IgE antibody and resistance to infection. I. Selective suppression of the IgE antibody response in rats diminishes the resistance and the eosinophil response to Trichinella spiralis infection.

Selective suppression of the total IgE antibody response has been achieved in rats by injection of rabbit anti-rat epsilon-chain antibodies. This IgE-specific suppression was maintained during the course of a natural infection by the nematode Trichinella spiralis. Depletion of the IgE antibody response resulted in a marked reduction of the number of eosinophils attracted to the T. spiralis larvae encysted in striated muscle. Blood eosinophilia following T. spiralis infection, although reaching normal peak levels, was abbreviated in IgE-suppressed animals. Moreover, IgE-depleted animals were more susceptible to the infection; they harbored two to three times more larvae encysted in their muscles than their control litter mates.

Endoglin differentially regulates TGF-ß-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes.

OBJECTIVE: Transforming growth factor-ß (TGF-ß) plays a critical role in cartilage homeostasis and deregulation of its signalling is implicated in osteoarthritis (OA). TGF-ß isoforms signal through a pair of transmembrane serine/threonine kinases known as the type I and type II TGF-ß receptors. Endoglin is a TGF-ß co-receptor that binds TGF-ß with high affinity in the presence of the type II TGF-ß receptor. We have previously shown that endoglin is expressed in human chondrocytes and that it forms a complex with the TGF-ß signalling receptors. However, the functional significance of endoglin expression in chondrocytes is unknown. Our objective was to determine whether endoglin regulates TGF-ß/Smad signalling and extracellular matrix (ECM) production in human chondrocytes and whether its expression varies with chondrocyte differentiation state. METHOD: Endoglin function was determined by overexpression or antisense morpholino/siRNA knockdown of endoglin in human chondrocytes and measuring TGF-ß-induced Smad phosphorylation, transcriptional activity and ECM production. Alterations in endoglin expression levels were determined during subculture-induced dedifferentiation of human chondrocytes and in normal vs OA cartilage samples. RESULTS: Endoglin enhances TGF-ß1-induced Smad1/5 phosphorylation and inhibits TGF-ß1-induced Smad2 phosphorylation, Smad3-driven transcriptional activity and ECM production in human chondrocytes. In addition, the enhancing effect of endoglin siRNA knockdown on TGF-ß1-induced Smad3-driven transcription is reversed by ALK1 overexpression. Furthermore, endoglin levels are increased in chondrocytes following subculture-induced dedifferentiation and in OA cartilage as compared to normal cartilage. CONCLUSION: Together, our results suggest that endoglin regulates the balance between TGF-ß/ALK1/Smad1/5 and ALK5/Smad2/3 signalling and ECM production in human chondrocytes and that endoglin may represent a marker for chondrocyte phenotype.

EM49, a new peptide antibiotic IV. The structure of EM49.

EM49 is a family of similar peptide antibiotics, each an octapeptide acylated with a beta-hydroxy fatty acid. This paper described the determination of the structure of the fatty acyl residue, the selective removal of this residue from the peptide portion of the molecule, and the sequential analysis of the peptide by the EDMAN method. The structure of EM49, 1, is derived by this degradation.

Phenacein--an angiotensin-converting enzyme inhibitor produced by a streptomycete. II. Isolation, structure determination and synthesis.

Phenacein, an inhibitor of angiotensin-converting enzyme, has been isolated from the fermentation broth of a Streptomyces species belonging to the Streptomyces tanashiensis-zaomyceticus group. The inhibitor was shown to be 3,6-dihydroxy-1-phenazinecarboxylic acid by spectroscopic, degradative and synthetic methods.

Aerocyanidin, a new antibiotic produced by Chromobacterium violaceum.

Aerocyanidin, a new antibiotic containing an isonitrile group, has been isolated from fermentations of Chromobacterium violaceum ATCC 53434. Structure 1 was assigned on the bais of spectroscopic characterization of the antibiotic and of a degradation product that results from treatment with base. The antibiotic is primarily active against Gram-positive bacteria.

Cepacin A and cepacin B, two new antibiotics produced by Pseudomonas cepacia.

Two new acetylenic antibiotics, cepacins A and B, have been isolated from the fermentation broth of Pseudomonas cepacia SC 11,783 and assigned structures 1 and 2. Cepacin A has good activity against staphylococci (MIC 0.2 micrograms/ml) but weak activity against streptococci (MIC 50 micrograms/ml) and the majority of Gram-negative organisms (MIC values 6.3 approximately greater than 50 micrograms/ml). Cepacin B has excellent activity against staphylococci (MIC less than 0.05 micrograms/ml) and some Gram-negative organisms (MIC values 0.1 approximately greater than 50 micrograms/ml).

Xylocandin: a new complex of antifungal peptides. II. Structural studies and chemical modifications.

Xylocandins A1, A2, B1, B2, C1, C2, D1 and D2 are new antifungal peptides isolated from Pseudomonas cepacia ATCC 39277. The molecular weights of the xylocandins were determined by fast atom bombardment mass spectrometry (A1 m/z 1,215; A2 1,199; B1 1,229; B2 1,213; C1 1,097; C2 1,081; D1 1,083; D2 1,067). Each xylocandin is a cyclic peptide containing glycine, serine, asparagine (1-3 residues), beta-hydroxytyrosine, and an unusual amino acid with the formula C18H37NO5. Additionally A1, A2, D1 and D2 contain 2,4-diaminobutyric acid; A1, B1, C1 and D1 contain erythro-beta-hydroxyasparagine; and A1, A2, B1 and B2 contain xylose. For each xylocandin pair, an erythro-beta-hydroxyasparagine residue in the first component of the pair is thus replaced by an asparagine in the second component, accounting for the 16 dalton mass difference for each pair. Chemical modification of A1 and A2 at the diaminobutyric acid and beta-hydroxytyrosine residues was used to probe structural requirements for activity.

Izumenolide-a novel beta-lactamase inhibitor produced by Micromonospora. I. Detection, isolation and characterization.

Micromonospora chalcea subsp. izumensis produces a novel beta-lactamase inhibitor izumenolide (EM4615). Isolation of izumenolide was performed by extraction into butanol under acidic conditions and then back extraction into water at neutrality. The compound was precipitated from the aqueous phase by the addition of calcium or barium salts. Further purification was achieved by distribution in BuOH - 1 N NaOH. Izumenolide is a macrolide containing sulfate ester groups.

Aloe vera as a biologically active vehicle for hydrocortisone acetate.

Aloe vera, as a biological vehicle for hydrocortisone 21-acetate, was tested topically and systemically against acute inflammation. Systemically, the combination of A. vera and hydrocortisone produced a maximum 88.1% inhibition of edema. Polymorphonuclear leukocyte infiltration was reduced 91.1%. The topical inhibition of edema peaked at 97%. The possibility that A. vera has significant potential as a biologically active vehicle for steroids is discussed.

Isolation of a stimulatory system in an Aloe extract.

The authors' previous work on a 50% ethanol extract of Aloe vera was done to evaluate anti-inflammatory activity using the croton oil-induced ear swelling assay. The anti-inflammatory activity was found in the supernatant fraction. The supernatant fraction decreased inflammation, when applied topically, by 29.2%, and the precipitate decreased inflammation by 12.1%. However, in the present work, the precipitate fraction decreased the wound diameter by an average of 47.1% (stimulatory system). Little or no wound healing activity was found in the supernatant. Aloe vera appears to act as a modulatory system toward wounds and inflammation and is a potentially valuable tool for managing lower extremity conditions.

The isolation of an active inhibitory system from an extract of aloe vera.

An Aloe vera extract was prepared with 50% ethanol. The resultant supernatant and precipitate were tested for anti-inflammatory activity using the croton oil-induced ear-swelling assay. The supernatant fraction decreased inflammation, when applied topically, by 29.2%, and the precipitate decreased inflammation by 12.1%. The authors have shown that the anti-inflammatory activity (inhibitory system) resides in the supernatant of a 50% ethanol extract.

Enzymatic preparation of 5-hydroxy-L-proline, N-Cbz-5-hydroxy-L-proline, and N-Boc-5-hydroxy-L-proline from (α-N-protected)-L-ornithine using a transaminase or an amine oxidase.

N-Cbz-4,5-dehydro-L-prolineamide or N-Boc-4,5-dehydro-L-prolineamide are alternative key intermediates for the synthesis of saxagliptin, a dipeptidyl peptidase IV (DPP4) inhibitor recently approved for treatment of type 2 diabetes mellitus. An efficient biocatalytic method was developed for conversion of L-ornithine, N-α-benzyloxycarbonyl (Cbz)-L-ornthine, and N-α-tert-butoxycarbonyl (Boc)-L-ornithine to 5-hydroxy-L-proline, N-Cbz-5-hydroxy-L-proline, and N-Boc-5-hydroxy-L-proline, respectively. Rec. Escherichia coli expressing lysine-ε-aminotransferase and rec Pichia pastoris expressing L-ornithine oxidase were used for these conversions. N-Cbz-5-hydroxy-L-proline, and N-Boc-5-hydroxy-L-proline were chemically converted to key intermediates N-Cbz-4,5-dehydro-L-prolineamide and N-Boc-4,5-dehydro-L-prolineamide, respectively.