| 19050293 |
The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis |
10.4049/jimmunol.181.12.8727. |
J Immunol |
The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis
Abstract
- Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1(G93A) transgenic rats). With end-stage disease, SOD1(G93A) rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.
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| 19056263 |
Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: potent inhibitors of the IGF-1R receptor tyrosine kinase |
10.1016/j.bmcl.2008.11.046. |
Bioorg Med Chem Lett |
Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: potent inhibitors of the IGF-1R receptor tyrosine kinase
Abstract
- The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
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| 19061646 |
CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation |
10.1016/j.molcel.2008.10.025. |
Mol Cell |
CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation
Abstract
- The neuronal gene repressor REST/NRSF recruits corepressors, including CoREST, to modify histones and repress transcription. REST also functions as a tumor suppressor, but the mechanism remains unclear. We identified chromodomain on Y-like (CDYL) as a REST corepressor that physically bridges REST and the histone methylase G9a to repress transcription. Importantly, RNAi knockdown of REST, CDYL, and G9a, but not CoREST, induced oncogenic transformation of immortalized primary human cells and derepression of the proto-oncogene TrkC. Significantly, transgenic expression of TrkC also induced transformation. This implicates CDYL-G9a, but not CoREST, in REST suppression of transformation, possibly by oncogene repression. CDYL knockdown also augments transformation in a cell culture model of cervical cancer, where loss of heterozygosity of the CDYL locus occurs. These findings demonstrate molecular strategies by which REST carries out distinct biological functions via different corepressors and provide critical insights into the role of histone-modifying complexes in regulating cellular transformation.
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| 19071018 |
Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity |
10.1016/j.bmcl.2008.11.077. |
Bioorg Med Chem Lett |
Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity
Abstract
- The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
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| 19071200 |
Identification of two suites of cyclotide precursor genes from metallophyte Viola baoshanensis: cDNA sequence variation, alternative RNA splicing and potential cyclotide diversity |
10.1016/j.gene.2008.11.005. |
Gene |
Identification of two suites of cyclotide precursor genes from metallophyte Viola baoshanensis: cDNA sequence variation, alternative RNA splicing and potential cyclotide diversity
Abstract
- Cyclotides are a novel family of plant-derived defense peptides that are biosynthetically produced via the processing of cyclotide precursor (CP) proteins containing one, two or three cyclotide domains. By screening a cDNA library of Viola baoshanensis roots and using RACE and RT-PCR methods, 23 cDNA clones were identified and then used to deduce full CP proteins containing one (VbCP1S-5), two (VbCP6S), or three (VbCP7S) cyclotide domains. RT-PCR and sequence analyses suggested that VbCP6S were resulted from the alternative splicing of VbCP7S RNA. The significance of VbCP7S RNA splicing is that it provides a mechanism for increasing the diversity of cyclotide expression via the recombination of N-terminal repeat (NTR) regions and cyclotide domains. After analyzing the full endoplasmic reticulum (ER) signals of known and novel CPs associated with RT-PCR tests, three primers encoding the conserved sequence ALVLIATFA, AAFALPA-LA and AAFALPA-AFA were proposed to be more efficient in cloning CP genes than the well-applied primer encoding AAFALPA. Cyclotide sequence analyses indicated that the cDNA clones encoded a variety of Möbius and bracelet cyclotides, which were likely involved in the known bioactivities of cyclotides, and also might play a previously unreported role in mediating the metal tolerance of V. baoshanensis. Overall, this study shows that CP genes are varied in V. baoshanensis and cyclotide expression is subject to transcriptional and post-transcriptional regulation in this plant.
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| 19071884 |
Population pharmacokinetic analysis of lanreotide Autogel in healthy subjects : evidence for injection interval of up to 2 months |
10.2165/0003088-200948010-00004. |
Clin Pharmacokinet |
Population pharmacokinetic analysis of lanreotide Autogel in healthy subjects : evidence for injection interval of up to 2 months
Abstract
- Lanreotide is a somatostatin analogue used for the treatment of acromegaly and neuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustained-release formulation lanreotide Autogel after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose.
This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 microg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel at a dose of 60, 90 or 120 mg. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4- to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel. Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM((R)) version VI software. The model was validated externally using data from patients with acromegaly.
In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel was 63%. The rate of absorption and bioavailability of lanreotide Autogel were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05).
Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 microg/kg) and the pharmacokinetics of lanreotide Autogel after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel was independent of the dose and was not affected by sex.
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| 19081074 |
A BBSome subunit links ciliogenesis, microtubule stability and acetylation. |
10.1016/j.devcel.2008.11.001 |
Dev. |
A BBSome subunit links ciliogenesis, microtubule stability and acetylation.
Abstract
- Primary cilium dysfunction affects the development and homeostasis of many organs in Bardet-Biedl syndrome (BBS). We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium. We have now discovered a BBSome subunit that we named BBIP10. Similar to other BBSome subunits, BBIP10 localizes to the primary cilium, BBIP10 is present exclusively in ciliated organisms, and depletion of BBIP10 yields characteristic BBS phenotypes in zebrafish. Unexpectedly, BBIP10 is required for cytoplasmic microtubule polymerization and acetylation, two functions not shared with any other BBSome subunits. Strikingly, inhibition of the tubulin deacetylase HDAC6 restores microtubule acetylation in BBIP10-depleted cells, and BBIP10 physically interacts with HDAC6. BBSome-bound BBIP10 may therefore function to couple acetylation of axonemal microtubules and ciliary membrane growth.
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| 19081374 |
A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression |
10.1016/j.neuron.2008.09.040. |
Neuron |
A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression
Abstract
- CREST plays a critical role in activity-dependent development, but its mechanism of action is not well understood. Here, we show that a CREST-BRG1 complex regulates promoter activation by orchestrating a calcium-dependent release of a repressor complex and a recruitment of an activator complex. In resting neurons, transcription of the c-fos promoter is inhibited by BRG1-dependent recruitment of a phospho-Rb-HDAC repressor complex. Upon calcium influx, Rb becomes dephosphorylated at serine 795 by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CBP, suggesting that this mechanism may be generally involved in regulating calcium-dependent transcription of neuronal genes.
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| 19093843 |
Hantupeptin A, a cytotoxic cyclic depsipeptide from a Singapore collection of Lyngbya majuscula |
10.1021/np800448t. |
J Nat Prod |
Hantupeptin A, a cytotoxic cyclic depsipeptide from a Singapore collection of Lyngbya majuscula
Abstract
- Chemical investigation of the marine cyanobacterium Lyngbya majuscula from Pulau Hantu Besar, Singapore, has led to the isolation of a cyclodepsipeptide, hantupeptin A (1). The planar structure of 1 was assigned on the basis of extensive 1D and 2D NMR spectroscopic experiments. The absolute configuration of the amino and hydroxyl acid residues in the molecule was determined by application of the advanced Marfey method, chiral HPLC analysis, and Mosher's method. Hantupeptin A showed cytotoxicity to MOLT-4 leukemia cells and MCF-7 breast cancer cells with IC(50) values of 32 and 4.0 microM, respectively.
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| 19098004 |
Inhibition of neuronal nicotinic acetylcholine receptor subtypes by alpha-Conotoxin GID and analogues |
10.1074/jbc.M804950200. |
J Biol Chem |
Inhibition of neuronal nicotinic acetylcholine receptor subtypes by alpha-Conotoxin GID and analogues
Abstract
- alpha-Conotoxins are small disulfide-rich peptides from the venom of the Conus species that target the nicotinic acetylcholine receptor (nAChR). They are valuable pharmacological tools and also have potential therapeutic applications particularly for the treatment of chronic pain. alpha-Conotoxin GID is isolated from the venom of Conus geographus and has an unusual N-terminal tail sequence that has been shown to be important for binding to the alpha4beta2 subtype of the nAChR. To date, only four conotoxins that inhibit the alpha4beta2 subtype have been characterized, but they are of considerable interest as it is the most abundant nAChR subtype in the mammalian brain and has been implicated in a range of diseases. In this study, analysis of alanine-scan and truncation mutants of GID reveals that a conserved proline in alpha-conotoxins is important for activity at the alpha7, alpha3beta2, and alpha4beta2 subtypes. Although the proline residue was the most critical residue for activity at the alpha3beta2 subtype, Asp(3), Arg(12), and Asn(14) are also critical at the alpha7 subtype. Interestingly, very few of the mutations tested retained activity at the alpha4beta2 subtype indicating a tightly defined binding site. This lack of tolerance to sequence variation may explain the lack of selective ligands discovered for the alpha4beta2 subtype to date. Overall, our findings contribute to the understanding of the structure-activity relationships of alpha-conotoxins and may be beneficial for the ongoing attempts to exploit modulators of the neuronal nAChRs as therapeutic agents.
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| 19099550 |
targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis. |
10.1186/1752-0509-2-109 |
BMC Syst. Biol. |
targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.
Abstract
- Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation.
Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.
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| 19113794 |
Pharmacology and antifungal properties of anidulafungin, a new echinocandin |
10.1592/phco.29.1.17. |
Pharmacotherapy |
Pharmacology and antifungal properties of anidulafungin, a new echinocandin
Abstract
- Anidulafungin is the third echinocandin antifungal agent to receive approval from the United States Food and Drug Administration. It is indicated for the treatment of esophageal candidiasis, candidemia, and other candidal infections. Anidulafungin is fungicidal against Candida species, including Candida glabrata and isolates resistant to azoles and polyenes. The drug's efficacy is comparable to that of fluconazole for the treatment of esophageal candidiasis, and it is effective in patients with invasive candidiasis and candidemia. Anidulafungin is distinct among the echinocandins in that it undergoes slow, nzymatic chemical degradation. As a consequence, impairments in renal or hepatic function do not substantially alter its pharmacokinetics. In addition, anidulafungin has not demonstrated any drug-drug interactions because it is not a substrate, inhibitor, or inducer of the cytochrome P450 enzyme system. Anidulafungin is well tolerated in adults and pediatric patients, with few reported adverse drug events. The safety, tolerability, and potent fungicidal activity of anidulafungin against Candida species make it a reasonable alternative in the treatment of patients with serious candidal infections.
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| 19115837 |
Homotyrosine-containing cyanopeptolins 880 and 960 and anabaenopeptins 908 and 915 from Planktothrix agardhii CYA 126/8 |
10.1021/np800557m. |
J Nat Prod |
Homotyrosine-containing cyanopeptolins 880 and 960 and anabaenopeptins 908 and 915 from Planktothrix agardhii CYA 126/8
Abstract
- Two homotyrosine-bearing cyanopeptolins are described from Planktothrix agardhii CYA 126/8. The compounds feature a common homotyrosine-containing cyclohexadepsipeptide and differ by sulfation of an exocyclically located 2-O-methyl-d-glyceric acid residue. In addition we describe two anabaenopeptins, which contain two homotyrosine residues, one of which is N-methylated. The anabaenopeptins have a common cyclopentapeptide portion and differ in the amino acid linked to it via an ureido bond, arginine and tyrosine, respectively.
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| 19117399 |
Arenamides A-C, cytotoxic NFkappaB inhibitors from the marine actinomycete Salinispora arenicola |
10.1021/np800617a. |
J Nat Prod |
Arenamides A-C, cytotoxic NFkappaB inhibitors from the marine actinomycete Salinispora arenicola
Abstract
- Three new cyclohexadepsipeptides, arenamides A-C (1-3), were isolated from the fermentation broth of a marine bacterial strain identified as Salinispora arenicola. The planar structures of these compounds were assigned by detailed interpretation of NMR and MS/MS spectroscopic data. The absolute configurations of the amino acids, and those of the chiral centers on the side chain, were established by application of the Marfey and modified Mosher methods. The effect of arenamides A and B on NFkappaB activity was studied with stably transfected 293/NFkappaB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNF). Arenamides A (1) and B (2) blocked TNF-induced activation in a dose- and time-dependent manner with IC(50) values of 3.7 and 1.7 microM, respectively. In addition, the compounds inhibited nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production with lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Moderate cytotoxicity was observed with the human colon carcinoma cell line HCT-116, but no cytotoxic effect was noted with cultured RAW cells. Taken together, these data suggest that the chemoprevention and anti-inflammatory characteristics of arenamides A and B warrant further investigation.
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| 19139222 |
Identification and characterization of lactocyclicin Q, a novel cyclic bacteriocin produced by Lactococcus sp. strain QU 12 |
10.1128/AEM.02299-08. |
Appl Environ Microbiol |
Identification and characterization of lactocyclicin Q, a novel cyclic bacteriocin produced by Lactococcus sp. strain QU 12
Abstract
- Lactococcus sp. strain QU 12, which was isolated from cheese, produced a novel cyclic bacteriocin termed lactocyclicin Q. By using cation-exchange chromatography, hydrophobic interaction chromatography, and reverse-phase high-performance liquid chromatography, lactocyclicin Q was purified from culture supernatant, and its molecular mass was determined to be 6,062.8 Da by mass spectrometry. Lactocyclicin Q has been characterized by its unique antimicrobial spectrum, high level of protease resistance, and heat stability compared to other reported bacteriocins of lactic acid bacteria. The amino acid sequence of lactocyclicin Q was determined chemically, and this compound is composed of 61 amino acid residues that have a cyclic structure with linkage between the N and C termini by a peptide bond. It showed no homology to any other antimicrobial peptide, including cyclic bacteriocins. On the basis of the amino acid sequences obtained, the sequence of the gene encoding the prepeptide lactocyclicin Q was obtained. This is the first report of a cyclic bacteriocin purified from a strain belonging to the genus Lactococcus.
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