Effect of benzatropine on the O-methylation of striatal dopamine]

After treatment by nialamid, benztropine administered to Rats produced an increase in the level of 3-O-methyldopamine in the corpus striatum. It produced a slight increase in the level of striatal dopamine and no change in the level of norepinephrine. The monoamine oxydase and catechol-O-methyltransferase activities of remaining brain showed no variations by benztropine. The results suggest the possible involvement of striatal dopamine and its extraneuronally catabolism in the antiparkinsonian effect of benztropine.     

The effect of L-dopa on pupillary diameter in mice

Summary Injection of L-dopa in mice produces dose-dependent mydriasis. Pre-treatment with peripheral dopa-decarboxylase inhibitors (carbidopa and benserazide) or with an alpha-adrenergic blocking agent (phentolamine) abolishes the pupillary dilation caused by L-dopa. Pretreatment with fusaric acid, an inhibitor of dopamine-beta-hydroxylase, also antagonizes the mydriatic effect of L-dopa. Thus, our results suggest that the mydriasis produced in mice following the injection of L-dopa is caused by its peripheral conversion to noradrenaline, which stimulates alpha-adrenergic receptors in the dilator iridis. There was no evidence that stimulation of specific dopaminergic receptors was involved.We are grateful to N. Rothschild, Head of Laboratory Animal Department, Sackler School of Medicine, for his help.     

Dopamine regulation of testicular activity in intact and hypophysectomized frogs,Rana esculenta

In intact frogs, both GnRHA and L-dopa were able to increase testicular and plasma androgen levels and to induce spermiation. The dopamine antagonist pimozide inhibited both the effects of L-dopa but not those of GnRHa. Hypophysectomy reduced androgen levels, but spermiation was still induced by both GnRHa and L-dopa, suggesting that these agents can directly influence the testis through a route not involving the pars distalis. Again, pimozide antagonised spermiation induced by L-dopa but not that induced by GnRHa.This work was supported (40% and 60%) by the Italian Ministry of Education and the C.N.R. Special Project.     

Ureteral contractions induced by rat urine in vitro: Probable involvement of renal kallikrein

Summary Rat urine, even at a 110 final dilution in Tyrode's solution, stimulates contraction of the ureteral musculature in vitro. This effect can be ascribed to the presence of kallikrein or a kallikrein-like enzyme in urine. Isometric contractions of ureters were prevented by previous addition of aprotinin to the organ bath. Urine also lost its activity after inactivation of enzymes by heat or acid treatment.Acknowledgments. Aprotinin (Trasylol^®) was kindly supplied by Baypropharm, Köln, W.-Germany. This work was supported by the German Research Foundation (SFB 90).     

Antioxidant survey to assess antagonism to redox stress using a prokaryotic and an eukaryotic system

Using a prokaryote (Escherichia coli) and a metazoa-resembling eukaryote (Ochromonas danica), we surveyed antioxidants which might overcome redox stress imposed by menadione sodium bisulphite (MD) and buthionine sulphoximine (BSO). BSO oxidant stress was evident only inO. danica; MD oxidant stress was evident in both organisms. Glutathione, its precursors, e.g. cysteine, homocysteine, and 2-oxo-4-thiazolidine carboxylic acid, and red blood cells, emerged as prime antioxidants for relieving BSO and MD oxidant stress. BSO and MD oxidant activity and antioxidant-annulling effect inO. danica were judged comparable to those found in animal cells whereas the resultsE. coli were not entirely equivalent. TheO. danica system emerged as a practical, rapid, and useful system for pinpointing oxidant stressors and antioxidants, and shows promise for studies with mammalian systems.     

Der Einfluss des Urin-pH auf die Aktivität von Urinenzymen

Summary The relationship between the pH of urine and the measured activity of ULDH, UAP and UAA was investigated in vivo and in vitro. The activity of ULDH and UAP is only half as much, or less, in acid urine (pH 4.8–5.1) as it is in alkaline urine (pH 7.0–8.1). The UAA activity, however, does not change in the pH range measured. The isoenzymes ULDH 2–4, present in alkaline urine of normal adults, does not appear in acid urine.     

Metabolism of 1,3,7-trimethyldihydrouric acid in the rat: New metabolic pathway of caffeine

Summary [1-CH₃-¹⁴C] 1,3,7-trimethyldihydrouric acid which, in quantity, is the most important caffeine metabolite, was isolated and purified from the urine of rats fed with [1-CH₃-¹⁴C] caffeine. The oral administration of this metabolite to rats showed that 1,3,7-trimethyldihydrouric acid was excreted unchanged in urine and was therefore an end product of caffeine metabolism. This result implies a new metabolic pathway of caffeine.     

Formation of indolyl-3-acetylaspartic acid in rats

Summary Indolyl-3-acetylaspartic acid (IAAsp) was detected in the urine of rats given indolyl-3-acetic acid (IAA) i.p. It was ascertained that the conversion of IAA into IAAsp could be carried out not only in plants but also in animals.     

Immunostimulating lipopeptide,LtriP (RP 56142): Comparison of the effect on hepatic cytochrome P 450 modulation and radioprotection in male and female of three mouse strains

The sex-dependent effect of lauroyl-L-Ala-D--Glu-L,L-A₂pmNH₂ (LtriP, RP 56142) on hepatic microsomal cytochromes P 450 (cyt P 450) was studied in three mouse strains NMRI, C3H/OuJ and C3H/HeJ. In NMRI and C3H/OuJ, strains which are responsive to bacterial lipopolysaccharides (LPS-responsive), regardless of the sex of the mouse, significant decrease in the amount of cyt P 450 was observed after LtriP treatment, with a concomitant reduction in ethoxyresorufin-O-deethylase (cyt P 450 1A-dependent) and 7-ethoxycoumarin-O-deethylase activities. This was not seen in C3H/HeJ (LPS-hyporesponsive) mice. These effects may be related to LtriP-dependent cytokine induction, since neither LtriP nor LPS stimulated interleukin-1 (IL-1) secretion by C3H/HeJ macrophages. 11- and 12-hydroxylations (11- and 12-OH) of lauric acid were compared in C3H/OuJ and C3H/HeJ mice. LtriP depressed the total enzymatic conversion of lauric acid in the two strains without modification of the 11/12-OH ratio for C3H/OuJ or male C3H/HeJ mice. However, in females C3H/HeJ mice this decrease was particularly significant and concerned especially the 12-OH activity (a marker of cyt P450 4A family). Although males of the three strains were more sensitive to irradiation than females, LtriP exerted a sex-independent radioprotection on NMRI and C3H/OuJ mice. Its radioprotective effect was illustrated by the preservation of all the enzymatic activities studied in treated NMRI mice, contrary to irradiated control animals. In contrast, for the C3H/HeJ strain, males were not protected by LtriP treatment and, furthermore, females showed a marked sensitization to irradiation.The effects in CH3/HeJ strain implicate LtriP in the control of cyt P 450 induction and of sensitivity to irradiation independently of IL-1 induction.     

Alkalosis and renal excretion of ammonia by rat kidney

Upon sulfate administration, UpH falls more in alkalotic rats than in controls. Alkalosis can lead to a reduction in UNH3 V at highly acidic urine. The significance of this process is doubtful at UpH ranging from about 6 to 7. At lower UpH less NH3 would be excreted, thereby less H+ would be trapped in urine and some acid would be conserved.     

Validating Policy‐Induced Economic Change Using Sequential General Equilibrium SAMs

We present a novel sequential approach that explores the capacity of Computable general equilibrium (CGE) models to track down policy‐induced economic changes and their ability to generate contrastable data. We use an empirical Social accounting matrix (SAM) of the region of Andalusia, in the south of Spain, to construct an initial CGE model. This model is then perturbed with a set of policy shocks related to EU Structural Funds invested into Andalusia. These shocks are accompanied by some parameter adjustments that pick up the main external changes not explained by the model. We generate a sequence of model‐produced virtual SAMs. We then compare the last virtual SAM in the sequence with a new available empirical SAM. This allows us to check relatedness, for the same year, between the model produced and the empirical SAMs. The results show a good fit to the empirical data, providing further support to the CGE modelling tool. Copyright © 2016 John Wiley & Sons, Ltd.     

An MD2-derived peptide promotes LPS aggregation,facilitates its internalization in THP-1 cells,and inhibits LPS-induced pro-inflammatory responses

MD2, a 160-residue accessory glycoprotein, is responsible for the recognition and binding of Gram-negative bacterial membrane component, lipopolysaccharide (LPS). Internalization of pathogen inside the mononuclear phagocytes has also been attributed to MD2 which leads to the clearance of pathogens from the host. However, not much is known about the segments in MD2 that are responsible for LPS interaction or internalization of pathogen inside the defense cells. A 16-residue stretch (MD54) from MD2 protein has been identified that possesses a short heptad repeat sequence and four cationic residues enabling it to participate in both hydrophobic and electrostatic interactions with LPS. An MD54 analog of the same size was also designed in which a leucine residue at a heptadic position was replaced with an alanine residue. MD54 but not its analog, MMD54 induced aggregation of LPS and aided in its internalization within THP-1 monocytes. Furthermore, MD54 inhibited LPS-induced nuclear translocation of NF-κB in PMA-treated THP-1 and TLR4/MD2/CD14-transfected HEK-293T cells and the production of pro-inflammatory cytokines. In addition, in in vivo experiments, MD54 showed marked protection and survival of mice against LPS-induced inflammation and death. Overall, we have identified a short peptide with heptad repeat sequence from MD2 that can cause aggregation of LPS and abet in its internalization within THP-1 cells, resulting in attenuation of LPS-induced pro-inflammatory responses in vitro and in vivo.     

Effects of retinoic acid on ascites cells of the TA3 mouse mammary carcinoma

Summary Retinoic acid caused a decrease in adhesiveness but no growth change in the allotransplantable TA3-Ha cell and no change in adhesiveness or growth in the strain specific TA3-St cell. The retinoic acid binding protein was detected in the TA3-Ha, but not the TA3-St, cell.This study was supported in pat by Public Health Service Grants CA-08418 and CA-18600 from the National Cancer Institute, National Institutes of Health. This is publication 955 of the Robert W. Lovett Group for the Study of Diseases Causing Deformities. We gratefully acknowledge the contributions of Drs Luigi M. De Luca and Anton M. Jetten of the Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD, without whose help this study would not have been possible.     

Effects of photoperiod, temperature and testosterone-treatment on plasma T3 and T4 levels in the Djungarian hamster, Phodopus sungorus

The effects of photoperiod, temperature and testosterone treatment on plasma T3 and T4 levels were investigated in the Djungarian hamster. Plasma T3 level was affected by temperature (25 degrees C less than 7 degrees C) but not by photoperiod. Plasma T4 level was affected by photoperiod (short day less than long day) at 25 degrees C. Administration of testosterone increased plasma T4 level under short photoperiod at 25 degrees C. Thus, higher plasma T4 level under long photoperiod at 25 degrees C might be induced by testosterone.     

Some properties ofBufo bufo tyrosinase during development

Summary Tyrosinase expression duringBufo bufo development has been investigated. Until stage 19, only 1 electrophoretic band is detectable, but at a later stage (25) 3 bands appear. The K_m for L-3,4-dihydroxyphenylalanine (L-dopa) was also determined.     

Molecular modelling and molecular dynamics of CFTR

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a member of the ATP-binding cassette (ABC) transporter superfamily that functions as an ATP-gated channel. Considerable progress has been made over the last years in the understanding of the molecular basis of the CFTR functions, as well as dysfunctions causing the common genetic disease cystic fibrosis (CF). This review provides a global overview of the theoretical studies that have been performed so far, especially molecular modelling and molecular dynamics (MD) simulations. A special emphasis is placed on the CFTR-specific evolution of an ABC transporter framework towards a channel function, as well as on the understanding of the effects of disease-causing mutations and their specific modulation. This in silico work should help structure-based drug discovery and design, with a view to develop CFTR-specific pharmacotherapeutic approaches for the treatment of CF in the context of precision medicine.     

Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.

A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported.     

Juvenile hormone: Evidence for a role in the feeding rhythm ofOncopeltus fasciatus (Dallas)

Summary The diurnal feeding rhythm of female milkweed bugs was damped when fed nonhost seeds. Juvenoid treatment partially restored the normal rhythm. Precocene II-treated milkweed seed-fed females fed arrhythmicly during the light phase without reduced total feeding activity. This effect was largely prevented by simultaneous treatment with JH III.I thank Dr Judith H. Willis, Univ. of Illinois, for providing facilities, Meyer Schwartz of ARS, USDA, Beltsville, MD, USA, for providing the precocene II, and Dr W. S. Bowers, formerly of ARS, USDA, Beltsville, MD, for supplying the juvenoid. This work was supported in part by grant AG-00248 from the National Institutes of Health to J. H. Willis.     

Periodate oxidation of lymphocyte membrane glycoconjugates]

Mouse spleen cells free of erythrocytes were suspended in PBS at a concentration of 2 X 10(7) cells/ml and mixed with an equal volume of sodium periodate in PBS for 10 min. at 4 degrees C to give a final concentration of periodate ranging from 10(-4) M to 5 X 10(-3) M. The cells were then washed and suspended (60 X 10(6) ml) in PBS containing 3H-labelled sodium borohydrate and incubated for 30 min, at 23 degrees C. Following this, the cells were washed and the pellets treated with H2SO4 0.1 N for 60 min. at 80 degrees C. Compounds liberated by such treatment, were identified by chromatography as derivates of sialic acid. The data provide direct evidence that the mitogenic effect of sodium periodate is associated to the oxidation of the sialic acid residues on the lymphocyte membrane.