Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic -cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of ³H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.Abbreviations CPH cyproheptadine - CPH-epoxide cyproheptadine-10-11-epoxide - DMCPH desmethylcyproheptadine - DMCPH-epoxide desmethylcyproheptadine-10,11-epoxide - HPLC high-performance liquid chromatography - KBB Krebs biocarbonate buffer Recipient of a Society of Toxicology Predoctoral Research Fellowship.Present address: Department of Biochemistry, The University of Hong Kong, Hong Kong.     

Second virial coefficient of alpha-crystallin

Light scattering studies were performed on bovine alpha-crystallin measuring the scattering intensities as a function of scattering angle, concentration, and temperature. The data yielded the molecular weight, radius of gyration, and second virial coefficient of alpha-crystallin at different temperatures. The second virial coefficient increased with increasing temperature. Both the enthalpy and entropy of solution of alpha-crystallin are positive. The Flory theta temperature was found to be 271 K.     

A vivid model of chiral recognition

Hands can be used to demonstrate the three-point model of chiral recognition. The points of attachment are thumb, forefinger, and middle finger. This vivid model has the advantages of simplicity, perspicuity, and availability at any time, although two persons are necessary. It can be shown that two interactions are not sufficient for chiral recognition but that three attractive or two attractive and one repulsive attraction are needed. It can also be used to explain some possibilities of weakening or elusion of the three-point model.     

Chiral stationary phase high-performance liquid chromatographic resolution and absolute configuration of enantiomeric benzo[a]pyrene diol-epoxides and tetrols

Enantiomers of diastereomeric benzo[a]pyrene (BP) diol-epoxides, r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydro-BP (BP 7,8-diol-anti-9,10-epoxide), r-7,t-8-dihydroxy-c-9,10-epoxy-7,8,9,10-tetrahydro-BP (BP 7,8-diol-syn-9,10-epoxide), r-9,t-10-dihydroxy-t-7,8-epoxy-7,8,9,10-tetrahydro-BP (BP 9,10-diol-anti-7,8-epoxide), and several 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrenes (BP tetrols) were resolved by high-performance liquid chromatography (HPLC) using columns packed with either (R)-N-(3,5-dinitrobenzoyl)phenylglycine[(R)-DNBPG] or (S)-N-(3,5-dinitrobenzoyl)leucine [(S)-DNBL], which is either ionically or covalently bonded to gamma-aminopropylsilanized silica. Resolution of enantiomers was confirmed by ultraviolet-visible absorption and circular dichroism spectral analyses. Resolved enantiomers of BP diol-epoxides were each hydrolyzed in acidic solution to a pair of diastereomeric tetrols which were separated by reversed-phase HPLC. Absolute stereochemistries of enantiomeric diol-epoxides were deduced by the absolute configuration of their hydrolysis products.     

Climate and vegetation in China II. Distribution of main vegetation types and thermal climate

The authors examined relationships between Kira's warmth index (WI) and four other important thermal indices: the sums of daily mean temperatures above 5°C and 10°C, Thornthwaite's potential evapotranspiration (PE) and Holdridge's annual biotemperature. The thermal records of 671 meteorological stations evenly located all over China were used to make these comparisons. Close correlations were found within the four relationships, and accordingly WI was used to analyse the thermal distributions of the main vegetation types. Vegetation types around the 671 stations were read from a vegetation map with a scale of 1/4000000. Vegetation types at 269 stations corresponded to the natural or seminatural vegetation, and 29 vegetation types were distinguished by arranging the 269 data into the same or similar types. The geographical distribution of these 29 types and the corresponding main climatic features were described. The relations between WI and distribution of these vegetation types were discussed in detail. As a result, WI values (°C month) corresponding to the vegetation zones could be summarized as follows: (1) arctic or alpine vegetation zone: 0–15; (2) boreal or subalpine vegetation zone: 15-(50–55); (3) cool-temperate vegetation zone: (50–55)–(80–90); (4) warm-temperate vegetation zone: (80–90)–(170–180). These values almost coincided with Kira's values. Chinese postgraduate student in Japan sent by the Chinese Government.     

The formation of flavonoids in cell suspension cultures ofPrunus x yedoensis matsum

Two lines of the red and pale yellow cell suspension cultures, prepared fromPrunus x yedoensis Matsum. callus induced by Murashige and Skoog's (1962) basal medium supplemented with 2, 4-dichlorophenoxyacetic acid (2, 4-D, 1.0 mg/l), kinetin (0.1 mg/l) and sucrose (30 g/l), were maintained on Schenk and Hildebrandt medium as modified by Mitchell and Gildow (1975). The red cell suspension culture produced cyanidin 3-monoglucoside, 5, 4′-dihydroxy-7-methoxyisoflavone 4′-glucoside (prunetrin), isoquercitrin, catechin, epicatechin, and procyanidin B-1, B-2, B-3 and B-4, while the pale yellow cells produced only a small amount of catechin and epicatechin as main flavonoids. These flavonoid compounds found in the red cell culture were present also in maturePrunus leaves. Maximum growth and maximum amount of total phenol and proanthocyanidin (procyanidins) were obtained with 0.3 mg/l of both 2,4-D and kinetin. Maximum concentration of anthocyanin was also obtained with 0.3 mg/l 2, 4-D regardless of kinetin concentration. Accumulation of proanthocyanidin was markedly stimulated by low concentrations of phosphate, which reduced growth by about half, and also by high concentrations of inorganic nitrogen. Production of both anthocyanin and proanthocyanidin was reduced by lowered nitrogen levels. Cell growth and production of all phenolics were inhibited when ammonium ion replaced nitrate in the medium.     

Mode of antitumor action of recombinant human tumor necrosis factor on the sarcoma Meth A transplanted in the mouse

The mode of antitumor action of rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation with respect to time course, dose-response relationships and selectivity of the effects. The maximal cytotoxic effect on tumor cells revealed by inhibition of DNA synthesis and maximal lesional effect on tumor vasculature revealed by change in blood pool-size in the tissue were detected at 30 min and I h after administration of rHu-TNF, respectively. The dose-response relationship between cytotoxic and tumoricidal effects of rHu-TNF was irrespective of administration route. ED₅₀s of these antitumor effects afteri.v. administration of rHu-TNF were about 50 times as high as ED₅₀s afteri.t. administration. ED₅₀ ofi.t. given rHu-TNF for vascular effect was about 20 times as high as that for cytotoxicity while ED₅₀ ofi.v. rHu-TNF for vascular effect was only 2–3 times as high as that for cytotoxicity. The whole body autoradiographies with [¹²⁵I] HSA giveni.v. to see the blood influx into tumor tissue and [¹⁴C]thymidine given i.v. to see DNA synthesis in the whole body after administration of rHu-TNF revealed that the distribution of radioactivity was markedly changed in the tumor alone without any detectable change in other whole body tissues.In conclusion, thein vivo antitumor effect of rHu-TNF giveni.t. ori.v., appears to be exerted through the direct action on Meth A sarcoma rather than indirectly on tumor vasculature. Under present conditions, the effect of rHu-TNF in the whole body tissues seems rather selective on cells and vasculature of the tumor.     

Tissue culture of Ecklonia radiata (Phaeophyceae,Laminariales): effects on growth of light,organic carbon source and vitamins

The effects of light quality and irradiance, and supply of organic carbon and vitamins on the growth of two forms of Ecklonia radiata in tissue culture were examined. A callus of unpigmented cells developed over the cut surface of newly excised explants of stipe. This growth was best in the dark but stopped after 10 weeks. Pigmented, mainly filamentous clumps of cells developed from explants after several weeks in culture. These required light for growth, with growth being enhanced by increasing photon flux density up to 30 μmol photon m^-2 s^-1, with the active spectral component being red light (> 600 nm). The addition to the medium of a range of organic carbon sources or vitamins did not stimulate growth of either culture type in the dark. author for correspondence     

Heptapeptide toxin production during the batch culture of two Microcystis species (Cyanobacteria)

Changes in the content of cyclic heptapeptide hepatotoxins called microcystins were investigated during batch culture of two Microcystis species using high performance liquid chromatography. After adsorption to ODS-silica gel cartridges and elution with methanol, the toxins were analyzed and quantified by HPLC. 35 μg per 100 mg dry cells of microcystin-RR, 34 μg of -YR and 43 μg of -LR were present at the beginning of the exponential growth phase of M. viridis. Microcystin-RR increased markedly towards the end of the exponential phase with the maximum content of 112 μg per 100 mg cells was measured at the late stage of the exponential phase. A remarkable increase of microcystin-YR from 130 μg per 100 mg cells to 1020 μg was observed during the exponential phase of a highly toxic strain of M. aeruginosa. However no clear differences were found in the pattern of change among the three toxins during the growth course.     

Characterization of a thermo-osmotic gas transport mechanism in Alnus glutinosa (L.) Gaertn.

Summary A gas transport system based upon the physico-chemical effect of thermo-osmosis of gases in described for the black alder, Alnus glutinosa (L.) Gaertn. Air is transported through the alder's stem to the roots, thus improving O₂ supply to respiring tissues of the root system. The gas transport system is investigated by means of a tracer gas technique (11% ethane in air, v/v). Gas transport depends on any source of radiant heat generating a temperature difference between the tree's stems and the atmosphere. The amount of gas transported in leafless trees is four times higher than the amount of gas reaching the roots by gas diffusion. Two-thirds of the gas is transported in the wood, only one-third in the bark. Intercellular spaces inside the porous lenticels of the bark are responsible for this kind of gas transport. Their diameters are estimated by the effusion rates of different tracer gases to be in the range of 1 m.