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961.
Claudia Vergelli Igor A. Schepetkin Antonella Iacovone Maria Paola Giovannoni Gabriella Guerrini 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):821-831
Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value =20?nM) and chemical stability in aqueous buffer (t1/2=8.9?h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups. 相似文献
962.
Manuel Ruiz-García Pablo Escobar-Armel Norberto Leguizamon Paola Manzur Myreya Pinedo-Castro Joseph M. Shostell 《Primates; journal of primatology》2014,55(3):415-435
We analyzed 115 Saguinus leucopus, from four Colombian departments (Antioquia, Bolivar, Caldas and Tolima ), for 701 bp of the mt COII gene and at 10 microsatellite loci to estimate gene diversity levels, possible molecular subspecies and historical demographic changes in this species. This endemic Colombian species showed an elevated gene diversity in this gene, although its geographical distribution is very restrictive and extremely threatened by habitat fragmentation. The mt COII gene did not show any geographical structure in the distribution of the haplotypes within this species, but it did show a noteworthy population expansion throughout the history of this species. A Bayesian analysis showed that the haplotype diversification of this species began around 1.6 million years ago (MYA), whilst a haplotype network gave the beginning of this diversification at around 0.5–0.6 MYA. Forty-seven individuals out of the 115 were analyzed for 10 DNA microsatellites. The genetic diversity was relatively elevated for this kind of marker too, and comparable to that found in other Neotropical monkeys with a wider geographical distribution. Two gene pools were detected with the microsatellites, one in the northern distribution area (Antioquia) and the other in the southern distribution area (Tolima). No tests detected any bottleneck affecting this population; however, two procedures (k test and Kimmel et al. 1998 test) detected significant population expansion for the microsatellite markers, like that seen with the mt COII gene. 相似文献
963.
Maria C. Veronesi Paola Dall'Ara Alessia Gloria Francesco Servida Elisabetta Sala Domenico Robbe 《Theriogenology》2014
Because immune transfer from jenny to donkey foal is mostly unknown, the aim of the present study was to evaluate, from 5 days before to 10 days after foaling, immunoglobulin (Ig)G, IgA, and lysozyme peripartal concentrations in serum and mammary secretions of 10 healthy, spontaneously foaling Martina Franca jennies and in serum of their mature, viable, healthy foals, in the first 10 days after birth. The results showed that, in jennies, mammary secretion of IgG levels (ranging between 16 and 75 mg/mL) and IgA (0.9–2 mg/mL), and IgG (6.8–13.5 mg/mL) and IgA (0.5–2.4 mg/mL) serum concentrations were not different along the time of study. Also, IgG concentrations in serum of foals did not show significant differences although a high level was observed at 12 hours after birth (8 mg/mL), and IgA concentrations in serum of foals did not show any significant difference, although a high level was observed at 12 hours after birth (1.2 mg/mL). Lysozyme increased significantly at Day 2 after parturition in mammary secretions of jennies (551.9 μg/mL) and at 12 hours in serum of foals (25.9 μg/mL). The study demonstrated that the pattern of passive immune transfer in donkey foals seems to be similar to that reported for the horse foal, with IgG predominating IgA in serum and mammary secretions of the jenny and also in serum of foals. The most significant early increase in foals' serum concerns lysozyme, which probably plays an important role in the innate immunity of the donkey foal in the first challenging hours after birth. 相似文献
964.
Paola Elisa Corneo Alberto Pellegrini Luca Cappellin Cesare Gessler Ilaria Pertot 《Microbial ecology》2014,67(3):659-670
Changes in the soil microbial community structure can lead to dramatic changes in the soil ecosystem. Temperature, which is projected to increase with climate change, is commonly assumed to affect microbial communities, but its effects on agricultural soils are not fully understood. We collected soil samples from six vineyards characterised by a difference of about 2 °C in daily soil temperature over the year and simulated in a microcosm experiment different temperature regimes over a period of 1 year: seasonal fluctuations in soil temperature based on the average daily soil temperature measured in the field; soil temperature warming (2 °C above the normal seasonal temperatures); and constant temperatures normally registered in these temperate soils in winter (3 °C) and in summer (20 °C). Changes in the soil bacterial and fungal community structures were analysed by automated ribosomal intergenic spacer analysis (ARISA). We did not find any effect of warming on soil bacterial and fungal communities, while stable temperatures affected the fungal more than the bacterial communities, although this effect was soil dependent. The soil bacterial community exhibited soil-dependent seasonal fluctuations, while the fungal community was mainly stable. Each soil harbours different microbial communities that respond differently to seasonal temperature fluctuations; therefore, any generalization regarding the effect of climate change on soil communities should be made carefully. 相似文献
965.
966.
Turco P Houssami N Bulgaresi P Troni GM Galanti L Cariaggi MP Cifarelli P Crocetti E Ciatto S 《Acta cytologica》2011,55(2):193-196
967.
Onoufriadis A Simpson MA Pink AE Di Meglio P Smith CH Pullabhatla V Knight J Spain SL Nestle FO Burden AD Capon F Trembath RC Barker JN 《American journal of human genetics》2011,(3):42594-437
Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention. 相似文献
968.
Tirassa P 《Archives italiennes de biologie》2011,149(2):205-213
The possibility to take advantage from the nerve growth factor (NGF) ability to induce recovery of damaged tissue has been largely explored in animal models and humans. Recently, the successful use of the ocular administration of NGF in ophthalmology, and the evidences that from the eyes NGF can access to the brain have stimulated new fields of research and open further perspectives to the clinical application of this neurotrophin. In our previous studies we have demonstrated the efficacy of NGF eye drop treatment to improved behavioural deficits and recover structural and biochemical alterations occurring follow brain lesion in animals. Since NGF exerts neuroreparative effects in brain by acting on mature neurons and neuronal precursors localised in germinal subventricular zone (SVZ), the present study has been aimed to evaluate the effects of NGF eye drop administration on the expression of the mitotic marker Ki67 in brain of adult rats. We found that a single ocular administration (10 μl) of 200 μg/mL NGF solution is sufficient to enhance the distribution of Ki67 positive cells also expressing p75 neurotrophin receptors in the proliferating layer of the SVZ. In addition, NGF treatment induces an increase of levels of brain derived neurotrophic factor (BDNF) in forebrain. This data further supports the efficacy of ocular applied NGF to affect brain activities and suggests that NGF also by inducing local factors, including BDNF, can activate the machinery regulating the proliferation and maturation of neuronal precursor in brain. 相似文献
969.
Morelli S Bilbao PS Katz S Lezcano V Roldán E Boland R Santillan G 《Archives of biochemistry and biophysics》2011,(2):248-253
We investigated the existence of a bisphosphonate (BP) target site in osteoblasts. Binding assays using [3H]-olpadronate ([3H]OPD) in whole cells showed the presence of specific, saturable and high affinity binding for OPD (Kd = 1.39 ± 0.33 μM) in osteoblasts. [3H]OPD was displaced from its binding site by micromolar concentrations of lidadronate, alendronate and etidronate (Kd = 1.42 ± 0.15 μM, 2.00 ± 0.2 μM and 2.4 ± 0.4 μM, respectively), and by millimolar concentrations of the non-permeant protein phosphatase (PP) substrates p-nitrophenylphosphate and α-naphtylphosphate. PP inhibitors orthovanadate, NaF or vpb(bipy) did not displace [3H]OPD.As expected, specific OPD binding was detected in the plasma membrane of ROS 17/2.8 cells, although significant BP binding was also found intracellularly. Moreover, OPD increased DNA synthesis in these cells with a temporal profile similar to the protein tyrosine phosphatase (PTP) inhibitors, Na3VO4 and vpb(bipy); but different from a general PP inhibitor (NaF). The stimulatory effect of OPD and PTP inhibitors on osteoblast proliferation was inhibited by the protein tyrosine kinase inhibitors genistein and geldanamycin. These results provide new evidence on the existence of a BP target in osteoblastic cells, presumably a PTP, which may be involved in the stimulatory action of BPs on osteoblast proliferation. 相似文献
970.
Pezzini F Gismondi F Tessa A Tonin P Carrozzo R Mole SE Santorelli FM Simonati A 《Biochemical and biophysical research communications》2011,416(1-2):159-164
Neuronal ceroid lipofuscinosis (NCL) are a group of progressive neurodegenerative disorders of childhood, characterized by the endo-lysosomal storage of autofluorescent material. Impaired mitochondrial function is often associated with neurodegeneration, possibly related to the apoptotic cascade. In this study we investigated the possible effects of lysosomal accumulation on the mitochondrial compartment in the fibroblasts of two NCL forms, CLN1 and CLN6. Fragmented mitochondrial reticulum was observed in all cells by using the intravital fluorescent marker Mitotracker, mainly in the perinuclear region. This was also associated with intense signal from the lysosomal markers Lysotracker and LAMP2. Likewise, mitochondria appeared to be reduced in number and shifted to the cell periphery by electron microscopy; moreover the mitochondrial markers VDCA and COX IV were reduced following quantitative Western blot analysis. Whilst there was no evidence of increased cell death under basal condition, we observed a significant increase in apoptotic nuclei following Staurosporine treatment in CLN1 cells only. In conclusion, the mitochondrial compartment is affected in NCL fibroblasts invitro, and CLN1 cells seem to be more vulnerable to the negative effects of stressed mitochondrial membrane than CLN6 cells. 相似文献