| 10348047 |
Mulundocandin, an echinocandin-like lipopeptide antifungal agent: biological activities in vitro |
10.7164/antibiotics.52.305. |
J Antibiot (Tokyo) |
Mulundocandin, an echinocandin-like lipopeptide antifungal agent: biological activities in vitro
Abstract
- Mulundocandin (MCN) is an antifungal lipopeptide which belongs to the echinocandin class of antimycotic agents. MCN exhibited good in vitro activity against Candida albicans and C. glabrata isolates with MIC ranges of 0.5-4.0 microg/ml and 2.0-4.0 microg/ml, respectively. MCN also exhibited some activity against C. tropicalis isolates (MIC range 1.0-8.0 microg/ml). However, MCN was poorly active against other non-albicans isolates and was inactive against Cryptococcus neoformans, Aspergillus species and Trichophyton. MCN appeared to exert its antifungal activity through preferential inhibition of germ tube formation (MIC-HY 0.015-0.03 microg/ml) and was typically less active on the yeast form (MIC 0.5-4.0 microg/ml). In kill-curve experiments 99.9% reductions in cell viability were observed following 8 hours exposure to MCN at 4 x MIC and 8 x MIC and after 5 hours exposure to 16 x MIC.
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| 10348510 |
Effect of local application of the antimicrobial peptide IB-367 on the incidence and severity of oral mucositis in hamsters |
10.1016/s1079-2104(99)70131-9. |
Oral Surg Oral Med Oral Pathol Oral Radiol Endod |
Effect of local application of the antimicrobial peptide IB-367 on the incidence and severity of oral mucositis in hamsters
Abstract
- The purpose of this animal study was to determine whether IB-367, an antimicrobial peptide, is able to ameliorate oral mucositis by reducing microflora densities on the mucosal surfaces of the mouth.\n \n \n \n \n Oral mucositis was induced in hamsters by intraperitoneal injection of 5-fluorouracil followed by superficial abrasion of the buccal mucosa. A test formulation was applied topically to the buccal mucosa 5 or 6 times per day starting 6 to 8 hours before abrasion.\n \n \n \n \n Mucositis scores were significantly lower (P < .05) in hamsters given formulations containing 0.5 or 2.0 mg/mL of IB-367 than in placebo-treated controls. Treatment with IB-367 produced a more than 100-fold reduction in oral microflora densities. In a second experiment, treatment of hamsters with a formulation containing IB-367 at 0.12, 0.5 or 2.0 mg/mL resulted in a dose-dependent reduction in mucositis severity.\n \n \n \n \n The results indicate that reduction of local microflora densities through use of IB-367 may improve clinical outcomes in patients at risk for the development of oral mucositis.
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| 10349859 |
Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability |
10.1046/j.1471-4159.1999.0722488.x. |
J Neurochem |
Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability
Abstract
- Mitochondria from different regions of the brain were prepared, and the activation of the mitochondrial permeability transition (MPT) by calcium was investigated by monitoring the associated mitochondrial swelling. In general, the properties of the MPT in brain mitochondria were found to be qualitatively similar to those observed in liver and heart mitochondria. Thus, swelling was inhibited by adenine nucleotides (AdNs) and low pH (<7.0), whereas thiol reagents and alkalosis facilitated swelling. Cyclosporin A and its nonimmunosuppressive analogue N-methyl-Val-4-cyclosporin A (PKF 220-384) both inhibited swelling and prevented the translocation of cyclophilin D from the matrix to the membranes of cortical mitochondria. However, the calcium sensitivity of the MPT differed in mitochondria from three brain regions (hippocampus > cortex > cerebellum) and is correlated with the susceptibility of these regions to ischemic damage. Depleting mitochondria of AdNs by treatment with pyrophosphate ions sensitized the MPT to Ca2+ and abolished regional differences, implying regional differences in mitochondrial AdN content. This was confirmed by measurements showing significant differences in AdN content among regions (cerebellum > cortex > hippocampus). Our data add to recent evidence that the MPT may be involved in neuronal death.
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| 10377137 |
Mouse beta-defensin 3 is an inducible antimicrobial peptide expressed in the epithelia of multiple organs |
10.1128/IAI.67.7.3542-3547.1999. |
Infect Immun |
Mouse beta-defensin 3 is an inducible antimicrobial peptide expressed in the epithelia of multiple organs
Abstract
- One component of host defense at mucosal surfaces is epithelium-derived peptides with antimicrobial activity called defensins. We describe in this report the isolation and characterization of a murine homologue of human beta-defensin 2 (hBD-2) called mouse beta-defensin 3 (mBD-3). The predicted amino acid sequence shows the hallmark features of other known epithelial defensins, including the ordered array of six cysteine residues. Analysis of a genomic clone of mBD-3 revealed two exons separated by a 1.7-kb intron. The mBD-3 gene is localized at the proximal portion of chromosome 8, the site where genes for mouse alpha- and beta-defensins are found. Under basal condition, mBD-3 transcripts were detected at low levels in epithelial cells of surface organs, such as the intestine and lung. After instillation of Pseudomonas aeruginosa PAO1 into mouse airways, mBD-3-specific mRNA was upregulated significantly not only in large airways but also in the small bowel and liver. Recombinant mBD-3 peptide, produced from a baculovirus expression system, showed antimicrobial activity against P. aeruginosa PAO1 (MIC of 8 micrograms/ml) and Escherichia coli D31 (MIC of 16 micrograms/ml) in a salt-dependent manner. This study demonstrates that a murine homologue of hBD-2 is present in the respiratory system and other mucosal surfaces. These similarities between murine and human host defense apparatus provide further impetus to evaluate the mouse as a model for studying the human innate host defense system.
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| 10381903 |
A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis |
10.1016/s0016-5085(99)70543-3. |
Gastroenterology |
A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis
Abstract
- Background & aims:
In pancreatitis, a key role has been attributed to the inappropriate conversion of trypsinogen to trypsin. Recently, two mutations of the cationic trypsinogen gene were found in families with hereditary pancreatitis. This study was conducted to determine the spectrum and frequency of cationic trypsinogen mutations in unrelated patients with idiopathic or hereditary chronic pancreatitis (CP).
Methods:
DNA samples from 44 unrelated children and adolescents with CP (30 patients with idiopathic CP and 14 with hereditary CP) and from 56 family members were investigated. The cationic trypsinogen gene was screened for mutations by single-strand conformation polymorphism analysis and DNA sequencing.
Results:
A mutation in the cationic trypsinogen gene was detected in 5 patients: in 2 patients with a family history of CP and in 3 patients with idiopathic CP. In 1 patient the formerly described R122H mutation was detected. In 4 patients a hitherto unknown mutation was found at the signal peptide cleavage site leading to an alanine to valine exchange in codon 16. The mutations were inherited in all cases. In 95 unrelated control individuals the A16V mutation was not found.
Conclusions:
Heterozygosity for the A16V mutation is strongly associated with CP. These results indicate that a significant percentage of patients with idiopathic CP may have a genetic basis for their disorder; therefore, genetic testing should be included in the diagnostic evaluation of these patients.
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| 10388029 |
Somatostatin Receptors in the Diagnosis and Therapy of Neuroendocrine Tumor |
None |
Oncologist |
Somatostatin Receptors in the Diagnosis and Therapy of Neuroendocrine Tumor
Abstract
- The expression of somatostatin receptors in neuroendocrine tumors has facilitated the diagnosis and surgical treatment of patients with these tumors. After injection of a radiolabeled long-acting somatostatin analog, (111)In-octreotide, scintigraphic tumor imaging can ben performed as well as intraoperative tumor localization. During localization studies very high (111)In concentration values were found in tumor tissues versus normal tissues, especially in carcinoid tumors and endocrine pancreatic tumors. Studies on such tumors in cell culture further indicated internalization of (111)In into tumor cells, which is a prerequisite for a radiobiological effect from short range Auger and conversion electrons. Attempts to systemic radionuclide therapy via somatostatin receptors in patients with neuroendocrine tumors have been initiated.
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| 10391209 |
Characterization of single-nucleotide polymorphisms in coding regions of human genes. |
10.1038/10290 |
Nat. Genet. |
Characterization of single-nucleotide polymorphisms in coding regions of human genes.
Abstract
- A major goal in human genetics is to understand the role of common genetic variants in susceptibility to common diseases. This will require characterizing the nature of gene variation in human populations, assembling an extensive catalogue of single-nucleotide polymorphisms (SNPs) in candidate genes and performing association studies for particular diseases. At present, our knowledge of human gene variation remains rudimentary. Here we describe a systematic survey of SNPs in the coding regions of human genes. We identified SNPs in 106 genes relevant to cardiovascular disease, endocrinology and neuropsychiatry by screening an average of 114 independent alleles using 2 independent screening
Methods. To ensure high accuracy, all reported SNPs were confirmed by DNA sequencing. We identified 560 SNPs, including 392 coding-region SNPs (cSNPs) divided roughly equally between those causing synonymous and non-synonymous changes. We observed different rates of polymorphism among classes of sites within genes (non-coding, degenerate and non-degenerate) as well as between genes. The cSNPs most likely to influence disease, those that alter the amino acid sequence of the encoded protein, are found at a lower rate and with lower allele frequencies than silent substitutions. This likely reflects selection acting against deleterious alleles during human evolution. The lower allele frequency of missense cSNPs has implications for the compilation of a comprehensive catalogue, as well as for the subsequent application to disease association.
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| 10395275 |
Structure elucidation of Sch 20561, a cyclic dehydropeptide lactone--a major component of W-10 antifungal antibiotic |
10.7164/antibiotics.52.398. |
J Antibiot (Tokyo) |
Structure elucidation of Sch 20561, a cyclic dehydropeptide lactone--a major component of W-10 antifungal antibiotic
Abstract
- Antibiotic W-10 is a fermentation complex produced by the bacterium Aeromonas sp. W-10. The cyclic dehydropeptide lactones Sch 20562 (1) and Sch 20561 (2) are the major components of this fermentation complex and are of biological interest in view of their unique structural features and potent antifungal activity. The chemical degradation studies that were utilized in the assignment of structure 2 for Sch 20561 are described here. The structure determination of 2 made use of the ozonolytic cleavage of the dehydropeptide units to form fragments that were sequenced by mass spectrometry. The cyclic dehydropeptide lactone Sch 20561 (2) was found to be the aglycone of Sch 20562 (1) and these two natural products were correlated by a chemical transformation involving the deglucosidation of 1 to form 2.
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| 10395476 |
Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic |
10.1021/jm991013u. |
J Med Chem |
Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic
Abstract
- Previous efforts in the search for molecules capable of blocking the associations between the activated tyrosine kinase growth factor receptors and the SH2 domain of Grb2 had resulted in the identification of 3-amino-Z-pTyr-Ac6c-Asn-NH2, a high-affinity and selective antagonist of this SH2 domain. In the present paper, we report the successful replacement of asparagine in this compound by a beta-amino acid mimetic, which brings us closer to our objective of identifying a Grb2-SH2 antagonist suitable for pharmacological investigations.
|
| 10397733 |
The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor. |
10.1073/pnas.95.12.7074 |
Blood |
The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor.
Abstract
- The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The
Results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the alpha5beta1 and alphavbeta3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.
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| 10400343 |
Antineoplastic agents. Part 409: Isolation and structure of montanastatin from a terrestrial actinomycete |
10.1016/s0968-0896(99)00024-3. |
Bioorg Med Chem |
Antineoplastic agents. Part 409: Isolation and structure of montanastatin from a terrestrial actinomycete
Abstract
- A Montana soil actinomycete, Streptomyces anulatus, produced (1 x 10(-2)% yield) a new cancer cell growth inhibitory cyclooctadepsipeptide named montanastatin (1) accompanied by the potent anticancer antibiotic valinomycin (2) in very high (5.1%) yields. Valinomycin but not montanastatin inhibited growth of a number of pathogenic bacteria and fungi. Interpretation of high-field (500 MHz) NMR and high-resolution FAB mass spectral data allowed assignment of the structure cyclo-(D-Val-L-Lac-L-Val-D-Hiv) to montanastatin. Valinomycin (2) was also isolated from actinomycetes cultured from a tree branch and animal feces collected in Malaysia. Streptomyces exfoliatus, isolated from the tree branch, was found to contain valinomycin in 1.6% yield, while the fecal isolate, S. anulatus, gave valinomycin in 0.9% yield.
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| 10424343 |
Unique molecular conformation of aureobasidin A, a highly amide N-methylated cyclic depsipeptide with potent antifungal activity: X-ray crystal structure and molecular modeling studies |
10.1034/j.1399-3011.1999.00046.x. |
J Pept Res |
Unique molecular conformation of aureobasidin A, a highly amide N-methylated cyclic depsipeptide with potent antifungal activity: X-ray crystal structure and molecular modeling studies
Abstract
- A structural feature of aureobasidins, cyclic depsipeptide antibiotics produced by Aureobasidium pullulans R106, is the N-methylation of four out of seven amide bonds. In order to investigate possible relationship between the molecular conformation and the amide N-methylation, aureobasidin A (AbA), which exhibits the potent antifungal activity, was subjected to X-ray crystal analysis. The crystal, recrystallized from ether (orthorhombic, space group P2(1)2(1)2(1), a = 21.643 (3) A, b = 49.865(10) A, c = 12.427 (1) A, z= 8), contained two independent conformers per asymmetric unit and they took on a similar arrowhead-like conformation. The conformation consisted of three secondary structures of antiparallel beta-sheet, and beta- and gamma-turns, and was stabilized by three intramolecular and transannular N-H O=C hydrogen bonds. The beta-hydroxy-N-methyl-l-valine residue, which is indispensable for its bioactivity, was located at the tip of the corner. Since a nearly identical conformation has been observed for aureobasidin E, a related cyclic depsipeptide, this arrowhead-like conformation may be energetically stable and important for biological activity. The contribution of the amide N-methylation to the conformation was investigated by model building and energy calculations. The energy-minimizations of AbA analogs, in which some (one to four) of four N-methylated amide bonds were replaced with usual amide bond, led to some conformers which are fairly different from the arrowhead form of AbA, although they are stabilized by three intramolecular N-H...O=C hydrogen bonds. This result explains the reason why four out of the seven amide bonds have to be methylated to manifest biological activity, i.e. the high N-methylation of aureobasidin is necessary to form only one well-defined conformation.
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| 10424344 |
Solid-phase total synthesis of polymyxin B1 |
10.1034/j.1399-3011.1999.00045.x. |
J Pept Res |
Solid-phase total synthesis of polymyxin B1
Abstract
- The total solid-phase synthesis of polymyxin B1 (PMB1) has been achieved in 20% yield using the orthogonal protecting group N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl-(Dde). This report demonstrates that a complex peptide macrocycle can be synthesized in high yields using solid-phase synthesis. According to MS and HPLC, the synthetic peptide was identical to the naturally occurring antibiotic.
|
| 10430870 |
An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides |
10.1073/pnas.96.16.8913. |
Proc Natl Acad Sci U S A |
An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides
Abstract
- Four macrocyclic cystine-knot peptides of 29-31 residues, kalata, circulin A and B (CirA and CirB), and cyclopsychotride, have been isolated from coffee plants but have undetermined physiological functions. These macrocycles and 10 of their analogs prepared by chemical synthesis were tested against nine strains of microbes. Kalata and CirA were specific for the Gram-positive Staphylococcus aureus with a minimum inhibition concentration of approximately 0.2 microM. They were relatively ineffective against Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa. However, CirB and cyclopsychotride were active against both Gram-positive and Gram-negative bacteria. In particular, CirB showed potent activity against E. coli with a minimum inhibitory concentration of 0.41 microM. All four cyclic peptides were moderately active against two strains of fungi, Candida kefyr and Candida tropicalis, but were inactive against Candida albicans. These macrocycles are cytotoxic and lysed human red blood cell with a lethal dose 50% of 400 microM. Modifying the Arg residue in kalata with a keto aldehyde significantly reduced its activity against S. aureus whereas blocking the arg in CirA produced no significant effect. The two-disulfide variants and their scrambled disulfide isomers exhibited antimicrobial profiles and potency similar to their native peptides. However, in high-salt assays (100 mM NaCl), few of these macrocyclic peptides, natives or analogs, retained antimicrobial activity. These results show that the macrocyclic peptides possess specific and potent antimicrobial activity that is salt-dependent and that their initial interactions with the microbial surfaces may be electrostatic, an effect commonly found in defensin antimicrobial peptides. Furthermore, their end-to-end cyclic structure with a cystine-knot motif represents a molecular structure of antimicrobials and may provide a useful template for the design of novel peptide antibiotics.
|
| 10443650 |
Progressive decline in insulin levels in Rabson-Mendenhall syndrome |
10.1210/jcem.84.8.5902. |
J Clin Endocrinol Metab |
Progressive decline in insulin levels in Rabson-Mendenhall syndrome
Abstract
- Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome, whose metabolic features include fasting hypoglycemia, post-prandial hyperglycemia, and extremely elevated insulin levels. Patients with Rabson-Mendenhall syndrome have a protracted course and eventually develop ketoacidosis. To determine the mechanism causing this progression and the paradoxical fasting hypoglycemia, we conducted a retrospective study in a patient with Rabson-Mendenhall syndrome, who was a compound heterozygous for two missense mutations affecting the kinase domain of the insulin receptor beta-subunit (I1115T and R1131W). At birth, the patient had fasting hypoglycemia and postprandial hyperglycemia. This was followed at approximately 3 yr of age by constant hyperglycemia and, at 6 yr of age, by constant ketoacidosis. Urinary organic acids during ketoacidosis resembled those of patients with type 1 diabetes. Plasma glucose levels increased (r2 = 0.31; P < 0.01), whereas insulin levels decreased with age (r2 = 0.51; P < 0.01). During periods ofhypoglycemia and hyperglycemia (0-1 yr of age), constant hyperglycemia (3-4 yr of age), and hyperglycemia with ketoacidosis (6-7 yr of age), insulin levels were significantly correlated with plasma glucose levels (P < 0.05). However, the slope of the regression and the predicted insulin level at zero glucose decreased with increasing age. When insulin levels were normalized for the plasma glucose concentrations, an exponential decrease in the insulin/glucose ratio was observed (r2 = 0.92; P < 0.01), with most of the decline occurring before 2 yr of age. These results indicate that the paradoxical fasting hypoglycemia of patients with Rabson-Mendenhall syndrome is associated with severely increased levels of circulating insulin and that the progression of this disease is due to a decline in insulin levels.
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