Novel sulphonamides incorporating triazene moieties show powerful carbonic anhydrase I and II inhibitory properties

Abstract

A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was confirmed by physico-chemical methods. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were evaluated against human isoforms hCA I and II. K_I values of these sulphonamides were in the range of 21?±?4–72?±?2?nM towards hCA I and in the range of 16?±?6–40?±?2?nM against hCA II. The 4-fluoro substituted derivative might be considered as an interesting lead due to its effective inhibitory action against both hCA I and hCA II (K_Is of 21?nM), a profile rarely seen among other sulphonamide CA inhibitors, making it of interest in systems where the activity of the two cytosolic isoforms is dysregulated.     

Troponin and Anti-Troponin Autoantibody Levels in Patients with Ventricular Noncompaction

Ventricular hypertrabeculation/noncompaction is a morphologic and functional anomaly of myocardium characterized by prominent trabeculae accompanied by deep recessus. Dilated cardiomyopathy with left ventricular failure is observed in these patients, while the cause or pathophysiologic nature of this complication is not known. Anti-troponin antibodies are formed against circulating cardiac troponins after an acute coronary event or conditions associated with chronic myocyte necrosis, such as dilated cardiomyopathy. In present study, we aimed to investigate cardiac troponins and anti troponin autoantibodies in ventricular noncompaction/hypertrabeculation patients with/without reduced ejection fraction. A total of 50 patients with ventricular noncompaction and 23 healthy volunteers were included in this study. Noncompaction/hypertrabeculation was diagnosed with two-dimensional echocardiography using appropriate criteria. Depending on ejection fraction, patients were grouped into noncompaction with preserved EF (LVEF >50%, n = 24) and noncompaction with reduced EF (LVEF <35%, n = 26) groups. Troponin I, troponin T, anti-troponin I IgM and anti-troponin T IgM were measured with sandwich immunoassay method using a commercially available kit. Patients with noncompaction had significantly higher troponin I (28.98±9.21 ng/ml in NCNE group and 28.11±10.42 ng/ml in NCLE group), troponin T (22.17±6.97 pg/ml in NCNE group and 22.78±7.76 pg/ml in NCLE group) and antitroponin I IgM (1.92±0.43 µg/ml in NCNE group and 1.79±0.36 µg/ml in NCLE group) levels compared to control group, while antitroponin T IgM and IgG were only elevated in patients with noncompaction and reduced EF (15.81±6.52 µg/ml for IgM and 16.46±6.25 µg/ml for IgG). Elevated cardiac troponins and anti-troponin I autoantibodies were observed in patients with noncompaction preceding the decline in systolic function and could indicate ongoing myocardial damage in these patients.     

Synthesis of polysubstituted β-amino cyclohexane carboxylic acids via Diels–Alder reaction using Ni(II)-complex stabilized β-alanine derived dienes

This paper describes the design and synthesis of a new class of β-alanine derived dienes stabilized by Ni(II)-complex. Preliminary study of their Diels–Alder cycloaddition reactions with several types of dienophiles demonstrates their significant synthetic potential for the preparation of various polyfunctional β-aminocyclohexane carboxylic acids.     

N-glycans modulate the function of human corticosteroid-binding globulin

Human corticosteroid-binding globulin (CBG), a heavily glycosylated protein containing six N-linked glycosylation sites, transports cortisol and other corticosteroids in blood circulation. Here, we investigate the biological importance of the N-glycans of CBG derived from human serum by performing a structural and functional characterization of CBG N-glycosylation. Liquid chromatography-tandem MS-based glycoproteomics and glycomics combined with exoglycosidase treatment revealed 26 complex type N-glycoforms, all of which were terminated with α2,3-linked neuraminic acid (NeuAc) residues. The CBG N-glycans showed predominantly bi- and tri-antennary branching, but higher branching was also observed. N-glycans from all six N-glycosylation sites were identified with high site occupancies (70.5-99.5%) and glycoforms from all sites contained a relatively low degree of core-fucosylation (0-34.9%). CBG showed site-specific glycosylation and the site-to-site differences in core-fucosylation and branching could be in silico correlated with the accessibility to the individual glycosylation sites on the maturely folded protein. Deglycosylated and desialylated CBG analogs were generated to investigate the biological importance of CBG N-glycans. As a functional assay, MCF-7 cells were challenged with native and glycan-modified CBG and the amount of cAMP, which is produced as a quantitative response upon CBG binding to its cell surface receptor, was used to evaluate the CBG:receptor interaction. The removal of both CBG N-glycans and NeuAc residues increased the production of cAMP significantly. This confirms that N-glycans are involved in the CBG:receptor interaction and indicates that the modulation is performed by steric and/or electrostatic means through the terminal NeuAc residues.     

Living bacterial sacrificial porogens to engineer decellularized porous scaffolds

Decellularization and cellularization of organs have emerged as disruptive methods in tissue engineering and regenerative medicine. Porous hydrogel scaffolds have widespread applications in tissue engineering, regenerative medicine and drug discovery as viable tissue mimics. However, the existing hydrogel fabrication techniques suffer from limited control over pore interconnectivity, density and size, which leads to inefficient nutrient and oxygen transport to cells embedded in the scaffolds. Here, we demonstrated an innovative approach to develop a new platform for tissue engineered constructs using live bacteria as sacrificial porogens. E.coli were patterned and cultured in an interconnected three-dimensional (3D) hydrogel network. The growing bacteria created interconnected micropores and microchannels. Then, the scafold was decellularized, and bacteria were eliminated from the scaffold through lysing and washing steps. This 3D porous network method combined with bioprinting has the potential to be broadly applicable and compatible with tissue specific applications allowing seeding of stem cells and other cell types.     

Tree-ring growth of Pinus nigra Arn. subsp. pallasiana under different climate conditions throughout western Anatolia

Pinus nigra Arn. subsp. pallasiana (black pine) is one of the most widely grown tree in Turkey. It is the third most widely distributed tree species after Quercus L. and Pinus brutia Ten. Black pine grows in 20% of all forested areas in Turkey. In this dendroecological study, we identified the most important climate factors affecting radial growth of black pine in western Anatolia and classified its responses to climate. Twenty-eight site chronologies developed by different researchers were used in the analysis. Response functions were calculated for each chronology to identify the effect of climate on radial growth. Hierarchical cluster analysis was used to sort response functions and to classify the chronologies into groups based on climate responses. The individual responses of these chronologies to temperature and precipitation were classified in four main groups. Climatic and phytogeographic differences were the major factors influencing the formation of clusters. The results suggest that the major limiting factor is drought caused by low precipitation, especially in May, in almost all sites. The drought effect is much stronger in the transition region to the steppe, Central Anatolia and Mediterranean Regions than the Black Sea Region. Black pine trees respond positively to higher temperature at the beginning of growing season in almost all areas except in transition region to the steppe.     

Alport Syndrome mutations in type IV tropocollagen alter molecular structure and nanomechanical properties

Alport Syndrome is a genetic disease characterized by breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to kidney failure in most patients. It is the second most inherited kidney disease in the US, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level structure–property relationships of this disease using a bottom-up computational materiomics approach implemented through large-scale molecular dynamics simulation. Since the GBM is under constant mechanical loading due to blood flow, changes in mechanical properties due to amino acid mutations may be critical in the symptomatic GBM breakdown seen in Alport Syndrome patients. Through full-atomistic simulations in explicit solvent, the effects of single-residue glycine substitution mutations of varying clinical severity are studied in short segments of type IV tropocollagen molecules. The segments with physiological amino acid sequences are equilibrated and then subjected to tensile loading. Major changes are observed at the single molecule level of the mutated sequence, including a bent shape of the structures after equilibration (with the kink located at the mutation site) and a significant alteration of the molecules’ stress–strain responses and stiffnesses. These results suggest that localized structural changes at amino acid level induce severe alterations of the molecular properties. Our study opens a new approach in pursuing a bottom-up multi-scale analysis of this disease.     

Side-by-side comparison of horizontal subsurface flow and free water surface flow constructed wetlands and artificial neural network (ANN) modelling approach

A horizontal subsurface flow (HSSF) and a free water surface flow (FWSF) constructed wetlands (4 m² of each) were set up on the campus of Harran University, Sanliurfa, Turkey. The main objective of the research was to compare the performance of two systems to decide the better one for future planning of wastewater treatment system on the campus. Both of the wetland systems were planted with Phragmites australis and Canna indica. During the observation period (10 months), environmental conditions such as pH, temperature and total chemical oxygen demand (COD), soluble COD, total biochemical oxygen demand (BOD), soluble BOD, total suspended solids (TSS), total phosphate (TP), total nitrogen (TN) removal efficiencies of the systems were determined. According to the results, average yearly removal efficiencies for the HSSF and the FWSF, respectively, were as follows: total COD (75.7% and 69.9%), soluble COD (85.4% and 84.3%), total BOD (79.6% and 87.6%), soluble BOD (87.7% and 95.3%), TN (33.2% and 39.4%), and TP (31.5% and 6.5%). Soluble COD and BOD removal efficiencies of both systems increased gradually since the start-up. After nine months of operation, above 90% removal of organic matters were observed. The treatment performances of the HSSF were better than that of the FWSF with regard to the removal of suspended solids and total COD at especially high temperatures. In FWSF systems, COD concentrations extremely exceeded the discharge limit values due to high concentrations of algae in spring months.The performance of the two systems was modelled using an artificial neural network-back-propagation algorithm. The ANN model was competent at providing reasonable match between the measured and the predicted concentrations of total COD (R = 0.90 for HSSF and R = 0.96 for FWSF), soluble COD (R = 0.90 for HSSF and R = 0.74 for FWSF) and total BOD (R = 0.94 for HSSF and R = 0.84 for FWSF) in the effluents of constructed wetlands.     

Performance of sulfidogenic anaerobic baffled reactor (ABR) treating acidic and zinc-containing wastewater

The applicability of anaerobic baffled reactor (ABR) was investigated for the treatment of acidic (pH 4.5–7.0) wastewater containing sulfate (1000–2000 mg/L) and Zn (65–200 mg/L) at 35 °C. The ABR consisted of four equal stages and lactate was supplemented (COD/SO₄²⁻ = 0.67) as carbon and energy source for sulfate reducing bacteria (SRB). The robustness of the system was studied by decreasing pH and increasing Zn, COD, and sulfate loadings. Sulfate-reduction efficiency quickly increased during the startup period and reached 80% within 45 days. Decreasing feed pH, increasing feed sulfate and Zn concentrations did not adversely affect system performance as sulfate reduction and COD removal efficiencies were within 62–90% and 80–95%, respectively. Although feed pH was steadily decreased from 7.0 to 4.5, effluent pH was always within 6.8–7.5. Over 99% Zn removal was attained throughout the study due to formation of Zn-sulfide precipitate.