Age-related differences in the urinary excretion of prostaglandin F2α catabolites in the rat

Summary Tritium-labelled PGF₂ was administered i.v. into rats of varying ages (2, 4, 6 weeks and adult). Urine was collected and assayed for radioactive products by thin-layer-chromatography. Results showed a distinctly different urinary profile between the 2-week-old and the adult rat. While the urinary pattern from the 2-week-old rat gave a single less polar product than PGF₂, the pattern from the adult rat gave products more polar than PGF₂. Urine from the 4- and 6-week-old rats gave a mixture of these types of products. These results indicate that some prostaglandin catabolic pathway (likely the -oxidative system) is activated in vivo within the 4–6-week postnatal period in the rat.Supported by a grant (MT-4181) to C.P.-A. from the Medical Research Council of Canada.This study is in partial fulfillment of the requirements for a Ph.D. degree in the Department of Pharmacology, University of Toronto.     

Stimulation of gastric secretion by prostaglandin F2 α in rats

Summary In rats with chronic gastric fistulas, prostaglandin F₂ stimulated the gastric acid secretion in graded doses of 50. 100, 200 and 400 g/kg b. wt, while higher doses above 1 mg/kg b. wt tended to inhibit significantly. The gastric antisecretory effect of prostaglandin E₁ could not be altered or modified by subsequent treatment of prostaglandin F₂ , while the latter alone without any prior treatment of the former, stimulated output of gastric juice, HCl and pepsin without significantly affecting the concentration of these components.Acknowledgement. The gift of the prostaglandin E₁ and prostaglandin F₂ is acknowledged to Dr J.E. Pike, Upjohn, USA. This paper was read at the IXth Annual Conference of the Indian Pharmacological Society held at Benares (1976) and abstracted in the Indian J. Pharmac.9, 73 (1977).     

Morphological effects of prostaglandins E1, E2 and F2α on fibroblast-like cultures of human synovial cells

Summary In medium supplemented with serum, PGE₁ and PGE₂ were equally potent in inducing cells with a fenestrated appearance, whereas PGF₂ was comparatively ineffective. In BSA without serum the effects were more persistent and characterized by a high proportion of astrocyte-like cells. The effects were reversed upon removal of the prostaglandins.This work was supported by the National Health and Medical Research Council of Australia.     

Dissection of the molecular mechanisms that control the nuclear accumulation of transport factors importin-α and CAS in stressed cells

The physiological state of eukaryotic cells controls nuclear trafficking of numerous cargos. For example, stress results in the inhibition of classical protein import, which is characterized by the redistribution of several transport factors. As such, importin-alpha and cellular apoptosis susceptibility protein (CAS) accumulate in nuclei of heat-shocked cells; however, the mechanisms underlying this relocation are not fully understood. We now show that heat upregulates the initial docking of importin-alpha at the nuclear envelope and stimulates the translocation of CAS into the nuclear interior. Moreover, heat exposure compromises the exit of importin-alpha from nuclei and drastically increases its retention in the nucleoplasm, whereas CAS nuclear exit and retention are less affected. Taken together, our results support the idea that heat shock regulates importin-alpha and CAS nuclear accumulation at several levels. The combination of different stress-induced changes leads to the nuclear concentration of both transport factors in heat-stressed cells.     

TNF-α modulates the migratory response of mesenchymal stem cells to TRAIL

The number of circulating mesenchymal stem cells (MSC), analyzed after acute myocardial infarction (AMI), was lower in AMI patients who developed heart failure (HF) in the follow-up. Conversely, the circulating levels of tumor necrosis factor (TNF)-α, and osteoprotegerin (OPG) were higher in AMI patients who developed HF with respect to the patients who did not develop HF. In vitro exposure to TNF-α enhanced the migration of MSC in response to TNF-related apoptosis-inducing ligand (TRAIL) and significantly increased the release of OPG by endothelial cells. On the contrary, OPG dose-dependently neutralized the in vitro pro-migratory activity of TRAIL. Thus, TNF-α exhibits opposite effects on MSC migration driven by TRAIL: it is capable of potentiating MSC migration as well as of inhibiting MSC migration as an indirect consequence of OPG induction, which might result in a suboptimal recruitment of circulating MSC after AMI in those patients who develop HF in the follow-up.     

Heavy water intake in tissues. II. H2O−D2O exchange in the myelinated nerve of the frog

Summary The kinetic parameters of D₂O intake in the frog sciatic nerve are obtained by means of infrared spectroscopy. 3 aqueous compartments: a non-exchangeable one (29%) and 2 compartments of quasi-free exchangeable water: 50% intracellular and 21% extracellular, are revealed.The first communication in this series is V. Vasilescu, D.-G. Mrgineanu and Eva Katona, Naturwiss.62, 187 (1975).For such derivations reference is made to the above mentioned mathematical model or to related works on compartmental analysis, reviewed by A. Rescigno and J. S. Beck, in: Foundations of Mathematical Biology, vol. II. Ed. R. Rosen, Academic Press, New York 1972.     

α-Particle track autoradiographic study of the distribution of a [211At]-astatinated drug in normal tissues of the mouse

Summary The microscopic distribution of the potential endoradiotherapeutic drug, 6-[²¹¹At]-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt) in normal tissues of the mouse has been studied by -particle track autoradiography. The uptake into critical radiosensitive tissues, especially bone marrow, colon and lung, was low.     

Isotope effect studies on the dehydrogenation of Δ1-tetrahydrocannabinol in the rat

Summary Isotope effect studies on the metabolic dehydrogenation of ¹-tetrahydrocannabinol in rats are described and its is shown that this process is confined to a very short period following i.v. administration. The implications of this finding are discussed.The authors are grateful for generous fifts of³H-¹-THC from Dr S. Burstein (Worcester Foundation for Experimental Biology, Massachusetts), and of¹⁴C-¹-THC from the National Institute on Drug Abuse. The authors thank the staff of the Small Animal Unit, Wallaceville Research Centre for their cooperation, and the U.S. National Institute on Drug Abuse for their support.     

Effects of PGE2 and PGF2α on the simulation by noradrenaline and oxytocin of human cervical muscle activity at term

Summary Cervical specimens were obtained by needle biopsy in connection with caesarean section at term pregnancy. The preparations were superfused in an organ chamber and contractions were registered isometrically. Prostaglandin (PG) E₂ and F₂ inhibited spontaneous contractions. The stimulatory action of noradrenaline was not influenced by PGF₂ but was reduced by PGE₂ whereas both PGs abolished the excitatory effect of oxytocin.     

Age- and sex-related differences in the content of prothymosinα in rat tissues

Differences in the tissue content of prothymosin during the early postnatal development of male and female rats are reported. Thymus and spleen have been found to contain significantly higher amounts of prothymosin in the newborn and prepubertal animals, as compared to adults, whereas liver has been found to contain low levels of prothymosin throughout development. These findings indicate a functional association of prothymosin with the proliferating lymphoid tissues of the young rat.     

Dissociation constants of water-insoluble carboxylic acids by13C-NMR. pK as of mesobiliverdin-XIIIα and mesobilirubin-XIIIα

High-field¹³C-NMR of¹³C-enriched compounds in dilute aqueousd ₆-Me₂SO solutions provides a simple, accurate method for measuring pK _as of sparingly soluble carboxylic acids. Using this method, we found the pK _as of mesobilirubin-XIII to be 4.2 and 4.9, much lower values than reported recently for bilirubin, and of mesobiliverdin-XIII to be 3.9 and 5.3.     

NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity

Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K⁺, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease.     

Dynamics of the interaction of γδ T cells with their neighbors in vivo

γδ T cells are a diverse component of the immune system in humans and mice with presumably important but still largely unknown functions. Understanding the dynamic interaction of γδ T cells with their neighbors should help to understand their physiological role. This review addresses recent advances and strategies to visualize the dynamic interactions of γδ T cells with their neighbors in vivo. Current knowledge regarding the dynamic contacts of tissue resident γδ T cells and epithelial cells, but also of the communication between circulating γδ T cells and DCs, monocytes and FoxP3⁺ regulatory T cells is revisited with emphasis on the role of γδ T cell motility.     

Novel role of cPLA2α in membrane and actin dynamics

Actin-directed processes such as membrane ruffling and cell migration are regulated by specific signal transduction pathways that become activated by growth factor receptors. The same signaling pathways that lead to modifications in actin dynamics also activate cPLA₂α. Moreover, arachidonic acid, the product of cPLA₂α activity, is involved in regulation of actin dynamics. Therefore, it was investigated whether cPLA₂α plays a role in actin dynamics, more specifically during growth factor-induced membrane ruffling and cell migration. Upon stimulation of ruffling and cell migration by growth factors, endogenous cPLA₂α and its active phosphorylated form were shown to relocate at protrusions of the cell membrane involved in actin and membrane dynamics. Inhibition of cPLA₂α activity with specific inhibitors blocked growth factor-induced membrane and actin dynamics, suggesting an important role for cPLA₂α in these processes.     

Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis

Protein kinase C ε (PKCε) has emerged as an oncogenic protein kinase and plays important roles in cancer cell survival, proliferation, and invasion. It is, however, still unknown whether PKCε affects cell proliferation via glucose metabolism in cancer cells. Here we report a novel function of PKCε that provides growth advantages for cancer cells by enhancing tumor cells glycolysis. We found that either PKCε or Smad2/3 promoted aerobic glycolysis, expression of the glycolytic genes encoding HIF-1α, HKII, PFKP and MCT4, and tumor cell proliferation, while overexpression of PKCε or Smad3 enhanced aerobic glycolysis and cell proliferation in a protein kinase D- or TGF-β-independent manner in PC-3M and DU145 prostate cancer cells. The effects of PKCε silencing were reversed by ectopic expression of Smad3. PKCε or Smad3 ectopic expression-induced increase in cell growth was antagonized by inhibition of lactate transportation. Furthermore, interaction of endogenous PKCε with Smad2/3 was primarily responsible for phosphorylation of Ser213 in the Samd3 linker region, and resulted in Smad3 binding to the promoter of the glycolytic genes, thereby promoting cell proliferation. Forced expression of mutant Smad3 (S213A) attenuated PKCε-stimulated protein overexpression of the glycolytic genes. Thus, our results demonstrate a novel PKCε function that promotes cell growth in prostate cancer cells by increasing aerobic glycolysis through crosstalk between PKCε and Smad2/3.     

Experiments concerning the incorporation of labelled adenine into ribonucleic acid in normal sea urchin embryos and in the hybridParacentrotus ♀ xArbacia ♂

Zusammenfassung Inkubation der Seeigelkeime mit¹⁴C-Adenin ergab, dass bei reinen Arten der Einbau der markierten Substanz in die RNS von der Mesenchymblastula bis zum Pluteus eindeutig zunimmt. Parallel zur DNS-Synthese verläuft die Zunahme beiParacentrotus undSphaerechinus viel rascher als beiArbacia. Beim Bastard PA nimmt dieser Einbauprozess mit Beginn der morphogenetischen Hemmung (nach ca. 26 h) rasch ab.