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101.
Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
Jung Dae Kim Chitoku Toda Giuseppe D’Agostino Caroline J. Zeiss Ralph J. DiLeone John D. Elsworth Richard G. Kibbey Owen Chan Brandon K. Harvey Christopher T. Richie Mari Savolainen Timo My?h?nen Jin Kwon Jeong Sabrina Diano 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(32):11876-11881
Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prepgt/gt) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, , impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prepgt/gt and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prepgt/gt and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prepgt/gt mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus–PREP reversed the glucose-intolerant phenotype of the Prepgt/gt mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.Prolyl endopeptidase (PREP; EC 3.4.21.26) is a highly conserved enzyme ( S170921). In humans and rodents it is highly expressed in the brain (2), including the cortex, striatum, hypothalamus, hippocampus, and amygdala (3–6). The physiological role of PREP remains elusive (7). Many studies have focused on the putative effect of PREP on neuropeptide levels because this enzyme could function to cleave virtually all neuropeptides shorter than 30 amino acids that contain an internal proline residue (8).However, much of our understanding of this enzyme is based on in vitro data. Because PREP’s putative targets regulate a large number of signaling pathways, PREP has the capacity to regulate a variety of cellular tasks.To gain a better understanding of the role of PREP in the hypothalamus, we analyzed the effect of PREP knockdown on hypothalamic mechanisms including glucose and energy metabolism. 相似文献
102.
Punjabi NH Taylor WR Murphy GS Purwaningsih S Picarima H Sisson J Olson JG Baso S Wangsasaputra F Lesmana M Oyofo BA Simanjuntak CH Subekti D Corwin AL Richie TL 《The American journal of tropical medicine and hygiene》2012,86(1):46-51
We conducted a prospective, inpatient fever study in malaria-endemic Papua, Indonesia to determine non-malaria fever etiologies. Investigations included malaria blood films, blood culture, paired serologic samples analysis for dengue, Japanese encephalitis, leptospirosis, scrub typhus, murine typhus, and spotted fever group rickettsia. During 1997-2000, 226 patients (127 males and 99 females) 1-80 years of age (median age = 25 years) were enrolled. Positive blood cultures (n = 34, 15%) were obtained for Salmonella Typhi (n = 13), Escherichia coli (n = 8), Streptococcus pneumoniae (n = 6), Staphylococcus aureus (n = 5), Streptococcus pyogenes (n = 1), and Klebsiella pneumoniae (n = 1). Twenty (8.8%) patients were positive for leptospirosis by polymerase chain reaction. Eighty (35.4%) of 226 patients had ≥ 1 positive serology, diagnostic for 15 rickettsial and 9 dengue cases. Acid-fast bacilli-positive sputum was obtained from three patients. Most common confirmed (81 of 226, 35.8%)/suspected diagnoses were typhoid fever (n = 41), pneumonia (n = 29), leptospirosis (n = 28), urinary tract infections (n = 20), rickettsioses (n = 19), dengue (n = 17), and meningitis/encephalitis (n = 15). There were 17 deaths, 7 (46.7%) were caused by meningitis/encephalitis. Multiple positive serologic results and few confirmed diagnoses indicate the need for improved diagnostics. 相似文献
103.
Aging represents a major risk factor for prostate cancer; however, mechanisms responsible for this relationship remain unclear. Preclinical and some clinical investigations support the protective role of selenium against prostate cancer possibly through the reduction of oxidative stress. While increased levels of oxidative stress together with decreases in selenium and the major cellular antioxidant glutathione (GSH) are common in tissues of old animals, there is little data available on these parameters in the prostate. In the present study we have compared the levels of selenium, GSH and protein-bound GSH (GSSP) in blood and prostate tissues in young (4-month), mature (12-month), old (18 month), and very old (24 month) male F344 rats. Each prostate lobe (dorsolateral, DL; anterior, AL; ventral, VL) was analyzed separately based upon their differing potential for prostate cancer development. At all ages, selenium levels were lowest in DL相似文献
104.
105.
106.
Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome 总被引:9,自引:0,他引:9
Drenth JP; van Deuren M; van der Ven-Jongekrijg J; Schalkwijk CG; van der Meer JW 《Blood》1995,85(12):3586-3593
The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome. 相似文献
107.
Renner C; Ohnesorge S; Held G; Bauer S; Jung W; Pfitzenmeier JP; Pfreundschuh M 《Blood》1996,88(1):236-241
To investigate the mechanisms underlying the deficiency of T lymphocytes from patients with Hodgkin's disease, we investigated the expression of the T-cell receptor (TCR) zeta chain in patients with Hodgkin's disease. By flow cytometry using an anti-zeta chain monoclonal antibody, peripheral blood T lymphocytes from patients with untreated Hodgkin's disease were shown to express decreased levels of the TCR zeta chain. After stimulation by combined CD3 and CD28 cross- linking, T cells from Hodgkin's disease patients upregulated zeta chain protein expression to normal values within 48 hours and achieved a cytolytic potential and levels of interleukin (IL)-2 secretion that were not different from T cells obtained from healthy controls. These results show that downregulation of the TCR zeta chain in Hodgkin's T lymphocytes is a reversible event. Costimulation of CD3 and CD28 is a novel approach for overcoming the T-cell deficiency in Hodgkin's disease and might be exploited clinically. As upregulation of the zeta chain can also be achieved using bispecific monoclonal antibodies (BI- MoAbs) with specificity for tumor antigens and CD3 and CD28, respectively, an immunotherapy with CD3/CD30 and CD28/CD30 Bi-MoAbs may overcome and should therefore, not be jeopardized by the inherent T- cell deficiency in patients with Hodgkin's disease. 相似文献
108.
de Koning JP; Dong F; Smith L; Schelen AM; Barge RM; van der Plas DC; Hoefsloot LH; Lowenberg B; Touw IP 《Blood》1996,87(4):1335-1342
109.
Alpha/beta T-cell antigen receptor gene and protein expression occurs at early stages of thymocyte differentiation. 总被引:7,自引:0,他引:7
E R Richie B McEntire N Crispe J Kimura L L Lanier J P Allison 《Proceedings of the National Academy of Sciences of the United States of America》1988,85(4):1174-1178
Alterations in gene expression that orchestrate eukaryotic cellular differentiation often require appropriate interactions between differentiating cells and a specialized microenvironment. During T-lymphocyte differentiation, immature thymocytes undergo a stringent intrathymic selection process that requires intimate contact with thymic stromal elements. Since this selection process generates T cells that are self-tolerant and recognize nominal antigen only within the context of self-major histocompatibility antigen complex molecules, it is possible that thymocyte/stromal cell interactions are mediated, in part, by antigen-specific receptors expressed on differentiating thymocytes. However, the developmental stage at which alpha/beta antigen-specific receptors are expressed during T-cell maturation has been a matter of debate. To address this issue, we have studied alpha/beta T-cell antigen receptor gene and protein expression on normal thymocyte subsets of AKR/J mice, as well as on a panel of AKR/J primary thymic lymphomas characterized for CD4 (L3T4) and CD8 (Lyt-2) differentiation antigen expression. The data unequivocally demonstrate that alpha/beta heterodimers are expressed not only on phenotypically mature thymocytes but also on the majority of CD4+8+ double-positive cells that comprise the predominant nonmature thymocyte subset. Furthermore, a fraction of thymocytes in the CD4-8- double-negative compartment, known to contain progenitor cells, also expresses readily detectable cell-surface alpha/beta receptors. Therefore, during the process of intrathymic selection, interactions between nonmature thymocytes and stromal cells via the antigen-receptor complex may play a pivotal role in T-cell differentiation and should be considered in formulating schemes for functional T-cell selection. 相似文献
110.
Bishop JF; Matthews JP; Young GA; Szer J; Gillett A; Joshua D; Bradstock K; Enno A; Wolf MM; Fox R 《Blood》1996,87(5):1710-1717
High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3-7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7-3-7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC- 3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3- 7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC- 3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML. 相似文献