The Relationship between Serum Carbonic Anhydrase I-II Autoantibody Levels and Diabetic Retinopathy in Type 1 Diabetes Patients.
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SUBMITTER: Turk A
PROVIDER: S-EPMC5384125 | biostudies-other | 2017 Apr
REPOSITORIES: biostudies-other
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Project description:PurposeCarbonic anhydrase is elevated in the vitreous of patients with proliferative diabetic retinopathy (PDR). This study aimed to determine if common polymorphisms in the carbonic anhydrase (CA) gene influence susceptibility to diabetic retinopathy (DR).MethodsIn this multicentered study, a total of 235 control subjects with no DR, 158 subjects with nonproliferative DR (NPDR), 132 with proliferative DR (PDR), and 93 with clinically significant macular edema (CSME) were recruited. Blinding DR was defined as severe NPDR, PDR or CSME. DR subjects were drawn from both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) populations. Ten tag single nucleotide polymorphisms were selected to cover the majority of genetic diversity across the CA gene.ResultsAfter adjustments were made for sex, disease duration, and HbA(1)c, no associations were found between any CA polymorphisms or haplotypes with any type of retinopathy in T1DM or T2DM.ConclusionsSequence variation in CA is not associated with the risk of developing retinopathy in T1DM or T2DM and increases the likelihood that elevated vitreous CA may be a consequence rather than cause of DR. Further genetic studies are required to have a better understanding of the pathogenesis of this debilitating diabetic complication.
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Project description:Fibroblast growth factor 21 (FGF21) is a major metabolic regulator that has been shown to be elevated in a number of metabolic disturbances including type 2 diabetes mellitus (T2DM) and the metabolic syndrome, but few studies about the relationship between serum FGF21 and the complications of diabetes have been done. Since the association between FGF21 and diabetic retinopathy is not clear, this study was conducted to investigate this relationship. In this cross-sectional study, 61 subjects (14 healthy controls, 22 diabetic patients without retinopathy, and 25 patients with diabetic retinopathy) were evaluated. All patients in the study were examined for the presence of diabetic retinopathy. Various clinical and biochemical parameters including FGF21 were evaluated and analyzed and compared between the study groups. Serum levels of FGF21 showed a significant difference between the three groups (P=0.003) but the difference between diabetic patients with and without retinopathy was not significant (P=0.122). Regression model was used to evaluate the role of FGF21 in predicting diabetic retinopathy. In the multivariate logistic regression model after adjustment of systolic blood pressure and fasting blood glucose, the level of FGF21 was not associated with diabetic retinopathy. In the multivariate model, only fasting blood glucose was associated with diabetic retinopathy (P=0.009). According to the results of this study, serum levels of FGF21 in diabetic patients was higher than the control group but these raised levels could not predict the presence of diabetic retinopathy.
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Project description:ObjectivePrevious reports have indicated that serum bilirubin levels may be associated with diabetic retinopathy. However, the detailed mechanism is not fully understood. In this study, we evaluated the relationship between the severity of diabetic retinopathy and various factors including bilirubin levels and factors influencing bilirubin metabolism.MethodsThe study participants consisted of 94 consecutive patients with diabetes mellitus admitted to Kyushu University Hospital from April 2011 to July 2012. The patients were classified into three groups: no retinopathy (NDR), simple retinopathy (SDR), and pre-proliferative or proliferative retinopathy (PDR). The relationship between the severity of retinopathy and various factors was evaluated using univariate and logistic regression analyses. In addition, multivariate regression analysis was performed to evaluate the significant determinants for bilirubin levels.ResultsIn univariate analysis, a significant difference was found among NDR, SDR and PDR in bilirubin levels, duration of diabetes, systolic blood pressure, and macroalbuminuria. Logistic regression analysis showed that PDR was significantly associated with bilirubin levels, duration of diabetes, and systolic blood pressure (OR 0.737, 95% CI 0.570-0.952, P = 0.012; OR 1.085, 95% CI 1.024-1.149, P = 0.006; OR 1.036, 95% CI 1.011-1.062, P = 0.005, respectively). In turn, multivariate regression analysis showed that bilirubin levels were negatively associated with high-sensitivity C-reactive protein levels and PDR, but positively correlated with urinary biopyrrin levels, oxidized metabolites of bilirubin.ConclusionPDR was negatively associated with bilirubin levels. This negative association may be due to a decreased production of bilirubin rather than its increased consumption considering the positive association between bilirubin and biopyrrin levels.
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Project description:Aim:This study aims to measure serum vascular endothelial growth factor (VEGF) levels in a sample of Jordanian patients and to determine their relationship with the different stages of diabetic retinopathy. It also explores the correlation between VEGF concentrations and different biochemical and demographic findings. Materials and Methods:A total of 167 adults participated in the study. Participants were divided into two main categories: patients with diabetes mellitus (DM) type 2 without diabetic retinopathy (DR) (N?=?62) and patients with DM type 2 affected by DR (N?=?105). DR patients were further subclassified into nonproliferative (N?=?41) and proliferative (N?=?64). Basic laboratory tests were measured to correlate with VEGF levels. Irisin, a hormone linked to diabetic retinopathy was also measured and correlated with VEGF. Results:Serum VEGF was found to positively correlate with the severity of diabetic retinopathy. The means of VEGF serum concentrations were 60?pg/mL for controls, 133?pg/mL for nonproliferative DR patients, and 229?pg/mL for proliferative DR patients. We found a significant positive correlation with glycosylated hemoglobin (HbA1c), and a significant negative correlation with high-density lipoprotein (HDL) levels, age, and irisin. Conclusion:In this cohort of Jordanian diabetics, serum VEGF concentrations strongly correlated with the presence and stages of diabetic retinopathy, suggesting it as an appropriate indicator for diabetic retinopathy early detection and management in this society. VEGF levels also significantly correlated with HbA1c, HDL, and irisin levels. Further studies are encouraged to explore these relationships in other ethnic groups and with different diabetic complications.
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Project description:Aims/introductionVaspin is linked to obesity and its metabolic abnormalities. However, the role of vaspin serum levels in diabetic retinopathy (DR) is unknown. In the present study, we investigated the association between serum levels of vaspin and both DR and vision-threatening DR.Materials and methodsThis was a cross-sectional single-center observational study from December 2018 to September 2019. We evaluated circulating serum levels of vaspin in 372 participants with type 2 diabetes. DR was screened through detailed ocular examination. DR patients were also divided two groups: vision-threatening DR and non-vision-threatening DR. The relationship between vaspin and DR was investigated by univariate and multivariate logistic regression analyses, and the results are shown as odds ratios with 95% confidence intervals.ResultsThe vaspin serum levels of 372 patients were obtained, with a median value of 1.50 ng/mL (interquartile range 0.94-2.18 ng/mL). The median age of those patients was 53 years (interquartile range 44-62 years), and 44.4% were women. Patients with DR and VDTR had significantly increased vaspin serum levels (P < 0.001 andP < 0.001). A multivariable regression model found that patients with high levels of vaspin were approximately 1.85-fold (odds ratio for per unit increase 1.85, 95% confidence interval 1.43-2.55; P < 0.001) more likely to experience DR, and 3.76-fold (odds ratio for per unit increase 3.76, 95% confidence interval 2.05-6.55; P < 0.001) more likely to experience VTDR. The predictive value of vaspin was stronger in women than in men.ConclusionHigher vaspin serum levels were associated with an increased risk of DR and VDTR in patients with type 2 diabetes, which showed that vaspin is an important indicator factor for DR.
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Project description:Carbonic anhydrase has been well studied structurally and functionally owing to its importance in respiration. A large number of X-ray crystallographic structures of carbonic anhydrase and its inhibitor complexes have been determined, some at atomic resolution. Structure determination of a sulfonamide-containing inhibitor complex has been carried out and the structure was refined at 0.9 A resolution with anisotropic atomic displacement parameters to an R value of 0.141. The structure is similar to those of other carbonic anhydrase complexes, with the inhibitor providing a fourth nonprotein ligand to the active-site zinc. Comparison of this structure with 13 other atomic resolution (higher than 1.25 A) isomorphous carbonic anhydrase structures provides a view of the structural similarity and variability in a series of crystal structures. At the center of the protein the structures superpose very well. The metal complexes superpose (with only two exceptions) with standard deviations of 0.01 A in some zinc-protein and zinc-ligand bond lengths. In contrast, regions of structural variability are found on the protein surface, possibly owing to flexibility and disorder in the individual structures, differences in the chemical and crystalline environments or the different approaches used by different investigators to model weak or complicated electron-density maps. These findings suggest that care must be taken in interpreting structural details on protein surfaces on the basis of individual X-ray structures, even if atomic resolution data are available.
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Project description:Carbonic anhydrase II (CAII) is a metalloenzyme that catalyzes the reversible hydration/dehydration of CO2/HCO3-. In addition, CAII is attributed to other catalytic reactions, including esterase activity. Aspirin (acetyl-salicylic acid), an everyday over-the-counter drug, has both ester and carboxylic acid moieties. Recently, compounds with a carboxylic acid group have been shown to inhibit CAII. Hence, we hypothesized that Aspirin could act as a substrate for esterase activity, and the product salicylic acid (SA), an inhibitor of CAII. Here, we present the crystal structure of CAII in complex with SA, a product of CAII crystals pre-soaked with Aspirin, to 1.35Å resolution. In addition, we provide kinetic data to support the observation that CAII converts Aspirin to its deacetylated form, SA. This data may also explain the short half-life of Aspirin, with CAII so abundant in blood, and that Aspirin could act as a suicide inhibitor of CAII.
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Project description:Human carbonic anhydrase II (hCAII) is a metalloenzyme essential to critical physiological processes in the body. hCA inhibitors are used clinically for the treatment of indications ranging from glaucoma to epilepsy. Targeted protein degraders have emerged as a promising means of inducing the degradation of disease-implicated proteins by using the endogenous quality control mechanisms of a cell. Here, a series of heterobifunctional degrader candidates targeting hCAII were developed from a simple aryl sulfonamide fragment. Degrader candidates were functionalized to produce either cereblon E3 ubiquitin ligase (CRBN) recruiting proteolysis targeting chimeras (PROTACs) or adamantyl-based hydrophobic tags (HyTs). Screens in HEK293 cells identified two PROTAC small-molecule degraders of hCA. Optimization of linker length and composition yielded a degrader with sub-nanomolar potency and sustained depletion of hCAII over prolonged treatments. Mechanistic studies suggest that this optimized degrader depletes hCAII through the same mechanism as previously reported CRBN-recruiting heterobifunctional degraders.
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Project description:Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25-65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.
| S-EPMC4505086 | biostudies-literature
Project description:Carbonic anhydrase (CA, general abbreviation for human carbonic anhydrase II) is a well-studied, zinc-dependent metalloenzyme that catalyzes hydrolysis of carbon dioxide to the bicarbonate ion. The apo-form of CA (apoCA, CA where Zn(2+) ion has been removed) is relatively easy to generate, and reconstitution of the human erythrocyte CA has been initially investigated. In the past, these studies have continually relied on equilibrium dialysis measurements to ascertain an extremely strong association constant (K(a) ≈ 1.2 × 10(12)) for Zn(2+). However, new reactivity data and isothermal titration calorimetry (ITC) data reported herein call that number into question. As shown in the ITC experiments, the catalytic site binds a stoichiometric quantity of Zn(2+) with a strong equilibrium constant (K(a) ≈ 2 × 10(9)) that is 3 orders of magnitude lower than the previously established value. Thermodynamic parameters associated with Zn(2+) binding to apoCA are unraveled from a series of complex equilibria associated with the in vitro metal binding event. This in-depth analysis adds clarity to the complex ion chemistry associated with zinc binding to carbonic anhydrase and validates thermochemical methods that accurately measure association constants and thermodynamic parameters for complex-ion and coordination chemistry observed in vitro. Additionally, the zinc sites in both the as-isolated and the reconstituted ZnCA (active CA containing a mononuclear Zn(2+) center) were probed using X-ray absorption spectroscopy. Both X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) analyses indicate the zinc center in the reconstituted carbonic anhydrase is nearly identical to that of the as-isolated protein and confirm the notion that the metal binding data reported herein is the reconstitution of the zinc active site of human CA II.
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