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The New England Journal of Medicine Oct 2015
Review
Topics: Animals; Fibrin; Fibrinogen; Fibrinolysis; Fracture Healing; Mice; Mice, Knockout; Plasminogen
PubMed: 26510027
DOI: 10.1056/NEJMcibr1510090 -
Proceedings of the National Academy of... Apr 2003Iron is essential to life, but poses severe problems because of its toxicity and the insolubility of hydrated ferric ions at neutral pH. In animals, a family of proteins... (Review)
Review
Iron is essential to life, but poses severe problems because of its toxicity and the insolubility of hydrated ferric ions at neutral pH. In animals, a family of proteins called transferrins are responsible for the sequestration, transport, and distribution of free iron. Comparison of the structure and function of transferrins with a completely unrelated protein hemopexin, which carries out the same function for heme, identifies molecular features that contribute to a successful protein system for iron acquisition, transport, and release. These include a two-domain protein structure with flexible hinges that allow these domains to enclose the bound ligand and provide suitable chemistry for stable binding and an appropriate trigger for release.
Topics: Binding Sites; Carrier Proteins; Heme; Hemopexin; Iron; Models, Molecular; Protein Folding; Protein Structure, Secondary; Transferrin
PubMed: 12642662
DOI: 10.1073/pnas.0637295100 -
Toxicology Dec 2023In humans, serum testosterone (T) is largely bound to the sex hormone binding globulin (SHBG) and human serum albumin (hSA), resulting in a 2-3 % of unbound or "free"...
In vitro binding analysis of legacy-linear and new generation-cyclic perfluoro-alkyl substances on sex hormone binding globulin and albumin, suggests low impact on serum hormone kinetics of testosterone.
In humans, serum testosterone (T) is largely bound to the sex hormone binding globulin (SHBG) and human serum albumin (hSA), resulting in a 2-3 % of unbound or "free" active quote (FT). Endocrine-disrupting chemicals, including perfluoro-alkyl substances (PFAS), are recognized to interfere with the hormonal axes, but the possible impact on the FT quote has not been addressed so far. Here we investigated the possible competition of two acknowledged PFAS molecules on T binding to SHBG and hSA. In particular, perfluoro-octanoic acid (PFOA) and acetic acid, 2,2-difluoro-2-((2,2,4,5-tetrafluoro-5(trifluoromethoxy)-1,3-dioxolan-4-yl)oxy)-ammonium salt (1:1) (C6O4) were used as, respectively, legacy-linear and new-generation-cyclic PFASs. Human recombinant SHBG 30-234 domain (SHBG), produced in HEK293-F cells, and delipidated recombinant hSA were used as in vitro protein models. Isothermal Titration Calorimetry (ITC) and tryptophan fluorescence quencing (TFQ) were used to evaluate the binding modes of T and PFAS to SHBG and hSA. ITC revealed the binding of T to SHBG with a K of 44 ± 2 nM whilst both PFOA and C6O4 showed no binding activity. Results were confirmed by TFQ, since only T modified the fluorescence profile of SHBG. In hSA, TFQ confirmed the binding of T on FA6 site of the protein. A similar binding mode was observed for PFOA but not for C6O4, as further verified by displacement experiments with T. Although both PFASs were previously shown to bind hSA, only PFOA is predicted to possibly compete with T for the binding to hSA. However, on the base of the binding stoichiometry and affinity of PFOA for hSA, this appears unlikely at the blood concentrations of the chemical documented to date.
Topics: Humans; Fluorocarbons; HEK293 Cells; Protein Binding; Serum Albumin, Human; Sex Hormone-Binding Globulin; Testosterone; Tryptophan
PubMed: 37931871
DOI: 10.1016/j.tox.2023.153664 -
Alzheimer's Research & Therapy Jun 2020Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding...
BACKGROUND
Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts.
METHODS
Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures.
RESULTS
Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit β (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOEε4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment.
CONCLUSIONS
In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Australia; Cognitive Dysfunction; Hemopexin; Humans; Proteomics; Transferrin
PubMed: 32517787
DOI: 10.1186/s13195-020-00634-1 -
Molecular Vision 2022A protein quantitative trait locus (pQTL) analysis recently revealed a strong association between hemopexin (HPX) levels and genetic variants at the complement factor H...
PURPOSE
A protein quantitative trait locus (pQTL) analysis recently revealed a strong association between hemopexin (HPX) levels and genetic variants at the complement factor H () locus. In this study, we aimed to determine HPX plasma levels in patients with age-related macular degeneration (AMD) and to compare them with those in controls. We also investigated whether genetic variants at the locus are associated with HPX plasma levels.
METHODS
HPX levels were quantified in 200 advanced AMD cases and 200 controls using an enzyme-linked immunosorbent assay and compared between the two groups. Furthermore, HPX levels were analyzed per genotype group of three HPX-associated variants (rs61818956, rs10494745, and rs10801582) and four AMD-associated variants (rs794362 [proxy for rs187328863], rs570618, rs10922109, and rs61818924 [proxy for rs61818925]) at the locus.
RESULTS
HPX levels were similar in the control group compared with the AMD group. The three variants at the locus, which were previously associated with the HPX levels, showed no association with the HPX levels in our data set. No significant differences in HPX levels were detected between the different genotype groups of AMD-associated variants at the locus.
CONCLUSIONS
In this study, HPX levels were not associated with AMD or AMD-associated variants at the locus. The finding of a previous pQTL study that variants at the locus were associated with HPX levels was also not confirmed in this study.
Topics: Humans; Hemopexin; Macular Degeneration; Genotype; Complement Factor H; Transcription Factors; Polymorphism, Single Nucleotide
PubMed: 37089696
DOI: No ID Found -
Frontiers in Endocrinology 2024Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational...
Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational studies have suggested an association between testosterone and sleep traits, but the causality of this relationship remains unclear. We aimed to explore the potential causal link between genetically determined sleep traits and testosterone levels in men using Mendelian randomization (MR) analysis from the UK Biobank dataset. Our exposures were genetic variants associated with sleep traits (chronotype and sleep duration), whereas our outcomes were traits of sex steroid hormones (total testosterone, TT; bioavailable testosterone, BAT; and sex hormone-binding globulin, SHBG). We employed inverse variance weighted (IVW) and weighted median (WM) methods to assess the causal associations. The IVW method offers a robust estimate of causality, whereas the WM method provides reliable results even when some genetic variants are invalid instruments. Our main analysis involving sex steroid hormones and chronotype identified 155 chronotype-related variants. The primary findings from the analysis, which used chronotype as the exposure and sex steroid hormones as the outcomes, showed that a genetically predicted chronotype score was significantly associated with an increased levels of TT (association coefficient β, 0.08; 95% confidence interval [CI], 0.02-0.14; = 0.008) and BAT (β, 0.08; 95% CI, 0.02-0.14; = 0.007), whereas there was no significant association with SHBG (β, 0.01; 95% CI, -0.02-0.03; = 0.64). Meanwhile, MR analysis of sex steroid hormones and sleep duration was performed, and 69 variants associated with sleep duration were extracted. There were no significant association between sleep duration and sex steroid hormones (TT, = 0.91; BAT, = 0.82; and SHBG, = 0.95). Our data support a causal association between chronotype and circulating testosterone levels in men. These findings underscore a potential causal relationship between chronotype and testosterone levels in men, suggesting that lifestyle adjustments are crucial for men's health. Recognizing factors that influence testosterone is essential. One limitation of this study is the use of one-sample MR, which can introduce potential bias due to non-independence of genetic associations for exposure and outcome. In conclusion, our findings indicate that a morning preference is correlated with circulating testosterone levels, emphasizing the potential impact of lifestyle habits on testosterone levels in men.
Topics: Humans; Mendelian Randomization Analysis; Male; Testosterone; Sleep; Sex Hormone-Binding Globulin; Middle Aged; Circadian Rhythm; Polymorphism, Single Nucleotide; Aged; Chronotype
PubMed: 38737549
DOI: 10.3389/fendo.2024.1264410 -
Immunology Apr 1966Immunoelectrophoretic analyses and complement titrations of whole human serum show that a number of physical, chemical and immunological agents affect the β/β-globulin...
Immunoelectrophoretic analyses and complement titrations of whole human serum show that a number of physical, chemical and immunological agents affect the β/β-globulin system which is considered to represent the third component of complement (C′). The transformation from β-globulin to β-globulin is the normal result of ageing, while antigen-antibody complexes, polylysine, hydrazine and cobra venom accelerate this change. In addition, α-globulin fragments of β-globulin appear after interaction of normal sera with antigen-antibody complexes, treatment with cobra venom, and by storage under nitrogen in glass tubes or in polyethylene containers. Similar α-fragments are seen in the aged sera of some patients with glomerulonephritis or renal allografts. With prolonged storage these α-fragments can reform β-globulin. On the other hand, 2-mercaptoethanol and penicillamine produce complete dissolution of β-globulin into rapidly migrating, poorly defined fragments in the α-globulin and albumin regions, and transform β-globulin into a stable β-globulin. The reduced fragments of β-globulin, if not alkylated, can subsequently form the β-globulin, but not the β-globulin. These results indicate that β-globulin is composed of several subunits, some of which are joined by disulphide bonds, but that the α-globulin fragments seen in some pathological sera are not a result of disulphide bond reduction.
Topics: Beta-Globulins; Complement System Proteins; Hot Temperature; Humans; Immunoelectrophoresis; In Vitro Techniques; Mercaptoethanol; Penicillamine; Peptides; Sulfhydryl Compounds; Venoms
PubMed: 4160445
DOI: No ID Found -
Climacteric : the Journal of the... Apr 2023This study aims to explore the associations between sex hormones and cognitive performance in older women. (Observational Study)
Observational Study
OBJECTIVE
This study aims to explore the associations between sex hormones and cognitive performance in older women.
METHODS
Associations between sex hormones, sex hormone binding globulin (SHBG) and cognitive performance were examined in women aged at least 70 years, without dementia and not using medications that influence sex hormones. Linear and generalized linear regression models included age, body mass index, education, smoking, alcohol, living circumstances, diabetes, hypertension, depression and impaired renal function.
RESULTS
The included 5511 women had a median (interquartile range) age of 73.9 (71.6-77.6) years. No associations were found for estrone, estradiol, testosterone or dehydroepiandrosterone and cognitive performance. SHBG concentrations above quartile 1 (Q1) were significantly inversely associated with processing speed (Q2, = -0.94, 95% confidence interval [CI] - 1.64 to -0.24, = 0.009; Q3, = -0.82, 95% CI -1.53 to -0.10, = 0.025; and Q4, = -0.95, 95% CI -1.70 to -0.20, = 0.013).
CONCLUSIONS
Sex hormones were not associated with cognitive performance. The finding that low SHBG is associated with better processing speed warrants further investigation. The null findings for the sex hormones establish a firm baseline to confidently explore the association between sex hormones and longitudinal cognitive performance in this population.
TRIAL REGISTRATION
International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and ClinicalTrials.gov (NCT01038583).
Topics: Female; Humans; Aged; Sex Hormone-Binding Globulin; Australia; Gonadal Steroid Hormones; Estradiol; Testosterone; Cognition
PubMed: 36716780
DOI: 10.1080/13697137.2023.2166824 -
Immunological Reviews Jan 2023Structures of alternative pathway proteins have offered a comprehensive structural basis for understanding the molecular mechanisms governing activation and regulation... (Review)
Review
Structures of alternative pathway proteins have offered a comprehensive structural basis for understanding the molecular mechanisms governing activation and regulation of the amplification pathway of the complement cascade. Although properdin (FP) is required in vivo to sustain a functional alternative pathway, structural studies have been lagging behind due to the extended structure and polydisperse nature of FP. We review recent progress with respect to structure determination of FP and its proconvertase/convertase complexes. These structures identify in detail regions in C3b, factor B and FP involved in their mutual interactions. Structures of FP oligomers obtained by integrative studies have shed light on how FP activity depends on its oligomerization state. The accumulated structural knowledge allows us to rationalize the effect of point mutations causing FP deficiency. The structural basis for FP inhibition by the tick CirpA proteins is reviewed and the potential of alphafold2 predictions for understanding the interaction of FP with other tick proteins and the NKp46 receptor on host immune cells is discussed. The accumulated structural knowledge forms a comprehensive basis for understanding molecular interactions involving FP, pathological conditions arising from low levels of FP, and the molecular strategies used by ticks to suppress the alternative pathway.
Topics: Humans; Properdin; Complement Activation; Complement Pathway, Alternative
PubMed: 36097870
DOI: 10.1111/imr.13129 -
Immunology Dec 1967Using gel filtration on Sephadex G-200 combined with antigen—antibody crossed electrophoresis of the fractions, serum β-globulin and the conversion products present...
Using gel filtration on Sephadex G-200 combined with antigen—antibody crossed electrophoresis of the fractions, serum β-globulin and the conversion products present in stored native serum and stored serum to which EDTA had been added, respectively, were analysed. The conversion products in the inter-β- and γ-zone demonstrated in EDTA serum after 1 days storage and after hydrazine treatment, respectively, could not be characterized by gel filtration, probably because of their lability. Sephadex filtration did not induce any conversion of β-globulin in serum. It was found that β- and β-globulin left the column in homogeneous peaks in the `7S' peak, the former slightly before the latter. The conversion product obtained in stored EDTA sera and on electrophoresis migrating in the α-zone was found in the right extension of the macroglobulin peak. The precipitation line produced by this component was diffuse and differed distinctly from the precipitation lines of the other components. The possibility of some kind of complex is discussed.
Topics: Antigen-Antibody Reactions; Beta-Globulins; Blood Protein Electrophoresis; Chromatography, Gel; Edetic Acid; Humans; Hydrazines
PubMed: 4169023
DOI: No ID Found