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Serum Albumin in Health and Disease: From Comparative Biochemistry to Translational Medicine 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (20 July 2024) | Viewed by 9818

Special Issue Editors


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Guest Editor
1. Research Institute of Hygiene, Occupational Pathology and Human Ecology of the Federal Medical Biological Agency, 188663 Saint Petersburg, Russia
2. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia
Interests: albumin; enzymes; esterases; endothelial cells; receptors; oxidative stress; apoptosis; diagnostics; organophosphates; pharmacology; therapy
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Guest Editor
Leicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK
Interests: biotransformations; enzymes; oxygenases; metabolic poisons; toxicokinetics; metalloids; human exposure
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. Torez 44, 194223 St. Petersburg, Russia
Interests: albumin; docking; molecular modelling; esterases; receptors; ligands; oxidative stress; organophosphates
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is a well-known fact that serum albumin is one of the main proteins in the human body and many animal species. It plays a decisive role in the transport of various ions, electrically neutral and charged molecules, and in maintaining the colloidal osmotic pressure of the blood. Albumin is able to bind almost all known drugs, many nutraceuticals and toxic substances, largely determining their pharmaco- and toxicokinetics. However, albumin is not only passive but also an active participant in pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities. Numerous experiments have shown the esterase or pseudoesterase activity of albumin towards a number of endogenous and exogenous esters. Moreover, it is an important participant in toxico- and pharmacodynamics and serves as a predictor of outcomes for many pathologies being one of the principal biomarkers in diagnostics. Due to the free thiol group, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. Glycated albumin makes a significant contribution to the pathogenesis of diabetes and other diseases. The interaction of albumin with blood cells, blood vessels and tissue cells outside the vascular bed is of great importance. Interaction with endothelial glycocalyx and vascular endothelial cells largely determines the integrative role of albumin.

However, despite experimental and clinical evidence, many molecular and epigenetic regulatory mechanisms of albumin activity remain to be fully elucidated. Albumin of humans and representatives of cattle and rodents have their own structural features that determine the species differences in their functional properties, which gives rise to the problem of how to adequately interpret the experimental data obtained with purified albumins in vitro or with laboratory animals in vivo. Hence, the need to fill this knowledge gap in order to devise adequate experimental methodology, and clinically successful diagnostics and treatment strategies for humans.

This Special Issue aims at expanding the current knowledge on serum albumin in both physiological and pathological conditions. Experimental studies in in vitro and in vivo models, review articles, as well as clinical studies, are all welcomed for consideration. Please keep in mind that IJMS is a journal of molecular science, thus pure clinical studies will not be suitable for this Special Issue. Nevertheless, clinical submissions with novel biomolecular experiments and/or interpretations are welcomed.

Dr. Nikolay V. Goncharov
Prof. Dr. Richard O. Jenkins
Dr. Daria Belinskaia
Guest Editors

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Keywords

  • albumin
  • oncotic pressure
  • (pseudo)esterase activity
  • molecular crowding
  • receptors and signaling
  • glycation
  • covalent adducts
  • oxidative stress
  • organophosphates
  • pharmacokinetics
  • toxicokinetics
  • diagnostics
  • metabolomics
  • therapy

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Published Papers (7 papers)

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16 pages, 2718 KiB  
Article
In Search for Low-Molecular-Weight Ligands of Human Serum Albumin That Affect Its Affinity for Monomeric Amyloid β Peptide
by Evgenia I. Deryusheva, Marina P. Shevelyova, Victoria A. Rastrygina, Ekaterina L. Nemashkalova, Alisa A. Vologzhannikova, Andrey V. Machulin, Alija A. Nazipova, Maria E. Permyakova, Sergei E. Permyakov and Ekaterina A. Litus
Int. J. Mol. Sci. 2024, 25(9), 4975; https://doi.org/10.3390/ijms25094975 - 2 May 2024
Cited by 1 | Viewed by 1069
Abstract
An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer’s disease (AD) patients leads to Aβ accumulation and the formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is the reduction of free Aβ [...] Read more.
An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer’s disease (AD) patients leads to Aβ accumulation and the formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is the reduction of free Aβ levels by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) in HSA to improve its affinity for Aβ. Here we develop this approach through a bioinformatic search for the clinically approved AD-related LMWLs in HSA, followed by classification of the candidates according to the predicted location of their binding sites on the HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aβ. The top 100 candidate LMWLs were classified into five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA–Aβ40 interaction: prednisone favors HSA–Aβ interaction, mefenamic acid shows the opposite effect, and levothyroxine exhibits bidirectional effects. Overall, the LMWLs in HSA chosen here provide a basis for drug repurposing for AD prevention, and for the search of medications promoting AD progression. Full article
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24 pages, 9184 KiB  
Article
Contrast Agents Based on Human Serum Albumin and Nitroxides for 1H-MRI and Overhauser-Enhanced MRI
by Dmitry Mitin, Friedemann Bullinger, Sergey Dobrynin, Jörn Engelmann, Klaus Scheffler, Mikhail Kolokolov, Olesya Krumkacheva, Kai Buckenmaier, Igor Kirilyuk and Alexey Chubarov
Int. J. Mol. Sci. 2024, 25(7), 4041; https://doi.org/10.3390/ijms25074041 - 5 Apr 2024
Viewed by 1532
Abstract
In cancer diagnostics, magnetic resonance imaging (MRI) uses contrast agents to enhance the distinction between the target tissue and background. Several promising approaches have been developed to increase MRI sensitivity, one of which is Overhauser dynamic nuclear polarization (ODNP)-enhanced MRI (OMRI). In this [...] Read more.
In cancer diagnostics, magnetic resonance imaging (MRI) uses contrast agents to enhance the distinction between the target tissue and background. Several promising approaches have been developed to increase MRI sensitivity, one of which is Overhauser dynamic nuclear polarization (ODNP)-enhanced MRI (OMRI). In this study, a macromolecular construct based on human serum albumin and nitroxyl radicals (HSA-NIT) was developed using a new synthesis method that significantly increased the modification to 21 nitroxide residues per protein. This was confirmed by electron paramagnetic resonance (EPR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry. Gel electrophoresis and circular dichroism showed no significant changes in the structure of HSA-NITs, and no oligomers were formed during modification. The cytotoxicity of HSA-NITs was comparable to that of native albumin. HSA-NITs were evaluated as potential “metal-free” organic radical relaxation-based contrast agents for 1H-MRI and as hyperpolarizing contrast agents for OMRI. Relaxivities (longitudinal and transversal relaxation rates r1 and r2) for HSA-NITs were measured at different magnetic field strengths (1.88, 3, 7, and 14 T). Phantoms were used to demonstrate the potential use of HSA-NIT as a T1- and T2-weighted relaxation-based contrast agent at 3 T and 14 T. The efficacy of 1H Overhauser dynamic nuclear polarization (ODNP) in liquids at an ultralow magnetic field (ULF, B0 = 92 ± 0.8 μT) was investigated for HSA-NIT conjugates. The HSA-NITs themselves did not show ODNP enhancement; however, under the proteolysis conditions simulating cancer tissue, HSA-NIT conjugates were cleaved into lower-molecular-weight (MW) protein fragments that activate ODNP capabilities, resulting in a maximum achievable enhancement |Emax| of 40–50 and a radiofrequency power required to achieve half of Emax, P1/2, of 21–27 W. The HSA-NIT with a higher degree of modification released increased the number of spin probes upon biodegradation, which significantly enhanced the Overhauser effect. Thus, HSA-NITs may represent a new class of MRI relaxation-based contrast agents as well as novel cleavable conjugates for use as hyperpolarizing contrast agents (HCAs) in OMRI. Full article
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9 pages, 698 KiB  
Communication
Albumin of People with Diabetes Mellitus Is More Reduced at Low HbA1c
by Margret Paar, Gerhard Cvirn, Gerd Hoerl, Gilbert Reibnegger, Harald Sourij, Caren Sourij, Harald Kojzar and Karl Oettl
Int. J. Mol. Sci. 2023, 24(22), 16256; https://doi.org/10.3390/ijms242216256 - 13 Nov 2023
Cited by 1 | Viewed by 1021
Abstract
Oxidative stress is involved in the development, progression, and complications of diabetes mellitus (DM). Oxidative modification of human serum albumin’s cysteine-34 is a marker for oxidative stress-related pathological conditions. We aimed to evaluate the redox state of albumin in patients with DM to [...] Read more.
Oxidative stress is involved in the development, progression, and complications of diabetes mellitus (DM). Oxidative modification of human serum albumin’s cysteine-34 is a marker for oxidative stress-related pathological conditions. We aimed to evaluate the redox state of albumin in patients with DM to investigate possible correlations with age, diabetes duration, and disease control status. Plasma aliquots were collected from 52 participants (26 type 1 and 26 type 2 DM). Patients were divided into two groups according to their glycated hemoglobin levels less than or equal to and greater than 58 mmol/L. Albumin redox state was assessed with high-performance liquid chromatography by fractionating it into human mercaptalbumin (HMA) and human nonmercaptalbumin 1 and 2 (HNA1 and HNA2). Albumin redox fractions were differently related to the age of study participants. In age-matched T1DM and T2DM groups, the albumin redox state was essentially the same. Irreversibly oxidized HNA2 was positively correlated with diabetes duration, especially in the T1DM group. HNA was increased in people with an increased HbA1c (>58 mmol/mol). Our results support the hypothesis that oxidative stress plays a crucial role in DM pathogenesis and emphasize the importance of diabetes control on systemic oxidative burden. Full article
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38 pages, 9671 KiB  
Article
Structure-Dependent Mechanism of Organophosphate Release from Albumin and Butyrylcholinesterase Adducts When Exposed to Fluoride Ion: A Comprehensive In Silico Study
by Daria A. Belinskaia, Nadezhda L. Koryagina, Nikolay V. Goncharov and Elena I. Savelieva
Int. J. Mol. Sci. 2023, 24(19), 14819; https://doi.org/10.3390/ijms241914819 - 1 Oct 2023
Viewed by 1255
Abstract
The most favorable targets for retrospectively determining human exposure to organophosphorus pesticides, insecticides, retardants, and other industrial organophosphates (OPs) are adducts of OPs with blood plasma butyrylcholinesterase (BChE) and human serum albumin (HSA). One of the methods for determining OP exposure is the [...] Read more.
The most favorable targets for retrospectively determining human exposure to organophosphorus pesticides, insecticides, retardants, and other industrial organophosphates (OPs) are adducts of OPs with blood plasma butyrylcholinesterase (BChE) and human serum albumin (HSA). One of the methods for determining OP exposure is the reactivation of modified BChE using a concentrated solution of KF in an acidic medium. It is known that under the action of fluoride ion, OPs or their fluoroanhydrides can be released not only from BChE adducts but also from the adducts with albumin; however, the contribution of albumin to the total pool of released OPs after plasma treatment with KF has not yet been studied. The efficiency of OP release can be affected by many factors associated with the experimental technique, but first, the structure of the adduct must be taken into account. We report a comparative analysis of the structure and conformation of organophosphorus adducts on HSA and BChE using molecular modeling methods and the mechanism of OP release after fluoride ion exposure. The conformational analysis of the organophosphorus adducts on HSA and BChE was performed, and the interaction of fluoride ions with modified proteins was studied by molecular dynamics simulation. The geometric and energy characteristics of the studied adducts and their complexes with fluoride ion were calculated using molecular mechanics and semiempirical approaches. The structural features of modified HSA and BChE that can affect the efficiency of OP release after fluoride ion exposure were revealed. Using the proposed approach, the expediency of using KF for establishing exposure to different OPs, depending on their structure, can be assessed. Full article
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14 pages, 2026 KiB  
Article
Time-Resolved Fluorescence Spectroscopy of Blood, Plasma and Albumin as a Potential Diagnostic Tool for Acute Inflammation in COVID-19 Pneumonia Patients
by Tomasz Wybranowski, Blanka Ziomkowska, Michał Cyrankiewicz, Jerzy Pyskir, Maciej Bosek, Marta Napiórkowska, Marta Pilaczyńska-Cemel, Grzegorz Przybylski and Stefan Kruszewski
Int. J. Mol. Sci. 2023, 24(19), 14703; https://doi.org/10.3390/ijms241914703 - 28 Sep 2023
Viewed by 1554
Abstract
Fluorescence lifetime measurements of blood or plasma offer valuable insights into the microenvironment and molecular interactions of fluorophores, particularly concerning albumin. Neutrophil- and hypoxia-induced oxidative stress in COVID-19 pneumonia patients leads to hyperinflammation, various oxidative modifications of blood proteins, and potential alterations in [...] Read more.
Fluorescence lifetime measurements of blood or plasma offer valuable insights into the microenvironment and molecular interactions of fluorophores, particularly concerning albumin. Neutrophil- and hypoxia-induced oxidative stress in COVID-19 pneumonia patients leads to hyperinflammation, various oxidative modifications of blood proteins, and potential alterations in the fluorescence lifetime of tryptophan-containing proteins, especially albumin. The objective of this study was to investigate the efficacy of time-resolved fluorescence spectroscopy of blood and plasma as a prompt diagnostic tool for the early diagnosis and severity assessment of COVID-19-associated pneumonia. This study examined a cohort of sixty COVID-19 patients with respiratory symptoms. To investigate whether oxidative stress is the underlying cause of the change in fluorescence lifetime, human serum albumin was treated with chloramine T. The time-resolved spectrometer Life Spec II (Edinburgh Instruments Ltd., Livingston, UK), equipped with a sub-nanosecond pulsed 280 nm diode, was used to measure the fluorescence lifetime of blood and plasma. The findings revealed a significant reduction in the fluorescence lifetime of blood (diluted 200 times) and plasma (diluted 20 times) at 360 nm in COVID-19 pneumonia patients compared with their respective values recorded six months post-infection and those of healthy individuals. Significant negative correlations were observed between the mean fluorescence lifetime of blood and plasma at 360 nm and several severity biomarkers and advanced oxidation protein products, while a positive correlation was found with albumin and the albumin–globulin ratio. The time-resolved fluorescence spectroscopy method demonstrates the potential to be used as a preliminary screening technique for identifying patients who are at risk of developing severe complications. Furthermore, the small amount of blood required for the measurements has the potential to enable a rapid fingerstick blood test. Full article
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15 pages, 1112 KiB  
Article
Exploring Albumin Functionality Assays: A Pilot Study on Sepsis Evaluation in Intensive Care Medicine
by Gerd Klinkmann, Katja Waterstradt, Sebastian Klammt, Kerstin Schnurr, Jens-Christian Schewe, Reinhold Wasserkort and Steffen Mitzner
Int. J. Mol. Sci. 2023, 24(16), 12551; https://doi.org/10.3390/ijms241612551 - 8 Aug 2023
Cited by 5 | Viewed by 1591
Abstract
Human serum albumin (HSA) as the most abundant plasma protein carries multifunctional properties. A major determinant of the efficacy of albumin relies on its potent binding capacity for toxins and pharmaceutical agents. Albumin binding is impaired in pathological conditions, affecting its function as [...] Read more.
Human serum albumin (HSA) as the most abundant plasma protein carries multifunctional properties. A major determinant of the efficacy of albumin relies on its potent binding capacity for toxins and pharmaceutical agents. Albumin binding is impaired in pathological conditions, affecting its function as a molecular scavenger. Limited knowledge is available on the functional properties of albumin in critically ill patients with sepsis or septic shock. A prospective, non-interventional clinical trial assessed blood samples from 26 intensive care patients. Albumin-binding capacity (ABiC) was determined by quantifying the unbound fraction of the fluorescent marker, dansyl sarcosine. Electron paramagnetic resonance fatty acid spin-probe evaluated albumin’s binding and detoxification efficiencies. Binding efficiency (BE) reflects the strength and amount of bound fatty acids, and detoxification efficiency (DTE) indicates the molecular flexibility of patient albumin. ABiC, BE, and DTE effectively differentiated control patients from those with sepsis or septic shock (AUROC > 0.8). The diagnostic performance of BE showed similarities to procalcitonin. Albumin functionality correlates with parameters for inflammation, hepatic, or renal insufficiency. Albumin-binding function was significantly reduced in critically ill patients with sepsis or septic shock. These findings may help develop patient-specific algorithms for new diagnostic and therapeutic approaches. Full article
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21 pages, 3957 KiB  
Systematic Review
Stable Nitroxide as Diagnostic Tools for Monitoring of Oxidative Stress and Hypoalbuminemia in the Context of COVID-19
by Ekaterina Georgieva, Julian Ananiev, Yovcho Yovchev, Georgi Arabadzhiev, Hristo Abrashev, Vyara Zaharieva, Vasil Atanasov, Rositsa Kostandieva, Mitko Mitev, Kamelia Petkova-Parlapanska, Yanka Karamalakova, Vanya Tsoneva and Galina Nikolova
Int. J. Mol. Sci. 2024, 25(15), 8045; https://doi.org/10.3390/ijms25158045 - 24 Jul 2024
Viewed by 734
Abstract
Oxidative stress is a major source of ROS-mediated damage to macromolecules, tissues, and the whole body. It is an important marker in the severe picture of pathological conditions. The discovery of free radicals in biological systems gives a “start” to studying various pathological [...] Read more.
Oxidative stress is a major source of ROS-mediated damage to macromolecules, tissues, and the whole body. It is an important marker in the severe picture of pathological conditions. The discovery of free radicals in biological systems gives a “start” to studying various pathological processes related to the development and progression of many diseases. From this moment on, the enrichment of knowledge about the participation of free radicals and free-radical processes in the pathogenesis of cardiovascular, neurodegenerative, and endocrine diseases, inflammatory conditions, and infections, including COVID-19, is increasing exponentially. Excessive inflammatory responses and abnormal reactive oxygen species (ROS) levels may disrupt mitochondrial dynamics, increasing the risk of cell damage. In addition, low serum albumin levels and changes in the normal physiological balance between reduced and oxidized albumin can be a serious prerequisite for impaired antioxidant capacity of the body, worsening the condition in patients. This review presents the interrelationship between oxidative stress, inflammation, and low albumin levels, which are hallmarks of COVID-19. Full article
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