Pituitary-adrenal stimulation induced by lethal doses of 1-aminocyclopentanecarboxylic acid

Zusammenfassung Hypophysenlose Ratten zeigten nach Injektion von 1-Aminocyclopentancarboxylsäure (NSC-1026) keine pathologischen Symptome, wie normale mit dieser Substanz behandelte Tiere. Vergleichsversuche mit Reserpin-vorbehandelten Ratten, nachbehandelt mit NSC-1026, erbrachten keine befriedigenden Resultate.     

A negative inotropic response of cat atria to sympathetic nerve stimulation or norepinephrine

Zusammenfassung Isolierte, sympathisch innervierte Katzenvorhöfe wurden durch den rechten Nervus accelerans mit Impulsen von 1–5 msec Dauer und mit einer Frequenz von 0.5–60 Impulsen/sec stimuliert. In allen Präparaten wurde eine positiv chronotrope Wirkung beobachtet, während nur in 52% der Fälle eine inotrope Wirkung nachweisbar war. Bei 26% war die Kontraktionsstärke nicht beeinflusst, während bei 22% eine negativ inotrope Wirkung festgestellt wurde, für deren Variieren bis jetzt keine Erklärung gefunden werden konnte.

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Formerly pre-doctoral Fellow (U.S.P.H.S. Grant No. 5-T4-CA-5012).

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Pre-doctoral Fellow (U.S.P.H.S. Grant No. 5-T4-CA-5012).

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Established investigator of the American Heart Association.     

Recruitment of Pyk2 to SHPS-1 signaling complex is required for IGF-I-dependent mitogenic signaling in vascular smooth muscle cells

In vascular smooth muscle cells, IGF-I stimulates SHPS-1/SHP2/Src complex formation which is required for IGF-I-stimulated cell proliferation. Using SHP2/Src silencing and a Pyk2/Y402F mutant, we showed that Pyk2 was also recruited to the SHPS-1 complex. Pyk2 recruitment to SHPS-1 is mediated via the interaction of Pyk2 Tyr402 and the Src in response to IGF-I. Following Src/Pyk2 association, Src phosphorylates Pyk2 on Tyr881 providing a binding site for Grb2. Cells expressing Pyk2/Y881F showed decreased Grb2 recruitment to SHPS-1 and impaired Shc/Grb2 association. This change led to reduced Erk1/2 (MAP kinase) activation and cell proliferation in response to IGF-I. Our results show that, following its recruitment to the SHPS-1 signaling complex, Pyk2 localizes Grb2 in close proximity to Shc thereby facilitating Shc/Grb2 association which leads to Erk1/2 activation in response to IGF-I. Thus, Pyk2 recruitment to SHPS-1 plays an important role in regulating the IGF-I-stimulated mitogenic response.     

Stimulation of immune response by polymannuronic-guluronic acid in mice

Zusammenfassung Bei Mäusen, die mit suboptimalen Antigendosen geimpft wurden, erhöhte Polymannuron-Guluronsäure (Alginsäure) die Anzahl der 19S-antikörperbildenden Zellen in der Milz bis auf das 44-fache.     

The STING pathway and regulation of innate immune signaling in response to DNA pathogens

The innate immune system has evolved a variety of sensing mechanisms to detect and counter microbial invasion. These include the Toll-like receptor (TLR), cytoplasmic, nucleotide binding oligomerization domain (NOD)-like receptor and RIG-I-like helicase (RLH) pathways. However, how the cell detects pathogen-associated DNA to trigger host defense, including the production of interferon, remains to be fully clarified. Understanding these processes could have profound implications into how we understand and treat a variety of microbial-related disease, including viral-associated cancers, as well as autoimmune disorders. Recently, an endoplasmic reticulum-associated molecule referred to as STING (for stimulator of interferon genes) was isolated and shown to be critical for regulating the production of IFN in response to cytoplasmic DNA. Here, we review recent discoveries relating to the detection of foreign DNA, including the importance of the STING and inflammasome pathways and the triggering of innate signaling processes.     

Specific immunosuppression of IgE response to hapten DNP by DNP linked to monoclonal IgG1 in rats

Summary The induction of the anti-DNP IgE in rat was suppressed by pretreatment of rats with the tolerogen synthesized by coupling DNP to rat IgG, i.e.; DNP_7–10-IgG. It was found that DNP₁₀-IgG₁ was an effective tolerogen, whereas other DNP conjugates, i.e. DNP₉-IgM, DNP₉-IgA, DNP₁₀-IgE, DNP₁₀-IgG_2c and DNP₁₀-IgG_2a were ineffective.This work was partly supported by a research grant from the Medical Council of Canada to W.Y.L.     

Arachidonic acid signaling is involved in the mechanism of imidazoline-induced K<Subscript>ATP</Subscript> channel-independent stimulation of insulin secretion

The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated. The roles of K_ATP channels, α₂-adrenoreceptors, the I₁-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied. Using SUR1^(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with K_ATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on α₂-adrenoreceptors, I₁-imidazoline receptors or PC-PLC. BL11282 significantly increased [³H]arachidonic acid production. This effect was abolished in the presence of the iPLA₂ inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is independent of concomitant changes in cytoplasmic free Ca²⁺ concentration, involves release of arachidonic acid by iPLA₂ and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway. Received 5 July 2007; received after revision 18 September 2007; accepted 20 September 2007     

Kinetics of BRCA1 regulation in response to UVC radiation

To investigate changes in BRCA1 following DNA damage, we exposed MCF-7 cells to increasing doses of ultraviolet C. We observed an increase in BRCA1 protein levels above 78 J/m². This increase was observed as early as 5 min after irradiation. BRCA1 levels were then observed to decrease after 2 h, consistent with the previously published data. By pretreating with cycloheximide prior to irradiation, we observed a decrease in the protein half-life, from 3.5 h to 53 min, suggesting that a decrease in protein half-life may cause the lower levels of BRCA1 after irradiation. We also observed an increase in BRCA1 mRNA within 15 min of irradiation, followed by a decrease after 4 h. These data suggest that newly translated protein may contribute to increases in BRCA1 protein levels. The very rapid changes in BRCA1 support its role as a sensor of DNA damage, as opposed to being a repair gene. Received 6 April 2000; received after revision 23 May 2000; accepted 23 May 2000     

Alpha 1-adrenergic stimulation of ketogenesis and fatty acid oxidation is associated with inhibition of lipogenesis in rat hepatocytes

The effect of norepinephrine on fatty acid synthesis (3H2O incorporation into fatty acids), on fatty acid oxidation to CO2 and on ketogenesis was studied in isolated hepatocytes of fed rats. After incubation with norepinephrine (50 microM), lipogenesis was lower (5.7 +/- 1.1 nmoles 3H2O incorporated into fatty acids/mg dry weight/30 min) than in controls (7.5 +/- 1.7; n = 6, p less than 0.02). In contrast, (1-14C) palmitate conversion into total ketone bodies was increased to 10.9 +/- 1.8 nmoles/mg/30 min with norepinephrine, vs 8.5 +/- 1.6 in controls (p less than 0.05), and more (1-14C) palmitate was converted to 14CO2 with norepinephrine than in controls (1.48 +/- 0.10 nmoles/mg/30 min vs 1.06 +/- 0.11, p less than 0.05). The inhibitory effect of norepinephrine on lipogenesis was abolished by addition of the alpha 1-receptor blocker prazosin, but not by alpha 2 or beta-blockers. The results demonstrate that the ketogenic effect of norepinephrine is coupled with an inhibitory effect on lipogenesis which may be explained by diminished activity of acetyl-CoA carboxylase, diminished formation of malonyl-CoA and decreased activity of carnitine palmitoyl transferase I.     

Changes in the concentration of vasoactive intestinal peptide in intestinal lymph in response to vagal stimulation in the calf

Summary Stimulation of both vagi caused a significant rise in arterial plasma vasoactive intestinal peptide (VIP) concentration in 3–5-week-old calves with cut splanchnic nerves. This was associated with a pronounced rise in the VIP concentration of intestinal lymph showing that vagal stimulation causes release of VIP from splanchnic viscera.Acknowledgment. This work has been supported by grants from the Agricultural Research Council and the Medical Research Council and we are indebted to Dr D.M. Burley (CIBA) for his continued support.     

Differential regulation of collagen types I and III expression in cardiac fibroblasts by AGEs through TRB3/MAPK signaling pathway

Advanced glycation end products (AGEs) play an important role in collagen deposition in diabetic cardiomyopathy. TRB3, a mammalian homolog of Drosophila tribbles, functions to increase glucose intolerance and regulates cell proliferation. We demonstrated that AGEs induce collagen type I expression but inhibit collagen type III expression, accompanied by increased TRB3 expression. Furthermore, the collagen type I induced byAGEs was down-regulated after inhibition of ERK and p38-MAPK, the collagen type III reduced by AGEs was up-regulated after inhibition of ERK. The expression of collagen types I and III regulated by AGEs through MAPK was partly reversed after treatment with TRB3 siRNA. It suggests that the TRB3/MAPK signaling pathway participates in the regulation of collagen types I and III by AGEs and may provide new therapeutic strategies for diabetic cardiomyopathy. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 08 May 2008; received after revision 25 June 2008; accepted 22 July 2008 M. Tang, M. Zhong: These two authors contributed equally to this work.