The interaction of polyaspartic acid 2 kDa (PASP) biopolymer with the major cationic constituent of natural fluids (H+, Na+, K+, Mg2+, Ca2+) were studied by ISE-H+ titrations. The acid-base ...properties of PASP were determined in different ionic media NaNO3, NaCl, KCl, (CH3)4NCl and (C2H5)4NI at different temperatures and ionic strengths. The data analysis was performed according to the diprotic like model, assuming that a monomeric unit consists of two α and two β aspartyl residues, finding four protonation constants in the range 2.0 < pH < 8.0. Corresponding thermodynamic data (ΔG0, ΔH0 and TΔS0) revealed a slightly endothermic process for the 1st and 2nd steps and a slightly exothermic process for the 3rd and 4th steps, suggesting that amino groups are not involved in the proton binding. The CaL species is more stable than the MgL one at low ionic strength and T = 298.15 K, the contrary is observed at I = 1.0 mol kg−1 and T = 318.15 K, indicating that the latter process is endothermic, while the former is exothermic. Finally, speciation diagrams in the conditions of sea water and human blood plasma are drawn. In sea water, for example, PASP is present as MgL (48%), CaL (41%), Na2L (8%) and NaL species (3%).
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•Diprotic like model was used to analyze potentiometric data of polyaspartate (PASP).•N-atoms are not involved in acid-base equilibria, PASP can be treated as a tetracarboxylate.•The stability trend is: Ca2+ ~ Mg2+ > Na+ ~ K+ > (CH3)4N+ > (C2H5)4N+.•PASP does not significantly lower the levels of free Ca2+ and Mg2+ in sea water.•A small, even significant, lowering (8–15%) occurs in blood plasma.
The acid-base properties and solubilities of 1,2,3-, 1,3,5-, 1,2,4-benzenetricarboxylic and 1,2,4,5-benzenetetracarboxylic acids at T = (298.15 ± 0.15) K in NaClaq, (CH3)4NClaq and in Synthetic Sea ...Water are reported. In synthetic sea water, the data were analyzed by means of the single salt approximation (BA). For each ligand, the total solubility (ST) was determined and only in some cases it was possible to calculate the neutral species solubility (S0) and the Setschenow coefficients, because the formation of sparingly soluble species formed with the cation of the supporting electrolytes was often observed. Different stoichiometry were proposed for the precipitates and their corresponding solubility products were calculated at the different experimental conditions. The dependence of the protonation constants and solubility products on ionic strength was analyzed by Debye-Hückel type equations. The formation constants of the complexes formed by the different deprotonated species of the ligands with the cation of the supporting electrolytes were also determined.
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•Acid-base behavior of benzenepolycarboxylate in NaClaq, (CH3)4NClaq and in SSW.•Determination of the total and neutral species solubility in the different ionic media.•Calculation of the solubility product of sparingly soluble species.•The stability constants of MpHiL species have been calculated at infinite dilution.•Modeling of the thermodynamic properties vs. ionic strength and medium.
A new polyaminocarboxylic bis-(3-hydroxy-4-pyridinone), derivative of DTPA, DTPA(PrHP)2, was synthesized starting from maltol by means of a coupling reaction of a protected 3-hydroxy-4-pyridinone and ...DTPA bis-anhydride. The DTPA(PrHP)2 acid-base behavior was investigated by UV–Vis spectrophotometry and spectrofluorimetry at I = 0.15 mol L−1 in NaCl(aq) at T = 298.15 K and T = 310.15 K. To confirm the speciation scheme, also 1H NMR measurements were performed at T = 298.15 K. The protonation constants obtained from the cited different analytical techniques showed good accordance and were also in agreement with data reported in the literature. The complexing ability of DTPA(PrHP)2 towards divalent (Ca2+, Cu2+, Zn2+) and trivalent (Al3+, Fe3+) cations was studied by potentiometric, UV–Vis spectrophotometric and 1H NMR titrations at T = 298.15 K and I = 0.15 mol L−1 in NaCl(aq). The fitting analysis of experimental data led to the determination of different speciation models consisting of MpLqHr(pn+r-5q) species with different stoichiometry and protonation stages, hydrolytic mixed and polynuclear complexes. The equilibrium model and complex formation constants, obtained from various analytical techniques, are in good agreement. The sequestering ability of the ligand towards the metal cations was assessed through the determination of the pL0.5 and pM parameters at different pH values and pH = 7.4, respectively, which showed to follow the trend Fe3+ > Al3+ > Cu2+ > Ca2+ > Zn2+. Finally, biodistribution studies were carried out in mice previously injected with the radiotracer 67Ga–citrate to evaluate the in vivo ability of DTPA(PrHP)2 as chelating agent towards trivalent metal cations.
Metal chelation capacity based on the pM values calculated vs. pH for different Mn+/bis-3-hydroxy-4-pyridinone (DTPA(PrHP)2) systems; in vivo M3+ sequestration. Display omitted
•A new polyaminocarboxylic bis-(3-hydroxy-4-pyridinone), derived from diethylenetriaminepentaacetic acid, was synthesized.•Its acid-base behavior and complexation towards M2+ and M3+ were investigated.•The sequestering ability of the ligand towards Mn+ was studied using the pL0.5 parameter determination at different pHs.•The pM values, calculated at physiological pH, follows the trend: Fe3+ > Al3+ > Cu2+ > Ca2+ > Zn2+.•Biodistribution studies indicated that the ligand has high in vivo chelating ability towards trivalent metal cations.
A potentiometric study on the acid–base properties and formation of complexes with alkali metals (i.e., Na+ and K+) of some poly(methyl vinyl ether-co-maleic) acids, namely, Gantrez AN169 (2000 ...kDa), S95 (220 kDa), and S97 (1200 kDa), was carried out under different experimental conditions consisting of the ionic medium, ionic strength, and temperature. Owing to the possible formation of micelles, the critical micelle concentration of Gantrez AN169 was determined by means of different techniques in pure water and at T = 298.15 K. The diprotic-like model was used for the elaboration of the experimental protonation data, and the best model was obtained by assuming that a monomeric unit consists of two methyl vinyl ether-co-maleic acid residues. Moreover, the protonation data of two poly(acrylic comaleic acids), PCA 3 kDa and 70 kDa (published in a previous paper), under different experimental conditions were reanalyzed. The trend in the protonation constants of polyelectrolytes in different ionic media is (C2H5)4N+ ≫ K+ > Na+. The variation of the protonation and complex formation constants with the ionic strength was interpreted in terms of both the variation of the activity coefficients and the formation of Na+- and K+-polymer complexes.
In this paper, the sequestering ability of amoxicillin and ampicillin toward Mg2+ in NaCl aqueous solutions at different ionic strengths I = (0 to 1.0) mol·kg–1 and temperatures of T = (288.15 to ...318.15) K was investigated by potentiometry (ISE-H+, glass electrode). The complex formation constants determined at different ionic strengths and temperatures were modeled by means of the Debye–Hückel equation and the Specific ion Interaction Theory (SIT). From the results, a weak ability of the two penicillins to bind the metal ion can be observed; in fact, the stability constants of the ML species (M = Mg2+ and L = amoxicillin or ampicillin) are log β = 4.348 and 3.242 at infinite dilution and T = 298.15 K, respectively. The dependence of the formation constants on the temperature was modeled by means of a van’t Hoff equation, which allowed us to calculate the enthalpy and entropy change values of formation of each species. The sequestering ability of amoxicillin and ampicillin toward Mg2+ in the different experimental conditions (pH, ionic strength, temperature) was quantified by means of a sigmoid equation and of the pL0.5 parameter. The pL0.5 values reflect the low stability constant values of the species; as an example at I = 0.15 mol·kg–1, pH = 7.4, and T = 298.15 K, we have pL0.5 = 2.52 and 2.78, for Mg2+/amox2− and Mg2+/amp− systems, respectively.
Abstract
Background and Aims
Kynurenine pathway of tryptophan metabolism is involved in the pathophysiology of chronic kidney disease (CKD) and diabetes mellitus (DM), mainly through the ...inflammation-induced activity of indoleamine 2,3-dioxygenase (IDO). Renin-angiotensin-aldosterone system inhibitors (RAASis) angiotensin converting enzyme inhibitors (ACEis) and angiotensin II receptor antagonists (ARBs) are recommended in these conditions to decrease proteinuria, slow CKD progression and reduce cardiovascular risk. The interactions between RAAS and the kynurenine pathway and the potential effects of RAASis have been reported in few experimental models but whether these drugs influence kynurenine levels in humans is unknown. We performed a single-centre cross-sectional observational study to evaluate tryptophan and kynurenine serum levels and IDO activity in CKD patients with and without type 2 DM, their correlations with markers of renal dysfunction, and their relationship with RAAS-inhibiting therapy.
Method
We enrolled 72 consecutive adult patients with CKD, of which 38 had DM, who were admitted to the Unit of Nephrology and Dialysis of our Hospital. Of them, 55 were receiving RAASis whereas 17 were not. Tryptophan was assessed by HPLC (high-performance liquid chromatography) analysis with an UltiMateTM 3000 chromatograph (Thermo Fisher Scientific, 168 Third Avenue Waltham, MA, USA); kynurenine was measured using an enzyme-linked immunosorbent assay (ELISA) kit (Catalogue n. K 7728; Immundiagnostik AG, Bensheim, Germany); IDO activity was calculated with the formula (kynurenine/tryptophan) x 100.
Results
Patients receiving RAASis and patients not under therapy only differed for frequency of arterial hypertension (100% vs 76.47%; P=0.002) and kynurenine levels, the latter being significantly lower in the treated group compared to the untreated one (1.56 ± 0.79 vs 2.16 ± 1.51 µmol/l; P=0.0378). Kynurenine did not correlate with estimated glomerular filtration rate (eGFR), proteinuria or albuminuria in the whole study cohort. Conversely, in patients not receiving RAASis it was inversely related to eGFR (r=-0.4862; P=0.0478) and directly related to proteinuria (ρ=0.493; P=0.0444) and albuminuria (ρ=0.542; P=0.0247); moreover, it varied across classes of albuminuria, being lower in patients with normoalbuminuria (0.98 ± 0.55 µmol/l) and higher in those with micro- (2.63 ± 1.53 µmol/l) and macroalbuminuria (3.09 ± 1.61 µmol/l) at the ANOVA test (F=4.008; P=0.042). In the same group, the relationship between IDO activity and eGFR was significant (ρ=-0.554; P=0.0210) and IDO activity differed across classes of albuminuria (F=3.702; P=0.05). Moreover, IDO activity was higher in patients with history of cardiovascular disease compared to those with no such history 10.22 (8.39 to 22.92) vs 7.57 (4.76 to 8.09) %; P=0.0343 whereas tryptophan had an opposite behaviour (17.00 ± 2.06 vs 22.00 ± 3.78 µmol/l; P=0.0036).
Figure:
Conclusion
We observed lower kynurenine levels in CKD patients treated with RAASis compared to untreated patients, independently of the presence of DM, and a significant association between kynurenine and markers of renal damage only in the group not receiving RAASis. We could hypothesize that kynurenine may play a role in the pathophysiology of renal damage, as already suggested, and that drugs interfering with RAAS activation may act also by reducing kynurenine levels, in addition to their already known effects at the renal level. Indeed, kynurenine synthesis results to be higher in states of inflammation and RAAS has pro-inflammatory and pro-fibrotic actions; accordingly, RAASis could reduce the enzymatic activity responsible for kynurenine increase and this could be one of the mechanisms mediating the beneficial effects of RAAS inhibition on CKD progression. This may be relevant because kynurenine has shown pro-thrombotic effects and is emerging as a potential new biomarker of CKD.
Diethylenetriamine-N,N,N′,N″,N″-pentakis(methylenephosphonic acid) (DTPMPA) is used in a wide range of industrial applications, mainly because of its binding ability toward several metal cations. ...Because of difficulties in its synthesis and purification, very little reliable data have been reported in the literature about the coordination chemistry of this ligand in aqueous solution. For these reasons, in this article, we report an efficient procedure for the synthesis and purification of DTPMPA. The pure product obtained was used to determine its acid–base properties in different aqueous ionic media, namely, (C2H5)4NI(aq), NaCl(aq), and KCl(aq), at 288.15 ≤ T/K ≤ 318.15 only T = 298.15 K for KCl(aq) by potentiometry (H+ ion-selective electrode, glass electrode) and at different ionic strengths (0 < I/mol L–1 ≤ 1.0). Measurements performed in alkali metal chlorides were also interpreted in terms of weak complex formation between DTPMPA and Na+ and K+, and further measurements were also performed in NaCl(aq) at T = 298.15 K and different ionic strengths (0 < I/mol L–1 ≤ 1.0) in the presence of Mg2+ or Ca2+, to determine the stability constants of species formed by DTPMPA and these cations. The protonation and complex-formation constants obtained at different ionic strengths and temperatures were modeled by different equations, providing all of the thermodynamic data necessary to define the solution behavior and the chemical speciation of DTPMPA under a wide number of variable conditions, such as those encountered in the very different industrial applications in which this chelating agent is used and those involving many natural fluids.
Trend of the deferiprone protonation constant (log K1H) vs. ionic strength (in the molal concentration scale) in NaCl (□), KCl (Δ) and (CH3)4NCl (○), at T=298.15K. Display omitted
•Thermodynamics, ...solubility and distribution of deferiprone in NaCl, KCl and (CH3)4NCl.•Deferiprone total solubility is 0.100mol·dm−3 in pure water and shows salting out.•The protonation process is entropic for the first step and enthalpic for the second.•Debye–Hückel, SIT and Pitzer approaches used for modelling of protonation constants.•Formation constants of three weak species were determined, Nadef, Kdef and H2defCl.
The acid base properties of 1,2-dimethyl-3-hydroxypyridin-4-one (also known as deferiprone, def, figure 1), together with the solubility and the distribution ratio have been studied potentiometrically at different temperatures and ionic strengths in NaCl, KCl and in (CH3)4NCl aqueous solutions. The total solubility of deferiprone is fairly high (0.100mol·dm−3 in pure water) and decreases with increasing salt concentration (salting out effect); this behaviour is greater in NaCl than in (CH3)4NCl aqueous solutions. From the analysis of the solubility and the distribution measurements it was possible to determine the Setschenow and the activity coefficients of the neutral species. Deferiprone shows two protonation steps, whose protonation constants are logK1H=10.088 and logK2H=3.656 at infinite dilution and T=298.15K. The ionic strength dependence of the protonation constants was interpreted both in terms of variation of the activity coefficients, using the Debye–Hückel, the SIT (Specific ion Interaction Theory) and the Pitzer approaches, or considering the formation of weak species with the ions of the supporting electrolyte (e.g. Na+, K+ and Cl−). Moreover, temperature gradients were provided for the two protonation constants. The stepwise protonation enthalpy values are negative in all cases (e.g. ΔH1=−19.2kJ·mol−1 and ΔH2=−13.8kJ·mol−1 at infinite dilution and T=298.15K) and become more negative increasing both temperature and ionic strength. It was observed that the proton binding process is mainly entropic in nature for the first protonation step and enthalpic for the second. The results are in good agreement with literature data.
Activity coefficients of adrenaline neutral species at different ionic strengths and temperatures. Legend: • T=310.15K and ■ T=298.15K. Display omitted
Solubility and acid–base properties of ...adrenaline were studied in NaCl aqueous solutions at different ionic strengths (0<I/molL−1<3.0) and temperatures (T=298.15 and 310.15K), by means of different techniques: potentiometry, UV-spectrophotometry and spectrofluorimetry. The intrinsic solubility of the ligand was calculated from simple mass balance equations, by using the free hydrogen concentration and the protonation constants of the ligand determined in the same experimental conditions of the solubility measurements. The salting-In or Out parameters and the activity coefficient of the neutral species were calculated by means of the Setschenow equation.
The dependence of the protonation constants on the ionic strength was modeled by means of the Debye–Hückel type equation and of the SIT (Specific ion Interaction Theory) approach. The specific interaction parameters of the ion pairs were also reported. For the protonation constants, the following thermodynamic values at infinite dilution were obtained: T=298.15K, logK1H0=10.674±0.018 and logK2H0=8.954±0.022; T=310.15K, logK1H0=10.355±0.018 and logK2H0=8.749±0.030.
Abstract
Background and Aims
Indole-3-acetic acid (IAA, also called auxin) is a protein-bound indolic uremic toxin deriving from tryptophan metabolism by the intestinal bacteria. Previous studies ...have shown that increased IAA is associated with enhanced tissue factor synthesis in endothelial and peripheral blood mononuclear cells, oxidative stress and endothelial inflammation with resulting higher risk of thrombotic events and both cardiovascular and all-cause mortality. An emerging biomarker of cardiovascular disease is the monocyte to high-density lipoprotein (HDL) ratio (MHR). Its prognostic value is related to the ability of monocytes to release several cytokines involved in inflammation and atherogenesis and to the protective role of HDL through removal of cholesterol from peripheral tissues and suppression of both monocyte progenitor cell proliferation and differentiation and monocyte activation. In this single-centre cross-sectional observational study, we investigated the potential association of IAA with MHR and other markers of cardiovascular risk in a cohort of patients with CKD and evaluated the effect of a single midweek dialysis session with AFB (Acetate-free Biofiltration) technique on IAA serum concentrations.
Method
We enrolled 61 non-dialysis CKD adult patients and 6 dialysis patients treated with AFB technique. IAA levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (Cat. number abx150354; Abbexa Ltd, Cambridge, UK). Post-dialysis IAA levels were corrected for haemoconcentration.
Results
In the whole cohort of 67 patients, IAA was directly related to creatinine (ρ = 0.247; P = 0.0441), potassium (r = 0.2871; P = 0.0185), Ca x P product (ρ = 0.256; P = 0.0365) and MHR (ρ = 0.321; P = 0.0082).
After adjustment for creatinine, the correlation between IAA and potassium became not significant (r = 0.1968; P = 0.1133). Stratifying patients according to the history of cardiovascular disease, in the 40 patients with previous cardiovascular events IAA levels correlated significantly with uric acid (r = 0.3952; P = 0.0116) and MHR (ρ = 0.380; P = 0.0157).
In the remaining 27 patients without history of cardiovascular disease, IAA only correlated with potassium (r = 0.3912; P=0.0481) and, though borderline significantly, with creatinine (ρ = 0.349; P = 0.0805). To assess whether IAA would independently predict MHR values, we evaluated potential correlations of MHR with risk factors for cardiovascular disease. MHR was related with fibrinogen (ρ = 0.426; P = 0.0010), arterial hypertension (ρ = 0.274; P = 0.0251), C-reactive protein (ρ = 0.332; P = 0.0061), gender (ρ = -0.375; P = 0.0017; 0 = male, 1 = female), and CKD stage (ρ = 0.260; P = 0.0337). A multiple regression analysis identified IAA as an independent predictor of MHR. Lastly, IAA levels were higher in dialysis patients compared to non-dialysis CKD patients (97.44 ± 21.58 versus 65.08 ± 24.38 ng/ml respectively; P = 0.0026) and it was significantly removed by a single AFB session (97.44 ± 21.58 versus 54.59 ± 21.74 ng/ml; P = 0.0028) with a reduction ratio of 43.80 ± 17.47%.
Conclusion
This study shows a statistically significant association between IAA and MHR. Based on previous experimental studies, such relationship could be explained by the activation of the transcription factor aryl hydrocarbon receptor. Indeed, IAA is a potent ligand of aryl hydrocarbon receptor and the latter has proinflammatory and proatherogenic activities and can reduce HDL levels. Moreover, AFB efficiently removes IAA during a single dialysis session. Prospective studies with appropriate sample size and sufficiently long period of observation are required to evaluate if decreasing IAA levels, through targeted therapeutic strategies in non dialysis CKD patients or by optimization of dialysis techniques and prescriptions in patients receiving renal replacement therapy, may reduce MHR levels and cardiovascular events and improve clinical outcomes and survival.
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