Diabetic nephropathy involves a renal inflammatory response induced by the diabetic milieu. Macrophages accumulate in diabetic kidneys in association with the local upregulation of monocyte ...chemoattractant protein-1 (MCP-1); however, the contribution of macrophages to renal injury and the importance of MCP-1 to their accrual are unclear. Therefore, we examined the progression of streptozotocin (STZ)-induced diabetic nephropathy in mice deficient in MCP-1 in order to explore the role of MCP-1-mediated macrophage accumulation in the development of diabetic kidney damage. Renal pathology was examined at 2, 8, 12 and 18 weeks after STZ treatment in MCP-1 intact (+/+) and deficient (-/-) mice with equivalent blood glucose and hemoglobin A1c levels. In MCP-1(+/+) mice, the development of diabetic nephropathy was associated with increased kidney MCP-1 production, which occurred mostly in tubules, consistent with our in vitro finding that elements of the diabetic milieu (high glucose and advanced glycation end products) directly stimulate tubular MCP-1 secretion. Diabetes of 18 weeks resulted in albuminuria and elevated plasma creatinine in MCP-1(+/+) mice, but these aspects of renal injury were largely suppressed in MCP-1(-/-) mice. Protection from nephropathy in diabetic MCP-1(-/-) mice was associated with marked reductions in glomerular and interstitial macrophage accumulation, histological damage and renal fibrosis. Diabetic MCP-1(-/-) mice also had a smaller proportion of kidney macrophages expressing markers of activation (inducible nitric oxide synthase or sialoadhesin) compared to diabetic MCP-1(+/+) mice. In conclusion, our study demonstrates that MCP-1-mediated macrophage accumulation and activation plays a critical role in the development of STZ-induced mouse diabetic nephropathy.
Aims
In the present work, the Libyan wild‐growing Thymus capitatus essential oil (EO) was evaluated for its biological properties.
Methods and Results
Carvacrol (68·19%) and thymol (12·29%) were ...found to be the main compounds of the oil. Antioxidant properties, determined by 2,2‐diphenylpicrylhydrazyl (DPPH) assay, revealed that IC50 values were 119, 403 and 105 μg ml−1 for oil, thymol and carvacrol respectively. Microdilution method showed strong antibacterial and especially antifungal potential. Tetrazolium (MTT) colorimetric assay indicated moderate cytotoxicity towards human cell lines MRC‐5, HCT 116 and HT‐29 (IC50 = 30–150 μg ml−1). In adhesion‐inhibition assay oil and main compounds reduced adhesion of Escherichia coli and Listeria monocytogenes on colon cells HT‐29 (51 and 39% of inhibition against L. monocytogenes and E. coli respectively).
Conclusions
Essential oil of Th. capitatus showed moderate cytotoxic activity, together with excellent antimicrobial effect, in particular against fungi, and significant potential to reduce pathogen colonization in colon.
Significance and Impact of the Study
This is the first report that EO of Th. capitatus could protect against colonization of pathogens to colon epithelium. Thymus capitatus from Libya should be recognized as possible new source of natural antioxidants, antimicrobials as well as possible source of new chemotherapeutics.
Aims/hypothesis Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) ...is a potent stimulator of macrophage recruitment. It is increased in adipose tissue during obesity and in diabetic kidneys, suggesting that inflammation of these tissues may be MCP-1-dependent. Based on these findings, the aim of this study was to examine whether a deficiency in MCP-1 would alter the development of type 2 diabetes and its renal complications. Materials and methods The role of MCP-1 in the progression of type 2 diabetes and its associated renal injury was assessed in obese db/db mice that were deficient in the gene encoding MCP-1 (Ccl2). Results The incidence and development of type 2 diabetes were similar in Ccl2 ⁺/⁺ and Ccl2 -/- db/db mice between 8 and 32 weeks of age. Body mass, hyperglycaemia, hyperinsulinaemia, glucose and insulin tolerance, plasma triacylglycerol and serum NEFA were not different between these strains. Pathological changes in epididymal adipose tissue, including increases in macrophage accumulation and Tnfa mRNA and reductions in Adipoq mRNA, were unaffected by the absence of MCP-1. In contrast, kidney macrophage accumulation and the progression of diabetic renal injury (albuminuria, histopathology, renal fibrosis) were substantially reduced in Ccl2 -/- compared with Ccl2 ⁺/⁺ db/db mice with equivalent diabetes. Conclusions/interpretation Our study demonstrates that MCP-1 promotes type 2 diabetic renal injury but does not influence the development of obesity, insulin resistance or type 2 diabetes in db/db mice. MCP-1 plays a critical role in inflammation of the kidney, but not adipose tissue, during the progression of type 2 diabetes.
A series of 278 organophosphate compounds acting as acetylcholinesterase inhibitors has been studied. The Monte Carlo method was used as a tool for building up one-variable quantitative ...structure-activity relationship (QSAR) models for acetylcholinesterase inhibition activity based on the principle that the target endpoint is treated as a random event. As an activity, bimolecular rate constants were used. The QSAR models were based on optimal descriptors obtained from Simplified Molecular Input-Line Entry System (SMILES) used for the representation of molecular structure. Two modelling approaches were examined: (1) 'classic' training-test system where the QSAR model was built with one random split into a training, test and validation set; and (2) the correlation balance based QSAR models were built with two random splits into a sub-training, calibration, test and validation set. The DModX method was used for defining the applicability domain. The obtained results suggest that studied activity can be determined with the application of QSAR models calculated with the Monte Carlo method since the statistical quality of all build models was very good. Finally, structural indicators for the increase and the decrease of the bimolecular rate constant are defined. The possibility of using these results for the computer-aided design of new organophosphate compounds is presented.
Cyclin-dependent kinase 5 (Cdk5) and its neuron-specific regulator p35 (refs 1-4) are essential for neuronal migration and for the laminar configuration of the cerebral cortex. In addition, p35/Cdk5 ...kinase concentrates at the leading edges of axonal growth cones and regulates neurite outgrowth in cortical neurons in culture. The Rho family of small GTPases is implicated in a range of cellular functions, including cell migration and neurite outgrowth. Here we show that the p35/Cdk5 kinase co-localizes with Rac in neuronal growth cones. Furthermore, p35 associates directly with Rac in a GTP-dependent manner. Another Rac effector, Pak1 kinase,, is also present in the Rac-p35/Cdk5 complexes and co-localizes with p35/Cdk5 and Rac at neuronal peripheries. The active p35/Cdk5 kinase causes Pak1 hyperphosphorylation in a Rac-dependent manner, which results in downregulation of Pak1 kinase activity. Because the Rho family of GTPases and the Pak kinases are implicated in actin polymerization, the modification of Pak1, imposed by the p35/Cdk5 kinase, is likely to have an impact on the dynamics of the reorganization of the actin cytoskeleton in neurons, thus promoting neuronal migration and neurite outgrowth.
Thallium bromide (TlBr) crystals subjected to hydrochloric acid (HCl) chemical treatments have been shown to advantageously affect device performance and longevity in TlBr‐based room temperature ...radiation detectors, yet the exact mechanisms of the improvements remain poorly understood. Here, we investigate the influence of several HCl chemical treatments on device‐grade TlBr and describe the changes in the composition and electronic structure of the surface. Composition analysis and depth profiles obtained from secondary ion mass spectrometry (SIMS) identify the extent to which each HCl etch condition affects the detector surface region and forms of a graded TlBr/TlBr1−xClx surface heterojunction. Using a combination of X‐ray photoemission spectroscopy (XPS) and hybrid density functional calculations, we are able to determine the valence band offsets, band gaps, and conduction band offsets as a function of Cl content over the entire composition range of TlBr1−xClx. This study establishes a strong correlation between device process conditions, surface chemistry, and electronic structure with the goal of further optimizing the long‐term stability and radiation response of TlBr‐based detectors.
ABSTRACT
The kinetics of the reaction of benzoic, 2‐methylbenzoic, phenylacetic, cyclohex‐1‐enecarboxylic, 2‐methylcyclohex‐1‐enecarboxylic, and cyclohex‐1‐eneacetic acids with diazodiphenylmethane ...was studied at 30, 33, 37, 40, and 45°C in a set of 12 protic and aprotic solvents. The reactions were found to follow the second‐order kinetics. The activation energy as well as the activation parameters, such as the standard entropy, the standard enthalpy, and the standard Gibbs energy of the activation, was calculated from the second‐order rate constants. The solvent and structural effects on the activation energy and the standard Gibbs energy of activation, for each examined compound, were analyzed. The results of Kamlet–Taft multiple correlation analysis show that the specific solvent–solute interactions play a dominant role in the governing of the reaction. The signs of the equation coefficients support the proposed reaction mechanism.
To evaluate the estimated absorbed radiation doses to the ovaries and skin entrance during uterine artery embolization (UAE) for leiomyomas.
Radiation dose was measured in 20 patients who underwent ...UAE for leiomyomas. Measurements were obtained by placing lithium fluoride dosimeters both into the posterior fornix of the vagina and on the skin at the beam entrance site. Patient doses were obtained with thermoluminescent dosimeters.
The mean fluoroscopic time was 21.89 minutes, and the mean number of angiographic exposures was 44. The mean estimated absorbed ovarian dose was 22.34 cGy, and the mean absorbed skin dose was 162.32 cGy. These values compare to published values for the assessed absorbed ovarian dose during hysterosalpingography (0.04-0.55 cGy), fallopian tube recanalization (0.2-2.75 cGy), computed tomography of the trunk (0.1-1.9 cGy), and pelvic irradiation for Hodgkin disease (263-3,500 cGy).
The estimated absorbed ovarian dose during UAE is greater than that during common fluoroscopic procedures. On the basis of the known risks of pelvic irradiation for Hodgkin disease, the dose associated with UAE is unlikely to result in acute or long-term radiation injury to the patient or to a measurable increase in the genetic risk to the patient's future children.
The energy resolution of room temperature radiation detectors is limited by material properties such as the atomic number of the constituent atoms, band gap, electrical transport coefficients and ...crystalline purity, which critically affect both the stopping distance of ionizing radiation and the carrier collection from the material. Thallium bromide (TlBr) possesses properties that satisfy these criteria and has emerged as a leading candidate for next‐generation detectors, but it currently suffers from degradation phenomena that limit long‐term performance. Chemical surface treatments can drastically improve the lifetime of TlBr‐based devices, with hydrochloric acid etching in particular shown to increase longevity, but the exact role of these treatments has remained poorly understood. Using a combination of experimental and theoretical methods, Varley et al. (pp. 1266–1271) address how these treatments influence the surface composition and the underlying electronic structure. Their results indicate that the etch treatment forms a TlBrxCl1‐x alloy at the surface whose composition is sensitive to the chemical conditions. The surface alloy suppresses hole injection but may also provide several other beneficial functions that will require further study.
•The highest cytotoxic activity in MRC5 fibroblasts and A375 melanoma was determined for 7,8-dihydroxy-4-phenyl coumarin.•SAR studies revealed the influence of phenyl group and hydroxyl group’s ...number and position on cytotoxic activity.•Docking studies showed that 4-phenyl hydroxycoumarins are potent cAMP-dependent protein kinase inhibitors.•Zebrafish embryotoxicity test results showed that 4-phenyl hydroxycoumarins were more embryotoxic in comparison to coumarin.•Examined 4-phenyl hydroxycoumarins can be considered as lead compounds for future development as pharmacophores.
A study of structure cytotoxic–activity relationship of three hydroxy 4-phenyl-coumarins and basic coumarin molecule against two human cell lines (MRC5 fibroblasts and A375 melanoma cells) is presented. Of all investigated compounds the highest cytotoxic activity in both cell lines was determined for 7,8-dihydroxy-4-phenyl coumarin. SAR studies revealed the influence of phenyl group and hydroxyl group’s number and position on cytotoxic activity. In addition, to get an insight about their binding preferences at the active site of the receptor (catalytic subunit of cAMP-dependent protein kinase) molecular docking studies were performed. Docking studies suggest that 4-phenyl hydroxycoumarins are potent cAMP-dependent protein kinase inhibitors, better than their analogs without phenyl group. The teratogenic potential was assessed in zebrafish embryo toxicity test and results showed that 4-phenyl dihydroxycoumarins were more while 7-hydroxy-4-phenyl coumarin was less embryo toxic in comparison to coumarin. In order to examine selected 4-phenyl hydroxycoumarins as a new lead compounds the druglikeness of selected 4-phenyl hydroxycoumarins was estimated by using Lipinski’s “rule of five”. All selected 4-phenyl hydroxycoumarins proved to have satisfying pharmacokinetic profile.
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