| 1. |
- Olowoyo, J. O., et al.
(författare)
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Blood lead concentrations in exposed forecourt attendants and taxi drivers in parts of South Africa
- 2024
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Ingår i: Journal of Trace Elements in Medicine and Biology. - 0946-672X .- 1878-3252. ; 81
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Tidskriftsartikel (refereegranskat)abstract
- Background: Leaded fuel was banned in South Africa in 2006, in order to improve human health and reduce environmental pollution. Lead (Pb) has been suggested to contribute to the development of neurodegenerative disorders, and the role of respiratory exposure to Pb from petrol fumes should not be neglected in this context. In addition to Pb, petrol contains various harmful chemicals including other neurotoxic metals and hydrocarbons.Objectives and Methods: Here, we investigated concentrations of Pb and other metals in blood from petrol station forecourt attendants (n = 38), taxi drivers (n = 21), and unexposed controls (n = 36). Taxi drivers and forecourt attendants were divided into three groups each, based on number of years worked. A questionnaire was designed to investigate the health status of the participants. Blood samples were collected by medical professionals and analyzed for metal concentrations by ICP-MS.Results: A positive correlation between number of years worked and Pb blood concentrations was found. The highest Pb concentration (60.2 µg/L) was observed in a forecourt attendant who had worked 11–20 years, and the average Pb concentration in this group (24.5 µg/L) was significantly (p < 0.05) higher than in forecourt attendants who had worked 2–5 years (10.4 µg/L). Some individuals had elevated concentrations of manganese, arsenic, cadmium, chromium and cobalt, yet not significantly elevated at the group level. The blood levels of arsenic appeared to be related to smoking. Mood swings, dizziness, headaches and tiredness were reported by the workers.Conclusion: Blood Pb concentrations in petrol station forecourt attendants and taxi drivers exposed to leaded petrol are elevated and correlate to exposure time. A health monitoring program should be erected for all individuals working in these industries, and preventive measures should be implemented to eliminate metal exposure from petrol.
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| 2. |
- Berntsson, Elina, et al.
(författare)
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Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4 : Similar Binding Affinities but Different Structure Induction Effects
- 2022
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 7:33, s. 28924-28931
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Tidskriftsartikel (refereegranskat)abstract
- Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with KD values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil–coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.
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| 3. |
- Biswas, Abhijit, et al.
(författare)
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Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery
- 2023
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.
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| 4. |
- Gielnik, Maciej, et al.
(författare)
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Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions
- 2023
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Ingår i: Biochemistry. - 0006-2960 .- 1520-4995. ; 62:11, s. 1689-1705
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Tidskriftsartikel (refereegranskat)abstract
- Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in PrPC misfolding. PrPC is a combined Cu(II) and Zn(II) metal-binding protein, where the main metal-binding site is located in the octarepeat (OR) region. Thus, the biological function of PrPC may involve the transport of divalent metal ions across membranes or buffering concentrations of divalent metal ions in the synaptic cleft. Recent studies have shown that an excess of Cu(II) ions can result in PrPC instability, oligomerization, and/or neuroinflammation. Here, we have used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region of PrPC. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Binding of the first metal ion results in a structural transition from the polyproline II helix to the β-turn structure, while the binding of additional metal ions induces the formation of β-sheet structures. Fluorescence spectroscopy data indicate that the OR region can bind both Cu(II) and Zn(II) ions at neutral pH, but under acidic conditions, it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of either metal ion to the OR region results in the formation of β-hairpin structures. As the formation of β-sheet structures can be a first step toward amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSE diseases.
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| 5. |
- Gielnik, Maciej, et al.
(författare)
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The engineered peptide construct NCAM1-Aβ inhibits fibrillization of the human prion protein (PrP)
- 2022
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Ingår i: Acta Biochimica Polonica. - : Polskie Towarzystwo Biochemiczne (Polish Biochemical Society). - 0001-527X .- 1734-154X. ; 69:1, s. 257-261
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Tidskriftsartikel (refereegranskat)abstract
- In prion diseases, the prion protein (PrP) becomes misfolded and forms fibrillar aggregates that are responsible for prion infectivity and pathology. So far, no drug or treatment procedures have been approved for prion disease treatment. We have previously shown that engineered cell-penetrating peptide constructs can reduce the amount of prion aggregates in infected cells. However, the molecular mechanism underlying this effect is unknown. Here, we use atomic force microscopy (AFM) imaging to show that the amyloid aggregation and fibrillization of the human PrP protein can be inhibited by equimolar amounts of the 25 residues long engineered peptide construct NCAM1-Aβ.
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| 6. |
- Gielnik, Maciej, et al.
(författare)
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Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The cellular prion protein (PrP(C)) is a mainly alpha-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrP(C) can undergo a structural transition into a toxic, beta-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrP(C) binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrP(C) and Zn(II) ions. Binding of a single Zn(II) ion to the PrP(C) N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal alpha-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrP(C) can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrP(C).
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| 7. |
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| 8. |
- Henning-Knechtel, Anja, et al.
(författare)
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Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity
- 2020
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Ingår i: Cell Reports Physical Science. - : Elsevier BV. - 2666-3864. ; 1:2
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid proteins and peptides are a major contributing factor to the development of various neurodegenerative disorders, including Alzheimer’s and prion diseases. Previously, a designed cell-penetrating peptide (CPP) comprising a hydrophobic signal sequence followed by a prion protein (PrP)-derived polycationic sequence (PrP23–28: KKRPKP) was shown to have potent anti-prion properties. Here, we extend this approach toward the amyloid-beta (Aβ) peptide amyloid formation, which is associated with Alzheimer’s disease. We characterized the interactions of the CPP with Aβ using complementary in vitro and in silico experiments. We report that the CPP stabilizes Aβ in a non-amyloid state and inhibits Aβ-induced neurotoxicity. Moreover, replacing PrP23–28 with a corresponding segment from Aβ results in a construct with similar CPP functionality and antagonism of Aβ aggregation and neurotoxicity. Our findings reveal a general underlying principle for inhibition of pathogenic protein aggregation that may facilitate the design of CPP-based therapeutics for amyloid diseases.
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| 9. |
- Koski, Lassi, et al.
(författare)
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Metal ratios as possible biomarkers for amyotrophic lateral sclerosis
- 2023
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Ingår i: Journal of Trace Elements in Medicine and Biology. - : Elsevier BV. - 0946-672X .- 1878-3252. ; 78
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown aetiology. Metals have been suspected to contribute to ALS pathogenesis since mid-19th century, yet studies on measured metal concentrations in ALS patients have often yielded conflicting results, with large individual variation in measured values. Calculating metal concentration ratios can unveil possible synergistic effects of neurotoxic metals in ALS pathogenesis. The aim of this study was to investigate if ratios of different metal concentrations in cerebrospinal fluid (CSF) and blood plasma, respectively, differ between ALS patients and healthy controls.Methods: Cerebrospinal fluid and blood plasma were collected from 17 ALS patients and 10 controls. Samples were analysed for 22 metals by high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS), and all possible 231 metal ratios calculated in each body fluid.Results: Fifty-three metal ratios were significantly elevated in ALS cases as compared to controls (p < 0.05); five in blood plasma, and 48 in CSF. The finding of fewer elevated ratios in blood plasma may indicate specific transport of metals into the central nervous system. The elevated metal ratios in CSF include Cd/Se (p = 0.031), and 16 ratios with magnesium, such as Mn/Mg (p = 0.005) and Al/Mg (p = 0.014).Conclusion: Metal ratios may be used as biomarkers in ALS diagnosis and as guidelines for preventive measures.
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| 10. |
- Koski, Lassi, et al.
(författare)
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Metals in ALS TDP-43 Pathology
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:22
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Forskningsöversikt (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.
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| 11. |
- Noormägi, Andra, et al.
(författare)
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Direct Competition of ATCUN Peptides with Human Serum Albumin for Copper(II) Ions Determined by LC-ICP MS
- 2023
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Ingår i: ACS Omega. - 2470-1343. ; 8:37, s. 33912-33919
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Tidskriftsartikel (refereegranskat)abstract
- Copper is an indispensable biometal, primarily serving as a redox-competent cofactor in numerous proteins. Apart from preformed copper-binding sites within the protein structures, small peptide motifs exist called ATCUN, which are composed of an N-terminal tripeptide XZH, able to bind Cu(II) ions in exchangeable form. These motifs are common for serum albumin, but they are also present in a wide range of proteins and peptides. These proteins and peptides can be involved in copper metabolism, and copper ions can affect their biological role. The distribution of copper between the ATCUN peptides, including truncated amyloid-β (Aβ) peptides Aβ4–42 and Aβ11–42, which may be involved in Alzheimer’s disease pathogenesis, is mainly determined by their concentrations and relative Cu(II)-binding affinities. The Cu(II)-binding affinity (log Kd) of several ATCUN peptides, determined by different methods and authors, varies by more than three orders of magnitude. This variation may be attributed to the chemical properties of peptides but can also be influenced by the differences in methods and experimental conditions used for the determination of Kd. In the current study, we performed direct competition experiments between selected ATCUN peptides and HSA by using an LC-ICP MS-based approach. We demonstrated that ATCUN and truncated Aβ peptides Aβ4–16 and Aβ11–15 bind Cu(II) ions with an affinity similar to that for HSA. Our results demonstrate that ATCUN motifs cannot compete with excess HSA for the binding of Cu(II) ions in the blood and cerebrospinal fluid.
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| 12. |
- Paul, Suman, et al.
(författare)
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13C- and 15N-labeling of amyloid-β and inhibitory peptides to study their interaction via nanoscale infrared spectroscopy
- 2023
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Ingår i: Communications Chemistry. - 2399-3669. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between molecules are fundamental in biology. They occur also between amyloidogenic peptides or proteins that are associated with different amyloid diseases, which makes it important to study the mutual influence of two polypeptides on each other's properties in mixed samples. However, addressing this research question with imaging techniques faces the challenge to distinguish different polypeptides without adding artificial probes for detection. Here, we show that nanoscale infrared spectroscopy in combination with C-13, N-15-labeling solves this problem. We studied aggregated amyloid-& beta; peptide (A & beta;) and its interaction with an inhibitory peptide (NCAM1-PrP) using scattering-type scanning near-field optical microscopy. Although having similar secondary structure, labeled and unlabeled peptides could be distinguished by comparing optical phase images taken at wavenumbers characteristic for either the labeled or the unlabeled peptide. NCAM1-PrP seems to be able to associate with or to dissolve existing A & beta; fibrils because pure A & beta; fibrils were not detected after mixing. Interactions of proteins or polypeptides with different secondary structures can be studied in a mixture by nanoscale infrared spectroscopy, however, this technique remains challenging for polypeptides with similar secondary structures. Here, the authors demonstrate clear discrimination of two polypeptides from a mixture by scattering-type scanning near-field optical microscopy when one of the components is labeled with C-13- and N-15-isotopes.
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| 13. |
- Petaros, Anja, et al.
(författare)
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Sexual dimorphism in mastoid process volumes measured from 3D models of dry crania from mediaeval Croatia
- 2021
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Ingår i: Homo (Stuttgart). - : Schweizerbart. - 0018-442X .- 1618-1301. ; 72:2, s. 113-127
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Tidskriftsartikel (refereegranskat)abstract
- 3D analysis of skeletal volumes has become an important field in digital anthropology studies. The volume of the mastoid process has been proposed to display significant sexual dimorphism, but it has a complex shape and to date no study has quantified the full mastoid volume for sex estimation purposes. In this study we compared three different ways to isolate the volume of the mastoid process from digital 3D models of dry crania, and then evaluated the performance of the three different volume definitions for sex estimation purposes. A total of 170 crania (86 male, 84 females) excavated from five medieval Croatian sites were CT-scanned and used to produce 3D stereolitographic models. The three different isolation techniques were based on various anatomical landmarks and planes, as well as the anatomy of the mastoid process itself. Measurements of the three different mastoid volumes yielded different accuracies and precisions. Interestingly, anatomical structures were sometimes more useful than classical landmarks as demarcators of mastoid volume. For all three volume definitions, male mastoid volumes were significantly larger than female volumes, in both relative and absolute numbers. Sex estimation based on mastoid volume showed a slightly higher precision and better accuracy (71% correct classifications) than visual scoring techniques (67%) and linear distance measurements (69%) of the mastoid process. Sex estimation based on cranial size performed even better (78%), and multifactorial analysis (cranium size + mastoid volume) reached up to 81% accuracy. These results show that measurements of the mastoid volume represent a promising metric to be used in multifactorial approaches for sex estimation of human remains.
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| 14. |
- Roos, Elin, et al.
(författare)
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Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya
- 2021
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Ingår i: Biological Trace Element Research. - : Springer Science and Business Media LLC. - 0163-4984 .- 1559-0720. ; 199, s. 3618-3624
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.
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| 15. |
- Wallin, Cecilia, et al.
(författare)
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Mercury and Alzheimer's Disease : Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization
- 2020
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Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Brains and blood of Alzheimer's disease (AD) patients have shown elevated mercury concentrations, but potential involvement of mercury exposure in AD pathogenesis has not been studied at the molecular level. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-beta (A beta) peptides aggregated into amyloid fibrils. A beta peptide fibrillization is known to be modulated by metal ions such as Cu(II) and Zn(II). Here, we study in vitro the interactions between A beta peptides and Hg(II) ions by multiple biophysical techniques. Fluorescence spectroscopy and atomic force microscopy (AFM) show that Hg(II) ions have a concentration-dependent inhibiting effect on A beta fibrillization: at a 1:1 A betaHg(II) ratio only non-fibrillar A beta aggregates are formed. NMR spectroscopy shows that Hg(II) ions interact with the N-terminal region of A beta(1-40) with a micromolar affinity, likely via a binding mode similar to that for Cu(II) and Zn(II) ions, i.e., mainly via the histidine residues His6, His13, and His14. Thus, together with Cu(II), Fe(II), Mn(II), Pb(IV), and Zn(II) ions, Hg(II) belongs to a family of metal ions that display residue-specific binding interactions with A beta peptides and modulate their aggregation processes.
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| 16. |
- Wärmländer, Sebastian K. T. S., 1970-, et al.
(författare)
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A 6th-8th c. wire-drawing iron plate with silver residue from a Vendel Period workshop in Old Uppsala, Sweden
- 2023
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Ingår i: Journal of Archaeological Science. - : Elsevier. - 2352-409X .- 2352-4103. ; 51
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Tidskriftsartikel (refereegranskat)abstract
- Metal wire is in modern society manufactured by drawing metal rods through dies with conical holes of decreasing diameters, until the desired thickness is obtained. The history and origin of this technique remains unclear, although it was likely developed from earlier wire-making techniques such as strip-drawing and rolldrawing. Proper wire-drawing was an established technology in Europe during the High Middle Ages, and numerous draw-plates have been found at Scandinavian Viking Age trading centers. Here, we report the technical examination of an iron draw-plate found in Uppsala in central Sweden. The draw-plate was excavated in a Vendel Period fine metals workshop, located immediately next to the royal hall in Old Uppsala, the central building of the royal estate in the 6th -8th c. X-ray and scanning electron microscopy (SEM) analysis of the draw-plate revealed silver particles in the plate's holes, indicating drawing of silver wire. The plate is dated to the 6th - 8th c., which makes it one of the oldest confirmed tools for wire-drawing so far encountered. The presence of this tool in the workshop indicates that some high-quality jewelry in this region was locally produced. Thus, the finding of this draw-plate increases our understanding of Vendel Period jewelry production, and of the social organization of this craft.
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| 17. |
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| 18. |
- Österlund, Nicklas, et al.
(författare)
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Cell-Penetrating Peptides with Unexpected Anti-Amyloid Properties
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:4
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Forskningsöversikt (refereegranskat)abstract
- Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer’s disease. These disease-modifying properties are so far observed in cell cultures and in vitro. The CPP sequences are composed of a hydrophobic signal sequence followed by a highly positively charged hexapeptide segment. The original signal sequence of the prion protein can be changed to the signal sequence of the NCAM1 protein without losing the anti-prion activity. Although the detailed molecular mechanisms of these CPP peptides are not fully understood, they do form amyloid aggregates by themselves, and molecular interactions between the CPPs and PrP/Aβ can be observed in vitro using various spectroscopic techniques. These initial intermolecular interactions appear to re-direct the aggregation pathways for prion/amyloid formation to less cell-toxic molecular structures (i.e., co-aggregates), which likely is why the disease-inducing PrP/Aβ aggregation is counteracted in vivo.
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