were synthesized and ...structurally characterized by different spectroscopic and electrochemical methods and their crystal structures were determined by single-crystal X-ray diffraction analysis. Their antimicrobial potential was evaluated against four bacterial and three
species, and the obtained results revealed that these complexes showed significant activity toward the Gram-positive
Gram-negative
and the investigated
species with minimal inhibitory concentration (MIC) values in the range 1.56-7.81 μg/mL. On the other hand, tia and 1,8-naph ligands were not active against the investigated strains, suggesting that their complexation with Ag(I) ion results in the formation of antimicrobial compounds. Moreover, low toxicity of the complexes was detected by in vivo model
. The interaction of the complexes with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied to evaluate their binding affinity towards these biomolecules for possible insights into the mode of antimicrobial activity. The binding affinity of
-
to BSA was higher than that for DNA, indicating that proteins could be more favorable binding sites for these complexes in comparison to the nucleic acids.
Infections of the cow udder leading to mastitis and lower milk quality are one of the biggest problems in the dairy industry worldwide. Unfortunately, therapeutic options for the treatment of cow ...mastitis are limited as a consequence of the development of pathogens that are resistant to conventionally used antibiotics. In the search for agents that will be active against cow mastitis associated pathogens, in the present study, five new silver(i) complexes with different chelating pyridine-4,5-dicarboxylate types of ligands, Ag(NO
)(py-2py)
(1), Ag(NO
)(py-2metz)
(2), Ag(CH
CN)(py-2py)BF
(3), Ag(py-2tz)
BF
(4) and Ag(py-2metz)
BF
(5), py-2py is dimethyl 2,2'-bipyridine-4,5-dicarboxylate, py-2metz is dimethyl 2-(4-methylthiazol-2-yl)pyridine-4,5-dicarboxylate and py-2tz is dimethyl 2-(thiazol-2-yl)pyridine-4,5-dicarboxylate, were synthesized, structurally characterized and assessed for in vitro antimicrobial activity using both standard bioassay and clinical isolates from a contaminated milk sample obtained from a cow with mastitis. These complexes showed remarkable activity against the standard panel of microorganisms and a selection of clinical isolates from the milk of the cow diagnosed with mastitis. With the aim of determining the therapeutic potential of silver(i) complexes, their toxicity in vivo against the model organism, Caenorhabditis elegans (C. elegans), was investigated. The complexes that had the best therapeutic profile, 2 and 5, induced bacterial membrane depolarization and the production of reactive oxygen species (ROS) in Candida albicans cells and inhibited the hyphae as well as the biofilm formation. Taken together, the presented data suggest that the silver(i) complexes with pyridine ligands could be considered for the treatment of microbial pathogens, which are causative agents of cow mastitis.
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