Pharmacological Classification and Activity Evaluation of Furan and Thiophene Amide Derivatives Applying Semi-Empirical ab initio Molecular Modeling Methods

Pharmacological and physicochemical classification of the furan and thiophene amide derivatives by multiple regression analysis and partial least square (PLS) based on semi-empirical ab initio molecular modeling studies and high-performance liquid chromatography (HPLC) retention data is proposed. Structural parameters obtained from the PCM (Polarizable Continuum Model) method and the literature values of biological activity (antiproliferative for the A431 cells) expressed as LD50 of the examined furan and thiophene derivatives was used to search for relationships. It was tested how variable molecular modeling conditions considered together, with or without HPLC retention data, allow evaluation of the structural recognition of furan and thiophene derivatives with respect to their pharmacological properties

Principal Component Analysis of HPLC Retention Data and Molecular Modeling Structural Parameters of Cardiovascular System Drugs in View of Their Pharmacological Activity

Abstract: Evaluation of relationships between molecular modeling structural parameters and high-performance liquid chromatography (HPLC) retention data of 11 cardiovascular system drugs by principal component analysis (PCA) in relation to their pharmacological activity was performed. The six retention data parameters were determined on three different HPLC columns (Nucleosil C18 AB with octadecylsilica stationary phase, IAM PC C10/C3 with chemically bounded phosphatidylcholine, and Nucleosil 100-5 OH with chemically bounded propanodiole), and using isocratically acetonitrile: Britton-Robinson buffer as the mobile phase. Additionally, molecular modeling studies were performed with the use of HyperChem software and MM+ molecular mechanics with the semi-empirical AM1 method deriving 20 structural descriptors. Factor analysis obtained with the use of various sets of parameters: structural parameters, HPLC retention data, and all 26 considered parameters, led to the extraction of two main factors. The first principal component (factor 1) accounted for 44-57 % of the variance in the data. The second principal component (factor 2) explained 29-33 % of data variance. Moreover, the total data variance explained by the first two factors was at the level of 73-90%. More importantly, Int. J. Mol. Sci. 2010, 11 268

Pharmacological Classification and Activity Evaluation of Furan and Thiophene Amide Derivatives Applying Semi-Empirical <em>ab initio</em> Molecular Modeling Methods

Pharmacological and physicochemical classification of the furan and thiophene amide derivatives by multiple regression analysis and partial least square (PLS) based on semi-empirical <em>ab initio</em> molecular modeling studies and high-performance liquid chromatography (HPLC) retention data is proposed. Structural parameters obtained from the PCM (Polarizable Continuum Model) method and the literature values of biological activity (antiproliferative for the A431 cells) expressed as LD<sub>50</sub> of the examined furan and thiophene derivatives was used to search for relationships. It was tested how variable molecular modeling conditions considered together, with or without HPLC retention data, allow evaluation of the structural recognition of furan and thiophene derivatives with respect to their pharmacological properties

Higher-Order Language Dysfunctions in Individuals with Alcohol Use Disorder

Patients with alcohol use disorders (AUD) have difficulties with certain aspects of higher-order language functions (HOLF) but there is no data on a wide range of these functions in this group. Therefore, the aim of this study was to compare different aspects of HOLF in patients with AUD and healthy controls (HC). A total of 31 patients with AUD and 44 HC took part in the study. We assessed HOLF with the Right Hemisphere Language Battery (RHLB) and measured control variables: depression using the Patient Health Questionnaire (PHQ) as well as the speed of processing and executive functions with the Color Trails Test (CTT). Patients with AUD had lower results on nine RHLB tests. Moreover, AUD patients had higher scores on PHQ and longer reaction times on CTT. The differences in most RHLB results remained significant after co-varying the control variables. Patients with AUD have difficulties with making inferences from the text, understanding the meaning of individual words, metaphorical content, and prosody, which may impede the comprehension and production of discourse in which linguistic elements must be integrated with non-verbal cues and contextual information. These disturbances may impact various spheres of everyday life and negatively influence social, private, and professional functioning

Urinary Metalloproteinases-9 and -2 and Their Inhibitors TIMP-1 and TIMP-2 are Markers of Early and Long-Term Graft Function After Renal Transplantation

Background/Aims: Renal ischemia-reperfusion (I-R) injury (IRI) is an inseparable feature of organ transplantation and may have a negative impact on the graft, its function and survival. Acute tubular necrosis, which is reversible thanks to the regenerative capacity of renal tubular epithelial cells, is the main cause of acute renal failure secondary to IRI. MMP-2 and MMP-9 are proteolytic enzymes involved in digesting proteins that are components of the extracellular matrix (ECM) and the basement membrane of the nephrons. This way post-reperfusion MMP activation allows the inflammatory process to spread. Methods: In our studies, we focused on identifying whether the concentrations of MMP-2 and MMP-9 and their natural inhibitors TIMP-1 and TIMP-2 in urine sample at day 1 and day 30 as well as after 12 months following renal transplantation are markers of early and long-term renal function during meanly five-years observation. Moreover, in urine sampled at months 6 and 12 after renal transplantation, we determined the content of TGF-β as a graft fibrosis indicator. Results: MMP-9 concentration in the early post-transplant period is a major marker of early and long-term function of the transplanted kidney. Its increased concentration was correlated with lesions related to tubular atrophy and fibrosis in renal biopsies performed at months 3 and 12 after transplantation. Its concentration is correlated with TGF-β content in a later period. Conclusions: TIMP-1 and-2 are primarily markers of an early function of the transplanted kidney. Early post-transplant concentration of MMP-2 is a marker of proteinuria in early and long-term post-transplant periods

Surface plasmon polaritons probed with cold atom

We report on an optical mirror for cold rubidium atoms based on a repulsive dipole potential created by means of a modified recordable digital versatile disc. Using the mirror, we have determined the absolute value of the surface plasmon polariton (SPP) intensity, reaching 90 times the intensity of the excitation laser beam. Furthermore, we have also directly measured thermo-plasmonic effects accompanying SPPs excitation on gold submicron structures

N-acetyl-beta-glucosaminidase urine activity as a marker of early proximal tubule damage and a predictor of the long-term function of the transplanted kidneys

Introduction: Ischaemia-reperfusion injury (IRI) is a factor leading to the damages of the transplanted kidney, what affects mainly the proximal tubules. Early monitoring of tubule damage can be an efficient tool to predict the allograft dysfunction. Present in proximal tubules, N-acetyl-beta-glucosaminidase (NAG) is a lysosomal enzyme whose excretion rises as a result of IRI or acute rejection. The aim of this study was to monitor the NAG urine activity to evaluate the early proximal tubule damage, and to try to predict the long-term function of the transplanted kidney. Material and methods: The study enrolled 87 Caucasian renal transplant recipients (61.7% males, 38.3% females, mean age 45.56±14.34 years). Urine samples were collected for NAG and creatinine analysis on the 1st day after transplantation, and then in the 3rd and 12th month. Protocol biopsies were performed in the 3rd and 12th month. Results: A significant positive correlation between NAG urine activity in the 3rd month after transplantation and creatinine concentration on the 14th (p=0.004) and 30th day (p=0.05), in the 3rd month (p=0.009) and after the 1st (p=0.005) and 2nd year (p=0.003) was observed. A statistically significantly higher urinary NAG activity in samples collected in the first 3 days and in the 3rd month after transplantation among patients with DGF (p=0.006 and p=0.03 respectively) was found. There was a significant positive correlation between NAG urine activity in the 3rd month and the grade of tubular atrophy in specimens collected in the 3rd (p=0.03) and 12th (p=0.04) month. Conclusions: Monitoring of NAG urine activity is useful in the evaluation of early proximal tubule damage and predicting the long-term function of the transplanted kidneys. Key words: allograft, CAD, DGF, kidney function, NAG. INTRODUCTION According to the United Network for Organ Sharing (UNOS) records, 40% of renal allografts are lost during the first decade after transplantation N-acetyl-beta-glucosaminidase (NAG) is a lysosomal enzyme present in the proximal tubules of the kidney, normally secreted in small concentrations as a consequence of a natural exocytosis process (Price 1992). It was shown that after administration of cadmium, contrast agents, aminoglycosides and other nephrotoxic drugs, excretion of NAG increases * e-mail: [email protected] Abbreviations: CAN, chronic allograft nephropathy; CIT, cold ischaemia; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IRI, Ischaemia-reperfusion injury; NAG, N-acetyl-beta-glucosaminidase; PRA, panel-reactive antibody; TA/IF, tubular atrophy and interstitial fibrosis Urine samples were collected for NAG and creatinine analysis on the 1st day after transplantation, and then in the 3rd and 12th month. Among subjects that did not produce urine because of delayed graft function (DGF), the first sample was collected when the amount of urine reached 500 ml per day, which was not later than on the 3rd day after the transplantation. These samples corresponded with the urine samples collected on the 1st day after transplantation from patients without DGF, and they were analysed together. The collected samples were centrifuged at 4000 rpm for 10 min, and urine without the sediment was stored at -80ºC until the time of analysis. The activity of NAG was measured by the Maruhn colorimetric method using p-nitrophenyl-N-acetyl-β-Dglucosamine (Sigma-Aldrich) as a substrate RESULTS The GFR and NAG activity during the study are presented in In regard to histopathological changes in renal allograft biopsies, there was a significant positive correlation between NAG urine activity in the 3rd month after transplantation and the grade of tubular atrophy in specimens collected in the 3rd (p=0.03) and 12th (p=0.04) month There was a significant positive correlation between NAG urine activity in the 3rd month after transplantation and the grade of proteinuria in single urine samples in the 3rd month after transplantation (p=0.05), and a significant positive correlation between NAG urine activity in the 12th month, and the grade of proteinuria in single urine samples in the 12th month after transplantation (p=0.01). Moreover, NAG urine activity in the 3rd month after transplantation correlated positively with the time of dialysis before transplantation (p=0.02), and negatively with the volume of residual diuresis (p=0.05). There was no correlation between urinary NAG activity and immunosuppressive agent concentrations. A higher NAG urine activity in the 3rd month after transplantation was observed in recipients of kidneys from donors with ischaemic or haemorrhagic stroke as a reason of death (p=0.03). DISCUSSIO

N-acetyl-beta-glucosaminidase urine activity as a marker of early proximal tubule damage and a predictor of the long-term function of the transplanted kidneys

Introduction: Ischaemia-reperfusion injury (IRI) is a factor leading to the damages of the transplanted kidney, what affects mainly the proximal tubules. Early monitoring of tubule damage can be an efficient tool to predict the allograft dysfunction. Present in proximal tubules, N-acetyl-beta-glucosaminidase (NAG) is a lysosomal enzyme whose excretion rises as a result of IRI or acute rejection. The aim of this study was to monitor the NAG urine activity to evaluate the early proximal tubule damage, and to try to predict the long-term function of the transplanted kidney. Material and methods: The study enrolled 87 Caucasian renal transplant recipients (61.7% males, 38.3% females, mean age 45.56±14.34 years). Urine samples were collected for NAG and creatinine analysis on the 1st day after transplantation, and then in the 3rd and 12th month. Protocol biopsies were performed in the 3rd and 12th month. Results: A significant positive correlation between NAG urine activity in the 3rd month after transplantation and creatinine concentration on the 14th (p=0.004) and 30th day (p=0.05), in the 3rd month (p=0.009) and after the 1st (p=0.005) and 2nd year (p=0.003) was observed. A statistically significantly higher urinary NAG activity in samples collected in the first 3 days and in the 3rd month after transplantation among patients with DGF (p=0.006 and p=0.03 respectively) was found. There was a significant positive correlation between NAG urine activity in the 3rd month and the grade of tubular atrophy in specimens collected in the 3rd (p=0.03) and 12th (p=0.04) month. Conclusions: Monitoring of NAG urine activity is useful in the evaluation of early proximal tubule damage and predicting the long-term function of the transplanted kidneys