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Showing papers on "Human serum albumin published in 2013"


Journal ArticleDOI
TL;DR: A critical review of the plasma thiol pool is provided with a focus on human serum albumin, an important target for oxidants and electrophiles due to its reactivity with a wide variety of species and its relatively high concentration.

519 citations


Journal ArticleDOI
TL;DR: 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.

355 citations


Journal ArticleDOI
TL;DR: Its role is being investigated in a large number of indications, which rely on its volume and nonvolume expansion functions such as stroke, severe sepsis, Alzheimer's disease, malaria, burns, and ovarian hyperstimulation syndrome.

328 citations


Journal ArticleDOI
TL;DR: This review examines work that has been conducted in the study and analysis of glycated HSA and considers the effects of glycation on the binding of HSA with drugs, fatty acids and other solutes and the potential clinical significance of these effects.

307 citations


Journal ArticleDOI
TL;DR: It is shown that biliverdin is the specific CD label of an additional drug binding area in subdomain IB, which implies that sub domain IB can be considered as the third major drug binding region of HSA featured with promiscuous ligand recognition ability.
Abstract: According to the conventional view, noncovalent association of small molecules with human serum albumin (HSA) occurs principally at the so-called Sudlow's sites located in subdomain IIA and IIIA. By employing a circular dichroism (CD) spectroscopic approach, it is shown that biliverdin is the specific CD label of an additional drug binding area in subdomain IB. CD competition experiments disclosed the entrapment of a diverse assortment of acidic, neutral, and basic molecules within subdomain IB including anticancer agents (camptothecin, doxorubicin, daunorubicin, teniposide, suramin, tyrosine kinase inhibitors), anticoagulants (dicoumarol), various steroids (bile acids, carbenoxolone), nonsteroidal antiinflammatory drugs, natural substances (aristolochic acid, glycyrrhetinic acid), and synthetic dyes (methyl orange, azocarmine B). These finding imply that subdomain IB can be considered as the third major drug binding region of HSA featured with promiscuous ligand recognition ability. Additionally, subdomain IB is allosterically coupled with the Sudlow's sites, the ligand binding of which is shown to alter the HSA binding mode and affinity of biliverdin and hemin. Brief case studies are presented to illustrate how the evaluation of spectral changes of tetrapyrrole CD probes gains new insight into the HSA binding properties of endogenous as well as pharmaceutical compounds.

269 citations


Journal ArticleDOI
TL;DR: Analysis of fluorescence spectra indicated that amaranth had a strong ability to quench the intrinsic fluorescence of HSA through a static quenching procedure, and results of CD and FT-IR spectra showed that binding ofAmaranth to HSA induced conformational changes ofHSA.

164 citations


Journal ArticleDOI
TL;DR: The findings suggest that a redox change in HSA is related to the oxidation of several amino acid residues by different oxidants, and the ratio of the oxidized form to the normal form of albumin (HMA/HNA) could serve as a useful marker for evaluating systemic redox states, which would be useful for the evaluation of disease progression and therapeutic efficacy.

163 citations


Journal ArticleDOI
TL;DR: It is necessary to give a more detailed explanation of albumin and its relations with oxidative stress and its interactions with Reactive Oxygen Species.
Abstract: Human serum albumin, a negative acute phase reactant and marker of nutritive status, presents at high concentrations in plasma. Albumin has always been used in many clinical states especially to improve circulatory failure. It has been showed that albumin is involved in many bioactive functions such as regulation of plasma osmotic pressure, binding and transport of various endogenous or exogenous compounds, and finally extracellular antioxidant defenses. Molecules like transferrin, caeruloplasmin, haptoglobin, uric acid, bilirubin, alpha-tocopherol, glucose, and albumin constitute extracellular antioxidant defenses in blood plasma but albumin is the most potent one. Most of the antioxidant properties of albumin can be attributed to its unique biochemical structure. The protein possesses antioxidant properties such as binding copper tightly and iron weakly, scavenging free radicals, e.g., hypochlorous acid (HOCl) and Peroxynitrite (ONOOH) and providing thiol group (-SH). Whether it is chronic or acute, during many pathological conditions, biomarkers of oxidative protein damage increase and this observation continues with considerable oxidation of human serum albumin. There is an important necessity to specify its interactions with Reactive Oxygen Species. Generally, it may lower the availability of pro-oxidants and be preferentially oxidized to protect other macromolecules but all these findings make it necessary that researchers give a more detailed explanation of albumin and its relations with oxidative stress.

128 citations


Journal ArticleDOI
TL;DR: Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity.
Abstract: Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na(+) analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration-UV-vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K(1)' = 5.3-5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event.

123 citations


Journal ArticleDOI
TL;DR: Subdomain IB is a major binding site for complex heterocyclic molecules in serum albumin and has important implications for drug design and development.

121 citations


Journal ArticleDOI
09 Aug 2013-PLOS ONE
TL;DR: The combined results provide that HA binds to HSA and thus its elimination is hindered and an increase in and is observed from DSC results that indicate increase in stability of HSA upon binding to HA.
Abstract: Binding of hippuric acid (HA), a uremic toxin, with human serum albumin (HSA) has been examined by isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), molecular docking, circular dichroism (CD) and fluorescence spectroscopy to understand the reason that govern its impaired elimination through hemodialysis. ITC results shows that the HA binds with HSA at high (Kb ∼104) and low affinity (Kb ∼103) sites whereas spectroscopic results predict binding at a single site (Kb∼103). The HA form complex with HSA that involves electrostatic, hydrogen and hydrophobic binding forces as illustrated by calculated thermodynamic parameters. Molecular docking and displacement studies collectively revealed that HA bound to both site I and site II; however, relatively strongly to the later. Esterase-like activity of HSA confirms the involvement of Arg410 and Tyr411 of Sudlow site II in binding of HA. CD results show slight conformational changes occurs in the protein upon ligation that may be responsible for the discrepancy in van’t Hoff and calorimetric enthalpy change. Furthermore, an increase in and is observed from DSC results that indicate increase in stability of HSA upon binding to HA. The combined results provide that HA binds to HSA and thus its elimination is hindered.

Journal ArticleDOI
TL;DR: It is found that fatty acids (FAs) compete with FcRn, revealing a clash between ligand binding and recycling, and that high-affinity HSA variants have significantly increased circulating half-lives in mice and monkeys.

Journal ArticleDOI
TL;DR: Two protein crystal structures of HSA in complex with either glucose or fructose reveal the presence of linear forms of sugar for both monosaccharides and propose a mechanism for glucose ring opening involving both residues Lys-195 and Lys-199.

Journal ArticleDOI
TL;DR: Investigating the binding mechanism of FUR to HSA revealed that in uremia, FUR indirectly Competes for Arg410, Lys414, and Ser489 with site II bound uremic toxins and directly competes for site I with site I bound uRemic toxins.
Abstract: Exogenous substances like drugs, when absorbed, enter into the circulatory system and bind reversibly and extensively to human serum albumin (HSA). But transport of various drugs like a diuretic, furosemide (FUR), via albumin in uremia is seriously compromised due to accumulation of uremic toxins. The reason behind it is explored by investigating the binding mechanism of FUR to HSA. Isothermal titration calorimetry results show that FUR binds with HSA at high (Kb ∼ 104) and low affinity (Kb ∼ 103) sites whereas spectroscopic results predict binding at a single site (Kb ∼ 105). Thermodynamic analysis shows that the HSA-FUR complex formation occurs via hydrogen bonds and hydrophobic interactions and undergoes slight structural changes, as evident by FTIR and far-UV CD. Further, the lifetime of HSA decreases only marginally and thus the magnitude of energy transfer efficiency is small, as obtained by time-resolved measurements. A displacement experiment predicts that the FUR binds mainly to site I but a new ...

Journal ArticleDOI
TL;DR: It was found from CD analysis that the bindings of MPT and GF drugs to HSA and HMG proteins altered the secondary structure of HSA, and the binding processes between protein and drug molecules were exothermic and spontaneous owing to negative ∆H and ∆G values.
Abstract: The interactions of metoprolol tartrate (MPT) and guaifenesin (GF) drugs with human serum albumin (HSA) and human hemoglobin (HMG) proteins at pH 7.4 were studied by fluorescence and circular dichroism (CD) spectroscopy. Drugs quenched the fluorescence spectra of HSA and HMG proteins through a static quenching mechanism. For each protein-drug system, the values of Stern-Volmer quenching constant, bimolecular quenching constant, binding constant and number of binding site on the protein molecules were determined at 288.15, 298.15, 310.15 and 318.15 K. It was found that the binding constants of HSA-MPT and HSA-GF systems were smaller than those of HMG-MPT and HMG-GF systems. For both drugs, the affinity of HMG was much higher than that of HSA. An increase in temperature caused a negative effect on the binding reactions. The number of binding site on blood proteins for MPT and GF drugs was approximately one. Thermodynamic parameters showed that MPT interacted with HSA through electrostatic attraction forces. However, hydrogen bonds and van der Waals forces were the main interaction forces in the formation of HSA-GF, HMG-MPT and HMG-GF complexes. The binding processes between protein and drug molecules were exothermic and spontaneous owing to negative ∆H and ∆G values, respectively. The values of binding distance between protein and drug molecules were calculated from Forster resonance energy transfer theory. It was found from CD analysis that the bindings of MPT and GF drugs to HSA and HMG proteins altered the secondary structure of HSA and HMG proteins.

Journal ArticleDOI
TL;DR: The ultrafiltration–HPLC technique reliably measures free serum concentrations of indoxyl sulfate and p‐cresyl sulfates and indicates that competition for this binding site could be used to augment free solute concentrations during dialysis, thus improving epuration.
Abstract: Indoxyl sulfate and p-cresyl sulfate are two uremic retention solutes implicated in the uremic syndrome. Removal during dialysis is limited, mainly due to protein binding. Binding characteristics to healthy albumin have recently been characterized. Whether uremia alters the binding characteristics of albumin is currently unknown. Moreover, protein binding values previously determined with ultrafiltration are in sharp contrast to recently reported values based on microcalorimetry. In the present study, indoxyl sulfate and p-cresyl sulfate binding were therefore quantified using both equilibrium dialysis and ultrafiltration. Deming regression demonstrated good agreement between equilibrium dialysis and ultrafiltration. Free serum concentrations of indoxyl sulfate (+26.6%) and p-cresyl sulfate (+19.7%) were slightly higher at body temperature compared with at room temperature. To investigate binding kinetics, the plasma of healthy individuals or hemodialysis patients was titrated with albumin solutions. Theoretical models of protein binding were fitted to observed titration curves. Binding coefficients of both toxins were highest in purified albumin, and were reduced from healthy to uremic plasma. In conclusion, the ultrafiltration-HPLC technique reliably measures free serum concentrations of indoxyl sulfate and p-cresyl sulfate. Albumin is the main binding protein, both in health and in advanced stages of chronic kidney disease. Modeling suggests that albumin contains two binding sites for both toxins, a single high affinity binding site and a second low affinity binding site. The high affinity binding site accounts for at least 90% of overall binding. Competition for this binding site could be used to augment free solute concentrations during dialysis, thus improving epuration.

Journal ArticleDOI
TL;DR: Human serum albumin is useful in detoxification reactions, for activating prodrugs, and for binding and activating drug conjugates, and can be used to construct smart nanotubes with enzymatic properties useful for biomedical applications.

Journal ArticleDOI
17 Jul 2013-DARU
TL;DR: Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy and results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PL GA nanoparticles.
Abstract: Background: Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues. Methods: PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells. Results: Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, �11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, �5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg). Conclusion: In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy.

Journal ArticleDOI
TL;DR: The results of CD analysis revealed that the addition of THC led to a significant conformational change in the secondary structure of HSA protein, on the contrary to HMG protein.
Abstract: The interactions of tramadol hydrochloride (THC) and 5-azacytidine (AZA) drugs with human serum albumin (HSA) and human hemoglobin (HMG) proteins were investigated by fluorescence, UV absorption and circular dichroism (CD) spectroscopy at pH 7.4 and different temperatures. The UV absorption spectra and the fluorescence quenching of HSA and HMG proteins indicated the formation of HSA–THC and HMG–THC complexes via static quenching mechanism. AZA did not interact with HSA and HMG proteins. It was found that the formation of HMG–THC complex was stronger than that of HSA–THC complex. The stability of HSA–THC and HMG–THC complexes decreased with increasing temperature. The number of binding site was found as one for HSA–THC and HMG–THC systems. Negative enthalpy change (Δ H ) and Gibbs free energy change (Δ G ) and positive entropy change (Δ S ) values were obtained for these systems. The binding of THC–HSA and HMG proteins was spontaneous and exothermic. In addition, electrostatic interactions between protein and drug molecules played an important role in the binding processes. The results of CD analysis revealed that the addition of THC led to a significant conformational change in the secondary structure of HSA protein, on the contrary to HMG protein.

Journal ArticleDOI
TL;DR: Circular dichroism analysis displayed that the addition of CQP led to a decrease in the α-helix amount of HSA and HMG proteins, indicating that electrostatic interactions play an important role in the binding processes.

Journal ArticleDOI
TL;DR: The changes in the secondary structure of HSA after its complexation with ligand were studied with CD spectroscopy, which indicate that osthole induced only a slight decrease in the helix structural content of the protein.

Journal ArticleDOI
TL;DR: Data suggest that normal albumin serves a role in preventing histone-induced platelet aggregation in a charge-dependent manner.

Journal ArticleDOI
TL;DR: The results of synchronous fluorescence, 3D fluorescence and FT-IR spectra show that the conformation of proteins has altered in the presence of tetrandrine, and the binding of TETD-HSA was strongly relied on the hydrophobic interaction.

Journal ArticleDOI
TL;DR: The results indicated that binding of ZNS to HSA caused strong fluorescence quenching of HSA through staticQuenching mechanism, hydrogen bonds and van der Waals contacts are the major forces in the stability of protein ZNS complex.

Journal ArticleDOI
08 Oct 2013-PLOS ONE
TL;DR: Far-UV circular dichroism data revealed increased thermal stability of the protein upon complexation with PS, and competitive drug displacement results suggested the binding site of PS on HSA as Sudlow’s site I, located at subdomain IIA, and was well supported by the molecular modelling data.
Abstract: Interaction of a pharmacologically important flavonoid, pinostrobin (PS) with the major transport protein of human blood circulation, human serum albumin (HSA) has been examined using a multitude of spectroscopic techniques and molecular docking studies. Analysis of the fluorescence quenching data showed a moderate binding affinity (1.03 × 105 M−1 at 25°C) between PS and HSA with a 1∶1 stoichiometry. Thermodynamic analysis of the binding data (ΔS = +44.06 J mol−1 K−1 and ΔH = −15.48 kJ mol−1) and molecular simulation results suggested the involvement of hydrophobic and van der Waals forces, as well as hydrogen bonding in the complex formation. Both secondary and tertiary structural perturbations in HSA were observed upon PS binding, as revealed by intrinsic, synchronous, and three-dimensional fluorescence results. Far-UV circular dichroism data revealed increased thermal stability of the protein upon complexation with PS. Competitive drug displacement results suggested the binding site of PS on HSA as Sudlow’s site I, located at subdomain IIA, and was well supported by the molecular modelling data.

Journal ArticleDOI
TL;DR: Structural details of the ligand binding functions of HSA to ligands such as warfarin, digoxin, halothane anesthetics, nitric oxide, bilirubin, free fatty acids, etc, can be used to develop a model to better understand protein-drug interactions, aid in the development of new drugs with improved pharmacokinetic effects, and ultimately beUsed to improve the quality of healthcare.

Journal ArticleDOI
TL;DR: The details of a novel reiterated stepwise equilibrium dialysis assay that has successfully been used to quantify liraglutide plasma protein binding are reported, which could have an application in the quantification of plasmaprotein binding of other highly lipophilic drug molecules.

Journal ArticleDOI
TL;DR: Results consistently indicate that [Ru2(p-cymene)2(L4)2]Cl2 is quite promising as a prospective metallodrug for cancer chemotherapy.
Abstract: Four complexes combining the {Ru(p-cym)} moiety (p-cym = para-cymene) with thiosemicarbazone (TSC) ligands containing the 5-nitrofuryl pharmacophore were investigated in vitro for their properties as prospective anti-tumour agents. The compounds are dimeric structures of general formula [Ru2(p-cym)2(L)2]X2 where X = Cl−, PF6− and L = deprotonated 5-nitrofuraldehyde TSC (L1), and the N-methyl (L2), N-ethyl (L3) and N-phenyl (L4) derivatives. The precursor [RuCl2(p-cym)]2, all TSC ligands L1–L4 and their corresponding complexes 1–4 were screened in vitro for their cytotoxicity against a range of human cancer cell lines (HL-60 acute promyelocytic leukemia, A2780 ovarian adenocarcinoma, MCF7 breast adenocarcinoma and PC3 grade IV prostate carcinoma). While the precursor complex was found to be inactive and L4 exhibited moderate activity only in the MCF7 cell line, the coordination of L4 to the {Ru(p-cym)} moiety remarkably enhanced the activity of the whole complex. In fact, complex 4 [Ru2(p-cym)2(L4)2]Cl2 was found to be the most active agent of the whole series, and was studied further (as well as complex 1 for comparison). Concerning the mode of action, the mechanism of cell death for both 1 and 4 seemed to be related to apoptotic processes, and they strongly interacted with tubulin (involved in the cell cycle) and with integrin (involved in the cytoskeleton formation). As an approach to their pharmacokinetics, the interaction of 1 and 4 with human serum albumin (HSA) was assessed. A quantitative model for the binding of 4 to HSA is proposed from Circular Dichroism data, and validated by fluorescence results. Models of Forster resonance energy transfer and fluorescence quenching afforded the distance of 4 to the lone Trp214 residue. Importantly, HSA binding enhanced the cytotoxicity of 4 and correlated well with the HSA binding data. Our results consistently indicate that [Ru2(p-cymene)2(L4)2]Cl2 is quite promising as a prospective metallodrug for cancer chemotherapy.

Journal ArticleDOI
TL;DR: Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour-targeting molecules like human serum albumin.

Journal ArticleDOI
TL;DR: It is shown that changes in anthocyanin structure or reductions in pH, which may occur in the region of inflammatory sites, have an effect on the binding of Anthocyanins to HSA.