Nitroimidazole-based inhibitors DTP338 and DTP348 are safe for zebrafish embryos and efficiently inhibit the activity of human CA IX in Xenopus oocytes

Carbonic anhydrase (CA) IX is a hypoxia inducible enzyme that is highly expressed in solid tumours. Therefore, it has been considered as an anticancer target using specific chemical inhibitors. The nitroimidazoles DTP338 and DTP348 have been shown to inhibit CA IX in nanomolar range in vitro and reduce extracellular acidification in hypoxia, and impair tumour growth. We screened these compounds for toxicity using zebrafish embryos and measured their in vivo effects on human CA IX in Xenopus oocytes. In the toxicity screening, the LD₅₀ for both compounds was 3.5?mM. Neither compound showed apparent toxicity below 300?µM concentration. Above this concentration, both compounds altered the movement of zebrafish larvae. The IC₅₀ was 0.14?±?0.02?µM for DTP338 and 19.26?±?1.97?µM for DTP348, suggesting that these compounds efficiently inhibit CA IX in vivo. Our results suggest that these compounds can be developed as drugs for cancer therapy.     

Occurrence of B-chromosomes in diploid Allium stracheyi Baker and their elimination in polyploids

Summary In a population of Allium stracheyi Baker (2n=14) growing in Darjeeling both diploids and polyploids occur. The diploids contain B-chromosomes varying from 2–10 in number. Polyploids are conspicuous by absence of B-chromosomes. These in diploids are found in the pollen mother cells and also in the pollen, and some are provided with subterminal constriction.Diploid individuals when brought from Darjeeling to Calcutta (i. e. from temperate to tropical regions) became polyploid within a month and the B-chromosomes were simultaneously lost. In order to confirm this unexpected result, the transfer experiment has been repeated thrice with fresh collections in each case and selection of diploid bulbs after cytological observation. In all cases the result has been the same. In rare cases one or two B-chromosomes were found in the polyploid cells which might represent intermediate steps of the disappearance.B-chromosomes in diploids possibly help the individual to compete with polyploids by enlarging the adaptive capacity.The sudden polyploidisation by transfer from the mountains to the plains might have been the result of a shock due to the temperature difference. The high temperature may be deleterious for the reproduction of B-chromosomes, and their degeneration products possibly contribute to cytoplasmic changes and the spindle disturbances which effect polyploidisation.     

N-(1,3-Diaryl-3-oxopropyl)amides as a new template for xanthine oxidase inhibitors

A series of forty two N-(1,3-diaryl-3-oxopropyl)amides were synthesized via an efficient, modified Dakin-West reaction and were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have been presented. Selected active xanthine oxidase inhibitors (3r, 3s, and 3zh) were assessed in vivo to study their anti-hyperuricemic effect in potassium oxonate induced hyperuricemic mice model. Compound 3s emerged as the most potent xanthine oxidase inhibitor (IC(50)=2.45 μM) as well as the most potent anti-hyperuricemic agent. The basis of significant inhibition of xanthine oxidase by 3s was rationalized by its molecular docking into catalytic site of xanthine oxidase.     

Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme

The abnormal accumulation of beta-amyloid (Abeta) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta accumulation is dependent not only on its production but also on its removal. In cell-based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity, we analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in Abeta levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting Abeta accumulation in the brain and also provides further insight into the factors involved in Abeta clearance in vivo.     

Antiinflammatory and antiulcer activities of phytic acid in rats

Maximum antiinflammatory activity of phytic acid (PA) was seen at an oral dose of 150 mg/kg in the carrageenan induced rat paw edema model. Although PA showed ability to prevent denaturation of proteins, it showed less antiinflammatory activity than ibuprofen. Ability of PA to bring down thermal denaturation of proteins might be a contributing factor in the mechanism of action against inflammation. PA, at all the doses tested, showed significant protection from ulcers induced by ibuprofen, ethanol and cold stress, with a maximum activity at 150 mg/kg. There was a significant increase in gastric tissue malondialdehyde levels in ethanol treated rats but these levels decreased following PA pretreatment. Moreover, pretreatment with PA significantly inhibited various effects of ethanol on gastric mucosa, such as, reduction in the concentration of nonprotein sulfhydryl groups, necrosis, erosions, congestion and hemorrhage. These results suggested that gastro-protective effect of PA could be mediated by its antioxidant activity and cytoprotection of gastric mucosa.     

Slo1 caveolin-binding motif, a mechanism of caveolin-1-Slo1 interaction regulating Slo1 surface expression

The large conductance, voltage- and Ca2+-activated potassium (MaxiK, BK) channel and caveolin-1 play important roles in regulating vascular contractility. Here, we hypothesized that the MaxiK alpha-subunit (Slo1) and caveolin-1 may interact with each other. Slo1 and caveolin-1 physiological association in native vascular tissue is strongly supported by (i) detergent-free purification of caveolin-1-rich domains demonstrating a pool of aortic Slo1 co-migrating with caveolin-1 to light density sucrose fractions, (ii) reverse co-immunoprecipitation, and (iii) double immunolabeling of freshly isolated myocytes revealing caveolin-1 and Slo1 proximity at the plasmalemma. In HEK293T cells, Slo1-caveolin-1 association was unaffected by the smooth muscle MaxiK beta1-subunit. Sequence analysis revealed two potential caveolin-binding motifs along the Slo1 C terminus, one equivalent, 1007YNMLCFGIY1015, and another mirror image, 537YTEYLSSAF545, to the consensus sequence, varphiXXXXvarphiXXvarphi. Deletion of 1007YNMLCFGIY1015 caused approximately 80% loss of Slo1-caveolin-1 association while preserving channel normal folding and overall Slo1 and caveolin-1 intracellular distribution patterns. 537YTEYLSSAF545 deletion had an insignificant dissociative effect. Interestingly, caveolin-1 coexpression reduced Slo1 surface and functional expression near 70% without affecting channel voltage sensitivity, and deletion of 1007YNMLCFGIY1015 motif obliterated channel surface expression. The results suggest 1007YNMLCFGIY1015 possible participation in Slo1 plasmalemmal targeting and demonstrate its role as a main mechanism for caveolin-1 association with Slo1 potentially serving a dual role: (i) maintaining channels in intracellular compartments downsizing their surface expression and/or (ii) serving as anchor of plasma membrane resident channels to caveolin-1-rich membranes. Because the caveolin-1 scaffolding domain is juxtamembrane, it is tempting to suggest that Slo1-caveolin-1 interaction facilitates the tethering of the Slo1 C-terminal end to the membrane.     

Treatment of low strength complex wastewater using an anaerobic baffled reactor (ABR)

Treatment of a low strength complex wastewater of chemical oxygen demand (COD) around 500mg/L was studied in a 10L capacity laboratory scale anaerobic baffled reactor (ABR). It was operated at hydraulic retention times (HRTs) of 20, 15, 10, 8 and 6h. Corresponding organic loading rates (OLRs) were 0.6, 0.8, 1.2, 1.5 and 2kg COD/m(3)d. At every HRT (or OLR), pseudo steady state (PSS) was achieved. Even at maximum OLR of 2kg COD/m(3)d, COD and biochemical oxygen demand (BOD) removals exceeded 88%. Removal of particulate fraction of organics was found to be greater than soluble fraction. Compartment-wise studies of various parameters revealed that if the OLR was larger, the number of initial compartments played significant role in the removal of organics. The values of volatile fatty acids (VFA) demonstrated that hydrolysis and acidogenesis were the main biochemical activities in the initial few compartments. Based on the tracer studies, dead space in the ABR was found to range from 23% to 34%. The flow pattern in the ABR was classified as intermediate between plug flow and perfectly mixed flows. Observations from scanning electron micrographs (SEM) also suggested that distinct phase separation takes place in an ABR. Study of organic and hydraulic shock loads revealed that ABR was capable of sustaining the type of shock loads generally experienced at a sewage treatment plant (STP).     

Secretion of a platelet-derived growth factor homologue by rat alveolar macrophages exposed to particulates in vitro

Lung macrophages secrete a homologue of platelet-derived growth factor (PDGF) which induces the proliferation of fibroblasts in vitro. In previous studies, we showed that such a PDGF homologue is produced by rat alveolar macrophages and that rat lung fibroblasts have specific receptors for the macrophage-derived PDGF. In this study, we demonstrate the biological and physicochemical properties of the growth factor, as well as the time-related production of this factor following macrophage activation in vitro by organic and inorganic particles. Alveolar macrophages (AMs) collected by saline lavage from the lungs of rats were cultured in serum-free Dulbecco's modified Eagle's medium (SF-DMEM) for varying periods of time up to 72 h. The SF-DMEM "conditioned" by the AMs was used to treat early passage rat lung fibroblasts (RLFs), which were rendered quiescent by culturing in 2% platelet-poor plasma (PPP). Alveolar macrophage conditioned media (AMCM) in the presence of PPP caused increases in the number of fibroblasts, the percent of labeled fibroblast nuclei and tritiated [3H]thymidine incorporation. AMCM alone caused no detectable changes in fibroblast growth rate. These results indicate that AMs release a "competence-like" growth factor. The AMs were left untreated or were exposed to opsonized zymosan, carbonyl iron spheres or chrysotile asbestos fibers. Macrophages attached to a plastic substrate spontaneously produced the factor, and subsequent addition of the organic and inorganic particles to the macrophage cultures significantly increased the fibroblast-stimulating activity of the AMCM. The growth factor was stable after concentration (100-fold), lyophilization and reconstitution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Energy analysis of solar water heating systems in india

This analysis can be called energy accounting of solar water heating systems. Five types of solar water heating systems have been considered. With the help of material balance, energy content has been found in these systems. Yearly output of systems has been found by conducting transient simulations using hourly data of radiation and ambient temperature. Such analysis has been done separately for one representative city of each of six climatic zones of India. The energy payback for India ranges from 0.73 to 4.16 years for the thirty cases considered here.