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61.
Raul A. Dulce Omer Yiginer Daniel R. Gonzalez Garrett Goss Ning Feng Meizi Zheng Joshua M. Hare 《The Journal of biological chemistry》2013,288(9):6522-6533
Although the combined use of hydralazine and isosorbide dinitrate confers important clinical benefits in patients with heart failure, the underlying mechanism of action is still controversial. We used two models of nitroso-redox imbalance, neuronal NO synthase-deficient (NOS1−/−) mice and spontaneously hypertensive heart failure rats, to test the hypothesis that hydralazine (HYD) alone or in combination with nitroglycerin (NTG) or isosorbide dinitrate restores Ca2+ cycling and contractile performance and controls superoxide production in isolated cardiomyocytes. The response to increased pacing frequency was depressed in NOS1−/− compared with wild type myocytes. Both sarcomere length shortening and intracellular Ca2+ transient (Δ[Ca2+]i) responses in NOS1−/− cardiomyocytes were augmented by HYD in a dose-dependent manner. NTG alone did not affect myocyte shortening but reduced Δ[Ca2+]i across the range of pacing frequencies and increased myofilament Ca2+ sensitivity thereby enhancing contractile efficiency. Similar results were seen in failing myocytes from the heart failure rat model. HYD alone or in combination with NTG reduced sarcoplasmic reticulum (SR) leak, improved SR Ca2+ reuptake, and restored SR Ca2+ content. HYD and NTG at low concentrations (1 μm), scavenged superoxide in isolated cardiomyocytes, whereas in cardiac homogenates, NTG inhibited xanthine oxidoreductase activity and scavenged NADPH oxidase-dependent superoxide more efficiently than HYD. Together, these results revealed that by reducing SR Ca2+ leak, HYD improves Ca2+ cycling and contractility impaired by nitroso-redox imbalance, and NTG enhanced contractile efficiency, restoring cardiac excitation-contraction coupling. 相似文献
62.
Saritha Tantravedi Saibal Chakraborty Niti H. Shah James C. Fishbein Ramachandra S. Hosmane 《Bioorganic & medicinal chemistry》2013,21(17):4893-4903
Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O5 oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O5 results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O5 considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a Ki value of 8.0 ± 1.5 μM against rabbit liver guanase. 相似文献
63.
《Archives of animal nutrition》2013,67(2):87-100
Three studies with each 96 weaning piglets were conducted to evaluate the combinatory effect of potassium diformate and high dietary doses of Cu on production performance. In Exp. 1, increasing dietary Cu (25, 75, 125, 175 ppm Cu) were tested at either no or 1.8% potassium diformate. In Exp. 2, rising dietary levels of potassium diformate (0%, 0.6%, 1.2% and 1.8%) were tested at either 25 or 175 ppm Cu. In Exp. 3, a basal dietary Cu content of 15 ppm was compared with dietary Cu levels of 95 or 175 ppm, each of them added as either Cu sulphate or Cu amino acid chelate or Cu formate. Rising dietary additions of potassium diformate and Cu improved weight gain, feed intake and feed conversion rate of piglets. The combination of potassium diformate and Cu failed to act additively at highest dose levels of the two supplements. Cu sulphate was efficient as growth stimulating additive in all 3 experiments, Cu formate failed to stimulate production performance, Cu chelate tended to depress production performance and to increase blood plasma Cu compared to equivalent amounts of Cu from Cu sulphate. 相似文献
64.
Sheree Yau Federico M Lauro Timothy J Williams Matthew Z DeMaere Mark V Brown John Rich John AE Gibson Ricardo Cavicchioli 《The ISME journal》2013,7(10):1944-1961
Organic Lake is a shallow, marine-derived hypersaline lake in the Vestfold Hills, Antarctica that has the highest reported concentration of dimethylsulfide (DMS) in a natural body of water. To determine the composition and functional potential of the microbial community and learn about the unusual sulfur chemistry in Organic Lake, shotgun metagenomics was performed on size-fractionated samples collected along a depth profile. Eucaryal phytoflagellates were the main photosynthetic organisms. Bacteria were dominated by the globally distributed heterotrophic taxa Marinobacter, Roseovarius and Psychroflexus. The dominance of heterotrophic degradation, coupled with low fixation potential, indicates possible net carbon loss. However, abundant marker genes for aerobic anoxygenic phototrophy, sulfur oxidation, rhodopsins and CO oxidation were also linked to the dominant heterotrophic bacteria, and indicate the use of photo- and lithoheterotrophy as mechanisms for conserving organic carbon. Similarly, a high genetic potential for the recycling of nitrogen compounds likely functions to retain fixed nitrogen in the lake. Dimethylsulfoniopropionate (DMSP) lyase genes were abundant, indicating that DMSP is a significant carbon and energy source. Unlike marine environments, DMSP demethylases were less abundant, indicating that DMSP cleavage is the likely source of high DMS concentration. DMSP cleavage, carbon mixotrophy (photoheterotrophy and lithoheterotrophy) and nitrogen remineralization by dominant Organic Lake bacteria are potentially important adaptations to nutrient constraints. In particular, carbon mixotrophy relieves the extent of carbon oxidation for energy production, allowing more carbon to be used for biosynthetic processes. The study sheds light on how the microbial community has adapted to this unique Antarctic lake environment. 相似文献
65.
Fluxes of major ions and nutrients were measured in the N-saturated mountain forest catchment-lake system of Čertovo Lake (Czech Republic) from 1998 to 2014. The lake has been rapidly recovering from atmospheric acidification due to a 90% decrease in sulphate (SO42−) deposition since the late 1980s and nitrate (NO3−) contribution to the pool of strong acid anion and leaching of dissolved organic carbon (DOC) have increased. Present concentrations of base cations, phosphorus (P), total organic N (TON), and ionic (Ali) and organically bound (Alo) aluminium in tributaries are thus predominantly governed by NO3− and DOC leaching. Despite a continuing recovery lasting 25 years, the Čertovo catchment is still a net source of protons (H+), producing 44 mmol m−2 yr−1 H+ on a catchment-area basis (corresponding to 35 μmol L−1 on a concentration basis). Retention of the deposited inorganic N in the catchment averages 20%, and ammonium consumption (51 mmol m−2 yr−1) and net NO3− production (28 mol m−2 yr−1) are together the dominant terrestrial H+ generating processes. In contrast, the importance of SO42− release from the soils on terrestrial H+ production is continuously decreasing, with an average of 47 mmol m−2 yr−1 during the study. The in-lake biogeochemical processes reduce the incoming acidity by ∼40%, neutralizing 23 μmol L−1 H+ (i.e., 225 mmol m−2 yr−1 on a lake-area basis). Denitrification and photochemical and microbial decomposition of DOC are the most important in-lake H+ consuming processes (50 and 39%, respectively), while hydrolysis of Ali (from tributaries and photochemically liberated from Alo) is the dominant in-lake H+ generating process. Because the trends in water chemistry and H+ balance in the catchment-lake system are increasingly related to variability in NO3− and DOC leaching, they have become sensitive to climate-related factors (drought, elevated runoff) and forest damage that significantly modify the leaching of these anions. During the study period, increased exports of NO3− (accompanied by Ali and base cations) from the Čertovo catchment occurred after a dry and hot summer, after forest damage, and during elevated winter runoff. Increasing DOC export due to decreasing acid deposition was further elevated during years with higher runoff (and especially during events with lateral flow), and was accompanied by P, TON, and Alo leaching. The climate-related processes, which originally “only” confounded chemical trends in waters recovering from acidification, may soon become the dominant variables controlling water composition in N-saturated catchments. 相似文献
66.
《Bioorganic & medicinal chemistry》2016,24(12):2595-2602
Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N6-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N6-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N6-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N6 and no attachment at N-1, or a combined C-10 at N6 and a CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N6 with a CH2Ph attached at N-1, would result in decrease of biological activity. 相似文献
67.
The terrestrial lizard Podarcis siculus is the most abundant reptile in Italy, where is considered a ubiquitous species. This lizard is widely distributed from the islands to the Apennines, from cultivated fields to anthropized areas such as gardens and city parks. For this reason, these animals are exposed to extensive physical and chemical stresses, as well as to the possibility of coming into contact with industrial pollutants and substances used in agricultural practices. Here, we review the health status of lizard specimens inhabiting natural non-anthropized areas and fields devoted to organic farming, considering the condition of (1) liver, representing the main detoxifying organ, directly influenced by feeding, and (2) gonads, essential for reproduction and, therefore, for the survival of the species. The morphological and biomolecular condition of these organs was then compared with those obtained from lizard specimens experimentally treated with nonylphenol, a co-formulant of many insecticides and plant protection products widely used in conventional farming, known to have harmful estrogenic effects. Taken together, data demonstrate that lizards inhabiting manured soil are in good health status and show a regular morphology of liver, testis, and ovary. Animals are found to be less exposed to the toxic heavy metals cadmium and lead if compared with specimens collected in areas not devoted to agriculture, but probably more exposed to vehicular traffic. However, manure, as well as nonylphenol, exerts a xeno-estrogenic effect, particularly evident in male specimens, more sensitive to estrogenic contamination. 相似文献
68.
69.
《Bioorganic & medicinal chemistry letters》2019,29(21):126667
Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM – antagonist mode) and D2 (compound 15, Ki = 7 nM – antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors. 相似文献
70.
Short-season fallow with legumes and/or grasses can restore the soil organic C and nitrogen (N) and improve soil structure. In this study, we accessed the effects of 2-season legume and grass fallow on structural properties and C/N relationships in aggregates of a sandy loam soil. Two legumes (Calopogonium mucunoides and Centrosema pubescens), and two grasses (Guinea grass (Panicum maximum) and goose grass (Eleusine indica) were used. Results showed that Calopogonium and Centrosema increased soil total porosity and reduced soil bulk densities, while goose grass increased bulk density and reduced total porosity of the soils at 0–15 and 15–30?cm depths. Guinea grass significantly increased the saturated hydraulic conductivity (50.4?cm?h?1) and water holding capacity of the soils. Aggregates, 4.75 to 0.5?mm were greater in Guinea grass and least in goose grass fallowed soils. Calopogonium increased macro-aggregates at 0–15?cm soils by 48%, and mean weight diameter (MWD) by 44%. Organic carbon in 0.5–0.25?mm and <0.25?mm aggregate sizes was higher in Guinea grass soils. Generally, grasses had 4-fold increases of C:N contents in dry aggregates. In conclusion, short-season fallow with Guinea grass, Calopogonium and Centrosema, increased soil C and N and protected them from losses in stable aggregates. 相似文献