Serum albumin is the most abundant protein in the blood and cerebrospinal fluid and plays a fundamental role in the distribution of essential transition metal ions in the human body. Human serum ...albumin (HSA) is an important physiological transporter of the essential metal ions Cu2+, and Zn2+ in the bloodstream. Its binding of metals like Ni2+, Co2+, or Cd2+ can occur in vivo, but is only of toxicological relevance. Moreover, HSA is one of the main targets and hence most studied binding protein for metallodrugs based on complexes with Au, Pt and V.
We discuss i) the four metal-binding sites so far described on HSA, their localization and metal preference, ii) the binding of the metal ions mentioned above, i.e. their stability constants and association/dissociation rates, their coordination chemistry and their selectivity versus the four binding sites iii) the methodology applied to study issues of items i and ii and iv) oligopeptide models of the N-terminal binding site.
Albumin has four partially selective metal binding sites with well-defined metal preferences. It is an important regulator of the blood transport of physiological Cu(II) and Zn(II) and toxic Ni(II) and Cd(II). It is also an important target for metal-based drugs containing Pt(II), V(IV)O, and Au(I).
The thorough understanding of metal binding properties of serum albumin, including the competition of various metal ions for specific binding sites is important for biomedical issues, such as new disease markers and design of metal-based drugs. This article is part of a Special Issue entitled Serum Albumin.
•Human Serum Albumin (HSA) is a versatile carrier of metal ions.•HSA contains four specific metal binding sites.•HSA binds and transports physiological, toxic and medicinal metals.•HSA may be a regulatory protein via crosstalk of metal and ligand binding.
The interactions between the Aβ1-40 molecules species and the copper ions (Cu(II)) were intensively investigated due to their potential role in the development of the Alzheimer Disease (AD). The rate ...and the mechanism of the Cu(II)-Aβ complexes formation determines the aggregation pathway of the Aβ species, starting from smaller but more cytotoxic oligomers and ending up in large Aβ plaques, being the main hallmark of the AD. In our study we exploit the existing knowledge on the Cu(II)-Aβ interactions and create the theoretical model of the initial phase of the copper- driven Aβ aggregation mechanism. The model is based on the direct solution of the Chemical Master Equations, which capture the inherent stochastics of the considered system. In our work we argue that due to a strong Cu(II) affinity to Aβ and temporal accessibility of the Cu(II) ions during normal synaptic activity the aggregation driven by Cu(II) dominates the pure Aβ aggregation. We also demonstrate the dependence of the formation of different Cu(II)-Aβ complexes on the concentrations of reagents and the synaptic activity. Our findings correspond to recent experimental results and give a sound hypothesis on the AD development mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Copper(II) binding to the amyloid-β peptide has been proposed to be a key event in the cascade leading to Alzheimer’s disease. As a direct consequence, the strength of the Cu(II) to Aβ interaction, ...that is, the Cu(II) affinity of Aβ, is a very important parameter to determine. Because Aβ peptide contain one Tyr fluorophore in its sequence and because Cu(II) does quench Tyr fluorescence, fluorescence measurements appear to be a straightforward way to obtain this parameter. However, this proved to be wrong, mainly because of data misinterpretation in some previous studies that leads to a conflicting situation. In the present paper, we have investigated in details a large set of fluorescence data that were analyzed with a new method taking into account the presence of two Cu(II) sites and the inner-filter effect. This leads to reinterpretation of the published data and to the determination of a unified affinity value in the 1010 M–1 range.
Tetrathiolate zinc fingers are potential targets of oxidative assault under cellular stress conditions. We used the synthetic 37-residue peptide representing the tetrathiolate zinc finger domain of ...the DNA repair protein XPA, acetyl-DYVICEECGKEFMSYLMNHFDLPTCDNCRDADDKHK-amide (XPAzf) as a working model to study the reaction of its Zn(II) complex (ZnXPAzf) with hydrogen peroxide and S-nitrosoglutathione (GSNO), as oxidative and nitrosative stress agents, respectively. We also used the Cd(II) substituted XPAzf (CdXPAzf) to assess the situation of cadmium assault, which is accompanied by oxidative stress. Using electrospray mass spectrometry (ESI-MS), HPLC, and UV-vis and circular dichroism spectroscopies we demonstrated that even very low levels of H2O2 and GSNO invariably cause irreversible thiol oxidation and concomitant Zn(II) release from ZnXPAzf. In contrast, CdXPAzf was more resistant to oxidation, demonstrating the absence of synergy between cadmium and oxidative stresses. Our results indicate that GSNO cannot act as a reversible modifier of XPA, and rather has a deleterious effect on DNA repair.
The development of tourism determines the cultural landscape transformation, spatial development of coastal localities, scale of recreational architecture and other forms of development related to ...tourism services. The article presents research aiming to analyze tourism development in the context of its impact on the cultural landscape of Polish coastal localities, taking into account the specificity of post-communist countries and supra-regional tendencies. The main objective of this study was to analyze the development of tourism in the context of its impact on the cultural landscape seaside towns and to identify, on the basis of the changes, the nature of tourism and forms of recreation in particular stages of the shaping of elements in coastal locality spaces and recreational architecture. The research was based on historical-interpretation studies, field studies of selected coastal localities, including urban-planning inventories, landscape, and functional and spatial analyses. The research carried out resulted in the identification of the stages of the cultural landscape transformation of coastal localities and indication of characteristic features of architecture and landscape. The journey along the coastline is a temporal journey through the changing nature of buildings, allowing observation of the stage-by-stage nature of investment processes in response to the changing needs of tourists.
Nickel is toxic to humans. Its compounds are carcinogenic. Furthermore, nickel allergy is a severe health problem that affects approximately 10–20% of humans. The mechanism by which these conditions ...develop remains unclear, but it may involve the cleavage of specific proteins by nickel ions. Ni(II) ions cleave the peptide bond preceding the Ser/Thr-Xaa-His sequence. Such sequences are present in all four enzymes of the melatonin biosynthesis pathway, i.e., tryptophan 5-hydroxylase 1, aromatic-l-amino-acid decarboxylase, serotonin N-acetyltransferase, and acetylserotonin O-methyltransferase. Moreover, fragments prone to Ni(II) are exposed on surfaces of these proteins. Our results indicate that all four studied fragments undergo cleavage within tens of hours at pH 8.2 and 37 °C, corresponding with the conditions in the mitochondrial matrix. Since melatonin, a potent antioxidant and anti-inflammatory agent, is synthesized within the mitochondria of virtually all human cells, depleting its supply may be detrimental, e.g., by raising the oxidative stress level. Intriguingly, Ni(II) ions have been shown to mimic hypoxia through the stabilization of HIF-1α protein, but melatonin prevents the action of HIF-1α. Considering all this, the enzymes of the melatonin biosynthesis pathway seem to be a toxicological target for Ni(II) ions.
The coastline of Western Pomerania has natural and cultural assets that have promoted the development of tourism, but also require additional measures to ensure the traditional features and ...characteristics are protected. This is to ensure that new developments conform to a more uniform set of spatial structures which are in line with the original culture. Today, seaside resorts are characterized by a rapid increase in development with a clear trend towards non-physiognomic architectural forms which continually expand and encroach on land closer to the coastline. This results in a blurring of the original concepts that characterized the founding seaside resort. This study evaluates 11 development projects (including a range of hotels, luxury residential buildings and hotel suites) built in 2009–2020 in the coastal area of Western Pomerania. An assessment of architecture-and-landscape integration for each development project was made, using four groups of evaluation criteria: aesthetic, socio-cultural, functional and locational factors. The study methodology included a historical and interpretative study (iconology, iconography, historiography) and an examination of architecture-and-landscape integration using a pre-prepared evaluation form. Each criterion was first assessed using both field surveys and desk research (including the analysis of construction plans and developer materials), and then compared with the original, traditional qualities of the town. This study demonstrates that it is possible to clearly identify the potential negative impact of tourism development on the cultural landscape of seaside resorts, and provides recommendations for future shaping, management and conservation of the landscape.
The tripeptide NH
-Gly-His-Lys-COOH (GHK),
-urocanic acid (
-UCA) and Cu(II) ions are physiological constituents of the human body and they co-occur (e.g., in the skin and the plasma). While GHK is ...known as Cu(II)-binding molecule, we found that urocanic acid also coordinates Cu(II) ions. Furthermore, both ligands create ternary Cu(II) complex being probably physiologically functional species. Regarding the natural concentrations of the studied molecules in some human tissues, together with the affinities reported here, we conclude that the ternary complex GHKCu(II)
-urocanic acid may be partly responsible for biological effects of GHK and urocanic acid described in the literature.
Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation contribute to pathogenesis. Mechanisms underlying the associated inflammation are not fully ...understood, and although Langerhans cells expressing the nonclassical major histocompatibility complex (MHC) family member CD1a are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. We observed that house dust mite (HDM) allergen generates neolipid antigens presented by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth in individuals with atopic dermatitis and showed rapid effector function, consistent with antigen-driven maturation. In HDM-challenged human skin, we observed phospholipase A2 (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2, and such cells infiltrated the skin after allergen challenge. Moreover, we observed that the skin barrier protein filaggrin, insufficiency of which is associated with atopic skin disease, inhibited PLA2 activity and decreased CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity suggest that nonpeptide stimulants of T cells act as haptens that modify peptides or proteins; however, our results show that HDM proteins may also generate neolipid antigens that directly activate T cells. These data define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach.
Silver-based materials are widely used in clinical medicine. Furthermore, the usage of silver containing materials and devices is widely recommended and clinically approved. The impact on human ...health of the increasing use of silver nanoparticles in medical devices remains understudied, even though Ag-containing dressings are known to release silver into the bloodstream. In this study, we detected a widespread and sometimes significant silver accumulation both in healthy and sick liver biopsies, levels being statistically higher in patients with various hepatic pathologies. 28 healthy and 44 cirrhotic liver samples were investigated. The median amount of 0.049 ppm Ag in livers was measured in cirrhotic livers while the median was 0.0016 ppm for healthy livers (a more than 30-fold difference). The mean tissue concentrations of essential metals, Fe and Zn in cirrhotic livers did not differ substantially from healthy livers, while Cu was positively correlated with Ag. The serum levels of gamma-glutamyl transpeptidase (GGTP) was also positively correlated with Ag in cirrhotic livers. The increased Ag accumulation in cirrhotic livers could be a side effect of wide application of silver in clinical settings. As recent studies indicated a significant toxicity of silver nanoparticles for human cells, the above observation could be of high importance for the public health.
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