Evaluation of potential thrombin inhibitors from the white mangrove (Laguncularia racemosa (L.) C.F. Gaertn.)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The long-term administration of calcineurin inhibitors decreases antioxidant enzyme activity in the rat parotid and submandibular salivary glands

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Redox-active biflavonoids from Garcinia brasiliensis as inhibitors of neutrophil oxidative burst and human erythrocyte membrane damage

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The 2',4'-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Tifton 419 Bermudagrass (Cynodon dactylon C. transvaaliensis) response to plant grow inhibitors

Tifton 419' bermudagrass cultivar [Cynodon dactylon (L.) Pers. x C. transvaalensis Burtt-Davy] is the most preferred turfgrass for sportive, commercial and residential lawns. On similar species, such as Stenotaphrum secundatum and Zoysia japonica, gibberellic acid-inhibiting plant growth regulators (PGRs) are used to decrease mowing frequency. A very limited research has been reported yet on the PGRs regarding seasonal effects of single vs. multiple applications of these products on turfgrass quality and clipping production on South America. This study aimed to evaluate the effect of sequential applications of different plant growth inhibitors during re-growth and flower rachis emission of 'Tifton 419' Bermudagrass. The treatment pattern includes an initial application followed by one sequential application at 14 days intervals, according to the following: prohexadione-calcium at 100+100 or 200+200 g a.i. ha-1, bispyribac-sodium at 40+40 or 60+60 g a.i. ha-1, trinexapac-ethyl at 113+113, 226+113, 226+226, 452+113, 452+226, 452+452, 678+0 or 904+0 g a.i. ha-1, and untreated control. The treatment effect was evaluated based on measurements of visual injury, height of plants, height and number of flower rachis, and clipping total dry mass production. The results showed that only bispyribac-sodium provided visual injury on 'Tifton 419' Bermudagrass, but the symptoms quickly tend towards zero at 21 days after second application (DASA). 'Tifton 419' Bermudagrass greens could be better handle by sequential application of trinexapac-ethyl, or prohexadione-calcium or bispyribac-sodium, once the height of plants, seedhead emission and total clipping dry mass reduction were over than 37%, 91% and 88%, respectively, for a period up to 60 DASA.

Review of issues concerning the use of reproductive inhibitors, with particular emphasis on resolving human-wildlife conflicts in North America

This manuscript provides an overview of past wildlife contraception efforts and discusses the current state of research. Two fertility control agents, an avian reproductive inhibitor containing the active ingredient nicarbazin and an immunocontraceptive vaccine, have received regulatory approval with the Environmental Protection Agency and are commercially available in the USA. OvoControl G Contraceptive Bait for Canada Geese and Ovo Control for pigeons are delivered as oral baits. An injectable immunocontraceptive vaccine (GonaCon Immunocontraceptive Vaccine) was registered with the Environmental Protection Agency for use in female white-tailed deer in September 2009. An injectable product (GonaCon Immunocontraceptive Vaccine) is registered for use in female white-tailed deer. Both products are labeled for use in urban/suburban areas where these species are overabundant. Several other compounds are currently being tested for use in wildlife in the USA, Europe, Australia and New Zealand that could have promise in the future. The development and use of reproductive inhibitors for resolving human–wildlife conflicts will depend on a number of factors, including meeting the requirements of regulatory agencies for use in the environment and on the biological and economical feasibility of their use. Use will also be dependent on health and safety issues and on public acceptance of the techniques.

Thermoperiod affects the diurnal cycle of nitrate reductase expression and activity in pineapple plants by modulating the endogenous levels of cytokinins

Nitrate reductase (NR, EC 1.6.6.1) activity in higher plants is regulated by a variety of environmental factors and oscillates with a characteristic diurnal rhythm. In this study, we have demonstrated that the diurnal cycle of NR expression and activity in pineapple (Ananas comosus, cv. Smooth Cayenne) can be strongly modified by changes in the day/night temperature regime. Plants grown under constant temperature (28 degrees C light/dark) showed a marked increase in the shoot NR activity (NRA) during the first half of the light period, whereas under thermoperiodic conditions (28 degrees C light/15 degrees C dark) significant elevations in the NRA were detected only in the root tissues at night. Under both conditions, increases in NR transcript levels occurred synchronically about 4 h prior to the corresponding elevation of the NRA. Diurnal analysis of endogenous cytokinins indicated that transitory increases in the levels of zeatin, zeatin riboside and isopentenyladenine riboside coincided with the accumulation of NR transcripts and preceded the rise of NRA in the shoot during the day and in the root at night, suggesting these hormones as mediators of the temperature-induced modifications of the NR cycle. Moreover, these cytokinins also induced NRA in pineapple when applied exogenously. Altogether, these results provide evidence that thermoperiodism can modify the diurnal cycle of NR expression and activity in pineapple both temporally and spatially, possibly by modulating the day/night changes in the cytokinin levels. A potential relationship between the day/night NR cycle and the photosynthetic pathway performed by the pineapple plants (C(3) or CAM) is also discussed.

A novel set of ss-N-biaryl ether sulfonamide hydroxamates as potential MMPs inhibitors: Molecular dynamics simulations and molecular properties evaluation

Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases involved in the extracellular matrix degradation. MMP-2 and MMP9 are overexpressed in several human cancer types, including melanoma, thus the development of new compounds to inhibit MMPs' activity is desirable. Molecular dynamic simulation and molecular properties calculations were performed on a set of novel beta-N-biaryl ether sulfonamide-based hydroxamates, reported as MMP-2 and MMP-9 inhibitors, for providing data to develop an exploratory analysis. Thermodynamic, electronic, and steric descriptors have significantly discriminated highly active from moderately and less active inhibitors of MMP-2 whereas apparent partition coefficient at pH 1.5 was also significant for the MMP-9 data set. Compound 47 was considered an outlier in all analysis, indicating the presence of a bulky substituent group in R3 is crucial to this set of inhibitors for the establishment of molecular interactions with the S1 subsite of both enzymes, but there is a limit. (C) 2012 Wiley Periodicals, Inc.

Pyridine Alkaloids from Senna multijuga As Acetylcholinesterase Inhibitors

As part of an ongoing research project on Senna and Cassia species, five new pyridine alkaloids, namely, 12'-hydroxy-7'-multijuguinol (1), 12'-hydroxy-8'-multijuguinol (2), methyl multijuguinate (3), 7'-multijuguinol (4), and 8'-multijuguinol (5), were isolated from the leaves of Senna multijuga (syn. Cassia multijuga). Their structures were elucidated on the basis of spectroscopic data analysis. Mass spectrometry was used for confirmation of the positions of the hydroxy groups in the side-chains of 1, 2, 4, and 5. All compounds exhibited weak in vitro acetylcholinesterase inhibitory activity as compared with the standard compound physostigmine.

EVALUATION OF IN VITRO AND IN VIVO EFFECTS OF SEMIPURIFIED PROTEINASE INHIBITORS FROM THEOBROMA SEEDS ON MIDGUT PROTEASE ACTIVITY OF LEPIDOPTERAN PEST INSECTS

We have characterized in vitro and in vivo effects of trypsin inhibitors from Theobroma seeds on the activity of trypsin- and chymotrypsin-like proteins from Lepidopteran pest insects. The action of semipurified trypsin inhibitors from Theobroma was evaluated by the inhibition of bovine trypsin and chymotrypsin activities determined by the hydrolysis of N-Benzoyl-DL-Arginine-p-Nitroanilide (BAPA) and N-Succinyl-Ala-Ala-Pho-Phe p-Nitroanilide (S-(Ala)2ProPhe-pNA). Proteinase inhibitor activities from Theobroma cacao and T. obovatum seeds were the most effective in inhibiting trypsin-like proteins, whereas those from T. obovatum and T. sylvestre were the most efficient against chymotrypsin-like proteins. All larvae midgut extracts showed trypsin-like proteolytic activities, and the putative trypsin inhibitors from Theobroma seeds significantly inhibited purified bovine trypsin. With respect to the influence of Theobroma trypsin inhibitors on intact insects, the inclusion of T. cacao extracts in artificial diets of velvet bean caterpillars (Anticarsia gemmatalis) and sugarcane borer (Diatraea saccharalis) produced a significant increase in the percentage of adult deformation, which is directly related to both the survival rate of the insects and oviposition.

DSD Due to 5 alpha-Reductase 2 Deficiency - from Diagnosis to Long Term Outcome

Most of the patients with 5 alpha-RD 2 deficiency are reared in the female social sex due to their severely undervirilized external genitalia but similar to 60% who have not been submitted to orchiectomy in childhood undergo male social sex change at puberty. In our cohort of 30 cases from 18 families, all subjects were registered in the female social sex except for two children-one who had an affected uncle and the other who was diagnosed before being registered. The majority of the patients were satisfied with the long-term results of their treatment and surprisingly, penile length was not associated with satisfactory or unsatisfactory sexual activity. Steroid 5 alpha-RD2 deficiency should be included in the differential diagnosis of all newborns with 46,XY DSD with normal testosterone production before gender assignment or any surgical intervention because these patients should be considered males at birth.

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Group cognitive-behavioral therapy versus selective serotonin reuptake inhibitors for obsessive-compulsive disorder: A practical clinical trial

Clinical effectiveness of group cognitive-behavioral therapy (GCBT) versus fluoxetine in obsessive-compulsive disorder outpatients that could present additional psychiatric comorbidities was assessed. Patients (18-65 years; baseline Yale-Brown Obsessive-Compulsive-Scale [Y-BOCS] scores >= 16; potentially presenting additional psychiatric comorbidities) were sequentially allocated for treatment with GCBT (n = 70) or fluoxetine (n = 88). Mean Y-BOCS scores decreased by 23.13% in the GCBT and 21.54% in the SSRI groups (p = 0.875). Patients presented a mean of 2.7 psychiatric comorbidities. and 81.4% showed at least one additional disorder. A reduction of at least 35% in baseline Y-BOCS scores and CGI ratings of 1 (much better) or 2 (better) was achieved by 33.3% of GCBT patients and 27.7% in the SSRI group (p = 0.463). The Y-BOCS reduction was significantly lower in patients with one or more psychiatric comorbidities (21.15%, and 18.73%, respectively) than in those with pure OCD (34.62%; p = 0.034). Being male, having comorbidity of Major Depression, Social Phobia, or Dysthymia predicted a worse response to both treatments. Response rates to both treatments were similar and lower than reported in the literature, probably due to the broad inclusion criteria and the resulting sample more similar to the real world population. (C) 2011 Elsevier Ltd. All rights reserved.

The Carmaphycins: New Proteasome Inhibitors Exhibiting an alpha,beta-Epoxyketone Warhead from a Marine Cyanobacterium

Two new peptidic proteasome inhibitors were isolated as trace components from a Curacao collection of the marine cyanobacterium Symploca sp. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived a,beta-epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the beta 5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell-line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.

Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.