| 27347076 |
Treatment effect of cyclosporine A in patients with painful bladder syndrome/interstitial cystitis: A systematic review |
10.3892/etm.2016.3301. |
Exp Ther Med |
Treatment effect of cyclosporine A in patients with painful bladder syndrome/interstitial cystitis: A systematic review
Abstract
- Cyclosporine A (CyA) is emerging as a potential therapeutic strategy for painful bladder syndrome/interstitial cystitis (PBS/IC), which is currently an incurable disease. The purpose of this systematic review was to evaluate the treatment effects of CyA in PBS/IC. Electronic and manual retrieval procedures were carried out to identify eligible references for the systematic review. The entire contents of the included articles were assessed, from study design to reported results. Eight studies, comprising three randomized controlled trials (RCTs), four prospective studies and one retrospective cohort study, were included, involving a total of 298 subjects. Meta-analysis was not implemented due to heterogeneity of the manner of reporting the outcome parameters. All studies reported an improvement in symptoms following treatment with CyA. The results of the three RCTs implied that the treatment effects of CyA were better than those of pentosan polysulfate sodium. Some adverse events, for example, elevation of serum creatinine levels and an increase in blood pressure, were noted in five studies. In conclusion, the evidence from the studies implied that treatment of CyA can result in a long-term benefit in patients of PBS/IC; however, further evidence is required to verify this.
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| 27373645 |
Total Synthesis of Thailandepsin B, a Potent HDAC Inhibitor Isolated from a Microorganism |
10.1248/cpb.c16-00060. |
Chem Pharm Bull (Tokyo) |
Total Synthesis of Thailandepsin B, a Potent HDAC Inhibitor Isolated from a Microorganism
Abstract
- Thailandepsin B, a bicyclic depsipeptide histone deacetylase inhibitor, was efficiently synthesized in 51% overall yield in eight steps, starting from commercially available D-norleucine methyl ester and known (S,E)-3-(4-methoxybenzyloxy)-7-(tritylthio)hept-4-enoic acid. The method features a convergent approach in which the corresponding seco-acid, a key precursor in macrolactonization, is directly assembled through the condensation of a D-allo-isoleucine-D-cysteine-containing segment with a D-norleucine-containing segment.
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| 27403748 |
Discovery, isolation, and structural characterization of cyclotides from Viola sumatrana Miq |
10.1002/bip.22914. |
Biopolymers |
Discovery, isolation, and structural characterization of cyclotides from Viola sumatrana Miq
Abstract
- Cyclotides are cyclic peptides from plants in the Violaceae, Rubiaceae, Fabaceae, Cucurbitaceae, and Solanaceae families. They are sparsely distributed in most of these families, but appear to be ubiquitous in the Violaceae, having been found in every plant so far screened from this family. However, not all geographic regions have been examined and here we report the discovery of cyclotides from a Viola species from South-East Asia. Two novel cyclotides (Visu 1 and Visu 2) and two known cyclotides (kalata S and kalata B1) were identified in V. sumatrana. NMR studies revealed that kalata S and kalata B1 had similar secondary structures. Their biological activities were determined in cytotoxicity assays; both had similar cytotoxic activity and were more toxic to U87 cells compared with other cell lines. Overall, the study strongly supports the ubiquity of cyclotides in the Violaceae and adds to our understanding of their distribution and cytotoxic activity.
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| 27428998 |
Anti-Inflammatory Activity of Cyanobacterial Serine Protease Inhibitors Aeruginosin 828A and Cyanopeptolin 1020 in Human Hepatoma Cell Line Huh7 and Effects in Zebrafish (Danio rerio) |
10.3390/toxins8070219. |
Toxins (Basel) |
Anti-Inflammatory Activity of Cyanobacterial Serine Protease Inhibitors Aeruginosin 828A and Cyanopeptolin 1020 in Human Hepatoma Cell Line Huh7 and Effects in Zebrafish (Danio rerio)
Abstract
- Intensive growth of cyanobacteria in freshwater promoted by eutrophication can lead to release of toxic secondary metabolites that may harm aquatic organisms and humans. The serine protease inhibitor aeruginosin 828A was isolated from a microcystin-deficient Planktothrix strain. We assessed potential molecular effects of aeruginosin 828A in comparison to another cyanobacterial serine protease inhibitor, cyanopeptolin 1020, in human hepatoma cell line Huh7, in zebrafish embryos and liver organ cultures. Aeruginosin 828A and cyanopeptolin 1020 promoted anti-inflammatory activity, as indicated by transcriptional down-regulation of interleukin 8 and tumor necrosis factor α in stimulated cells at concentrations of 50 and 100 µmol·L(-1) aeruginosin 828A, and 100 µmol·L(-1) cyanopeptolin 1020. Aeruginosin 828A induced the expression of CYP1A in Huh7 cells but did not affect enzyme activity. Furthermore, hatched zebrafish embryos and zebrafish liver organ cultures were exposed to aeruginosin 828A. The transcriptional responses were compared to those of cyanopeptolin 1020 and microcystin-LR. Aeruginosin 828A had only minimal effects on endoplasmic reticulum stress. In comparison to cyanopeptolin 1020 our data indicate that transcriptional effects of aeruginosin 828A in zebrafish are very minor. The data further demonstrate that pathways that are influenced by microcystin-LR are not affected by aeruginosin 828A.
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| 27463109 |
Labor stimulation with oxytocin: effects on obstetrical and neonatal outcomes |
10.1590/1518-8345.0765.2744. |
Rev Lat Am Enfermagem |
Labor stimulation with oxytocin: effects on obstetrical and neonatal outcomes
Abstract
- to evaluate the effects of labor stimulation with oxytocin on maternal and neonatal outcomes.
descriptive and analytical study with 338 women who gave birth at a tertiary hospital. Obstetric and neonatal variables were measured and compared in women submitted and non-submitted to stimulation with oxytocin. Statistics were performed using Chi-square test, Fisher exact test, Student t-test; and crude Odds Ratio with 95% confidence interval were calculated. A p < 0.05 was considered statistically significant.
stimulation with oxytocin increases the rates of cesarean sections, epidural anesthesia and intrapartum maternal fever in primiparous and multiparous women. It has also been associated with low pH values of umbilical cord blood and with a shorter duration of the first stage of labor in primiparous women. However, it did not affect the rates of 3rd and 4th degree perineal lacerations, episiotomies, advanced neonatal resuscitation, 5-minute Apgar scores and meconium.
stimulation with oxytocin should not be used systematically, but only in specific cases. These findings provide further evidence to health professionals and midwives on the use of oxytocin during labor. Under normal conditions, women should be informed of the possible effects of labor stimulation with oxytocin.
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| 27466123 |
Human commensals producing a novel antibiotic impair pathogen colonization |
10.1038/nature18634. |
Nature |
Human commensals producing a novel antibiotic impair pathogen colonization
Abstract
- The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.
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| 27487329 |
Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies |
10.1002/bip.22927. |
Biopolymers |
Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies
Abstract
- Cyclotides are plant-derived host defense peptides displaying exceptional stability due to their cyclic cystine knot comprising three intertwined disulfide bonds and a cyclic backbone. Their six conserved cysteine residues are separated by backbone loops with diverse sequences. Prototypical cyclotides from the Möbius (kalata B1) and trypsin inhibitor (MCoTI-II) subfamilies lack sequence homology with one another, but both are able to penetrate cells, apparently via different mechanisms. To delineate the influence of the sequences of the loops on the structure and cell internalization of these two cyclotide subfamilies, a series of Möbius/trypsin inhibitor loop-chimeras of kalata B1 and MCoTI-II were synthesized, and structurally and functionally characterized. NMR analysis showed that the structural fold of the majority of chimeric peptides was minimally affected by the loop substitutions. Substituting loops 3, 5, or 6 of MCoTI-II into the corresponding loops of kalata B1 attenuated its hemolytic and cytotoxic activities, and greatly reduced its cell-penetrating properties. On the other hand, replacing loops of MCoTI-II with the corresponding loops of kalata B1 did not introduce cytotoxicity into the chimeras. Loops 2, 3, and 4 of MCoTI-II were found to contribute little to cell-penetrating properties. Overall, this study provides valuable insights into the structural basis for the hemolytic, cytotoxic, and cell-penetrating properties of kalata B1 and MCoTI-II, which could be useful for future engineering of cyclotides to carry bioactive epitopes to intracellular targets.
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| 27489998 |
Oryzamides A-E, Cyclodepsipeptides from the Sponge-Derived Fungus Nigrospora oryzae PF18 |
10.1021/acs.jnatprod.6b00349. |
J Nat Prod |
Oryzamides A-E, Cyclodepsipeptides from the Sponge-Derived Fungus Nigrospora oryzae PF18
Abstract
- Three new cyclohexadepsipeptides, oryzamides A-C (1-3), two isolation artifacts, oryzamides D (4) and E (5), and the known congener scopularide A (6), all possessing a rare 3-hydroxy-4-methyldecanoic acid (HMDA) substructure, were isolated from the mycelial extract of the sponge-derived fungus Nigrospora oryzae PF18. Their planar structures were elucidated by spectroscopic analysis and comparison with the literature data. The absolute configurations were determined using the advanced Marfey's method and single-crystal X-ray diffraction analysis. Among them, oryzamides D (4) and E (5) were a pair of diastereomers at the sulfur atom of the l-methionine sulfoxide residue, which showcased the possible separation of a pair of methionine sulfoxide diastereomers. The X-ray crystal structure of scopularide A (6) was obtained for the first time, thereby establishing its relative and absolute configuration at C-4 of the HMDA residue. Oryzamides A-C (1-3) did not display cytotoxic, antibacterial, antiparasitic, and NF-κB inhibitory activities.
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| 27512793 |
The Insulin Receptor and Its Signal Transduction Network |
None |
|
The Insulin Receptor and Its Signal Transduction Network
Abstract
- Insulin is an anabolic peptide hormone secreted by the b cells of the pancreas acting through a receptor located in the membrane of target cells - major ones being liver (where it promotes glucose storage into glycogen and decreases glucose output), as well as skeletal muscle and fat (where it stimulates glucose transport through translocation of GLUT4), but also b cells, brain cells and in fact most cells, where it has pleiotropic effects.
The receptor belongs to the receptor tyrosine kinase superfamily and has orthologues in all metazoans. The structure of the unbound extracellular domain ("apo-receptor") has been solved. Insulin binds to two distinct sites on each a subunit of the receptor, crosslinking the two receptor halves to create high affinity. The structure of the site 1 interface has also been solved, as well as the structure of the inactive and activated tyrosine kinase, revealing the activation by phosphorylation of an autoinhibitory loop.
The receptor activates a complex intracellular signaling network through IRS proteins and the canonical PI3K and ERK cascades. Overall and tissue-specific targeted gene disruption in mice has explored the role of many of the signaling proteins in creating the type 2 diabetes phenotype, with some surprising results. Insulin signaling in the liver and b cell is emerging as the major determinant in preventing type 2 diabetes, through the integrative role of molecules like IRS2 and FOXO, preventing b cell dedifferentiation. The emerging new biology of diabetes opens novel therapeutic opportunities for the 442 million type 2 diabetics worldwide. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, .
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| 27554590 |
Cloning and characterization of novel cyclotides genes from South American plants |
10.1002/bip.22938. |
Biopolymers |
Cloning and characterization of novel cyclotides genes from South American plants
Abstract
- Cyclotides are multifunctional plant cyclic peptides containing 28-37 amino acid residues and a pattern of three disulfide bridges, forming a motif known as the cyclic cystine knot. Due to their high biotechnological potential, the sequencing and characterization of cyclotide genes are crucial not only for cloning and establishing heterologous expression strategies, but also to understand local plant evolution in the context of host-pathogen relationships. Here, two species from the Brazilian Cerrado, Palicourea rigida (Rubiaceae) and Pombalia lanata (A.St.-Hil.) Paula-Souza (Violaceae), were used for cloning and characterizing novel cyclotide genes. Using 3' and 5' RACE PCR and sequencing, two full cDNAs, named parigidin-br2 (P. rigida) and hyla-br1 (P. lanata), were isolated and shown to have similar genetic structures to other cyclotides. Both contained the conserved ER-signal domain, N-terminal prodomain, mature cyclotide domain and a C-terminal region. Genomic sequencing of parigidin-br2 revealed two different gene copies: one intronless allele and one presenting a rare 131-bp intron. In contrast, genomic sequencing of hyla-br1 revealed an intronless gene-a common characteristic of members of the Violaceae family. Parigidin-br2 5' and 3' UTRs showed the presence of 12 putative candidate sites for binding of regulatory proteins, suggesting that the flanking and intronic regions of the parigidin-br2 gene must play important roles in transcriptional rates and in the regulation of temporal and spatial gene expression. The high degree of genetic similarity and structural organization among the cyclotide genes isolated in the present study from the Brazilian Cerrado and other well-characterized plant cyclotides may contribute to a better understanding of cyclotide evolution.
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| 27665378 |
The importance of cyclic structure for Labaditin on its antimicrobial activity against Staphylococcus aureus |
10.1016/j.colsurfb.2016.09.017. |
Colloids Surf B Biointerfaces |
The importance of cyclic structure for Labaditin on its antimicrobial activity against Staphylococcus aureus
Abstract
- Antimicrobial resistance has reached alarming levels in many countries, thus leading to a search for new classes of antibiotics, such as antimicrobial peptides whose activity is exerted by interacting specifically with the microorganism membrane. In this study, we investigate the molecular-level mechanism of action for Labaditin (Lo), a 10-amino acid residue cyclic peptide from Jatropha multifida with known bactericidal activity against Streptococcus mutans. We show that Lo is also effective against Staphylococcus aureus (S. aureus) but this does not apply to its linear analogue (L). Using polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), we observed with that the secondary structure of Lo was preserved upon interacting with Langmuir monolayers from a phospholipid mixture mimicking S. aureus membrane, in contrast to L. This structure preservation for the rigid, cyclic Lo is key for the self-assembly of peptide nanotubes that induce pore formation in large unilamellar vesicles (LUVs), according to permeability assays and dynamic light scattering measurements. In summary, the comparison between Labaditin (Lo) and its linear analogue L allowed us to infer that the bactericidal activity of Lo is more related to its interaction with the membrane. It does not require specific metabolic targets, which makes cyclic peptides promising for antibiotics without bacteria resistance.
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| 27715057 |
Structure Determinants of Lagunamide A for Anticancer Activity and Its Molecular Mechanism of Mitochondrial Apoptosis |
10.1021/acs.molpharmaceut.6b00564. |
Mol Pharm |
Structure Determinants of Lagunamide A for Anticancer Activity and Its Molecular Mechanism of Mitochondrial Apoptosis
Abstract
- Marine natural products are served as attractive source of anticancer therapeutics, with the great success of "first-in-class" drugs, such as Yondelis, Halaven, and Brentuximab vendotin. Lagunamides A-C from marine cyanobacterium, Lyngbya majuscula, exhibit exquisite growth inhibitory activities against cancer cells. In this study, we have systematically investigated the structure-activity relationships (SARs) of a concise collection of lagunamide A and its analogues constructed by total chemical synthesis against a broad panel of cancer cells derived from various tissues or organs, including A549, HeLa, U2OS, HepG2, BEL-7404, BGC-823, HCT116, MCF-7, HL-60, and A375. The R configuration of lagunamide A at C-39 position was found to be the structure determinant for anticancer activity. Further molecular mechanism study in A549 cells revealed that lagunamide A induced caspase-mediated mitochondrial apoptosis. Accompanied with the dissipation of mitochondrial membrane potential (Δφm) and overproduction of reactive oxygen species (ROS), lagunamide A led to mitochondrial dysfunction and finally caused cell death. Moreover, both anti- and pro-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins participated in lagunamide A-induced mitochondrial apoptosis, especially myeloid cell leukemia-1 (Mcl-1). Overexpression of Mcl-1 partly rescued A549 cells from lagunamide A-induced apoptosis. This study suggests that lagunamide A may exert anticancer property through mitochondrial apoptosis. Together, our findings would provide insightful information for the design of new anticancer drugs derived from lagunamides.
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| 27720433 |
Autumnalamide targeted proteins of the immunophilin family |
10.1016/j.imbio.2016.09.016. |
Immunobiology |
Autumnalamide targeted proteins of the immunophilin family
Abstract
- Previous works with autumnalamide reported that Store Operated Calcium (SOC) channels were blocked through mitochondrial modulation. In the present paper we studied the effect of autumnalamide on ionomycin Ca fluxes. Thus, autumnalamide did not modify ionomycin-sensitive intracellular pools while the ionomycin-induced Ca influx was blocked with similar potency whether the incubation was done before or after ionomycin-sensitive pools depletion. Nevertheless, autumnalamide was not able to inhibit ionomycin-induced Ca influx once the membrane channels were activated. Moreover, the compound efficiently inhibited flufenamic acid (FFA) Ca release induced in this organelle but no the next influx. Since in previous work the effect of autumnalamide was inhibited by cyclosporine A (CsA), structures that target this drug were studied. Therefore, the affinity of autumnalamide for cyclophilin D (Cyp D) was examined. The K obtained for Cyp D- autumnalamide was 1.51±1.399. Moreover, the K for Cyp A- autumnalamide was calculated. The peptide had a similar order of Cyp A binding affinity than CsA (8.08±1.23 and 6.85±1.1μM respectively). After testing autumnalamide-binding capacity for Cyp A, the activity of this compound on Cyp A pathway was tested. Thus, the effect on interleukin (IL)-2 release on activated T-lymphocytes was checked. Autumnalamide was able to reduce IL-2 levels near to T cells in resting conditions. Next, the effect over calcineurin and NFATc1 was also evaluated. While CsA inhibits both calcineurin and NFATc1, autumnalamide did not produce any effect. From these results we can conclude that, autumnalamide targeted mitochondrion and prevent T-cells from IL-2 production through the modulation of SOC Ca channels.
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| 27727162 |
Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs |
10.3390/md14100173. |
Mar Drugs |
Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs
Abstract
- Nicotinic acetylcholine receptors (nAChRs) are targets for developing new drugs to treat severe pain, nicotine addiction, Alzheimer disease, epilepsy, etc. α-Conotoxins are biologically and chemically diverse. With 12-19 residues and two disulfides, they can be specifically selected for different nAChRs. Acetylcholine-binding proteins from (Ac-AChBP) are homologous to the ligand-binding domains of nAChRs and pharmacologically similar. X-ray structures of the α-conotoxin in complex with Ac-AChBP in addition to computer modeling have helped to determine the binding site of the important residues of α-conotoxin and its affinity for nAChR subtypes. Here, we present the various α-conotoxin residues that are selective for Ac-AChBP or nAChRs by comparing the structures of α-conotoxins in complex with Ac-AChBP and by modeling α-conotoxins in complex with nAChRs. The knowledge of these binding sites will assist in the discovery and design of more potent and selective α-conotoxins as drug leads.
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| 27786475 |
Insights into the Biosynthetic Origin of 3-(3-Furyl)alanine in Stachylidium sp. 293 K04 Tetrapeptides |
10.1021/acs.jnatprod.6b00601. |
J Nat Prod |
Insights into the Biosynthetic Origin of 3-(3-Furyl)alanine in Stachylidium sp. 293 K04 Tetrapeptides
Abstract
- The marine-sponge-derived fungus Stachylidium sp. 293 K04 produces the N-methylated peptides endolide A (1) and endolide B (2), showing affinity for the vasopressin receptor 1A and serotonin receptor 5HT, respectively. Both peptides feature the rare amino acid 3-(3-furyl)alanine. Isotope labeling experiments, employing several C-enriched precursors, revealed that this unprecedented heterocyclic amino acid moiety in endolide A (1) is synthesized from a cyclic intermediate of the shikimate pathway, but not from phenylalanine. Two new tetrapeptide analogues, endolides C and D (3 and 4), were characterized, as well as the previously described hirsutide (5).
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