Hydrogen Peroxide Stimulates Exosomal Cathepsin B Regulation of the Receptor for Advanced Glycation End‐Products (RAGE)

Exosomes are nano‐sized vesicles that are secreted into the extracellular environment. These vesicles contain various biological effector molecules that can regulate intracellular signaling pathways in recipient cells. The aim of this study was to examine a correlation between exosomal cathepsin B activity and the receptor for advanced glycation end‐products (RAGE). Type 1 alveolar epithelial (R3/1) cells were treated with or without hydrogen peroxide and exosomes isolated from the cell conditioned media were characterized by NanoSight analysis. Lipidomic and proteomic analysis showed exosomes released from R3/1 cells exposed to oxidative stress induced by hydrogen peroxide or vehicle differ in their lipid and protein content, respectively. Cathepsin B activity was detected in exosomes isolated from hydrogen peroxide treated cells. The mRNA and protein expression of RAGE increased in cultured R3/1 cells treated with exosomes containing active cathepsin B while depletion of exosomal cathepsin B attenuated RAGE mRNA and protein expression. These results suggest exosomal cathepsin B regulates RAGE in type 1 alveolar cells under conditions of oxidative stress. J. Cell. Biochem. 119: 599–606, 2018. © 2017 Wiley Periodicals, Inc.     

Enhanced spectrofluorimetric determination of two novel combination therapies for the treatment of benign prostatic hyperplasia containing tamsulosin hydrochloride

Two novel combination therapies for the treatment of benign prostatic hyperplasia were analyzed using simple and enhanced spectrofluorimetric methods based on derivative and derivative ratio techniques. The two combinations contained tamsulosin hydrochloride (TAM) as a minor component with tolterodine tartrate (TOL) or solifenacin succinate (SOL). The fluorescence of the three drugs under study was measured in methanolic water solution. For the TAM and SOL mixture, successful resolution between both drugs was achieved by derivative manipulation of both ratio and zero‐order emission spectra with good linearity in the ranges of 0.75–3.50 and 2.5–15.0 μg ml^?1 for TAM and SOL, respectively. Extensive emission spectral overlap was observed for the TAM and TOL mixture. Therefore, only derivative application of the ratio emission spectra resolved such overlap and quantitated TAM and TOL simultaneously in the ranges 0.75–3.50 and 2.5–20.0 μg ml^–1 for TAM and TOL, respectively. Optimization of various experimental parameters that affected the fluorescence intensity of the three drugs was performed. Successful application of all proposed methods was achieved for analysis of the two drugs in each combination therapy in their laboratory‐prepared mixtures and dosage forms with good accuracy and precision.     

Novel Regioselective Formation of S- and N-Hydroxyl-Alkyls of 5-(3-Chlorobenzo[b]Thien-2-yl)-3-Mercapto-4H-1,2,4-Triazole and A Facile Synthesis of Triazolo-Thiazoles and Thiazolo-Triazoles. Role of Catalyst and Microwave

Regioselective alkylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (1) with hydroxy alkylating agents 2, 3, 13, and the 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (10) afforded the corresponding S-alkylated derivatives 6, 7, 11, and 14 under both conventional and microwave irradiation conditions; bentonite as a solid support gave better results, with no change in regioselectivity. A facile intramolecular dehydrative ring closure of 6, 7, 11, and 14 using K₂CO₃ in DMF afforded the corresponding fused triazolo-thiazines and thiazolo-triazole 17–19. The isopropylidenes and acetyl derivatives of the products were prepared.     

Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma

Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression.     

Effect of D,L-carnitine, acetyl-D,L-beta-methylcholine chloride and glycine betaine on some processes of carbohydrate metabolism of humans and goats.

Oral administration of carnitine in normal and diabetic subjects showed a marked decrease in the level of blood glucose during the oral glucose tolerance test (OGTT) except for the three hour samples in diabetic subjects, while a decrease in the level of subsequent blood pyruvate samples was observed during the OGTT in normal and diabetic subjects after the administration of carnitine. During the OGTT, the peak of blood glucose and blood pyruvate level was generally delayed in the diabetic subjects. Furthermore, the mean blood pyruvate levels were elevated above those of normal subjects during the late stages of the test. The mean levels of blood glucose and blood pyruvate of all samples after the administration of carnitine were significantly higher in diabetics than the corresponding values in noramls. Carnitine administration decreased the total blood amino acid nitrogen level only in diabetic subjects. Carnitine caused a highly significant increase in the activity of serum alanine aminotransferase in normal and diabetic subjects, while it had no effect on the activity of serum aspartate aminotransferase. In goats, the level of blood glucose during the intravenous glucose tolerance test (IVGTT) was not affected by carnitine (1,3 or 6 mg/kg body weight). Carnitine in all doses used had no effect on the total blood amino acid nitrogen during the IVGTT, or on the activity of serum alanine aminotransferase and serum aspartate aminotransferase in the fasting samples. Acetyl-D,L-beta-methylcholine had no effect on the level of blood glucose, total blood amino acid nitrogen, the activity of serum alanine aminotransferase or serum aspartate aminotransferase in normal and diabetic subjects. The level of blood pyruvate decreased both in normal and diabetic subjects, in the samples that represented the peak of the curve. Glycine betaine had no effect on blood glucose, pyruvate, total blood amino acid nitrogen and the activity of serum alanine aminotransferase or serum aspartate amino transferase in normal and diabetic subjects or in goats.     

Differential modulation by estrogen of alpha2-adrenergic and I1-imidazoline receptor-mediated hypotension in female rats.

We have recently shown that estrogen negatively modulates the hypotensive effect of clonidine (mixed alpha2-/I1-receptor agonist) in female rats and implicates the cardiovascular autonomic control in this interaction. The present study investigated whether this effect of estrogen involves interaction with alpha2- and/or I1-receptors. Changes evoked by a single intraperitoneal injection of rilmenidine (600 microg/kg) or alpha-methyldopa (100 mg/kg), selective I1- and alpha2-receptor agonists, respectively, in blood pressure, hemodynamic variability, and locomotor activity were assessed in radiotelemetered sham-operated and ovariectomized (Ovx) Sprague-Dawley female rats with or without 12-wk estrogen replacement. Three time domain indexes of hemodynamic variability were employed: the standard deviation of mean arterial pressure as a measure of blood pressure variability and the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive differences in R-wave-to-R-wave intervals as measures of heart rate variability. In sham-operated rats, rilmenidine or alpha-methyldopa elicited similar hypotension that lasted at least 5 h and was associated with reductions in standard deviation of mean arterial pressure. SDRR was reduced only by alpha-methyldopa. Ovx significantly enhanced the hypotensive response to alpha-methyldopa, in contrast to no effect on rilmenidine hypotension. The enhanced alpha-methyldopa hypotension in Ovx rats was paralleled with further reduction in SDRR and a reduced locomotor activity. Estrogen replacement (17beta-estradiol subcutaneous pellet, 14.2 microg/day, 12 wk) of Ovx rats restored the hemodynamic and locomotor effects of alpha-methyldopa to sham-operated levels. These findings suggest that estrogen downregulates alpha2- but not I1-receptor-mediated hypotension and highlight a role for the cardiac autonomic control in alpha-methyldopa-estrogen interaction.     

A glucoside of urospermal A

The aerial parts of Urospermum picroides afforded, in addition to urospermal A a p-hydroxylphenyl acetate of a glucoside of urospermal A.     

Androgen binding protein, sperm production, semen output and LH and testosterone profiles in young postpubertal bulls

An androgen binding protein (ABP), which binds 5alpha-dihydrotestosterone with high affinity (Ka = 0.3 x 10(9) M(-1)), has been demonstrated in testicular and epididymal cytosols of 5 young post pubertal bulls (15-17 months old) of the Montbeliarde dairy breed. Simultaneously, daily sperm production (DSP), semen output and plasma LH and testosterone concentrations (from frequent samplings) were determined. ABP levels were 21 fmoles/mg protein in testis and 59, 22 and 43 fmoles/mg, respectively, in caput, corpus and cauda epididymis. Mean DSP, per gram of testis, was 16.6 x 10(6) spermatozoa, and the mean sperm output was approximately 1.5 x 10(9) spermatozoa per ejaculate. Mean LH and testosterone levels were 1.5 ng/ml and 2.1 ng/ml, respectively. One bull (882) was clearly distinguishable from the others, in showing higher ABP and testosterone levels together with a lower daily sperm production. Results of this study may (1) suggest a physiological role of ABP in sperm epididymal maturation and (2) give a new parameter in the evaluation of individual bulls testicular function.     

Ecology of the rampant weed Nymphaea lotus L. Willdenow in natural and ricefield habitats of the Nile delta, Egypt

In a field study conducted around Lake Manzala (Egypt) during 1995–1996, the distribution of the floating-leafed lotus (Nymphaea lotus L.) in irrigation canals and ricefields was analyzed by classification and ordination methods. Environmental factors associated with its abundance and distribution were evaluated. A data set of 30 stands of lotus and nine environmental variables was analyzed by Canonical Correspondence Analysis (CCA) ordination relating environmental factors to the occurrence of the weed. Ordination analysis detected a strong association between soil organic matter and fine sediment (silt + clay) in the distribution of lotus. Water variables were less important. The density of lotus averaged 3.3±0.49 plants m−2 in the irrigation canals and 6.6±1.4 plants m−2 in the ricefields. The phytomass of lotus ranged from 877 g m−2 in the pure stands to 226 g m−2 in ricefield habitats. The highest proportion of lotus phytomass was allocated to leaf blade, with values reaching 40% of total phytomass in the infested ricefields. Allocation proportions to other plant organs varied between natural and ricefield habitats. Lotus plants allocated more dry matter to vegetative reproduction than to sexual reproduction. The ratio of vegetative to sexual reproduction ranged from 3.48 in the pure stands to 9.63 in infested ricefields. Populations of lotus showed wider variation in leaf area classes in pure stands than in rice stands. Presence of lotus as a weed in ricefields significantly reduced the growth and grain yield of the crop, indicating the risk of its spreading as an invasive weed. This revised version was published online in July 2006 with corrections to the Cover Date.