Calbistrins, novel antifungal agents produced by Penicillium restrictum. I. Production, taxonomy of the producing organism and biological activity

Over a 14-year period, from 1971 to 1985, there were 15 patients referred to the Princess Margaret Hospital in Toronto for postoperative radiotherapy to the cervical lymph nodes following radical neck surgery for metastatic cancer. An intensive investigation failed to yield a primary site in any patient. All of the patients had extensive neck disease with significant indications for postoperative radiotherapy (massive neck nodes, invasion of extra nodal structures or fixation to unresectable adjacent structures). Of this highly selected group of patients with advanced neck disease: 4/15 (27%) died within one year of uncontrolled local disease, a further 2/15 (13%) died within four years of metastatic/recurrent disease, 6/15 (33%) died of intercurrent disease and 3/15 (20%) were alive with at least four years follow-up. Although all patients presented with advanced disease, survival and significant palliation was possible in this select group of patients.     

MS-681a, b, c and d, new inhibitors of myosin light chain kinase from Myrothecium sp. KY6568. I. Characterization of producing strain and production, isolation and biological activities

Novel compounds MS-681a, b, c and d were isolated from the culture broth of a fungal strain KY6568. The strain was identified as Myrothecium sp. from its morphological characteristics. MS-681a, b, c and d inhibited the activity of purified smooth muscle myosin light chain kinase with IC50 values of 0.11, 0.29, 0.095 and 0.26 microM, respectively. Cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase and protein kinase C were not inhibited at 100 microM by MS-681 compounds.     

A new antibiotic XK-90 I. Taxonomy of the producing organism, fermentation, isolation and physicochemical and biological properties

A new antibiotic XK-90 is produced by Streptomyces sp. MK-90 and is active against Gram-positive and Gram-negative bacteria. The taxonomy of the organism, fermentation, isolation and physiochemical and biological properties are described.     

GE3, a novel hexadepsipeptide antitumor antibiotic, produced by Streptomyces sp. I. Taxonomy, production, isolation, physico-chemical properties, and biological activities

GE3, a novel cyclic hexadepsipeptide antibiotic, was isolated from the culture broth of Streptomyces sp. GE3. GE3 was weakly active against some Gram-positive and Gram-negative bacteria and showed potent cytotoxicity against human tumor cell lines. GE3 also exhibited antitumor activity against human pancreatic carcinoma, PSN-1, in vivo. GE3B, a linear peptide form of GE3, which was isolated from the same culture broth with GE3, showed no antibiotic and cytotoxic activities, suggesting the necessity of the cyclic structure of GE3 for its biological activities.     

Kanchanamycins, new polyol macrolide antibiotics produced by Streptomyces olivaceus Tü 4018. I. Taxonomy, fermentation, isolation and biological activities

The kanchanamycins, a group of novel 36-membered polyol macrolide antibiotics were detected in the culture filtrate and mycelium of Streptomyces olivaceus Tü 4018 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The compounds show antibacterial and antifungal activities, and are especially effective against Pseudomonas fluorescens. Besides the kanchanamycin complex, strain Tü 4018 produces the 42-membered macrolactones, oasomycin A and desertomycin A, as well as tryptophan-dehydrobutyrine diketopiperazine and daidzein.     

EI-1511-3, -5 and EI-1625-2, novel interleukin-1 beta converting enzyme inhibitors produced by Streptomyces sp. E-1511 and E-1625. I. Taxonomy of producing strain, fermentation and isolation

The culture conditions which are able to support the differentiation of bovine intramuscular (i.m.) stromal-vascular (S-V) cells into adipocytes were investigated. Bovine i. m. S-V cells were able to undergo adipose conversion, assessed by emergence of lipid droplets and induction of glycerol-3-phosphate dehydrogenase (GPDH) activity, when treated with 0.25 microM dexamethasone and 0.5 mM 1-methyl-3-isobutylxanthine in a serum-deprived (0.1%) medium containing 850 nM insulin and 1 mM octanoate. Octanoate was essential for morphological differentiation and addition of 25 microM of cholesterol with octanoate induced higher GPDH activity. The differentiation of the cells was not observed in the medium containing 10% fetal calf serum which supported the cell proliferation of undifferentiated cells even after confluence. Similarly, both bovine brain extracts and muscle extracts inhibited the differentiation of S-V cells in the serum-deprived condition. These results suggest that the existence of lipids such as octanoate and the process of growth-arrest in preadipocytes and/or other cells are necessary for the differentiation of bovine S-V cells into adipocytes in culture.     

A novel macrolactam-disaccharide antifungal antibiotic. Taxonomy, fermentation, isolation, physico-chemical properties, structure elucidation and biological activity

A novel natural product (1), with antifungal activity was isolated from the culture broth of an actinomadurae. The active compound was separated from broth by n-butanol extraction and purified by silica gel and multicoil counter current chromatography. Physico-chemical data suggested the structure of this compound to be a novel macrolactam disaccharide related to Sch 38518 (3). The structure was determined by spectroscopic studies on the acetate derivative. It was active against Candida spp. (MIC's, 4 approximately 64 micrograms/ml) but less than the monosaccharide, Sch 38518 (MIC's, 1 approximately 16 micrograms/ml).     

Fattiviracin A1, a novel antiherpetic agent produced by Streptomyces microflavus Strain No. 2445. I. Taxonomy, fermentation, isolation, physico-chemical properties and structure elucidation

A 67-old man was referred to our hospital because of dyspnea on exertion and severe hypoxia. He had been given, tegafur and OK 432 for seven years following an operation for gastric cancer. Pulmonary hypertension was noted by right heart catheterization. The findings of a transbronchial lung biopsy resulted in a diagnosis of pulmonary veno-occlusive disease. Pulmonary hemodynamic studies were performed for five different agents: nifedipine, beroprast sodium (PGI2), nitroglycerin, theophylline, and isosorbide dinitrate. However, none of these agents showed significant effects on pulmonary arterial pressure or pulmonary vascular resistance. Treatment with glucocorticoid relieved the patient's symptoms without any apparent effect on pulmonary hemodynamics. The long-term administration of anticancerous agents (tegafur) were thought to have caused pulmonary veno-occlusive disease to develop in this patient.     

A new anthracycline antibiotic, IT-62-B, converts the morphology of ras-transformed cells back to normal: taxonomy, fermentation, isolation, structure elucidation and biological characterization

beta-(2-Hydroxyethoxy)-5 alpha-cholest-8(14)-en-15-one, a synthetic inhibitor of cholesterol biosynthesis, was shown to exhibit a high affinity to oxysterol binding protein. This was proved by ultracentrifugation of the protein fraction from rabbit liver in the presence of the 3H-labeled inhibitor, 3 beta-(2-hydroxy-2-[3H]ethoxy)-5 alpha-cholest-8(14)-en-15-one, or by the substitution of the [3H]-25-hydroxycholesterol in its complex with the oxysterol binding protein. In human hepatoma Hep G2 cells, the inhibitor decreased activity of 3-hydroxy-3-methylglutaryl CoA reductase [ID50 (2.7 +/- 0.7) x 10(-5) M] and was transformed into 3 beta-[2-(9-Z-octadecenoyloxy)ethoxy]-5 alpha-cholest-8(14)-en-15-one.     

MR566A and MR566B, new melanin synthesis inhibitors produced by Trichoderma harzianum. I. Taxonomy, fermentation, isolation and biological activities

Epitestosterone, a C19-steroid with anti-androgenic activity, was determined in the plasma of 234 boys and men from the ages of 6-86 years, and in the prostate tissue of 15 men 55-82 years of age. It was documented that, while in adulthood the concentration of epitestosterone is about ten times lower than the concentration of testosterone, in the pre-pubertal period the level of epitestosterone is similar or even higher than that of testosterone. In the hyperplastic prostate tissue the content of epitestosterone is comparable to that of androstenedione, it is about twice as high as the content of testosterone and approximately half that of the content of dihydrotestosterone. At least in the case of pre-pubertal boys and in the prostatic tissue it is therefore possible to include epitestosterone into consideration as a regulatory factor for the androgen-dependent events.     

Thiazohalostatin, a new cytoprotective substance produced by Actinomadura. I. Taxonomy, production, isolation and biological activities

Thiazohalostatin has been isolated from the culture broth of Actinomadura sp. by a screening program designed to find novel cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as colorless powder. Thiazohalostatin prevented cell death caused by calcium overload and exhibited an inhibitory activity against lipid peroxidation.     

Brasilinolide A, a new macrolide antibiotic produced by Nocardia brasiliensis: producing strain, isolation and biological activity

A new 32-membered macrolide antibiotic, brasilinolide A was isolated from the fermentation broth of Nocardia sp. IFM 0406. The producer was identified as Nocardia brasiliensis. The antibiotic was only active against Aspergillus niger, but not active against other fungi including yeasts as well as other filamentous like fungi and bacteria. Brasilinolide A exerted an immunosuppressive activity in the assay system of a mixed lymphocyte reaction (MLR).     

Tetrafibricin: a nonpeptidic fibrinogen receptor inhibitor from Streptomyces neyagawaensis. (II). Its antiplatelet activities

Tetrafibricin; a nonpeptidic fibrinogen inhibitor from microbial origin, showed potent antiaggregation activities on human platelet aggregation induced by either ADP, thrombin or collagen (IC50s = 5.6, 7.6 and 11 microM, respectively) in platelet rich plasma. The ability to inhibit aggregation in platelets treated with chymotrypsin confirmed the GPIIb/IIIa blockage of tetrafibricin. Tetrafibricin blocked the release of serotonin induced by ADP but it did not block the release reaction induced by thrombin. When added to platelets formerly aggregated with ADP, tetrafibricin caused rapid and complete deaggregation. As for the selectivity among other Arg-Gly-Asp -dependent integrins, tetrafibricin seems to be more specific for glycoprotein (GP) IIb/IIIa than RGDS is. This is because it had no effect on adhesion of bovine aortic endothelial cells to RGD-containing proteins. Tetrafibricin is the first nonpeptidic fibrinogen receptor inhibitor that may be valuable for the study on platelet aggregation inhibitors.     

Oswaldocruzia venezuelensis sp. n. (Nematoda:Trichostrongylina, Molineoidea), a parasite of Bufo marinus from Venezuela

A new species of Oswaldocruzia Travassos, 1917, a parasite of Bufo marinus L. from Venezuela, is described. Like most Neotropical Oswaldocruzia, Oswaldocruzia venezuelensis sp. n. is characterized by spicules with three principal branches: blade, shoe and fork, and by a division of the fork within the distal third of the spicule length. O. vaucheri Ben Slimane et Durette-Desset, 1993 is the most closely related species due to its caudal bursa of type II and its cervical alae of the same shape but it differs in the following characters: the position of the papillae of rays 4 situated nearer the papillae of rays 3 rather than rays 5, a higher percentage of the ridges in the oesophageal region, the cervical alae three times longer and sharp and the spicular fork divided less deeply.     

R1128 substances, novel non-steroidal estrogen-receptor antagonists produced by a Streptomyces. III. Pharmacological properties and antitumor activities

R1128 B (1,3,6-trihydroxy-8-n-butylanthraquinone), a new antibiotic produced by Streptomyces sp. No. 1128, inhibited estrogen binding to its receptor. The IC50 value of R1128 B for partially purified rat uterine cytosol receptor was 1.2 x 10(-7) M. However, the IC50 value of R1128 B against androgen-receptor binding was about 50-fold greater than that against estrogen-receptor binding. R1128 B was a competitive inhibitor against estrogen-receptor binding. R1128 B inhibited the growth of estrogen-responsive human mammary adenocarcinoma MCF-7 cells in soft agar. This inhibition, however, was reversed when estradiol was added to the culture medium. R1128 B showed antitumor activities against MCF-7 both xenografted to nude mice and implanted in subrenal capsule of mice (SRC assay). The potency of R1128 B was about 8-fold lower than that of tamoxifen both in vitro and in vivo.     

Sphaerechinorhynchus ophiograndis n. sp. (Acanthocephala:Plagiorhynchidae:Sphaerechinorhynchinae), described from the intestine of a king cobra, Ophiophagus hannah

BACKGROUND/AIMS: The mechanism of action of recombinant interferon-alpha (rIFN alpha) treatment in chronic hepatitis C is not fully understood, and may include modulation of the immune system as well as a direct antiviral effect. We have therefore evaluated the plasma concentrations of pro- and anti-inflammatory cytokines in patients with chronic hepatitis C before and during treatment with rIFN alpha. METHODS: Twenty-three patients were studied. Plasma concentrations of IL-1 beta, IL-6, TNF, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptors (sTNFRs) type I and type II were determined twice before rIFN alpha treatment (on day -11 and day 1), and on days 11, 32 and 120 of treatment. RESULTS: IL-1 beta, IL-6 and TNF plasma concentrations were rarely increased before treatment (in one, six and seven patients, respectively), and usually declined during treatment. sTNFRs I and II plasma concentrations were not increased either before or during treatment. This was not the case for IL-1RA. In untreated patients, the plasma concentration of IL-1RA was higher than normal in 16 out of 23 patients. When rIFN alpha treatment was initiated, there was a constant and dramatic increase in IL-1RA levels, which reached 8 times the upper limit of the normal range (p < 0.001 as compared to pretreatment values). This increase was sustained up to day 120. CONCLUSIONS: These results indicate that induction of an anti-inflammatory status through modulation of the IL-1/IL-1RA balance may be a key mechanism of action of rIFN alpha treatment in chronic hepatitis C.     

Fusaricidin A, a new depsipeptide antibiotic produced by Bacillus polymyxa KT-8. Taxonomy, fermentation, isolation, structure elucidation and biological activity

PURPOSE: This study was designed to examine variations in operative mortality among surgical specialists who perform colorectal surgery. METHODS: Mortality rates were compared between six board-certified colorectal surgeons and 33 other institutional surgeons using comparable colorectal procedure codes and a validated database indicating patient severity of illness. Thirty-five ICD-9-CM procedure codes were used to identify 2,805 patients who underwent colorectal surgery as their principal procedure between July 1986 and April 1994. Atlas, a state-legislated outcome database, was used by the hospital's Quality Assurance Department to rank the Admission Severity Group (ASG) of 1,753 patients from January 1989 to April 1994 (higher ASG, 0 to 4, indicates increasing medical instability). RESULTS: Colorectal surgeons had an eight-year mean in-hospital mortality rate of 1.4 percent compared with 7.3 percent by other institutional surgeons (P = 0.0001). There was a significantly lower mortality rate for colorectal surgeons compared with other institutional surgeons in ASG 2 (0.8 and 3.8 percent, respectively; P = 0.026) and ASG 3 (5.7 and 16.4 percent, respectively; P = 0.001). CONCLUSIONS: Board-certified colorectal surgeons had a lower in-hospital mortality rate than other institutional surgeons as patients' severity of illness increased.     

Monoecocestus thomasi sp. n. (Cestoda: Anoplocephalidae) from the northern flying squirrel, Glaucomys sabrinus (Shaw), in Oregon

Monoecocestus thomasi sp. n. (Cestoda: Anoplocephalidae), from the northern flying squirrel, Glaucomys sabrinus (Shaw), in Oregon, is described and distinguished from its congeners. Monoecocestus thomasi is the sixth species of Monoecocestus to be described from nearctic rodents, and the first from a member of the family Sciuridae. Our comparisons of taxonomic characters of the nominal species of Monoecocestus in North American rodents have shown that M. giganticus Buhler 1970 is a synonym of M. americanus (Stiles 1895), both from the porcupine, Erethizon dorsatum (Linnaeus). Insemination in Monoecocestus ssp. is discussed, with the conclusion that it takes place only by way of the vagina in early immature segments.     

In vitro and in vivo prolonged biological activities of novel vitamin C derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), in cosmetic fields

The biological activity of the novel vitamin C derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), was evaluated in vitro and in vivo. The percutaneous absorption of AA-2G was determined in five Japanese males. The excretion of ascorbic acid (AA) in the subjects administered AA-2G was sustained for a longer period than in the subjects administered ascorbic acid 2-phosphate (AA-2P), which is a conventional vitamin C derivative. An analysis of the distribution of AA in the skin showed that small black specks assumed to be AA were observed in the epidermis even 3 d after applying AA-2G. The melanin synthesis in B16 melanoma cells was inhibited more by AA-2G than by AA-2P, and AA-2G also prevented more UV-induced damage of human skin keratinocytes and fibroblasts than AA-2P did. From these in vivo and in vitro results, it is supposed that the conversion of AA-2G to AA is sustained for a long time compared with that of AA-2P, and that AA-2G is an effective and available compound having vitamin C activity in human subjects.