Molecular dynamics and transport coefficients change significantly around the so-called Arrhenius crossover in glass-forming systems. In this article, we revisit the dynamic processes occurring in a glass-forming macrocyclic crown thiaether MeBzS2O above its glass transition, revealing two crossover temperatures: TB at 309 and TA at 333 K. We identify the second one as the Arrhenius crossover that is closely related to the normal-to-supercooled liquid transition in this compound. We show that the transformation occurring at this point goes far beyond molecular dynamics (where the temperature dependence of structural relaxation times changes its character from activation-like to super-Arrhenius), being reflected also in the internal structure and diffraction pattern. In this respect, we found a twofold local organization of the nearest-neighbor molecules via weak van der Waals forces, without the formation of any medium-range order or mesophases. The nearest surrounding of each molecule evolves structurally in time due to the ongoing fast conformational changes. We identify several conformers of MeBzS2O, demonstrating that its lowest-energy conformation is preferred mainly at lower temperatures, i.e., in the supercooled liquid state. Its increased prevalence modifies locally the short-range intermolecular order and promotes vitrification. Consequently, we indicate that the Arrhenius transition is fuelled rather by conformational changes in this glass-forming macrocyclic crown thiaether, which is a different scenario from the so-far existing concepts. Our studies combine broadband dielectric spectroscopy (BDS), X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations.
A series of four alcohols, n-propanol and its halogen (Cl, Br, and I) derivatives, were selected to study the effects of variation in polarity and halogen-driven interactions on the hydrogen bonding pattern and supramolecular structure by means of experimental and theoretical methods. It was demonstrated on both grounds that the average strength of H-bonds remains the same but dissociation enthalpy, the size of molecular nanoassemblies, as well as long-range correlations between dipoles vary with the molecular weight of halogen atom. Further molecular dynamics simulations indicated that it is connected to the variation in the molecular order introduced by specific halogen-based hydrogen bonds and halogen-halogen interactions. Our results also provided important experimental evidence supporting the assumption of the transient chain model on the molecular origin of the structural process in self-assembling alcohols.
Tumor necrosis factor α inhibitor (TNFαI) therapy is associated with a significant inhibition of radiographic progression, resulting in improved physical function and quality of life among patients with rheumatoid arthritis (RA). The mechanism by which TNFαI prevent joint destruction is still unknown. In this study, the effect of 15-month anti-TNF-α therapy in combination with methotrexate on circulating levels of biochemical markers of cartilage turnover in female RA patients was assessed. Serum levels of collagen type II C-terminal cleavage neoepitope (C2C), C-terminal propeptide of type II collagen (PIICP), cartilage oligomeric matrix protein (COMP), and matrix metalloproteinase-3 (MMP-3) were evaluated using immunoassays at baseline and 15 months after the start of TNFαI treatment. Baseline COMP, C2C, and MMP-3 levels and C2C/PIICP ratios were significantly higher in women with RA compared with those observed in the healthy subjects. No differences in PIICP levels between the controls and the women with RA were observed. After 15 months of TNFαI treatment, serum levels of C2C, COMP, and MMP-3 decreased, whereas the levels of PIICP increased but were still not different from those of the controls. These changes were accompanied by significantly reduced C2C/PIICP ratios. Before the start of TNFαI therapy, serum levels of COMP significantly correlated with the patients' ages (p < 0.05) and their 28-joint disease activity score values based on their erythrocyte sedimentation rates (DAS28-ESR; p < 0.05). Moreover, multiple linear regression analysis showed that baseline COMP levels retained a significant association with DAS28-ESR value (ß = 287.74, p = 0.022, R2 model = 0.25) after model adjustments. The largest area under the ROC curve was obtained for C2C/PIICP ratios (AUC: 0.830, 95% CI: 0.727-0.932, p < 0.001). Our results suggest that long-term anti-TNF-α therapy combined with MTX has a beneficial effect on cartilage remodeling that is associated with clinical improvement among RA patients. Serum C2C/PIICP ratios may help to monitor the effectiveness of anti-TNF-α treatment among RA patients.
Sulfated glycosaminoglycans (sGAGs) are likely to play an important role in the development and progression of rheumatoid arthritis (RA)-associated atherosclerosis. The present study investigated the effect of anti-tumor necrosis factor-α (anti-TNF-α) therapy in combination with methotrexate on plasma sGAG levels and serum markers of endothelial dysfunction. Among sGAG types, plasma chondroitin/dermatan sulfate (CS/DS) and heparan sulfate/heparin (HS/H) were characterized using electrophoretic fractionation. Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and asymmetric dimethylarginine (ADMA) were measured by immunoassays. The measurements were carried out four times: at baseline and after 3, 9 and 15 months of anti-TNF-α therapy. All analyzed parameters, excluding ADMA, were significantly elevated in patients with RA before the implementation of biological therapy compared to healthy subjects. Performed anti-TNF-α treatment led to a successive decrease in HS/H levels toward normal values, without any effect on CS/DS levels in female RA patients. The treatment was also effective at lowering the serum levels of sVCAM-1, MCP-1, MMP-9 and ADMA. Moreover, a significant positive correlation was found between the circulating HS/H and the 28 joint disease activity score based on the erythrocyte sedimentation rate (DAS28-ESR, r = 0.408; p <0.05), MCP-1 (r = 0.398; p <0.05) and ADMA (r = 0.396; p <0.05) in patients before the first dose of TNF-α inhibitor. In conclusion, a beneficial effect of anti-TNF-α therapy on cell-surface heparan sulfate proteoglycans (HSPGs)/HS turnover and endothelial dysfunction was observed in this study. This was manifested by a decrease in blood HS/H levels and markers of endothelial activation, respectively. Moreover, the decrease in the concentration of HS/H in the blood of patients during treatment, progressing with the decline in disease activity, indicates that the plasma HS/H profile may be useful for monitoring the efficacy of anti-TNF-α treatment in patients with RA.
The aim of this study was to evaluate the effect of anti-tumor necrosis factor α (anti-TNF-α) therapy in combination with methotrexate on bone remodeling and osteoclastogenesis in female patients with RA. Serum levels of bone turnover markers (i.e., C- and N-terminal propeptides of type I procollagen (PICP and PINP), C- and N-terminal cross-linking telopeptides of type I collagen (CTX-I and NTX-I), and soluble receptor activator of nuclear factor κB ligand (sRANKL) and osteoprotegerin (OPG)) were determined by immunoassay at baseline and 15 months after initiation of treatment. Bone mineral density was measured by dual-energy x-ray absorptiometry. We found a significant decrease in serum PINP levels, a biomarker of bone formation, and higher levels of CTX-I and sRANKL indicative of increased bone resorption in RA patients prior to TNFαI treatment compared to the controls. Anti-TNF-α therapy was effective in improving bone metabolism in RA patients as reflected in a decrease in CTX-I (at least partially due to the RANKL/OPG reduction) and a concomitant increase in PINP levels. The bone metabolism changes were independent of the type of TNFαI used. PINP and CTX-I were found to be useful markers of bone metabolism, which may prove the effectiveness of TNF-α therapy earlier than the bone density assessment.
A series of five alcohols (3-methyl-2-butanol, 1-cyclopropylethanol, 1-cyclopentylethanol, 1-cyclohexylethanol, and 1-phenylethanol) was used to study the impact of the size of steric hindrance and its aromaticity on self-assembling phenomena in the liquid phase. In this Letter, we have explicitly shown that the phenyl ring exerts a much stronger effect on the self-organization of molecules via the O-H···O scheme than any other type of steric hindrance, leading to a significant decline in the size and concentration of the H-bonded clusters. Given the combination of calorimetric, dielectric, infrared, and diffraction studies, this phenomenon was ascribed to its additional proton-acceptor function for the competitive intermolecular O-H···π interactions. The consequence of this is a different packing of molecules on the short- and medium-range scale.
This study was performed to evaluate the effects of 15-month anti-tumor necrosis factor α (anti-TNF-α) therapy on the aggrecan turnover of female rheumatoid arthritis (RA) patients. Serum was obtained from healthy subjects and female RA patients treated with TNF-α inhibitors (TNFαI) in combination with methotrexate. We measured serum levels of aggrecan chondroitin sulfate 846 epitope (CS846), aggrecan fragments (AGC), disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and 5 (ADAMTS-5), as well as their natural inhibitor, known as tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), using immunoassay methods. Serum levels of CS846, AGC, ADAMTS-4, ADAMTS-5 and TIMP-3 were higher in female patients with RA before the treatment in comparison to healthy subjects. Ratio of ADAMTS-5 to TIMP-3 was significantly higher in RA women than in controls, whereas ADAMTS-4/TIMP-3 ratio did not differ from that in controls. During the anti-TNF-α therapy, the serum levels of 846 epitope increased, whereas levels of AGC decreased in female RA patients. Furthermore, 15 months of treatment with TNFαI downregulated serum levels of both ADAMTS, without any effect on TIMP-3 levels. These changes were accompanied by significantly reduced ratios of ADAMTS to TIMP-3. According to our results, anti-TNF-α therapy has a beneficial impact on aggrecan remodeling during RA.
BACKGROUND: In this study, the effect of 15-month anti-tumor necrosis factor alpha (TNF-α) treatment on circulating levels of plasma sulfated glycosaminoglycans (GAGs) and the nonsulfated GAG hyaluronic acid (HA) in female rheumatoid arthritis (RA) patients was assessed. METHODS: Plasma was obtained from healthy subjects and RA women treated with TNF-α antagonists (etanercept or adalimumab or certolizumab pegol) in combination with methotrexate. GAGs were isolated from plasma samples using ion exchange low-pressure liquid chromatography. Total sulfated GAGs were quantified using a hexuronic acid assay. Plasma levels of keratan sulfate (KS) and HA were measured using immunoassay kits. RESULTS: Total sulfated GAGs and HA levels were higher in female RA patients before treatment in comparison to healthy subjects. KS levels did not differ between RA women and controls. Anti-TNF-α treatment resulted in normalization of plasma total GAG and HA levels in RA patients, without any effect on KS levels. CONCLUSIONS: Our results suggest that anti-TNF-α therapy has a beneficial effect on extracellular matrix remodeling in the course of RA.
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/drug therapy , Glycosaminoglycans/blood , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab/administration & dosage , Adult , Biomarkers/blood , Certolizumab Pegol/administration & dosage , Drug Therapy, Combination , Etanercept/administration & dosage , Female , Humans , Methotrexate/administration & dosage , Middle Aged , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/metabolism
OBJECTIVES: The influence of age and gender factor on the urinary excretion of total glycosaminoglycans (uGAGs) and their particular types: chondroitin/dermatan sulfates (CS/DSs), heparan sulfates (HSs) and hyaluronan (HA) was analyzed in healthy pediatric and adolescent population. DESIGN AND METHODS: Urine samples were collected from 95 healthy children. Sulfated GAGs excreted in the urine were quantitated using standardized dye-binding method, while the concentrations of HA were determined by immunoassay. RESULTS: Age-dependent decline in total uGAG excretion (r=-0.686; p<0.001), resulting from a decrease in particular GAG fractions i.e. CS/DS (r=-0.757; p<0.001), HS (r=-0.401; p<0.05) and HA (r=-0.638; p<0.001), was found in healthy subjects. The observed differences were not gender specific with the exception of HS, in which excretion declines with age in males (r=-0.501; p<0.05) and does not change in females. Changes in the distribution pattern of uGAG were also found. CS/DS were the predominant uGAG's fraction, representing from 55% to 76% of the total GAGs. Children up to 3 years excreted more GAGs than older subjects and with a higher proportion of CS/DS and less content of HS. Moreover, the relative contribution of HA was increased twofold in adolescents, aged 15-18, as compared to younger subjects. A negative correlation existed between uGAG excretion and body height, except for HS, for which this relationship was found only in males. CONCLUSIONS: Changes in urinary distribution pattern of particular GAG types during physiological human growth and development were found. Evaluation of urinary GAG screening procedures during pathological conditions should be based on the GAG/creatinine ratios with age and gender taken into account.
Glycosaminoglycans/urine , Urinary Tract/metabolism , Adolescent , Child , Child, Preschool , Chondroitin/urine , Dermatan Sulfate/urine , Female , Heparitin Sulfate/urine , Humans , Hyaluronic Acid/urine , Infant , Male
