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Sample records for paracrine mesendoderm inducing

  1. ROCK inhibitor primes human induced pluripotent stem cells to selectively differentiate towards mesendodermal lineage via epithelial-mesenchymal transition-like modulation.

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    Maldonado, Maricela; Luu, Rebeccah J; Ramos, Michael E P; Nam, Jin

    2016-09-01

    Robust control of human induced pluripotent stem cell (hIPSC) differentiation is essential to realize its patient-tailored therapeutic potential. Here, we demonstrate a novel application of Y-27632, a small molecule Rho-associated protein kinase (ROCK) inhibitor, to significantly influence the differentiation of hIPSCs in a lineage-specific manner. The application of Y-27632 to hIPSCs resulted in a decrease in actin bundling and disruption of colony formation in a concentration and time-dependent manner. Such changes in cell and colony morphology were associated with decreased expression of E-cadherin, a cell-cell junctional protein, proportional to the increased exposure to Y-27632. Interestingly, gene and protein expression of pluripotency markers such as NANOG and OCT4 were not downregulated by an exposure to Y-27632 up to 36h. Simultaneously, epithelial-to-mesenchymal (EMT) transition markers were upregulated with an exposure to Y-27632. These EMT-like changes in the cells with longer exposure to Y-27632 resulted in a significant increase in the subsequent differentiation efficiency towards mesendodermal lineage. In contrast, an inhibitory effect was observed when cells were subjected to ectodermal differentiation after prolonged exposure to Y-27632. Collectively, these results present a novel method for priming hIPSCs to modulate their differentiation potential with a simple application of Y-27632. Copyright © 2016 Helmholtz Zentrum München. Published by Elsevier B.V. All rights reserved.

  2. ROCK inhibitor primes human induced pluripotent stem cells to selectively differentiate towards mesendodermal lineage via epithelial-mesenchymal transition-like modulation

    Directory of Open Access Journals (Sweden)

    Maricela Maldonado

    2016-09-01

    Full Text Available Robust control of human induced pluripotent stem cell (hIPSC differentiation is essential to realize its patient-tailored therapeutic potential. Here, we demonstrate a novel application of Y-27632, a small molecule Rho-associated protein kinase (ROCK inhibitor, to significantly influence the differentiation of hIPSCs in a lineage-specific manner. The application of Y-27632 to hIPSCs resulted in a decrease in actin bundling and disruption of colony formation in a concentration and time-dependent manner. Such changes in cell and colony morphology were associated with decreased expression of E-cadherin, a cell-cell junctional protein, proportional to the increased exposure to Y-27632. Interestingly, gene and protein expression of pluripotency markers such as NANOG and OCT4 were not downregulated by an exposure to Y-27632 up to 36 h. Simultaneously, epithelial-to-mesenchymal (EMT transition markers were upregulated with an exposure to Y-27632. These EMT-like changes in the cells with longer exposure to Y-27632 resulted in a significant increase in the subsequent differentiation efficiency towards mesendodermal lineage. In contrast, an inhibitory effect was observed when cells were subjected to ectodermal differentiation after prolonged exposure to Y-27632. Collectively, these results present a novel method for priming hIPSCs to modulate their differentiation potential with a simple application of Y-27632.

  3. Aberrant Hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish.

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    In Hye Jung

    Full Text Available Hedgehog (Hh signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR, in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1, Smoothened (Smo, and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs, especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1 only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4. Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of

  4. Attenuation of radiation-induced DNA damage due to paracrine interactions between normal human epithelial and stromal cells

    International Nuclear Information System (INIS)

    Saenko, V.A.; Nakazawa, Yu.; Rogounovitch, T.I.; Suzuki, K.; Mitsutake, N.; Matsuse, M.; Yamashita, S.

    2007-01-01

    Complete text of publication follows. Objective: Developmentally, every tissue accommodates different types of cells, such as epitheliocytes and stromal cells in parenchymal organs. To better understand the complexity of radiation response, it is necessary to evaluate possible cross-talk between different tissue components. This work was set out to investigate reciprocal influence of normal human epithelial cells and fibroblasts on the extent of radiation-induced DNA damage. Methods: Model cultures of primary human thyrocytes (PT), normal diploid fibroblasts (BJ), PT/BJ cell co-culture and conditioned medium transfer were used to examine DNA damage in terms of γ-H2AX foci number per cell or by Comet assay after exposure to different doses of γ-rays. Results: In co-cultures, the kinetics of γ-H2AX foci number change was dose-dependent and similar to that in individual PT and BJ cultures. The number of γ-H2AX foci in co-cultures was significantly lower (∼25%) in both types of cells comparing to individual cultures. Reciprocal conditioned medium transfer to individual counterpart cells prior to irradiation resulted in approximately 35% reduction in the number γ-H2AX foci at 1 Gy and lower doses in both PT and BJ demonstrating the role of paracrine soluble factors. Comet assay corroborated the results of γ-H2AX foci counting in conditioned medium transfer experiments. In contrast to medium conditioned on PT cells, conditioned medium collected from several human thyroid cancer cell lines failed to establish DNA-protected state in BJ fibroblasts. In its turn, medium conditioned on BJ cells did not change the extent of radiation-induced DNA damage in cancer cell lines tested. Conclusion: The results imply the existence of a network of soluble factor-mediated paracrine interactions between normal epithelial and stromal cells that could be a part of natural mechanism by which cells protect DNA from genotoxic stress.

  5. Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells.

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    Wen, Juan; Zhao, Yuan; Li, Jinghe; Weng, Chunyan; Cai, Jingjing; Yang, Kan; Yuan, Hong; Imperato-McGinley, Julianne; Zhu, Yuan-Shan

    2013-07-01

    Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer. Copyright © 2013 Wiley Periodicals, Inc.

  6. Interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic PCa cells.

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    Delk, Nikki A; Farach-Carson, Mary C

    2012-04-01

    Autophagy reallocates nutrients and clears normal cells of damaged proteins and organelles. In the context of metastatic disease, invading cancer cells hijack autophagic processes to survive and adapt in the host microenvironment. We sought to understand how autophagy is regulated in the metastatic niche for prostate cancer (PCa) cells where bone marrow stromal cell (BMSC) paracrine signaling induces PCa neuroendocrine differentiation (NED). In PCa, this transdifferentiation of metastatic PCa cells to neuronal-like cells correlates with advanced disease. Because autophagy provides a survival advantage for cancer cells and promotes cell differentiation, we hypothesized that autophagy mediates PCa NED in the bone. Thus, we determined the ability of paracrine factors in conditioned media (CM) from two separate BMSC subtypes, HS5 and HS27a, to induce autophagy in C4-2 and C4-2B bone metastatic PCa cells by characterizing the autophagy marker, LC3. Unlike HS27a CM, HS5 CM induced LC3 accumulation in PCa cells, suggesting autophagy was induced and indicating that HS5 and HS27a secrete a different milieu of paracrine factors that influence PCa autophagy. We identified interleukin-6 (IL-6), a cytokine more highly expressed in HS5 cells than in HS27a cells, as a paracrine factor that regulates PCa autophagy. Pharmacological inhibition of STAT3 activity did not attenuate LC3 accumulation, implying that IL-6 regulates NED and autophagy through different pathways. Finally, chloroquine inhibition of autophagic flux blocked PCa NED; hence autophagic flux maintains NED. Our studies imply that autophagy is cytoprotective for PCa cells in the bone, thus targeting autophagy is a potential therapeutic strategy.

  7. Hyperplasia of epithelium adjacent to transitional cell carcinoma can be induced by growth factors through paracrine pathways

    NARCIS (Netherlands)

    W.I. de Boer (Pim); J.M.J. Rebel (Annemarie); C.D.E.M. Thijssen (C. D E M); M. Vermey; Th.H. van der Kwast (Theo); A.J.M. van den Eijnden-van Raaij (Janny)

    1994-01-01

    textabstractHyperplasia of transitional cell epithelium adjacent to human transitional cell carcinomas (TCC) is a common finding in pathology. This hyperplasia may be a precancerous aberration. Alternatively, it has been suggested that the hyperplasia is due to paracrine action of tumour-derived

  8. Liver heterotopia in the head of a patient with osteosarcoma of the maxilla. A paracrine tumor-induced hepatogenesis?

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    Corsi, Alessandro; Riminucci, Mara

    2017-02-01

    Heterotopia of liver tissue is uncommon. It has been reported at various sites, more frequently near the orthotopic liver, including gallbladder, hepatic ligaments, omentum, and retroperitoneum, rarely within the diaphragm and the thoracic cavity, and never within the head. We report here a 22-year-old patient surgically treated for a maxillary osteosarcoma in which microscopic liver tissue islands were incidentally detected in the respiratory mucosa of the surgical margin. The islands comprised well-differentiated HepPar-1-positive hepatocytes and were surrounded by cytokeratin-7- and cytokeratin-19-positive bile duct-like structures. This case, which is unique in the medical literature, may suggest an inductive paracrine effect of the osteosarcoma cells by secretion of factors promoting hepatocyte specification of primitive endodermal progenitors and subsequent liver morphogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways.

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    Yu, Li; Liu, Qi; Canning, Brendan J

    2018-03-05

    Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways. By direct measures of histamine, cysteinyl-leukotriene and thromboxane release and with studies of allergen-evoked contractions of airway smooth muscle, we describe a complex interplay amongst these autacoids. Notably, we observed an autocrine effect of the cysteinyl-leukotrienes acting through cysLT 1 receptors on mast cell leukotriene release. We confirmed the results of previous studies demonstrating a marked enhancement of mast cell mediator release following cyclooxygenase inhibition, but we have extended these results by showing that COX-2 derived eicosanoids inhibit cysteinyl-leukotriene release and yet are without effect on histamine release. Given the prominent role of COX-1 inhibition in aspirin-sensitive asthma, these data implicate preformed mediators stored in granules as the initial drivers of these adverse reactions. Finally, we describe the paracrine signaling cascade leading to thromboxane synthesis in the guinea pig airways following allergen challenge, which occurs indirectly, secondary to cysLT 1 receptor activation on structural cells and/ or leukocytes within the airway wall, and a COX-2 dependent synthesis of the eicosanoid. The results highlight the importance of cell-cell and autocrine interactions in regulating allergic responses in the airways. Copyright © 2017. Published by Elsevier B.V.

  10. Role of TRIM33 in Wnt signaling during mesendoderm differentiation.

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    Xia, Xiaojie; Zuo, Feifei; Luo, Maoguo; Sun, Ye; Bai, Jianbo; Xi, Qiaoran

    2017-10-01

    Tripartite motif 33 (TRIM33), a member of the transcription intermediate factor 1 (TIF1) family of transcription cofactors, mediates transforming growth factor-beta (TGF-β) signaling through its PHD-Bromo cassette in mesendoderm differentiation during early mouse embryonic development. However, the role of the TRIM33 RING domain in embryonic differentiation is less clear. Here, we report that TRIM33 mediates Wnt signaling by directly regulating the expression of a specific subset of Wnt target genes, and this action is independent of its RING domain. We show that TRIM33 interacts with β-catenin, a central player in Wnt signaling in mouse embryonic stem cells (mESCs). In contrast to previous reports in cancer cell lines, the RING domain does not appear to function as the E3 ligase for β-catenin, since neither knockout nor overexpression of TRIM33 had an effect on β-catenin protein levels in mESCs. Furthermore, we show that although TRIM33 seems to be dispensable for Wnt signaling through a reporter assay, loss of TRIM33 significantly impairs the expression of a subset of Wnt target genes, including Mixl1, in a Wnt signaling-dependent manner. Together, our results indicate that TRIM33 regulates Wnt signaling independent of the E3 ligase activity of its RING domain for β-catenin in mESCs.

  11. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation.

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    Bailey-Downs, Lora C; Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2013-07-01

    Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet-fed obese C57BL/6 mice. High-fat diet-induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet-induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals.

  12. Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells

    NARCIS (Netherlands)

    van Kooten, C.; Rensink, I.; Aarden, L.; van Oers, R.

    1992-01-01

    The proliferative response of purified malignant B cells from 26 patients with chronic lymphocytic leukemia (CLL) was investigated in vitro. In the majority of these patients, a proliferative response could be induced by the combination of tumor necrosis factor (TNF)-alpha and PMA. The concentration

  13. Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats.

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    Luciana A Reis

    Full Text Available This study evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs or their conditioned medium (CM on the repair and prevention of Acute Kidney Injury (AKI induced by gentamicin (G. Animals received daily injections of G up to 20 days. On the 10(th day, injections of BMSCs, CM, CM+trypsin, CM+RNase or exosome-like microvesicles extracted from the CM were administered. In the prevention groups, the animals received the BMSCs 24 h before or on the 5(th day of G treatment. Creatinine (Cr, urea (U, FENa and cytokines were quantified. The kidneys were evaluated using hematoxylin/eosin staining and immunohystochemistry. The levels of Cr, U and FENa increased during all the periods of G treatment. The BMSC transplantation, its CM or exosome injections inhibited the increase in Cr, U, FENa, necrosis, apoptosis and also increased cell proliferation. The pro-inflammatory cytokines decreased while the anti-inflammatory cytokines increased compared to G. When the CM or its exosomes were incubated with RNase (but not trypsin, these effects were blunted. The Y chromosome was not observed in the 24-h prevention group, but it persisted in the kidney for all of the periods analyzed, suggesting that the injury is necessary for the docking and maintenance of BMSCs in the kidney. In conclusion, the BMSCs and CM minimized the G-induced renal damage through paracrine effects, most likely through the RNA carried by the exosome-like microvesicles. The use of the CM from BMSCs can be a potential therapeutic tool for this type of nephrotoxicity, allowing for the avoidance of cell transplantations.

  14. Cysteamine induces cholecystokinin release from the duodenum. Evidence for somatostatin as an inhibitory paracrine regulator of cholecystokinin secretion in the rat

    International Nuclear Information System (INIS)

    Abucham, J.; Reichlin, S.

    1990-01-01

    To determine whether cholecystokinin secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced in vivo with cysteamine (250 mg/kg body wt, IV) or anti-somatostatin antiserum in anaesthetized rats and in vitro with cysteamine (30 micrograms/mL) in a rat duodenum-incubation system. Cholecystokinin secretion was assessed in vivo by measuring amylase in duodenal perfusates collected at 10-minute intervals for 1 hour and in vitro by a carboxy-terminal radioimmunoassay. Cysteamine induced a marked decrease in duodenal immunoreactive somatostatin both in vivo (50%) and in vitro (60%). The rate of amylase secretion increased from 9.7 +/- 2.1 U (mean +/- SE) to 28.0 +/- 4.8 U at 20 minutes (P less than 0.001). The cholecystokinin-receptor antagonist CR-1392 abolished amylase response for 30 minutes, whereas the more potent antagonists Asperlicin (18.0 mg/kg body wt, IV) and L-364,718 (0.25 mg/kg body wt, IV) caused prolonged blockade. The rate of amylase secretion in gastrectomized animals increased from 7.2 +/- 2.0 U to 15.0 +/- 2.2 U 20 minutes after cysteamine administration (P less than 0.01), indicating that the effect was not due to the presence of gastrin. In vitro, cysteamine caused a nearly fourfold increase in cholecystokinin secretion compared with controls (63.1 +/- 4.9 vs. 15.2 +/- 3.7, respectively; P less than 0.001). In vivo immunoneutralization of circulating somatostatin with a high-affinity and high-capacity antiserum produced no significant change in the rate of amylase secretion. These results suggest that cholecystokinin secretion is tonically inhibited by somatostatin and that this effect is mediated by locally secreted (paracrine) but not by circulating somatostatin

  15. Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

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    Xiaoyan Jiao

    2017-12-01

    Full Text Available Background/Aims: Cisplatin-induced acute kidney injury (AKI involves damage to tubular cells via excess reactive oxygen species (ROS generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC-derived conditioned medium (CM against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data

  16. Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury.

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    Jiao, Xiaoyan; Cai, Jieru; Yu, Xiaofang; Ding, Xiaoqiang

    2017-01-01

    Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data showed that the tubular β-catenin level was lower in

  17. Myostatin acts as an autocrine/paracrine negative regulator in myoblast differentiation from human induced pluripotent stem cells

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    Gao, Fei; Kishida, Tsunao; Ejima, Akika [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan); Gojo, Satoshi [Department of Cardiac Support, Kyoto Prefectural University of Medicine, Kyoto (Japan); Mazda, Osam, E-mail: mazda@koto.kpu-m.ac.jp [Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto (Japan)

    2013-02-08

    Highlights: ► iPS-derived cells express myostatin and its receptor upon myoblast differentiation. ► Myostatin inhibits myoblast differentiation by inhibiting MyoD and Myo5a induction. ► Silencing of myostatin promotes differentiation of human iPS cells into myoblasts. -- Abstract: Myostatin, also known as growth differentiation factor (GDF-8), regulates proliferation of muscle satellite cells, and suppresses differentiation of myoblasts into myotubes via down-regulation of key myogenic differentiation factors including MyoD. Recent advances in stem cell biology have enabled generation of myoblasts from pluripotent stem cells, but it remains to be clarified whether myostatin is also involved in regulation of artificial differentiation of myoblasts from pluripotent stem cells. Here we show that the human induced pluripotent stem (iPS) cell-derived cells that were induced to differentiate into myoblasts expressed myostatin and its receptor during the differentiation. An addition of recombinant human myostatin (rhMyostatin) suppressed induction of MyoD and Myo5a, resulting in significant suppression of myoblast differentiation. The rhMyostatin treatment also inhibited proliferation of the cells at a later phase of differentiation. RNAi-mediated silencing of myostatin promoted differentiation of human iPS-derived embryoid body (EB) cells into myoblasts. These results strongly suggest that myostatin plays an important role in regulation of myoblast differentiation from iPS cells of human origin. The present findings also have significant implications for potential regenerative medicine for muscular diseases.

  18. Myostatin acts as an autocrine/paracrine negative regulator in myoblast differentiation from human induced pluripotent stem cells

    International Nuclear Information System (INIS)

    Gao, Fei; Kishida, Tsunao; Ejima, Akika; Gojo, Satoshi; Mazda, Osam

    2013-01-01

    Highlights: ► iPS-derived cells express myostatin and its receptor upon myoblast differentiation. ► Myostatin inhibits myoblast differentiation by inhibiting MyoD and Myo5a induction. ► Silencing of myostatin promotes differentiation of human iPS cells into myoblasts. -- Abstract: Myostatin, also known as growth differentiation factor (GDF-8), regulates proliferation of muscle satellite cells, and suppresses differentiation of myoblasts into myotubes via down-regulation of key myogenic differentiation factors including MyoD. Recent advances in stem cell biology have enabled generation of myoblasts from pluripotent stem cells, but it remains to be clarified whether myostatin is also involved in regulation of artificial differentiation of myoblasts from pluripotent stem cells. Here we show that the human induced pluripotent stem (iPS) cell-derived cells that were induced to differentiate into myoblasts expressed myostatin and its receptor during the differentiation. An addition of recombinant human myostatin (rhMyostatin) suppressed induction of MyoD and Myo5a, resulting in significant suppression of myoblast differentiation. The rhMyostatin treatment also inhibited proliferation of the cells at a later phase of differentiation. RNAi-mediated silencing of myostatin promoted differentiation of human iPS-derived embryoid body (EB) cells into myoblasts. These results strongly suggest that myostatin plays an important role in regulation of myoblast differentiation from iPS cells of human origin. The present findings also have significant implications for potential regenerative medicine for muscular diseases

  19. Myostatin acts as an autocrine/paracrine negative regulator in myoblast differentiation from human induced pluripotent stem cells.

    Science.gov (United States)

    Gao, Fei; Kishida, Tsunao; Ejima, Akika; Gojo, Satoshi; Mazda, Osam

    2013-02-08

    Myostatin, also known as growth differentiation factor (GDF-8), regulates proliferation of muscle satellite cells, and suppresses differentiation of myoblasts into myotubes via down-regulation of key myogenic differentiation factors including MyoD. Recent advances in stem cell biology have enabled generation of myoblasts from pluripotent stem cells, but it remains to be clarified whether myostatin is also involved in regulation of artificial differentiation of myoblasts from pluripotent stem cells. Here we show that the human induced pluripotent stem (iPS) cell-derived cells that were induced to differentiate into myoblasts expressed myostatin and its receptor during the differentiation. An addition of recombinant human myostatin (rhMyostatin) suppressed induction of MyoD and Myo5a, resulting in significant suppression of myoblast differentiation. The rhMyostatin treatment also inhibited proliferation of the cells at a later phase of differentiation. RNAi-mediated silencing of myostatin promoted differentiation of human iPS-derived embryoid body (EB) cells into myoblasts. These results strongly suggest that myostatin plays an important role in regulation of myoblast differentiation from iPS cells of human origin. The present findings also have significant implications for potential regenerative medicine for muscular diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Nodal-dependent mesendoderm specification requires the combinatorial activities of FoxH1 and Eomesodermin.

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    Christopher E Slagle

    2011-05-01

    Full Text Available Vertebrate mesendoderm specification requires the Nodal signaling pathway and its transcriptional effector FoxH1. However, loss of FoxH1 in several species does not reliably cause the full range of loss-of-Nodal phenotypes, indicating that Nodal signals through additional transcription factors during early development. We investigated the FoxH1-dependent and -independent roles of Nodal signaling during mesendoderm patterning using a novel recessive zebrafish FoxH1 mutation called midway, which produces a C-terminally truncated FoxH1 protein lacking the Smad-interaction domain but retaining DNA-binding capability. Using a combination of gel shift assays, Nodal overexpression experiments, and genetic epistasis analyses, we demonstrate that midway more accurately represents a complete loss of FoxH1-dependent Nodal signaling than the existing zebrafish FoxH1 mutant schmalspur. Maternal-zygotic midway mutants lack notochords, in agreement with FoxH1 loss in other organisms, but retain near wild-type expression of markers of endoderm and various nonaxial mesoderm fates, including paraxial and intermediate mesoderm and blood precursors. We found that the activity of the T-box transcription factor Eomesodermin accounts for specification of these tissues in midway embryos. Inhibition of Eomesodermin in midway mutants severely reduces the specification of these tissues and effectively phenocopies the defects seen upon complete loss of Nodal signaling. Our results indicate that the specific combinations of transcription factors available for signal transduction play critical and separable roles in determining Nodal pathway output during mesendoderm patterning. Our findings also offer novel insights into the co-evolution of the Nodal signaling pathway, the notochord specification program, and the chordate branch of the deuterostome family of animals.

  1. Paracrine signaling in a bacterium.

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    López, Daniel; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

    2009-07-15

    Cellular differentiation is triggered by extracellular signals that cause target cells to adopt a particular fate. Differentiation in bacteria typically involves autocrine signaling in which all cells in the population produce and respond to the same signal. Here we present evidence for paracrine signaling in bacterial populations-some cells produce a signal to which only certain target cells respond. Biofilm formation in Bacillus involves two centrally important signaling molecules, ComX and surfactin. ComX triggers the production of surfactin. In turn, surfactin causes a subpopulation of cells to produce an extracellular matrix. Cells that produced surfactin were themselves unable to respond to it. Likewise, once surfactin-responsive cells commenced matrix production, they no longer responded to ComX and could not become surfactin producers. Insensitivity to ComX was the consequence of the extracellular matrix as mutant cells unable to make matrix responded to both ComX and surfactin. Our results demonstrate that extracellular signaling was unidirectional, with one subpopulation producing a signal and a different subpopulation responding to it. Paracrine signaling in a bacterial population ensures the maintenance, over generations, of particular cell types even in the presence of molecules that would otherwise cause those cells to differentiate into other cell types.

  2. IL1-and TGF beta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'Bystander senescence'

    Czech Academy of Sciences Publication Activity Database

    Hubáčková, Soňa; Krejčíková, Kateřina; Bartek, Jiří; Hodný, Zdeněk

    2012-01-01

    Roč. 4, č. 12 (2012), 932-951 ISSN 1945-4589 R&D Projects: GA ČR GA204/08/1418; GA ČR GAP301/10/1525 Institutional support: RVO:68378050 Keywords : senescence-associated secretome * DNA damage response * cytokines * JAK/STAT3 * TGF beta * NF kappa B * IL6 * IL beta * Nox4 * autocrine and paracrine signaling * tumor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.696, year: 2012

  3. Bone Marrow-Derived Mesenchymal Stem Cells Repaired but Did Not Prevent Gentamicin-Induced Acute Kidney Injury through Paracrine Effects in Rats

    OpenAIRE

    Reis, Luciana A.; Borges, Fernanda T.; Simões, Manuel J.; Borges, Andrea A.; Sinigaglia-Coimbra, Rita; Schor, Nestor

    2012-01-01

    This study evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs) or their conditioned medium (CM) on the repair and prevention of Acute Kidney Injury (AKI) induced by gentamicin (G). Animals received daily injections of G up to 20 days. On the 10(th) day, injections of BMSCs, CM, CM+trypsin, CM+RNase or exosome-like microvesicles extracted from the CM were administered. In the prevention groups, the animals received the BMSCs 24 h before or on the 5(th) day of G treatmen...

  4. Neural stem cells induce bone-marrow-derived mesenchymal stem cells to generate neural stem-like cells via juxtacrine and paracrine interactions

    International Nuclear Information System (INIS)

    Alexanian, Arshak R.

    2005-01-01

    Several recent reports suggest that there is far more plasticity that previously believed in the developmental potential of bone-marrow-derived cells (BMCs) that can be induced by extracellular developmental signals of other lineages whose nature is still largely unknown. In this study, we demonstrate that bone-marrow-derived mesenchymal stem cells (MSCs) co-cultured with mouse proliferating or fixed (by paraformaldehyde or methanol) neural stem cells (NSCs) generate neural stem cell-like cells with a higher expression of Sox-2 and nestin when grown in NS-A medium supplemented with N2, NSC conditioned medium (NSCcm) and bFGF. These neurally induced MSCs eventually differentiate into β-III-tubulin and GFAP expressing cells with neuronal and glial morphology when grown an additional week in Neurobasal/B27 without bFGF. We conclude that juxtacrine interaction between NSCs and MSCs combined with soluble factors released from NSCs are important for generation of neural-like cells from bone-marrow-derived adherent MSCs

  5. Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Massimiliano Cadamuro

    2017-01-01

    Full Text Available Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment.

  6. miR-373 is regulated by TGFβ signaling and promotes mesendoderm differentiation in human Embryonic Stem Cells

    Science.gov (United States)

    Rosa, Alessandro; Papaioannou, Marilena D.; Krzyspiak, Joanna E.; Brivanlou, Ali H.

    2014-01-01

    MicroRNAs (miRNAs) belonging to the evolutionary conserved miR-302 family play important functions in Embryonic Stem Cells (ESCs). The expression of some members, such as the human miR-302 and mouse miR-290 clusters, is regulated by ESC core transcription factors. However, whether miRNAs act downstream of signaling pathways involved in human ESC pluripotency remains unknown. The maintenance of pluripotency in hESCs is under the control of the TGFβ pathway. Here, we show that inhibition of the Activin/Nodal branch of this pathway affects the expression of a subset of miRNAs in hESCs. Among them, we found miR-373, a member of the miR-302 family. Proper levels of miR-373 are crucial for the maintenance of hESC pluripotency, since its overexpression leads to differentiation towards the mesendodermal lineage. Among miR-373 predicted targets, involved in TGFβ signaling, we validated the Nodal inhibitor Lefty. Our work suggests a crucial role for the interplay between miRNAs and signaling pathways in ESCs. PMID:24709321

  7. Zinc as a paracrine effector in pancreatic islet cell death.

    Science.gov (United States)

    Kim, B J; Kim, Y H; Kim, S; Kim, J W; Koh, J Y; Oh, S H; Lee, M K; Kim, K W; Lee, M S

    2000-03-01

    Because of a huge amount of Zn2+ in secretory granules of pancreatic islet beta-cells, Zn2+ released in certain conditions might affect the function or survival of islet cells. We studied potential paracrine effects of endogenous Zn2+ on beta-cell death. Zn2+ induced insulinoma/islet cell death in a dose-dependent manner. Chelation of released endogenous Zn2+ by CaEDTA significantly decreased streptozotocin (STZ)-induced islet cell death in an in vitro culture system simulating in vivo circumstances but not in the conventional culture system. Zn2+ chelation in vivo by continuous CaEDTA infusion significantly decreased the incidence of diabetes after STZ administration. N-(6-methoxy-quinolyl)-para-toluene-sulfonamide staining revealed that Zn2+ was densely deposited in degenerating islet cells 24 h after STZ treatment, which was decreased by CaEDTA infusion. We show here that Zn2+ is not a passive element for insulin storage but an active participant in islet cell death in certain conditions, which in time might contribute to the development of diabetes in aged people.

  8. The endocrine and paracrine control of menstruation.

    Science.gov (United States)

    Henriet, Patrick; Gaide Chevronnay, Héloïse P; Marbaix, Etienne

    2012-07-25

    During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells

    International Nuclear Information System (INIS)

    Nakanishi, Chiaki; Yamagishi, Masakazu; Yamahara, Kenichi; Hagino, Ikuo; Mori, Hidezo; Sawa, Yoshiki; Yagihara, Toshikatsu; Kitamura, Soichiro; Nagaya, Noritoshi

    2008-01-01

    Mesenchymal stem cells (MSC) transplantation has been proved to be promising strategy to treat the failing heart. The effect of MSC transplantation is thought to be mediated mainly in a paracrine manner. Recent reports have suggested that cardiac progenitor cells (CPC) reside in the heart. In this study, we investigated whether MSC had paracrine effects on CPC in vitro. CPC were isolated from the neonatal rat heart using an explant method. MSC were isolated from the adult rat bone marrow. MSC-derived conditioned medium promoted proliferation of CPC and inhibited apoptosis of CPC induced by hypoxia and serum starvation. Chemotaxis chamber assay demonstrated that MSC-derived conditioned medium enhanced migration of CPC. Furthermore, MSC-derived conditioned medium upregulated expression of cardiomyocyte-related genes in CPC such as β-myosin heavy chain (β-MHC) and atrial natriuretic peptide (ANP). In conclusion, MSC-derived conditioned medium had protective effects on CPC and enhanced their migration and differentiation

  10. Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

    Science.gov (United States)

    Liu, Yangfan P.; Tsai, I-Chun; Morleo, Manuela; Oh, Edwin C.; Leitch, Carmen C.; Massa, Filomena; Lee, Byung-Hoon; Parker, David S.; Finley, Daniel; Zaghloul, Norann A.; Franco, Brunella; Katsanis, Nicholas

    2014-01-01

    Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients. PMID:24691443

  11. Microbioreactor arrays for full factorial screening of exogenous and paracrine factors in human embryonic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Drew M Titmarsh

    Full Text Available Timed exposure of pluripotent stem cell cultures to exogenous molecules is widely used to drive differentiation towards desired cell lineages. However, screening differentiation conditions in conventional static cultures can become impractical in large parameter spaces, and is intrinsically limited by poor spatiotemporal control of the microenvironment that also makes it impossible to determine whether exogenous factors act directly or through paracrine-dependent mechanisms. We detail here the development of a continuous flow microbioreactor array platform that combines full-factorial multiplexing of input factors with progressive accumulation of paracrine factors through serially-connected culture chambers, and further, the use of this system to explore the combinatorial parameter space of both exogenous and paracrine factors involved in human embryonic stem cell (hESC differentiation to a MIXL1-GFP(+ primitive streak-like population. We show that well known inducers of primitive streak (BMP, Activin and Wnt signals do not simply act directly on hESC to induce MIXL1 expression, but that this requires accumulation of surplus, endogenous factors; and, that conditioned medium or FGF-2 supplementation is able to offset this. Our approach further reveals the presence of a paracrine, negative feedback loop to the MIXL1-GFP(+ population, which can be overcome with GSK-3β inhibitors (BIO or CHIR99021, implicating secreted Wnt inhibitory signals such as DKKs and sFRPs as candidate effectors. Importantly, modulating paracrine effects identified in microbioreactor arrays by supplementing FGF-2 and CHIR in conventional static culture vessels resulted in improved differentiation outcomes. We therefore demonstrate that this microbioreactor array platform uniquely enables the identification and decoding of complex soluble factor signalling hierarchies, and that this not only challenges prevailing strategies for extrinsic control of hESC differentiation, but

  12. Photodynamic therapy potentiates the paracrine endothelial stimulation by colorectal cancer

    Science.gov (United States)

    Lamberti, María Julia; Florencia Pansa, María; Emanuel Vera, Renzo; Belén Rumie Vittar, Natalia; Rivarola, Viviana Alicia

    2014-11-01

    Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death worldwide. Recurrence is a major problem and is often the ultimate cause of death. In this context, the tumor microenvironment influences tumor progression and is considered as a new essential feature that clearly impacts on treatment outcome, and must therefore be taken into consideration. Photodynamic therapy (PDT), oxygen, light and drug-dependent, is a novel treatment modality when CRC patients are inoperable. Tumor vasculature and parenchyma cells are both potential targets of PDT damage modulating tumor-stroma interactions. In biological activity assessment in photodynamic research, three-dimensional (3D) cultures are essential to integrate biomechanical, biochemical, and biophysical properties that better predict the outcome of oxygen- and drug-dependent medical therapies. Therefore, the objective of this study was to investigate the antitumor effect of methyl 5-aminolevulinic acid-PDT using a light emitting diode for the treatment of CRC cells in a scenario that mimics targeted tissue complexity, providing a potential bridge for the gap between 2D cultures and animal models. Since photodynamic intervention of the tumor microenvironment can effectively modulate the tumor-stroma interaction, it was proposed to characterize the endothelial response to CRC paracrine communication, if one of these two populations is photosensitized. In conclusion, we demonstrated that the dialogue between endothelial and tumor populations when subjected to lethal PDT conditions induces an increase in angiogenic phenotype, and we think that it should be carefully considered for the development of PDT therapeutic protocols.

  13. Oxygen Tension Regulates Human Mesenchymal Stem Cell Paracrine Functions.

    Science.gov (United States)

    Paquet, Joseph; Deschepper, Mickael; Moya, Adrien; Logeart-Avramoglou, Delphine; Boisson-Vidal, Catherine; Petite, Hervé

    2015-07-01

    : Mesenchymal stem cells (MSCs) have captured the attention and research endeavors of the scientific world because of their differentiation potential. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly due to the multitude of bioactive mediators secreted by these cells. Because the paracrine potential of MSCs is closely related to their microenvironment, the present study investigated and characterized select aspects of the human MSC (hMSC) secretome and assessed its in vitro and in vivo bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. In contrast to supernatant conditioned media (CM) obtained from hMSCs cultured at either 5% or 21% of O2, CM from hMSCs cultured under near anoxia exhibited significantly (p mesenchymal stem cell (hMSC) secretome and assessed its in vitro and in vivo biological bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. The present study provided the first evidence of a shift of the hMSC cytokine signature induced by oxygen tension, particularly near anoxia (0.1% O2). Conditioned media obtained from hMSCs cultured under near anoxia exhibited significantly enhanced chemotactic and proangiogenic properties and a significant decrease in the inflammatory mediator content. These findings provide new evidence that elucidates aspects of great importance for the use of MSCs in regenerative medicine, could contribute to improving the efficacy of such therapies, and most importantly highlighted the interest in using conditioned media in therapeutic modalities. ©AlphaMed Press.

  14. Plant natriuretic peptides are apoplastic and paracrine stress response molecules

    KAUST Repository

    Wang, Yuhua

    2011-04-07

    Higher plants contain biologically active proteins that are recognized by antibodies against human atrial natriuretic peptide (ANP). We identified and isolated two Arabidopsis thaliana immunoreactive plant natriuretic peptide (PNP)-encoding genes, AtPNP-A and AtPNP-B, which are distantly related members of the expansin superfamily and have a role in the regulation of homeostasis in abiotic and biotic stresses, and have shown that AtPNP-A modulates the effects of ABA on stomata. Arabidopsis PNP (PNP-A) is mainly expressed in leaf mesophyll cells, and in protoplast assays we demonstrate that it is secreted using AtPNP-A:green fluorescent protein (GFP) reporter constructs and flow cytometry. Transient reporter assays provide evidence that AtPNP-A expression is enhanced by heat, osmotica and salt, and that AtPNP-A itself can enhance its own expression, thereby generating a response signature diagnostic for paracrine action and potentially also autocrine effects. Expression of native AtPNP-A is enhanced by osmotica and transiently by salt. Although AtPNP-A expression is induced by salt and osmotica, ABA does not significantly modulate AtPNP-A levels nor does recombinant AtPNP-A affect reporter expression of the ABA-responsive RD29A gene. Together, these results provide experimental evidence that AtPNP-A is stress responsive, secreted into the apoplastic space and can enhance its own expression. Furthermore, our findings support the idea that AtPNP-A, together with ABA, is an important component in complex plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions. © 2011 The Author.

  15. Paracrine action of mesenchymal stromal cells delivered by microspheres contributes to cutaneous wound healing and prevents scar formation in mice.

    Science.gov (United States)

    Huang, Sha; Wu, Yan; Gao, Dongyun; Fu, Xiaobing

    2015-07-01

    Accumulating evidence suggests that mesenchymal stromal cells (MSCs) participate in wound healing to favor tissue regeneration and inhibit fibrotic tissue formation. However, the evidence of MSCs to suppress cutaneous scar is extremely rare, and the mechanism remains unidentified. This study aimed to demonstrate whether MSCs-as the result of their paracrine actions on damaged tissues-would accelerate wound healing and prevent cutaneous fibrosis. For efficient delivery of MSCs to skin wounds, microspheres were used to maintain MSC potency. Whether MSCs can accelerate wound healing and alleviate cutaneous fibrosis through paracrine action was investigated with the use of a Transwell co-culture system in vitro and a murine model in vivo. MSCs cultured on gelatin microspheres fully retained their cell surface marker expression profile, proliferation, differentiation and paracrine potential. Co-cultures of MSCs and fibroblasts indicated that the benefits of MSCs on suppressing fibroblast proliferation and its fibrotic behavior induced by inflammatory cytokines probably were caused by paracrine actions. Importantly, microspheres successfully delivered MSCs into wound margins and significantly accelerated wound healing and concomitantly reduced the fibrotic activities of cells within the wounds and excessive accumulation of extracellular matrix as well as the transforming growth factor-β1/transforming growth factor-β3 ratio. This study provides insight into what we believe to be a previously undescribed, multifaceted role of MSC-released protein in reducing cutaneous fibrotic formation. Paracrine action of MSCs delivered by microspheres may thus qualify as a promising strategy to enhance tissue repair and to prevent excessive fibrosis during cutaneous wound healing. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  16. Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

    Directory of Open Access Journals (Sweden)

    Kenichiro Ishii

    2018-04-01

    Full Text Available Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers.

  17. Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4

    Directory of Open Access Journals (Sweden)

    Ravshan Burikhanov

    2014-01-01

    Full Text Available The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53−/− or Par-4−/− mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors.

  18. Paracrine effects of bone marrow-derived endothelial progenitor cells: cyclooxygenase-2/prostacyclin pathway in pulmonary arterial hypertension.

    Directory of Open Access Journals (Sweden)

    Dong-Mei Jiang

    Full Text Available BACKGROUND: Endothelial dysfunction is the pathophysiological characteristic of pulmonary arterial hypertension (PAH. Some paracrine factors secreted by bone marrow-derived endothelial progenitor cells (BMEPCs have the potential to strengthen endothelial integrity and function. This study investigated whether BMEPCs have the therapeutic potential to improve monocrotaline (MCT-induced PAH via producing vasoprotective substances in a paracrine fashion. METHODS AND RESULTS: Bone marrow-derived mononuclear cells were cultured for 7 days to yield BMEPCs. 24 hours or 3 weeks after exposure to BMEPCs in vitro or in vivo, the vascular reactivity, cyclooxygenase-2 (COX-2 expression, prostacyclin (PGI2 and cAMP release in isolated pulmonary arteries were examined respectively. Treatment with BMEPCs could improve the relaxation of pulmonary arteries in MCT-induced PAH and BMEPCs were grafted into the pulmonary bed. The COX-2/prostacyclin synthase (PGIS and its progenies PGI2/cAMP were found to be significantly increased in BMEPCs treated pulmonary arteries, and this action was reversed by a selective COX-2 inhibitor, NS398. Moreover, the same effect was also observed in conditioned medium obtained from BMEPCs culture. CONCLUSIONS: Implantation of BMEPCs effectively ameliorates MCT-induced PAH. Factors secreted in a paracrine fashion from BMEPCs promote vasoprotection by increasing the release of PGI2 and level of cAMP.

  19. Probing Embryonic Stem Cell Autocrine and Paracrine Signaling Using Microfluidics

    Science.gov (United States)

    Przybyla, Laralynne; Voldman, Joel

    2012-07-01

    Although stem cell fate is traditionally manipulated by exogenously altering the cells' extracellular signaling environment, the endogenous autocrine and paracrine signals produced by the cells also contribute to their two essential processes: self-renewal and differentiation. Autocrine and/or paracrine signals are fundamental to both embryonic stem cell self-renewal and early embryonic development, but the nature and contributions of these signals are often difficult to fully define using conventional methods. Microfluidic techniques have been used to explore the effects of cell-secreted signals by controlling cell organization or by providing precise control over the spatial and temporal cellular microenvironment. Here we review how such techniques have begun to be adapted for use with embryonic stem cells, and we illustrate how many remaining questions in embryonic stem cell biology could be addressed using microfluidic technologies.

  20. Biology of primate relaxin: A paracrine signal in early pregnancy?

    Directory of Open Access Journals (Sweden)

    Hayes Eric S

    2004-06-01

    Full Text Available Abstract Relaxin is a peptide hormone that exerts numerous effects in a variety of tissues across a broad range of species. Although first identified more than 75 years ago interest in relaxin biology has waxed and waned over the years consistent with peaks and troughs of new experimental data on its wide-ranging biological effects and advances in relaxin enabling technologies. Recent insights into species-dependent differences in relaxin biology during pregnancy have once again stimulated a relative surge of interest in the study of relaxin's reproductive biology. Identification and pharmacological characterization of orphaned relaxin receptors and exploration of its paracrine effects on pregnancy using genomic and proteomic technologies have succeeded in fueling current interest in relaxin research. Primates and non-primate vertebrates exhibit very disparate profiles of relaxin genomics, proteomics and functional biology. Non-human primates appear to exhibit a very close similarity to humans with respect to relaxin reproductive biology but the similarities and subtle differences are only just beginning to be understood. We, and others, have shown that relaxin produces significant changes to the non-human primate endometrium during the peri-implantation period that are consistent with relaxin's long perceived role as a paracrine modulator of pregnancy. The purpose of this review is to summarize the reproductive biology of relaxin in non-human primates with a specific emphasis on the paracrine role of ovarian and endometrial relaxin during embryo implantation and early pregnancy.

  1. Paracrine control of vascularization and neurogenesis by neurotrophins.

    Science.gov (United States)

    Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

    2003-10-01

    The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

  2. High cell density suppresses BMP4-induced differentiation of human pluripotent stem cells to produce macroscopic spatial patterning in a unidirectional perfusion culture chamber.

    Science.gov (United States)

    Tashiro, Shota; Le, Minh Nguyen Tuyet; Kusama, Yuta; Nakatani, Eri; Suga, Mika; Furue, Miho K; Satoh, Taku; Sugiura, Shinji; Kanamori, Toshiyuki; Ohnuma, Kiyoshi

    2018-04-19

    Spatial pattern formation is a critical step in embryogenesis. Bone morphogenetic protein 4 (BMP4) and its inhibitors are major factors for the formation of spatial patterns during embryogenesis. However, spatial patterning of the human embryo is unclear because of ethical issues and isotropic culture environments resulting from conventional culture dishes. Here, we utilized human pluripotent stem cells (hiPSCs) and a simple anisotropic (unidirectional perfusion) culture chamber, which creates unidirectional conditions, to measure the cell community effect. The influence of cell density on BMP4-induced differentiation was explored during static culture using a conventional culture dish. Immunostaining of the early differentiation marker SSEA-1 and the mesendoderm marker BRACHYURY revealed that high cell density suppressed differentiation, with small clusters of differentiated and undifferentiated cells formed. Addition of five-fold higher concentration of BMP4 showed similar results, suggesting that suppression was not caused by depletion of BMP4 but rather by high cell density. Quantitative RT-PCR array analysis showed that BMP4 induced multi-lineage differentiation, which was also suppressed under high-density conditions. We fabricated an elongated perfusion culture chamber, in which proteins were transported unidirectionally, and hiPSCs were cultured with BMP4. At low density, the expression was the same throughout the chamber. However, at high density, SSEA-1 and BRACHYURY were expressed only in upstream cells, suggesting that some autocrine/paracrine factors inhibited the action of BMP4 in downstream cells to form the spatial pattern. Human iPSCs cultured in a perfusion culture chamber might be useful for studying in vitro macroscopic pattern formation in human embryogenesis. Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  3. Bone marrow transplantation rescues intestinal mucosa after whole body radiation via paracrine mechanisms

    International Nuclear Information System (INIS)

    Chang, Ya Hui; Lin, Li-Mei; Lou, Chi-Wen; Chou, Chuan-Kai; Ch’ang, Hui-Ju

    2012-01-01

    Purpose: Our previous study reveals bone marrow transplantation (BMT) recruits host marrow-derived myelomonocytic cells to radiation-injured intestine, enhancing stromal proliferation, leading secondarily to epithelial regeneration. In this study, we propose BMT ameliorates intestinal damage via paracrine mechanisms. Materials and methods: Angiogenic cytokines within the intestinal mucosa of mice after whole body irradiation (WBI) with or without BMT were measured by cytokine array and ELISA. BM conditioned medium (BMCM) with or without treatment with neutralizing antibodies to angiogenic cytokines were continuously infused into mice for three days after radiation. Carrageenan was used to deplete myelomonocytic cells of mice. Results: BMT increased VEGF, bFGF and other angiogenic and chemotactic cytokines in the intestinal mucosa within 24 h after WBI. Infusion of BMCM ameliorated radiation-induced intestinal damage with improved stromal activity and prolonged survival of mice. Neutralization of bFGF, PDGF and other angiogenic cytokines within BMCM abolished the mitigating effect to the intestine. Pretreatment of carrageenan to recipient mice reversed some of the cytokine levels, including VEGF, bFGF and IGF within the intestinal mucosa after BMT. Conclusions: Our result suggests BMT recruits host myelomonocytic cells and enhances intestinal stroma proliferation after radiation by secreting cytokines enhancing angiogenesis and chemotaxis. Host myelomonocytic cells further uplift the paracrine effect to enhance intestinal mucosal recovery.

  4. Angiotensin peptides in the non-gravid uterus: Paracrine actions beyond circulation.

    Science.gov (United States)

    Casalechi, Maíra; Dela Cruz, Cynthia; Lima, Luiza C; Maciel, Luciana P; Pereira, Virgínia M; Reis, Fernando M

    2018-03-01

    The renin-angiotensin system (RAS) involves a complex network of precursors, peptides, enzymes and receptors comprising a systemic (endocrine) and a local (paracrine/autocrine) system. The local RAS plays important roles in tissue modulation and may operate independently of or in close interaction with the circulatory RAS, acting in a complementary fashion. Angiotensin (Ang) II, its receptor AT 1 and Ang-(1-7) expression in the endometrium vary with menstrual cycle, and stromal cell decidualization in vitro is accompanied by local synthesis of angiotensinogen and prorenin. Mas receptor is unlikely to undergo marked changes accompanying the cyclic ovarian steroid hormone fluctuations. Studies investigating the functional relevance of the RAS in the non-gravid uterus show a number of paracrine effects beyond circulation and suggest that RAS peptides may be involved in the pathophysiology of proliferative and fibrotic diseases. Endometrial cancer is associated with increased expression of Ang II, Ang-converting enzyme 1 and AT 1 in the tumoral tissue compared to neighboring non-neoplastic endometrium, and also with a gene polymorphism that enhances AT 1 signal. Ang II induces human endometrial cells to transdifferentiate into cells with myofibroblast phenotype and to synthetize extracellular matrix components that might contribute to endometrial fibrosis. Altogether, these findings point to a fully operating RAS within the uterus, but since many concepts rely on preliminary evidence further studies are needed to clarify the role of the local RAS in uterine physiology and pathophysiology. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. The role of H1 linker histone subtypes in preserving the fidelity of elaboration of mesendodermal and neuroectodermal lineages during embryonic development.

    Directory of Open Access Journals (Sweden)

    Giang D Nguyen

    Full Text Available H1 linker histone proteins are essential for the structural and functional integrity of chromatin and for the fidelity of additional epigenetic modifications. Deletion of H1c, H1d and H1e in mice leads to embryonic lethality by mid-gestation with a broad spectrum of developmental alterations. To elucidate the cellular and molecular mechanisms underlying H1 linker histone developmental functions, we analyzed embryonic stem cells (ESCs depleted of H1c, H1d and H1e subtypes (H1-KO ESCs by utilizing established ESC differentiation paradigms. Our study revealed that although H1-KO ESCs continued to express core pluripotency genes and the embryonic stem cell markers, alkaline phosphatase and SSEA1, they exhibited enhanced cell death during embryoid body formation and during specification of mesendoderm and neuroectoderm. In addition, we demonstrated deregulation in the developmental programs of cardiomyocyte, hepatic and pancreatic lineage elaboration. Moreover, ectopic neurogenesis and cardiomyogenesis occurred during endoderm-derived pancreatic but not hepatic differentiation. Furthermore, neural differentiation paradigms revealed selective impairments in the specification and maturation of glutamatergic and dopaminergic neurons with accelerated maturation of glial lineages. These impairments were associated with deregulation in the expression profiles of pro-neural genes in dorsal and ventral forebrain-derived neural stem cell species. Taken together, these experimental observations suggest that H1 linker histone proteins are critical for the specification, maturation and fidelity of organ-specific cellular lineages derived from the three cardinal germ layers.

  6. Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential

    Directory of Open Access Journals (Sweden)

    Tom J. Burdon

    2011-01-01

    Full Text Available During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.

  7. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

    Science.gov (United States)

    Zhou, Bin; Honor, Leah B.; He, Huamei; Ma, Qing; Oh, Jin-Hee; Butterfield, Catherine; Lin, Ruei-Zeng; Melero-Martin, Juan M.; Dolmatova, Elena; Duffy, Heather S.; von Gise, Alexander; Zhou, Pingzhu; Hu, Yong Wu; Wang, Gang; Zhang, Bing; Wang, Lianchun; Hall, Jennifer L.; Moses, Marsha A.; McGowan, Francis X.; Pu, William T.

    2011-01-01

    The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection. PMID:21505261

  8. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

    International Nuclear Information System (INIS)

    Brady, Robert T.; O'Brien, Fergal J.; Hoey, David A.

    2015-01-01

    Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

  9. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Brady, Robert T. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); O' Brien, Fergal J. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Hoey, David A., E-mail: david.hoey@ul.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); The Centre for Applied Biomedical Engineering Research, University of Limerick (Ireland); Materials & Surface Science Institute, University of Limerick (Ireland)

    2015-03-27

    Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

  10. Paracrine effect of carbon monoxide - astrocytes promote neuroprotection through purinergic signaling in mice.

    Science.gov (United States)

    Queiroga, Cláudia S F; Alves, Raquel M A; Conde, Sílvia V; Alves, Paula M; Vieira, Helena L A

    2016-08-15

    The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not with CO. The CO-pre-treated astrocytes reduced neuronal cell death, and the cellular mechanisms were investigated, focusing on purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture medium. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection through astrocytes. Likewise, knocking down expression of the neuronal P1 adenosine receptor A2A-R (encoded by Adora2a) reverted the neuroprotective effects of CO-exposed astrocytes. The neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolism into adenosine. Finally, the neuronal downstream event involves TrkB (also known as NTRK2) receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptors reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio of BDNF to pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism through purinergic signaling. © 2016. Published by The Company of Biologists Ltd.

  11. Paracrine and autocrine signals promoting full chondrogenic differentiation of a mesoblastic cell line.

    Science.gov (United States)

    Locker, Morgane; Kellermann, Odile; Boucquey, Marie; Khun, Huot; Huerre, Michel; Poliard, Anne

    2004-01-01

    The pluripotent mesoblastic C1 cell line was used under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to drive chondrogenesis. Sequential addition of two systemic hormones, dexamethasone and triiodothyronine, permits full chondrogenic differentiation. The cell intrinsic activation of the BMP signaling pathway and Sox9 expression occurring on mesoblastic condensation is insufficient for recruitment of the progenitors. Dexamethasone-dependent Sox9 upregulation is essential for chondrogenesis. Differentiation of lineage stem cells relies on cell autonomous regulations modulated by external signals. We used the pluripotent mesoblastic C1 cell line under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to induce differentiation of a precursor clone along the chondrogenic lineage. C1 cells, cultured as aggregates, were induced toward chondrogenesis by addition of 10(-7) M dexamethasone in serum-free medium. After 30 days, dexamethasone was replaced by 10 nM triiodothyronine to promote final hypertrophic conversion. Mature and hypertrophic phenotypes were characterized by immunocytochemistry using specific antibodies against types II and X collagens, respectively. Type II collagen, bone morphogenetic proteins (BMPs), BMP receptors, Smads, and Sox9 expression were monitored by reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot, and/or Western blot analysis. Once C1 cells have formed nodules, sequential addition of two systemic hormones is sufficient to promote full chondrogenic differentiation. In response to dexamethasone, nearly 100% of the C1 precursors engage in chondrogenesis and convert within 30 days into mature chondrocytes, which triggers a typical cartilage matrix. On day 25, a switch in type II procollagen mRNA splicing acted as a limiting step in the acquisition of the mature chondrocyte phenotype. On day 30, substitution of dexamethasone with

  12. Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells.

    Science.gov (United States)

    Gervois, P; Wolfs, E; Dillen, Y; Hilkens, P; Ratajczak, J; Driesen, R B; Vangansewinkel, T; Bronckaers, A; Brône, B; Struys, T; Lambrichts, I

    2017-06-01

    Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)-sensitive, Na + current. Moreover, conditioned medium (CM)-hDPSC-maturated SH-SY5Y cells developed distinct features including, Cd 2+ -sensitive currents, which suggests that CM-hDPSC-maturated SH-SY5Y acquired voltage-gated Ca 2+ channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular

  13. Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs.

    Science.gov (United States)

    Qazi, Taimoor H; Mooney, David J; Duda, Georg N; Geissler, Sven

    2017-09-01

    Mesenchymal stromal cells (MSCs) secrete paracrine factors that play crucial roles during tissue regeneration. Whether this paracrine function is influenced by the properties of biomaterials in general, and those used for cell delivery in particular, largely remains unexplored. Here, we investigated if three-dimensional culture in distinct microenvironments - nanoporous hydrogels (mean pore size ∼5 nm) and macroporous scaffolds (mean pore size ∼120 μm) - affects the secretion pattern of MSCs, and consequently leads to differential paracrine effects on target progenitor cells such as myoblasts. We report that compared to MSCs encapsulated in hydrogels, scaffold seeded MSCs show an enhanced secretion profile and exert beneficial paracrine effects on various myoblast functions including migration and proliferation. Additionally, we show that the heightened paracrine effects of scaffold seeded cells can in part be attributed to N-cadherin mediated cell-cell interactions during culture. In hydrogels, this physical interaction between cells is prevented by the encapsulating matrix. Functionally blocking N-cadherin negatively affected the secretion profile and paracrine effects of MSCs on myoblasts, with stronger effects observed for scaffold seeded compared to hydrogel encapsulated cells. Together, these findings demonstrate that the therapeutic potency of MSCs can be enhanced by biomaterials that promote cell-cell interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. MCP-1 expressed by osteoclasts stimulates osteoclastogenesis in an autocrine/paracrine manner

    International Nuclear Information System (INIS)

    Miyamoto, Kana; Ninomiya, Ken; Sonoda, Koh-Hei; Miyauchi, Yoshiteru; Hoshi, Hiroko; Iwasaki, Ryotaro; Miyamoto, Hiroya

    2009-01-01

    Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays a critical role in the recruitment and activation of leukocytes. Here, we describe that multinuclear osteoclast formation was significantly inhibited in cells derived from MCP-1-deficient mice. MCP-1 has been implicated in the regulation of osteoclast cell-cell fusion; however defects of multinuclear osteoclast formation in the cells from mice deficient in DC-STAMP, a seven transmembrane receptor essential for osteoclast cell-cell fusion, was not rescued by recombinant MCP-1. The lack of MCP-1 in osteoclasts resulted in a down-regulation of DC-STAMP, NFATc1, and cathepsin K, all of which were highly expressed in normal osteoclasts, suggesting that osteoclast differentiation was inhibited in MCP-1-deficient cells. MCP-1 alone did not induce osteoclastogenesis, however, the inhibition of osteoclastogenesis in MCP-1-deficient cells was restored by addition of recombinant MCP-1, indicating that osteoclastogenesis was regulated in an autocrine/paracrine manner by MCP-1 under the stimulation of RANKL in osteoclasts.

  15. Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling.

    Science.gov (United States)

    Arno, Anna I; Amini-Nik, Saeid; Blit, Patrick H; Al-Shehab, Mohammed; Belo, Cassandra; Herer, Elaine; Tien, Col Homer; Jeschke, Marc G

    2014-02-24

    The prevalence of nonhealing wounds is predicted to increase due to the growing aging population. Despite the use of novel skin substitutes and wound dressings, poorly vascularized wound niches impair wound repair. Mesenchymal stem cells (MSCs) have been reported to provide paracrine signals to promote wound healing, but the effect of human Wharton's jelly-derived MSCs (WJ-MSCs) has not yet been described in human normal skin. Human WJ-MSCs and normal skin fibroblasts were isolated from donated umbilical cords and normal adult human skin. Fibroblasts were treated with WJ-MSC-conditioned medium (WJ-MSC-CM) or nonconditioned medium. Expression of genes involved in re-epithelialization (transforming growth factor-β2), neovascularization (hypoxia-inducible factor-1α) and fibroproliferation (plasminogen activator inhibitor-1) was upregulated in WJ-MSC-CM-treated fibroblasts (P≤0.05). WJ-MSC-CM enhanced normal skin fibroblast proliferation (P≤0.001) and migration (P≤0.05), and promoted wound healing in an excisional full-thickness skin murine model. Under our experimental conditions, WJ-MSCs enhanced skin wound healing in an in vivo mouse model.

  16. Endothelial cells activate the cancer stem cell-associated NANOGP8 pathway in colorectal cancer cells in a paracrine fashion.

    Science.gov (United States)

    Wang, Rui; Bhattacharya, Rajat; Ye, Xiangcang; Fan, Fan; Boulbes, Delphine R; Xia, Ling; Ellis, Lee M

    2017-08-01

    In colorectal cancer (CRC), cancer stem cells (CSCs) have been hypothesized to mediate cell survival and chemoresistance. Previous studies from our laboratory described a role for liver parenchymal endothelial cells (LPECs) in mediating the CSC phenotype in CRC cells in a paracrine/angiocrine fashion. The objectives of this study were to determine whether endothelial cells (ECs) from different organs can induce the CSC phenotype in CRC cells and to elucidate the signaling pathways involved. We treated a newly developed CRC cell line (HCP-1) and established CRC cell lines (HT29 and SW480) with conditioned medium (CM) from primary ECs isolated from nonmalignant liver, lung, colon mucosa, and kidney. Our results showed that CM from ECs from all organs increased the number of CSCs, as determined by sphere formation, and protein levels of NANOG and OCT4 in CRC cells. With the focus of further elucidating the role of the liver vascular network in mediating the CSC phenotype, we demonstrated that CM from LPECs increased resistance to 5-fluorouracil in CRC cells. Moreover, we showed that LPEC CM specifically induced NANOGP8 expression in CRC cells by specific enzyme digestion and a luciferase reporter assay using a vector containing the NANOGP8 promoter. Lastly, we found that LPEC CM-induced NANOGP8 expression and sphere formation were mediated by AKT activation. Our studies demonstrated a paracrine role for ECs in regulating the CSC phenotype and chemoresistance in CRC cells by AKT-mediated induction of NANOGP8. These studies suggest a more specific approach to target CSCs by blocking the expression of NANOGP8 in cancer cells. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  17. The effects of high dose ionizing radiation on transcriptional regulation and paracrine signaling in human peripheral blood mononuclear cells

    International Nuclear Information System (INIS)

    Beer, L.

    2015-01-01

    While it has long been accepted that direct cell-cell interactions and the replacement of injured tissues with injected cells exerts therapeutic effects, it is currently believed that, in addition, paracrine factors released from different cell types activate cytoprotective and regenerative processes. Cells are now seen as bioreactors that produce and release soluble factors which might be used as therapeutics. We have previously shown that peripheral blood mononuclear cells (PBMCs) release a plethora of paracrine factors that enhance wound healing, attenuate myocardial damage following acute myocardial infarction, abolish microvascular obstruction, improve neurological outcome after acute ischemic stroke and spinal cord injury and protect mice from experimental autoimmune myocarditis. These PBMC derived paracrine factors may exert their effects via the induction of cytoprotective pathways, augmentation of angiogenesis, induction of NO-depended vasodilation and inhibition of VASP dependent platelet aggregation, as well as driving auto-reactive CD4+ cells into apoptosis. To enhance the cellular secretory capacity, treatments which induce stress responses, such as hypoxic preconditioning or ionizing irradiation (IR), have been developed. Although these effects have been evaluated in several disease states there is little data available on the cellular effects of ionizing irradiation on human PBMCs and their secretome. In this study, we have thus undertaken to investigate the effects of IR on human PBMCs in terms of the induction of transcriptional changes and release of pleiotropic paracrine factors. There are three primary aims of this doctoral thesis: 1. To investigate cellular processes activated or repressed in human PBMCs following high dose ionizing radiation (60Gy) and high density cell cultivation (25*10"6 cells/ml) for up to 24 hours. 2. To identify paracrine factors released from these cells using a multi-methodical biochemical/bioinformatics approach. 3

  18. Autocrine-paracrine regulation of the mammary gland.

    Science.gov (United States)

    Weaver, S R; Hernandez, L L

    2016-01-01

    autocrine-paracrine regulation of the mammary gland, with an examination of both foundational work and the progress made within the last 10 to 20 yr of research. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  19. The Paracrine Induction of TRAIL by Genotoxic Agents

    National Research Council Canada - National Science Library

    Spalding, Aaron

    2002-01-01

    TNF related apoptosis inducing ligand, TRAIL, is a recently cloned cytokine that has been shown to induce apoptosis in a synergistic fashion with chemotherapeutic agents on several cancer cell lines...

  20. Endothelin-3 production by human rhabdomyosarcoma: a possible new marker with a paracrine role.

    Science.gov (United States)

    Palladini, Arianna; Astolfi, Annalisa; Croci, Stefania; De Giovanni, Carla; Nicoletti, Giordano; Rosolen, Angelo; Sartori, Francesca; Lollini, Pier-Luigi; Landuzzi, Lorena; Nanni, Patrizia

    2006-03-01

    Several autocrine and paracrine growth factor circuits have been found in human rhabdomyosarcoma cells. In this study we show that endothelin-3 (ET-3), a vasoactive peptide, is produced by human rhabdomyosarcoma cell lines, whereas it is not expressed by human sarcoma cell lines of non-muscle origin. We did not find evidence of a significant autocrine loop; nevertheless ET-3 produced by rhabdomyosarcoma cells can act as a paracrine factor, since it promotes migration of endothelial cells. Moreover ET-3 is present in plasma of mice bearing xenografts of human rhabdomyosarcoma cells, and may be potential new marker of the human rhabdomyosarcoma to be studied further.

  1. Compensatory Paracrine Mechanisms That Define The Urothelial Response to Injury in Partial Bladder Outlet Obstruction

    Energy Technology Data Exchange (ETDEWEB)

    Bassuk, James; Lendvay, Thomas S.; Sweet, Robert; Han, Chang-Hee; Soygur, Tarkan; Cheng, Jan-Fang; Plaire, J. Chadwick; Charleston, Jay S.; Charleston, Lynne B.; Bagai, Shelly; Cochrane, Kimberly; Rubio, Eric; Bassuk, James A.; Fuchs, Elaine

    2007-06-21

    Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo.To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.

  2. Paracrine-mediated osteoclastogenesis by the osteosarcoma MG63 cell line: is RANKL/RANK signalling really important?

    Science.gov (United States)

    Costa-Rodrigues, J; Teixeira, C A; Fernandes, M H

    2011-08-01

    Although in the past little attention has been paid to the influence of osteosarcoma cells in osteoclast function, recent studies suggest a close relationship between osteosarcoma aggressiveness and osteoclastic activity. The present study addresses the paracrine effects of MG63 cells, a human osteosarcoma-derived cell line, on the differentiation of peripheral blood osteoclast precursor cells (PBMC). PBMC were cultured for 21 days in the presence of conditioned media from MG63 cell cultures (CM) collected at 48 h (CM_MG1), 7 days (CM_MG2) and 14 days (CM_MG3). MG63 cell cultures displayed the expression of ALP and BMP-2 and, also, the osteoclastogenic genes M-CSF and RANKL, although with a low expression of RANKL. PBMC cultures supplemented with CM presented an evident osteoclastogenic behavior, which was dependent on the culture period of the MG63 cells. The inductive effect appeared to be more relevant for the differentiation and activation genes, c-myc and c-src, and lower for genes associated with osteoclast function. In addition, PBMC cultures displayed increased functional parameters, including calcium phosphate resorbing activity. Assessment of the PBMC cultures in the presence of U0126, PDTC, and indomethacin suggested that in addition to MEK and NFkB pathways, other signaling mechanisms, probably not involving RANKL/RANK interaction, might be activated in the presence of conditioned medium from MG63. In conclusion, MG63 cell line appears to induce a significant paracrine-mediated osteoclastogenic response. Understanding the mechanisms underlying the interaction of osteosarcoma cells and osteoclasts may contribute to the development of new potential approaches in the treatment of such bone metabolic diseases.

  3. Oxygen Tension Regulates Human Mesenchymal Stem Cell Paracrine Functions

    OpenAIRE

    Paquet, Joseph; Deschepper, Mickael; Moya, Adrien; Logeart-Avramoglou, Delphine; Boisson-Vidal, Catherine; Petite, Hervé

    2015-01-01

    This study examined the shift of the human mesenchymal stem cell (hMSC) cytokine signature induced by oxygen tension. Conditioned media obtained from hMSCs cultured under near anoxia exhibited significantly enhanced chemotactic and proangiogenic properties and a significant decrease in the inflammatory mediator content. These results elucidate important aspects of using MSCs in regenerative medicine, contribute to improving the efficacy of such therapies, and highlight the interest in using c...

  4. STAT3 can be activated through paracrine signaling in breast epithelial cells

    International Nuclear Information System (INIS)

    Lieblein, Jacqueline C; Ball, Sarah; Hutzen, Brian; Sasser, A Kate; Lin, Huey-Jen; Huang, Tim HM; Hall, Brett M; Lin, Jiayuh

    2008-01-01

    Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood. Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis. Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells. These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with

  5. Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators

    DEFF Research Database (Denmark)

    Hess, AP; Hamilton, AE; Talbi, S

    2007-01-01

    During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important...... a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and were further treated with conditioned media (CM) from human trophoblasts (TCM) or, as a control, with conditioned media (CCM) from non-decidualized stromal cells...... regulated groups. The data demonstrate a significant induction of pro-inflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune...

  6. Osteoblast-secreted collagen upregulates paracrine Sonic hedgehog signaling by prostate cancer cells and enhances osteoblast differentiation

    Directory of Open Access Journals (Sweden)

    Zunich Samantha M

    2012-07-01

    Full Text Available Abstract Background Induction of osteoblast differentiation by paracrine Sonic hedgehog (Shh signaling may be a mechanism through which Shh-expressing prostate cancer cells initiate changes in the bone microenvironment and promote metastases. A hallmark of osteoblast differentiation is the formation of matrix whose predominant protein is type 1 collagen. We investigated the formation of a collagen matrix by osteoblasts cultured with prostate cancer cells, and its effects on interactions between prostate cancer cells and osteoblasts. Results In the presence of exogenous ascorbic acid (AA, a co-factor in collagen synthesis, mouse MC3T3 pre-osteoblasts in mixed cultures with human LNCaP prostate cancer cells or LNCaP cells modified to overexpress Shh (LNShh cells formed collagen matrix with distinct fibril ultrastructural characteristics. AA increased the activity of alkaline phosphatase and the expression of the alkaline phosphatase gene Akp2, markers of osteoblast differentiation, in MC3T3 pre-osteoblasts cultured with LNCaP or LNShh cells. However, the AA-stimulated increase in Akp2 expression in MC3T3 pre-osteoblasts cultured with LNShh cells far exceeded the levels observed in MC3T3 cells cultured with either LNCaP cells with AA or LNShh cells without AA. Therefore, AA and Shh exert a synergistic effect on osteoblast differentiation. We determined whether the effect of AA on LNShh cell-induced osteoblast differentiation was mediated by Shh signaling. AA increased the expression of Gli1 and Ptc1, target genes of the Shh pathway, in MC3T3 pre-osteoblasts cultured with LNShh cells to at least twice their levels without AA. The ability of AA to upregulate Shh signaling and enhance alkaline phosphatase activity was blocked in MC3T3 cells that expressed a dominant negative form of the transcription factor GLI1. The AA-stimulated increase in Shh signaling and Shh-induced osteoblast differentiation was also inhibited by the specific collagen synthesis

  7. Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism

    Energy Technology Data Exchange (ETDEWEB)

    De Siena, Rocco; Balducci, Luigi; Blasi, Antonella; Montanaro, Manuela Gessica; Saldarelli, Marilisa [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Saponaro, Vittorio [Department of Veterinary Medicine, University of Bari, 70010 Valenzano, Bari (Italy); Martino, Carmela [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Logrieco, Gaetano [Department of Surgery, Hospital ' F. Miulli' 70021 AcquaViva delle Fonti, Bari (Italy); Soleti, Antonio; Fiobellot, Simona [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Madeddu, Paolo [Experimental Cardiovascular Medicine, Bristol Heart Institute, Bristol BS2 8WH (United Kingdom); Rossi, Giacomo [Department of Pathology, University of Camerino, 63100 Ascoli Piceno (Italy); Ribatti, Domenico [Department of Human Anatomy, University of Bari, 70125 Bari (Italy); Crovace, Antonio [Department of Veterinary Medicine, University of Bari, 70010 Valenzano, Bari (Italy); Cristini, Silvia; Invernici, Gloria; Parati, Eugenio Agostino [Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute ' Carlo Besta' , 20133 Milan (Italy); Alessandri, Giulio, E-mail: cisiamo2@yahoo.com [Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute ' Carlo Besta' , 20133 Milan (Italy)

    2010-07-01

    Cell-based therapy could be a valid option to treat myocardial infarct (MI). Adipose-derived stromal cells (ADStCs) have demonstrated tissue regenerative potential including cardiomyogenesis. Omentum is an extremely rich source of visceral fat and its accumulation seems to correlate with cardiovascular diseases. We investigated the capacity of human fat Omentum-derived StCs (FOStCs) to affect heart function upon acute infarct in pigs induced by permanent ligation of the anterior interventricular artery (IVA). We demonstrated for the first time that the local injection of 50 x 10{sup 6} of FOStCs ameliorates the functional parameters of post-infarct heart. Most importantly, histology of FOStCs treated hearts demonstrated a substantial improvement of cardiomyogenesis. In culture, FOStCs produced an impressive number and amount of angiogenic factors and cytokines. Moreover, the conditioned medium of FOStCs (FOStCs-CM) stimulates in vitro cardiac endothelial cells (ECs) proliferation and vascular morphogenesis and inhibits monocytes, EC activation and cardiomyocyte apoptosis. Since FOStCs in vivo did not trans-differentiate into cardiomyocyte-like cells, we conclude that FOStCs efficacy was presumably mediated by a potent paracrine mechanism involving molecules that concomitantly improved angiogenesis, reduced inflammation and prevented cardiomyocytes death. Our results highlight for the first time the important role that human FOStCs may have in cardiac regeneration.

  8. Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells

    OpenAIRE

    Gervois, Pascal; Wolfs, Esther; Dillen, Yörg; Hilkens, Petra; Ratajczak, Jessica; Driesen, Ronald; Vangansewinkel, Tim; Bronckaers, Annelies; Brône, Bert; Struys, Tom; Lambrichts, Ivo

    2017-01-01

    Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC s...

  9. Vasohibin 2 promotes human luminal breast cancer angiogenesis in a non-paracrine manner via transcriptional activation of fibroblast growth factor 2.

    Science.gov (United States)

    Tu, Min; Lu, Cheng; Lv, Nan; Wei, Jishu; Lu, Zipeng; Xi, Chunhua; Chen, Jianmin; Guo, Feng; Jiang, Kuirong; Li, Qiang; Wu, Junli; Song, Guoxin; Wang, Shui; Gao, Wentao; Miao, Yi

    2016-12-28

    Vasohibin 2 (VASH2) is an angiogenic factor and cancer-related protein that acts via paracrine mechanisms. Here, we investigated the angiogenic function and mechanism of action of VASH2 in 200 human breast cancer tissues by performing immunohistochemical staining, western blot, indirect sandwich enzyme-linked immunosorbent assay (ELISA), and a semi-quantitative sandwich-based antibody array. Breast cancer cells stably overexpressing VASH2 or with knocked-down VASH2 were established and used for in vivo and in vitro models. In human luminal tissue, but not in HER2-positive or basal-like breast cancer tissues, VASH2 was positively correlated with CD31-positive microvascular density, induced angiogenesis in xenograft tumors, and promoted human umbilical vein endothelial cell tube formation in vitro. VASH2 expression was absent in the concentrated conditioned medium collected from knocked-down VASH2 and VASH2-overexpressing luminal breast cancer cells. Further, VASH2 regulated the expression of fibroblast growth factor 2 (FGF2) in human luminal breast cancer cells, and the pro-angiogenic effect induced by VASH2 overexpression was blocked by FGF2 neutralization in vitro. Additionally, dual luciferase reporter assay and Chromatin immunoprecipitation analysis results showed that FGF2 promoter was transcriptionally activated by VASH2 via histone modifications. In conclusion, VASH2 expression is positively correlated with FGF2 expression and promotes angiogenesis in human luminal breast cancer by transcriptional activation of fibroblast growth factor 2 through non-paracrine mechanisms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms

    Directory of Open Access Journals (Sweden)

    Zhi-yuan Guo

    2015-01-01

    Full Text Available Human umbilical cord-derived mesenchymal stem cells (hUCMSCs represent a promising young-state stem cell source for cell-based therapy. hUCMSC transplantation into the transected sciatic nerve promotes axonal regeneration and functional recovery. To further clarify the paracrine effects of hUCMSCs on nerve regeneration, we performed human cytokine antibody array analysis, which revealed that hUCMSCs express 14 important neurotrophic factors. Enzyme-linked immunosorbent assay and immunohistochemistry showed that brain-derived neurotrophic factor, glial-derived neurotrophic factor, hepatocyte growth factor, neurotrophin-3, basic fibroblast growth factor, type I collagen, fibronectin and laminin were highly expressed. Treatment with hUCMSC-conditioned medium enhanced Schwann cell viability and proliferation, increased nerve growth factor and brain-derived neurotrophic factor expression in Schwann cells, and enhanced neurite growth from dorsal root ganglion explants. These findings suggest that paracrine action may be a key mechanism underlying the effects of hUCMSCs in peripheral nerve repair.

  11. Lung-derived growth factors: possible paracrine effectors of fetal lung development

    International Nuclear Information System (INIS)

    Montes, A.M.

    1985-01-01

    A potential role for paracrine secretions in lung organogenesis has been hypothesized (Alescio and Piperno, 1957). These studies present direct support for the paracrine model by demonstrating the presence of locally produced mitogenic/maturational factors in fetal rat lung tissue. Conditioned serum free medium (CSFM) from nineteen-day fetal rat lung cultures was shown to contain several bioactive peptides as detected by 3 H-Thymidine incorporation into chick embryo and rat lung fibroblasts, as well as 14 C-choline incorporation into surfactant in mixed cell cultures. Using ion-exchange chromatography and Sephadex gel filtration, a partially purified mitogen, 11-III, was obtained. The partially purified 11-III stimulates mitosis in chick embryo fibroblasts and post-natal rat lung fibroblasts. Multiplication in fetal rat lung fibroblasts cultures is stimulated only when these are pre-incubated with a competence factor or unprocessed CSFM. This suggests the existence of an endogenously produced competence factor important in the regulation of fetal lung growth. Preparation 11-III does not possess surfactant stimulating activity as assessed by 3 H-choline incorporation into lipids in predominantly type-II cell cultures. These data demonstrate the presence of a maturational/mitogenic factor, influencing type-II mixed cell cultures. In addition, 11-III had been shown to play an autocrine role stimulating the proliferation of fetal lung fibroblasts. Finally, these data suggest the existence of a local produced competence factor

  12. A paracrine mechanism involving renal tubular cells, adipocytes and macrophages promotes kidney stone formation in a simulated metabolic syndrome environment.

    Science.gov (United States)

    Zuo, Li; Tozawa, Keiichi; Okada, Atsushi; Yasui, Takahiro; Taguchi, Kazumi; Ito, Yasuhiko; Hirose, Yasuhiko; Fujii, Yasuhiro; Niimi, Kazuhiro; Hamamoto, Shuzo; Ando, Ryosuke; Itoh, Yasunori; Zou, Jiangang; Kohri, Kenjiro

    2014-06-01

    We developed an in vitro system composed of renal tubular cells, adipocytes and macrophages to simulate metabolic syndrome conditions. We investigated the molecular communication mechanism of these cells and their involvement in kidney stone formation. Mouse renal tubular cells (M-1) were cocultured with adipocytes (3T3-L1) and/or macrophages (RAW264.7). Calcium oxalate monohydrate crystals were exposed to M-1 cells after 48-hour coculture and the number of calcium oxalate monohydrate crystals adherent to the cells was quantified. The expression of cocultured medium and M-1 cell inflammatory factors was analyzed by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. The inflammatory markers MCP-1, OPN and TNF-α were markedly up-regulated in cocultured M-1 cells. OPN expression increased in M-1 cells cocultured with RAW264.7 cells while MCP-1 and TNF-α were over expressed in M-1 cells cocultured with 3T3-L1 cells. Coculturing M-1 cells simultaneously with 3T3-L1 and RAW264.7 cells resulted in a significant increase in calcium oxalate monohydrate crystal adherence to M-1 cells. Inflammatory cytokine changes were induced by coculturing renal tubular cells with adipocytes and/or macrophages without direct contact, indicating that crosstalk between adipocytes/macrophages and renal tubular cells was mediated by soluble factors. The susceptibility to urolithiasis of patients with metabolic syndrome might be due to aggravated inflammation of renal tubular cells triggered by a paracrine mechanism involving these 3 cell types. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  13. Mechanisms of cytolysin-induced cell damage -- a role for auto- and paracrine signalling

    DEFF Research Database (Denmark)

    Skals, Marianne Gerberg; Prætorius, Helle

    2013-01-01

    Cytolysins inflict cell damage by forming pores in the plasma membrane. The Na(+) conductivity of these pores results in an ion influx that exceeds the capacity of the Na(+) /K(+) -pump to extrude Na(+) . This net load of intracellular osmolytes results in swelling and eventual lysis of the attac...

  14. Increased Paracrine Immunomodulatory Potential of Mesenchymal Stromal Cells in Three-Dimensional Culture

    DEFF Research Database (Denmark)

    Follin, Bjarke; Juhl, Morten; Cohen, Smadar

    2016-01-01

    Mesenchymal stromal/stem cells (MSCs) have been investigated extensively through the past years, proving to have great clinical therapeutic potential. In vitro cultivation of MSCs in three-dimensional (3D) culture systems, such as scaffolds, hydrogels, or spheroids, have recently gained attention...... for tissue engineering applications. Studies on MSC spheroids demonstrated that such cultivation increased the paracrine immunomodulatory potential of the MSCs, accompanied by phenotypic alterations. In this review, we gather results from recent experimental studies on the immunomodulatory abilities of MSCs...... when cultured as spheroids or in biomaterials like scaffolds or hydrogels compared to regular two-dimensional (2D) culture and show that alterations occurring to MSCs in spheroids also occur in MSCs in biomaterials. We provide a brief description of known mechanisms of MSC immunomodulatory capacity...

  15. Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells

    International Nuclear Information System (INIS)

    Lin Nan; Tang Zhaofeng; Deng Meihai; Zhong Yuesi; Lin Jizong; Yang Xuhui; Xiang Peng; Xu Ruiyun

    2008-01-01

    During liver injury, bone marrow-derived mesenchymal stem cells (MSCs) can migrate and differentiate into hepatocytes. Hepatic stellate cell (SC) activation is a pivotal event in the development of liver fibrosis. Therefore, we hypothesized that SCs may play an important role in regulating MSC proliferation and differentiation through the paracrine signaling pathway. We demonstrate that MSCs and SCs both express hedgehog (Hh) pathway components, including its ligands, receptors, and target genes. Transwell co-cultures of SCs and MSCs showed that the SCs produced sonic hedgehog (Shh), which enhanced the proliferation and differentiation of MSCs. These findings demonstrate that SCs indirectly modulate the activity of MSCs in vitro via the Hh pathway, and provide a plausible explanation for the mechanisms of transplanted MSCs in the treatment of liver fibrosis

  16. The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

    DEFF Research Database (Denmark)

    Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder

    2013-01-01

    Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment...

  17. Predictions for optimal mitigation of paracrine inhibitory signalling in haemopoietic stem cell cultures.

    Science.gov (United States)

    Berry, Joseph D; Godara, Pankaj; Liovic, Petar; Haylock, David N

    2015-04-16

    Recent studies in the literature have highlighted the critical role played by cell signalling in determining haemopoietic stem cell (HSC) fate within ex vivo culture systems. Stimulatory signals can enhance proliferation and promote differentiation, whilst inhibitory signals can significantly limit culture output. Numerical models of various mitigation strategies are presented and applied to determine effectiveness of these strategies toward mitigation of paracrine inhibitory signalling inherent in these culture systems. The strategies assessed include mixing, media-exchange, fed-batch and perfusion. The models predict that significant spatial concentration gradients exist in typical cell cultures, with important consequences for subsequent cell expansion. Media exchange is shown to be the most effective mitigation strategy, but remains labour intensive and difficult to scale-up for large culture systems. The fed-batch strategy is only effective at very small Peclet number, and its effect is diminished as the cell culture volume grows. Conversely, mixing is effective at high Peclet number, and ineffective at low Peclet number. The models predict that cell expansion in fed-batch cultures becomes independent of increasing dilution rate, consistent with experimental results previously reported in the literature. In contrast, the models predict that increasing the flow rate in perfused cultures will lead to increased cell expansion, indicating the suitability of perfusion for use as an automated, tunable strategy. The effect of initial cell seeding density is also investigated, with the model showing that perfusion outperforms dilution for all densities considered. The models predict that the impact of inhibitory signalling in HSC cultures can be mitigated against using media manipulation strategies, with the optimal strategy dependent upon the protein diffusion time-scale relative to the media manipulation time-scale. The key messages from this study can be applied to

  18. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.

    Science.gov (United States)

    Bavik, Claes; Coleman, Ilsa; Dean, James P; Knudsen, Beatrice; Plymate, Steven; Nelson, Peter S

    2006-01-15

    The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate

  19. Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia.

    Science.gov (United States)

    Ryu, Jae Choon; Davidson, Brian P; Xie, Aris; Qi, Yue; Zha, Daogang; Belcik, J Todd; Caplan, Evan S; Woda, Juliana M; Hedrick, Catherine C; Hanna, Richard N; Lehman, Nicholas; Zhao, Yan; Ting, Anthony; Lindner, Jonathan R

    2013-02-12

    Stem cells are thought to enhance vascular remodeling in ischemic tissue in part through paracrine effects. Using molecular imaging, we tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPCs) promotes recovery of blood flow through the recruitment of proangiogenic monocytes. Hind-limb ischemia was produced in mice by iliac artery ligation, and MAPCs were administered intramuscularly on day 1. Optical imaging of luciferase-transfected MAPCs indicated that cells survived for 1 week. Contrast-enhanced ultrasound on days 3, 7, and 21 showed a more complete recovery of blood flow and greater expansion of microvascular blood volume in MAPC-treated mice than in controls. Fluorescent microangiography demonstrated more complete distribution of flow to microvascular units in MAPC-treated mice. On ultrasound molecular imaging, expression of endothelial P-selectin and intravascular recruitment of CX(3)CR-1-positive monocytes were significantly higher in MAPC-treated mice than in the control groups at days 3 and 7 after arterial ligation. Muscle immunohistology showed a >10-fold-greater infiltration of monocytes in MAPC-treated than control-treated ischemic limbs at all time points. Intravital microscopy of ischemic or tumor necrosis factor-α-treated cremaster muscle demonstrated that MAPCs migrate to perimicrovascular locations and potentiate selectin-dependent leukocyte rolling. In vitro migration of human CD14(+) monocytes was 10-fold greater in response to MAPC-conditioned than basal media. In limb ischemia, MAPCs stimulate the recruitment of proangiogenic monocytes through endothelial activation and enhanced chemotaxis. These responses are sustained beyond the MAPC lifespan, suggesting that paracrine effects promote flow recovery by rebalancing the immune response toward a more regenerative phenotype.

  20. Substance P enhances proliferation and paracrine potential of adipose-derived stem cells in vitro

    International Nuclear Information System (INIS)

    Kim, Suna; Piao, Jiyuan; Son, Youngsook; Hong, Hyun Sook

    2017-01-01

    Stem cells have tremendous promise to treat intractable diseases. Notably, adipose-derived stem cells (ADSCs) are actively being investigated because of ease of sampling and high repopulation capacity in vitro. ADSCs can exert a therapeutic effect through differentiation and paracrine potential, and these actions have been proven in many diseases, including cutaneous and inflammatory diseases. Transplantation of ADSCs necessitates therapeutic quantities and thus, long term ex vivo culture of ADSCs. However, this procedure can impair the activity of ADSCs and provoke cellular senescence, leading to low efficacy in vivo. Accordingly, strategies to restore cellular activity and inhibit senescence of stem cells during ex vivo culture are needed for stem cell-based therapies. This study evaluated a potential supplementary role of Substance P (SP) in ADSC ex vivo culture. After confirming that the ADSC cell cycle was damaged by passage 6 (p6), ADSCs at p6 were cultured with SP, and their proliferation rates, cumulative cell numbers, cytokine profiles, and impact on T/endothelial cells were assessed. Long-term culture weakened proliferation ability and secretion of the cytokines, transforming growth factor-beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF), and stromal cell derived factor-1 alpha (SDF-1alpha) in ADSCs. However, SP treatment reduced the population doubling time (PDT), enabling gain of a sufficient number of ADSCs at early passages. In addition, SP restored cytokine secretion, enhancing the ADSC-mediated paracrine effect on T cell and human umbilical vein endothelial cells (HUVECs). Taken together, these results suggest that SP can retain the therapeutic effect of ADSCs by elevating their proliferative and paracrine potential in ex vivo culture. - Highlights: • Long-term culture of ADSCs leads to cell senescence. • Paracrine potential of ADSC decreases as passage number increases. • SP enhances the weakened proliferation capacity of

  1. Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A.

    Science.gov (United States)

    Moravek, Molly B; Yin, Ping; Coon, John S; Ono, Masanori; Druschitz, Stacy A; Malpani, Saurabh S; Dyson, Matthew T; Rademaker, Alfred W; Robins, Jared C; Wei, Jian-Jun; Kim, J Julie; Bulun, Serdar E

    2017-05-01

    Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown. To define differential gene expression and signaling pathways in leiomyoma cell populations. Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b-, and CD34-/CD49b-. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2'-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma. Research laboratory. Eight African American women. None. Gene expression patterns, cell proliferation, and differentiation. A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b- intermediary cells, which then terminally differentiate to CD34-/CD49b- cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b- vs CD34-/CD49b- cells (83-fold; P leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas. Copyright © 2017 by the Endocrine Society

  2. Carvacrol promotes angiogenic paracrine potential and endothelial differentiation of human mesenchymal stem cells at low concentrations.

    Science.gov (United States)

    Matluobi, Danial; Araghi, Atefeh; Maragheh, Behnaz Faramarzian Azimi; Rezabakhsh, Aysa; Soltani, Sina; Khaksar, Majid; Siavashi, Vahid; Feyzi, Adel; Bagheri, Hesam Saghaei; Rahbarghazi, Reza; Montazersaheb, Soheila

    2018-01-01

    Phenolic monoterpene compound, named Carvacrol, has been found to exert different biological outcomes. It has been accepted that the angiogenic activity of human mesenchymal stem cells was crucial in the pursuit of appropriate regeneration. In the current experiment, we investigated the contribution of Carvacrol on the angiogenic behavior of primary human mesenchymal stem cells. Mesenchymal stem cells were exposed to Carvacrol in a dose ranging from 25 to 200μM for 48h. We measured cell survival rate by MTT assay and migration rate by a scratch test. The oxidative status was monitored by measuring SOD, GPx activity. The endothelial differentiation was studied by evaluating the level of VE-cadherin and vWF by real-time PCR and ELISA analyses. The content of VEGF and tubulogenesis behavior was monitored in vitro. We also conducted Matrigel plug in vivo CAM assay to assess the angiogenic potential of conditioned media from human mesenchymal stem cells after exposure to Carvacrol. Carvacrol was able to increase mesenchymal stem cell survival and migration rate (pcells by detecting vWF and VE-cadherin expression (pmesenchymal stem cells conditioned media improved angiogenesis tube formation in vitro (pmesenchymal stem cells by modulating cell differentiation and paracrine angiogenic response. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium.

    Directory of Open Access Journals (Sweden)

    Shanmugasundaram Nallasamy

    Full Text Available The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2(d/d, the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2(d/d mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.

  4. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium.

    Science.gov (United States)

    Nallasamy, Shanmugasundaram; Li, Quanxi; Bagchi, Milan K; Bagchi, Indrani C

    2012-01-01

    The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2(d/d)), the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2(d/d) mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.

  5. Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes.

    Science.gov (United States)

    Ronca, Roberto; Van Ginderachter, Jo A; Turtoi, Andrei

    2018-01-01

    Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions. Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells. Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.

  6. Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

    Science.gov (United States)

    Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

    2008-10-01

    The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.

  7. Effect of Serum and Oxygen Concentration on Gene Expression and Secretion of Paracrine Factors by Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Patrick Page

    2014-01-01

    Full Text Available Mesenchymal stem cells (MSC secrete paracrine factors that may exert a protective effect on the heart after coronary artery occlusion. This study was done to determine the effect of hypoxia and serum levels on the mRNA expression and secretion of paracrine factors. Mouse bone marrow MSC were cultured with 5% or 20% serum and in either normoxic (21% O2 or hypoxic (1% O2 conditions. Expression of mRNA for vascular endothelial growth factor (VEGF, monocyte chemotactic protein-1 (MCP-1, macrophage inflammatory protein-1α (MIP-1α, MIP-1β, and matrix metalloproteinase-2 (MMP-2 was determined by RT-qPCR. Secretion into the culture media was determined by ELISA. Hypoxia caused a reduction in gene expression for MCP-1 and an increase for VEGF (5% serum, MIP-1α, MIP-1β, and MMP-2. Serum reduction lowered gene expression for VEGF (normoxia, MCP-1 (hypoxia, MIP-1α (hypoxia, MIP-1β (hypoxia, and MMP-2 (hypoxia and increased gene expression for MMP-2 (normoxia. The level of secretion of these factors into the media generally paralleled gene expression with some exceptions. These data demonstrate that serum and oxygen levels have a significant effect on the gene expression and secretion of paracrine factors by MSC which will affect how MSC interact in vivo during myocardial ischemia.

  8. Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF

    Science.gov (United States)

    Chellini, Flaminia; Mazzanti, Benedetta; Nistri, Silvia; Nosi, Daniele; Saccardi, Riccardo; Quercioli, Franco; Zecchi-Orlandini, Sandra; Formigli, Lucia

    2012-01-01

    Mesenchymal stromal cells (MSCs) are the leading cell candidates in the field of regenerative medicine. These cells have also been successfully used to improve skeletal muscle repair/regeneration; however, the mechanisms responsible for their beneficial effects remain to be clarified. On this basis, in the present study, we evaluated in a co-culture system, the ability of bone-marrow MSCs to influence C2C12 myoblast behavior and analyzed the cross-talk between the two cell types at the cellular and molecular level. We found that myoblast proliferation was greatly enhanced in the co-culture as judged by time lapse videomicroscopy, cyclin A expression and EdU incorporation. Moreover, myoblasts immunomagnetically separated from MSCs after co-culture expressed higher mRNA and protein levels of Notch-1, a key determinant of myoblast activation and proliferation, as compared with the single culture. Notch-1 intracellular domain and nuclear localization of Hes-1, a Notch-1 target gene, were also increased in the co-culture. Interestingly, the myoblastic response was mainly dependent on the paracrine release of vascular endothelial growth factor (VEGF) by MSCs. Indeed, the addition of MSC-derived conditioned medium (CM) to C2C12 cells yielded similar results as those observed in the co-culture and increased the phosphorylation and expression levels of VEGFR. The treatment with the selective pharmacological VEGFR inhibitor, KRN633, resulted in a marked attenuation of the receptor activation and concomitantly inhibited the effects of MSC-CM on C2C12 cell growth and Notch-1 signaling. In conclusion, this study provides novel evidence for a role of MSCs in stimulating myoblast cell proliferation and suggests that the functional interaction between the two cell types may be exploited for the development of new and more efficient cell-based skeletal muscle repair strategies. PMID:22815682

  9. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions.

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    Bodi Zhang

    Full Text Available Mast cells are hematopoietically-derived tissue immune cells that participate in acquired and innate immunity, as well as in inflammation through release of many chemokines and cytokines, especially in response to the pro-inflammatory peptide substance P (SP. Inflammation is critical in the pathogenesis of many diseases, but the trigger(s is often unknown. We investigated if mast cell stimulation leads to secretion of mitochondrial components and whether these could elicit autocrine and/or paracrine inflammatory effects. Here we show that human LAD2 mast cells stimulated by IgE/anti-IgE or by the SP led to secretion of mitochondrial particles, mitochondrial (mt mtDNA and ATP without cell death. Mitochondria purified from LAD2 cells and, when mitochondria added to mast cells trigger degranulation and release of histamine, PGD(2, IL-8, TNF, and IL-1β. This stimulatory effect is partially inhibited by an ATP receptor antagonist and by DNAse. These results suggest that the mitochondrial protein fraction may also contribute. Purified mitochondria also stimulate IL-8 and vascular endothelial growth factor (VEGF release from cultured human keratinocytes, and VEGF release from primary human microvascular endothelial cells. In order to investigate if mitochondrial components could be secreted in vivo, we injected rats intraperiotoneally (ip with compound 48/80, which mimicks the action of SP. Peritoneal mast cells degranulated and mitochondrial particles were documented by transimission electron microscopy outside the cells. We also wished to investigate if mitochondrial components secreted locally could reach the systemic circulation. Administration ip of mtDNA isolated from LAD2 cells in rats was detected in their serum within 4 hr, indicating that extravascular mtDNA could enter the systemic circulation. Secretion of mitochondrial components from stimulated live mast cells may act as "autopathogens" contributing to the pathogenesis of inflammatory

  10. Paracrine Mechanisms of Intravenous Bone Marrow-Derived Mononuclear Stem Cells in Chronic Ischemic Stroke

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    Ashu Bhasin

    2016-10-01

    Full Text Available Background: The emerging role of stem cell technology and transplantation has helped scientists to study their potential role in neural repair and regeneration. The fate of stem cells is determined by their niche, consisting of surrounding cells and the secreted trophic growth factors. This interim report evaluates the safety, feasibility and efficacy (if any of bone marrow-derived mononuclear stem cells (BM-MNC in chronic ischemic stroke by studying the release of serum vascular endothelial growth factor (VEGF and brain-derived neurotrophic growth factor (BDNF. Methods: Twenty stroke patients and 20 age-matched healthy controls were recruited with the following inclusion criteria: 3 months to 1.5 years from the index event, Medical Research Council (MRC grade of hand muscles of at least 2, Brunnstrom stage 2-5, conscious, and comprehendible. They were randomized to one group receiving autologous BM-MNC (mean 60-70 million and to another group receiving saline infusion (placebo. All patients were administered a neuromotor rehabilitation regime for 8 weeks. Clinical assessments [Fugl Meyer scale (FM, modified Barthel index (mBI, MRC grade, Ashworth tone scale] were carried out and serum VEGF and BDNF levels were assessed at baseline and at 8 weeks. Results: No serious adverse events were observed during the study. There was no statistically significant clinical improvement between the groups (FM: 95% CI 15.2-5.35, p = 0.25; mBI: 95% CI 14.3-4.5, p = 0.31. VEGF and BDNF expression was found to be greater in group 1 compared to group 2 (VEGF: 442.1 vs. 400.3 pg/ml, p = 0.67; BDNF: 21.3 vs. 19.5 ng/ml without any statistically significant difference. Conclusion: Autologous mononuclear stem cell infusion is safe and tolerable by chronic ischemic stroke patients. The released growth factors (VEGF and BDNF in the microenvironment could be due to the paracrine hypothesis of stem cell niche and neurorehabilitation regime.

  11. XIAP gene expression and function is regulated by autocrine and paracrine TGF-β signaling

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    Van Themsche Céline

    2010-08-01

    Full Text Available Abstract Background X-linked inhibitor of apoptosis protein (XIAP is often overexpressed in cancer cells, where it plays a key role in survival and also promotes invasiveness. To date however, the extracellular signals and intracellular pathways regulating its expression and activity remain incompletely understood. We have previously showed that exposure to each of the three TGF-β (transforming growth factor beta isoforms upregulates XIAP protein content in endometrial carcinoma cells in vitro. In the present study, we have investigated the clinical relevance of TGF-β isoforms in endometrial tumours and the mechanisms through which TGF-β isoforms regulate XIAP content in uterine cancer cells. Methods TGF-β isoforms immunoreactivity in clinical samples from endometrial tumours was assessed using immunofluorescence. Two model cancer cell lines (KLE endometrial carcinoma cells and HeLa cervical cancer cells and pharmacological inhibitors were used to investigate the signalling pathways regulating XIAP expression and activity in response to autocrine and paracrine TGF-β in cancer cell. Results We have found immunoreactivity for each TGF-β isoform in clinical samples from endometrial tumours, localizing to both stromal and epithelial/cancer cells. Blockade of autocrine TGF-β signaling in KLE endometrial carcinoma cells and HeLa cervical cancer cells reduced endogenous XIAP mRNA and protein levels. In addition, each TGF-β isoform upregulated XIAP gene expression when given exogenously, in a Smad/NF-κB dependent manner. This resulted in increased polyubiquitination of PTEN (phosphatase and tensin homolog on chromosome ten, a newly identified substrate for XIAP E3 ligase activity, and in a XIAP-dependent decrease of PTEN protein levels. Although each TGF-β isoform decreased PTEN content in a XIAP- and a Smad-dependent manner, decrease of PTEN levels in response to only one isoform, TGF-β3, was blocked by PI3-K inhibitor LY294002. Conclusions

  12. Immunohistochemical evidence for an endocrine/paracrine role for ghrelin in the reproductive tissues of sheep

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    Brown Yvonne A

    2005-10-01

    tissues of the adult and fetal sheep. In addition, the data indicate that testicular expression of ghrelin and its receptor is physiologically regulated in the adult and developmentally regulated in the fetus. Therefore, the ghrelin ligand/receptor system may have a role (endocrine and/or paracrine in the development (cellular proliferation and function of the reproductive axis of the sheep.

  13. Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

    DEFF Research Database (Denmark)

    Corsino, P.; Davis, B.; Law, M.

    2007-01-01

    ) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV-cyclin D1-Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may...... sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGF beta and HGF, resulting in desmoplasia. The MMTV-DIK2 mice should provide a useful model system...

  14. A late requirement for Wnt and FGF signalling during activin-induced formation of foregut endoderm from mouse embryonic stem cells

    DEFF Research Database (Denmark)

    Hansson, Mattias; Petersen, Dorthe Rønn; Peterslund, Janny M.L.

    2009-01-01

    Here we examine how BMP, Wnt, and FGF signaling modulate activin-induced mesendodermal differentiation of mouse ES cells grown under defined conditions in adherent monoculture. We monitor ES cells containing reporter genes for markers of primitive streak (PS) and its progeny and extend previous...... is found at the lowest activin concentration. The expression of Gsc and other anterior markers induced by activin is prevented by treatment with BMP4, which induces T expression and subsequent mesodermal development. We show that canonical Wnt signaling is required only during late stages of activin....... Notably, activin induction of Gsc-GFP(+) cells appears refractory to inhibition of canonical Wnt signaling but shows a dependence on early as well as late FGF signaling. Additionally, we find a late dependence on FGF signaling during induction of Sox17(+) cells by activin while BMP4-induced T expression...

  15. Adipose-derived stem cells enhance myogenic differentiation in the mdx mouse model of muscular dystrophy via paracrine signaling

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    Ji-qing Cao

    2016-01-01

    Full Text Available Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells (6 × 10 6 were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle fibers. Phosphorylation levels of Akt, mammalian target of rapamycin (mTOR, eIF-4E binding protein 1 and S6 kinase 1 were increased, and the Akt/mTOR pathway was activated. Simultaneously, myogenin levels were increased, whereas cleaved caspase 3 and vimentin levels were decreased. Necrosis and fibrosis were reduced in the muscle fibers. These findings suggest that adipose-derived stem cells promote the regeneration and survival of muscle cells by inhibiting apoptosis and fibrosis, thereby alleviating muscle damage in muscular dystrophy.

  16. The paracrine feedback loop between vitamin D₃ (1,25(OH)₂D₃) and PTHrP in prehypertrophic chondrocytes

    NARCIS (Netherlands)

    Bach, Frances C; Rutten, Kirsten; Hendriks, Kristyanne; Riemers, Frank M; Cornelissen, Peter; de Bruin, Alain; Arkesteijn, Ger J; Wubbolts, Richard; Horton, William A; Penning, Louis C; Tryfonidou, Marianna A

    2014-01-01

    The endocrine feedback loop between vitamin D3(1,25(OH)2D3) and parathyroid hormone (PTH) plays a central role in skeletal development. PTH-related protein (PTHrP) shares homology and its receptor (PTHR1) with PTH. The aim of this study was to investigate whether there is a functional paracrine

  17. Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

    Science.gov (United States)

    Isensee, Jörg; Wenzel, Carsten; Buschow, Rene; Weissmann, Robert; Kuss, Andreas W.; Hucho, Tim

    2014-01-01

    Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination

  18. Curcumin Triggers p16-Dependent Senescence in Active Breast Cancer-Associated Fibroblasts and Suppresses Their Paracrine Procarcinogenic Effects

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    Siti-Fauziah Hendrayani

    2013-06-01

    Full Text Available Activated cancer-associated fibroblasts (CAFs or myofibroblasts not only facilitate tumor growth and spread but also affect tumor response to therapeutic agents. Therefore, it became clear that efficient therapeutic regimens should also take into account the presence of these supportive cells and inhibit their paracrine effects. To this end, we tested the effect of low concentrations of curcumin, a pharmacologically safe natural product, on patient-derived primary breast CAF cells. We have shown that curcumin treatment upregulates p16INK4A and other tumor suppressor proteins while inactivates the JAK2/STAT3 pathway. This reduced the level of alpha-smooth muscle actin (α-SMA and the migration/invasion abilities of these cells. Furthermore, curcumin suppressed the expression/secretion of stromal cell-derived factor-1 (SDF-1, interleukin-6 (IL-6, matrix metalloproteinase-2 (MMP-2, MMP-9, and transforming growth factor-β, which impeded their paracrine procarcinogenic potential. Intriguingly, these effects were sustained even after curcumin withdrawal and cell splitting. Therefore, using different markers of senescence [senescence-associated β-galactosidase (SA-β-gal activity, Ki-67 and Lamin B1 levels, and bromodeoxyuridine incorporation], we have shown that curcumin markedly suppresses Lamin B1 and triggers DNA damage-independent senescence in proliferating but not quiescent breast stromal fibroblasts. Importantly, this curcumin-related senescence was p16INK4A-dependent and occurred with no associated inflammatory secretory phenotype. These results indicate the possible inactivation of cancer-associated myofibroblasts and present the first indication that curcumin can trigger DNA damage-independent and safe senescence in stromal fibroblasts.

  19. Chemokine CXCL3 mediates prostate cancer cells proliferation, migration and gene expression changes in an autocrine/paracrine fashion.

    Science.gov (United States)

    Xin, Hua; Cao, Yu; Shao, Ming-Liang; Zhang, Wei; Zhang, Chun-Bin; Wang, Jing-Tao; Liang, Li-Chun; Shao, Wen-Wu; Qi, Ya-Ling; Li, Yue; Zhang, Ze-Yu; Yang, Zhe; Sun, Yu-Hong; Zhang, Peng-Xia; Jia, Lin-Lin; Wang, Wei-Qun

    2018-05-01

    We have previously indicated that CXCL3 was upregulated in the tissues of prostate cancer, and exogenous administration of CXCL3 played a predominant role in the tumorigenicity of prostate cancer cells. In the present study, we further explored the role and the underlying mechanism of CXCL3 overexpression in the oncogenic potential of prostate cancer in an autocrine/paracrine fashion. CXCL3-overexpressing prostate cancer cell line PC-3 and immortalized prostate stromal cell line WPMY-1 were established by gene transfection. CCK-8, transwell assays and growth of tumor xenografts were conducted to characterize the effects of CXCL3 on PC-3 cells' proliferation and migration. Western blotting was conducted to test whether CXCL3 could affect the expression of tumorigenesis-associated genes. The results showed that CXCL3 overexpression in PC-3 cells and the PC-3 cells treated with the supernatants of CXCL3-transfected WPMY-1 cells stimulated the proliferation and migration of PC-3 cells in vitro and in a nude mouse xenograft model. Western blotting revealed higher levels of p-ERK, Akt and Bcl-2 and lower levels of Bax in the tumor xenografts transplanted with CXCL3-transfected PC-3 cells. Moreover, the tumor xenografts derived from the PC-3 cells treated with supernatants of CXCL3-transfected WPMY-1 cells showed higher expression of ERK, Akt and Bcl-2 and lower expression of Bax. These findings suggest that CXCL3 autocrine/paracrine pathways are involved in the development of prostate cancer by regulating the expression of the target genes that are related to the progression of malignancies.

  20. Both Autocrine Signaling and Paracrine Signaling of HB-EGF Enhance Ocular Neovascularization.

    Science.gov (United States)

    Inoue, Yuki; Shimazawa, Masamitsu; Nakamura, Shinsuke; Takata, Shinsuke; Hashimoto, Yuhei; Izawa, Hiroshi; Masuda, Tomomi; Tsuruma, Kazuhiro; Sakaue, Tomohisa; Nakayama, Hironao; Higashiyama, Shigeki; Hara, Hideaki

    2018-01-01

    The incidence of blindness is increasing because of the increase in abnormal ocular neovascularization. Anti-VEGF (vascular endothelial growth factor) therapies have led to good results, although they are not a cure for the blindness. The purpose of this study was to determine what role HB-EGF (heparin-binding epidermal growth factor-like growth factor) plays in ocular angiogenesis. We examined the role played by HB-EGF in ocular neovascularization in 2 animal models of neovascularization: laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy. We also studied human retinal microvascular endothelial cells in culture. Our results showed that the neovascularization was decreased in both the CNV and oxygen-induced retinopathy models in HB-EGF conditional knockout mice compared with that in wild-type mice. Moreover, the expressions of HB-EGF and VEGF were increased after laser-induced CNV and oxygen-induced retinopathy, and their expression sites were located around the neovascular areas. Exposure of human retinal microvascular endothelial cells to HB-EGF and VEGF increased their proliferation and migration, and CRM-197 (cross-reactive material-197), an HB-EGF inhibitor, decreased the HB-EGF-induced and VEGF-induced cell proliferation and migration. VEGF increased the expression of HB-EGF mRNA. VEGF-dependent activation of EGFR (epidermal growth factor receptor)/ERK1/2 (extracellular signal-regulated kinase 1/2) signaling and cell proliferation of endothelial cells required stimulation of the ADAM17 (a disintegrin and metalloprotease) and ADAM12. CRM-197 decreased the grades of the fluorescein angiograms and size of the CNV areas in marmoset monkeys. These findings suggest that HB-EGF plays an important role in the development of CNV. Therefore, further investigations of HB-EGF are needed as a potential therapeutic target in the treatment of exudative age-related macular degeneration. © 2017 American Heart Association, Inc.

  1. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines

    DEFF Research Database (Denmark)

    Brown, J Mark; Boysen, Maria Sandberg; Chung, Soonkyu

    2004-01-01

    of MEK/ERK could be attenuated by pretreatment with U0126 and pertussis toxin. In parallel, pretreatment with U0126 blocked the ability of trans-10, cis-12 CLA to alter gene expression and attenuate glucose and fatty acid uptake of the cultures. Intriguingly, the induction by CLA of MEK/ERK signaling...

  2. Ghrelin is involved in the paracrine communication between neurons and glial cells.

    Science.gov (United States)

    Avau, B; De Smet, B; Thijs, T; Geuzens, A; Tack, J; Vanden Berghe, P; Depoortere, I

    2013-09-01

    Ghrelin is the only known peripherally active orexigenic hormone produced by the stomach that activates vagal afferents to stimulate food intake and to accelerate gastric emptying. Vagal sensory neurons within the nodose ganglia are surrounded by glial cells, which are able to receive and transmit chemical signals. We aimed to investigate whether ghrelin activates or influences the interaction between both types of cells. The effect of ghrelin was compared with that of leptin and cholecystokinin (CCK). Cultures of rat nodose ganglia were characterized by immunohistochemistry and the functional effects of peptides, neurotransmitters, and pharmacological blockers were measured by Ca(2+) imaging using Fluo-4-AM as an indicator. Neurons responded to KCl and were immunoreactive for PGP-9.5 whereas glial cells responded to lysophosphatidic acid and had the typical SOX-10-positive nuclear staining. Neurons were only responsive to CCK (31 ± 5%) whereas glial cells responded equally to the applied stimuli: ghrelin (27 ± 2%), leptin (21 ± 2%), and CCK (30 ± 2%). In contrast, neurons stained more intensively for the ghrelin receptor than glial cells. ATP induced [Ca(2+) ]i rises in 90% of the neurons whereas ACh and the NO donor, SIN-1, mainly induced [Ca(2+) ]i changes in glial cells (41 and 51%, respectively). The percentage of ghrelin-responsive glial cells was not affected by pretreatment with suramin, atropine, hexamethonium or 1400 W, but was reduced by l-NAME and by tetrodotoxin. Neurons were shown to be immunoreactive for neuronal NO-synthase (nNOS). Our data show that ghrelin induces Ca(2+) signaling in glial cells of the nodose ganglion via the release of NO originating from the neurons. © 2013 John Wiley & Sons Ltd.

  3. Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases.

    Science.gov (United States)

    Conese, Massimo; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

    2013-01-01

    Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders. Copyright © 2013 S. Karger AG, Basel.

  4. A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells

    Science.gov (United States)

    Yu, Shu-Han; Zheng, Qizhi; Esopi, David; Macgregor-Das, Anne; Luo, Jun; Antonarakis, Emmanuel S.; Drake, Charles G.; Vessella, Robert; Morrissey, Colm; De Marzo, Angelo M.; Sfanos, Karen S.

    2015-01-01

    Correlative human studies suggest that the pleiotropic cytokine interleukin-6 (IL6) contributes to the development and/or progression of prostate cancer. However, the source of IL6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded (FFPE) tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR (q-RT-PCR) showed that benign prostate tissues often had higher expression of IL6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL6 mRNA. IL6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment – including endothelial cells and macrophages among other cell types. The number of IL6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined and IL6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL6 production is likely associated with any role for the cytokine in disease progression. PMID:26048576

  5. The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

    Science.gov (United States)

    Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder; Sabourin, David; Collas, Philippe; Bruus, Henrik; Dufva, Martin

    2013-01-01

    Introduction High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. Methods and results Adipogenic differentiation of human adipose-derived stem cells (ASCs) cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium). Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin). The positive effects of conditioned medium were observed early in the differentiation process. Conclusions Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment phase of the differentiation process. PMID:23723991

  6. The role of paracrine and autocrine signaling in the early phase of adipogenic differentiation of adipose-derived stem cells.

    Directory of Open Access Journals (Sweden)

    Mette Hemmingsen

    Full Text Available INTRODUCTION: High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. METHODS AND RESULTS: Adipogenic differentiation of human adipose-derived stem cells (ASCs cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium. Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin. The positive effects of conditioned medium were observed early in the differentiation process. CONCLUSIONS: Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s were shown to act in the recruitment phase of the differentiation process.

  7. Glioblastoma Stem Cells Microenvironment: The Paracrine Roles of the Niche in Drug and Radioresistance

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    Alessia Fidoamore

    2016-01-01

    Full Text Available Among all solid tumors, the high-grade glioma appears to be the most vascularized one. In fact, “microvascular hyperplasia” is a hallmark of GBM. An altered vascular network determines irregular blood flow, so that tumor cells spread rapidly beyond the diffusion distance of oxygen in the tissue, with the consequent formation of hypoxic or anoxic areas, where the bulk of glioblastoma stem cells (GSCs reside. The response to this event is the induction of angiogenesis, a process mediated by hypoxia inducible factors. However, this new capillary network is not efficient in maintaining a proper oxygen supply to the tumor mass, thereby causing an oxygen gradient within the neoplastic zone. This microenvironment helps GSCs to remain in a “quiescent” state preserving their potential to proliferate and differentiate, thus protecting them by the effects of chemo- and radiotherapy. Recent evidences suggest that responses of glioblastoma to standard therapies are determined by the microenvironment of the niche, where the GSCs reside, allowing a variety of mechanisms that contribute to the chemo- and radioresistance, by preserving GSCs. It is, therefore, crucial to investigate the components/factors of the niche in order to formulate new adjuvant therapies rendering more efficiently the gold standard therapies for this neoplasm.

  8. Prognostic factors of craniopharyngioma with special reference to autocrine/paracrine signaling: underestimated implication of growth hormone receptor.

    Science.gov (United States)

    Ogawa, Yoshikazu; Watanabe, Mika; Tominaga, Teiji

    2015-10-01

    Craniopharyngioma is a slow-growing tumor classified as benign, but tight adhesion and significant local infiltration to the vital structures are common. In spite of improvement of modern microsurgery techniques and precise anatomical understanding not few cases of this tumor recur, and long-term tumor control and maintenance of quality of life are sometimes difficult. However, very little is known about the effects of the molecular characters of craniopharyngioma on the prognosis. Ninety eight cases of craniopharyngioma surgically treated at the Department of Neurosurgery, Tohoku University Hospital and Kohnan Hospital from April 1996 to May 2014, 45 males and 53 females aged from 2 to 80 years (mean, 40.84 years) were retrospectively reviewed, and postoperative outcomes and the possible involvement of the autocrine/paracrine mechanism were investigated. The patients were followed up at intervals of 6 months to assess tumor recurrence, and clinical outcomes were correlated with the findings of immunohistochemical examinations used growth hormone receptor (GHR) and downstream hormones. The follow-up period ranged from 3 to 209 months. Hormone expression was examined in 88 patients, of which 46 specimens (52.3 %) showed high expression of GHR. The GHR high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.007). Simultaneous high expression of growth hormone (GH) and GHR was found in 33 specimens (37.5 %), and the high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.011). No other hormones showed statistically significant differences in outcomes. High expression of GHR is associated with shorter duration of postoperative stable disease in patients with craniopharyngioma. If the surgical specimens were craniopharyngiomas with high GHR expression, GH supplementation

  9. Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation.

    Directory of Open Access Journals (Sweden)

    Simon D Tran

    Full Text Available BACKGROUND: There are reports that bone marrow cell (BM transplants repaired irradiated salivary glands (SGs and re-established saliva secretion. However, the mechanisms of action behind these reports have not been elucidated. METHODS: To test if a paracrine mechanism was the main effect behind this reported improvement in salivary organ function, whole BM cells were lysed and its soluble intracellular contents (termed as "BM Soup" injected into mice with irradiation-injured SGs. The hypothesis was that BM Soup would protect salivary cells, increase tissue neovascularization, function, and regeneration. Two minor aims were also tested a comparing two routes of delivering BM Soup, intravenous (I.V. versus intra-glandular injections, and b comparing the age of the BM Soup's donors. The treatment-comparison group consisted of irradiated mice receiving injections of living whole BM cells. Control mice received irradiation and injections of saline or sham-irradiation. All mice were followed for 8 weeks post-irradiation. RESULTS: BM Soup restored salivary flow rates to normal levels, protected salivary acinar, ductal, myoepithelial, and progenitor cells, increased cell proliferation and blood vessels, and up-regulated expression of tissue remodeling/repair/regenerative genes (MMP2, CyclinD1, BMP7, EGF, NGF. BM Soup was as an efficient therapeutic agent as injections of live BM cells. Both intra-glandular or I.V. injections of BM Soup, and from both young and older mouse donors were as effective in repairing irradiated SGs. The intra-glandular route reduced injection frequency/dosage by four-fold. CONCLUSION: BM Soup, which contains only the cell by-products, can be advantageously used to repair irradiation-damaged SGs rather than transplanting whole live BM cells which carry the risk of differentiating into unwanted/tumorigenic cell types in SGs.

  10. Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation.

    Science.gov (United States)

    Tran, Simon D; Liu, Younan; Xia, Dengsheng; Maria, Ola M; Khalili, Saeed; Wang, Renee Wan-Jou; Quan, Vu-Hung; Hu, Shen; Seuntjens, Jan

    2013-01-01

    There are reports that bone marrow cell (BM) transplants repaired irradiated salivary glands (SGs) and re-established saliva secretion. However, the mechanisms of action behind these reports have not been elucidated. To test if a paracrine mechanism was the main effect behind this reported improvement in salivary organ function, whole BM cells were lysed and its soluble intracellular contents (termed as "BM Soup") injected into mice with irradiation-injured SGs. The hypothesis was that BM Soup would protect salivary cells, increase tissue neovascularization, function, and regeneration. Two minor aims were also tested a) comparing two routes of delivering BM Soup, intravenous (I.V.) versus intra-glandular injections, and b) comparing the age of the BM Soup's donors. The treatment-comparison group consisted of irradiated mice receiving injections of living whole BM cells. Control mice received irradiation and injections of saline or sham-irradiation. All mice were followed for 8 weeks post-irradiation. BM Soup restored salivary flow rates to normal levels, protected salivary acinar, ductal, myoepithelial, and progenitor cells, increased cell proliferation and blood vessels, and up-regulated expression of tissue remodeling/repair/regenerative genes (MMP2, CyclinD1, BMP7, EGF, NGF). BM Soup was as an efficient therapeutic agent as injections of live BM cells. Both intra-glandular or I.V. injections of BM Soup, and from both young and older mouse donors were as effective in repairing irradiated SGs. The intra-glandular route reduced injection frequency/dosage by four-fold. BM Soup, which contains only the cell by-products, can be advantageously used to repair irradiation-damaged SGs rather than transplanting whole live BM cells which carry the risk of differentiating into unwanted/tumorigenic cell types in SGs.

  11. The paracrine effect of exogenous growth hormone alleviates dysmorphogenesis caused by tbx5 deficiency in zebrafish (Danio rerio embryos

    Directory of Open Access Journals (Sweden)

    Tsai Tzu-Chun

    2012-07-01

    Full Text Available Abstract Background Dysmorphogenesis and multiple organ defects are well known in zebrafish (Danio rerio embryos with T-box transcription factor 5 (tbx5 deficiencies, mimicking human Holt-Oram syndrome. Methods Using an oligonucleotide-based microarray analysis to study the expression of special genes in tbx5 morphants, we demonstrated that GH and some GH-related genes were markedly downregulated. Zebrafish embryos microinjected with tbx5-morpholino (MO antisense RNA and mismatched antisense RNA in the 1-cell stage served as controls, while zebrafish embryos co-injected with exogenous growth hormone (GH concomitant with tbx5-MO comprised the treatment group. Results The attenuating effects of GH in tbx5-MO knockdown embryos were quantified and observed at 24, 30, 48, 72, and 96 h post-fertilization. Though the understanding of mechanisms involving GH in the tbx5 functioning complex is limited, exogenous GH supplied to tbx5 knockdown zebrafish embryos is able to enhance the expression of downstream mediators in the GH and insulin-like growth factor (IGF-1 pathway, including igf1, ghra, and ghrb, and signal transductors (erk1, akt2, and eventually to correct dysmorphogenesis in various organs including the heart and pectoral fins. Supplementary GH also reduced apoptosis as determined by a TUNEL assay and decreased the expression of apoptosis-related genes and proteins (bcl2 and bad according to semiquantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis, respectively, as well as improving cell cycle-related genes (p27 and cdk2 and cardiomyogenetic genes (amhc, vmhc, and cmlc2. Conclusions Based on our results, tbx5 knockdown causes a pseudo GH deficiency in zebrafish during early embryonic stages, and supplementation of exogenous GH can partially restore dysmorphogenesis, apoptosis, cell growth inhibition, and abnormal cardiomyogenesis in tbx5 knockdown zebrafish in a paracrine manner.

  12. ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice.

    Science.gov (United States)

    Gomes, P; Chevalier, J; Boesmans, W; Roosen, L; van den Abbeel, V; Neunlist, M; Tack, J; Vanden Berghe, P

    2009-08-01

    The importance of dynamic interactions between glia and neurons is increasingly recognized, both in the central and enteric nervous system. However, apart from their protective role, little is known about enteric neuro-glia interaction. The aim was to investigate neuro-glia intercellular communication in a mouse culture model using optical techniques. Complete embryonic (E13) guts were enzymatically dissociated, seeded on coverslips and studied with immunohistochemistry and Ca(2+)-imaging. Putative progenitor-like cells (expressing both PGP9.5 and S-100) differentiated over approximately 5 days into glia or neurons expressing typical cell-specific markers. The glia-neuron ratio could be manipulated by specific supplements (N2, G5). Neurons and glia were functionally identified both by their Ca(2+)-response to either depolarization (high K(+)) or lysophosphatidic acid and by the expression of typical markers. Neurons responded to ACh, DMPP, 5-HT, ATP and electrical stimulation, while glia responded to ATP and ADPbetas. Inhibition of glial responses by MRS2179 suggests involvement of P2Y1 receptors. Neuronal stimulation also caused delayed glial responses, which were reduced by suramin and by exogenous apyrases that catalyse nucleotide breakdown. Conversely, glial responses were enhanced by ARL-67156, an ecto-ATPase inhibitor. In this mouse enteric co-culture, functional glia and neurons can be easily monitored using optical techniques. Glial cells can be activated directly by ATP or ADPbetas. Activation of neuronal cells (DMPP, K(+)) causes secondary responses in glial cells, which can be modulated by tuning ATP and ADP breakdown. This strongly supports the involvement of paracrine purinergic communication between enteric neurons and glia.

  13. A low-density culture method of cerebellar granule neurons with paracrine support applicable for the study of neuronal morphogenesis.

    Science.gov (United States)

    Kubota, Kenta; Seno, Takeshi; Konishi, Yoshiyuki

    2013-11-20

    Cerebellar granule neuronal cultures have been used to study the molecular mechanisms underlying neuronal functions, including neuronal morphogenesis. However, a limitation of this system is the difficulty to analyze isolated neurons because these are required to be maintained at a high density. Therefore, in the present study, we aimed to develop a simple and cost-effective method for culturing low-density cerebellar granule neurons. Cerebellar granule cells at two different densities (low- and high-density) were co-cultivated in order for the low-density culture to be supported by the paracrine signals from the high-density culture. This method enabled morphology analysis of isolated cerebellar granule neurons without astrocytic feeder cultures or supplements such as B27. Using this method, we investigated the function of a polarity factor. Studies using hippocampal neurons suggested that glycogen synthase kinase-3 (GSK-3) is an essential regulator of neuronal polarity, and inhibition of GSK-3 results in the formation of multiple axons. Pharmacological inhibitors for GSK-3 (6-bromoindirubin-3'-oxime and lithium chloride) did not cause the formation of multiple axons of cerebellar granule neurons but significantly reduced their length. Consistent results were obtained by introducing kinase-dead form of GSK-3 beta (K85A). These results indicated that GSK-3 is not directly involved in the control of neuronal polarity in cerebellar granule neurons. Overall, this study provides a simple method for culturing low-density cerebellar granule neurons and insights in to the neuronal-type dependent function of GSK-3 in neuronal morphogenesis. © 2013 Elsevier B.V. All rights reserved.

  14. c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling.

    Directory of Open Access Journals (Sweden)

    Nanako Kawaguchi

    2010-12-01

    Full Text Available Resident c-kit positive (c-kitpos cardiac stem cells (CSCs could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway.

  15. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    International Nuclear Information System (INIS)

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C.

    2013-01-01

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level

  16. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani [Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhassett, NY (United States); Gupta, Sanjeev [Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY (United States); Singhal, Pravin C., E-mail: psinghal@nshs.edu [Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhassett, NY (United States)

    2013-08-15

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.

  17. EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF.

    Science.gov (United States)

    Chen, Yanke; Gou, Xingchun; Kong, Derek Kai; Wang, Xiaofei; Wang, Jianhui; Chen, Zeming; Huang, Chen; Zhou, Jiangbing

    2015-10-20

    EMMPRIN, a cell adhesion molecule highly expressed in a variety of tumors, is associated with poor prognosis in cancer patients. Mechanistically, EMMPRIN has been characterized to contribute to tumor development and progression by controlling the expression of MMPs and VEGF. In the present study, by using fluorescently labeled bone marrow-derived cells (BMDCs), we found that the down-regulation of EMMPRIN expression in cancer cells reduces tumor growth and metastasis, and is associated with the reduced recruitment of BMDCs. Further protein profiling studies suggest that EMMPRIN controls BMDC recruitment through regulating the secretion of soluble factors, notably, VEGF and SDF-1. We demonstrate that the expression and secretion of SDF-1 in tumor cells are regulated by EMMPRIN. This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF.

  18. Paracrine interactions between LNCaP prostate cancer cells and bioengineered bone in 3D in vitro culture reflect molecular changes during bone metastasis.

    Science.gov (United States)

    Sieh, Shirly; Taubenberger, Anna V; Lehman, Melanie L; Clements, Judith A; Nelson, Colleen C; Hutmacher, Dietmar W

    2014-06-01

    As microenvironmental factors such as three-dimensionality and cell-matrix interactions are increasingly being acknowledged by cancer biologists, more complex 3D in vitro models are being developed to study tumorigenesis and cancer progression. To better understand the pathophysiology of bone metastasis, we have established and validated a 3D indirect co-culture model to investigate the paracrine interactions between prostate cancer (PCa) cells and human osteoblasts. Co-culture of the human PCa, LNCaP cells embedded within polyethylene glycol hydrogels with human osteoblasts in the form of a tissue engineered bone construct (TEB), resulted in reduced proliferation of LNCaP cells. LNCaP cells in both monoculture and co-culture were responsive to the androgen analog, R1881, as indicated by an increase in the expression (mRNA and/or protein induction) of androgen-regulated genes including prostate specific antigen and fatty acid synthase. Microarray gene expression analysis further revealed an up-regulation of bone markers and other genes associated with skeletal and vasculature development and a significant activation of transforming growth factor β1 downstream genes in LNCaP cells after co-culture with TEB. LNCaP cells co-cultured with TEB also unexpectedly showed similar changes in classical androgen-responsive genes under androgen-deprived conditions not seen in LNCaP monocultures. The molecular changes of LNCaP cells after co-culturing with TEBs suggest that osteoblasts exert a paracrine effect that may promote osteomimicry and modulate the expression of androgen-responsive genes in LNCaP cells. Taken together, we have presented a novel 3D in vitro model that allows the study of cellular and molecular changes occurring in PCa cells and osteoblasts that are relevant to metastatic colonization of bone. This unique in vitro model could also facilitate cancer biologists to dissect specific biological hypotheses via extensive genomic or proteomic assessments to

  19. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

    Science.gov (United States)

    Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M.; Hao, Hongying

    2016-01-01

    The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma. PMID:27063098

  20. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Cleary, Margot P. [Hormel Institute, University of Minnesota, Austin, MN 55912 (United States); Gonzalez-Perez, Ruben R. [Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30314 (United States); Torroella-Kouri, Marta, E-mail: mtorroella@med.miami.edu [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136 (United States)

    2015-01-15

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

  1. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    International Nuclear Information System (INIS)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity

  2. Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells.

    Science.gov (United States)

    Vázquez-Cuevas, Francisco G; Martínez-Ramírez, Angélica S; Robles-Martínez, Leticia; Garay, Edith; García-Carrancá, Alejandro; Pérez-Montiel, Delia; Castañeda-García, Carolina; Arellano, Rogelio O

    2014-11-01

    P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability. © 2014 Wiley Periodicals, Inc.

  3. Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes.

    Science.gov (United States)

    Feng, Allen L; Xiang, Yun-Yan; Gui, Le; Kaltsidis, Gesthika; Feng, Qingping; Lu, Wei-Yang

    2017-06-01

    This study aimed to elucidate the mechanism of increased proliferation of alpha cells in recent-onset type 1 diabetes. Pancreatic beta cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits alpha cell secretion of glucagon. We explored the roles of GABA in alpha cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro. Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10 mg/kg daily) for 12 days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2 days. The effects of GABA treatment on STZ-induced alpha cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 cell proliferation was also examined. STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta cells 12 h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the alpha cells at day 1, and a significant increase in alpha cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive cells, alpha cell mass and hyperglucagonaemia. STZ treatment also increased alpha cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca 2+ and p-mTOR, and decreased the proliferation rate of αTC1-6 cells. GABA signalling critically controls the alpha cell population in pancreatic islets. Low intraislet GABA may contribute to alpha cell hyperplasia in early type 1 diabetes.

  4. Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells.

    Science.gov (United States)

    Shen, Lei; Zeng, Wen; Wu, Yang-Xiao; Hou, Chun-Li; Chen, Wen; Yang, Ming-Can; Li, Li; Zhang, Ya-Fang; Zhu, Chu-Hong

    2013-01-01

    Angiogenesis is a major obstacle for wound healing in patients with diabetic foot wounds. Mesenchymal stem cells (MSCs) have an important function in wound repair, and neurotrophin-3 (NT-3) can promote nerve regeneration and angiogenesis. We investigated the effect of NT-3 on accelerating wound healing in the diabetic foot by improving human bone marrow MSC (hMSC) activation. In vitro, NT-3 significantly promoted VEGF, NGF, and BDNF secretion in hMSCs. NT-3 improved activation of the hMSC conditioned medium, promoted human umbilical vein endothelial cell (HUVEC) proliferation and migration, and significantly improved the closure rate of HUVEC scratches. In addition, we produced nanofiber mesh biological tissue materials through the electrospinning technique using polylactic acid, mixed silk, and collagen. The hMSCs stimulated by NT-3 were implanted into the material. Compared with the control group, the NT-3-stimulated hMSCs in the biological tissue material significantly promoted angiogenesis in the feet of diabetic C57BL/6J mice and accelerated diabetic foot wound healing. These results suggest that NT-3 significantly promotes hMSC secretion of VEGF, NGF, and other vasoactive factors and that it accelerates wound healing by inducing angiogenesis through improved activation of vascular endothelial cells. The hMSCs stimulated by NT-3 can produce materials that accelerate wound healing in the diabetic foot and other ischemic ulcers.

  5. Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

    International Nuclear Information System (INIS)

    Zhao, Liyan; Liu, Xiaolin; Zhang, Yuelin; Liang, Xiaoting; Ding, Yue; Xu, Yan; Fang, Zhen; Zhang, Fengxiang

    2016-01-01

    Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.

  6. Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Liyan; Liu, Xiaolin [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zhang, Yuelin [Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong (China); Liang, Xiaoting; Ding, Yue [Pudong District Clinical Translational Medical Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai (China); Xu, Yan; Fang, Zhen [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Zhang, Fengxiang, E-mail: njzfx6@njmu.edu.cn [Section of Pacing and Electrophysiology, Division of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2016-05-15

    Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.

  7. Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability.

    Directory of Open Access Journals (Sweden)

    Ori Nov

    Full Text Available The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1β was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF mice exhibited a preferential increase of IL-1β in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT transplant. These results raised a putative endocrine function for visceral fat-derived IL-1β in regulating hepatic gluconeogenic flux. IL-1βKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers, Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1β within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1βKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI-KO mice suggested only a minor direct effect of adipose-derived IL-1β on hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4 that were decreased by HFF in WT, were paradoxically elevated in IL-1βKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin

  8. Three-dimensional spheroid cell culture of umbilical cord tissue-derived mesenchymal stromal cells leads to enhanced paracrine induction of wound healing.

    Science.gov (United States)

    Santos, Jorge M; Camões, Sérgio P; Filipe, Elysse; Cipriano, Madalena; Barcia, Rita N; Filipe, Mariana; Teixeira, Mariana; Simões, Sandra; Gaspar, Manuela; Mosqueira, Diogo; Nascimento, Diana S; Pinto-do-Ó, Perpétua; Cruz, Pedro; Cruz, Helder; Castro, Matilde; Miranda, Joana P

    2015-05-09

    The secretion of trophic factors by mesenchymal stromal cells has gained increased interest given the benefits it may bring to the treatment of a variety of traumatic injuries such as skin wounds. Herein, we report on a three-dimensional culture-based method to improve the paracrine activity of a specific population of umbilical cord tissue-derived mesenchymal stromal cells (UCX®) towards the application of conditioned medium for the treatment of cutaneous wounds. A UCX® three-dimensional culture model was developed and characterized with respect to spheroid formation, cell phenotype and cell viability. The secretion by UCX® spheroids of extracellular matrix proteins and trophic factors involved in the wound-healing process was analysed. The skin regenerative potential of UCX® three-dimensional culture-derived conditioned medium (CM3D) was also assessed in vitro and in vivo against UCX® two-dimensional culture-derived conditioned medium (CM2D) using scratch and tubulogenesis assays and a rat wound splinting model, respectively. UCX® spheroids kept in our three-dimensional system remained viable and multipotent and secreted considerable amounts of vascular endothelial growth factor A, which was undetected in two-dimensional cultures, and higher amounts of matrix metalloproteinase-2, matrix metalloproteinase-9, hepatocyte growth factor, transforming growth factor β1, granulocyte-colony stimulating factor, fibroblast growth factor 2 and interleukin-6, when compared to CM2D. Furthermore, CM3D significantly enhanced elastin production and migration of keratinocytes and fibroblasts in vitro. In turn, tubulogenesis assays revealed increased capillary maturation in the presence of CM3D, as seen by a significant increase in capillary thickness and length when compared to CM2D, and increased branching points and capillary number when compared to basal medium. Finally, CM3D-treated wounds presented signs of faster and better resolution when compared to untreated and CM

  9. Wnt1 inhibits hydrogen peroxide-induced apoptosis in mouse cardiac stem cells.

    Directory of Open Access Journals (Sweden)

    Jingjin Liu

    Full Text Available BACKGROUND: Because of their regenerative and paracrine abilities, cardiac stem cells (CSCs are the most appropriate, optimal and promising candidates for the development of cardiac regenerative medicine strategies. However, native and exogenous CSCs in ischemic hearts are exposed to various pro-apoptotic or cytotoxic factors preventing their regenerative and paracrine abilities. METHODS AND RESULTS: We examined the effects of H2O2 on mouse CSCs (mCSCs, and observed that hydrogen peroxide (H2O2 treatment induces mCSCs apoptosis via the caspase 3 pathway, in a dose-dependent manner. We then examined the effects of Wnt1 over-expression on H2O2-induced apoptosis in mCSCs and observed that Wnt1 significantly decreased H2O2-induced apoptosis in mCSCs. On the other hand, inhibition of the canonical Wnt pathway by the secreted frizzled related protein 2 (SFRP2 or knockdown of β-catenin in mCSCs reduced cells resistance to H2O2-induced apoptosis, suggesting that Wnt1 predominantly prevents H2O2-induced apoptosis through the canonical Wnt pathway. CONCLUSIONS: Our results provide the first evidences that Wnt1 plays an important role in CSCs' defenses against H2O2-induced apoptosis through the canonical Wnt1/GSK3β/β-catenin signaling pathway.

  10. Adipocyte induced arterial calcification is prevented with sodium thiosulfate

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Neal X., E-mail: xuechen@iupui.edu [Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN (United States); O’Neill, Kalisha; Akl, Nader Kassis [Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN (United States); Moe, Sharon M. [Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN (United States); Roudebush VA Medical Center, Indianapolis, IN (United States)

    2014-06-20

    Highlights: • High phosphorus can induce calcification of adipocytes, even when fully differentiated. • Adipocytes can induce vascular calcification in an autocrine manner. • Sodium thiosulfate inhibits adipocyte calcification. - Abstract: Background: Calcification can occur in fat in multiple clinical conditions including in the dermis, breasts and in the abdomen in calciphylaxis. All of these are more common in patients with advanced kidney disease. Clinically, hyperphosphatemia and obesity are risk factors. Thus we tested the hypothesis that adipocytes can calcify in the presence of elevated phosphorus and/or that adipocytes exposed to phosphorus can induce vascular smooth muscle cell (VSMC) calcification. Methods: 3T3-L1 preadipocytes were induced into mature adipocytes and then treated with media containing high phosphorus. Calcification was assessed biochemically and PCR performed to determine the expression of genes for osteoblast and adipocyte differentiation. Adipocytes were also co-cultured with bovine VSMC to determine paracrine effects, and the efficacy of sodium thiosulfate was determined. Results: The results demonstrated that high phosphorus induced the calcification of differentiated adipocytes with increased expression of osteopontin, the osteoblast transcription factor Runx2 and decreased expression of adipocyte transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (CEBPα), indicating that high phosphorus led to a phenotypic switch of adipocytes to an osteoblast like phenotype. Sodium thiosulfate, dose dependently decreased adipocyte calcification and inhibited adipocyte induced increase of VSMC calcification. Co-culture studies demonstrated that adipocytes facilitated VSMC calcification partially mediated by changes of secretion of leptin and vascular endothelial growth factor (VEGF) from adipocytes. Conclusion: High phosphorus induced calcification of mature adipocytes, and

  11. Contrast medium-induced nephropathy: the pathophysiology

    DEFF Research Database (Denmark)

    Persson, P B; Tepel, Martin

    2006-01-01

    A widespread, rather general, definition of contrast-induced nephropathy (CIN) is an impairment in renal function occurring within 3 days following the intravascular administration of contrast media (CM) and the absence of an alternative aetiology. In spite of the vast clinical importance of CIN...... haemodynamics, regional hypoxia, auto-, and paracrine factors (adenosine, endothelin, reactive oxygen species) to direct cytotoxic effects. Although these potential mediators of CIN will be discussed separately, several factors may act in concert to perturb kidney function after exposure to contrast media. From...... the current knowledge of the mechanisms causing CIN, it is not possible to recommend a certain class of contrast media, except to avoid large doses of CM of the first generation. From a pathophysiological perspective, volume expansion is effective in avoiding CIN, since water permeability of the collecting...

  12. Exercise-induced myokines in health and metabolic diseases

    Directory of Open Access Journals (Sweden)

    Byunghun So

    2014-12-01

    Full Text Available Skeletal muscle has been emerging as a research field since the past 2 decades. Contraction of a muscle, which acts as a secretory organ, stimulates production, secretion, and expression of cytokines or other muscle fiber-derived peptides, i.e., myokines. Exercise-induced myokines influence crosstalk between different organs in an autocrine, endocrine, or paracrine fashion. Myokines are recently recognized as potential candidates for treating metabolic diseases through their ability to stimulate AMP-activated protein kinase signaling, increase glucose uptake, and improve lipolysis. Myokines may have positive effects on metabolic disorders, type 2 diabetes, or obesity. Numerous studies on myokines suggested that myokines offer a potential treatment option for preventing metabolic diseases. This review summarizes the current understanding of the positive effects of exercise-induced myokines, such as interleukin-15, brain-derived neurotrophic factor, leukemia inhibitory factor, irisin, fibroblast growth factor 21, and secreted protein acidic and rich in cysteine, on metabolic diseases.

  13. Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity

    International Nuclear Information System (INIS)

    Gatti, Monica; Pattarozzi, Alessandra; Bajetto, Adriana; Würth, Roberto; Daga, Antonio; Fiaschi, Pietro; Zona, Gianluigi; Florio, Tullio; Barbieri, Federica

    2013-01-01

    Cancer stem cells (CSCs) or tumor initiating cells (TICs) drive glioblastoma (GBM) development, invasiveness and drug resistance. Distinct molecular pathways might regulate CSC biology as compared to cells in the bulk tumor mass, representing potential therapeutic targets. Chemokine CXCL12 and its receptor CXCR4 control proliferation, invasion and angiogenesis in GBM cell lines and primary cultures, but little is known about their activity in GBM CSCs. We demonstrate that CSCs, isolated from five human GBMs, express CXCR4 and release CXCL12 in vitro, although different levels of expression and secretion were observed in individual cultures, as expected for the heterogeneity of GBMs. CXCL12 treatment induced Akt-mediated significant pro-survival and self-renewal activities, while proliferation was induced at low extent. The role of CXCR4 signaling in CSC survival and self-renewal was further demonstrated using the CXCR4 antagonist AMD3100 that reduced self-renewal and survival with greater efficacy in the cultures that released higher CXCL12 amounts. The specificity of CXCL12 in sustaining CSC survival was demonstrated by the lack of AMD3100-dependent inhibition of viability in differentiated cells derived from the same GBMs. These findings, although performed on a limited number of tumor samples, suggest that the CXCL12/CXCR4 interaction mediates survival and self-renewal in GBM CSCs with high selectivity, thus emerging as a candidate system responsible for maintenance of cancer progenitors, and providing survival benefits to the tumor

  14. Choline Phospholipid Metabolites of Human Vascular Endothelial Cells Altered by Cyclooxygenase Inhibition, Growth Factor Depletion, and Paracrine Factors Secreted by Cancer Cells

    Directory of Open Access Journals (Sweden)

    Noriko Mori

    2003-04-01

    Full Text Available Magnetic resonance studies have previously shown that solid tumors and cancer cells in culture typically exhibit high phosphocholine and total choline. Treatment of cancer cells with the anti-inflammatory agent, indomethacin (INDO, reverted the phenotype of choline phospholipid metabolites in cancer cells towards a less malignant phenotype. Since endothelial cells form a key component of tumor vasculature, in this study, we used MR spectroscopy to characterize the phenotype of choline phospholipid metabolites in human umbilical vein endothelial cells (HUVECs. We determined the effect of growth factors, the anti-inflammatory agent INDO, and conditioned media obtained from a malignant cell line, on choline phospholipid metabolites. Growth factor depletion or treatment with INDO induced similar changes in the choline phospholipid metabolites of HUVECs. Treatment with conditioned medium obtained from MDA-MB-231 cancer cells induced changes similar to the presence of growth factor supplements. These results suggest that cancer cells secrete growth factors and/or other molecules that influence the choline phospholipid metabolism of HUVECs. The ability of INDO to alter choline phospholipid metabolism in the presence of growth factor supplements suggests that the inflammatory response pathways of HUVECs may play a role in cancer cell-HUVEC interaction and in the response of HUVECs to growth factors.

  15. Engineered myocardium model to study the roles of HIF-1α and HIF1A-AS1 in paracrine-only signaling under pathological level oxidative stress.

    Science.gov (United States)

    Acun, Aylin; Zorlutuna, Pinar

    2017-08-01

    Studying heart tissue is critical for understanding and developing treatments for cardiovascular diseases. In this work, we fabricated precisely controlled and biomimetic engineered model tissues to study how cell-cell and cell-matrix interactions influence myocardial cell survival upon exposure to pathological level oxidative stress. Specifically, the interactions of endothelial cells (ECs) and cardiomyocytes (CMs), and the role of hypoxia inducible factor-1α (HIF-1α), with its novel alternative regulator, HIF-1α antisense RNA1 (HIF1A-AS1), in these interactions were investigated. We encapsulated CMs in photo-crosslinkable, biomimetic hydrogels with or without ECs, then exposed to oxidative stress followed by normoxia. With precisely controlled microenvironment provided by the model tissues, cell-cell interactions were restricted to be solely through the secreted factors. CM survival after oxidative stress was significantly improved, in the presence of ECs, when cells were in the model tissues that were functionalized with cell attachment motifs. Importantly, the cardioprotective effect of ECs was reduced when HIF-1α expression was knocked down suggesting that HIF-1α is involved in cardioprotection from oxidative damage, provided through secreted factors conferred by the ECs. Using model tissues, we showed that cell survival increased with increased cell-cell communication and enhanced cell-matrix interactions. In addition, whole genome transcriptome analysis showed, for the first time to our knowledge, a possible role for HIF1A-AS1 in oxidative regulation of HIF-1α. We showed that although HIF1A-AS1 knockdown helps CM survival, its effect is overridden by CM-EC bidirectional interactions as we showed that the conditioned media taken from the CM-EC co-cultures improved CM survival, regardless of HIF1A-AS1 expression. Cardiovascular diseases, most of which are associated with oxidative stress, is the most common cause of death worldwide. Thus, understanding

  16. Factitious thyrotoxicosis induced by mesotherapy: a case report.

    Science.gov (United States)

    Danilovic, Debora Lucia Seguro; Bloise, Walter; Knobel, Meyer; Marui, Suemi

    2008-06-01

    Mesotherapy consists of cutaneous injections of a mixture of compounds and has recently been used for cosmetic purposes to reduce local fat and cellulite. To date, several reports have described only local adverse events related to this therapy. We describe the first report of a female patient who developed thyrotoxicosis due to cosmetic mesotherapy with triiodothyroacetic acid in its formulation. Apart from mechanical rupture of the epidermal barrier, a disturbance of type III deiodinase activity or skin fibroblast paracrine function and vascular alterations related to simultaneously injected vasoactive compounds were observed. These findings could be related to thyroid hormone metabolite absorption and systemic consequences in the reported case. We describe factitious thyrotoxicosis induced by mesotherapy, to raise awareness of a systemic adverse effect resulting from this widespread cosmetic practice.

  17. Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut.

    Science.gov (United States)

    Yue, Mengfan; Xia, Yufeng; Shi, Can; Guan, Chunge; Li, Yunfan; Liu, Rui; Wei, Zhifeng; Dai, Yue

    2017-09-01

    Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg -1 , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. © 2017 Federation of European Biochemical Societies.

  18. Mechanisms of palmitate-induced cell death in human osteoblasts

    Science.gov (United States)

    Gunaratnam, Krishanthi; Vidal, Christopher; Boadle, Ross; Thekkedam, Chris; Duque, Gustavo

    2013-01-01

    Summary Lipotoxicity is an overload of lipids in non-adipose tissues that affects function and induces cell death. Lipotoxicity has been demonstrated in bone cells in vitro using osteoblasts and adipocytes in coculture. In this condition, lipotoxicity was induced by high levels of saturated fatty acids (mostly palmitate) secreted by cultured adipocytes acting in a paracrine manner. In the present study, we aimed to identify the underlying mechanisms of lipotoxicity in human osteoblasts. Palmitate induced autophagy in cultured osteoblasts, which was preceded by the activation of autophagosomes that surround palmitate droplets. Palmitate also induced apoptosis though the activation of the Fas/Jun kinase (JNK) apoptotic pathway. In addition, osteoblasts could be protected from lipotoxicity by inhibiting autophagy with the phosphoinositide kinase inhibitor 3-methyladenine or by inhibiting apoptosis with the JNK inhibitor SP600125. In summary, we have identified two major molecular mechanisms of lipotoxicity in osteoblasts and in doing so we have identified a new potential therapeutic approach to prevent osteoblast dysfunction and death, which are common features of age-related bone loss and osteoporosis. PMID:24285710

  19. Induced Abortion

    Science.gov (United States)

    ... Education & Events Advocacy For Patients About ACOG Induced Abortion Home For Patients Search FAQs Induced Abortion Page ... Induced Abortion FAQ043, May 2015 PDF Format Induced Abortion Special Procedures What is an induced abortion? What ...

  20. Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

    Science.gov (United States)

    Shi, Q; Zhang, W; Guo, S; Jian, Z; Li, S; Li, K; Ge, R; Dai, W; Wang, G; Gao, T; Li, C

    2016-01-01

    Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H2O2-induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo. PMID:26315342

  1. JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice.

    Science.gov (United States)

    Langiewicz, Magda; Graf, Rolf; Humar, Bostjan; Clavien, Pierre A

    2018-04-27

    To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (coined ALPPS; Associated Liver Partition and Portal vein ligation for Staged hepatectomy) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. JNK1 activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK diminution to substantiate their relationship during accelerated liver regeneration. Mining linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in ASMA-positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. JNK1-mediated induction of IHH paracrine signaling from HSCs is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. ALPPS, a novel two-staged hepatectomy, induces an unprecedented acceleration of liver regeneration to enable treatment of unresectable liver tumors. Here, we demonstrate JNK1-IHH signaling as a mechanism underlying the regenerative acceleration induced by ALPPS. Copyright © 2018 European

  2. Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis.

    Science.gov (United States)

    Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J; Stübig, Thomas; Prassolov, Vladimir; Fehse, Boris; Kozak, Christine A; Kröger, Nicolaus; Stocking, Carol

    2014-06-10

    The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdc(scid) and Il2rg(null) alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.

  3. Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis.

    Science.gov (United States)

    Skorupa, Alexandra; Urbach, Serge; Vigy, Oana; King, Matthew A; Chaumont-Dubel, Séverine; Prehn, Jochen H M; Marin, Philippe

    2013-10-08

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting lower and upper motoneurons. Recent studies have shown that both motor neurons and non-neuronal neighbouring cells such as astrocytes and microglia contribute to disease pathology. Loss-of-function mutations in the angiogenin (ANG) gene have been identified in ALS patients. Angiogenin is enriched in motor neurons and exerts neuroprotective effects in vitro and in vivo. We have recently shown that motoneurons secrete angiogenin, and that secreted angiogenin is exclusively taken up by astrocytes, suggesting a paracrine mechanism of neuroprotection. To gain insights into astrocyte effectors of angiogenin-induced neuroprotection, we examined alterations in the astrocyte secretome induced by angiogenin treatment using quantitative proteomics based on Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC). We identified 2128 proteins in conditioned media from primary cultured mouse astrocytes, including 1247 putative secreted proteins. Of these, 60 proteins showed significant regulation of secretion in response to angiogenin stimulation. Regulated proteins include chemokines and cytokines, proteases and protease inhibitors as well as proteins involved in reorganising the extracellular matrix. In conclusion, this proteomic analysis increases our knowledge of the astrocyte secretome and reveals potential molecular substrates underlying the paracrine, neuroprotective effects of angiogenin. This study provides the most extensive list of astrocyte-secreted proteins available and reveals novel potential molecular substrates of astrocyte-neuron communication. It also identifies a set of astrocyte-derived proteins that might slow down ALS disease progression. It should be relevant to a large readership of neuroscientists and clinicians, in particular those with an interest in the physiological and pathological roles of astrocytes and in the molecular and cellular mechanisms underlying

  4. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension.

    Science.gov (United States)

    El Kasmi, Karim C; Pugliese, Steven C; Riddle, Suzette R; Poth, Jens M; Anderson, Aimee L; Frid, Maria G; Li, Min; Pullamsetti, Soni S; Savai, Rajkumar; Nagel, Maria A; Fini, Mehdi A; Graham, Brian B; Tuder, Rubin M; Friedman, Jacob E; Eltzschig, Holger K; Sokol, Ronald J; Stenmark, Kurt R

    2014-07-15

    Macrophage accumulation is not only a characteristic hallmark but is also a critical component of pulmonary artery remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Using multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, and primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive pulmonary arteries (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL-6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL-4/IL-13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation, complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, and deficiency in C/EBPβ or HIF1 attenuated fibroblast-driven macrophage activation. These findings challenge the current paradigm of IL-4/IL-13-STAT6-mediated alternative macrophage activation as the sole driver of vascular remodeling in PH, and uncover a cross-talk between adventitial fibroblasts and macrophages in which paracrine IL-6-activated STAT3, HIF1α, and C/EBPβ signaling are critical for macrophage activation and polarization. Thus, targeting IL-6 signaling in macrophages by completely inhibiting C/EBPβ or HIF1α or by partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL-6 and absent IL-4/IL-13 signaling. Copyright © 2014 by The American Association of Immunologists

  5. Adventitial Fibroblasts induce a distinct Pro-inflammatory/Pro-fibrotic Macrophage Phenotype in Pulmonary Hypertension

    Science.gov (United States)

    El Kasmi, Karim C.; Pugliese, Steven C.; Riddle, Suzette R.; Poth, Jens M.; Anderson, Aimee L.; Frid, Maria G.; Li, Min; Pullamsetti, Soni S.; Savai, Rajkumar; Nagel, Maria A.; Fini, Mehdi A.; Graham, Brian B.; Tuder, Rubin M.; Friedman, Jacob E.; Eltzschig, Holger K.; Sokol, Ronald J.; Stenmark, Kurt R.

    2014-01-01

    Macrophage accumulation is not only a characteristic hallmark but also a critical component of pulmonary artery (PA) remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Utilizing multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, as well as primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive Pas (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL4/IL13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation while complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, while deficiency in C/EBPβ or HIF1 attenuated fibroblast driven macrophage activation. These findings challenge the current paradigm of IL4/IL13-STAT6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3, HIF1, and C/EBPβ signaling is critical for macrophage activation and polarization. Thus, targeting IL6 signaling in macrophages by completely inhibiting C/EBPβ, HIF1a or partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL6 and absent IL4/IL13 signaling. PMID:24928992

  6. Progranulin shows cytoprotective effects on trophoblast cells in vitro but does not antagonize TNF-α-induced apoptosis.

    Science.gov (United States)

    Stubert, Johannes; Waldmann, Kathrin; Dieterich, Max; Richter, Dagmar-Ulrike; Briese, Volker

    2014-11-01

    The glycoprotein progranulin directly binds to TNF-receptors and thereby can antagonize the inflammatory effects of TNF-α. Here we analyzed the impact of both cytokines on cytotoxicity and viability of trophoblast cells. Isolated villous first trimester human trophoblast cells and the human choriocarcinoma cell line BeWo were treated with recombinant human progranulin and TNF-α. Analyses were performed by LDH- and MTT-assay and measurement of caspase-8-activity. Progranulin treatment showed some cytoprotective effects on isolated trophoblast cells. However, TNF-α-induced apoptosis was not antagonized by addition of progranulin. Effects were similar, but more pronounced in BeWo cells. The cytoprotective activity of progranulin on trophoblast cells in vitro was only weak and of doubtful biologic relevance. It was not able to antagonize TNF-α. Future studies should focus on possible paracrine activities of progranulin.

  7. Hypoxic preconditioning protects photoreceptors against light damage independently of hypoxia inducible transcription factors in rods.

    Science.gov (United States)

    Kast, Brigitte; Schori, Christian; Grimm, Christian

    2016-05-01

    Hypoxic preconditioning protects photoreceptors against light-induced degeneration preserving retinal morphology and function. Although hypoxia inducible transcription factors 1 and 2 (HIF1, HIF2) are the main regulators of the hypoxic response, photoreceptor protection does not depend on HIF1 in rods. Here we used rod-specific Hif2a single and Hif1a;Hif2a double knockout mice to investigate the potential involvement of HIF2 in rods for protection after hypoxic preconditioning. To identify potential HIF2 target genes in rods we determined the retinal transcriptome of hypoxic control and rod-specific Hif2a knockouts by RNA sequencing. We show that rods do not need HIF2 for hypoxia-induced increased survival after light exposure. The transcriptomic analysis revealed a number of genes that are potentially regulated by HIF2 in rods; among those were Htra1, Timp3 and Hmox1, candidates that are interesting due to their connection to human degenerative diseases of the retina. We conclude that neither HIF1 nor HIF2 are required in photoreceptors for protection by hypoxic preconditioning. We hypothesize that HIF transcription factors may be needed in other cells to produce protective factors acting in a paracrine fashion on photoreceptor cells. Alternatively, hypoxic preconditioning induces a rod-intrinsic response that is independent of HIF transcription factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Production of interleukin-1alpha by human endometrial stromal cells is triggered during menses and dysfunctional bleeding and is induced in culture by epithelial interleukin-1alpha released upon ovarian steroids withdrawal.

    Science.gov (United States)

    Pretto, Chrystel M; Gaide Chevronnay, Héloïse P; Cornet, Patricia B; Galant, Christine; Delvaux, Denis; Courtoy, Pierre J; Marbaix, Etienne; Henriet, Patrick

    2008-10-01

    Endometrial breakdown during menstruation and dysfunctional bleeding is triggered by the abrupt expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1). The paracrine induction of MMP-1 in stromal cells via epithelium-derived IL-1alpha is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1alpha expression and bioactivity remains unknown. Variations of endometrial IL-1alpha mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1beta and IL-1 receptor antagonist. IL-1alpha is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1alpha only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1alpha, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1alpha released upon EP withdrawal. Our experiments in cultured endometrium suggest that IL-1alpha released by epithelial cells triggers the production of IL-1alpha by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.

  9. Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

    Directory of Open Access Journals (Sweden)

    Kyeung Min Joo

    Full Text Available Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

  10. Involvement of growth factors and their receptors in radon-induced rat lung tumors

    International Nuclear Information System (INIS)

    Leung, F.C.; Dagle, G.E.; Cross, F.T.

    1992-01-01

    In this paper we examine the role of growth factors (GF) and their receptors (GFR) in radon-induced rat lung tumors. Inhalation exposure of radon and its daughters induced lung tumors in rats, but the molecule/cellular mechanisms are not known. Recent evidence suggests that GF/GFR play a critical role in the growth and development of lung cancer in humans and animals. We have developed immunocytochemical methods for identifying sites of production and action of GF/GFR at the cellular level; for example, the avidin-biotin horseradish peroxidase technique. In radon-induced rat epidermoid carcinomas, epidermal growth factor (EGF), EGF-receptors (EGF-R), transforming growth factor alpha (TGF-α), and bombesin were found to be abnormally expressed. These abnormal expressions, mainly associated with epidermoid carcinomas of the lung, were not found in any other lung tumor types. Our data suggest that EGF, EGF-R, TGF-α, and bombesin are involved in radon oncogenesis in rat lungs, especially in epidermoid carcinomas, possibly through the autocrine/paracrine pathway

  11. Induced Seismicity

    Science.gov (United States)

    Keranen, Katie M.; Weingarten, Matthew

    2018-05-01

    The ability of fluid-generated subsurface stress changes to trigger earthquakes has long been recognized. However, the dramatic rise in the rate of human-induced earthquakes in the past decade has created abundant opportunities to study induced earthquakes and triggering processes. This review briefly summarizes early studies but focuses on results from induced earthquakes during the past 10 years related to fluid injection in petroleum fields. Study of these earthquakes has resulted in insights into physical processes and has identified knowledge gaps and future research directions. Induced earthquakes are challenging to identify using seismological methods, and faults and reefs strongly modulate spatial and temporal patterns of induced seismicity. However, the similarity of induced and natural seismicity provides an effective tool for studying earthquake processes. With continuing development of energy resources, increased interest in carbon sequestration, and construction of large dams, induced seismicity will continue to pose a hazard in coming years.

  12. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells

    International Nuclear Information System (INIS)

    Chen Yixing; Zeng Zhaochong; Sun Jing; Huang Yan; Zhang Zhenyu; Zeng Haiying

    2015-01-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. (author)

  13. MRP transporters as membrane machinery in the bradykinin-inducible export of ATP.

    Science.gov (United States)

    Zhao, Yumei; Migita, Keisuke; Sun, Jing; Katsuragi, Takeshi

    2010-04-01

    Adenosine triphosphate (ATP) plays the role of an autocrine/paracrine signal molecule in a variety of cells. So far, however, the membrane machinery in the export of intracellular ATP remains poorly understood. Activation of B2-receptor with bradykinin-induced massive release of ATP from cultured taenia coli smooth muscle cells. The evoked release of ATP was unaffected by gap junction hemichannel blockers, such as 18alpha-glycyrrhetinic acid and Gap 26. Furthermore, the cystic fibrosis transmembrane regulator (CFTR) coupled Cl(-) channel blockers, CFTR(inh)172, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, Gd3(+) and glibenclamide, failed to suppress the export of ATP by bradykinin. On the other, the evoked release of ATP was greatly reduced by multidrug resistance protein (MRP) transporter inhibitors, MK-571, indomethacin, and benzbromarone. From western blotting analysis, blots of MRP 1 protein only, but not MRP 2 and MRP 3 protein, appeared at 190 kD. However, the MRP 1 protein expression was not enhanced after loading with 1 muM bradykinin for 5 min. Likewise, niflumic acid and fulfenamic acid, Ca2(+)-activated Cl(-) channel blockers, largely abated the evoked release of ATP. The possibility that the MRP transporter system couples with Ca2(+)-activated Cl(-) channel activities is discussed here. These findings suggest that MRP transporters, probably MRP 1, unlike CFTR-Cl(-) channels and gap junction hemichannels, may contribute as membrane machinery to the export of ATP induced by G-protein-coupled receptor stimulation.

  14. Human-Induced Pluripotent Stem Cell Technology and Cardiomyocyte Generation: Progress and Clinical Applications

    Directory of Open Access Journals (Sweden)

    Angela Di Baldassarre

    2018-05-01

    Full Text Available Human-induced pluripotent stem cells (hiPSCs are reprogrammed cells that have hallmarks similar to embryonic stem cells including the capacity of self-renewal and differentiation into cardiac myocytes. The improvements in reprogramming and differentiating methods achieved in the past 10 years widened the use of hiPSCs, especially in cardiac research. hiPSC-derived cardiac myocytes (CMs recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models and useful tools for drug discovery and toxicology testing. In addition, hiPSCs can be used as sources of cells for cardiac regeneration in animal models. Here, we review the advances in the genetic and epigenetic control of cardiomyogenesis that underlies the significant improvement of the induced reprogramming of somatic cells to CMs; the methods used to improve scalability of throughput assays for functional screening and drug testing in vitro; the phenotypic characteristics of hiPSCs-derived CMs and their ability to rescue injured CMs through paracrine effects; we also cover the novel approaches in tissue engineering for hiPSC-derived cardiac tissue generation, and finally, their immunological features and the potential use in biomedical applications.

  15. Human-Induced Pluripotent Stem Cell Technology and Cardiomyocyte Generation: Progress and Clinical Applications.

    Science.gov (United States)

    Di Baldassarre, Angela; Cimetta, Elisa; Bollini, Sveva; Gaggi, Giulia; Ghinassi, Barbara

    2018-05-25

    Human-induced pluripotent stem cells (hiPSCs) are reprogrammed cells that have hallmarks similar to embryonic stem cells including the capacity of self-renewal and differentiation into cardiac myocytes. The improvements in reprogramming and differentiating methods achieved in the past 10 years widened the use of hiPSCs, especially in cardiac research. hiPSC-derived cardiac myocytes (CMs) recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models and useful tools for drug discovery and toxicology testing. In addition, hiPSCs can be used as sources of cells for cardiac regeneration in animal models. Here, we review the advances in the genetic and epigenetic control of cardiomyogenesis that underlies the significant improvement of the induced reprogramming of somatic cells to CMs; the methods used to improve scalability of throughput assays for functional screening and drug testing in vitro; the phenotypic characteristics of hiPSCs-derived CMs and their ability to rescue injured CMs through paracrine effects; we also cover the novel approaches in tissue engineering for hiPSC-derived cardiac tissue generation, and finally, their immunological features and the potential use in biomedical applications.

  16. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells.

    Science.gov (United States)

    Lugini, Luana; Valtieri, Mauro; Federici, Cristina; Cecchetti, Serena; Meschini, Stefania; Condello, Maria; Signore, Michele; Fais, Stefano

    2016-08-02

    Cancer cells, including colorectal cancer ones (CRC), release high amounts of nanovesicles (exosomes), delivering biochemical messages for paracrine or systemic crosstalk. Mesenchymal stromal cells (MSCs) have been shown to play contradicting roles in tumor progression. CRC exosomes induce in cMSCs: i) atypical morphology, higher proliferation, migration and invasion; ii) formation of spheroids; iii) an acidic extracellular environment associated with iv) a plasma membrane redistribution of vacuolar H+-ATPase and increased expression of CEA. Colon cancer derived MSCs, which were isolated from tumor masses, produce umbilicated spheroids, a future frequently observed in the inner core of rapidly growing tumors and recapitulate the changes observed in normal colonic MSCs exposed to CRC exosomes. Tissue specific colonic (c)MSCs were exposed to primary or metastatic CRC exosomes and analysed by light and electron microscopy, proliferation in 2D and 3D cultures, migration and invasion assays, Western blot and confocal microscopy for vacuolar H+-ATPase expression. CRC exosomes are able to induce morphological and functional changes in colonic MSCs, which may favour tumor growth and its malignant progression. Our results suggest that exosomes are actively involved in cancer progression and that inhibiting tumor exosome release may represent a way to interfere with cancer.

  17. Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice.

    Science.gov (United States)

    Rouf, Rosanne; MacFarlane, Elena Gallo; Takimoto, Eiki; Chaudhary, Rahul; Nagpal, Varun; Rainer, Peter P; Bindman, Julia G; Gerber, Elizabeth E; Bedja, Djahida; Schiefer, Christopher; Miller, Karen L; Zhu, Guangshuo; Myers, Loretha; Amat-Alarcon, Nuria; Lee, Dong I; Koitabashi, Norimichi; Judge, Daniel P; Kass, David A; Dietz, Harry C

    2017-08-03

    Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.

  18. Effects of Human Mesenchymal Stem Cells Coculture on Calcium-Induced Differentiation of Normal Human Keratinocytes.

    Science.gov (United States)

    Sah, Shyam Kishor; Kim, Hae Young; Lee, Ji Hae; Lee, Seong-Wook; Kim, Hyung-Sik; Kim, Yeon-Soo; Kang, Kyung-Sun; Kim, Tae-Yoon

    2017-06-01

    The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we cocultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes to evaluate their paracrine effect in the presence of high extracellular calcium (Ca 2+ ) concentration. High Ca 2+ environment to keratinocytes can disrupt normal skin barrier function due to abnormal/premature differentiation of keratinocytes. Surprisingly, we found that MSCs suppress both proliferation and differentiation of keratinocytes under a high Ca 2+ environment in transforming growth factors β1 (TGFβ1)-dependent manner. Furthermore, we determined that MSCs can regulate the mitogen-activated protein kinases, phosphatidylinositol 3-kinase/protein kinase B, and protein kinase C pathways in Ca 2+ -induced differentiated keratinocytes. Knockdown of TGFβ1 from MSCs results in decreased suppression of differentiation with significantly increased proliferation of keratinocytes compared with control MSCs. MSCs-derived TGFβ1 further induced growth inhibition of keratinocyte in high extracellular Ca 2+ environment as analyzed by a decrease in DNA synthesis, accumulation of phosphorylated retinoblastoma protein, cdc2, and increased mRNA level of p21, and independent of TGFβ1/SMAD pathway. Taken together, we found that MSCs-derived TGFβ1 is a critical regulator of keratinocyte function, and involves multiple proximal signaling cascades. Stem Cells 2017;35:1592-1602. © 2017 AlphaMed Press.

  19. Trimetazidine Protects Umbilical Cord Mesenchymal Stem Cells Against Hypoxia and Serum Deprivation Induced Apoptosis by Activation of Akt

    Directory of Open Access Journals (Sweden)

    Xuhe Gong

    2014-12-01

    Full Text Available Background: Mesenchymal stem cell (MSC transplantation is a promising therapy for cardiac repair. However, the efficacy is limited by the poor viability of MSCs in the infarcted heart. Recent findings have implicated that trimetazidine (TMZ enhanced the survival of the stem cells under various conditions. However, as the stem cells in these studies were animal-derived, little information is available about the effects of TMZ on human MSCs. Herein, we propose that TMZ may protect human MSCs against apoptosis induced by Hypoxia/Serum deprivation (H/SD. Methods: Human umbilical cord MSCs (UC-MSCs from Wharton's jelly were pretreated with 10µM TMZ of H/SD with or without the Akt inhibitor LY294002. The morphological changes were assessed using Hoechst 33342. Apoptosis was evaluated via Annexin V/PI staining; and apoptosis-related proteins were detected using Western-blot. Protein chip technology was used to screen for differences between the cell supernatants. Results: TMZ had a significant protective effect against H/SD-induced apoptosis, accompanied by an increase in Bcl-2 and p-Akt. The TMZ-mediated anti-apoptotic effect on MSCs could be attenuated by treatment with LY294002. Moreover, protein chip assays showed that TMZ treatment increased the paracrine functions of MSCs. Conclusion: Trimetazidine protects human UC-MSCs from H/SD-induced apoptosis via the Akt pathway and may therefore be a potentially useful therapeutic adjunct for transplanting MSCs into damaged heart after myocardial infarction.

  20. Experimental Study of the Effects of EIPA, Losartan, and BQ-123 on Electrophysiological Changes Induced by Myocardial Stretch.

    Science.gov (United States)

    Chorro, Francisco J; Canto, Irene Del; Brines, Laia; Such-Miquel, Luis; Calvo, Conrado; Soler, Carlos; Zarzoso, Manuel; Trapero, Isabel; Tormos, Álvaro; Such, Luis

    2015-12-01

    Mechanical response to myocardial stretch has been explained by various mechanisms, which include Na(+)/H(+) exchanger activation by autocrine-paracrine system activity. Drug-induced changes were analyzed to investigate the role of these mechanisms in the electrophysiological responses to acute myocardial stretch. Multiple epicardial electrodes and mapping techniques were used to analyze changes in ventricular fibrillation induced by acute myocardial stretch in isolated perfused rabbit hearts. Four series were studied: control (n = 9); during perfusion with the angiotensin receptor blocker losartan (1 μM, n = 8); during perfusion with the endothelin A receptor blocker BQ-123 (0.1 μM, n = 9), and during perfusion with the Na(+)/H(+) exchanger inhibitor EIPA (5-[N-ethyl-N-isopropyl]-amiloride) (1 μM, n = 9). EIPA attenuated the increase in the dominant frequency of stretch-induced fibrillation (control=40.4%; losartan=36% [not significant]; BQ-123=46% [not significant]; and EIPA=22% [PII receptor antagonist losartan and the endothelin A receptor blocker BQ-123 did not modify these effects. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  1. Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse

    Directory of Open Access Journals (Sweden)

    Xufeng Fu

    2018-02-01

    Full Text Available Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP. The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the

  2. Autocrine and Paracrine Hh Signaling Regulate Prostate Development

    Science.gov (United States)

    2010-09-01

    Rev. Mol. Cell. Biol. 6, 306–317 7. Wang, B. E., Shou, J., Ross, S., Koeppen, H., De Sauvage, F. J., and Gao, W. Q. (2003) J. Biol. Chem. 278, 18506...and Placzek, M. (2006) Nat. Rev. Genet. 7, 841–850 13. Callahan, C. A., Ofstad, T., Horng, L.,Wang, J. K., Zhen, H. H., Coulombe , P. A., and Oro, A. E...Albig, A. R., and Schiemann, W. P. (2005)Mol. Biol. Cell 16, 609–625 45. Olsen, M. W., Ley , C. D., Junker, N., Hansen, A. J., Lund, E. L., and Krist

  3. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals

    OpenAIRE

    Shao, Jian-Su; Cheng, Su-Li; Pingsterhaus, Joyce M.; Charlton-Kachigian, Nichole; Loewy, Arleen P.; Towler, Dwight A.

    2005-01-01

    In diabetic LDLR–/– mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg+) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg+ mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity...

  4. Cellular observations enabled by microculture: paracrine signaling and population demographics†

    Science.gov (United States)

    Domenech, Maribella; Yu, Hongmei; Warrick, Jay; Badders, Nisha M.; Meyvantsson, Ivar; Alexander, Caroline M.; Beebe, David J.

    2009-01-01

    The cellular microenvironment plays a critical role in shaping and directing the process of communication between the cells. Soluble signals are responsible for many cellular behaviors such as cell survival, proliferation and differentiation. Despite the importance of soluble signals, canonical methods are not well suited to the study of soluble factor interactions between multiple cell types. Macro-scale technology often puts cells into a convective environment that can wash away and dilute soluble signals from their targets, minimizing local concentrations of important factors. In addition, current methods such as transwells, require large numbers of cells and are limited to studying just two cell types. Here, we present data supporting the use of microchannels to study soluble factor signaling providing improved sensitivity as well as the ability to move beyond existing co-culture and conditioned medium paradigms. In addition, we present data suggesting that microculture can be used to unmask effects of population demographics. In this example the data support the hypothesis that a growth promoting subpopulation of cells exists in the mouse mammary gland. PMID:20011455

  5. Cellular observations enabled by microculture: paracrine signaling and population demographics.

    Science.gov (United States)

    Domenech, Maribella; Yu, Hongmei; Warrick, Jay; Badders, Nisha M; Meyvantsson, Ivar; Alexander, Caroline M; Beebe, David J

    2009-03-01

    The cellular microenvironment plays a critical role in shaping and directing the process of communication between the cells. Soluble signals are responsible for many cellular behaviors such as cell survival, proliferation and differentiation. Despite the importance of soluble signals, canonical methods are not well suited to the study of soluble factor interactions between multiple cell types. Macro-scale technology often puts cells into a convective environment that can wash away and dilute soluble signals from their targets, minimizing local concentrations of important factors. In addition, current methods such as transwells, require large numbers of cells and are limited to studying just two cell types. Here, we present data supporting the use of microchannels to study soluble factor signaling providing improved sensitivity as well as the ability to move beyond existing co-culture and conditioned medium paradigms. In addition, we present data suggesting that microculture can be used to unmask effects of population demographics. In this example the data support the hypothesis that a growth promoting subpopulation of cells exists in the mouse mammary gland.

  6. Plant natriuretic peptides are apoplastic and paracrine stress response molecules

    KAUST Repository

    Wang, Yuhua; Gehring, Christoph A; Irving, Helen R.

    2011-01-01

    plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions. © 2011 The Author.

  7. Both cardiomyocyte and endothelial cell Nox4 mediate protection against hemodynamic overload-induced remodelling.

    Science.gov (United States)

    Zhang, Min; Mongue-Din, Heloise; Martin, Daniel; Catibog, Norman; Smyrnias, Ioannis; Zhang, Xiaohong; Yu, Bin; Wang, Minshu; Brandes, Ralf P; Schröder, Katrin; Shah, Ajay M

    2018-03-01

    NADPH oxidase-4 (Nox4) is an important reactive oxygen species (ROS) source that is upregulated in the haemodynamically overloaded heart. Our previous studies using global Nox4 knockout (Nox4KO) mice demonstrated a protective role of Nox4 during chronic abdominal aortic banding, involving a paracrine enhancement of myocardial capillary density. However, other authors who studied cardiac-specific Nox4KO mice reported detrimental effects of Nox4 in response to transverse aortic constriction (TAC). It has been speculated that these divergent results are due to cell-specific actions of Nox4 (i.e. cardiomyocyte Nox4 detrimental but endothelial Nox4 beneficial) and/or differences in the model of pressure overload (i.e. abdominal banding vs. TAC). This study aimed to (i) investigate whether the effects of Nox4 on pressure overload-induced cardiac remodelling vary according to the pressure overload model and (ii) compare the roles of cardiomyocyte vs. endothelial cell Nox4. Global Nox4KO mice subjected to TAC developed worse cardiac remodelling and contractile dysfunction than wild-type littermates, consistent with our previous results with abdominal aortic banding. Next, we generated inducible cardiomyocyte-specific Nox4 KO mice (Cardio-Nox4KO) and endothelial-specific Nox4 KO mice (Endo-Nox4KO) and studied their responses to pressure overload. Both Cardio-Nox4KO and Endo-Nox4KO developed worse pressure overload-induced cardiac remodelling and dysfunction than wild-type littermates, associated with significant decrease in protein levels of HIF1α and VEGF and impairment of myocardial capillarization. Cardiomyocyte as well as endothelial cell Nox4 contributes to protection against chronic hemodynamic overload-induced cardiac remodelling, at least in part through common effects on myocardial capillary density. © The Author 2017 Published by Oxford University Press on behalf of the European Society of Cardiology.

  8. Microparticle-Induced Activation of the Vascular Endothelium Requires Caveolin-1/Caveolae.

    Directory of Open Access Journals (Sweden)

    Allison M Andrews

    Full Text Available Microparticles (MPs are small membrane fragments shed from normal as well as activated, apoptotic or injured cells. Emerging evidence implicates MPs as a causal and/or contributing factor in altering normal vascular cell phenotype through initiation of proinflammatory signal transduction events and paracrine delivery of proteins, mRNA and miRNA. However, little is known regarding the mechanism by which MPs influence these events. Caveolae are important membrane microdomains that function as centers of signal transduction and endocytosis. Here, we tested the concept that the MP-induced pro-inflammatory phenotype shift in endothelial cells (ECs depends on caveolae. Consistent with previous reports, MP challenge activated ECs as evidenced by upregulation of intracellular adhesion molecule-1 (ICAM-1 expression. ICAM-1 upregulation was mediated by activation of NF-κB, Poly [ADP-ribose] polymerase 1 (PARP-1 and the epidermal growth factor receptor (EGFR. This response was absent in ECs lacking caveolin-1/caveolae. To test whether caveolae-mediated endocytosis, a dynamin-2 dependent process, is a feature of the proinflammatory response, EC's were pretreated with the dynamin-2 inhibitor dynasore. Similar to observations in cells lacking caveolin-1, inhibition of endocytosis significantly attenuated MPs effects including, EGFR phosphorylation, activation of NF-κB and upregulation of ICAM-1 expression. Thus, our results indicate that caveolae play a role in mediating the pro-inflammatory signaling pathways which lead to EC activation in response to MPs.

  9. Endothelial stress induces the release of vitamin D-binding protein, a novel growth factor

    International Nuclear Information System (INIS)

    Raymond, Marc-Andre; Desormeaux, Anik; Labelle, Andree; Soulez, Mathilde; Soulez, Gilles; Langelier, Yves; Pshezhetsky, Alexey V.; Hebert, Marie-Josee

    2005-01-01

    Endothelial cells (EC) under stress release paracrine mediators that facilitate accumulation of vascular smooth muscle cells (VSCM) at sites of vascular injury. We found that medium conditioned by serum-starved EC increase proliferation and migration of VSCM in vitro. Fractionation of the conditioned medium followed by mass spectral analysis identified one bioactive component as vitamin D-binding protein (DBP). DBP induced both proliferation and migration of VSMC in vitro in association with increased phosphorylation of ERK 1/2. PD 98059, a biochemical inhibitor of ERK 1/2, abrogated these proliferative and migratory responses in VSMC. DBP is an important carrier for the vitamin-D sterols, 25-hydroxyvitamin-D, and 1α,25-dihydroxyvitamin-D. Both sterols inhibited the activity of DBP on VSMC, suggesting that vitamin D binding sites are important for initiating the activities of DBP on VSMC. Release of DBP at sites of endothelial injury represents a novel pathway favoring accumulation of VSMC at sites of vascular injury

  10. Effects of mesenchymal stem cells conditioned medium on behavioral aspects of inflammatory arthritic pain induced by CFA adjuvant

    Directory of Open Access Journals (Sweden)

    Vida Nazemian

    2016-07-01

    Full Text Available Background: Rheumatoid arthritis is a type of inflammatory pain and is an autoimmune and chronic inflammatory disease which can lead to hyperalgesia, edema and decreased motor activity in affected area. Mesenchymal stem cells conditioned medium (MSC-CM has anti-inflammatory mediators which can regulate the immune responses, alleviate inflammatory symptoms and has a paracrine effects too. The aim of this study was to evaluate the effects of mesenchymal stem cells conditioned medium on behavioral aspects of inflammatory arthritic pain which induced by CFA adjuvant.Materials and Methods: Complete Freund’s adjuvant (CFA-induced arthritis (AA was caused by single subcutaneous injection of CFA into the rats hind paw on day zero. MSC-CM was administered daily and intraperitoneal during the 21 days of the study after CFA injection. Hyperalgesia and edema were assessed on days 0, 7, 14 and 21 of the study respectively with radian heat and plethysmometer instrument.Results: The results of this study indicated the significant roles of MSC-CM in betterment of inflammatory symptoms such as hyperalgesia and edema during different stages of inflammation caused by CFA. The continuing injection of MSC-CM could reduce the inflammatory symptoms.Conclusion: Long term treatment by MSC-CM can alleviate hyperalgesia and edema and decrease those to the level of the time before induction of inflammation.   

  11. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression.

    Science.gov (United States)

    Hung, Shun-Pei; Yang, Muh-Hwa; Tseng, Kuo-Fung; Lee, Oscar K

    2013-01-01

    In solid tumors, a decreased oxygen and nutrient supply creates a hypoxic microenvironment in the central region. This hypoxic condition induces molecular responses of normal and cancer cells in the local area, including angiogenesis, metabolic changes, and metastasis. In addition, other cells including mesenchymal stem cells (MSCs) have been reported to be recruited into the hypoxic area of solid tumors. In our previous study, we found that hypoxic condition induces the secretion of growth factors and cytokines in MSCs, and here we demonstrate that elevated secretion of transforming growth factor-β1 (TGF-β1) by MSCs under hypoxia promotes the growth, motility, and invasive ability of breast cancer cells. It was found that TGF-β1 promoter activity was regulated by hypoxia, and the major hypoxia-regulated element was located between bp -1030 to -666 in front of the TGF-β1 promoter region. In ChIP assay, the results revealed that HIF-1 was bound to the hypoxia response element (HRE) of TGF-β1 promoter. Collectively, the results indicate that hypoxia microenvironment can enhance cancer cell growth through the paracrine effects of the MSCs by driving their TGF-β1 gene expression and secretion. Therefore, extra caution has to be exercised when considering hypoxia pretreatment of MSCs before cell transplantation into patients for therapeutic purposes, particularly in patients susceptible to tumor growth.

  12. Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury.

    Science.gov (United States)

    Wu, Xiaodan; Wang, Zhiming; Qian, Mengjia; Wang, Lingyan; Bai, Chunxue; Wang, Xiangdong

    2014-08-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) could modulate inflammation in experimental lung injury. On the other hand, adrenergic receptor agonists could increase DNA synthesis of stem cells. Therefore, we investigated the therapeutic role of adrenaline-stimulated BMSCs on lipopolysaccharide (LPS)-induced lung injury. BMSCs were cultured with adrenergic receptor agonists or antagonists. Suspensions of lung cells or sliced lung tissue from animals with or without LPS-induced injury were co-cultured with BMSCs. LPS-stimulated alveolar macrophages were co-cultured with BMSCs (with adrenaline stimulation or not) in Transwell for 6 hrs. A preliminary animal experiment was conducted to validate the findings in ex vivo study. We found that adrenaline at 10 μM enhanced proliferation of BMSCs through both α- and β-adrenergic receptors. Adrenaline promoted the migration of BMSCs towards LPS-injured lung cells or lung tissue. Adrenaline-stimulated BMSCs decreased the inflammation of LPS-stimulated macrophages, probably through the expression and secretion of several paracrine factors. Adrenaline reduced the extent of injury in LPS-injured rats. Our data indicate that adrenaline-stimulated BMSCs might contribute to the prevention from acute lung injury through the activation of adrenergic receptors, promotion of proliferation and migration towards injured lung, and modulation of inflammation. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  13. Specific enkephalin-degrading aminopeptidase activity in the HPT and HPO axes of rats with breast cancer induced by N-methyl nitrosourea.

    Science.gov (United States)

    Carrera, María del Pilar; Ramírez-Expósito, María Jesús; Valenzuela, María Teresa; García, María Jesús; Mayas, María Dolores; Arias de Saavedra, José Manuel; Sánchez, Rafael; Pérez, María del Carmen; Martínez-Martos, José Manuel

    2005-01-15

    State and function of breast depend on an endocrinological balance, the upsetting of which can be a factor favorable to the development of cancer. Enkephalins (ENK) have been considered as a particular form of adaptation to defense to the organism against neoplastic processes. However, ENK may modify the endocrine functions of glands such as the ovary or the thyroid through the hypothalamus-pituitary axis, acting direct or indirectly as endocrine, paracrine or autocrine stimulatory growth factors. The present work analyses enkephalin-degrading tyrosyl aminopeptidase (EDA) activity in the hypothalamus-pituitary-thyroid (HPT) and hypothalamus-pituitary-ovary (HPO) axes in a rat model of breast cancer induced by N-methyl-nitrosourea (NMU) to state the relationship between ENK levels modification through EDA activity at different neuroendocrine levels and breast cancer. Results obtained show a decrease in EDA activity in hypothalamus, anterior and posterior pituitary, thyroid and ovary, suggesting increased levels of ENK in all these locations. These ENK may induce breast cancer cell growth and progression not only at breast level, but also acting at several neuroendocrine levels such as the HPT and HPO axes, inducing an unbalance of several other hormones, which could also facilitate the progression of cancer as an undesirable concomitant effect.

  14. The Potential Role of Contraction-Induced Myokines in the Regulation of Metabolic Function for the Prevention and Treatment of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Brian P. Carson

    2017-05-01

    Full Text Available Skeletal muscle represents the largest organ in the body, comprises 36–42% of body weight, and has recently been recognized as having an endocrine function. Proteins expressed and released by muscle that have autocrine, paracrine, and endocrine bioactivities have been termed myokines. It is likely that muscle contraction represents the primary stimulus for the synthesis and secretion of myokines to enable communication with other organs such as the liver, adipose tissue, brain, and auto-regulation of muscle metabolism. To date, several hundred myokines in the muscle secretome have been identified, a sub-population of which are specifically induced by skeletal muscle contraction. However, the bioactivity of many of these myokines and the mechanism through which they act has either not yet been characterized or remains poorly understood. Physical activity and exercise are recognized as a central tenet in both the prevention and treatment of type 2 diabetes (T2D. Recent data suggest humoral factors such as muscle-derived secretory proteins may mediate the beneficial effects of exercise in the treatment of metabolic diseases. This mini-review aims to summarize our current knowledge on the role of contraction-induced myokines in mediating the beneficial effects of physical activity and exercise in the prevention and treatment of T2D, specifically glucose and lipid metabolism. Future directions as to how we can optimize contraction-induced myokine secretion to inform exercise protocols for the prevention and treatment of T2D will also be discussed.

  15. Reciprocal Signaling between the Ectoderm and a Mesendodermal Left-Right Organizer Directs Left-Right Determination in the Sea Urchin Embryo

    Science.gov (United States)

    Bessodes, Nathalie; Haillot, Emmanuel; Duboc, Véronique; Röttinger, Eric; Lahaye, François; Lepage, Thierry

    2012-01-01

    During echinoderm development, expression of nodal on the right side plays a crucial role in positioning of the rudiment on the left side, but the mechanisms that restrict nodal expression to the right side are not known. Here we show that establishment of left-right asymmetry in the sea urchin embryo relies on reciprocal signaling between the ectoderm and a left-right organizer located in the endomesoderm. FGF/ERK and BMP2/4 signaling are required to initiate nodal expression in this organizer, while Delta/Notch signaling is required to suppress formation of this organizer on the left side of the archenteron. Furthermore, we report that the H+/K+-ATPase is critically required in the Notch signaling pathway upstream of the S3 cleavage of Notch. Our results identify several novel players and key early steps responsible for initiation, restriction, and propagation of left-right asymmetry during embryogenesis of a non-chordate deuterostome and uncover a functional link between the H+/K+-ATPase and the Notch signaling pathway. PMID:23271979

  16. Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

    Science.gov (United States)

    Bernardo, Ana R; Cosgaya, José M; Aranda, Ana; Jiménez-Lara, Ana M

    2017-07-01

    Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

  17. IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17

    Directory of Open Access Journals (Sweden)

    Sandifer Tracy

    2007-07-01

    Full Text Available Abstract Background The pleiotrophic cytokine interleukin (IL-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-α (TGFα from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFα exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM17 responsible for this processing in a variety of tissues. Methods In this study, normal human bronchial epithelial (NHBE cells grown in air/liquid interface (ALI culture were used to examine the mechanisms whereby IL-13 induces release of TGFα and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFα and ADAM17 were visualized by confocal microscopy. Results IL-13 was found to induce proliferation of NHBE cells, and release of TGFα, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFα expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation. Conclusion Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFα shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13 induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFα to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13

  18. Inducing autophagy

    DEFF Research Database (Denmark)

    Harder, Lea M; Bunkenborg, Jakob; Andersen, Jens S.

    2014-01-01

    catabolism, which has recently been found to induce autophagy in an MTOR independent way and support cancer cell survival. In this study, quantitative phosphoproteomics was applied to investigate the initial signaling events linking ammonia to the induction of autophagy. The MTOR inhibitor rapamycin was used...... as a reference treatment to emphasize the differences between an MTOR-dependent and -independent autophagy-induction. By this means 5901 phosphosites were identified of which 626 were treatment-specific regulated and 175 were coregulated. Investigation of the ammonia-specific regulated sites supported that MTOR...

  19. Ectopic Overexpression of Sonic Hedgehog (Shh Induces Stromal Expansion and Metaplasia in the Adult Murine Pancreas

    Directory of Open Access Journals (Sweden)

    Volker Fendrich

    2011-10-01

    Full Text Available Ligand-dependent activation of the Hedgehog (Hh signaling pathway has been implicated in both tumor initiation and metastasis of pancreatic ductal adenocarcinoma (PDAC. Prior studies in genetically engineered mouse models (GEMMs have assessed the role of Hh signaling by cell autonomous expression of a constitutively active Gli2 within epithelial cells. On the contrary, aberrant pathway reactivation in the human exocrine pancreas occurs principally as a consequence of Sonic Hh ligand (Shh overexpression from epithelial cells. To recapitulate the cognate pathophysiology of Hh signaling observed in the human pancreas, we examined GEMM where Hh ligand is conditionally overexpressed within the mature exocrine pancreas using a tamoxifen-inducible Elastase-Cre promoter (Ela-CreERT2;LSL-mShh. We also facilitated potential cell autonomous epithelial responsiveness to secreted Hh ligand by generating compound transgenic mice with concomitant expression of the Hh receptor Smoothened (Ela-CreERT2;LSL-mShh;LSL-mSmo. Of interest, none of these mice developed intraductal precursor lesions or PDAC during the follow-up period of up to 12 months after tamoxifen induction. Instead, all animals demonstrated marked expansion of stromal cells, consistent with the previously described epithelial-to-stromal paracrine Hh signaling. Hh responsiveness was mirrored by the expression of primary cilia within the expanded mesenchymal compartment and the absence within mature acinar cells. In the absence of cooperating mutations, Hh ligand overexpression in the mature exocrine pancreas is insufficient to induce neoplasia, even when epithelial cells coexpress the Smo receptor. This autochthonous model serves as a platform for studying epithelial stromal interactions in pancreatic carcinogenesis.

  20. Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Steven D Kunkel

    Full Text Available Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II, blood vessel recruitment (Vegfa and autocrine/paracrine IGF-I signaling (Igf1. As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

  1. S100ß and fibroblast growth factor-2 are present in cultured Schwann cells and may exert paracrine actions on the peripheral nerve injury S100ß e fator de crescimento de fibroblasto-2 estão presentes nas células de Schwann cultivadas e exercem ações parácrinas na lesão do nervo

    Directory of Open Access Journals (Sweden)

    Tatiana Duobles

    2008-12-01

    Full Text Available PURPOSE: The neurotrophic factor fibroblast growth factor-2 (FGF-2, bFGF and Ca++ binding protein S100ß are expressed by the Schwann cells of the peripheral nerves and by the satellite cells of the dorsal root ganglia (DRG. Recent studies have pointed out the importance of the molecules in the paracrine mechanisms related to neuronal maintenance and plasticity of lesioned motor and sensory peripheral neurons. Moreover, cultured Schwann cells have been employed experimentally in the treatment of central nervous system lesions, in special the spinal cord injury, a procedure that triggers an enhanced sensorymotor function. Those cells have been proposed to repair long gap nerve injury. METHODS: Here we used double labeling immunohistochemistry and Western blot to better characterize in vitro and in vivo the presence of the proteins in the Schwann cells and in the satellite cells of the DRG as well as their regulation in those cells after a crush of the rat sciatic nerve. RESULTS: FGF-2 and S100ß are present in the Schwann cells of the sciatic nerve and in the satellite cells of the DRG. S100ß positive satellite cells showed increased size of the axotomized DRG and possessed elevated amount of FGF-2 immunoreactivity. Reactive satellite cells with increased FGF-2 labeling formed a ring-like structure surrounding DRG neuronal cell bodies.Reactive S100ß positive Schwann cells of proximal stump of axotomized sciatic nerve also expressed higher amounts of FGF-2. CONCLUSION: Reactive peripheral glial cells synthesizing FGF-2 and S100ß may be important in wound repair and restorative events in the lesioned peripheral nerves.OBJETIVO: O fator neurotrófico fator de crescimento de fibroblastos-2 (FGF-2, bFGF e a proteína ligante de Ca++ S100ß são expressos pelas células de Schwann dos nervos e por células satélites do gânglio da raiz dorsal (GRD. Estudos recentes indicam a importância das moléculas nos mecanismos parácrinos relacionados

  2. Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

    Science.gov (United States)

    Carrera, M P; Ramírez-Expósito, M J; Valenzuela, M T; García, M J; Mayas, M D; Arias de Saavedra, J M; Sánchez, R; Pérez, M C; Martínez-Martos, J M

    2005-02-01

    Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

  3. Anti-inflammatory and antiproliferative activities of date palm pollen (Phoenix dactylifera) on experimentally-induced atypical prostatic hyperplasia in rats

    Science.gov (United States)

    2011-01-01

    Background Atypical prostatic hyperplasia (APH) is a pseudoneoplastic lesion that can mimic prostate adenocarcinoma because of its cytologic and architectural features. Suspension of date palm pollen (DPP) is an herbal mixture that is widely used in folk medicine for male infertility. The aim of the present study was to evaluate the effect of DPP suspension and extract on APH-induced rats. Methods APH was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100mg/kg), DPP suspension (250, 500 and 1000 mg/kg), and lyophilized DPP extract (150,300 and 600 mg/kg) were given orally daily for 30 days. All medications were started 7 days after castration and along with testosterone and citral. Results The histopathological feature in APH-induced prostate rats showed evidence of hyperplasia and inflammation. Immunohistochemical examination revealed that the expressions of IL-6, IL-8, TNF-α, IGF-1 and clusterin were increased, while the expression of TGF-β1 was decreased that correlates with presence of inflammation. Moreover, histopathological examination revealed increased cellular proliferation and reduced apoptosis in ventral prostate. Both saw palmetto and DPP treatment has ameliorated these histopathological and immunohistochemical changes in APH-induced rats. These improvements were not associated with reduction in the prostatic weight that may be attributed to the persistence of edema. Conclusion DPP may have a potential protective effect in APH-induced Wistar rats through modulation of cytokine expression and/or upregulation of their autocrine/paracrine receptors. PMID:22195697

  4. Anti-inflammatory and antiproliferative activities of date palm pollen (Phoenix dactylifera on experimentally-induced atypical prostatic hyperplasia in rats

    Directory of Open Access Journals (Sweden)

    Elberry Ahmed A

    2011-12-01

    Full Text Available Abstract Background Atypical prostatic hyperplasia (APH is a pseudoneoplastic lesion that can mimic prostate adenocarcinoma because of its cytologic and architectural features. Suspension of date palm pollen (DPP is an herbal mixture that is widely used in folk medicine for male infertility. The aim of the present study was to evaluate the effect of DPP suspension and extract on APH-induced rats. Methods APH was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day and smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100mg/kg, DPP suspension (250, 500 and 1000 mg/kg, and lyophilized DPP extract (150,300 and 600 mg/kg were given orally daily for 30 days. All medications were started 7 days after castration and along with testosterone and citral. Results The histopathological feature in APH-induced prostate rats showed evidence of hyperplasia and inflammation. Immunohistochemical examination revealed that the expressions of IL-6, IL-8, TNF-α, IGF-1 and clusterin were increased, while the expression of TGF-β1 was decreased that correlates with presence of inflammation. Moreover, histopathological examination revealed increased cellular proliferation and reduced apoptosis in ventral prostate. Both saw palmetto and DPP treatment has ameliorated these histopathological and immunohistochemical changes in APH-induced rats. These improvements were not associated with reduction in the prostatic weight that may be attributed to the persistence of edema. Conclusion DPP may have a potential protective effect in APH-induced Wistar rats through modulation of cytokine expression and/or upregulation of their autocrine/paracrine receptors.

  5. Growth hormone reverses excitotoxic damage induced by kainic acid in the green iguana neuroretina.

    Science.gov (United States)

    Ávila-Mendoza, José; Mora, Janeth; Carranza, Martha; Luna, Maricela; Arámburo, Carlos

    2016-08-01

    It is known that growth hormone (GH) is expressed in extrapituitary tissues, including the nervous system and ocular tissues, where it is involved in autocrine/paracrine actions related to cell survival and anti-apoptosis in several vertebrates. Little is known, however, in reptiles, so we analyzed the expression and distribution of GH in the eye of green iguana and its potential neuroprotective role in retinas that were damaged by the intraocular administration of kainic acid (KA). It was found, by Western blotting, that GH-immunoreactivity (GH-IR) was expressed as two isoforms (15 and 26kDa, under reducing conditions) in cornea, vitreous, retina, crystalline, iris and sclera, in varying proportions. Also, two bands for the growth hormone receptor (GHR)-IR were observed (70 and 44kDa, respectively) in the same tissues. By immunofluorescence, GH-IR was found in neurons present in several layers of the neuroretina (inner nuclear [INL], outer nuclear [ONL] and ganglion cell [GCL] layers) as determined by its co-existence with NeuN, but not in glial cells. In addition, GH and GHR co-expression was found in the same cells, suggesting paracrine/autocrine interactions. KA administration induced retinal excitotoxic damage, as determined by a significant reduction of the cell density and an increase in the appearance of apoptotic cells in the INL and GCL. In response to KA injury, both endogenous GH and Insulin-like Growth Factor I (IGF-I) expression were increased by 70±1.8% and 33.3±16%, respectively. The addition of exogenous GH significantly prevented the retinal damage produced by the loss of cytoarchitecture and cell density in the GCL (from 4.9±0.79 in the control, to 1.45±0.2 with KA, to 6.35±0.49cell/mm(2) with KA+GH) and in the INL (19.12±1.6, 10.05±1.9, 21.0±0.8cell/mm(2), respectively) generated by the long-term effect of 1mM KA intraocular administration. The co-incubation with a specific anti-GH antibody, however, blocked the protective effect of GH

  6. Protein- and diabetes-induced glomerular hyperfiltration: role of glucagon, vasopressin, and urea.

    Science.gov (United States)

    Bankir, Lise; Roussel, Ronan; Bouby, Nadine

    2015-07-01

    A single protein-rich meal (or an infusion of amino acids) is known to increase the glomerular filtration rate (GFR) for a few hours, a phenomenon known as "hyperfiltration." It is important to understand the factors that initiate this upregulation because it becomes maladaptive in the long term. Several mediators and paracrine factors have been shown to participate in this upregulation, but they are not directly triggered by protein intake. Here, we explain how a rise in glucagon and in vasopressin secretion, directly induced by protein ingestion, might be the initial factors triggering the hepatic and renal events leading to an increase in the GFR. Their effects include metabolic actions in the liver and stimulation of sodium chloride reabsorption in the thick ascending limb. Glucagon is not only a glucoregulatory hormone. It is also important for the excretion of nitrogen end products by stimulating both urea synthesis in the liver (along with gluconeogenesis from amino acids) and urea excretion by the kidney. Vasopressin allows the concentration of nitrogenous end products (urea, ammonia, etc.) and other protein-associated wastes in a hyperosmotic urine, thus allowing a very significant water economy characteristic of all terrestrial mammals. No hyperfiltration occurs in the absence of one or the other hormone. Experimental results suggest that the combined actions of these two hormones, along with the complex intrarenal handling of urea, lead to alter the composition of the tubular fluid at the macula densa and to reduce the intensity of the signal activating the tubuloglomerular feedback control of GFR, thus allowing GFR to raise. Altogether, glucagon, vasopressin, and urea contribute to set up the best compromise between efficient urea excretion and water economy. Copyright © 2015 the American Physiological Society.

  7. Modeling Stem/Progenitor Cell-Induced Neovascularization and Oxygenation Around Solid Implants

    KAUST Repository

    Jain, Harsh Vardhan

    2012-07-01

    Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O(2)) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O(2)-sensitive crystals, consisting of a polymeric capsule limited by a nanoporous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells in order to stimulate peri-implant neovascularization. The sensor provided local partial O(2) pressure (pO(2)) using noninvasive electron paramagnetic resonance signal measurements. A consistently higher level of peri-implant oxygenation was observed in the cell-treatment case than in the control over a 10-week period. To provide a mechanistic explanation of these experimental observations, we present in this article a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a foreign body reaction, while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO(2) to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem cell-treated cases.

  8. Modeling Stem/Progenitor Cell-Induced Neovascularization and Oxygenation Around Solid Implants

    KAUST Repository

    Jain, Harsh Vardhan; Moldovan, Nicanor I.; Byrne, Helen M.

    2012-01-01

    Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O(2)) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O(2)-sensitive crystals, consisting of a polymeric capsule limited by a nanoporous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells in order to stimulate peri-implant neovascularization. The sensor provided local partial O(2) pressure (pO(2)) using noninvasive electron paramagnetic resonance signal measurements. A consistently higher level of peri-implant oxygenation was observed in the cell-treatment case than in the control over a 10-week period. To provide a mechanistic explanation of these experimental observations, we present in this article a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a foreign body reaction, while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO(2) to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem cell-treated cases.

  9. Modeling Stem/Progenitor Cell-Induced Neovascularization and Oxygenation Around Solid Implants

    Science.gov (United States)

    Moldovan, Nicanor I.; Byrne, Helen M.

    2012-01-01

    Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O2) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O2-sensitive crystals, consisting of a polymeric capsule limited by a nanoporous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells in order to stimulate peri-implant neovascularization. The sensor provided local partial O2 pressure (pO2) using noninvasive electron paramagnetic resonance signal measurements. A consistently higher level of peri-implant oxygenation was observed in the cell-treatment case than in the control over a 10-week period. To provide a mechanistic explanation of these experimental observations, we present in this article a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a foreign body reaction, while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO2 to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem cell-treated cases. PMID:22224628

  10. Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

    Directory of Open Access Journals (Sweden)

    Janina Müller-Deile

    2016-12-01

    Full Text Available Background: TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143 is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. Methods: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. Results: We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. Conclusion: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

  11. Exercise-Induced Asthma

    Science.gov (United States)

    ... Videos for Educators Search English Español Exercise-Induced Asthma KidsHealth / For Parents / Exercise-Induced Asthma What's in ... Exercise-Induced Asthma Print What Is Exercise-Induced Asthma? Most kids and teens with asthma have symptoms ...

  12. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis.

    Science.gov (United States)

    Jarmalavičiūtė, Akvilė; Tunaitis, Virginijus; Pivoraitė, Ugnė; Venalis, Algirdas; Pivoriūnas, Augustas

    2015-07-01

    Stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) have unique neurogenic properties that could be potentially exploited for therapeutic use. The importance of paracrine SHED signaling for neuro-regeneration has been recognized, but the exact mechanisms behind these effects are presently unknown. In the present study, we investigated the neuro-protective potential of exosomes and micro-vesicles derived from SHEDs on human dopaminergic neurons during oxidative stress-induced by 6-hydroxy-dopamine (6-OHDA). ReNcell VM human neural stem cells were differentiated into dopaminergic neurons and treated with 100 μmol/L of 6-OHDA alone or in combination with exosomes or micro-vesicles purified by ultracentrifugation from SHEDs cultivated in serum-free medium under two conditions: in standard two-dimensional culture flasks or on laminin-coated micro-carriers in a bioreactor. Real-time monitoring of apoptosis was performed with the use of time-lapse confocal microscopy and the CellEvent Caspase-3/7 green detection reagent. Exosomes but not micro-vesicles derived from SHEDs grown on the laminin-coated three-dimensional alginate micro-carriers suppressed 6-OHDA-induced apoptosis in dopaminergic neurons by approximately 80% throughout the culture period. Strikingly, no such effects were observed for the exosomes derived from SHEDs grown under standard culture conditions. Our results suggest that exosomes derived from SHEDs are considered as new potential therapeutic tool in the treatment of Parkinson's disease. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  13. Orphan nuclear receptor NR4A1 is a negative regulator of DHT-induced rat preantral follicular growth.

    Science.gov (United States)

    Xue, Kai; Liu, Jia-yin; Murphy, Bruce D; Tsang, Benjamin K

    2012-12-01

    Nuclear receptor subfamily 4 group A member1 (NR4A1), an orphan nuclear receptor, is involved in the transcriptional regulation of thecal cell androgen biosynthesis and paracrine factor insulin-like 3 (INSL3) expression. Androgens are known to play an important regulatory role in ovarian follicle growth. Using a chronically androgenized rat model, a preantral follicle culture model and virus-mediated gene delivery, we examined the role and regulation of NR4A1 in the androgenic control of preantral follicular growth. In the present study, Ki67 staining was increased in preantral follicles on ovarian sections from 5α-dihydrotestosterone (DHT)-treated rats. Preantral follicles from DHT-treated rats cultured for 4 d exhibited increased growth and up-regulation of mRNA abundance of G(1)/S-specific cyclin-D2 (Ccnd2) and FSH receptor (Fshr). Similarly, DHT (1 μm) increased preantral follicular growth and Ccnd2 and Fshr mRNA abundance in vitro. The NR4A1 expression was high in theca cells and was down-regulated by DHT in vivo and in vitro. Forced expression of NR4A1 augmented preantral follicular growth, androstenedione production, and Insl3 expression in vitro. Inhibiting the action of androgen (with androgen receptor antagonist flutamide) or INSL3 (with INSL3 receptor antagonist INSL3 B-chain) reduced NR4A1-induced preantral follicular growth. Furthermore, NR4A1 overexpression enhanced DHT-induced preantral follicular growth, a response attenuated by inhibiting INSL3. In conclusion, DHT promotes preantral follicular growth and attenuates thecal NR4A1 expression in vivo and in vitro. Our findings are consistent with the notion that NR4A1 serves as an important point of negative feedback to minimize the excessive preantral follicle growth in hyperandrogenism.

  14. Transplanted Adipose-Derived Stem Cells Ameliorate Testicular Dysfunction In A D-Galactose-Induced Aging Rat Model.

    Science.gov (United States)

    Yang, Chun; Du, Yi-Kuan; Wang, Jun; Luan, Ping; Yang, Qin-Lao; Huang, Wen-Hua; Yuan, Lin

    2015-10-01

    Glycation product accumulation during aging of slowly renewing tissues may be an important mechanism underlying aging of the testis. Adipose-derived stem cells (ADSCs) have shown promise in a novel tissue regenerative technique and may have utility in treating sexual dysfunction. ADSCs have also been found to be effective in antiaging therapy, although the mechanism underlying their effects remains unknown. This study was designed to investigate the anti-aging effect of ADSCs in a D-galactose (D-gal)-induced aging animal model and to clarify the underlying mechanism. Randomly selected 6-week-old male Sprague-Dawley rats were subcutaneously injected with D-gal daily for 8 weeks. Two weeks after completion of treatment, D-gal-induced aging rats were randomized to receive caudal vein injections of 3 × 10(6) 5-bromo 2'deoxy-uridine-labeled ADSCs or an equal volume of phosphate-buffered saline. Serum testosterone level, steroidogenic enzymes (3-β-hydroxysteroid dehydrogenase), and superoxide dismutase (SOD) activity decreased significantly in aging rats compared with the control group; serum lipid peroxidation, spermatogenic cell apoptosis, and methane dicarboxylic aldehyde (MDA) expression increased significantly. ADSCs increased the SOD level and reduced the MDA level in the aging animal model and restored levels of serum testosterone, steroidogenic enzymes, and spermatogenic cell apoptosis. These results demonstrate that ADSCs can contribute to testicular regeneration during aging. ADSCs also provide functional benefits through glycation suppression and antioxidant effects in a rat model of aging. Although some ADSCs differentiated into Leydig cells, the paracrine pathway seems to play a main role in this process, resulting in the reduction of apoptosis. © 2015 Wiley Periodicals, Inc.

  15. Prenatal Stress Induces Long-Term Effects in Cell Turnover in the Hippocampus-Hypothalamus-Pituitary Axis in Adult Male Rats

    Science.gov (United States)

    Baquedano, Eva; García-Cáceres, Cristina; Diz-Chaves, Yolanda; Lagunas, Natalia; Calmarza-Font, Isabel; Azcoitia, Iñigo; Garcia-Segura, Luis M.; Argente, Jesús; Chowen, Julie A.; Frago, Laura M.

    2011-01-01

    Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations. PMID:22096592

  16. Biological Mechanisms Underlying the Ultraviolet Radiation-Induced Formation of Skin Wrinkling and Sagging II: Over-Expression of Neprilysin Plays an Essential Role

    Directory of Open Access Journals (Sweden)

    Genji Imokawa

    2015-04-01

    Full Text Available Our previous studies strongly indicated that the up-regulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. Fortunately, we succeeded in identifying human skin fibroblast-derived elastase as a previously known enzyme, neprilysin or neutral endopeptidase (NEP. We have also characterized epithelial-mesenchymal paracrine cytokine interactions between UVB-exposed-keratinocytes and dermal fibroblasts and found that interleukin-1α and granulocyte macrophage colony stimulatory factor (GM-CSF are intrinsic cytokines secreted by UVB-exposed keratinocytes that stimulate the expression of neprilysin by fibroblasts. On the other hand, direct UVA exposure of human fibroblasts significantly stimulates the secretion of IL-6 and also elicits a significant increase in the gene expression of matrix metallo-protease(MMP-1 as well as neprilysin (to a lesser extent, which is followed by distinct increases in their protein and enzymatic activity levels. Direct UVA exposure of human keratinocytes also stimulates the secretion of IL-6, IL-8 and GM-CSF but not of IL-1 and endothelin-1. These findings suggest that GM-CSF secreted by UVA-exposed keratinocytes as well as IL-6 secreted by UVA-exposed dermal fibroblasts play important and additional roles in UVA-induced sagging and wrinkling by up-regulation of neprilysin and MMP-1, respectively, in dermal fibroblasts.

  17. Engineered FGF-2 expression induces glandular epithelial hyperplasia in the murine prostatic dorsal lobe.

    NARCIS (Netherlands)

    Takahashi, N.; Takeuchi, T.; Nishimatsu, H.; Kamijo, T.; Tomita, K.; Schalken, J.A.; Teshima, S.; Kitamura, T.

    2004-01-01

    OBJECTIVE: It is known that androgens and stromal-epithelial interactions are required for the formation and growth of the prostate. FGF-2 is overexpressed in prostatic stromal cells in benign prostatic hypertrophy (BPH)/prostate cancer. This supports the paracrine/autocrine growth of prostatic

  18. Systems Biology Reveals Cigarette Smoke-Induced Concentration-Dependent Direct and Indirect Mechanisms That Promote Monocyte-Endothelial Cell Adhesion.

    Science.gov (United States)

    Poussin, Carine; Laurent, Alexandra; Peitsch, Manuel C; Hoeng, Julia; De Leon, Hector

    2015-10-01

    Cigarette smoke (CS) affects the adhesion of monocytes to endothelial cells, a critical step in atherogenesis. Using an in vitro adhesion assay together with innovative computational systems biology approaches to analyze omics data, our study aimed at investigating CS-induced mechanisms by which monocyte-endothelial cell adhesion is promoted. Primary human coronary artery endothelial cells (HCAECs) were treated for 4 h with (1) conditioned media of human monocytic Mono Mac-6 (MM6) cells preincubated with low or high concentrations of aqueous CS extract (sbPBS) from reference cigarette 3R4F for 2 h (indirect treatment, I), (2) unconditioned media similarly prepared without MM6 cells (direct treatment, D), or (3) freshly generated sbPBS (fresh direct treatment, FD). sbPBS promoted MM6 cells-HCAECs adhesion following I and FD, but not D. In I, the effect was mediated at a low concentration through activation of vascular inflammation processes promoted in HCAECs by a paracrine effect of the soluble mediators secreted by sbPBS-treated MM6 cells. Tumor necrosis factor α (TNFα), a major inducer, was actually shed by unstable CS compound-activated TNFα-converting enzyme. In FD, the effect was triggered at a high concentration that also induced some toxicity. This effect was mediated through an yet unknown mechanism associated with a stress damage response promoted in HCAECs by unstable CS compounds present in freshly generated sbPBS, which had decayed in D unconditioned media. Aqueous CS extract directly and indirectly promotes monocytic cell-endothelial cell adhesion in vitro via distinct concentration-dependent mechanisms. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland

    Energy Technology Data Exchange (ETDEWEB)

    Konishi, Hiroyuki, E-mail: konishi@med.osaka-cu.ac.jp [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); The 21st Century COE Program ' Base to Overcome Fatigue' , Osaka City University Graduate School of Medicine, Osaka (Japan); Department of Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya (Japan); Ogawa, Tokiko, E-mail: togawa@med.osaka-cu.ac.jp [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); The 21st Century COE Program ' Base to Overcome Fatigue' , Osaka City University Graduate School of Medicine, Osaka (Japan); Kawahara, Shinichi, E-mail: kawahara@med.osaka-cu.ac.jp [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); Matsumoto, Sakiko, E-mail: s-matsumoto@med.osaka-cu.ac.jp [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); Department of Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya (Japan); Kiyama, Hiroshi, E-mail: kiyama@med.osaka-cu.ac.jp [Department of Anatomy and Neurobiology, Osaka City University Graduate School of Medicine, Osaka (Japan); The 21st Century COE Program ' Base to Overcome Fatigue' , Osaka City University Graduate School of Medicine, Osaka (Japan); Department of Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya (Japan)

    2011-04-01

    Research highlights: {yields} We focused on the rat pituitary intermediate lobe (IL) under continuous stress (CS). {yields} CS induced PAP-I and PAP-II expression in melanotrophs of the IL. {yields} This gene induction was triggered by CS-related dopamine dysregulation. {yields} PAP-I and PAP-II may sustain homeostasis of the IL under CS. -- Abstract: Under continuous stress (CS) in rats, melanotrophs, the predominant cell-type in the intermediate lobe (IL) of the pituitary, are hyperactivated to secrete {alpha}-melanocyte-stimulating hormone and thereafter degenerate. Although these phenomena are drastic, the molecular mechanisms underlying the cellular changes are mostly unknown. In this study, we focused on the pancreatitis-associated protein (PAP) family members of the secretory lectins and characterized their expression in the IL of CS model rats because we had identified two members of this family as up-regulated genes in our previous microarray analysis. RT-PCR and histological studies demonstrated that prominent PAP-I and PAP-II expression was induced in melanotrophs in the early stages of CS, while another family member, PAP-III, was not expressed. We further examined the regulatory mechanisms of PAP-I and PAP-II expression and revealed that both were induced by the decreased dopamine levels in the IL under CS. Because the PAP family members are implicated in cell survival and proliferation, PAP-I and PAP-II secreted from melanotrophs may function to sustain homeostasis of the IL under CS conditions in an autocrine or a paracrine manner.

  20. Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland

    International Nuclear Information System (INIS)

    Konishi, Hiroyuki; Ogawa, Tokiko; Kawahara, Shinichi; Matsumoto, Sakiko; Kiyama, Hiroshi

    2011-01-01

    Research highlights: → We focused on the rat pituitary intermediate lobe (IL) under continuous stress (CS). → CS induced PAP-I and PAP-II expression in melanotrophs of the IL. → This gene induction was triggered by CS-related dopamine dysregulation. → PAP-I and PAP-II may sustain homeostasis of the IL under CS. -- Abstract: Under continuous stress (CS) in rats, melanotrophs, the predominant cell-type in the intermediate lobe (IL) of the pituitary, are hyperactivated to secrete α-melanocyte-stimulating hormone and thereafter degenerate. Although these phenomena are drastic, the molecular mechanisms underlying the cellular changes are mostly unknown. In this study, we focused on the pancreatitis-associated protein (PAP) family members of the secretory lectins and characterized their expression in the IL of CS model rats because we had identified two members of this family as up-regulated genes in our previous microarray analysis. RT-PCR and histological studies demonstrated that prominent PAP-I and PAP-II expression was induced in melanotrophs in the early stages of CS, while another family member, PAP-III, was not expressed. We further examined the regulatory mechanisms of PAP-I and PAP-II expression and revealed that both were induced by the decreased dopamine levels in the IL under CS. Because the PAP family members are implicated in cell survival and proliferation, PAP-I and PAP-II secreted from melanotrophs may function to sustain homeostasis of the IL under CS conditions in an autocrine or a paracrine manner.

  1. Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.

    Science.gov (United States)

    Chung, Chih-Ling; Wang, Shih-Wei; Sun, Wei-Chih; Shu, Chih-Wen; Kao, Yu-Chen; Shiao, Meng-Shin; Chen, Chun-Lin

    2018-04-18

    Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Drug-induced thrombocytopenia

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Andersen, M; Hansen, P B

    1997-01-01

    induced by non-cytotoxic drugs is characterised by heterogeneous clinical picture and recovery is generally rapid. Although corticosteroids seem inefficient, we still recommend that severe symptomatic cases of drug-induced thrombocytopenia are treated as idiopathic thrombocytopenic purpura due...

  3. Exercise-Induced Bronchoconstriction (EIB)

    Science.gov (United States)

    ... Conditions & Treatments ▸ Conditions Dictionary ▸ Exercise-Induced Bronchoconstriction Share | Exercise-Induced Bronchoconstriction (EIB) « Back to A to Z Listing Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced ...

  4. Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

    Directory of Open Access Journals (Sweden)

    Andreas eStengel

    2013-01-01

    Full Text Available Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G-protein coupled somatostatin receptor subtypes (sst1-5 that are widely expressed in the brain and peripheral organs. The characterization of somatostatin’s effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points towards a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin in rats. By contrast, stimulation of peripheral somatostatin-sst2 signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin in rats. The peripheral sst2-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D-cell derived somatostatin acting on sst2 bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst1-5 also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

  5. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets

    Science.gov (United States)

    Möhle, Robert; Green, David; Moore, Malcolm A. S.; Nachman, Ralph L.; Rafii, Shahin

    1997-01-01

    We have shown that coculture of bone marrow microvascular endothelial cells with hematopoietic progenitor cells results in proliferation and differentiation of megakaryocytes. In these long-term cultures, bone marrow microvascular endothelial cell monolayers maintain their cellular integrity in the absence of exogenous endothelial growth factors. Because this interaction may involve paracrine secretion of cytokines, we evaluated megakaryocytic cells for secretion of vascular endothelial growth factor (VEGF). Megakaryocytes (CD41a+) were generated by ex vivo expansion of hematopoietic progenitor cells with kit-ligand and thrombopoietin for 10 days and further purified with immunomagnetic microbeads. Using reverse transcription–PCR, we showed that megakaryocytic cell lines (Dami, HEL) and purified megakaryocytes expressed mRNA of the three VEGF isoforms (121, 165, and 189 amino acids). Large quantities of VEGF (>1 ng/106 cells/3 days) were detected in the supernatant of Dami cells, ex vivo-generated megakaryocytes, and CD41a+ cells isolated from bone marrow. The constitutive secretion of VEGF by CD41a+ cells was stimulated by growth factors of the megakaryocytic lineage (interleukin 3, thrombopoietin). Western blotting of heparin–Sepharose-enriched supernatant mainly detected the isoform VEGF165. In addition, immunohistochemistry showed intracytoplasmic VEGF in polyploid megakaryocytes. Thrombin stimulation of megakaryocytes and platelets resulted in rapid release of VEGF within 30 min. We conclude that human megakaryocytes produce and secrete VEGF in an inducible manner. Within the bone marrow microenvironment, VEGF secreted by megakaryocytes may contribute to the proliferation of endothelial cells. VEGF delivered to sites of vascular injury by activated platelets may initiate angiogenesis. PMID:9012841

  6. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

    Science.gov (United States)

    2013-01-01

    Background Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. Methods Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. Results LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. Conclusions We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF. PMID:23363775

  7. Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice.

    Science.gov (United States)

    Hubert, Astrid; Bochenek, Magdalena L; Schütz, Eva; Gogiraju, Rajinikanth; Münzel, Thomas; Schäfer, Katrin

    2017-09-01

    Obesity is associated with elevated circulating leptin levels and hypothalamic leptin resistance. Leptin receptors (LepRs) are expressed on endothelial cells, and leptin promotes neointima formation in a receptor-dependent manner. Our aim was to examine the importance of endothelial LepR (End.LepR) signaling during vascular remodeling and to determine whether the cardiovascular consequences of obesity are because of hyperleptinemia or endothelial leptin resistance. Mice with loxP-flanked LepR alleles were mated with mice expressing Cre recombinase controlled by the inducible endothelial receptor tyrosine kinase promoter. Obesity was induced with high-fat diet. Neointima formation was examined after chemical carotid artery injury. Morphometric quantification revealed significantly greater intimal hyperplasia, neointimal cellularity, and proliferation in End.LepR knockout mice, and similar findings were obtained in obese, hyperleptinemic End.LepR wild-type animals. Analysis of primary endothelial cells confirmed abrogated signal transducer and activator of transcription-3 phosphorylation in response to leptin in LepR knockout and obese LepR wild-type mice. Quantitative PCR, ELISA, and immunofluorescence analyses revealed increased expression and release of endothelin-1 in End.LepR-deficient and LepR-resistant cells, and ET receptor A/B antagonists abrogated their paracrine effects on murine aortic smooth muscle cell proliferation. Reduced expression of peroxisome proliferator-activated receptor-γ and increased nuclear activator protein-1 staining was observed in End.LepR-deficient and LepR-resistant cells, and peroxisome proliferator-activated receptor-γ antagonization increased endothelial endothelin-1 expression. Our findings suggest that intact endothelial leptin signaling limits neointima formation and that obesity represents a state of endothelial leptin resistance. These observations and the identification of endothelin-1 as soluble mediator of the

  8. M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop.

    Science.gov (United States)

    Carroll, Molly J; Kapur, Arvinder; Felder, Mildred; Patankar, Manish S; Kreeger, Pamela K

    2016-12-27

    In ovarian cancer, a high ratio of anti-inflammatory M2 to pro-inflammatory M1 macrophages correlates with poor patient prognosis. The mechanisms driving poor tumor outcome as a result of the presence of M2 macrophages in the tumor microenvironment remain unclear and are challenging to study with current techniques. Therefore, in this study we utilized a micro-culture device previously developed by our lab to model concentrated paracrine signaling in order to address our hypothesis that interactions between M2 macrophages and ovarian cancer cells induce tumor cell proliferation. Using the micro-culture device, we determined that co-culture with M2-differentiated primary macrophages or THP-1 increased OVCA433 proliferation by 10-12%. This effect was eliminated with epidermal growth factor receptor (EGFR) or heparin-bound epidermal growth factor (HB-EGF) neutralizing antibodies and HBEGF expression in peripheral blood mononuclear cells from ovarian cancer patients was 9-fold higher than healthy individuals, suggesting a role for HB-EGF in tumor progression. However, addition of HB-EGF at levels secreted by macrophages or macrophage-conditioned media did not induce proliferation to the same extent, indicating a role for other factors in this process. Matrix metalloproteinase-9, MMP-9, which cleaves membrane-bound HB-EGF, was elevated in co-culture and its inhibition decreased proliferation. Utilizing inhibitors and siRNA against MMP9 in each population, we determined that macrophage-secreted MMP-9 released HB-EGF from macrophages, which increased MMP9 in OVCA433, resulting in a positive feedback loop to drive HB-EGF release and increase proliferation in co-culture. Identification of multi-cellular interactions such as this may provide insight into how to most effectively control ovarian cancer progression.

  9. Induced pluripotency with endogenous and inducible genes

    International Nuclear Information System (INIS)

    Duinsbergen, Dirk; Eriksson, Malin; Hoen, Peter A.C. 't; Frisen, Jonas; Mikkers, Harald

    2008-01-01

    The recent discovery that two partly overlapping sets of four genes induce nuclear reprogramming of mouse and even human cells has opened up new possibilities for cell replacement therapies. Although the combination of genes that induce pluripotency differs to some extent, Oct4 and Sox2 appear to be a prerequisite. The introduction of four genes, several of which been linked with cancer, using retroviral approaches is however unlikely to be suitable for future clinical applications. Towards developing a safer reprogramming protocol, we investigated whether cell types that express one of the most critical reprogramming genes endogenously are predisposed to reprogramming. We show here that three of the original four pluripotency transcription factors (Oct4, Klf4 and c-Myc or MYCER TAM ) induced reprogramming of mouse neural stem (NS) cells exploiting endogenous SoxB1 protein levels in these cells. The reprogrammed neural stem cells differentiated into cells of each germ layer in vitro and in vivo, and contributed to mouse development in vivo. Thus a combinatorial approach taking advantage of endogenously expressed genes and inducible transgenes may contribute to the development of improved reprogramming protocols

  10. Diet induced thermogenesis

    Directory of Open Access Journals (Sweden)

    Westerterp KR

    2004-08-01

    Full Text Available Objective Daily energy expenditure consists of three components: basal metabolic rate, diet-induced thermogenesis and the energy cost of physical activity. Here, data on diet-induced thermogenesis are reviewed in relation to measuring conditions and characteristics of the diet. Methods Measuring conditions include nutritional status of the subject, physical activity and duration of the observation. Diet characteristics are energy content and macronutrient composition. Results Most studies measure diet-induced thermogenesis as the increase in energy expenditure above basal metabolic rate. Generally, the hierarchy in macronutrient oxidation in the postprandial state is reflected similarly in diet-induced thermogenesis, with the sequence alcohol, protein, carbohydrate, and fat. A mixed diet consumed at energy balance results in a diet induced energy expenditure of 5 to 15 % of daily energy expenditure. Values are higher at a relatively high protein and alcohol consumption and lower at a high fat consumption. Protein induced thermogenesis has an important effect on satiety. In conclusion, the main determinants of diet-induced thermogenesis are the energy content and the protein- and alcohol fraction of the diet. Protein plays a key role in body weight regulation through satiety related to diet-induced thermogenesis.

  11. Induced quantum conformal gravity

    International Nuclear Information System (INIS)

    Novozhilov, Y.V.; Vassilevich, D.V.

    1988-11-01

    Quantum gravity is considered as induced by matter degrees of freedom and related to the symmetry breakdown in the low energy region of a non-Abelian gauge theory of fundamental fields. An effective action for quantum conformal gravity is derived where both the gravitational constant and conformal kinetic term are positive. Relation with induced classical gravity is established. (author). 15 refs

  12. Induced radioactivity at CERN

    CERN Multimedia

    1970-01-01

    A description of some of the problems and some of the advantages associated with the phenomenon of induced radioactivity at accelerator centres such as CERN. The author has worked in this field for several years and has recently written a book 'Induced Radioactivity' published by North-Holland.

  13. Diet induced thermogenesis

    NARCIS (Netherlands)

    Westerterp, K.R.

    2004-01-01

    OBJECTIVE: Daily energy expenditure consists of three components: basal metabolic rate, diet-induced thermogenesis and the energy cost of physical activity. Here, data on diet-induced thermogenesis are reviewed in relation to measuring conditions and characteristics of the diet. METHODS: Measuring

  14. Bleomycin-induced pneumonitis

    NARCIS (Netherlands)

    S. Sleijfer (Stefan)

    2001-01-01

    textabstractThe cytotoxic agent bleomycin is feared for its induction of sometimes fatal pulmonary toxicity, also known as bleomycin-induced pneumonitis (BIP). The central event in the development of BIP is endothelial damage of the lung vasculature due to bleomycin-induced

  15. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

    Directory of Open Access Journals (Sweden)

    Shi Yandong

    2012-12-01

    Full Text Available Abstract Background Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. Methods The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. Results We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the

  16. Induced abortion in Taiwan.

    Science.gov (United States)

    Wang, P D; Lin, R S

    1995-04-01

    Induced abortion is widely practised in Taiwan; however, it had been illegal until 1985. It was of interest to investigate induced abortion practices in Taiwan after its legalization in 1985 in order to calculate the prevalence rate and ratio of induced abortion to live births and to pregnancies in Taiwan. A study using questionnaires through personal interviews was conducted on more than seventeen thousand women who attended a family planning service in Taipei metropolitan areas between 1991 and 1992. The reproductive history and sexual behaviour of the subjects were especially focused on during the interviews. Preliminary findings showed that 46% of the women had a history of having had an induced abortion. Among them, 54.8% had had one abortion, 29.7% had had two, and 15.5% had had three or more. The abortion ratio was 379 induced abortions per 1,000 live births and 255 per 1,000 pregnancies. The abortion ratio was highest for women younger than 20 years of age, for aboriginal women and for nulliparous women. When logistic regression was used to control for confounding variables, we found that the number of previous live births is the strongest predictor relating to women seeking induced abortion. In addition, a significant positive association exists between increasing number of induced abortions and cervical dysplasia.

  17. Photon induced reactions

    International Nuclear Information System (INIS)

    Mecking, B.A.

    1982-04-01

    Various aspects of medium energy nuclear reactions induced by real photons are reviewed. Special emphasis is put on high accuracy experiments that will become possible with the next generation of electron accelerators. (orig.)

  18. Induced Noise Control

    National Research Council Canada - National Science Library

    Maidanik, G

    2002-01-01

    The induced noise control parameter is defined in terms of the ratio of the stored energy in a master dynamic system, when it is coupled to an adjunct dynamic system, to that stored energy when the coupling is absent...

  19. Beam induced RF heating

    CERN Document Server

    Salvant, B; Arduini, G; Assmann, R; Baglin, V; Barnes, M J; Bartmann, W; Baudrenghien, P; Berrig, O; Bracco, C; Bravin, E; Bregliozzi, G; Bruce, R; Bertarelli, A; Carra, F; Cattenoz, G; Caspers, F; Claudet, S; Day, H; Garlasche, M; Gentini, L; Goddard, B; Grudiev, A; Henrist, B; Jones, R; Kononenko, O; Lanza, G; Lari, L; Mastoridis, T; Mertens, V; Métral, E; Mounet, N; Muller, J E; Nosych, A A; Nougaret, J L; Persichelli, S; Piguiet, A M; Redaelli, S; Roncarolo, F; Rumolo, G; Salvachua, B; Sapinski, M; Schmidt, R; Shaposhnikova, E; Tavian, L; Timmins, M; Uythoven, J; Vidal, A; Wenninger, J; Wollmann, D; Zerlauth, M

    2012-01-01

    After the 2011 run, actions were put in place during the 2011/2012 winter stop to limit beam induced radio frequency (RF) heating of LHC components. However, some components could not be changed during this short stop and continued to represent a limitation throughout 2012. In addition, the stored beam intensity increased in 2012 and the temperature of certain components became critical. In this contribution, the beam induced heating limitations for 2012 and the expected beam induced heating limitations for the restart after the Long Shutdown 1 (LS1) will be compiled. The expected consequences of running with 25 ns or 50 ns bunch spacing will be detailed, as well as the consequences of running with shorter bunch length. Finally, actions on hardware or beam parameters to monitor and mitigate the impact of beam induced heating to LHC operation after LS1 will be discussed.

  20. Vitiligo, drug induced (image)

    Science.gov (United States)

    ... this person's face have resulted from drug-induced vitiligo. Loss of melanin, the primary skin pigment, occasionally ... is the case with this individual. The typical vitiligo lesion is flat and depigmented, but maintains the ...

  1. Radiation induced microvascular damage in the rat spinal cord: cellular and secretory factors

    International Nuclear Information System (INIS)

    Pfeffer, M. Raphael; Siegal, Tali; Meltzer, A; Shezen, E; Ovadia, Haim

    1996-01-01

    is a marked imbalance in the endothelium derived mediators of vascular tone which probably induces chronic vasoconstriction and local pro coagulation. Microglial proliferation may account for continued release of superoxide. These factors may influence the consequent loss of function manifested by increased vascular permeability that is corrected with SOD. Astrocytic proliferation may be a response to the mitogenic effect of endothelin and microglial derived paracrine effect of cytokines

  2. Terahertz Induced Electromigration

    DEFF Research Database (Denmark)

    Strikwerda, Andrew; Zalkovskij, Maksim; Iwaszczuk, Krzysztof

    2014-01-01

    We report the first observation of THz-field-induced electromigration in subwavelength metallic gap structures after exposure to intense single-cycle, sub-picosecond electric field transients of amplitude up to 400 kV/cm.......We report the first observation of THz-field-induced electromigration in subwavelength metallic gap structures after exposure to intense single-cycle, sub-picosecond electric field transients of amplitude up to 400 kV/cm....

  3. Diet induced thermogenesis

    OpenAIRE

    Westerterp KR

    2004-01-01

    Objective Daily energy expenditure consists of three components: basal metabolic rate, diet-induced thermogenesis and the energy cost of physical activity. Here, data on diet-induced thermogenesis are reviewed in relation to measuring conditions and characteristics of the diet. Methods Measuring conditions include nutritional status of the subject, physical activity and duration of the observation. Diet characteristics are energy content and macronutrient composition. Resu...

  4. Laser-induced interactions

    International Nuclear Information System (INIS)

    Green, W.R.

    1979-01-01

    This dissertation discusses some of the new ways that lasers can be used to control the energy flow in a medium. Experimental and theoretical considerations of the laser-induced collision are discussed. The laser-induced collision is a process in which a laser is used to selectively transfer energy from a state in one atomic or molecular species to another state in a different species. The first experimental demonstration of this process is described, along with later experiments in which lasers were used to create collisional cross sections as large as 10 - 13 cm 2 . Laser-induced collisions utilizing both a dipole-dipole interaction and dipole-quadrupole interaction have been experimentally demonstrated. The theoretical aspects of other related processes such as laser-induced spin-exchange, collision induced Raman emission, and laser-induced charge transfer are discussed. Experimental systems that could be used to demonstrate these various processes are presented. An experiment which produced an inversion of the resonance line of an ion by optical pumping of the neutral atom is described. This type of scheme has been proposed as a possible method for constructing VUV and x-ray lasers

  5. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature

    OpenAIRE

    Lobov, Ivan B.; Rao, Sujata; Carroll, Thomas J.; Vallance, Jefferson E.; Ito, Masataka; Ondr, Jennifer K.; Kurup, Savita; Glass, Donald A.; Patel, Millan S.; Shu, Weiguo; Morrisey, Edward E.; McMahon, Andrew P.; Karsenty, Gerard; Lang, Richard A.

    2005-01-01

    Macrophages have a critical role in inflammatory and immune responses through their ability to recognize and engulf apoptotic cells1. Here we show that macrophages initiate a cell-death programme in target cells by activating the canonical WNT pathway. We show in mice that macrophage WNT7b is a short-range paracrine signal required for WNT-pathway responses and programmed cell death in the vascular endothelial cells of the temporary hyaloid vessels of the developing eye. These findings indica...

  6. Radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Ohyama, Harumi

    1995-01-01

    Apoptosis is an active process of gene-directed cellular self-destruction that can be induced in many cell types via numerous physiological and pathological stimuli. We found that interphasedeath of thymocytes is a typical apoptosis showing the characteristic features of apoptosis including cell shrinkage, chromatin condensation and DNA degradation. Moderate dose of radiation induces extensive apoptosis in rapidly proliferating cell population such as the epithelium of intestinal crypt. Recent reports indicate that the ultimate form of radiation-induced mitotic death in several cells is also apoptosis. One of the hallmarks of apoptosis is the enzymatic internucleosomal degradation of chromatin DNA. We identified an endonuclease responsible for the radiation-induced DNA degradation in rat thymocytes. The death-sparing effects of interrupting RNA and protein synthesis suggested a cell genetic program for apoptosis. Apoptosis of thymocytes initiated by DNA damage, such as radiation and radio mimetic substance, absolutely requires the protein of p53 cancer suppresser gene. The cell death induced by glucocorticoid, or aging, has no such requirement. Expression of oncogene bcl-2 rescues cells from the apoptosis. Massive apoptosis in radiosensitive cells induced by higher dose radiation may be fatal. It is suggested that selective apoptotic elimination of cells would play an important role for protection against carcinogenesis and malformation through removal of cells with unrepaired radiation-induced DNA damages. Data to evaluate the significance of apoptosis in the radiation risk are still poor. Further research should be done in order to clarify the roles of the cell death on the acute and late effects of irradiation. (author)

  7. Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction

    Directory of Open Access Journals (Sweden)

    Melissa Touvron

    2012-07-01

    Cardiac fibrosis is critically involved in the adverse remodeling accompanying dilated cardiomyopathies (DCMs, which leads to cardiac dysfunction and heart failure (HF. Connective tissue growth factor (CTGF, a profibrotic cytokine, plays a key role in this deleterious process. Some beneficial effects of IGF1 on cardiomyopathy have been described, but its potential role in improving DCM is less well characterized. We investigated the consequences of expressing a cardiac-specific transgene encoding locally acting IGF1 propeptide (muscle-produced IGF1; mIGF1 on disease progression in a mouse model of DCM [cardiac-specific and inducible serum response factor (SRF gene disruption] that mimics some forms of human DCM. Cardiac-specific mIGF1 expression substantially extended the lifespan of SRF mutant mice, markedly improved cardiac functions, and delayed both DCM and HF. These protective effects were accompanied by an overall improvement in cardiomyocyte architecture and a massive reduction of myocardial fibrosis with a concomitant amelioration of inflammation. At least some of the beneficial effects of mIGF1 transgene expression were due to mIGF1 counteracting the strong increase in CTGF expression within cardiomyocytes caused by SRF deficiency, resulting in the blockade of fibroblast proliferation and related myocardial fibrosis. These findings demonstrate that SRF plays a key role in the modulation of cardiac fibrosis through repression of cardiomyocyte CTGF expression in a paracrine fashion. They also explain how impaired SRF function observed in human HF promotes fibrosis and adverse cardiac remodeling. Locally acting mIGF1 efficiently protects the myocardium from these adverse processes, and might thus represent a therapeutic avenue to counter DCM.

  8. Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human beta-defensin 2 in middle ear epithelial cells

    Directory of Open Access Journals (Sweden)

    Park Raekil

    2006-01-01

    Full Text Available Abstract Background We recently showed that beta-defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi and that interleukin 1 alpha (IL-1 alpha up-regulates the transcription of beta-defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on beta-defensin 2 up-regulation by the bacterial components. Methods The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media (OM. Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure. Real time quantitative PCR was done to compare the induction of IL-1 alpha or beta-defensin 2 mRNAs and to identify the signaling pathways involved. Direct activation of the beta-defensin 2 promoter was monitored using a beta-defensin 2 promoter-Luciferase construct. An IL-1 alpha blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB4 induction. Results Middle ear epithelial cells released IL-1 alpha when stimulated by NTHi components and this cytokine acted in an autocrine/paracrine synergistic manner with NTHi to up-regulate beta-defensin 2. This synergistic effect of IL-1 alpha on NTHi-induced beta-defensin 2 up-regulation appeared to be mediated by the p38 MAP kinase pathway. Conclusion We demonstrate that IL-1 alpha is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate beta-defensin 2 via the p38 MAP kinase pathway.

  9. Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet-induced obesity model.

    Science.gov (United States)

    Daltro, P S; Barreto, B C; Silva, P G; Neto, P Chenaud; Sousa Filho, P H F; Santana Neta, D; Carvalho, G B; Silva, D N; Paredes, B D; de Alcantara, A C; Freitas, L A R; Couto, R D; Santos, R R; Souza, B S F; Soares, M B P; Macambira, S G

    2017-10-01

    Obesity is associated with numerous cardiac complications, including arrhythmias, cardiac fibrosis, remodeling and heart failure. Here we evaluated the therapeutic potential of mesenchymal stromal cells (MSCs) and their conditioned medium (CM) to treat cardiac complications in a mouse model of high-fat diet (HFD)-induced obesity. After obesity induction and HFD withdrawal, obese mice were treated with MSCs, CM or vehicle. Cardiac function was assessed using electrocardiography, echocardiography and treadmill test. Body weight and biochemical parameters were evaluated. Cardiac tissue was used for real time (RT)-polymerase chain reaction (PCR) and histopathologic analysis. Characterization of CM by protein array showed the presence of different cytokines and growth factors, including chemokines, osteopontin, cystatin C, Serpin E1 and Gas 6. HFD-fed mice presented cardiac arrhythmias, altered cardiac gene expression and fibrosis reflected in physical exercise incapacity associated with obesity and diabetes. Administration of MSCs or CM improved arrhythmias and exercise capacity. This functional improvement correlated with normalization of GATA4 gene expression in the hearts of MSC- or CM-treated mice. The gene expression of connexin 43, troponin I, adiponectin, transforming growth factor (TGF) β, peroxisome proliferator activated receptor gamma (PPARγ), insulin-like growth factor 1 (IGF-1), matrix metalloproteinase-9 (MMP9) and tissue inhibitor of metalloproteinases 1 (TIMP1) were significantly reduced in MSCs, but not in CM-treated mice. Moreover, MSC or CM administration reduced the intensity of cardiac fibrosis. Our results suggest that MSCs and CM have a recovery effect on cardiac disturbances due to obesity and corroborate to the paracrine action of MSCs in heart disease models. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  10. Mesenchymal stem cells induce dermal fibroblast responses to injury

    International Nuclear Information System (INIS)

    Smith, Andria N.; Willis, Elise; Chan, Vincent T.; Muffley, Lara A.; Isik, F. Frank; Gibran, Nicole S.; Hocking, Anne M.

    2010-01-01

    Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.

  11. Chemical-induced Vitiligo

    Science.gov (United States)

    Harris, John E.

    2016-01-01

    Synopsis Chemical-induced depigmentation of the skin has been recognized for over 75 years, first as an occupational hazard but then extending to those using household commercial products as common as hair dyes. Since their discovery, these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance. The importance of recognizing this phenomenon was highlighted during an outbreak of vitiligo in Japan during the summer of 2013, when over 16,000 users of a new skin lightening cosmetic cream developed skin depigmentation at the site of contact with the cream and many in remote areas as well. Depigmenting chemicals appear to be analogs of the amino acid tyrosine that disrupt melanogenesis and result in autoimmunity and melanocyte destruction. Because chemical-induced depigmentation is clinically and histologically indistinguishable from non-chemically induced vitiligo, and because these chemicals appear to induce melanocyte autoimmunity, this phenomenon should be known as “chemical-induced vitiligo”, rather than less accurate terms that have been previously used. PMID:28317525

  12. IGF-binding proteins mediate TGF-beta 1-induced apoptosis in bovine mammary epithelial BME-UV1 cells.

    Science.gov (United States)

    Gajewska, Małgorzata; Motyl, Tomasz

    2004-10-01

    TGF-beta 1 is an antiproliferative and apoptogenic factor for mammary epithelial cells (MEC) acting in an auto/paracrine manner and thus considered an important local regulator of mammary tissue involution. However, the apoptogenic signaling pathway induced by this cytokine in bovine MEC remains obscure. The present study was focused on identification of molecules involved in apoptogenic signaling of transforming growth factor-beta 1 (TGF-beta 1) in the model of bovine mammary epithelial cell line (BME-UV1). Laser scanning cytometry (LSC), Western blot and electrophoretic mobility shift assay (EMSA) were used for analysis of expression and activity of TGF-beta 1-related signaling molecules. The earliest response occurring within 1-2 h after TGF-beta 1 administration was an induction and activation of R-Smads (Smad2 and Smad3) and Co-Smad (Smad4). An evident formation of Smad-DNA complexes began from 2nd hour after MEC exposure to TGF-beta 1. Similarly to Smads, proteins of AP1 complex: phosphorylated c-Jun and JunD appeared to be early reactive molecules; however, an increase in their expression was detected only in cytosolic fraction. In the next step, an increase of IGF binding protein-3 (IGFBP-3) and IGFBP-4 expression was observed from 6th hour followed by a decrease in the activity of protein kinase B (PKB/Akt), which occurred after 24 h of MEC exposure to TGF-beta 1. The decrease in PKB/Akt activity coincided in time with the decline of phosphorylated Bad expression (inactive form). Present study supported additional evidence that stimulation of insulin-like growth factor I (IGF-I) was associated with complete abrogation of TGF-beta 1-induced activation of Bad and Bax and in the consequence protection against apoptosis. In conclusion, apoptotic effect of TGF-beta 1 in bovine MEC is mediated by IGFBPs and occurs through IGF-I sequestration, resulting in inhibition of PKB/Akt-dependent survival pathway.

  13. [Drug induced diarrhea].

    Science.gov (United States)

    Morard, Isabelle; Hadengue, Antoine

    2008-09-03

    Diarrhea is a frequent adverse event involving the most frequently antibiotics, laxatives and NSAI. Drug induced diarrhea may be acute or chronic. It may be due to expected, dose dependant properties of the drug, to immuno-allergic or bio-genomic mechanisms. Several pathophysiological mechanisms have been described resulting in osmotic, secretory or inflammatory diarrhea, shortened transit time, or malabsorption. Histopathological lesions sometimes associated with drug induced diarrhea are usually non specific and include ulcerations, inflammatory or ischemic lesions, fibrous diaphragms, microscopic colitis and apoptosis. The diagnosis of drug induced diarrhea, sometimes difficult to assess, relies on the absence of other obvious causes and on the rapid disappearance of the symptoms after withdrawal of the suspected drug.

  14. CD1d-restricted IFN-γ-secreting NKT cells promote immune complex-induced acute lung injury by regulating macrophage-inflammatory protein-1α production and activation of macrophages and dendritic cells.

    Science.gov (United States)

    Kim, Ji Hyung; Chung, Doo Hyun

    2011-02-01

    Immune complex-induced acute lung injury (IC-ALI) has been implicated in various pulmonary disease states. However, the role of NKT cells in IC-ALI remains unknown. Therefore, we explored NKT cell functions in IC-ALI using chicken egg albumin and anti-chicken egg albumin IgG. The bronchoalveolar lavage fluid of CD1d(-/-) and Jα18(-/-) mice contained few Ly6G(+)CD11b(+) granulocytes, whereas levels in B6 mice were greater and were increased further by α-galactosyl ceramide. IFN-γ and MIP-1α production in the lungs was greater in B6 than CD1d(-/-) mice. Adoptive transfer of wild type (WT) but not IFN-γ-, MIP-1α-, or FcγR-deficient NKT cells into CD1d(-/-) mice caused recruitment of inflammatory cells to the lungs. Moreover, adoptive transfer of IFN-γR-deficient NKT cells enhanced MIP-1α production and cell recruitment in the lungs of CD1d(-/-) or CD1d(-/-)IFN-γ(-/-) mice, but to a lesser extent than WT NKT cells. This suggests that IFN-γ-producing NKT cells enhance MIP-1α production in both an autocrine and a paracrine manner. IFN-γ-deficient NKT cells induced less IL-1β and TNF-α production by alveolar macrophages and dendritic cells in CD1d(-/-) mice than did WT NKT cells. Taken together, these data suggest that CD1d-restricted IFN-γ-producing NKT cells promote IC-ALI by producing MIP-1α and enhancing proinflammatory cytokine production by alveolar macrophages and dendritic cells.

  15. In vivo evidence suggesting reciprocal renal hypoxia-inducible factor-1 upregulation and signal transducer and activator of transcription 3 activation in response to hypoxic and non-hypoxic stimuli.

    Science.gov (United States)

    Nechemia-Arbely, Yael; Khamaisi, Mogher; Rosenberger, Christian; Koesters, Robert; Shina, Ahuva; Geva, Carmit; Shriki, Anat; Klaus, Stephen; Rosen, Seymour; Rose-John, Stefan; Galun, Eithan; Axelrod, Jonathan H; Heyman, Samuel N

    2013-04-01

    In vitro studies suggest that combined activation of hypoxia-inducible factor (HIF) and signal transducer and activator of transcription 3 (STAT3) promotes the hypoxia response. However, their interrelationship in vivo remains poorly defined. The present study investigated the possible relationship between HIF-1 upregulation and STAT3 activation in the rodent kidney in vivo. Activation of HIF-1 and STAT3 was analysed by immunohistochemical staining and western blot analysis in: (i) models of hypoxia-associated kidney injury induced by radiocontrast media or rhabdomyolysis; (ii) following activation of STAT3 by the interleukin (IL)-6-soluble IL-6 receptor complex; or (iii) following HIF-1α stabilization using hypoxic and non-hypoxic stimuli (mimosine, FG-4497, CO, CoCl(2)) and in targeted von Hippel-Lindau-knockout mice. Western blot analysis and immunostaining revealed marked induction of both transcription factors under all conditions tested, suggesting that in vivo STAT3 can trigger HIF and vice versa. Colocalization of HIF-1α and phosphorylated STAT3 was detected in some, but not all, renal cell types, suggesting that in some cells a paracrine mechanism may be responsible for the reciprocal activation of the two transcription factors. Nevertheless, in several cell types spatial concordance was observed under the majority of conditions tested, suggesting that HIF-1 and STAT3 may act as cotranscription factors. These in vivo studies suggest that, in response to renal hypoxic-stress, upregulation of HIF-1 and activation of STAT3 may be both reciprocal and cell type dependent. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.

  16. A slow-releasing form of prostacyclin agonist (ONO1301SR) enhances endogenous secretion of multiple cardiotherapeutic cytokines and improves cardiac function in a rapid-pacing-induced model of canine heart failure.

    Science.gov (United States)

    Shirasaka, Tomonori; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Shiozaki, Motoko; Kawaguchi, Naomasa; Matsuura, Nariaki; Nakatani, Satoshi; Sakai, Yoshiki; Daimon, Takashi; Okita, Yutaka; Sawa, Yoshiki

    2013-08-01

    Cardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM. ONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area. Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  17. Rosuvastatin-induced pemphigoid.

    LENUS (Irish Health Repository)

    Murad, Aizuri A

    2012-01-01

    Statins are widely prescribed medications and very well tolerated. Rosuvastatin is another member of this drug used to treat dyslipidaemia. It is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. Immunobullous disease is usually idiopathic but can be drug-induced. Both idiopathic and iatrogenic forms share common clinical and immunohistological features. The authors report a case of pemphigoid induced by rosuvastatin, a commonly prescribed medication. To our knowledge, there is limited report on rosuvastatin associated with pemphigoid in the literature.

  18. Cervical osteophyte induced dysphagia

    International Nuclear Information System (INIS)

    Davies, R.P.; Sage, M.R.; Brophy, B.P.

    1989-01-01

    Although cervical spondylosis is a common disorder, dysphagia induced by osteophyte formation is uncommon. Fewer than one hundred cases of cervical osteophyte induced dysphagia have been reported, with little attention to the diagnosis by barium swallow. The radiological features of two cases treated surgically with good results are described. Both cases complained of dysphagia while one had associated respiratory obstruction on forward flexion of his neck. The features on barium study of cervical osteophytes causing dysphagia include deformity at the level of osteophyte formation, in both AP and lateral projections. Tracheal aspirations due to deformity at the laryngeal inlet and interference with epiglottic retroversion may be present. 8 refs., 3 figs

  19. Exercise-induced rhabdomyolysis.

    Science.gov (United States)

    Lee, George

    2014-11-03

    Exercise-induced rhabdomyolysis, or exertional rhabdomyolysis (ER), is a clinical entity typically considered when someone presents with muscle stiffness, swelling, and pain out of proportion to the expected fatigue post exercise. The diagnosis is confirmed by myoglobinuria, and an elevated serum Creatinine Phosphokinase (CPK) level, usually 10 times the normal range. However, an elevation in CPK is seen in most forms of strenuous exercise, up to 20 times the upper normal range. Therefore, there is no definitive pathologic CPK cut-off. Fortunately the dreaded complication of acute renal failure is rare compared to other forms rhabdomyolysis. We review the risks, diagnosis, clinical course and treatment for exercise- induced rhabdomyolysis.

  20. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

    Arngrim, Nanna; Schytz, Henrik Winther; Britze, Josefine

    2016-01-01

    in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...... and possible aura in 4 of 15 patients. Hypoxia did not change glutamate concentration in the visual cortex compared to sham, but increased lactate concentration (P = 0.028) and circumference of the cranial arteries (P ... suggests that hypoxia may provoke migraine headache and aura symptoms in some patients. The mechanisms behind the migraine-inducing effect of hypoxia should be further investigated....

  1. Airbag induced corneal ectasia.

    Science.gov (United States)

    Mearza, Ali A; Koufaki, Fedra N; Aslanides, Ioannis M

    2008-02-01

    To report a case of airbag induced corneal ectasia. Case report. A patient 3 years post-LASIK developed bilateral corneal ectasia worse in the right eye following airbag deployment in a road traffic accident. At last follow up, best corrected vision was 20/40 with -4.00/-4.00 x 25 in the right eye and 20/25 with -1.25/-0.50 x 135 in the left eye. This is a rare presentation of trauma induced ectasia in a patient post-LASIK. It is possible that reduction in biomechanical integrity of the cornea from prior refractive surgery contributed to this presentation.

  2. Sleep-inducing factors.

    Science.gov (United States)

    García-García, Fabio; Acosta-Peña, Eva; Venebra-Muñoz, Arturo; Murillo-Rodríguez, Eric

    2009-08-01

    Kuniomi Ishimori and Henri Piéron were the first researchers to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This substance was named hypnotoxin. Currently, the variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some substances of lipidic nature, many of which are well known for their involvement in other biological activities. In this chapter, we describe the sleep-inducing properties of the vasoactive intestinal peptide, prolactin, adenosine and anandamide.

  3. Ace inhibitors and cardiovascular regulation : the importance of autocrine and paracrine mechanisms

    NARCIS (Netherlands)

    Wijngaarden, Jan van

    1992-01-01

    As demonstrated in a large number of clinical studies, angiotensin converting enzyme (ACE) inhibitors are of great value for the treatment of cardiovascular disorders. Although the clinical merits of these drugs are now well recognized, their mechanism of action is not yet completely understood. The

  4. Evidence for paracrine/autocrine regulation of GLP-1-producing cells

    DEFF Research Database (Denmark)

    Kappe, Camilla; Zhang, Qimin; Holst, Jens Juul

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent...... studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin...... as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our...

  5. alpha-Tocopheryl succinate inhibits angiogenesis by disrupting paracrine FGF2 signalling

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Swettenham, E.; Wang, X.F.; Dong, L.F.; Stapelberg, M.

    2007-01-01

    Roč. 581, č. 24 (2007), s. 4611-4615 ISSN 0014-5793 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mitocans * proliferating endothelial cells * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.263, year: 2007

  6. Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency

    NARCIS (Netherlands)

    Damhofer, Helene; Veenstra, Veronique L.; Tol, Johanna A. M. G.; van Laarhoven, Hanneke W. M.; Medema, Jan Paul; Bijlsma, Maarten F.

    2015-01-01

    Members of the Hedgehog (Hh) family of morphogens play crucial roles in development but are also involved in the progression of certain types of cancer. Despite being synthesized as hydrophobic dually lipid-modified molecules, and thus being strongly membrane-associated, Hh ligands are able to

  7. Cholecystokinin inhibits gastrin secretion independently of paracrine somatostatin secretion in the pig

    DEFF Research Database (Denmark)

    Schmidt, P T; Hansen, L; Hilsted, L

    2004-01-01

    BACKGROUND: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin....... METHODS: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. RESULTS: CCK infusion...... at 10(-9) M and 10(-8) M decreased gastrin output to 70.5% +/- 7.6% (n = 8) and 76.3% +/- 3.6% (n = 7) of basal output, respectively. CCK at 10(-10) M had no effect (n = 6). Somatostatin secretion was dose-dependently increased by CCK infusion and increased to 268 +/- 38.2% (n = 7) of basal secretion...

  8. Endocrine and paracrine regulation of zebrafish spermatogenesis : The Sertoli cell perspective

    NARCIS (Netherlands)

    Schulz, R. W.; Nóbrega, R. H.; Vidal de Souza Morais, Roberto Daltro; De Waal, P. P.; França, L. R.; Bogerd, J.

    2015-01-01

    Spermatogonial stem cells (SSCs) either self-renew or differentiate into spermatogonia that further develop into spermatozoa. Self-renewal occurs when residing in a specific micro-environment (niche) while displacement from the niche would tip the signalling balance towards differentiation.

  9. Autocrine and Paracrine Control of Breast Cancer Growth by Sex Hormone-Binding Globulin

    National Research Council Canada - National Science Library

    Rosner, Wiliam

    2003-01-01

    We propose that the expression of Sex Hormone-Binding Globulin (SHBG) by breast cancer cells is biologically regulated and that this SHBG functions to alter the effects of estrogens within the breast cancer cell...

  10. Autocine and Paracrine Control of Breast Cancer Growth by Sex Hormone-Binding Globulin

    National Research Council Canada - National Science Library

    Rosner, William

    2004-01-01

    We propose that the expression of Sex Hormone-Binding Globulin (SHBG) by breast cancer cells is biologically regulated and this SHBG functions to alter the effects of estrogens within the breast cancer cell...

  11. Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signalling

    DEFF Research Database (Denmark)

    Arregi, Igor; Climent, Maria; Iliev, Dobromir

    2016-01-01

    Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here we show that Retinol dehydrogenase-10 (Rdh......10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis...... and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early...

  12. How the turtle forms its shell: a paracrine hypothesis of carapace formation.

    Science.gov (United States)

    Cebra-Thomas, Judith; Tan, Fraser; Sistla, Seeta; Estes, Eileen; Bender, Gunes; Kim, Christine; Riccio, Paul; Gilbert, Scott F

    2005-11-15

    We propose a two-step model for the evolutionary origin of the turtle shell. We show here that the carapacial ridge (CR) is critical for the entry of the ribs into the dorsal dermis. Moreover, we demonstrate that the maintenance of the CR and its ability to attract the migrating rib precursor cells depend upon fibroblast growth factor (FGF) signaling. Inhibitors of FGF allow the CR to degenerate, with the consequent migration of ribs along the ventral body wall. Beads containing FGF10 can rearrange rib migration in the chick, suggesting that the CR FGF10 plays an important role in attracting the rib rudiments. The co-ordinated growth of the carapacial plate and the ribs may be a positive feedback loop (similar to that of the limbs) caused by the induction of Fgf8 in the distal tips of the ribs by the FGF10-secreting mesenchyme of the CR. Once in the dermis, the ribs undergo endochrondral ossification. We provide evidence that the ribs act as signaling centers for the dermal ossification and that this ossification is due to bone morphogenetic proteins secreted by the rib. Thus, once the ribs are within the dermis, the ossification of the dermis is not difficult to achieve. This relatively rapid means of carapace formation would allow for the appearance of turtles in the fossil record without obvious intermediates. Copyright 2005 Wiley-Liss, Inc.

  13. Inducible laryngeal obstruction

    DEFF Research Database (Denmark)

    Halvorsen, Thomas; Walsted, Emil Schwarz; Bucca, Caterina

    2017-01-01

    Inducible laryngeal obstruction (ILO) describes an inappropriate, transient, reversible narrowing of the larynx in response to external triggers. ILO is an important cause of a variety of respiratory symptoms and can mimic asthma. Current understanding of ILO has been hampered by imprecise nomenc...

  14. Drug-induced apnea.

    Science.gov (United States)

    Boutroy, M J

    1994-01-01

    Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

  15. Metronidazole-Induced Pancreatitis

    Directory of Open Access Journals (Sweden)

    E. O'Halloran

    2010-01-01

    Conclusion. This case provides the eighth report of Metronidazole induced pancreatitis. All of the cases were reported in females and ran a benign course.Early diagnosis, discontinuation of the drug and supportive care will lead to a successful recovery in the majority of cases.

  16. XTC-induced hepatitis

    NARCIS (Netherlands)

    Oranje, W.A.; van Pol, V.; van der Wurff, A.A.; Zeijen, R.N.; Stockbrügger, R.W.; Arends, J.W.

    1994-01-01

    XTC-induced hepatitis. Oranje WA, von Pol P, vd Wurff A, Zeijen RN, Stockbrugger RW, Arends JW. Department of Internal Medicine, University Hospital, Maastricht, Netherlands. An increasing number of severe complications associated with the use of XTC is being reported. After 11 earlier case reports

  17. Bowthruster-induced damage

    NARCIS (Netherlands)

    Schokking, L.A.; Janssen, P.C.; Verhagen, H.J.

    2003-01-01

    The stability of stones in propeller-induced jet wash is still difficult to predict. Especially the trend of bowthrusters increasing in size and power in sea going ships (especially ferries) over the last years may be a reason for concern when dealing with the protection of slopes and beds. But also

  18. Muon-induced fission

    International Nuclear Information System (INIS)

    Polikanov, S.

    1980-01-01

    A review of recent experimental results on negative-muon-induced fission, both of 238 U and 232 Th, is given. Some conclusions drawn by the author are concerned with muonic atoms of fission fragments and muonic atoms of the shape isomer of 238 U. (author)

  19. Calotropis procera -induced keratitis

    Directory of Open Access Journals (Sweden)

    Pandey Nidhi

    2009-01-01

    Full Text Available Calotropis procera produces copious amounts of latex, which has been shown to possess several pharmacological properities. Its local application produces intense inflammatory response. In the 10 cases of Calotropis procera -induced keratitis reported here, the clinical picture showed corneal edema with striate keratopathy without any evidence of intraocular inflammation. The inflammation was reversed by the local application of steroid drops.

  20. Induced nuclear beta decay

    International Nuclear Information System (INIS)

    Reiss, H.R.

    1986-01-01

    Certain nuclear beta decay transitions normally inhibited by angular momentum or parity considerations can be induced to occur by the application of an electromagnetic field. Such decays can be useful in the controlled production of power, and in fission waste disposal

  1. Hyperthermia-induced apoptosis

    NARCIS (Netherlands)

    Nijhuis, E.H.A.

    2008-01-01

    This thesis describes a number of studies that investigated several aspects of heat-induced apoptosis in human lymphoid malignancies. Cells harbour both pro- and anti-apoptotic proteins and the balance between these proteins determines whether a cell is susceptible to undergo apoptosis. In this

  2. Drug induced aseptic meningitis

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-09-29

    Sep 29, 2013 ... Abstract. Drug-induced aseptic meningitis (DIAM) is a rare but important and often challenging diagnosis for the physician. Intake of antimicrobials, steroids, anal- gesics amongst others has been implicated. Signs and symptoms generally develop within 24-48 hours of drug ingestion. The pa- tient often ...

  3. Contrast induced nephropathy

    DEFF Research Database (Denmark)

    Stacul, Fulvio; van der Molen, Aart J; Reimer, Peter

    2011-01-01

    PURPOSE: The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 1999 guidelines on contrast medium-induced nephropathy (CIN). AREAS COVERED: Topics reviewed include the definition of CIN, the choice of contrast medium, the prophylactic me...

  4. Radiation-induced pneumothorax

    International Nuclear Information System (INIS)

    Epstein, D.M.; Littman, P.; Gefter, W.B.; Miller, W.T.; Raney, R.B. Jr.

    1983-01-01

    Pneumothorax is an uncommon complication of radiation therapy to the chest. The proposed pathogenesis is radiation-induced fibrosis promoting subpleural bleb formation that ruptures resulting in pneumothorax. We report on two young patients with primary sarcomas without pulmonary metastases who developed spontaneous pneumothorax after irradiation. Neither patient had antecedent radiographic evidence of pulmonary fibrosis

  5. Irradiation-Induced Nanostructures

    Energy Technology Data Exchange (ETDEWEB)

    Birtcher, R.C.; Ewing, R.C.; Matzke, Hj.; Meldrum, A.; Newcomer, P.P.; Wang, L.M.; Wang, S.X.; Weber, W.J.

    1999-08-09

    This paper summarizes the results of the studies of the irradiation-induced formation of nanostructures, where the injected interstitials from the source of irradiation are not major components of the nanophase. This phenomena has been observed by in situ transmission electron microscopy (TEM) in a number of intermetallic compounds and ceramics during high-energy electron or ion irradiations when the ions completely penetrate through the specimen. Beginning with single crystals, electron or ion irradiation in a certain temperature range may result in nanostructures composed of amorphous domains and nanocrystals with either the original composition and crystal structure or new nanophases formed by decomposition of the target material. The phenomenon has also been observed in natural materials which have suffered irradiation from the decay of constituent radioactive elements and in nuclear reactor fuels which have been irradiated by fission neutrons and other fission products. The mechanisms involved in the process of this nanophase formation are discussed in terms of the evolution of displacement cascades, radiation-induced defect accumulation, radiation-induced segregation and phase decomposition, as well as the competition between irradiation-induced amorphization and recrystallization.

  6. Lupus induced by medicaments

    International Nuclear Information System (INIS)

    Canas D, Carlos Alberto; Perafan B, Pablo Eduardo

    2001-01-01

    We describe a 55 years old female patient who consulted by fever syndrome, artralgias and the presence of high tittles positives antinuclear antibodies. She had arterial hypertension in treatment with captopril. We suspected the clinical diagnoses of drug-induced lupus; the withdraw of captopril was associated with the remission of the clinical and laboratory manifestations

  7. Glucocorticoid-induced hyperglycaemia

    NARCIS (Netherlands)

    Gerards, M.C.

    2018-01-01

    This thesis contains studies on current practice, clinical implications and treatment of excess glucocorticoid receptor (GCR) stimulation, with a focus on glucocorticoid-induced hyperglycaemia (GCIH). Chapter 1 is a general introduction to the glucocorticoid hormone. In chapter 2 , we have

  8. Understanding induced seismicity

    NARCIS (Netherlands)

    Elsworth, Derek; Spiers, Christopher J.|info:eu-repo/dai/nl/304829323; Niemeijer, Andre R.|info:eu-repo/dai/nl/370832132

    2016-01-01

    Fluid injection–induced seismicity has become increasingly widespread in oil- and gas-producing areas of the United States (1–3) and western Canada. It has shelved deep geothermal energy projects in Switzerland and the United States (4), and its effects are especially acute in Oklahoma, where

  9. Geomagnetism and Induced Voltage

    Science.gov (United States)

    Abdul-Razzaq, W.; Biller, R. D.

    2010-01-01

    Introductory physics laboratories have seen an influx of "conceptual integrated science" over time in their classrooms with elements of other sciences such as chemistry, biology, Earth science, and astronomy. We describe a laboratory to introduce this development, as it attracts attention to the voltage induced in the human brain as it…

  10. INDUCED ABORTION IN NIGERIA

    African Journals Online (AJOL)

    2014-06-01

    Jun 1, 2014 ... 95% of women would have had an induced abortion. (10), which ... who were fluent in both English and the local language were chosen ... the woman and society. The Muslims ... that “traditional methods are only effective at the early stages of ... modern and traditional family planning services. However ...

  11. Advertising-Induced Embarrassment

    NARCIS (Netherlands)

    Puntoni, S.; Hooge, de I.E.; Verbeke, W.J.M.I.

    2015-01-01

    Abstract Consumer embarrassment is a concern for many advertisers. Yet little is known about ad-induced embarrassment. The authors investigate when and why consumers experience embarrassment as a result of exposure to socially sensitive advertisements. The theory distinguishes between viewing

  12. Uterine contraction induced by Tanzanian plants used to induce abortion

    DEFF Research Database (Denmark)

    Nikolajsen, Tine; Nielsen, Frank; Rasch, Vibeke

    2011-01-01

    Women in Tanzania use plants to induce abortion. It is not known whether the plants have an effect.......Women in Tanzania use plants to induce abortion. It is not known whether the plants have an effect....

  13. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis.

    Science.gov (United States)

    Zhu, Yu; Wang, Yuchen; Zhao, Bizeng; Niu, Xin; Hu, Bin; Li, Qing; Zhang, Juntao; Ding, Jian; Chen, Yunfeng; Wang, Yang

    2017-03-09

    Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA. Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse-sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively. The majority of iMSC-Exos and SMMSC-Exos were approximately 50-150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect. The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA.

  14. Signaling factors and pathways of α-particle irradiation induced bilateral bystander responses between Beas-2B and U937 cells

    International Nuclear Information System (INIS)

    Fu, Jiamei; Wang, Juan; Wang, Xiangdong; Wang, Ping; Xu, Jinping; Zhou, Cuiping; Bai, Yang; Shao, Chunlin

    2016-01-01

    Highlights: • Radiation damage of Beas-2B cells was enhanced by macrophage-mediated bilateral bystander responses. • Expressions of TNF-α and IL-8 in the α-irradiated Beas-2B cells were dependent on ERK and p38 pathways. • The neighboring U937 cells further increased the generation of TNF-α and IL-8 in the α-irradiated Beas-2B cells. • NF-κB dependent upregulation of TNF-α and IL-8 was induced in the bystander U937 cells. - Abstract: Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral

  15. Signaling factors and pathways of α-particle irradiation induced bilateral bystander responses between Beas-2B and U937 cells

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Jiamei; Wang, Juan; Wang, Xiangdong; Wang, Ping; Xu, Jinping; Zhou, Cuiping; Bai, Yang; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

    2016-07-15

    Highlights: • Radiation damage of Beas-2B cells was enhanced by macrophage-mediated bilateral bystander responses. • Expressions of TNF-α and IL-8 in the α-irradiated Beas-2B cells were dependent on ERK and p38 pathways. • The neighboring U937 cells further increased the generation of TNF-α and IL-8 in the α-irradiated Beas-2B cells. • NF-κB dependent upregulation of TNF-α and IL-8 was induced in the bystander U937 cells. - Abstract: Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral

  16. [Hydroxyurea-induced pneumonia].

    Science.gov (United States)

    Girard, A; Ricordel, C; Poullot, E; Claeyssen, V; Decaux, O; Desrues, B; Delaval, P; Jouneau, S

    2014-05-01

    Hydroxyurea is an antimetabolite drug used in the treatment of myeloproliferative disorders. Common adverse effects include haematological, gastrointestinal cutaneous manifestations, and fever. Hydroxyurea-induced pneumonitis is unusual. A female patient was treated with hydroxyurea for polycythemia vera. She was admitted 20 days after commencing treatment with a high fever, productive cough, clear sputum and nausea. A chest CT-scan showed diffuse ground-glass opacities. Microbiological investigations were negative. The symptoms disappeared a few days after discontinuation of the drug and rechallenge led to a relapse of symptoms. Our case and 15 earlier cases of hydroxyurea-induced pneumonitis are reviewed. Two patterns of this disease may exist: an acute febrile form occurring within 1 month of introduction of hydroxyurea and a subacute form without fever. Even if uncommon, one should be aware of this complication of hydroxyurea. Copyright © 2013. Published by Elsevier Masson SAS.

  17. Hydroxychloroquine-induced erythroderma.

    Science.gov (United States)

    Pai, Sunil B; Sudershan, Bhuvaneshwari; Kuruvilla, Maria; Kamath, Ashwin; Suresh, Pooja K

    2017-01-01

    Erythroderma is characterized by diffuse erythema and scaling of the skin involving more than 90% of the total body skin surface area. Drug-induced erythroderma has rarely been reported with hydroxychloroquine. We report a case of a 50-year-old female patient, with systemic lupus erythematosus, who developed itchy lesions all over the body 1 month after starting treatment with hydroxychloroquine. Drug-induced erythroderma was suspected. Hydroxychloroquine was withdrawn and the patient was treated with emollients, mid-potency corticosteroids, and oral antihistamines. A biopsy was done which confirmed the diagnosis of erythroderma. She recovered with treatment and was discharged. A careful history and clinical examination to search for potential causative factors will help prevent disabling sequelae in erythroderma.

  18. Mild induced hypothermia

    DEFF Research Database (Denmark)

    Johansen, Maria E; Jensen, Jens-Ulrik; Bestle, Morten H

    2014-01-01

    INTRODUCTION: Coagulopathy associates with poor outcome in sepsis. Mild induced hypothermia has been proposed as treatment in sepsis but it is not known whether this intervention worsens functional coagulopathy. MATERIALS AND METHODS: Interim analysis data from an ongoing randomized controlled...... trial; The Cooling And Surviving Septic shock (CASS) study. Patients suffering severe sepsis/septic shock are allocated to either mild induced hypothermia (cooling to 32-34°C for 24hours) or control (uncontrolled temperature). TRIAL REGISTRATION: NCT01455116. Thrombelastography (TEG) is performed three....... At enrollment, 3%, 38%, and 59% had a hypocoagulable, normocoagulable, and hypercoagulable TEG clot strength (MA), respectively. In the hypothermia group, functional coagulopathy improved during the hypothermia phase, measured by R and MA, in patients with hypercoagulation as well as in patients...

  19. Time Domain Induced Polarization

    DEFF Research Database (Denmark)

    Fiandaca, Gianluca; Auken, Esben; Christiansen, Anders Vest

    2012-01-01

    Time-domain-induced polarization has significantly broadened its field of reference during the last decade, from mineral exploration to environmental geophysics, e.g., for clay and peat identification and landfill characterization. Though, insufficient modeling tools have hitherto limited the use...... of time-domaininduced polarization for wider purposes. For these reasons, a new forward code and inversion algorithm have been developed using the full-time decay of the induced polarization response, together with an accurate description of the transmitter waveform and of the receiver transfer function......, to reconstruct the distribution of the Cole-Cole parameters of the earth. The accurate modeling of the transmitter waveform had a strong influence on the forward response, and we showed that the difference between a solution using a step response and a solution using the accurate modeling often is above 100...

  20. Topiramate Induced Excessive Sialorrhea

    Directory of Open Access Journals (Sweden)

    Ersel Dag

    2015-11-01

    Full Text Available It is well-known that drugs such as clozapine and lithium can cause sialorrhea. On the other hand, topiramate has not been reported to induce sialorrhea. We report a case of a patient aged 26 who was given antiepileptic and antipsychotic drugs due to severe mental retardation and intractable epilepsy and developed excessive sialorrhea complaint after the addition of topiramate for the control of seizures. His complaints continued for 1,5 years and ended after giving up topiramate. We presented this case since it was a rare sialorrhea case induced by topiramate. Clinicians should be aware of the possibility of sialorrhea development which causes serious hygiene and social problems when they want to give topiramate to the patients using multiple drugs.

  1. Noise-Induced Hearing Loss

    Science.gov (United States)

    ... Home » Health Info » Hearing, Ear Infections, and Deafness Noise-Induced Hearing Loss On this page: What is ... I find additional information about NIHL? What is noise-induced hearing loss? Every day, we experience sound ...

  2. Induced quantum torsion

    International Nuclear Information System (INIS)

    Denardo, G.; Spallucci, E.

    1985-07-01

    We study pregeometry in the framework of a Poincare gauge field theory. The Riemann-Cartan space-time is shown to be an ''effective geometry'' for this model in the low energy limit. By using Heat Kernel techniques we find the induced action for curvature and torsion. We obtain in this way the usual Einstein-Hilbert action plus an axial Maxwell term describing the propagation of a massless, axial vector torsion field. (author)

  3. Cisplatin Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Seyed Seifollah Beladi Mousavi

    2014-02-01

    The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with the administration of full intravenous isotonic saline before and after cisplatin administration. Although a number of pharmacologic agents including sodium thiosulfate, N-acetylcysteine, theophylline and glycine have been evaluated for prevention of nephrotoxicity, none have proved to have an established role, thus, additional clinical studies will be required to confirm their probable effects.

  4. Amitriptyline induced cervical dystonia

    Directory of Open Access Journals (Sweden)

    Shivanand B Hiremath

    2016-01-01

    Full Text Available Tricyclic antidepressants (TCAs, such as amitriptyline, have many side effects. But extrapyramidal tract symptom is an uncommon side effect of these drugs. Here, we report a case of a 28-year-old male who is suffering from amitriptyline induced cervical dystonia. Though rare, this side effect is an uncomfortable condition and may influence drug compliance. So clinicians should be aware of this side effect while treating a patient with amitriptyline.

  5. Polycation induced actin bundles

    OpenAIRE

    Muhlrad, Andras; Grintsevich, Elena E.; Reisler, Emil

    2011-01-01

    Three polycations, polylysine, the polyamine spermine and the polycationic protein lysozyme were used to study the formation, structure, ionic strength sensitivity and dissociation of polycation-induced actin bundles. Bundles form fast, simultaneously with the polymerization of MgATP-G-actins, upon addition of polycations to solutions of actins at low ionic strength conditions. This indicates that nuclei and/or nascent filaments bundle due to attractive, electrostatic effect of polycations an...

  6. Induced current heating probe

    International Nuclear Information System (INIS)

    Thatcher, G.; Ferguson, B.G.; Winstanley, J.P.

    1984-01-01

    An induced current heating probe is of thimble form and has an outer conducting sheath and a water flooded flux-generating unit formed from a stack of ferrite rings coaxially disposed in the sheath. The energising coil is made of solid wire which connects at one end with a coaxial water current tube and at the other end with the sheath. The stack of ferrite rings may include non-magnetic insulating rings which help to shape the flux. (author)

  7. Induced QCD I: theory

    Energy Technology Data Exchange (ETDEWEB)

    Brandt, Bastian B. [Institute for Theoretical Physics, Goethe-University of Frankfurt,60438 Frankfurt (Germany); Institute for Theoretical Physics, University of Regensburg,93040 Regensburg (Germany); Lohmayer, Robert; Wettig, Tilo [Institute for Theoretical Physics, University of Regensburg,93040 Regensburg (Germany)

    2016-11-14

    We explore an alternative discretization of continuum SU(N{sub c}) Yang-Mills theory on a Euclidean spacetime lattice, originally introduced by Budzcies and Zirnbauer. In this discretization the self-interactions of the gauge field are induced by a path integral over N{sub b} auxiliary boson fields, which are coupled linearly to the gauge field. The main progress compared to earlier approaches is that N{sub b} can be as small as N{sub c}. In the present paper we (i) extend the proof that the continuum limit of the new discretization reproduces Yang-Mills theory in two dimensions from gauge group U(N{sub c}) to SU(N{sub c}), (ii) derive refined bounds on N{sub b} for non-integer values, and (iii) perform a perturbative calculation to match the bare parameter of the induced gauge theory to the standard lattice coupling. In follow-up papers we will present numerical evidence in support of the conjecture that the induced gauge theory reproduces Yang-Mills theory also in three and four dimensions, and explore the possibility to integrate out the gauge fields to arrive at a dual formulation of lattice QCD.

  8. Laser induced energy transfer

    International Nuclear Information System (INIS)

    Falcone, R.W.

    1979-01-01

    Two related methods of rapidly transferring stored energy from one excited chemical species to another are described. The first of these, called a laser induced collision, involves a reaction in which the energy balance is met by photons from an intense laser beam. A collision cross section of ca 10 - 17 cm 2 was induced in an experiment which demonstrated the predicted dependence of the cross section on wavelength and power density of the applied laser. A second type of laser induced energy transfer involves the inelastic scattering of laser radiation from energetically excited atoms, and subsequent absorption of the scattered light by a second species. The technique of producing the light, ''anti-Stokes Raman'' scattering of visible and infrared wavelength laser photons, is shown to be an efficient source of narrow bandwidth, high brightness, tunable radiation at vacuum ultraviolet wavelengths by using it to excite a rare gas transition at 583.7 A. In addition, this light source was used to make the first measurement of the isotopic shift of the helium metastable level at 601 A. Applications in laser controlled chemistry and spectroscopy, and proposals for new types of lasers using these two energy transfer methods are discussed

  9. Radiation-induced myelopathy

    Energy Technology Data Exchange (ETDEWEB)

    Gaenshirt, H [Heidelberg Univ. (F.R. Germany). Neurologische Klinik

    1975-10-01

    12 cases of radiation-induced myelopathy after /sup 60/Co teletherapy are reported on. Among these were 10 thoracal lesions, one cerviothoracal lesion, and one lesion of the medulla oblongata. In 9 cases, Hodgkin's disease had been the primary disease, tow patients had been irradiated because of suspected vertebral metastases of cancer of the breast, and one patient had suffered from a glomus tumour of the petrous bone. The spinal doses had exceeded the tolerance doses recommended in the relevant literature. There was no close correlation between the radiation dose and the course of the disease. The latency periods between the end of the radiotherapy and the onset of the neurological symptons varied from 6 to 16 mouths and were very constant in 7 cases with 6 to 9 months. The segmental height of the lesion corresponded to the level of irradiation. The presenting symptons of radiation-induced myelopathy are buruing dysaesthesias and Brown-Sequard's paralysis which may develop into transverse lesion of the cord with paraplegia still accompanied by dissociated perception disorders. The disease developed intermittently. Disturbances of the bladder function are frequent. The fluid is normal in most cases. Myelographic examinations were made in 8 cases. 3 cases developed into stationary cases exhibiting. Brown-Sequard syndrome, while 9 patients developed transverse lesion of the cord with paraplegia. 3 patients have died; antopsy findings are given for two of these. In the pathogenesis of radiation-induced myelopathy, the vascular factor is assumed to be of decisive importance.

  10. Baby universes with induced gravity

    International Nuclear Information System (INIS)

    Gao Yihong; Gao Hongbo

    1989-01-01

    In this paper some quantum effects of baby universes with induced gravity are discussed. It is proved that the interactions between the baby-parent universes are non-local, and argue that the induced low-energy cosmological constant is zero. This argument does not depend on the detail of the induced potential

  11. Cell Free DNA of Tumor Origin Induces a 'Metastatic' Expression Profile in HT-29 Cancer Cell Line.

    Directory of Open Access Journals (Sweden)

    István Fűri

    Full Text Available Epithelial cells in malignant conditions release DNA into the extracellular compartment. Cell free DNA of tumor origin may act as a ligand of DNA sensing mechanisms and mediate changes in epithelial-stromal interactions.To evaluate and compare the potential autocrine and paracrine regulatory effect of normal and malignant epithelial cell-related DNA on TLR9 and STING mediated pathways in HT-29 human colorectal adenocarcinoma cells and normal fibroblasts.DNA isolated from normal and tumorous colonic epithelia of fresh frozen surgically removed tissue samples was used for 24 and 6 hour treatment of HT-29 colon carcinoma and HDF-α fibroblast cells. Whole genome mRNA expression analysis and qRT-PCR was performed for the elements/members of TLR9 signaling pathway. Immunocytochemistry was performed for epithelial markers (i.e. CK20 and E-cadherin, DNA methyltransferase 3a (DNMT3a and NFκB (for treated HDFα cells.Administration of tumor derived DNA on HT29 cells resulted in significant (p<0.05 mRNA level alteration in 118 genes (logFc≥1, p≤0.05, including overexpression of metallothionein genes (i.e. MT1H, MT1X, MT1P2, MT2A, metastasis-associated genes (i.e. TACSTD2, MACC1, MALAT1, tumor biomarker (CEACAM5, metabolic genes (i.e. INSIG1, LIPG, messenger molecule genes (i.e. DAPP, CREB3L2. Increased protein levels of CK20, E-cadherin, and DNMT3a was observed after tumor DNA treatment in HT-29 cells. Healthy DNA treatment affected mRNA expression of 613 genes (logFc≥1, p≤0.05, including increased expression of key adaptor molecules of TLR9 pathway (e.g. MYD88, IRAK2, NFκB, IL8, IL-1β, STING pathway (ADAR, IRF7, CXCL10, CASP1 and the FGF2 gene.DNA from tumorous colon epithelium, but not from the normal epithelial cells acts as a pro-metastatic factor to HT-29 cells through the overexpression of pro-metastatic genes through TLR9/MYD88 independent pathway. In contrast, DNA derived from healthy colonic epithelium induced TLR9 and STING signaling

  12. Polycation induced actin bundles.

    Science.gov (United States)

    Muhlrad, Andras; Grintsevich, Elena E; Reisler, Emil

    2011-04-01

    Three polycations, polylysine, the polyamine spermine and the polycationic protein lysozyme were used to study the formation, structure, ionic strength sensitivity and dissociation of polycation-induced actin bundles. Bundles form fast, simultaneously with the polymerization of MgATP-G-actins, upon the addition of polycations to solutions of actins at low ionic strength conditions. This indicates that nuclei and/or nascent filaments bundle due to attractive, electrostatic effect of polycations and the neutralization of repulsive interactions of negative charges on actin. The attractive forces between the filaments are strong, as shown by the low (in nanomolar range) critical concentration of their bundling at low ionic strength. These bundles are sensitive to ionic strength and disassemble partially in 100 mM NaCl, but both the dissociation and ionic strength sensitivity can be countered by higher polycation concentrations. Cys374 residues of actin monomers residing on neighboring filaments in the bundles can be cross-linked by the short span (5.4Å) MTS-1 (1,1-methanedyl bismethanethiosulfonate) cross-linker, which indicates a tight packing of filaments in the bundles. The interfilament cross-links, which connect monomers located on oppositely oriented filaments, prevent disassembly of bundles at high ionic strength. Cofilin and the polysaccharide polyanion heparin disassemble lysozyme induced actin bundles more effectively than the polylysine-induced bundles. The actin-lysozyme bundles are pathologically significant as both proteins are found in the pulmonary airways of cystic fibrosis patients. Their bundles contribute to the formation of viscous mucus, which is the main cause of breathing difficulties and eventual death in this disorder. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Induced mutations in citrus

    International Nuclear Information System (INIS)

    Spiegel-Roy, P.; Vardi, Aliza

    1990-01-01

    Full text: Parthenocarpic tendency is an important prerequisite for successful induction of seedlessness in breeding and especially in mutation breeding. A gene for asynapsis and accompanying seedless fruit has been found by us in inbred progeny of cv. 'Wilking'. Using budwood irradiation by gamma rays, seedless mutants of 'Eureka' and 'Villafranca' lemon (original clone of the latter has 25 seeds) and 'Minneola' tangelo have been obtained. Ovule sterility of the three mutants is nearly complete, with some pollen fertility still remaining. A semi-compact mutant of Shamouti orange has been obtained by irradiation. A programme for inducing seedlessness in easy peeling citrus varieties and selections has been initiated. (author)

  14. Shear-induced chaos

    International Nuclear Information System (INIS)

    Lin, Kevin K; Young, Lai-Sang

    2008-01-01

    Guided by a geometric understanding developed in earlier works of Wang and Young, we carry out numerical studies of shear-induced chaos in several parallel but different situations. The settings considered include periodic kicking of limit cycles, random kicks at Poisson times and continuous-time driving by white noise. The forcing of a quasi-periodic model describing two coupled oscillators is also investigated. In all cases, positive Lyapunov exponents are found in suitable parameter ranges when the forcing is suitably directed

  15. Shear-induced chaos

    Science.gov (United States)

    Lin, Kevin K.; Young, Lai-Sang

    2008-05-01

    Guided by a geometric understanding developed in earlier works of Wang and Young, we carry out numerical studies of shear-induced chaos in several parallel but different situations. The settings considered include periodic kicking of limit cycles, random kicks at Poisson times and continuous-time driving by white noise. The forcing of a quasi-periodic model describing two coupled oscillators is also investigated. In all cases, positive Lyapunov exponents are found in suitable parameter ranges when the forcing is suitably directed.

  16. Xerostomia induced by radiotherapy

    Directory of Open Access Journals (Sweden)

    Alimi D

    2015-08-01

    Full Text Available David Alimi Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USAWe read with great interest the excellent review on xerostomia induced by radiotherapy, by Pinna et al.1 The authors should be congratulated for a very detailed review of the physiopathology, clinical symptoms, and therapeutic management of an extremely difficult condition. Although we agree that the use of anticholinergic medication represents treatment, it requires the patient to have residual salivary gland function. Unfortunately, it is well established that in most cases radiotherapy destroys most of the salivary gland and associated salivary secretions.     

  17. Cannabis induced asystole.

    Science.gov (United States)

    Brancheau, Daniel; Blanco, Jessica; Gholkar, Gunjan; Patel, Brijesh; Machado, Christian

    2016-01-01

    Cannabis or marijuana is the most used recreational, and until recently illegal, drug in the United States. Although cannabis has medicinal use, its consumption has been linked to motor vehicle accidents in dose dependent fashion. Marijuana and other cannabinoids produce a multitude of effects on the human body that may result in these motor vehicle accidents. Some of the effects that marijuana has been known to cause include altered sensorium, diminished reflexes, and increased vagal tone. We present a case of cannabis induced asystole from hypervagotonia. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Pacing-induced Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Alex Koo

    2017-10-01

    Full Text Available We present a case of pacing-induced cardiomyopathy. The patient presented with clinical symptoms of dyspnea, leg swelling, and orthopnea several months after a dual-chambered pacemaker was placed for third-degree heart block. The echocardiogram demonstrated a depressed ejection fraction. Coronary angiography was performed, which showed widely patent vessels. Single- and dual-chambered pacemakers create ventricular dyssynchrony, which in turn can cause structural, molecular changes leading to cardiomyopathy. With early intervention of biventricular pacemaker replacement, these changes can be reversible; thus, a timely diagnosis and awareness is warranted.

  19. Induced skeletal mutations

    International Nuclear Information System (INIS)

    Selby, P.B.

    1979-01-01

    This paper describes a large-scale experiment that, by means of breeding tests, confirmed that many dominant skeletal mutations are induced by large-dose radiation exposure. The author also discusses: (1) the major advantages and disadvantages of the skeletal method in improving estimates of genetic hazard to man; (2) future uses of the skeletal method; (3) direct estimation of risk beyond the first generation using the skeletal method; and (4) the possibility of using the skeletal method as a quick and easy screen for chemical mutagens

  20. Trauma Induced Coagulopathy

    DEFF Research Database (Denmark)

    Genét, Gustav Folmer; Johansson, Per; Meyer, Martin Abild Stengaard

    2013-01-01

    It remains debated whether traumatic brain injury (TBI) induces a different coagulopathy compared to non-TBI. This study investigated traditional coagulation tests, biomarkers of coagulopathy and endothelial damage in trauma patients with and without TBI. Blood from 80 adult trauma patients were...... sampled (median of 68 min (IQR 48-88) post-injury) upon admission to our trauma centre. Plasma/serum were retrospectively analysed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (protein C, activated protein C, tissue...

  1. Trastuzumab-induced cardiomyopathy.

    Science.gov (United States)

    Guglin, Maya; Cutro, Raymond; Mishkin, Joseph D

    2008-06-01

    Trastuzumab is a recombinant humanized monoclonal antibody used for the treatment of advanced breast cancer. It improves survival and increases response to chemotherapy. The major side effect of trastuzumab is cardiotoxicity manifesting as a reduction in left ventricular systolic function, either asymptomatic or with signs and symptoms of heart failure. Although reversible in most cases, cardiotoxicity frequently results in the discontinuation of trastuzumab. The objective of this review is to summarize facts about trastuzumab-induced cardiotoxicity and to highlight the areas of future investigations. We searched PubMed for trials involving trastuzumab used as an adjuvant therapy for breast cancer, including the metastatic breast cancer setting, and focused on cardiotoxicity.

  2. Docetaxel-induced neuropathy

    DEFF Research Database (Denmark)

    Eckhoff, Lise; Feddersen, Søren; Knoop, Ann

    2015-01-01

    Background. Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral...... neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in GSTP1 and ABCB1 on DIPN. Material and methods. DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two...

  3. Chemotherapy-induced polyneuropathy

    DEFF Research Database (Denmark)

    Zedan, Ahmed; Vilholm, Ole Jakob

    2014-01-01

    Chemotherapy-induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most...... frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. Therefore, the aim of this MiniReview was to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant...

  4. Contrast induced nephropathy

    DEFF Research Database (Denmark)

    Stacul, Fulvio; van der Molen, Aart J; Reimer, Peter

    2011-01-01

    PURPOSE: The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 1999 guidelines on contrast medium-induced nephropathy (CIN). AREAS COVERED: Topics reviewed include the definition of CIN, the choice of contrast medium, the prophylactic me....../min/1.73 m (2) is CIN risk threshold for intravenous contrast medium. • Hydration with either saline or sodium bicarbonate reduces CIN incidence. • Patients with eGFR = 60 ml/min/1.73 m (2) receiving contrast medium can continue metformin normally....

  5. Ion induced Auger spectroscopy

    International Nuclear Information System (INIS)

    Thomas, E.W.; Legg, K.O.; Metz, W.A.

    1980-01-01

    Auger electron spectra are induced by impact of heavy ions (e.g. Ar + ) on surfaces; it has been suggested that analysis of such spectra would be a useful technique for surface analysis. We have examined the Auger spectra for various projectile-target combinations and present as representative data the spectra for 100 keV Ar + impact on Al, Cr, Mn, Fe and Co. For a projectile incident on a species of higher nuclear charge the spectrum is dominated by Auger lines from the projectile, broadened considerably by the Doppler effect due to the projectile's motion. The spectra are not characteristic of the target and therefore offer no opportunity for surface analysis. For a projectile incident on a target of lower nuclear charge the spectrum is that of the target species but the spectrum is consistent with the source being sputtered excited atoms; the Auger electrons do not come from the surface. We conclude that the ion induced Auger spectra are in general not a convenient method for surface analysis. (orig.)

  6. Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner

    International Nuclear Information System (INIS)

    Xu, Heyang; Lai, Wei; Zhang, Yang; Liu, Lu; Luo, Xingxi; Zeng, Yujie; Wu, Heng; Lan, Qiusheng; Chu, Zhonghua

    2014-01-01

    metastasis of CRC induced by PRL-3 through the TNF-α mediated secretion of IL-6 and IL-8 in a paracrine manner

  7. Induced Seismicity Monitoring System

    Science.gov (United States)

    Taylor, S. R.; Jarpe, S.; Harben, P.

    2014-12-01

    There are many seismological aspects associated with monitoring of permanent storage of carbon dioxide (CO2) in geologic formations. Many of these include monitoring underground gas migration through detailed tomographic studies of rock properties, integrity of the cap rock and micro seismicity with time. These types of studies require expensive deployments of surface and borehole sensors in the vicinity of the CO2 injection wells. Another problem that may exist in CO2 sequestration fields is the potential for damaging induced seismicity associated with fluid injection into the geologic reservoir. Seismic hazard monitoring in CO2 sequestration fields requires a seismic network over a spatially larger region possibly having stations in remote settings. Expensive observatory-grade seismic systems are not necessary for seismic hazard deployments or small-scale tomographic studies. Hazard monitoring requires accurate location of induced seismicity to magnitude levels only slightly less than that which can be felt at the surface (e.g. magnitude 1), and the frequencies of interest for tomographic analysis are ~1 Hz and greater. We have developed a seismo/acoustic smart sensor system that can achieve the goals necessary for induced seismicity monitoring in CO2 sequestration fields. The unit is inexpensive, lightweight, easy to deploy, can operate remotely under harsh conditions and features 9 channels of recording (currently 3C 4.5 Hz geophone, MEMS accelerometer and microphone). An on-board processor allows for satellite transmission of parameter data to a processing center. Continuous or event-detected data is kept on two removable flash SD cards of up to 64+ Gbytes each. If available, data can be transmitted via cell phone modem or picked up via site visits. Low-power consumption allows for autonomous operation using only a 10 watt solar panel and a gel-cell battery. The system has been successfully tested for long-term (> 6 months) remote operations over a wide range

  8. Traffic forecasts ignoring induced demand

    DEFF Research Database (Denmark)

    Næss, Petter; Nicolaisen, Morten Skou; Strand, Arvid

    2012-01-01

    the model calculations included only a part of the induced traffic, the difference in cost-benefit results compared to the model excluding all induced traffic was substantial. The results show lower travel time savings, more adverse environmental impacts and a considerably lower benefitcost ratio when...... induced traffic is partly accounted for than when it is ignored. By exaggerating the economic benefits of road capacity increase and underestimating its negative effects, omission of induced traffic can result in over-allocation of public money on road construction and correspondingly less focus on other...... performance of a proposed road project in Copenhagen with and without short-term induced traffic included in the transport model. The available transport model was not able to include long-term induced traffic resulting from changes in land use and in the level of service of public transport. Even though...

  9. Paliperidone palmitate-induced sialorrhoea

    Directory of Open Access Journals (Sweden)

    Cengiz Cengisiz

    2016-03-01

    Full Text Available Extrapyramidal, metabolic, and cardiac side effects were reported for atypical antipsychotics; although a few resources show paliperidone-induced sialorrhea, there are no resources that show paliperidone palmitate-induced sialorrhea. In this paper, we present the paliperidone palmitate-induced sialorrhea side effects of a patient who applied on our clinic [Cukurova Med J 2016; 41(0.100: 8-13

  10. Radiation-induced cancer

    International Nuclear Information System (INIS)

    Dutrillaux, B.; CEA Fontenay-aux-Roses, 92

    1998-01-01

    The induction of malignant diseases is one of the most concerning late effects of ionising radiation. A large amount of information has been collected form atomic bomb survivors, patients after therapeutic irradiation, occupational follow-up and accidentally exposed populations. Major uncertainties persist in the (very) low range i.e, population and workers radioprotection. A review of the biological mechanisms leading to cancer strongly suggests that the vast majority of radiation-induced malignancies arise as a consequence of recessive mutations can be unveiled by ageing, this process being possibly furthered by constitutional or acquired genomic instability. The individual risk is likely to be very low, probably because of the usual dose level. However, the magnitude of medical exposure and the reliance of our societies on nuclear industry are so high that irreproachable decision-making processes and standards for practice are inescapable. (author)

  11. Radiation-induced nondisjunction

    International Nuclear Information System (INIS)

    Uchida, I.A.

    1979-01-01

    The methodology and results of epidemiological studies of the effects of preconception diagnostic x-rays of the abdomen on chromosome segregation in humans are described. The vast majority of studies show the same positive, though not significant, trend to increased nondisjunction among the offspring of irradiated women. The results of the various studies, however, cannot be pooled because of differing methodologies used. Abnormal chromosome segregation during mitotic division has been inducted experimentally by the in vitro exposure of human lymphocytes to a low dose of 50 R gamma irradiation. First meiotic nondisjunction has been successfully induced by whole body exposure of female mice to a low dose of radiation. The question of time-related repair of the mechanism involved in chromosome segregation is raised

  12. Radiation induced oral mucositis

    Directory of Open Access Journals (Sweden)

    P S Satheesh Kumar

    2009-01-01

    Full Text Available Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii who also received concomitant chemotherapy; (iii who received a total dose over 5,000 cGy; and (iv who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene

  13. Laser induced nuclear reactions

    International Nuclear Information System (INIS)

    Ledingham, Ken; McCanny, Tom; Graham, Paul; Fang Xiao; Singhal, Ravi; Magill, Joe; Creswell, Alan; Sanderson, David; Allott, Ric; Neely, David; Norreys, Peter; Santala, Marko; Zepf, Matthew; Watts, Ian; Clark, Eugene; Krushelnick, Karl; Tatarakis, Michael; Dangor, Bucker; Machecek, Antonin; Wark, Justin

    1998-01-01

    Dramatic improvements in laser technology since 1984 have revolutionised high power laser technology. Application of chirped-pulse amplification techniques has resulted in laser intensities in excess of 10 19 W/cm 2 . In the mid to late eighties, C. K. Rhodes and K. Boyer discussed the possibility of shining laser light of this intensity onto solid surfaces and to cause nuclear transitions. In particular, irradiation of a uranium target could induce electro- and photofission in the focal region of the laser. In this paper it is shown that μCi of 62 Cu can be generated via the (γ,n) reaction by a laser with an intensity of about 10 19 Wcm -2

  14. Radiation induced pesticidal microbes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ki Yup; Lee, Y. K.; Kim, J. S.; Kim, J. K.; Lee, S. J.; Lim, D. S

    2001-01-01

    To isolate pesticidal microbes against plant pathogenic fungi, 4 strains of bacteria(K1. K3, K4, YS1) were isolated from mushroom compost and hot spring. K4, K1, K3, YS1 strain showed wide antifungal spectrum and high antifungal activities against 12 kinds of fungi. Specific proteins and the specific transcribed genes were found from the YS1 and its radiation-induced mutants. And knock-out mutants of antifungal activity were derived by transposon mutagenesis. From these knock-out mutants, the antifungal activity related genes and its modification by gamma-ray radiation are going to be studied. These results suggested that radiation could be an useful tool for the induction of functional mutants.

  15. Radiation induced microbial pesticide

    International Nuclear Information System (INIS)

    Kim, Ki Yup; Lee, Young Keun; Kim, Jae Sung; Kim, Jin Kyu; Lee, Sang Jae

    2000-01-01

    To control plant pathogenic fungi, 4 strains of bacteria (K1, K3, K4, YS1) were isolated from mushroom compost and hot spring. K4, K1, K3, YS1 strain showed wide antifungal spectrum and high antifungal activities against 13 kinds of fungi. Mutants of K1 and YS1 strains were induced by gamma-ray radiation and showed promising antifungal activities. These wild type and mutants showed resistant against more than 27 kinds of commercial pesticides among 30 kinds of commercial pesticides test particularly, YS1-1006 mutant strain showed resistant against hydrogen oxide. And mutants had increased antifungal activity against Botryoshaeria dothidea. These results suggested that radiation could be an useful method for the induction of functional mutants. (author)

  16. Aripiprazole-induced priapism

    Directory of Open Access Journals (Sweden)

    Satya K Trivedi

    2016-01-01

    Full Text Available Priapism is a urologic emergency representing a true disorder of penile erection that persists beyond or is unrelated to sexual interest or stimulation. A variety of psychotropic drugs are known to produce priapism, albeit rarely, through their antagonistic action on alpha-1 adrenergic receptors. We report such a case of priapism induced by a single oral dose of 10 mg aripiprazole, a drug with the least affinity to adrenergic receptors among all atypical antipsychotics. Polymorphism of alpha-2A adrenergic receptor gene in schizophrenia patients is known to be associated with sialorrhea while on clozapine treatment. Probably, similar polymorphism of alpha-1 adrenergic receptor gene could contribute to its altered sensitivity and resultant priapism. In future, pharmacogenomics-based approach may help in personalizing the treatment and effectively prevent the emergence of such side effects.

  17. [Cannabis-induced disorders].

    Science.gov (United States)

    Soyka, M; Preuss, U; Hoch, E

    2017-03-01

    Use and misuse of cannabis and marihuana are frequent. About 5% of the adult population are current users but only 1.2% are dependent. The medical use of cannabis is controversial but there is some evidence for improvement of chronic pain and spasticity. The somatic toxicity of cannabis is well proven but limited and psychiatric disorders induced by cannabis are of more relevance, e.g. cognitive disorders, amotivational syndrome, psychoses and delusional disorders as well as physical and psychological dependence. The withdrawal symptoms are usually mild and do not require pharmacological interventions. To date there is no established pharmacotherapy for relapse prevention. Psychosocial interventions include psychoeducation, behavioral therapy and motivational enhancement. The CANDIS protocol is the best established German intervention among abstinence-oriented therapies.

  18. Induced seismicity. Final report

    International Nuclear Information System (INIS)

    Segall, P.

    1997-01-01

    The objective of this project has been to develop a fundamental understanding of seismicity associated with energy production. Earthquakes are known to be associated with oil, gas, and geothermal energy production. The intent is to develop physical models that predict when seismicity is likely to occur, and to determine to what extent these earthquakes can be used to infer conditions within energy reservoirs. Early work focused on earthquakes induced by oil and gas extraction. Just completed research has addressed earthquakes within geothermal fields, such as The Geysers in northern California, as well as the interactions of dilatancy, friction, and shear heating, on the generation of earthquakes. The former has involved modeling thermo- and poro-elastic effects of geothermal production and water injection. Global Positioning System (GPS) receivers are used to measure deformation associated with geothermal activity, and these measurements along with seismic data are used to test and constrain thermo-mechanical models

  19. Macroscopic Optomechanically Induced Transparency

    Science.gov (United States)

    Pate, Jacob; Castelli, Alessandro; Martinez, Luis; Thompson, Johnathon; Chiao, Ray; Sharping, Jay

    Optomechanically induced transparency (OMIT) is an effect wherein the spectrum of a cavity resonance is modified through interference between coupled excitation pathways. In this work we investigate a macroscopic, 3D microwave, superconducting radio frequency (SRF) cavity incorporating a niobium-coated, silicon-nitride membrane as the flexible boundary. The boundary supports acoustic vibrational resonances, which lead to coupling with the microwave resonances of the SRF cavity. The theoretical development and physical understanding of OMIT for our macroscopic SRF cavity is the same as that for other recently-reported OMIT systems despite vastly different optomechanical coupling factors and device sizes. Our mechanical oscillator has a coupling factor of g0 = 2 π . 1 ×10-5 Hz and is roughly 38 mm in diameter. The Q = 5 ×107 for the SRF cavity allows probing of optomechanical effects in the resolved sideband regime.

  20. [Glucocorticoid induced osteoporosis].

    Science.gov (United States)

    Anić, Branimir; Mayer, Miroslav

    2014-01-01

    Secondary osteoporosis most often develops due to glucocorticoid therapy. Glucocorticoids affect all stages of the bone remodeling cycle, its formation and resorption. Osteoblasts are primarily affected, decreasing their activity and enhancing apoptosis. Patients treated with glucocorticoids have lower bone mineral density and increased fracture risk. Glucocorticoid-induced osteoporosis can be prevented by administering the minimal effective dose of glucocorticoids, calcium and vitamin D supplementation or, if possible, by hormone replace- ment therapy. Moreover, appropriate physical activity should be encouraged. Patients who are at higher risk for low-energy fractures (for example post-menopausal women) have to be actively treated, usually with antiresorptive drugs among which bisphosphonates are currently the first line therapy.

  1. Radiation induced genomic instability

    International Nuclear Information System (INIS)

    Morgan, W.

    2003-01-01

    This presentation will focus on delayed genetic effects occurring in the progeny of cells after exposure to ionizing radiation. We have developed a model system for investigating those genetic effects occurring multiple generations after radiation exposure. The presentation will describe some of the delayed effects observed after radiation exposures including delayed chromosomal rearrangements, and recombination events as determined by a plasmid based assay system. We will present new data on how changes in gene expression as measured by differential display and DNA microarray analysis provides a mechanism by which cells display a memory of irradiation, and introduce candidate genes that may play a role in initiating and perpetuation the unstable phenotype. These results will be discussed in terms of the recently described non-targeted Death Inducing Effect (DIE) where by secreted factors from clones of unstable cells can elicit effects in non irradiated cells and may serve to perpetuate the unstable phenotype in cells that themselves were not irradiated

  2. Radiation induced pesticidal microbes

    International Nuclear Information System (INIS)

    Kim, Ki Yup; Lee, Y. K.; Kim, J. S.; Kim, J. K.; Lee, S. J.; Lim, D. S.

    2001-01-01

    To isolate pesticidal microbes against plant pathogenic fungi, 4 strains of bacteria(K1. K3, K4, YS1) were isolated from mushroom compost and hot spring. K4, K1, K3, YS1 strain showed wide antifungal spectrum and high antifungal activities against 12 kinds of fungi. Specific proteins and the specific transcribed genes were found from the YS1 and its radiation-induced mutants. And knock-out mutants of antifungal activity were derived by transposon mutagenesis. From these knock-out mutants, the antifungal activity related genes and its modification by gamma-ray radiation are going to be studied. These results suggested that radiation could be an useful tool for the induction of functional mutants

  3. Alcohol-Induced Blackout

    Directory of Open Access Journals (Sweden)

    Dai Jin Kim

    2009-11-01

    Full Text Available For a long time, alcohol was thought to exert a general depressant effect on the central nervous system (CNS. However, currently the consensus is that specific regions of the brain are selectively vulnerable to the acute effects of alcohol. An alcohol-induced blackout is the classic example; the subject is temporarily unable to form new long-term memories while relatively maintaining other skills such as talking or even driving. A recent study showed that alcohol can cause retrograde memory impairment, that is, blackouts due to retrieval impairments as well as those due to deficits in encoding. Alcoholic blackouts may be complete (en bloc or partial (fragmentary depending on severity of memory impairment. In fragmentary blackouts, cueing often aids recall. Memory impairment during acute intoxication involves dysfunction of episodic memory, a type of memory encoded with spatial and social context. Recent studies have shown that there are multiple memory systems supported by discrete brain regions, and the acute effects of alcohol on learning and memory may result from alteration of the hippocampus and related structures on a cellular level. A rapid increase in blood alcohol concentration (BAC is most consistently associated with the likelihood of a blackout. However, not all subjects experience blackouts, implying that genetic factors play a role in determining CNS vulnerability to the effects of alcohol. This factor may predispose an individual to alcoholism, as altered memory function during intoxication may affect an individual‟s alcohol expectancy; one may perceive positive aspects of intoxication while unintentionally ignoring the negative aspects. Extensive research on memory and learning as well as findings related to the acute effects of alcohol on the brain may elucidate the mechanisms and impact associated with the alcohol- induced blackout.

  4. Radiation induced nano structures

    International Nuclear Information System (INIS)

    Ibragimova, E.M.; Kalanov, M.U.; Khakimov, Z.

    2006-01-01

    Full text: Nanometer-size silicon clusters have been attracting much attention due to their technological importance, in particular, as promising building blocks for nano electronic and nano photonic systems. Particularly, silicon wires are of great of interest since they have potential for use in one-dimensional quantum wire high-speed field effect transistors and light-emitting devices with extremely low power consumption. Carbon and metal nano structures are studied very intensely due to wide possible applications. Radiation material sciences have been dealing with sub-micron objects for a long time. Under interaction of high energy particles and ionizing radiation with solids by elastic and inelastic mechanisms, at first point defects are created, then they form clusters, column defects, disordered regions (amorphous colloids) and finally precipitates of another crystal phase in the matrix. Such irradiation induced evolution of structure defects and phase transformations was observed by X-diffraction techniques in dielectric crystals of quartz and corundum, which exist in and crystal modifications. If there is no polymorphism, like in alkali halide crystals, then due to radiolysis halogen atoms are evaporated from the surface that results in non-stoichiometry or accumulated in the pores formed by metal vacancies in the sub-surface layer. Nano-pores are created by intensive high energy particles irradiation at first chaotically and then they are ordered and in part filled by inert gas. It is well-known mechanism of radiation induced swelling and embrittlement of metals and alloys, which is undesirable for construction materials for nuclear reactors. Possible solution of this problem may come from nano-structured materials, where there is neither swelling nor embrittlement at gas absorption due to very low density of the structure, while strength keeps high. This review considers experimental observations of radiation induced nano-inclusions in insulating

  5. Prolactin induces adrenal hypertrophy

    Directory of Open Access Journals (Sweden)

    E.J. Silva

    2004-02-01

    Full Text Available Although adrenocorticotropic hormone is generally considered to play a major role in the regulation of adrenal glucocorticoid secretion, several reports have suggested that other pituitary hormones (e.g., prolactin also play a significant role in the regulation of adrenal function. The aim of the present study was to measure the adrenocortical cell area and to determine the effects of the transition from the prepubertal to the postpubertal period on the hyperprolactinemic state induced by domperidone (4.0 mg kg-1 day-1, sc. In hyperprolactinemic adult and young rats, the adrenals were heavier, as determined at necropsy, than in the respective controls: adults (30 days: 0.16 ± 0.008 and 0.11 ± 0.007; 46 days: 0.17 ± 0.006 and 0.12 ± 0.008, and 61 days: 0.17 ± 0.008 and 0.10 ± 0.004 mg for treated and control animals, respectively; P < 0.05, and young rats (30 days: 0.19 ± 0.003 and 0.16 ± 0.007, and 60 days: 0.16 ± 0.006 and 0.13 ± 0.009 mg; P < 0.05. We selected randomly a circular area in which we counted the nuclei of adrenocortical cells. The area of zona fasciculata cells was increased in hyperprolactinemic adult and young rats compared to controls: adults: (61 days: 524.90 ± 47.85 and 244.84 ± 9.03 µm² for treated and control animals, respectively; P < 0.05, and young rats: (15 days: 462.30 ± 16.24 and 414.28 ± 18.19; 60 days: 640.51 ± 12.91 and 480.24 ± 22.79 µm²; P < 0.05. Based on these data we conclude that the increase in adrenal weight observed in the hyperprolactinemic animals may be due to prolactin-induced adrenocortical cell hypertrophy.

  6. Congruence properties of induced representations

    DEFF Research Database (Denmark)

    Mayer, Dieter; Momeni, Arash; Venkov, Alexei

    In this paper we study representations of the projective modular group induced from the Hecke congruence group of level 4 with Selberg's character. We show that the well known congruence properties of Selberg's character are equivalent to the congruence properties of the induced representations...

  7. Laser-induced nuclear fusion

    International Nuclear Information System (INIS)

    Jablon, Claude

    1977-01-01

    Research programs on laser-induced thermonuclear fusion in the United States, in Europe and in USSR are reviewed. The principle of the fusion reactions induced is explained, together with the theoretical effects of the following phenomena: power and type of laser beams, shape and size of the solid target, shock waves, and laser-hydrodynamics coupling problems [fr

  8. Force induced DNA melting

    International Nuclear Information System (INIS)

    Santosh, Mogurampelly; Maiti, Prabal K

    2009-01-01

    When pulled along the axis, double-strand DNA undergoes a large conformational change and elongates by roughly twice its initial contour length at a pulling force of about 70 pN. The transition to this highly overstretched form of DNA is very cooperative. Applying a force perpendicular to the DNA axis (unzipping), double-strand DNA can also be separated into two single-stranded DNA, this being a fundamental process in DNA replication. We study the DNA overstretching and unzipping transition using fully atomistic molecular dynamics (MD) simulations and argue that the conformational changes of double-strand DNA associated with either of the above mentioned processes can be viewed as force induced DNA melting. As the force at one end of the DNA is increased the DNA starts melting abruptly/smoothly above a critical force depending on the pulling direction. The critical force f m , at which DNA melts completely decreases as the temperature of the system is increased. The melting force in the case of unzipping is smaller compared to the melting force when the DNA is pulled along the helical axis. In the case of melting through unzipping, the double-strand separation has jumps which correspond to the different energy minima arising due to sequence of different base pairs. The fraction of Watson-Crick base pair hydrogen bond breaking as a function of force does not show smooth and continuous behavior and consists of plateaus followed by sharp jumps.

  9. Chemotherapy-induced hypocalcemia.

    Science.gov (United States)

    Ajero, Pia Marie E; Belsky, Joseph L; Prawius, Herbert D; Rella, Vincent

    2010-01-01

    To present a unique case of transient, asymptomatic chemotherapy-induced hypocalcemia not attributable to hypomagnesemia or tumor lysis syndrome and review causes of hypocalcemia related to cancer with and without use of chemotherapy. We present a case detailing the clinical and laboratory findings of a patient who had severe hypocalcemia during chemotherapy and discuss causes of hypocalcemia with an extensive literature review of chemotherapeutic agents associated with this biochemical abnormality. In a 90-year-old man, hypocalcemia developed during 2 courses of chemotherapy for Hodgkin lymphoma, with partial recovery between courses and normal serum calcium 10 months after completion of treatment. Magnesium, vitamin D, and parathyroid hormone levels were low normal. There was no evidence of tumor lysis syndrome. Of the various agents administered, vinca alkaloids seemed the most likely cause. Serial testing suggested that the underlying mechanism may have been acquired, reversible hypoparathyroidism. No other similar case was found in the published literature. The severe hypocalcemia in our patient could not be attributed to hypomagnesemia or tumor lysis syndrome, and it was clearly associated with the timing of his chemotherapeutic regimen. Possibilities include direct parathyroid hormone suppression or alteration of calcium sensing by the chemotherapeutic drugs. Serum calcium surveillance before and during chemotherapeutic management of cancer patients may reveal more instances and provide insight into the exact mechanism of this lesser known yet striking complication.

  10. Collision-induced coherence

    International Nuclear Information System (INIS)

    Bloembergen, N.

    1985-01-01

    Collision-induced coherence is based on the elimination of phase correlations between coherent Feynman-type pathways which happen to interfere destructively in the absence of damping for certain nonlinear processes. One consequence is the appearance of the extra resonances in four-wave light mixing experiments, for which the intensity increases with increasing buffer gas pressure. These resonances may occur between a pair of initially unpopulated excited states, or between a pair of initially equally populated ground states. The pair of levels may be Zeeman substrates which became degenerate in zero magnetic field. The resulting collision-enhanced Hanle resonances can lead to very sharp variations in the four-wave light mixing signal as the external magnetic field passes through zero. The theoretical description in terms of a coherence grating between Zeeman substrates is equivalent to a description in terms of a spin polarization grating obtained by collision-enhanced transverse optical pumping. The axis of quantization in the former case is taken perpendicular to the direction of the light beams; in the latter case is taken parallel to this direction

  11. Linezolid induced retinopathy.

    Science.gov (United States)

    Park, Dae Hyun; Park, Tae Kwann; Ohn, Young-Hoon; Park, Jong Sook; Chang, Jee Ho

    2015-12-01

    While optic neuropathy is a well-known cause of visual disturbances in linezolid-treated patients, the possibility of linezolid-related retinopathy has not been investigated. Here, we report a case of retinopathy demonstrated by multifocal electroretinogram (mfERG) in a linezolid-treated patient. A 61-year-old man with extensively drug-resistant pulmonary tuberculosis treated with linezolid for 5 months presented with painless loss of vision in both eyes. The patient's best corrected visual acuity was 20/50 in the right eye and 20/100 in the left eye. Fundus examination revealed mild disc edema, and color vision was defective in both eyes. Humphrey visual field tests showed a superotemporal field defect in the right eye and central and pericentral field defect in the left eye. Optical coherence tomography (OCT) revealed only mild optic disc swelling. In mfERG, central amplitudes were depressed in both eyes. Four months after the cessation of linezolid, visual acuity was restored to 20/20 right eye and 20/25 left eye. The color vision and visual field had improved. The OCT and mfEFG findings improved as well. Although the clinical features were similar to linezolid-induced optic neuropathy, the mfERG findings suggest the possibility of a retinopathy through cone dysfunction.

  12. Food-induced anaphylaxis.

    Science.gov (United States)

    Järvinen, Kirsi M

    2011-06-01

    Food-induced anaphylaxis is the leading single cause of anaphylaxis treated in emergency departments and increasing in prevalence. Food allergy is an increasing problem in westernized countries around the world, with a cumulative prevalence of 3-6%. Peanut, tree nuts, and shellfish are the most commonly implicated foods in anaphylaxis, although milk is a common trigger in children. Asthmatics, adolescents, and those with a prior reaction are at increased risk for more severe reactions. Most first reactions and reactions in children most commonly occur at home, whereas most subsequent reactions and reactions in adults occur outside home. Studies on schools have identified inadequate management plans and symptom recognition whereas those on restaurants report lack of prior notification by allergic individuals and lack in staff education. Epinephrine, although underutilized is the drug of choice with multiple doses needed in up to one-fifth of reactions. Diagnosis is currently based on convincing history and allergy testing supported by elevated serum tryptase, if available. Long-term management includes strict avoidance and emergency action plan. With a growing population of food-allergic children and adults, markers to predict which individuals are at increased risk for anaphylaxis as well as new therapies are vigorously sought.

  13. Methaemoglobinemia Induced by MDMA?

    Directory of Open Access Journals (Sweden)

    L. L. W. Verhaert

    2011-01-01

    Full Text Available Case. A 45-year-old man with a blank medical history presented at the emergency room with dizziness and cyanosis. Physical examination showed cyanosis with a peripheral saturation (SpO2 of 85%, he did not respond to supplemental oxygen. Arterial blood gas analysis showed a striking chocolate brown colour. Based on these data, we determined the arterial methaemoglobin concentration. This was 32%. We gave 100% oxygen and observed the patient in a medium care unit. The next day, patient could be discharged in good condition. Further inquiry about exhibitions and extensive history revealed that the patient used MDMA (3,4- methylenedioxymethamphetamine, the active ingredient of ecstasy. Conclusion. Acquired methaemoglobinemia is a condition that occurs infrequently, but is potentially life threatening. Different nutrients, medications, and chemicals can induce methaemoglobinemia by oxidation of haemoglobin. The clinical presentation of a patient with methaemoglobinemia is due to the impossibility of O2 binding and transport, resulting in tissue hypoxia. Important is to think about methaemoglobin in a patient who presents with cyanosis, a peripheral saturation of 85% that fails to respond properly to the administration of O2. Because methaemoglobin can be reduced physiologically, it is usually sufficient to remove the causative agent, to give O2, and to observe the patient.

  14. Induced mutations in castor

    International Nuclear Information System (INIS)

    Ganesan, K.; Javad Hussain, H.S.; Vindhiyavarman, P.

    2001-01-01

    Castor (Ricinus communis L.) is an important oilseed crop in India. To create variability mutations were induced in two cultivars 'TMV5' (maturing in 130-140 days) and 'CO1' (perennial type). Gamma rays and diethyl sulphate and ethidium bromide were used for seed treatment. Ten doses, from 100 to 1000 Gy were employed. For chemical mutagenesis five concentrations of mutagenes from 10 to 50 mM were tried. No economic mutants could be isolated after treatment with the chemical mutagens. The following economic mutants were identified in the dose 300 Gy of gamma rays. Annual types from perennial CO 1 castor CO 1 is a perennial variety (8-10 years) with bold seeds (100 seed weight 90 g) and high oil content (57%). Twenty-one lines were isolated with annual types (160-180 days) with high yield potential as well as bold seeds and high oil content. These mutants, identified in M 3 generation were bred true in subsequent generations up to M 8 generation. Critical evaluation of the mutants in yield evaluation trials is in progress

  15. Laughter-induced syncope.

    Science.gov (United States)

    Kim, Alexander J; Frishman, William H

    2012-01-01

    Reported cases of syncope caused directly by laughter are rare. The common scenario described in a few reports involved episodes of fortuitous laughter, sometimes followed by a short prodrome of lightheadedness, facial flushing, and dizziness, followed by an episode of definite syncope. There were no seizure-like movements, automatisms, or bladder or bowel incontinence. After the syncopal episodes that were seconds in length, the patients regained consciousness, and at that point were fully oriented. These episodes could recur in a similar situation with such laughter. Many of these patients subsequently underwent full syncope workups, without elucidating a primary cardiac or neurologic cause. In this review of laughter-induced syncope, we describe a patient of ours who fit these descriptions. This phenomenon is likely a subtype of benign Valsalva-related syncope, with autonomic reflex arcs coming into play that ultimately result in global cerebral hypoperfusion. Besides the Valsalva produced by a great fit of laughter, laughter itself has its own neuroendocrine and vasculature effects that may play a role.

  16. Radiation-induced cerebrovasculopathy

    International Nuclear Information System (INIS)

    Ikeyama, Yukihide; Abiko, Seisho; Kurokawa, Yasushi; Okamura, Tomomi; Watanabe, Kohsaku; Inoue, Shinichi; Fujii, Yasuhiro.

    1993-01-01

    We reported a patient who suffered from cerebrovasculopathy after irradiation therapy for astrocytoma located at the left temporal lobe. An eleven year-old boy who presented with headache and vomiting received partial removal of a tumor. Histological diagnosis of the tumor was astrocytoma (grade II). His preoperative cerebral angiograms showed mass sign solely, without stenosis or occlusion of the cerebral vessel. Postoperatively, he was treated with irradiation therapy involving the whole brain with a total of 30 Gy, and gamma knife therapy. Six months after irradiation, he started suffering from frequent cerebral ischemic attacks, but there was no regrowth of the tumor visible on CT scans. Cerebral angiograms were made again, and revealed multifocal stenoses in the bilateral internal carotid arteries, middle cerebral arteries, and the anterior cerebral artery. His symptoms did not improve after conservative treatment with steroids, calcium antagonist, or low molecular weight dextran. Although he received a superficial temporal artery-middle cerebral artery (STA-MCA) anastomoses bilaterally, multiple cerebral infarctions appeared. Although irradiation therapy is acceptable in patients with brain tumor, cerebrovasculopathy after irradiation should be considered as one of the most important complications, and the risk incurred by irradiation therapy should lead to more careful consideration and caution when treating intracranial brain tumors, especially in children. From our experience, the usefulness of bypass surgery for radiation-induced cerebrovasculopathy is still controversial. (author)

  17. Temozolomide-Induced Myelodysplasia

    Directory of Open Access Journals (Sweden)

    Ethan A. Natelson

    2010-01-01

    Full Text Available A patient who had received temozolomide (TMZ as a single agent in treatment of malignant glioma developed therapy-induced myelodysplasia (T-MDS. TMZ is an orally active imidazotetrazine which methylates guanine residues in DNA, ultimately causing single and double-strand DNA breaks leading to apoptotic cell death. TMZ does not chemically cross-link DNA and is considered a nonclassical alkylating agent, similar in structure and activity to dacarbazine. Observations on this patient, and on similarly treated others, suggest that the cumulative dose threshold (CDT for TMZ that predisposes to T-MDS and which may potentially lead to acute myeloid leukemia (T-AML is around 18000 to 20000 mg/sq m. Although the incidence of T-MDS and the predisposing CDT of TMZ may differ from that of other potentially leukemogenic compounds currently and formerly used as chemotherapeutic agents, all alkylating agents, including TMZ, should be considered potentially leukemogenic when administered long term.

  18. Microbiologically induced corrosion

    International Nuclear Information System (INIS)

    Stein, A.A.

    1988-01-01

    Biological attack is a problem that can affect all metallic materials in a variety of environments and systems. In the power industry, corrosion studies have focused on condensers and service water systems where slime, barnacles, clams, and other macro-organisms are easily detected. Efforts have been made to eliminate the effect of these organisms through the use of chlorination, backflushing, organic coating, or thermal shock. The objective is to maintain component performance by eliminating biofouling and reducing metallic corrosion. Recently, corrosion of power plant components by micro-organisms (bacteria) has been identified even in very clean systems. A system's first exposure to microbiologically induced corrosion (MIC) occurs during its first exposure to an aqueous environment, such as during hydrotest or wet layup. Corrosion of buried pipelines by sulfate-reducing bacteria has been studied by the petrochemical industry for years. This paper discusses various methods of diagnosing, monitoring, and controlling MIC in a variety of systems, as well as indicates areas where further study is needed

  19. Doxycycline induced Esophagitis

    Directory of Open Access Journals (Sweden)

    Banu Karakus Yilmaz

    2014-02-01

    Full Text Available Esophagitis is a hazardous condition such as acid reflux of esophageal mucosa, infection, systemic diseases, radiation, drugs and trauma. Drug- induced esophagial injury (DIEI is a disease with the use of variety of drugs that caused serious damage and ulcer in the mucosa of the esophagus. The most commonly implicated drugs are non-steroidal anti-inflammatory drugs (NSAIDs, chloride and especially antibiotics. Thirty-six year-old female patient presented to the emergency department with odynophagia during swallowing and complaining of retrosternal pain. One week before 100 mg doxycycline (2x1 PO for therapeutic abortion were prescribed. It was learned that in the third day of the initiation of medication, the patient\\'s symptoms began and stopped using drug by the fourth day due to advers effect of drugs, but her symptoms didn’t regressed although she didn’t use them. Endoscopy appointment was taken, proton pump inhibitor and antiacid treatment was given, than patient was discharged from the emergency department. In the endoscopy, 20 mm segment esophageal ulcer was seen approximately in the 30.th cm of the esophagius. DIEI is a relatively common, although under-recognized, so this case was presented for remainding DIEI to emergency medicine personals and reweiving its diagnosis, treatment and follow-up.

  20. Ceftazidime-induced thrombocytopenia.

    Science.gov (United States)

    Domingo-Chiva, E; Díaz-Rangel, M; Monsalve-Naharro, J Á; Cuesta-Montero, P; Catalá-Ripoll, J V; García-Martínez, E M

    2017-12-01

    Ceftazidime is an antibiotic belonging to the group of third generation cephalosporins, frequently used in clinical practice for its broad antibacterial spectrum. A case report is presented on a 78-year-old man who entered the intensive care unit due to respiratory failure secondary to nosocomial pneumonia in the postoperative period of a laparoscopic hepatic bisegmentectomy for a hepatocarcinoma. It required invasive mechanical ventilation and was treated with ceftazidime, developing a progressive decrease in platelet count after the onset of this drug and after re-exposure to it, not coinciding with the introduction of other drugs. The adverse reaction was reported to the Spanish pharmacosurveillance system and according to the Naranjo algorithm the causal relationship was probable. Since no case of ceftazidime-induced thrombocytopenia was found in the literature, we consider knowledge of it relevant as an adverse effect to be taken into account given its potential severity, especially when it cannot be explained by other causes. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. Neutron induced electron radiography

    International Nuclear Information System (INIS)

    Andrade, Marcos Leandro Garcia

    2008-01-01

    In the present paper a new radiography technique, the 'Neutron Induced Electron Radiography' - NIER, to inspect low thickness samples on the order of micra, has been developed. This technique makes use of low energy electrons as penetrating radiation generated from metallic gadolinium screens when irradiated by thermal neutrons. The conditions to obtain the best image for the conventional X-ray film Kodak-AA were determined by using a digital system to quantify the darkening level of the film. The irradiations have been performed at a radiography equipment installed at the beam-hole no. 8 of the 5 MW IEA-R1 nuclear research reactor of IPEN-CNEN/SP. The irradiation time to obtain the best radiography was 100 seconds and for such condition the technique was able to discern 1 μm in 24 μm of aluminum at a resolution of 32 μm. By visual comparison the images obtained by the NIER shown a higher quality when compared with the ones from other usual techniques the make use of electrons a penetrating radiation and films for image registration. Furthermore the use of the digital system has provided a smaller time for data acquisition and data analysis as well as an improvement in the image visualization. (author)

  2. Ion-induced sputtering

    International Nuclear Information System (INIS)

    Yamamura, Yasumichi; Shimizu, Ryuichi; Shimizu, Hazime; Ito, Noriaki.

    1983-01-01

    The research on ion-induced sputtering has been continued for a long time, since a hundred or more years ago. However, it was only in 1969 by Sigmund that the sputtering phenomena were theoretically arranged into the present form. The reason why the importance of sputtering phenomena have been given a new look recently is the application over wide range. This paper is a review centering around the mechanism of causing sputtering and its characteristics. Sputtering is such a phenomenon that the atoms in the vicinity of a solid surface are emitted into vacuum by receiving a part of ion energy, or in other words, it is a kind of irradiation damage in the vicinity of a solid surface. In this meaning, it can be considered that the sputtering based on the ions located on the clean surface of a single element metal is simple, and has already been basically understood. On the contrary, the phenomena can not be considered to be fully understood in the case of alloys and compounds, because these surface conditions under irradiation are not always clear due to segregation and others. In the paper, the physical of sputtering, single element sputtering, the sputtering in alloys and compounds, and the behaviour of emitted particles are explained. Finally, some recent topics of the sputtering measurement by laser resonant excitation, the sputtering by electron excitation, chemical sputtering, and the sputtering in nuclear fusion reactors are described. (Wakatsuki, Y.)

  3. Tumor-induced osteomalacia

    Science.gov (United States)

    Chong, William H; Molinolo, Alfredo A; Chen, Clara C; Collins, Michael T

    2012-01-01

    Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed. PMID:21490240

  4. Laxative-induced rhabdomyolysis

    Directory of Open Access Journals (Sweden)

    Alfonso Merante

    2010-03-01

    Full Text Available Alfonso Merante1, Pietro Gareri2,3, Norma Maria Marigliano2, Salvatore De Fazio2, Elvira Bonacci1, Carlo Torchia1, Gaetano Russo1, Pasquale Lacroce1, Roberto Lacava3, Alberto Castagna3, Giovambattista De Sarro2, Giovanni Ruotolo11Geriatrist, Geriatric Unit “Pugliese-Ciaccio” Hospital, Catanzaro, Italy; 2Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University Magna Graecia of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini University Hospital, Catanzaro, Italy; 3Geriatrist, Operative Unit Elderly Health Care, Catanzaro, ItalyAbstract: The present study describes a case of laxative-induced rhabdomyolysis in an elderly patient. An 87-year-old woman was hospitalized for the onset of confusion, tremors, an inability to walk, and a fever that she had been experiencing for 36 hours. She often took high dosages of lactulose and sorbitol syrup as a laxative (about 70 g/day. During her physical examination, the patient was confused, drowsy, and she presented hyposthenia in her upper and lower limbs, symmetric and diffuse moderate hyporeflexia, and her temperature was 37.8°C. Laboratory tests revealed severe hyponatremia with hypokalemia, hypocalcemia, hypochloremia, and metabolic alkalosis. Moreover, rhabdomyolysis markers were found. The correction of hydroelectrolytic imbalances with saline, potassium and sodium chlorure, calcium gluconate was the first treatment. During her hospitalization the patient presented acute delirium, treated with haloperidol and prometazine chloridrate intramuscularly. She was discharged 12 days later, after resolution of symptoms, and normalized laboratory tests. Over-the-counter drugs such as laxatives are usually not considered dangerous; on the other hand, they may cause serum electrolytic imbalance and rhabdomyolysis. A careful monitoring of all the drugs taken by the elderly is one of the most important duties of a physician since drug interactions and

  5. Tumour-induced osteomalacia.

    Science.gov (United States)

    Minisola, Salvatore; Peacock, Munro; Fukumoto, Seijii; Cipriani, Cristiana; Pepe, Jessica; Tella, Sri Harsha; Collins, Michael T

    2017-07-13

    Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

  6. Catecholamine induced cardiomyopathy in pheochromocytoma

    Directory of Open Access Journals (Sweden)

    Ron Thomas Varghese

    2013-01-01

    Full Text Available Catecholamine induced cardiomyopathy in the setting of pheochromocytoma is an unusual clinical entity. Earlier studies have reported left ventricular dysfunction in around 10% of subjects with pheochromocytoma. [1] Catecholamine induced vasoconstriction, direct toxic effect of byproducts of catecholamine degradation and direct receptor-mediated mechanisms are thought to contribute to cardiomyopathy in subjects with pheochromocytoma. The presentation remains a diagnostic challenge as patients may already have hypertensive heart disease and acute coronary syndrome on account of uncontrolled secondary hypertension. We report a case of a 42-year-old male, who presented with features of pheochromocytoma induced cardiomyopathy.

  7. Cisplatin-Induced Eosinophilic Pneumonia

    Directory of Open Access Journals (Sweden)

    Hideharu Ideguchi

    2014-01-01

    Full Text Available A 67-year-old man suffering from esophageal cancer was admitted to our hospital complaining of dyspnea and hypoxemia. He had been treated with cisplatin, docetaxel, and fluorouracil combined with radiotherapy. Chest computed tomography revealed bilateral ground-glass opacity, and bronchoalveolar lavage fluid showed increased eosinophils. Two episodes of transient eosinophilia in peripheral blood were observed after serial administration of anticancer drugs before the admission, and drug-induced lymphocyte stimulation test to cisplatin was positive. Thus cisplatin-induced eosinophilic pneumonia was suspected, and corticosteroid was effectively administered. To our knowledge, this is the first reported case of cisplatin-induced eosinophilic pneumonia.

  8. Systemic resistance induced by rhizosphere bacteria

    NARCIS (Netherlands)

    Loon, L.C. van; Bakker, P.A.H.M.; Pieterse, C.M.J.

    1998-01-01

    Nonpathogenic rhizobacteria can induce a systemic resistance in plants that is phenotypically similar to pathogen-induced systemic acquired resistance (SAR). Rhizobacteria-mediated induced systemic resistance (ISR) has been demonstrated against fungi, bacteria, and viruses in Arabidopsis, bean,

  9. Tumor-induced osteomalacia

    Directory of Open Access Journals (Sweden)

    Pablo Florenzano

    2017-12-01

    Full Text Available Tumor-induced osteomalacia (TIO is a rare paraneoplastic syndrome clinically characterized by bone pain, fractures and muscle weakness. It is caused by tumoral overproduction of fibroblast growth factor 23 (FGF23 that acts primarily at the proximal renal tubule, decreasing phosphate reabsorption and 1α-hydroxylation of 25 hydroxyvitamin D, thus producing hypophosphatemia and osteomalacia. Lesions are typically small, benign mesenchymal tumors that may be found in bone or soft tissue, anywhere in the body. In up to 60% of these tumors, a fibronectin-1(FN1 and fibroblast growth factor receptor-1 (FGFR1 fusion gene has been identified that may serve as a tumoral driver. The diagnosis is established by the finding of acquired chronic hypophosphatemia due to isolated renal phosphate wasting with concomitant elevated or inappropriately normal blood levels of FGF23 and decreased or inappropriately normal 1,25-OH2-Vitamin D (1,25(OH2D. Locating the tumor is critical, as complete removal is curative. For this purpose, a step-wise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging. Suspicious lesions should be confirmed by anatomical imaging, and if needed, selective venous sampling with measurement of FGF23. If the tumor is not localized, or surgical resection is not possible, medical therapy with phosphate and active vitamin D is usually successful in healing the osteomalacia and reducing symptoms. However, compliance is often poor due to the frequent dosing regimen and side effects. Furthermore, careful monitoring is needed to avoid complications such us secondary/tertiary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Novel therapeutical approaches are being developed for TIO patients, such as image-guided tumor ablation and medical treatment with the anti-FGF23 monoclonal antibody KRN23 or anti FGFR medications. The case of a patient with TIO is presented to

  10. Infrasonic induced ground motions

    Science.gov (United States)

    Lin, Ting-Li

    On January 28, 2004, the CERI seismic network recorded seismic signals generated by an unknown source. Our conclusion is that the acoustic waves were initiated by an explosive source near the ground surface. The meteorological temperature and effective sound speed profiles suggested existence of an efficient near-surface waveguide that allowed the acoustic disturbance to propagate to large distances. An explosion occurring in an area of forest and farms would have limited the number of eyewitnesses. Resolution of the source might be possible by experiment or by detailed analysis of the ground motion data. A seismo-acoustic array was built to investigate thunder-induced ground motions. Two thunder events with similar N-wave waveforms but different horizontal slownesses are chosen to evaluate the credibility of using thunder as a seismic source. These impulsive acoustic waves excited P and S reverberations in the near surface that depend on both the incident wave horizontal slowness and the velocity structure in the upper 30 meters. Nineteen thunder events were chosen to further investigate the seismo-acoustic coupling. The consistent incident slowness differences between acoustic pressure and ground motions suggest that ground reverberations were first initiated somewhat away from the array. Acoustic and seismic signals were used to generate the time-domain transfer function through the deconvolution technique. Possible non-linear interaction for acoustic propagation into the soil at the surface was observed. The reverse radial initial motions suggest a low Poisson's ratio for the near-surface layer. The acoustic-to-seismic transfer functions show a consistent reverberation series of the Rayleigh wave type, which has a systematic dispersion relation to incident slownesses inferred from the seismic ground velocity. Air-coupled Rayleigh wave dispersion was used to quantitatively constrain the near-surface site structure with constraints afforded by near-surface body

  11. [Medical induced abortion].

    Science.gov (United States)

    Bettahar, K; Pinton, A; Boisramé, T; Cavillon, V; Wylomanski, S; Nisand, I; Hassoun, D

    2016-12-01

    Updated clinical recommendations for medical induced abortion procedure. A systematic review of French and English literature, reviewing the evidence relating to the provision of medical induced abortion was carried out on PubMed, Cochrane Library and international scientific societies recommendations. The effectiveness of medical abortion is higher than 95% when the protocols are adjusted to gestational age (EL1). Misoprostol alone is less effective than a combination of mifepristone and misoprostol (EL1). Gemeprost is less effective than misoprostol (EL2). The dose of 200mg of mifepristone should be preferred to 600mg (NP1, Rank A). Mifepristone can be taken at home (professional agreement). The optimum interval between mifepristone and misoprostol intake should be 24 to 48 hours (EL1, grade A). Before 7 weeks LMP, the dose of 400μg misoprostol should be given orally (EL1, grade A) eventually repeated after 3hours if no bleeding occurs. For optimal effectiveness between 7 and 14 LMP, the interval between mifepristone and misoprostol should not be shortened to less than 8hours (grade 1). An interval of 24 to 48hours will not affect the effectiveness of the method provided misoprostol dosage is 800μg (EL1). Vaginal, sublingual or buccal routes of administration are more effective and better tolerated than the oral route, which should be abandoned (EL1). An amount of 800μg sublingual or buccal misoprostol route has the same effectiveness than the vaginal route but more gastrointestinal side effects (EL1, grade A). Between 7 and 9 LMP, it does not seem necessary to repeat misoprostol dose whereas it should be repeated beyond 9 SA (grade B). Between 9 and 14 LMP, the dose of 400μg misoprostol given either vaginally, buccally or sublingually should be repeated every 3hours if needed (with a maximum of 5 doses) (EL2, grade B). There is no strong evidence supporting routine antibiotic prophylaxis for medical abortion (professional agreement). Rare contraindications

  12. Mutations induced in plant breeding

    International Nuclear Information System (INIS)

    Barriga B, P.

    1984-01-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented. (Author)

  13. Mutations induced in plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Barriga B, P. (Universidad Austral de Chile, Valdivia. Inst. de Produccion y Sanidad Vegetal)

    1984-10-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented.

  14. Holographic Two-Photon Induced Photopolymerization

    Data.gov (United States)

    Federal Laboratory Consortium — Holographic two-photon-induced photopolymerization (HTPIP) offers distinct advantages over conventional one-photon-induced photopolymerization and current techniques...

  15. Mitochondrial Swelling Induced by Glutathione

    Science.gov (United States)

    Lehninger, Albert L.; Schneider, Marion

    1959-01-01

    Reduced glutathione, in concentrations approximating those occurring in intact rat liver, causes swelling of rat liver mitochondria in vitro which is different in kinetics and extent from that yielded by L-thyroxine. The effect is also given by cysteine, which is more active, and reduced coenzyme A, but not by L-ascorbate, cystine, or oxidized glutathione. The optimum pH is 6.5, whereas thyroxine-induced swelling is optimal at pH 7.5. The GSH-induced swelling is not inhibited by DNP or dicumarol, nor by high concentrations of sucrose, serum albumin, or polyvinylpyrrolidone, in contrast to thyroxine-induced swelling. ATP inhibits the GSH swelling, but ADP and AMP are ineffective. Mn-+ is a very potent inhibitor, but Mg++ is ineffective. Ethylenediaminetetraacetate is also an effective inhibitor of GSH-induced swelling. The respiratory inhibitors amytal and antimycin A do not inhibit the swelling action of GSH, but cyanide does; these findings are consistent with the view that the oxidation-reduction state of the respiratory chain between cytochrome c and oxygen is a determinant of GSH-induced swelling. Reversal of GSH-induced swelling by osmotic means or by ATP in KCl media could not be observed. Large losses of nucleotides and protein occur during the swelling by GSH, suggesting that the action is irreversible. The characteristically drastic swelling action of GSH could be prevented if L-thyroxine was also present in the medium. PMID:13630941

  16. Induced mutations in sesame breeding

    International Nuclear Information System (INIS)

    Ashri, A.

    2001-01-01

    The scope of induced mutations in sesame (Sesamum indicum L.) breeding is reviewed. So far in Egypt, India, Iraq, Rep. of Korea, and Sri Lanka, 14 officially released varieties have been developed through induced mutations: 12 directly and 2 through cross breeding (one using the 'dt45' induced mutant from Israel). For another variety released in China there are no details. The induced mutations approach was adopted primarily in order to obtain genetic variability that was not available in the germplasm collection. The mutagens commonly applied have been gamma rays, EMS and sodium azide. Sesame seeds can withstand high mutagen doses, and there are genotypic differences in sensitivity between varieties. The mutants induced in the above named countries and others include better yield, improved seed retention, determinate habit, modified plant architecture and size, more uniform and shorter maturation period, earliness, resistance to diseases, genic male sterility, seed coat color, higher oil content and modified fatty acids composition. Some of the induced mutants have already given rise to improved varieties, the breeding value of other mutants is now being assessed and still others can serve as useful markers in genetic studies and breeding programmes. (author)

  17. Victim-induced criminality.

    Science.gov (United States)

    Fooner, M

    1966-09-02

    about the probable effects on the administration of criminal justice. These are pragmatic problems; there is a third problem which may at this time seem speculative, but is, nevertheless, quite important. 3) To what extent will a particular proposal for victim compensation contribute to a temptation-opportunity pattern in victim behavior? In previous studies it has been pointed out that large numbers of our fellow Americans have tended to acquire casual money-handling habits-generically designated "carelessness"-which contribute to the national growth of criminality. How the victim helps the criminal was sketched in reports of those studies (10). It was made abundantly clear that human beings in our affluent society cannot be assumed to be prudent or self-protective against the hazards of crime. Even when the "victim" is not overtly acting to commit a crime-as in the case of the property owner who hires an arsonist-he often tempts the offender. Among the victims of burglary-statistically the most prevalent crime in the United States-are a substantial number of Americans who keep cash, jewelry, and other valuables carelessly at home or in hotel rooms to which the burglar has easy access through door or window. Victims of automobile theft-one of the fastest growing classes of crime-include drivers who leave the vehicle or its contents invitingly accessible to thieves. And so on with other classes of crime. As pointed out in previous studies, when victim behavior follows a temptation-opportunity pattern, it (i) contributes to a "climate of criminal inducements," (ii) adds to the economic resources available to criminal societies, and (iii) detracts from the ability of lawenforcement agencies to suppress the growth of crime.

  18. Diet-induced obesity attenuates fasting-induced hyperphagia.

    Science.gov (United States)

    Briggs, D I; Lemus, M B; Kua, E; Andrews, Z B

    2011-07-01

    Obesity impairs arcuate (ARC) neuropeptide Y (NPY)/agouti-releated peptide (AgRP) neuronal function and renders these homeostatic neurones unresponsive to the orexigenic hormone ghrelin. In the present study, we investigated the effect of diet-induced obesity (DIO) on feeding behaviour, ARC neuronal activation and mRNA expression following another orexigenic stimulus, an overnight fast. We show that 9 weeks of high-fat feeding attenuates fasting-induced hyperphagia by suppressing ARC neuronal activation and hypothalamic NPY/AgRP mRNA expression. Thus, the lack of appropriate feeding responses in DIO mice to a fast is caused by failure ARC neurones to recognise and/or respond to orexigenic cues. We propose that fasting-induced hyperphagia is regulated not by homeostatic control of appetite in DIO mice, but rather by changes in the reward circuitry. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

  19. Sociocultural determinants of induced abortion.

    Science.gov (United States)

    Korejo, Razia; Noorani, Khurshid Jehan; Bhutta, Shereen

    2003-05-01

    To determine the frequency of induced abortion and identify the role of sociocultural factors contributing to termination of pregnancy and associated morbidity and mortality in hospital setting. Prospective observational study. The study was conducted in the Department of Obstetrics and Gynaecology, Jinnah Postgraduate Medical Centre, Karachi from January 1999 to June 2001. The patients who were admitted for induced abortion were interviewed in privacy. On condition of anonymity they were asked about the age, parity, family setup and relationships, with particular emphasis on sociocultural reasons and factors contributing to induction of abortion. Details of status of abortionist and methods used for termination of pregnancy, the resulting complications and their severity were recorded. Out of total admissions, 57(2.35%) gave history of induced abortion. All women belonged to low socioeconomic class and 59.6% of them were illiterate. Forty-three (75.5%) of these women had never practiced contraception. Twenty-four (42%) were grandmultiparae and did not want more children. In 29 women (50.9%) the decision for abortion had been supported by the husband. In 25 women (43.8%) abortion was carried out by Daiyan (traditional midwives). Serious complications like uterine perforation with or without bowel injury were encountered in 25 (43.8%) of these women. During the study period illegally induced abortion accounted for 6 (10.5%) maternal deaths. Prevalence of poverty, illiteracy, grand multiparity and non-practice of contraception are strong determinants of induced abortion.

  20. Sociocultural determinants of induced abortion

    International Nuclear Information System (INIS)

    Korejo, R.; Noorani, K.J.; Bhutta, S.

    2003-01-01

    Objective: To determine the frequency of induced abortion and identity the role of sociocultural factors contributing to termination of pregnancy and associated morbidity and mortality in hospital setting. Subjects and Methods: The patients who were admitted for induced abortion were interviewed in privacy. On condition of anonymity they were asked about the age, parity, family setup and relationships, with particular emphasis on sociocultural reasons and factors contributing to induction of abortion. Details of status of abortionist and methods used for termination of pregnancy, the resulting complications and their severity were recorded. Results: Out of total admissions, 57(2.35%) gave history of induced abortion. All women belonged to low socioeconomic class and 59.6% of them were illiterate. Forty-three (75.5%) of these women had never practiced concentration. Twenty-four (42%) were grandmultiparae and did not want more children. In 29 women (50.9%) the decision for abortion had been supported by the husband. In 25 (43.8%) abortion was carried out by Daiyan (traditional midwives). Serious complications like uterine perforation with or without bowel injury were encouraged in 25 (43.8%) of these women. During the study period illegally induced abortion accounted for 6 (10.5%) maternal deaths. Conclusion: Prevalence of poverty, illiteracy, grand multiparity and non-practice of contraception are strong determinants of induced abortion. (author)

  1. Hydroxyurea-Induced Replication Stress

    Directory of Open Access Journals (Sweden)

    Kenza Lahkim Bennani-Belhaj

    2010-01-01

    Full Text Available Bloom's syndrome (BS displays one of the strongest known correlations between chromosomal instability and a high risk of cancer at an early age. BS cells combine a reduced average fork velocity with constitutive endogenous replication stress. However, the response of BS cells to replication stress induced by hydroxyurea (HU, which strongly slows the progression of replication forks, remains unclear due to publication of conflicting results. Using two different cellular models of BS, we showed that BLM deficiency is not associated with sensitivity to HU, in terms of clonogenic survival, DSB generation, and SCE induction. We suggest that surviving BLM-deficient cells are selected on the basis of their ability to deal with an endogenous replication stress induced by replication fork slowing, resulting in insensitivity to HU-induced replication stress.

  2. Uterine contraction induced by Ghanaian plants used to induce abortion

    DEFF Research Database (Denmark)

    Larsen, Birgitte HV; Soelberg, Jens; Kristiansen, Uffe

    2016-01-01

    Ethnomedicinal observations from the time of the Atlantic slave trade show women in Ghana historically used plants as emmenagogues (menstruation stimulants) and to induce abortion. This study investigates the effect of four of these plants on uterine contraction. The historically used plants were...

  3. Pump cavitation and inducer design

    International Nuclear Information System (INIS)

    Heslenfeld, M.W.; Hes, M. de

    2002-01-01

    Details of past work on sodium pump development and cavitation studies executed mainly for SNR 300 were reported earlier. Among the requirements for large sodium pumps are long life (200000 hours up to 300000 hours) and small size of impeller and pump, fully meeting the process and design criteria. These criteria are the required 'Q, H, r characteristics' in combination with a low NPSH value and the avoidance of cavitation damage to the pump. The pump designer has to develop a sound hydraulic combination consisting of suction arrangement, impeller design and diffuser. On the other hand the designer is free to choose an optimal pump speed. The pump speed in its turn influences the rotor dynamic pump design and the pump drive. The introduction of the inducer as an integral part of the pump design is based on following advantages: no tip cavitation; (possible) cavitation bubbles move to the open centre due to centrifugal forces on the fluid; the head of the inducer improves the inlet conditions of the impeller. The aim of an inducer is the increase in the suction specific speed (SA value) of a pump whereby the inducer functions as a pressure source improving the impeller inlet conditions. With inducer-impeller combinations values up to SA=15000 are realistic. With the use of an inducer the overall pump sizes can be reduced with Ca. 30%. Pumps commonly available have SA values up to a maximum of ca. 10000. A development programme was executed for SNR 300 in order to reach an increase of the suction specific speed of the impeller from SA 8200 to SA 11000. Further studies to optimize pumps design for the follow up line introduced the 'inducer acting as a pre-impeller' development. This programme was executed in the period 1979-1981. At the FDO premises a scale 1 2.8 inducer impeller combination with a suction specific speed SA=15000 was developed, constructed and tested at the water test rig. This water test rig is equipped with a perspex pipe allowing also visualisation

  4. Induced piezoelectricity in isotropic biomaterial.

    Science.gov (United States)

    Zimmerman, R L

    1976-01-01

    Isotropic material can be made to exhibit piezoelectric effects by the application of a constant electric field. For insulators, the piezoelectric strain constant is proportional to the applied electric field and for semiconductors, an additional out-of-phase component of piezoelectricity is proportional to the electric current density in the sample. The two induced coefficients are proportional to the strain-dependent dielectric constant (depsilon/dS + epsilon) and resistivity (drho/dS - rho), respectively. The latter is more important at frequencies such that rhoepsilonomega less than 1, often the case in biopolymers.Signals from induced piezoelectricity in nature may be larger than those from true piezoelectricity. PMID:990389

  5. Drug-induced hair loss.

    Science.gov (United States)

    2016-05-01

    Hair loss can have major psychological consequences. It can be due to a wide variety of causes, including hormonal disorders, dietary factors, infections, inflammation, trauma, emotional factors, and cancer. Drugs can also induce hair loss, by interacting with the hair growth cycle. Drug-induced hair loss may be immediate or delayed, sudden or gradual, and diffuse or localised. It is usually reversible after drug discontinuation. The drugs most often implicated in hair loss are anticancer agents, interferon, azole antifungals, lithium, immunosuppressants, and many other drugs belonging to a variety of pharmacological classes.

  6. Induced radioactivity in LDEF components

    Science.gov (United States)

    Harmon, B. A.; Fishman, G. J.; Parnell, T. A.; Laird, C. E.

    1992-01-01

    A systematic study of the induced radioactivity of the Long Duration Exposure Facility (LDEF) is being carried out in order to gather information about the low earth orbit radiation environment and its effects on materials. The large mass of the LDEF spacecraft, its stabilized configuration, and long mission duration have presented an opportunity to determine space radiation-induced radioactivities with a precision not possible before. Data presented include preliminary activities for steel and aluminum structural samples, and activation subexperiment foils. Effects seen in the data show a clear indication of the trapped proton anisotropy in the South Atlantic Anomaly and suggest contributions from different sources of external radiation fluxes.

  7. Cyclophosphamide-induced pulmonary toxicity

    International Nuclear Information System (INIS)

    Siemann, D.W.; Macler, L.; Penney, D.P.

    1986-01-01

    Unlike radiation effects, pulmonary toxicity following drug treatments may develop soon after exposure. The dose-response relationship between Cyclophosphamide and lung toxicity was investigated using increased breathing frequency assays used successfully for radiation induced injury. The data indicate that release of protein into the alveolus may play a significant role in Cy induced pulmonary toxicity. Although the mechanism responsible for the increased alveolar protein is as yet not identified, the present findings suggest that therapeutic intervention to inhibit protein release may be an approach to protect the lungs from toxic effects. (UK)

  8. Induced modules over group algebras

    CERN Document Server

    Karpilovsky, Gregory

    1990-01-01

    In 1898 Frobenius discovered a construction which, in present terminology, associates with every module of a subgroup the induced module of a group. This construction proved to be of fundamental importance and is one of the basic tools in the entire theory of group representations.This monograph is designed for research mathematicians and advanced graduate students and gives a picture of the general theory of induced modules as it exists at present. Much of the material has until now been available only in research articles. The approach is not intended to be encyclopedic, rather each topic is

  9. Exorcising ghosts in induced gravity

    Energy Technology Data Exchange (ETDEWEB)

    Narain, Gaurav [Chinese Academy of Sciences (CAS), Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Beijing (China)

    2017-10-15

    Unitarity of the scale-invariant coupled theory of higher-derivative gravity and matter is investigated. A scalar field coupled with a Dirac fermion is taken as the matter sector. Following the idea of induced gravity the Einstein-Hilbert term is generated via dynamical symmetry breaking of scale invariance. The renormalisation group flows are computed and one-loop RG improved effective potential of scalar is calculated. The scalar field develops a new minimum via the Coleman-Weinberg procedure inducing the Newton constant and masses in the matter sector. The spin-2 problematic ghost and the spin-0 mode of the metric fluctuation get a mass in the broken phase of the theory. The energy dependence of the vacuum expectation value in the RG improved scenario implies a running for the induced parameters. This sets up platform to ask whether it is possible to evade the spin-2 ghost by keeping its mass always above the running energy scale? In broken phase this question is satisfactorily answered for a large domain of coupling parameter space where the ghost is evaded. The spin-0 mode can be made physically realisable or not depending upon the choice of the initial parameters. The induced Newton constant is seen to vanish in the ultraviolet case. By properly choosing parameters it is possible to make the matter fields physically unrealisable. (orig.)

  10. Eye changes induced by radium

    International Nuclear Information System (INIS)

    Taylor, G.N.; Lloyd, R.D.; Shabestari, Lorraine; Angus, Walter; Muggenburg, B.A.

    1989-01-01

    This report presents some features of the radium induced eye syndrome observed in beagles, including the prominence of intraocular pigmentary lesions and compares these with the results of rodent studies (Onychomys leucogaster) featuring a heavily pigmented uvea, and with the radiation syndrome reported in humans. (author)

  11. On condensation-induced waves

    NARCIS (Netherlands)

    Cheng, W.; Luo, X.; Dongen, van M.E.H.

    2010-01-01

    Complex wave patterns caused by unsteady heat release due to cloud formation in confined compressible flows are discussed. Two detailed numerical studies of condensation-induced waves are carried out. First, the response of a flow of nitrogen in a slender Laval nozzle to a sudden addition of water

  12. Hydralazine-induced constrictive pericarditis

    NARCIS (Netherlands)

    Franssen, CFC; ElGamal, MIH; Gans, ROB; Hoorntje, SJ

    A 59-year-old man was diagnosed as having constrictive pericarditis 17 months after a typical hydralazine-induced autoimmune syndrome, This late complication of hydralazine has been reported only once. Ten years later the patient was found to have anti-neutrophil cytoplasmic antibodies directed

  13. SPS Ion Induced Desorption Experiment

    CERN Multimedia

    Maximilien Brice

    2003-01-01

    This experiment will give a study about the induced desorption from heavy ion (Indium ion run from week 45 in SPS T4-H8 area) impacting LHC type graphite collimator. 4 different samples are located in the 4 chambers 90° one to each other: pure graphite, graphite with copper coating, graphite with NEG coating, 316LN stainless steal (reference).

  14. Food-Induced Acute Pancreatitis.

    Science.gov (United States)

    Manohar, Murli; Verma, Alok K; Upparahalli Venkateshaiah, Sathisha; Goyal, Hemant; Mishra, Anil

    2017-12-01

    Food allergy, a commonly increasing problem worldwide, defined as an adverse immune response to food. A variety of immune-related effector cells such as mast cells, eosinophils, neutrophils, and T cells are involved in food-related allergic responses categorized as IgE mediated, non-IgE mediated, and mixed (IgE and non-IgE) depending upon underlying immunological mechanisms. The dietary antigens mainly target the gastrointestinal tract including pancreas that gets inflamed due to food allergy and leads acute pancreatitis. Reports indicate several food proteins induce pancreatitis; however, detailed underlying mechanism of food-induced pancreatitis is unexplored. The aim of the review is to understand and update the current scenario of food-induced pancreatitis. A comprehensive literature search of relevant research articles has been performed through PubMed, and articles were chosen based on their relevance to food allergen-mediated pancreatitis. Several cases in the literature indicate that acute pancreatitis has been provoked after the consumption of mustard, milk, egg, banana, fish, and kiwi fruits. Food-induced pancreatitis is an ignored and unexplored area of research. The review highlights the significance of food in the development of pancreatitis and draws the attention of physicians and scientists to consider food allergies as a possible cause for initiation of pancreatitis pathogenesis.

  15. Local Anesthetic-Induced Neurotoxicity

    NARCIS (Netherlands)

    Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

    2016-01-01

    This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk

  16. Ventilator and viral induced inflammation

    NARCIS (Netherlands)

    Hennus, M.P.

    2013-01-01

    This thesis expands current knowledge on ventilator induced lung injury and provides insights on the immunological effects of mechanical ventilation during viral respiratory infections. The experimental studies in the first part of this thesis improve our understanding of how mechanical ventilation

  17. UV-induced skin damage

    International Nuclear Information System (INIS)

    Ichihashi, M.; Ueda, M.; Budiyanto, A.; Bito, T.; Oka, M.; Fukunaga, M.; Tsuru, K.; Horikawa, T.

    2003-01-01

    Solar radiation induces acute and chronic reactions in human and animal skin. Chronic repeated exposures are the primary cause of benign and malignant skin tumors, including malignant melanoma. Among types of solar radiation, ultraviolet B (290-320 nm) radiation is highly mutagenic and carcinogenic in animal experiments compared to ultraviolet A (320-400 nm) radiation. Epidemiological studies suggest that solar UV radiation is responsible for skin tumor development via gene mutations and immunosuppression, and possibly for photoaging. In this review, recent understanding of DNA damage caused by direct UV radiation and by indirect stress via reactive oxygen species (ROS) and DNA repair mechanisms, particularly nucleotide excision repair of human cells, are discussed. In addition, mutations induced by solar UV radiation in p53, ras and patched genes of non-melanoma skin cancer cells, and the role of ROS as both a promoter in UV-carcinogenesis and an inducer of UV-apoptosis, are described based primarily on the findings reported during the last decade. Furthermore, the effect of UV on immunological reaction in the skin is discussed. Finally, possible prevention of UV-induced skin cancer by feeding or topical use of antioxidants, such as polyphenols, vitamin C, and vitamin E, is discussed

  18. Spaceflight-Induced Intracranial Hypertension.

    Science.gov (United States)

    Michael, Alex P; Marshall-Bowman, Karina

    2015-06-01

    Although once a widely speculated about and largely theoretical topic, spaceflight-induced intracranial hypertension has gained acceptance as a distinct clinical phenomenon, yet the underlying physiological mechanisms are still poorly understood. In the past, many terms were used to describe the symptoms of malaise, nausea, vomiting, and vertigo, though longer duration spaceflights have increased the prevalence of overlapping symptoms of headache and visual disturbance. Spaceflight-induced visual pathology is thought to be a manifestation of increased intracranial pressure (ICP) because of its similar presentation to cases of known intracranial hypertension on Earth as well as the documentation of increased ICP by lumbar puncture in symptomatic astronauts upon return to gravity. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood-brain barrier breakdown, and disruption to CSF flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown, though other factors recently posited to contribute include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. This review article attempts to consolidate the literature regarding spaceflight-induced intracranial hypertension and distinguish it from other pathologies with similar symptomatology. It discusses the proposed physiological causes and the pathological manifestations of increased ICP in the spaceflight environment and provides considerations for future long-term space travel. In the future, it will be critical to develop countermeasures so that astronauts can participate at their peak potential and return safely to Earth.

  19. Isolating highly connected induced subgraphs

    DEFF Research Database (Denmark)

    Penev, Irena; Thomasse, Stephan; Trotignon, Nicolas

    2016-01-01

    We prove that any graph G of minimum degree greater than 2k(2) - 1 has a (k + 1)-connected induced subgraph H such that the number of vertices of H that have neighbors outside of H is at most 2k(2) - 1. This generalizes a classical result of Mader, which states that a high minimum degree implies ...

  20. Ultrasound-induced radical polymerization

    NARCIS (Netherlands)

    Kuijpers, M.W.A.; Kemmere, M.F.; Keurentjes, J.T.F.

    2004-01-01

    Sonochemistry comprises all chemical effects that are induced by ultrasound. Most of these effects are caused by cavitations, ie, the collapse of microscopic bubbles in a liquid. The chemical effects of ultrasound include the formation of radicals and the enhancement of reaction rates at ambient

  1. Transdermal hyoscine induced unilateral mydriasis.

    LENUS (Irish Health Repository)

    Hannon, Breffni

    2012-03-20

    The authors present a case of unilateral mydriasis in a teenager prescribed transdermal hyoscine hydrobromide (scopolamine) for chemotherapy induced nausea and vomiting. The authors discuss the ocular side-effects associated with this particular drug and delivery system and the potential use of transdermal hyoscine as an antiemetic agent in this group.

  2. Late onset startle induced tics

    NARCIS (Netherlands)

    Tijssen, MAJ; Brown, P; Morris, HR; Lees, A

    1999-01-01

    Three cases of late onset Gilles de la Tourette's syndrome are presented. The motor ties were mainly induced by an unexpected startling stimulus, but the startle reflex was not exaggerated. The ties developed after physical trauma or a period of undue emotional stress. Reflex ties may occur in

  3. Late onset startle induced tics

    NARCIS (Netherlands)

    Tijssen, M. A.; Brown, P.; Morris, H. R.; Lees, A.

    1999-01-01

    Three cases of late onset Gilles de la Tourette's syndrome are presented. The motor tics were mainly induced by an unexpected startling stimulus, but the startle reflex was not exaggerated. The tics developed after physical trauma or a period of undue emotional stress. Reflex tics may occur in

  4. Visualization of induced electric fields

    NARCIS (Netherlands)

    Deursen, van A.P.J.

    2005-01-01

    A cylindrical electrolytic tank between a set of Helmholtz coils provides a classroom demonstration of induced, nonconservative electric fields. The field strength is measured by a sensor consisting of a pair of tiny spheres immersed in the liquid. The sensor signal depends on position, frequency,

  5. Lithium-induced downbeat nystagmus.

    Science.gov (United States)

    Schein, Flora; Manoli, Pierre; Cathébras, Pascal

    2017-09-01

    We report the case of a 76-year old lady under lithium carbonate for a bipolar disorder who presented with a suspected optic neuritis. A typical lithium-induced downbeat nystagmus was observed. Discontinuation of lithium therapy resulted in frank improvement in visual acuity and disappearance of the nystagmus.

  6. Fluid injection and induced seismicity

    Science.gov (United States)

    Kendall, Michael; Verdon, James

    2016-04-01

    The link between fluid injection, or extraction, and induced seismicity has been observed in reservoirs for many decades. In fact spatial mapping of low magnitude events is routinely used to estimate a stimulated reservoir volume. However, the link between subsurface fluid injection and larger felt seismicity is less clear and has attracted recent interest with a dramatic increase in earthquakes associated with the disposal of oilfield waste fluids. In a few cases, hydraulic fracturing has also been linked to induced seismicity. Much can be learned from past case-studies of induced seismicity so that we can better understand the risks posed. Here we examine 12 case examples and consider in particular controls on maximum event size, lateral event distributions, and event depths. Our results suggest that injection volume is a better control on maximum magnitude than past, natural seismicity in a region. This might, however, simply reflect the lack of baseline monitoring and/or long-term seismic records in certain regions. To address this in the UK, the British Geological Survey is leading the deployment of monitoring arrays in prospective shale gas areas in Lancashire and Yorkshire. In most cases, seismicity is generally located in close vicinity to the injection site. However, in some cases, the nearest events are up to 5km from the injection point. This gives an indication of the minimum radius of influence of such fluid injection projects. The most distant events are never more than 20km from the injection point, perhaps implying a maximum radius of influence. Some events are located in the target reservoir, but most occur below the injection depth. In fact, most events lie in the crystalline basement underlying the sedimentary rocks. This suggests that induced seismicity may not pose a leakage risk for fluid migration back to the surface, as it does not impact caprock integrity. A useful application for microseismic data is to try and forecast induced seismicity

  7. Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

    DEFF Research Database (Denmark)

    Corsino, P.; Davis, B.; Law, M.

    2007-01-01

    Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1-Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMITV...

  8. Virally and physically transgenized equine adipose-derived stromal cells as a cargo for paracrine secreted factors

    Directory of Open Access Journals (Sweden)

    Cavirani Sandro

    2010-09-01

    Full Text Available Abstract Background Adipose-Derived Stromal Cells have been shown to have multiple lineage differentiation properties and to be suitable for tissues regeneration in many degenerative processes. Their use has been proposed for the therapy of joint diseases and tendon injuries in the horse. In the present report the genetic manipulation of Equine Adipose-Derived Stromal Cells has been investigated. Results Equine Adipose-Derived Stromal Cells were successfully virally transduced as well as transiently and stably transfected with appropriate parameters, without detrimental effect on their differentiation properties. Moreover, green fluorescent protein alone, fused to neo gene, or co-expressed as bi-cistronic reporter constructs, driven by viral and house-keeping gene promoters, were tested. The better expressed cassette was employed to stably transfect Adipose-Derived Stromal Cells for cell therapy purposes. Stably transfected Equine Adipose-Derived Stromal Cells with a heterologous secreted viral antigen were able to immunize horses upon injection into the lateral wall of the neck. Conclusion This study provides the methods to successfully transgenize Adipose-Derived Stromal Cells both by lentiviral vector and by transfection using optimized constructs with suitable promoters and reporter genes. In conclusion these findings provide a working platform for the delivery of potentially therapeutic proteins to the site of cells injection via transgenized Equine Adipose-Derived Stromal Cells.

  9. Paracrine effects of oocyte secreted factors and stem cell factor on porcine granulosa and theca cells in vitro

    Directory of Open Access Journals (Sweden)

    Webb Bob

    2003-08-01

    Full Text Available Abstract Oocyte control of granulosa and theca cell function may be mediated by several growth factors via a local feedback loop(s between these cell types. This study examined both the role of oocyte-secreted factors on granulosa and thecal cells, cultured independently and in co-culture, and the effect of stem cell factor (SCF; a granulosa cell derived peptide that appears to have multiple roles in follicle development. Granulosa and theca cells were isolated from 2–6 mm healthy follicles of mature porcine ovaries and cultured under serum-free conditions, supplemented with: 100 ng/ml LR3 IGF-1, 10 ng/ml insulin, 100 ng/ml testosterone, 0–10 ng/ml SCF, 1 ng/ml FSH (granulosa, 0.01 ng/ml LH (theca or 1 ng/ml FSH and 0.01 ng/ml LH (co-culture and with/without oocyte conditioned medium (OCM or 5 oocytes. Cells were cultured in 96 well plates for 144 h, after which viable cell numbers were determined. Medium was replaced every 48 h and spent medium analysed for steroids. Oocyte secreted factors were shown to stimulate both granulosa cell proliferation (P

  10. Antiseptic solutions modulate the paracrine-like activity of bone chips: differential impact of chlorhexidine and sodium hypochlorite.

    Science.gov (United States)

    Sawada, Kosaku; Caballé-Serrano, Jordi; Bosshardt, Dieter D; Schaller, Benoit; Miron, Richard J; Buser, Daniel; Gruber, Reinhard

    2015-09-01

    Chemical decontamination increases the availability of bone grafts; however, it remains unclear whether antiseptic processing changes the biological activity of bone. Bone chips were incubated with four different antiseptic solutions including (1) povidone-iodine (0.5%), (2) chlorhexidine diguluconate (0.2%), (3) hydrogen peroxide (1%) and (4) sodium hypochlorite (0.25%). After 10 min. of incubation, changes in the capacity of the bone-conditioned medium (BCM) to modulate gene expression of gingival fibroblasts was investigated. Conditioned medium obtained from freshly prepared bone chips increased the expression of TGF-β target genes interleukin 11 (IL11), proteoglycan4 (PRG4), NADPH oxidase 4 (NOX4), and decreased the expression of adrenomedullin (ADM), and pentraxin 3 (PTX3) in gingival fibroblasts. Incubation of bone chips with 0.2% chlorhexidine, followed by vigorously washing resulted in a BCM with even higher expression of IL11, PRG4 and NOX4. These findings were also detected with a decrease in cell viability and an activation of apoptosis signalling. Chlorhexidine alone, at low concentrations, increased IL11, PRG4 and NOX4 expression, independent of the TGF-β receptor I kinase activity. In contrast, 0.25% sodium hypochlorite almost entirely abolished the activity of BCM, whereas the other two antiseptic solutions, 1% hydrogen peroxide and 0.5% povidone-iodine, had relatively no impact respectively. These in vitro findings demonstrate that incubation of bone chips with chlorhexidine differentially affects the activity of the respective BCM compared to the other antiseptic solutions. The data further suggest that the main effects are caused by chlorhexidine remaining in the BCM after repeated washing of the bone chips. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Calcium alginate gels as stem cell matrix-making paracrine stem cell activity available for enhanced healing after surgery.

    Directory of Open Access Journals (Sweden)

    Andreas Schmitt

    Full Text Available Regeneration after surgery can be improved by the administration of anabolic growth factors. However, to locally maintain these factors at the site of regeneration is problematic. The aim of this study was to develop a matrix system containing human mesenchymal stem cells (MSCs which can be applied to the surgical site and allows the secretion of endogenous healing factors from the cells. Calcium alginate gels were prepared by a combination of internal and external gelation. The gelling behaviour, mechanical stability, surface adhesive properties and injectability of the gels were investigated. The permeability of the gels for growth factors was analysed using bovine serum albumin and lysozyme as model proteins. Human MSCs were isolated, cultivated and seeded into the alginate gels. Cell viability was determined by AlamarBlue assay and fluorescence microscopy. The release of human VEGF and bFGF from the cells was determined using an enzyme-linked immunoassay. Gels with sufficient mechanical properties were prepared which remained injectable through a syringe and solidified in a sufficient time frame after application. Surface adhesion was improved by the addition of polyethylene glycol 300,000 and hyaluronic acid. Humans MSCs remained viable for the duration of 6 weeks within the gels. Human VEGF and bFGF was found in quantifiable concentrations in cell culture supernatants of gels loaded with MSCs and incubated for a period of 6 weeks. This work shows that calcium alginate gels can function as immobilization matrices for human MSCs.

  12. n-3 Polyunsaturated Fatty Acids and Mechanisms to Mitigate Inflammatory Paracrine Signaling in Obesity-Associated Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jennifer M. Monk

    2014-10-01

    Full Text Available Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

  13. Radiation-induced thermoacoustic imaging

    International Nuclear Information System (INIS)

    Bowen, T.

    1984-01-01

    This invention provides a new technique for obtaining information non-invasively on the composition and structures of a material or body by detecting radiation-induced thermoacoustic image features. This is accomplished by utilizing the acoustic wave generated by sudden thermal stress. The sudden thermal stress is induced by a pulse of radiation which deposits energy causing a rapid, but very small, rise of temperature (typically, ΔT approximately 10sup(-6) - 10sup(-5) deg C). The radiation may be ionizing radiation, such as high energy electrons, photons (x-rays), neutrons, or other charged particles or it may be non-ionizing radiation, such as R.F. and microwave electromagnetic radiation and ultrasonic radiation. The choice of radiation depends on the nature of the body to be imaged and the type of information desired

  14. Esomeprazole-induced photoallergic dermatitis

    Directory of Open Access Journals (Sweden)

    Shukla A

    2010-01-01

    Full Text Available There are no published case reports of esomeprazole-induced photoallergic dermatitis. We report here a 58-year-old lady with prior history of propylthiouracil and carbimazole-induced photoallergy, who presented with heartburn and dysphagia. She was diagnosed to have erosive esophagitis and was treated with esomeprazole, following which she developed photoallergic dermatitis. It improved on cessation of the drug and did not recur on subsequent treatment with ranitidine. Naranjo score for this adverse drug event was 8, thereby making it a probable adverse drug reaction. This reaction may be due to sulphur moiety, which is common to all these drugs. Physicians must be aware of this possible side-effect, especially in patients with prior history of photoallergy to other drugs.

  15. Prediction of pilot induced oscillations

    Directory of Open Access Journals (Sweden)

    Valentin PANĂ

    2011-03-01

    Full Text Available An important problem in the design of flight-control systems for aircraft under pilotedcontrol is the determination of handling qualities and pilot-induced oscillations (PIO tendencieswhen significant nonlinearities exist in the vehicle description. The paper presents a method to detectpossible pilot-induced oscillations of Category II (with rate and position limiting, a phenomenonusually due to a misadaptation between the pilot and the aircraft response during some tasks in whichtight closed loop control of the aircraft is required from the pilot. For the analysis of Pilot in the LoopOscillations an approach, based on robust stability analysis of a system subject to uncertainparameters, is proposed. In this analysis the nonlinear elements are substituted by linear uncertainparameters. This approach assumes that PIO are characterized by a limit cycle behavior.

  16. Taxane-Induced Peripheral Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Roser Velasco

    2015-04-01

    Full Text Available Taxane-derived agents are chemotherapy drugs widely employed in cancer treatment. Among them, paclitaxel and docetaxel are most commonly administered, but newer formulations are being investigated. Taxane antineoplastic activity is mainly based on the ability of the drugs to promote microtubule assembly, leading to mitotic arrest and apoptosis in cancer cells. Peripheral neurotoxicity is the major non-hematological adverse effect of taxane, often manifested as painful neuropathy experienced during treatment, and it is sometimes irreversible. Unfortunately, taxane-induced neurotoxicity is an uncertainty prior to the initiation of treatment. The present review aims to dissect current knowledge on real incidence, underlying pathophysiology, clinical features and predisposing factors related with the development of taxane-induced neuropathy.

  17. Eye changes induced by radium

    International Nuclear Information System (INIS)

    Taylor, G.N.; Lloyd, R.D.; Shabestari, L.; Angus, W.; Muggenburg, B.A.

    1989-01-01

    Radium-induced intraocular neoplasia has not been reported in people, nor were the intraocular pigmentary changes observed in the beagles described in the dial painters or the radium 226 iatrogenic cases. However, Spiess (1969) has observed a 25% incidence of multiple pigmented naevi in the iris of the radium 224 German cases and Stefani, Spiess and Mays (1986) have noted an abnormal incidence of cataracts in this same group of patients. The reasons for the absence of the much less severe radium-induced eye changes in man as compared to the dog has not been determined. Reference is also made to the authors radium 226 rodent studies with mouse strain onychomys leucogaster. (author)

  18. Molecular mechanisms of induced pluripotency.

    Science.gov (United States)

    Kulcenty, Katarzyna; Wróblewska, Joanna; Mazurek, Sylwia; Liszewska, Ewa; Jaworski, Jacek

    2015-01-01

    Growing knowledge concerning transcriptional control of cellular pluripotency has led to the discovery that the fate of differentiated cells can be reversed, which has resulted in the generation, by means of genetic manipulation, of induced pluripotent stem cells. Overexpression of just four pluripotency-related transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc (Yamanaka factors, OKSM), in fibroblasts appears sufficient to produce this new cell type. Currently, we know that these factors induce several changes in genetic program of differentiated cells that can be divided in two general phases: the initial one is stochastic, and the subsequent one is highly hierarchical and organised. This review briefly discusses the molecular events leading to induction of pluripotency in response to forced presence of OKSM factors in somatic cells. We also discuss other reprogramming strategies used thus far as well as the advantages and disadvantages of laboratory approaches towards pluripotency induction in different cell types.

  19. CEREBRAL CORTEX DAMAGE INDUCED BY ACUTE ORAL ...

    African Journals Online (AJOL)

    2018-02-28

    Feb 28, 2018 ... This study examines alcohol-induced cerebral cortex damage and the association with oxidative ... alcohol has profound effects on the function ... Chronic use of ..... Alcohol induced brain damage and liver damage in young.

  20. Induced disease resistance signaling in plants

    NARCIS (Netherlands)

    Verhagen, B.W.M.; Loon, L.C. van; Pieterse, C.M.J.

    2006-01-01

    To protect themselves from disease, plants have evolved sophisticated inducible defense mechanisms in which the signal molecules salicylic acid, jasmonic acid and ethylene often play crucial roles. Elucidation of signaling pathways controlling induced disease resistance is a major objective in

  1. Inducing Lactation: Breastfeeding for Adoptive Moms

    Science.gov (United States)

    ... Dynamics > Adoption & Foster Care > Inducing Lactation: Breastfeeding for Adoptive Moms Family Life Listen Español Text Size Email Print Share Inducing Lactation: Breastfeeding for Adoptive Moms Page Content Article Body A growing number ...

  2. Induced Mutations in Thai Rice

    International Nuclear Information System (INIS)

    Klakhaeng, Kanchana

    2014-01-01

    Rice is the primary source of food for more than half of the world's population. It benefits greatly from technological inputs in the area of breeding such as induced mutation. Induced mutation can produce mutants with significant improvement in plant type, maturity, yields and protein ratio when compared to the parent. These improved traits enable the mutants to fit into farming systems with either shorter or longer growing seasons. Three induced mutant rice varieties, including RD6, RD10 and RD15, are well accepted by farmers and consumers in Thailand. RD6 and RD15 were aromatic, photosensitive varieties which were derived from KDML105 by acute irradiation of 20 and 15 kilorad gamma ray, respectively. After induced mutation, pedigree selection was applied. RD6 showed drought tolerance and also good grain quality including softness and good aroma with a higher average yield than the famous glutinous variety, San-Pah-Tong. Additionally, it was resistant to blast and brown spot diseases with an average yield of 4.19 tons/ha. RD15 showed drought tolerance and resistance to brown spot disease with the highest yield of 3.5 tons/ha. These two mutant varieties are currently the most famous aromatic rice varieties in Thailand. On the other hand, RD10 is a glutinous, photoperiod insensitive rice variety which was derived from RD1 by irradiation of 1 kilorad fast neutrons. RD10 showed good grain quality such as softness and stickiness with the yield of 4.25 tons/ha. As an on-going project, recommended rice varieties were irradiated with electron beam for anaerobic germination ability, submergence tolerance, stagnant-flood tolerance and also internode elongation.

  3. Abacavir-induced liver toxicity

    Directory of Open Access Journals (Sweden)

    Maria Diletta Pezzani

    2016-09-01

    Full Text Available Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

  4. Cough-induced rib fractures.

    Science.gov (United States)

    Hanak, Viktor; Hartman, Thomas E; Ryu, Jay H

    2005-07-01

    To define the demographic, clinical, and radiological features of patients with cough-induced rib fractures and to assess potential risk factors. For this retrospective, single-center study, we identified all cases of cough-induced rib fractures diagnosed at the Mayo Clinic in Rochester, Minn, over a 9-year period between January 1, 1996, and January 31, 2005. Bone densitometry data from patients' medical records were analyzed, and T scores were used to classify patients into bone density categories. The mean +/- SD age of the 54 study patients at presentation was 55+/-17 years, and 42 patients (78%) were female. Patients presented with chest wall pain after onset of cough. Rib fracture was associated with chronic cough (> or =3 weeks' duration) in 85% of patients. Rib fractures were documented by chest radiography, rib radiography, computed tomography, or bone scan. Chest radiography had been performed in 52 patients and revealed rib fracture in 30 (58%). There were 112 fractured ribs in 54 patients. One half of patients had more than one fractured rib. Right-sided rib fractures alone were present in 17 patients (26 fractured ribs), left-sided in 23 patients (35 fractured ribs), and bilateral in 14 patients (51 fractured ribs). The most commonly fractured rib on both sides was rib 6. The fractures were most common at the lateral aspect of the rib cage. Bone densitometry was done in 26 patients and revealed osteopenia or osteoporosis in 17 (65%). Cough-induced rib fractures occur primarily in women with chronic cough. Middle ribs along the lateral aspect of the rib cage are affected most commonly. Although reduced bone density is likely a risk factor, cough-induced rib fractures can occur in the presence of normal bone density.

  5. Radiation induced crosslinking of polytetrafluoroethylene

    International Nuclear Information System (INIS)

    Oshima, Akihiro; Tabata, Yoneho; Ikeda, Shigetoshi; Otsuhata, Kazushige; Kudoh, Hisaaki; Seguchi, Tadao.

    1995-01-01

    The Irradiation temperature effect on polytetrafluoroethylene (PTFE) from room temperature to 380degC was investigated by tensile test and thermal analysis. The behavior of tensile properties and changes of crystallinity on irradiation indicated the formation of a network structure in PTFE by radiation induced crosslinking in inert gas in the molten state just above the melting temperature of PTFE (327degC). The crosslinked PTFE showed a much improved radiation resistance in an atmospheric radiation field. (author)

  6. Peculiarities of radiation induced craniopharyngioma

    Energy Technology Data Exchange (ETDEWEB)

    Sataev, N.M. (Uzbekskij Nauchno-Issledovatel' skij Inst. Onkologii i Radiologii, Tashkent (USSR))

    1982-03-01

    Due to intracranial implantation of a radiosource in rabbit brain craniopharyngioma appeared. Its specific feature is grandular differentiation of embryonal epithelium of residuals of hypophysical (craniopharyngial) passage and the presence of focuses of blood vessel tumor degeneration of hemangioma type in its stroma. It is suggested that radiation craniopharyngioma is developed along the way of epigenetic changes of cellular elements of embryonal epithelium induced by radiation.

  7. Peculiarities of radiation induced craniopharyngioma

    International Nuclear Information System (INIS)

    Sataev, N.M.

    1982-01-01

    Due to intracranial implantation of a radiosource in rabbit brain craniopharyngioma appeared. Its specific feature is grandular differentiation of embryonal epithelium of residuals of hypophysical (craniopharyngial) passage and the presence of focuses of blood vessel tumor degeneration of hemangioma type in its stroma. It is suggested that radiation craniopharyngioma is developed along the way of epigenetic changes of cellular elements of embryonal epithelium induced by radiation

  8. MRI-induced retrocalcaneal bursitis

    International Nuclear Information System (INIS)

    Tol, J.L.; Dijk, C.N. van; Maas, M.

    1999-01-01

    This case report describes a patient with acute retrocalcaneal bursitis, which developed after MRI examination of the ankle. The sagittal T2*-weighted gradient echo sequence revealed an extensive susceptibility artifact in the area surrounding the Achilles tendon near its insertion at the os calcis. This artifact was caused by postsurgical metallic particles. We postulate that these particles were mechanically stimulated by the magnetic field and induced the inflammatory response. (orig.)

  9. MRI-induced retrocalcaneal bursitis

    Energy Technology Data Exchange (ETDEWEB)

    Tol, J.L.; Dijk, C.N. van [Dept. of Orthopaedic Surgery, University of Amsterdam (Netherlands); Maas, M. [Dept. of Radiology, University of Amsterdam (Netherlands)

    1999-10-01

    This case report describes a patient with acute retrocalcaneal bursitis, which developed after MRI examination of the ankle. The sagittal T2*-weighted gradient echo sequence revealed an extensive susceptibility artifact in the area surrounding the Achilles tendon near its insertion at the os calcis. This artifact was caused by postsurgical metallic particles. We postulate that these particles were mechanically stimulated by the magnetic field and induced the inflammatory response. (orig.)

  10. Teriparatide Induced Delayed Persistent Hypercalcemia

    Directory of Open Access Journals (Sweden)

    Nirosshan Thiruchelvam

    2014-01-01

    Full Text Available Teriparatide, a recombinant PTH, is an anabolic treatment for osteoporosis that increases bone density. Transient hypercalcemia is a reported side effect of teriparatide that is seen few hours following administration of teriparatide and resolves usually within 16 hours of drug administration. Persistent hypercalcemia, although not observed in clinical trials, is rarely reported. The current case describes a rare complication of teriparatide induced delayed persistent hypercalcemia.

  11. Laser-induced multiphoton transitions

    International Nuclear Information System (INIS)

    Stenholm, S.

    1978-06-01

    Laser induced multiphoton processes are reviewed. The effects of strong fields on atoms are discussed. The perturbation treatment is presented and also its generalization to treat intermediate resonances. The influence of atomic coherence is discussed heuristically and the relation between quantal and classical descriptions of the field is elucidated by reference to the dressed atom description. Atomic ionization experiments are reviewed and the present understanding of multiphoton dissociation of molecules is explained. Finally some prospects for the future are discussed. (author)

  12. Drug-induced liver injury

    DEFF Research Database (Denmark)

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome....

  13. Risperidone-induced reversible neutropenia.

    Science.gov (United States)

    Kattalai Kailasam, Vasanth; Chima, Victoria; Nnamdi, Uchechukwu; Sharma, Kavita; Shah, Kairav

    2017-01-01

    This case report presents a 44-year-old man with a history of schizophrenia who developed neutropenia on risperidone therapy. The patient's laboratory reports showed a gradual decline of leukocytes and neutrophils after resolution and rechallenging. This was reversed with the discontinuation of risperidone and by switching to olanzapine. In this case report, we also discuss the updated evidence base for management of risperidone-induced neutropenia.

  14. Induced draught circular cooling tower

    International Nuclear Information System (INIS)

    Blanquet, J.C.

    1980-01-01

    Induced draught atmospheric cooling towers are described, to wit those in which the circulation is by power fans. This technique with fans grouped together in the centre enables a single tower to be used and provides an excellent integration of the steam wreath into the atmosphere. This type of cooling tower has been chosen for fitting out two 900 MW units of the Chinon power station in France [fr

  15. Secondary pseudomyopia induced by amisulpride.

    Science.gov (United States)

    Stratos, Aimilianos A; Peponis, Vasileios G; Portaliou, Dimitra M; Stroubini, Theodora E; Skouriotis, Sotirios; Kymionis, George D

    2011-11-01

    To report a case of pseudomyopia induced by antipsychotic drug administration. A 30-year-old woman was referred to our ophthalmology department complaining of blurred vision, especially at distance, in both eyes. The patient had been prescribed antipsychotic drugs (haloperidol and biperiden) as treatment for her schizophrenic symptoms and had recently undergone a change of treatment to amisulpride. She had a manifest refraction of -4.00/-1.00 × 180 in the OD and -3.75/-1.25 × 175 in the OS whereas her cycloplegic refraction was -1.75/-1.00 × 180 in the OD and -1.00/-1.25 × 175 in the OS, respectively. A diagnosis of likely drug-induced pseudomyopia was made. Therefore, the patient was advised to visit her psychiatrist, who added an extra 2 mg of biperiden, an anticholinergic agent, to the pre-existing amisulpride treatment, achieving a cessation of the visual symptoms a few days later. Pseudomyopia can be induced by the antipsychotic drug amisulpride. Additional treatment with anticholinergic agents can be used to eliminate this side effect.

  16. Radiation-induced chromosomal instability

    International Nuclear Information System (INIS)

    Ritter, S.

    1999-01-01

    Recent studies on radiation-induced chromosomal instability in the progeny of exposed mammalian cells were briefly described as well as other related studies. For the analysis of chromosomal damage in clones, cells were seeded directly after exposure in cell well-dish to form single cell clones and post-irradiation chromosome aberrations were scored. Both exposure to isoeffective doses of X-ray or 270 MeV/u C-ions (13 keV/μm) increased the number of clones with abnormal karyotype and the increase was similar for X-ray and for C-ions. Meanwhile, in the progeny of cells for mass cultures, there was no indication of a delayed expression of chromosomal damage up to 40 population doublings after the exposure. A high number of aberrant cells were only observed directly after exposure to 10.7 MeV/u O-ions, i.e. in the first cycle cells and decreased with subsequent cell divisions. The reason for these differences in the radiation-induced chromosomal instability between clonal isolates and mass culture has not been clarified. Recent studies indicated that genomic instability occurs at a high frequency in the progeny of cells irradiated with both sparsely and densely ionizing radiation. Such genomic instability is thought likely to increase the risk of carcinogenesis, but more data are required for a well understanding of the health risks resulting from radiation-induced delayed instability. (M.N.)

  17. Induced mutation of Dendrobium orchid

    International Nuclear Information System (INIS)

    Sakinah Ariffin; Mohd Nazir Basiran

    2000-01-01

    Dendrobiiim orchids serve as the main orchid cut flower export of Malaysia. The wide range of colour and forms presently available in the market are obtained through hybridisation. Induced mutation breeding program was initiated on a commercial variety Dendrobium 'Sonia Kai' to explore the possibilities of obtaining new colour and forms. Matured seeds from self pollination were cultured and irradiated at 35 Gy at the protocorm-like bodies (PLBS) stage. Selection of induced mutations was done after the first flowering of the plants regenerated from the irradiated protocorms. Results showed changes in flower colour, shape and size. Most of these chances are expressed in different combinations in the petals, sepals and lip of the flowers. Thus, resulting. in a very wide spectrum of mutations. Some of these chances are not stable. To date, mutants that showed stable characteristics changes are grouped into 11 categories based on flower colour and form. These results show that the combination of its vitro technique and induced mutation can be applied in orchid breeding to produce new interesting and attractive variety for the market

  18. [Secondary osteoporosis induced by anticoagulants?].

    Science.gov (United States)

    Riess, H; Loew, A; Himmelreich, G

    2001-07-01

    Generalized osteoporosis is a result of different causes and pathogenic mechanisms, which often combine forces to become clinically relevant. Among the different exogenic factors, drugs play an important role, frequently in connection with other factors such as immobilization or pregnancy. It has been suggested that anticoagulation therapy with heparins or coumarins may induce osteoporotic changes or enhance the development of osteoporosis for other reasons. According to in vitro experiments, preclinical trials, and clinical investigations, it seems reasonable to assume that heparins induce increased bone loss in a time- and dose-related manner. Low-molecular-weight heparins most likely have less effect on bone turnover when compared to unfractionated heparin. Oral anticoagulation therapy with vitamin K-antagonists is believed to have a weak effect on induction of osteoporosis, but clinical studies are contradictory. In spite of the fact that a relevant effect of these drugs on the induction of osteoporosis is questionable, it must be taken into consideration that anticoagulant drugs may enhance the negative effects on bone density of other risk factors capable of inducing osteoporosis such as immobilization, pregnancy, or endocrinological disorders.

  19. Radiation-induced heart injury

    International Nuclear Information System (INIS)

    Suzuki, Yoshihiko; Niibe, Hideo

    1975-01-01

    In order to identify radiation-induced heart injury and to differentiate it from heart disease, an attempt was made to clarify post-irradiation heart injury by investigating the histological changes which occur during the internal between the irradiation and the time of demonstrable histological changes. A study was made of 83 autopsies in which most of the primary neoplasms were breast cancers, lung cancers and mediastinal tumors. In 43 of these autopsies the heart had been irradiated. Sixty eight dd-strain mice were also used for microautoradiographic study. Histological changes in the heart were observed in 27 of the 43 cases receiving irradiation. The limit of the tolerance dose to the heart for indicating histological changes was 1220 ret in humans. The latent period without histological changes was 2.7 months after initiation of radiation therapy. Greater heart injury was observed after re-irradiation or after the combined therapy of radiation and chemotherapy especially mitomycin (MMC). The histological findings after treatment with MMC were similar to those of radiation-induced heart injury. Results of the study indicate that the damage is secondary to radiation-induced changes of the vascula connective tissue. (Evans, G.)

  20. Could visual neglect induce amblyopia?

    Science.gov (United States)

    Bier, J C; Vokaer, M; Fery, P; Garbusinski, J; Van Campenhoudt, G; Blecic, S A; Bartholomé, E J

    2004-12-01

    Oculomotor nerve disease is a common cause of diplopia. When strabismus is present, absence of diplopia has to induce the research of either uncovering of visual fields or monocular suppression, amblyopia or blindness. We describe the case of a 41-year-old woman presenting with right oculomotor paresis and left object-centred visual neglect due to a right fronto-parietal haemorrhage expanding to the right peri-mesencephalic cisterna caused by the rupture of a right middle cerebral artery aneurysm. She never complained of diplopia despite binocular vision and progressive recovery of strabismus, excluding uncovering of visual fields. Since all other causes were excluded in this case, we hypothesise that the absence of diplopia was due to the object-centred visual neglect. Partial internal right oculomotor paresis causes an ocular deviation in abduction; the image being perceived deviated contralaterally to the left. Thus, in our case, the neglect of the left image is equivalent to a right monocular functional blindness. However, bell cancellation test clearly worsened when assessed in left monocular vision confirming that eye patching can worsen attentional visual neglect. In conclusion, our case argues for the possibility of a functional monocular blindness induced by visual neglect. We think that in presence of strabismus, absence of diplopia should induce the search for hemispatial visual neglect when supratentorial lesions are suspected.

  1. [Drug-induced oral ulcerations].

    Science.gov (United States)

    Madinier, I; Berry, N; Chichmanian, R M

    2000-06-01

    Different side effects of drugs have been described in the oral cavity, including oral ulcerations. Direct contact between drugs and oral mucosa may induce chemical burn or local hypersensitivity. Less frequently, these drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. Solitary oral ulcerations usually appear after few weeks of treatment. In most of cases, these lesions resist to conventional treatments, with a rapid healing following the suppression of the responsible drug. This diagnosis is usually difficult, particularly with patients receiving multiple drug therapy. Besides, special attention must be paid to new drugs. Oral ulcerations following symptoms of burning mouth, metallic taste, dysgueusia or agueusia are strongly suggestive of a pharmacological origin. Most of the molecules able to induce solitary oral ulcerations are commonly prescribed in a) rheumatology: NSAI (diclofenac, flurbiprofen, indomethacin, naproxen), long-term rheumatoid arthritis therapy (azathioprine, methotrexate, penicillamine, gold compounds, tiopronin); b) cardiology: angiotensin-converting-enzyme inhibitors (captopril, enalapril), angiotensin 2-receptor antagonist (losartan), anti-angorous (nicorandil), c) psychiatry: antidepressants (fluoxetine, lithium), d) AIDS therapy (foscarnet, zalcitabine).

  2. Second-order nonlinearity induced transparency.

    Science.gov (United States)

    Zhou, Y H; Zhang, S S; Shen, H Z; Yi, X X

    2017-04-01

    In analogy to electromagnetically induced transparency, optomechanically induced transparency was proposed recently in [Science330, 1520 (2010)SCIEAS0036-807510.1126/science.1195596]. In this Letter, we demonstrate another form of induced transparency enabled by second-order nonlinearity. A practical application of the second-order nonlinearity induced transparency is to measure the second-order nonlinear coefficient. Our scheme might find applications in quantum optics and quantum information processing.

  3. Diffuse Transcranial Electrical Stimulation (DTES)-induced ...

    African Journals Online (AJOL)

    Higher voltages were needed to induce convulsion in pretreated animals than in normal animals. It is therefore suggestive that DTES-induced hypermotility can be used as an animal model for testing drugs that can be of advantage in the management of non convulsive (petit mal) status epilepticus (SE), and DTES induced ...

  4. Mutations induced by ultraviolet light

    International Nuclear Information System (INIS)

    Pfeifer, Gerd P.; You, Young-Hyun; Besaratinia, Ahmad

    2005-01-01

    The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA

  5. Statistical Seismology and Induced Seismicity

    Science.gov (United States)

    Tiampo, K. F.; González, P. J.; Kazemian, J.

    2014-12-01

    While seismicity triggered or induced by natural resources production such as mining or water impoundment in large dams has long been recognized, the recent increase in the unconventional production of oil and gas has been linked to rapid rise in seismicity in many places, including central North America (Ellsworth et al., 2012; Ellsworth, 2013). Worldwide, induced events of M~5 have occurred and, although rare, have resulted in both damage and public concern (Horton, 2012; Keranen et al., 2013). In addition, over the past twenty years, the increase in both number and coverage of seismic stations has resulted in an unprecedented ability to precisely record the magnitude and location of large numbers of small magnitude events. The increase in the number and type of seismic sequences available for detailed study has revealed differences in their statistics that previously difficult to quantify. For example, seismic swarms that produce significant numbers of foreshocks as well as aftershocks have been observed in different tectonic settings, including California, Iceland, and the East Pacific Rise (McGuire et al., 2005; Shearer, 2012; Kazemian et al., 2014). Similarly, smaller events have been observed prior to larger induced events in several occurrences from energy production. The field of statistical seismology has long focused on the question of triggering and the mechanisms responsible (Stein et al., 1992; Hill et al., 1993; Steacy et al., 2005; Parsons, 2005; Main et al., 2006). For example, in most cases the associated stress perturbations are much smaller than the earthquake stress drop, suggesting an inherent sensitivity to relatively small stress changes (Nalbant et al., 2005). Induced seismicity provides the opportunity to investigate triggering and, in particular, the differences between long- and short-range triggering. Here we investigate the statistics of induced seismicity sequences from around the world, including central North America and Spain, and

  6. Ion beam induced luminescence: Relevance to radiation induced bystander effects

    Science.gov (United States)

    Ahmad, S. B.; McNeill, F. E.; Byun, S. H.; Prestwich, W. V.; Seymour, C.; Mothersill, C. E.

    2012-10-01

    The aim of this work is quantify the light emitted as a result of charged particle interaction in materials which may be of relevance to radiation induced "bystander effects" studies. We have developed a system which employs single photon counting to measure the light emitted from samples irradiated under vacuum by a charged particle beam. The system uses a fast photomultiplier tube with a peak cathode response at 420 nm. It has been tested in a proof-of-principle experiment using polystyrene targets. Light output, as a result of irradiation, was measured. The luminescence yield appears to have a non-linear behavior with the incident ion fluence: it rises exponentially to an asymptotic value. The target was irradiated with beam energies varying from 1 to 2 MeV and showed saturation at or before an incident fluence rate of 3 × 1013 H+/cm2 s. The average saturation value for the photon output was found to be 40 × 106 cps. Some measurements were performed using filters to study the emission at specific wavelengths. In the case of filtered light measurements, the photon output was found to saturate at 28 × 103, 10 × 106, and 35 × 106 cps for wavelengths of 280 ± 5 nm, 320 ± 5 nm and 340 ± 5 nm respectively. The light output reaches a maximum value because of damage induced in the polymer. Our measurements indicate a "damage cross section" of the order of 10-14 cm2. The average radiant intensity was found to increase at wavelengths of 280 and 320 nm when the proton energy was increased. This was not found to occur at 340 nm. In conclusion, the light emission at specific wavelengths was found to depend upon the incident proton fluence and the proton energy. The wavelengths of the emitted light measured in this study have significance for the understanding of radiation induced bystander effects.

  7. Sad music induces pleasant emotion.

    Science.gov (United States)

    Kawakami, Ai; Furukawa, Kiyoshi; Katahira, Kentaro; Okanoya, Kazuo

    2013-01-01

    In general, sad music is thought to cause us to experience sadness, which is considered an unpleasant emotion. As a result, the question arises as to why we listen to sad music if it evokes sadness. One possible answer to this question is that we may actually feel positive emotions when we listen to sad music. This suggestion may appear to be counterintuitive; however, in this study, by dividing musical emotion into perceived emotion and felt emotion, we investigated this potential emotional response to music. We hypothesized that felt and perceived emotion may not actually coincide in this respect: sad music would be perceived as sad, but the experience of listening to sad music would evoke positive emotions. A total of 44 participants listened to musical excerpts and provided data on perceived and felt emotions by rating 62 descriptive words or phrases related to emotions on a scale that ranged from 0 (not at all) to 4 (very much). The results revealed that the sad music was perceived to be more tragic, whereas the actual experiences of the participants listening to the sad music induced them to feel more romantic, more blithe, and less tragic emotions than they actually perceived with respect to the same music. Thus, the participants experienced ambivalent emotions when they listened to the sad music. After considering the possible reasons that listeners were induced to experience emotional ambivalence by the sad music, we concluded that the formulation of a new model would be essential for examining the emotions induced by music and that this new model must entertain the possibility that what we experience when listening to music is vicarious emotion.

  8. Sad music induces pleasant emotion

    Science.gov (United States)

    Kawakami, Ai; Furukawa, Kiyoshi; Katahira, Kentaro; Okanoya, Kazuo

    2013-01-01

    In general, sad music is thought to cause us to experience sadness, which is considered an unpleasant emotion. As a result, the question arises as to why we listen to sad music if it evokes sadness. One possible answer to this question is that we may actually feel positive emotions when we listen to sad music. This suggestion may appear to be counterintuitive; however, in this study, by dividing musical emotion into perceived emotion and felt emotion, we investigated this potential emotional response to music. We hypothesized that felt and perceived emotion may not actually coincide in this respect: sad music would be perceived as sad, but the experience of listening to sad music would evoke positive emotions. A total of 44 participants listened to musical excerpts and provided data on perceived and felt emotions by rating 62 descriptive words or phrases related to emotions on a scale that ranged from 0 (not at all) to 4 (very much). The results revealed that the sad music was perceived to be more tragic, whereas the actual experiences of the participants listening to the sad music induced them to feel more romantic, more blithe, and less tragic emotions than they actually perceived with respect to the same music. Thus, the participants experienced ambivalent emotions when they listened to the sad music. After considering the possible reasons that listeners were induced to experience emotional ambivalence by the sad music, we concluded that the formulation of a new model would be essential for examining the emotions induced by music and that this new model must entertain the possibility that what we experience when listening to music is vicarious emotion. PMID:23785342

  9. Cetirizine-Induced atrial fibrillation

    Directory of Open Access Journals (Sweden)

    Altuğ Osken

    2016-01-01

    Full Text Available Atrial fibrillation (AF is the most common observed arrhythmia in clinical practice. In the literature, AF events associated with drug induction are available. Cetirizine is a second-generation histamine antagonist used in the treatment of allergies, angioedema, and urticaria. We wish to present an atypical case who took cetirizine medication for relieving symptoms of upper tract respiratory system infection, experienced rapid ventricular response AF and treated successfully. To best of our knowledge, this is the first case of cetirizine-induced AF.

  10. Current-Induced Membrane Discharge

    DEFF Research Database (Denmark)

    Andersen, Mathias Bækbo; van Soestbergen, M.; Mani, A.

    2012-01-01

    . Salt depletion leads to a large electric field resulting in a local pH shift within the membrane with the effect that the membrane discharges and loses its ion selectivity. Since salt co-ions, H+ ions, and OH- ions contribute to OLC, CIMD interferes with electrodialysis (salt counterion removal...... neglects chemical effects and remains to be quantitatively tested. Here, we show that charge regulation and water self-ionization can lead to OLC by "current-induced membrane discharge'' (CIMD), even in the absence of fluid flow, in ion-exchange membranes much thicker than the local Debye screening length...

  11. Adsorption-induced step formation

    DEFF Research Database (Denmark)

    Thostrup, P.; Christoffersen, Ebbe; Lorensen, Henrik Qvist

    2001-01-01

    Through an interplay between density functional calculations, Monte Carlo simulations and scanning tunneling microscopy experiments, we show that an intermediate coverage of CO on the Pt(110) surface gives rise to a new rough equilibrium structure with more than 50% step atoms. CO is shown to bind...... so strongly to low-coordinated Pt atoms that it can break Pt-Pt bonds and spontaneously form steps on the surface. It is argued that adsorption-induced step formation may be a general effect, in particular at high gas pressures and temperatures....

  12. Psychological sequelae of induced abortion.

    Science.gov (United States)

    Romans-Clarkson, S E

    1989-12-01

    This article reviews the scientific literature on the psychological sequelae of induced abortion. The methodology and results of studies carried out over the last twenty-two years are examined critically. The unanimous consensus is that abortion does not cause deleterious psychological effects. Women most likely to show subsequent problems are those who were pressured into the operation against their own wishes, either by relatives or because their pregnancy had medical or foetal contraindications. Legislation which restricts abortion causes problems for women with unwanted pregnancies and their doctors. It is also unjust, as it adversely most affects lower socio-economic class women.

  13. Plasma generation induced by triboelectrification

    DEFF Research Database (Denmark)

    Kusano, Yukihiro; Singh, Shailendra Vikram; Michelsen, Poul

    2009-01-01

    A gas discharge plasma can be induced by triboelectrification around a sliding contact. The detailed physical mechanism of triboelectrification is unknown, but an empirical classification scheme can be referred to in practice. It is reported that intense ultra-violet emission from a plasma...... is observed adjacent to the sliding contact, of which the location has a gap ranging from approximately 1 μm to 11 μm. When the gap is short enough, a theory predicts that the breakdown voltage can monotonically decrease with a decrease in the gap. However, when the gap is comparable to electron’s mean free...

  14. Clozapine-induced late leukopenia.

    LENUS (Irish Health Repository)

    Latif, Z

    2012-03-01

    A patient with a 28-year history of schizophrenia was treated with a wide range of antipsychotic medications since diagnosis. She had experienced no clinically significant symptomatic relief until she commenced treatment on clozapine. Her psychotic symptoms, self care, and general sense of well-being improved significantly. After 6 years of successful treatment, she developed leukopenia and clozapine was discontinued. The following issues will be discussed in the article: rechallenge with clozapine following leukopenia during previous therapy and the choice of and haematological monitoring needs with other antipsychotic medications after clozapine-induced blood dyscrasia.

  15. CRBRP flow induced vibration program

    Energy Technology Data Exchange (ETDEWEB)

    Novendstern, E H [Westinghouse Advanced Reactor Division, Madison, PA (United States); Grochowski, F A; Yang, T M [General Electric Co., Fast Breeder Reactor Department, Sunnyvale, CA (United States); Ryan, J A; Mulcahy, T M

    1977-12-01

    The program to assure the structural adequacy of Clinch River Breeder Reactor (CRBRP) components during its planned 30 years of operation is described. The program includes (1) an assessment of reactor components relative to their susceptibility to FIV, (2) designing to minimize component excitation due to Fluid induced vibrations (FIV), (3) scale model tests to measure structural response during simulated operating conditions and (4) preoperational tests. An overview of the CRBRP test program is described. Additionally, details of scale model testing of reactor internals and the steam generator is described in more detail. (author)

  16. Drug-induced peripheral neuropathy

    DEFF Research Database (Denmark)

    Vilholm, Ole Jakob; Christensen, Alex Alban; Zedan, Ahmed

    2014-01-01

    Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical...... substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated...

  17. Basic reactions induced by radiation

    International Nuclear Information System (INIS)

    Charlesby, A.

    1980-01-01

    This paper summarises some of the basic reactions resulting from exposure to high energy radiation. In the initial stages energy is absorbed, but not necessarily at random, giving radical and ion species which may then react to promote the final chemical change. However, it is possible to intervene at intermediate stages to modify or reduce the radiation effect. Under certain conditions enhanced reactions are also possible. Several expressions are given to calculate radiation yield in terms of energy absorbed. Some analogies between radiation-induced reactions in polymers, and those studied in radiobiology are outlined. (author)

  18. Diseases induced by ionising radiation

    International Nuclear Information System (INIS)

    1984-11-01

    An interim report is presented by the Industrial Injuries Advisory Council in accordance with Section 141 of the Social Security Act 1975 on the question whether the terms of prescription for occupational diseases induced by ionising radiation should be amended to cover a wider range of conditions. A lack of persuasive statistical data has prevented reliable estimates of health risks of radiation workers in the UK to be made. However the report gives details of the progress made so far and the difficulties encountered. (U.K.)

  19. Radiation Induced Polymerization of Pyrrole

    International Nuclear Information System (INIS)

    Sarada Idris; Ratnam, C.T.; Ahmad Ashrif Abu Bakar

    2016-01-01

    We demonstrate the polymerization of pyrrole by gamma irradiation. The pyrrole films were exposed to gamma ray from cobalt 60 source at doses ranging from 0 to 150 kGy. The films were subjected to structural and morphological analyses by using FTIR, SEM and AFM techniques. Similar studies were also made on pristine pyrrole film which serve as control. Results revealed that pyrrole has been successfully polymerized through irradiation induced reactions. The SEM images depicted the formation of cauliflower shape upon gamma irradiation. The structural changes of pyrrole also evidenced by FTIR spectra. Surface topography and roughness of pyrrole before and after gamma irradiation found to show significant differences. (author)

  20. [Pregnancy-induced haemolytic anaemia].

    Science.gov (United States)

    Karagiozova, J; Masseva, A; Ivanov, St; Marinov, B; Kulinska, R; Boiadjiev, D; Jordanova, D

    2014-01-01

    This is the clinical case of a primiparous eight month pregnant female, presenting with symptoms of pregnancy-induced acute haemolytic anaemia (haemolytic aneamia provoked by an immune mechanism, intra- and extra-erythrocyte defects, and HELLP syndrome were excluded). The anaemia progressed to become life-threatening for both the pregnant women and the foetus, which brought the following questions into consideration: diagnosis of anaemia during pregnancy; dosing of corticosteroid therapy; possibility of giving birth to a viable foetus and prognosis for next pregnancies. Owing to the inter-disciplinary efforts, the life and health of this pregnant woman were preserved, but the foetus was lost.

  1. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development

    Science.gov (United States)

    Reissmann, Eva; Jörnvall, Henrik; Blokzijl, Andries; Andersson, Olov; Chang, Chenbei; Minchiotti, Gabriella; Persico, M. Graziella; Ibáñez, Carlos F.; Brivanlou, Ali H.

    2001-01-01

    Nodal proteins have crucial roles in mesendoderm formation and left–right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1). Receptor reconstitution experiments indicate that ALK7 collaborates with ActRIIB to confer responsiveness to Xnr1 and Nodal. Both receptors can independently bind Xnr1. In addition, Cripto, an extracellular protein genetically implicated in Nodal signaling, can independently interact with both Xnr1 and ALK7, and its expression greatly enhances the ability of ALK7 and ActRIIB to respond to Nodal ligands. The Activin receptor ALK4 is also able to mediate Nodal signaling but only in the presence of Cripto, with which it can also interact directly. A constitutively activated form of ALK7 mimics the mesendoderm-inducing activity of Xnr1 in Xenopus embryos, whereas a dominant-negative ALK7 specifically blocks the activities of Nodal and Xnr1 but has little effect on other related ligands. In contrast, a dominant-negative ALK4 blocks all mesoderm-inducing ligands tested, including Nodal, Xnr1, Xnr2, Xnr4, and Activin. In agreement with a role in Nodal signaling, ALK7 mRNA is localized to the ectodermal and organizer regions of Xenopus gastrula embryos and is expressed during early stages of mouse embryonic development. Therefore, our results indicate that both ALK4 and ALK7 can mediate signal transduction by Nodal proteins, although ALK7 appears to be a receptor more specifically dedicated to Nodal signaling. PMID:11485994

  2. Ion beam induced luminescence: Relevance to radiation induced bystander effects

    Energy Technology Data Exchange (ETDEWEB)

    Ahmad, S.B., E-mail: ahmad.rabilal@gmail.com [Medical Physics and Applied Radiation Sciences, University of McMaster, Hamilton, Ontario (Canada); McNeill, F.E., E-mail: fmcneill@mcmaster.ca [Medical Physics and Applied Radiation Sciences, University of McMaster, Hamilton, Ontario (Canada); Byun, S.H., E-mail: soohyun@mcmaster.ca [Medical Physics and Applied Radiation Sciences, University of McMaster, Hamilton, Ontario (Canada); Prestwich, W.V., E-mail: prestwic@mcmaster.ca [Medical Physics and Applied Radiation Sciences, University of McMaster, Hamilton, Ontario (Canada); Seymour, C., E-mail: seymouc@mcmaster.ca [Medical Physics and Applied Radiation Sciences, University of McMaster, Hamilton, Ontario (Canada); Mothersill, C.E., E-mail: mothers@mcmaster.ca [Medical Physics and Applied Radiation Sciences, University of McMaster, Hamilton, Ontario (Canada)

    2012-10-01

    The aim of this work is quantify the light emitted as a result of charged particle interaction in materials which may be of relevance to radiation induced 'bystander effects' studies. We have developed a system which employs single photon counting to measure the light emitted from samples irradiated under vacuum by a charged particle beam. The system uses a fast photomultiplier tube with a peak cathode response at 420 nm. It has been tested in a proof-of-principle experiment using polystyrene targets. Light output, as a result of irradiation, was measured. The luminescence yield appears to have a non-linear behavior with the incident ion fluence: it rises exponentially to an asymptotic value. The target was irradiated with beam energies varying from 1 to 2 MeV and showed saturation at or before an incident fluence rate of 3 Multiplication-Sign 10{sup 13} H{sup +}/cm{sup 2} s. The average saturation value for the photon output was found to be 40 Multiplication-Sign 10{sup 6} cps. Some measurements were performed using filters to study the emission at specific wavelengths. In the case of filtered light measurements, the photon output was found to saturate at 28 Multiplication-Sign 10{sup 3}, 10 Multiplication-Sign 10{sup 6}, and 35 Multiplication-Sign 10{sup 6} cps for wavelengths of 280 {+-} 5 nm, 320 {+-} 5 nm and 340 {+-} 5 nm respectively. The light output reaches a maximum value because of damage induced in the polymer. Our measurements indicate a 'damage cross section' of the order of 10{sup -14} cm{sup 2}. The average radiant intensity was found to increase at wavelengths of 280 and 320 nm when the proton energy was increased. This was not found to occur at 340 nm. In conclusion, the light emission at specific wavelengths was found to depend upon the incident proton fluence and the proton energy. The wavelengths of the emitted light measured in this study have significance for the understanding of radiation induced bystander effects.

  3. On the Induced Gravitational Collapse

    Directory of Open Access Journals (Sweden)

    M. Becerra Laura

    2018-01-01

    Full Text Available The induced gravitational collapse (IGC paradigm has been applied to explain the long gamma ray burst (GRB associated with type Ic supernova, and recently the Xray flashes (XRFs. The progenitor is a binary systems of a carbon-oxygen core (CO and a neutron star (NS. The CO core collapses and undergoes a supernova explosion which triggers the hypercritical accretion onto the NS companion (up to 10-2 M⊙s-1. For the binary driven hypernova (BdHNe, the binary system is enough bound, the NS reach its critical mass, and collapse to a black hole (BH with a GRB emission characterized by an isotropic energy Eiso > 1052 erg. Otherwise, for binary systems with larger binary separations, the hypercritical accretion onto the NS is not sufficient to induced its gravitational collapse, a X-ray flash is produced with Eiso < 1052 erg. We’re going to focus in identify the binary parameters that limits the BdHNe systems with the XRFs systems.

  4. Cough-induced rib fractures.

    Science.gov (United States)

    Sano, Atsushi; Tashiro, Ken; Fukuda, Tsutomu

    2015-10-01

    Occasionally, patients who complain of chest pain after the onset of coughing are diagnosed with rib fractures. We investigated the characteristics of cough-induced rib fractures. Between April 2008 and December 2013, 17 patients were referred to our hospital with chest pain after the onset of coughing. Rib radiography was performed, focusing on the location of the chest pain. When the patient had other signs and symptoms such as fever or persistent cough, computed tomography of the chest was carried out. We analyzed the data retrospectively. Rib fractures were found in 14 of the 17 patients. The age of the patients ranged from 14 to 86 years (median 39.5 years). Ten patients were female and 4 were male. Three patients had chronic lung disease. There was a single rib fracture in 9 patients, and 5 had two or more fractures. The middle and lower ribs were the most commonly involved; the 10th rib was fractured most frequently. Cough-induced rib fractures occur in every age group regardless of the presence or absence of underlying disease. Since rib fractures often occur in the lower and middle ribs, rib radiography is useful for diagnosis. © The Author(s) 2015.

  5. Induced gravity II: grand unification

    Energy Technology Data Exchange (ETDEWEB)

    Einhorn, Martin B. [Kavli Institute for Theoretical Physics, Kohn Hall,University of California,Santa Barbara, CA 93106-4030 (United States); Jones, D.R. Timothy [Kavli Institute for Theoretical Physics, Kohn Hall,University of California,Santa Barbara, CA 93106-4030 (United States); Dept. of Mathematical Sciences, University of Liverpool,Peach Street, Liverpool L69 3BX (United Kingdom)

    2016-05-31

    As an illustration of a renormalizable, asymptotically-free model of induced gravity, we consider an SO(10) gauge theory interacting with a real scalar multiplet in the adjoint representation. We show that dimensional transmutation can occur, spontaneously breaking SO(10) to SU(5)⊗U(1), while inducing the Planck mass and a positive cosmological constant, all proportional to the same scale v. All mass ratios are functions of the values of coupling constants at that scale. Below this scale (at which the Big Bang may occur), the model takes the usual form of Einstein-Hilbert gravity in de Sitter space plus calculable corrections. We show that there exist regions of parameter space in which the breaking results in a local minimum of the effective action giving a positive dilaton (mass){sup 2} from two-loop corrections associated with the conformal anomaly. Furthermore, unlike the singlet case we considered previously, some minima lie within the basin of attraction of the ultraviolet fixed point. Moreover, the asymptotic behavior of the coupling constants also lie within the range of convergence of the Euclidean path integral, so there is hope that there will be candidates for sensible vacua. Although open questions remain concerning unitarity of all such renormalizable models of gravity, it is not obvious that, in curved backgrounds such as those considered here, unitarity is violated. In any case, any violation that may remain will be suppressed by inverse powers of the reduced Planck mass.

  6. Inducer Hydrodynamic Load Measurement Devices

    Science.gov (United States)

    Skelley, Stephen E.; Zoladz, Thomas F.

    2002-01-01

    Marshall Space Flight Center (MSFC) has demonstrated two measurement devices for sensing and resolving the hydrodynamic loads on fluid machinery. The first - a derivative of the six component wind tunnel balance - senses the forces and moments on the rotating device through a weakened shaft section instrumented with a series of strain gauges. This "rotating balance" was designed to directly measure the steady and unsteady hydrodynamic loads on an inducer, thereby defining both the amplitude and frequency content associated with operating in various cavitation modes. The second device - a high frequency response pressure transducer surface mounted on a rotating component - was merely an extension of existing technology for application in water. MSFC has recently completed experimental evaluations of both the rotating balance and surface-mount transducers in a water test loop. The measurement bandwidth of the rotating balance was severely limited by the relative flexibility of the device itself, resulting in an unexpectedly low structural bending mode and invalidating the higher frequency response data. Despite these limitations, measurements confirmed that the integrated loads on the four-bladed inducer respond to both cavitation intensity and cavitation phenomena. Likewise, the surface-mount pressure transducers were subjected to a range of temperatures and flow conditions in a non-rotating environment to record bias shifts and transfer functions between the transducers and a reference device. The pressure transducer static performance was within manufacturer's specifications and dynamic response accurately followed that of the reference.

  7. Chaos for induced hyperspace maps

    International Nuclear Information System (INIS)

    Banks, John

    2005-01-01

    For (X,d) be a metric space, f:X->X a continuous map and (K(X),H) the space of non-empty compact subsets of X with the Hausdorff metric, one may study the dynamical properties of the induced map (*)f-bar :K(X)->K(X):A-bar f(A).H. Roman-Flores [A note on in set-valued discrete systems. Chaos, Solitons and Fractals 2003;17:99-104] has shown that if f-bar is topologically transitive then so is f, but that the reverse implication does not hold. This paper shows that the topological transitivity of f-bar is in fact equivalent to weak topological mixing on the part of f. This is proved in the more general context of an induced map on some suitable hyperspace H of X with the Vietoris topology (which agrees with the topology of the Hausdorff metric in the case discussed by Roman-Flores

  8. Condensation induced water hammer safety

    International Nuclear Information System (INIS)

    Gintner, M.A.

    1997-01-01

    Condensation induced water hammer events in piping systems can cause catastrophic steam system failures which can result in equipment damage, personal injury, and even death. As an industry, we have learned to become accustomed to the ''banging'' that we often hear in our steam piping systems, and complacent in our actions to prevent it. It is unfortunate that lives are lost needlessly, as this type of water hammer event is preventable if one only applies some basic principles when operating and maintaining their steam systems. At the U. S. Department of Energy's Hanford Site where I work, there was one such accident that occurred in 1993 which took the life of a former co-worker and friend of mine. Hanford was established as part of the Manhattan Project during World War II. it is a 560 square mile complex located along the banks of the Columbia River in Southeastern Washington State. For almost 45 years, hanford's mission was to produce weapons grade plutonium for our nations defense programs. Today, Hanford no longer produces plutonium, but is focused on site clean-up and economic diversification. Hanford still uses steam for heating and processing activities, utilizing over 20 miles of piping distribution systems similar to those found in industry. Although these aging systems are still sound, they cannot stand up to the extreme pressure pulses developed by a condensation induced water hammer

  9. Psychosocial aspects of induced abortion.

    Science.gov (United States)

    Stotland, N L

    1997-09-01

    US anti-abortion groups have used misinformation on the long-term psychological impact of induced abortion to advance their position. This article reviews the available research evidence on the definition, history, cultural context, and emotional and psychiatric sequelae of induced abortion. Notable has been a confusion of normative, transient reactions to unintended pregnancy and abortion (e.g., guilt, depression, anxiety) with serious mental disorders. Studies of the psychiatric aspects of abortion have been limited by methodological problems such as the impossibility of randomly assigning women to study and control groups, resistance to follow-up, and confounding variables. Among the factors that may impact on an unintended pregnancy and the decision to abort are ongoing or past psychiatric illness, poverty, social chaos, youth and immaturity, abandonment issues, ongoing domestic responsibilities, rape and incest, domestic violence, religion, and contraceptive failure. Among the risk factors for postabortion psychosocial difficulties are previous or concurrent psychiatric illness, coercion to abort, genetic or medical indications, lack of social supports, ambivalence, and increasing length of gestation. Overall, the literature indicates that serious psychiatric illness is at least 8 times more common among postpartum than among postabortion women. Abortion center staff should acknowledge that the termination of a pregnancy may be experienced as a loss even when it is a voluntary choice. Referrals should be offered to women who show great emotional distress, have had several previous abortions, or request psychiatric consultation.

  10. Drug-induced hepatic injury

    DEFF Research Database (Denmark)

    Friis, Henrik; Andreasen, P B

    1992-01-01

    The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.......5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.......7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected...

  11. Condensation induced water hammer safety

    Energy Technology Data Exchange (ETDEWEB)

    Gintner, M.A.

    1997-03-10

    Condensation induced water hammer events in piping systems can cause catastrophic steam system failures which can result in equipment damage, personal injury, and even death. As an industry, we have learned to become accustomed to the ''banging'' that we often hear in our steam piping systems, and complacent in our actions to prevent it. It is unfortunate that lives are lost needlessly, as this type of water hammer event is preventable if one only applies some basic principles when operating and maintaining their steam systems. At the U. S. Department of Energy's Hanford Site where I work, there was one such accident that occurred in 1993 which took the life of a former co-worker and friend of mine. Hanford was established as part of the Manhattan Project during World War II. it is a 560 square mile complex located along the banks of the Columbia River in Southeastern Washington State. For almost 45 years, hanford's mission was to produce weapons grade plutonium for our nations defense programs. Today, Hanford no longer produces plutonium, but is focused on site clean-up and economic diversification. Hanford still uses steam for heating and processing activities, utilizing over 20 miles of piping distribution systems similar to those found in industry. Although these aging systems are still sound, they cannot stand up to the extreme pressure pulses developed by a condensation induced water hammer.

  12. Shear induced phase transitions induced in edible fats

    Science.gov (United States)

    Mazzanti, Gianfranco; Welch, Sarah E.; Marangoni, Alejandro G.; Sirota, Eric B.; Idziak, Stefan H. J.

    2003-03-01

    The food industry crystallizes fats under different conditions of temperature and shear to obtain products with desired crystalline phases. Milk fat, palm oil, cocoa butter and chocolate were crystallized from the melt in a temperature controlled Couette cell. Synchrotron x-ray diffraction studies were conducted to examine the role of shear on the phase transitions seen in edible fats. The shear forces on the crystals induced acceleration of the alpha to beta-prime phase transition with increasing shear rate in milk fat and palm oil. The increase was slow at low shear rates and became very strong above 360 s-1. In cocoa butter the acceleration between beta-prime-III and beta-V phase transition increased until a maximum of at 360 s-1, and then decreased, showing competition between enhanced heat transfer and viscous heat generation.

  13. Amoxicillin-induced aseptic meningoencephalitis

    Directory of Open Access Journals (Sweden)

    Radi Shahien

    2010-06-01

    Full Text Available Radi Shahien1, Vetaly Vieksler1, Abdalla Bowirrat11Department of Neurology and Neurophysiology, Ziv Medical Center, Safed, IsraelAbstract: Meningitis is usually produced by an infectious agent, but there are multiple noninfectious causes. Drug-induced aseptic meningitis (DIAM is an important entity and has been reported as an uncommon adverse reaction with numerous agents. Thus, DIAM constitutes a diagnostic and patient management challenge. We present a patient with three episodes of aseptic meningitis due to amoxicillin, and then review the literature on this rare idiosyncratic event which may occur after local or systemic drug administration. A 77-year-old man was admitted to our hospital with fever, headache, and neck stiffness. Seven days before admission he had a dental and gingival inflammation. He was treated with two oral doses of 500 mg daily of amoxicillin for one week. The seventh day he awoke with the complaints that prompted hospital admittance. Amoxicillin was stopped 1 day before his admission. From his history we knew of two similar episodes: The first episode was after a dental procedure 3 months before this incident. He had received a 1-week course of postprocedure amoxicillin of 500 mg daily and had similar headache, fever, and chills during the entire course of treatment. He wasn’t admitted to the hospital, because he stopped taking amoxicillin and he felt spontaneous pain relief after taking symptomatic pain treatment. The second episodes was 6 months after his first admission, he had been admitted to our hospital with the same symptoms. Amoxicillin was stopped and changed with intravenous (IV ceftriaxone (CTRX for 10 days due to suspected partial untreated meningitis. The patient improved rapidly within 2 days and was discharged from the hospital. On the basis of these three confirmed episodes of meningitis after recurrent exposure to amoxicillin, with repetitive negative testing for viral, bacterial, and mycobacterial

  14. Hemolysis induced by PMIVSD occluder

    Directory of Open Access Journals (Sweden)

    D. Sheshagiri Rao

    2016-09-01

    Full Text Available Hemolysis related to occluder, prosthetic valve, and prosthetic ring used for mitral valve annuloplasty are not very unusual. However, hemolysis related to transcathetor closure of post-myocardial infarction ventricular septal defect (PMIVSD is infrequent. A close follow-up for spontaneous resolution with or without blood transfusion has been reported in a few cases. Occasionally, surgical retrieval is unavoidable or lifelong blood transfusion is required if surgery cannot be done because of higher risk. In this illustration, we have showed a close follow-up of a case of hemolysis induced by atrial septal occluder used for VSD closure after myocardial infarction. Despite successful device closure of PMIVSD which is difficult, a close watch is needed for complications like residual leak, device embolization, and hemolysis.

  15. Hemolysis induced by PMIVSD occluder.

    Science.gov (United States)

    Rao, D Sheshagiri; Barik, Ramachandra; Siva Prasad, Akula

    2016-09-01

    Hemolysis related to occluder, prosthetic valve, and prosthetic ring used for mitral valve annuloplasty are not very unusual. However, hemolysis related to transcathetor closure of post-myocardial infarction ventricular septal defect (PMIVSD) is infrequent. A close follow-up for spontaneous resolution with or without blood transfusion has been reported in a few cases. Occasionally, surgical retrieval is unavoidable or lifelong blood transfusion is required if surgery cannot be done because of higher risk. In this illustration, we have showed a close follow-up of a case of hemolysis induced by atrial septal occluder used for VSD closure after myocardial infarction. Despite successful device closure of PMIVSD which is difficult, a close watch is needed for complications like residual leak, device embolization, and hemolysis. Copyright © 2016 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

  16. Rice breeding with induced mutations

    Energy Technology Data Exchange (ETDEWEB)

    1968-06-01

    The Joint FAO/IAEA Division of Atomic Energy in Food and Agriculture decided in 1964 to organize a co-ordinated research programme on the use of induced mutations in rice breeding. The programme was organized within the framework of activities of the International Rice Commission. This is a report of the Third Co-ordination Meeting of the participants, which was held in Taipei, 5-9 June 1967. As the projects, which together make up the co-ordinated programme, are at different stages of progress, the report contains a variety of papers including completed studies, field and progress reports, and highlights of the discussions with some additional recommendations prepared by the participants. Refs, figs and tabs.

  17. Uncommon vancomycin: induced side effects

    Directory of Open Access Journals (Sweden)

    Rocha Jaime Luís Lopes

    2002-01-01

    Full Text Available Vancomycin has been used with increased frequency during the past 15 years and the most common toxicity with this drug is the "red man syndrome". Other adverse effects include neutropenia, fever, phlebitis, nephrotoxicity, ototoxicity, thrombocytopenia, interstitial nephritis, lacrimation, linear IgA bullous dermatosis, necrotizing cutaneous vasculitis and toxic epidermal necrolysis. Only two cases of vancomycin-induced Stevens-Johnson syndrome and one case of pancytopenia have been reported in the medical literature. The treatment for both situations is based on cessation of the vancomycin therapy; in cases of Stevens-Johnson syndrome, antihistamine and/or steroid agents can be used. This article reports a case of pancytopenia and a case of erythema major associated with neutropenia.

  18. Typhoon-Induced Ground Deformation

    Science.gov (United States)

    Mouyen, M.; Canitano, A.; Chao, B. F.; Hsu, Y.-J.; Steer, P.; Longuevergne, L.; Boy, J.-P.

    2017-11-01

    Geodetic instruments now offer compelling sensitivity, allowing to investigate how solid Earth and surface processes interact. By combining surface air pressure data, nontidal sea level variations model, and rainfall data, we systematically analyze the volumetric deformation of the shallow crust at seven borehole strainmeters in Taiwan induced by 31 tropical cyclones (typhoons) that made landfall to the island from 2004 to 2013. The typhoon's signature consists in a ground dilatation due to air pressure drop, generally followed by a larger ground compression. We show that this compression phase can be mostly explained by the mass loading of rainwater that falls on the ground and concentrates in the valleys towards the strainmeter sensitivity zone. Further, our analysis shows that borehole strainmeters can help quantifying the amount of rainwater accumulating and flowing over a watershed during heavy rainfalls, which is a useful constraint for building hydrological models.

  19. Mental disorders induced by carbamazepine.

    Science.gov (United States)

    Mizukami, K; Naito, Y; Yoshida, M; Nakanishi, T; Koizumi, J

    1990-03-01

    We present here a case with various physical and neuropsychiatric symptoms caused by the administration of carbamazepine. The patient suffering from right ophthalmic neuralgia showed fever, eczema, erythema, lymphoadenopathy, eosinophilia, vomiting, headache, dizziness, nystagmus, and various mental disorders which consisted of emotional instability, personality change, delusions of reference and persecution, depressive state, and hyperventilation syndrome during the administration of carbamazepine. The physical symptoms in the present case were conformable to the side effect of carbamazepine. The mental disorders appeared in a few days from the start of carbamazepine administration and disappeared after the discontinuation of the administration of this drug without antipsychotic therapy and have never relapsed until now. The mental disorders and the physical symptoms were in parallel with their clinical course. This kind of mental disorders induced by carbamazepine has not yet been reported.

  20. Antiphospholipid Antibody Induced by Nivolumab

    Directory of Open Access Journals (Sweden)

    Ahmed Aburahma

    2018-01-01

    Full Text Available Nivolumab is a monoclonal antibody against the programmed death protein 1 and is used for patients with advanced melanoma. It is associated with potentially immune-related adverse events, including disorders of the skin, GI tract, and the thyroid; these disorders were successfully treated with prednisone and infliximab. Other immunotherapeutic agents were observed to induce the formation of antiphospholipid antibody (APA including α-interferon and interleukin-2. We present a case of APA development after the third dose of nivolumab in a 71-year-old male with advanced melanoma. The APA was detected after finding a prolonged aPTT; the lupus anticoagulant assay tested positive. The patient was treated with prednisone but, unfortunately, he expired a few days later.

  1. Human-induced Arctic moistening.

    Science.gov (United States)

    Min, Seung-Ki; Zhang, Xuebin; Zwiers, Francis

    2008-04-25

    The Arctic and northern subpolar regions are critical for climate change. Ice-albedo feedback amplifies warming in the Arctic, and fluctuations of regional fresh water inflow to the Arctic Ocean modulate the deep ocean circulation and thus exert a strong global influence. By comparing observations to simulations from 22 coupled climate models, we find influence from anthropogenic greenhouse gases and sulfate aerosols in the space-time pattern of precipitation change over high-latitude land areas north of 55 degrees N during the second half of the 20th century. The human-induced Arctic moistening is consistent with observed increases in Arctic river discharge and freshening of Arctic water masses. This result provides new evidence that human activity has contributed to Arctic hydrological change.

  2. Valproic Acid-induced Agranulocytosis

    Directory of Open Access Journals (Sweden)

    Hui-Chuan Hsu

    2009-06-01

    Full Text Available Valproic acid is considered to be the most well-tolerated antiepileptic drug. However, few cases of neutropenia or leukopenia caused by valproic acid have been reported. We present a patient who took valproic acid to treat a complication of brain surgery and in whom severe agranulocytosis occurred after 2.5 months. Valproic acid was stopped immediately, and granulocyte colony-stimulating factor was administered for 2 days. The patient's white blood cell count returned to normal within 2 weeks. The result of bone marrow aspiration was compatible with drug-induced agranulocytosis. This case illustrates that patients who take valproic acid may need regular checking of complete blood cell count.

  3. Magnetic field induced dynamical chaos.

    Science.gov (United States)

    Ray, Somrita; Baura, Alendu; Bag, Bidhan Chandra

    2013-12-01

    In this article, we have studied the dynamics of a particle having charge in the presence of a magnetic field. The motion of the particle is confined in the x-y plane under a two dimensional nonlinear potential. We have shown that constant magnetic field induced dynamical chaos is possible even for a force which is derived from a simple potential. For a given strength of the magnetic field, initial position, and velocity of the particle, the dynamics may be regular, but it may become chaotic when the field is time dependent. Chaotic dynamics is very often if the field is time dependent. Origin of chaos has been explored using the Hamiltonian function of the dynamics in terms of action and angle variables. Applicability of the present study has been discussed with a few examples.

  4. Gravity induced wave function collapse

    Science.gov (United States)

    Gasbarri, G.; Toroš, M.; Donadi, S.; Bassi, A.

    2017-11-01

    Starting from an idea of S. L. Adler [in Quantum Nonlocality and Reality: 50 Years of Bell's Theorem, edited by M. Bell and S. Gao (Cambridge University Press, Cambridge, England 2016)], we develop a novel model of gravity induced spontaneous wave function collapse. The collapse is driven by complex stochastic fluctuations of the spacetime metric. After deriving the fundamental equations, we prove the collapse and amplification mechanism, the two most important features of a consistent collapse model. Under reasonable simplifying assumptions, we constrain the strength ξ of the complex metric fluctuations with available experimental data. We show that ξ ≥10-26 in order for the model to guarantee classicality of macro-objects, and at the same time ξ ≤10-20 in order not to contradict experimental evidence. As a comparison, in the recent discovery of gravitational waves in the frequency range 35 to 250 Hz, the (real) metric fluctuations reach a peak of ξ ˜10-21.

  5. Molecular Mechanisms of Induced Pluripotency

    Science.gov (United States)

    Muchkaeva, I.A.; Dashinimaev, E.B.; Terskikh, V.V.; Sukhanov, Y.V.; Vasiliev, A.V.

    2012-01-01

    In this review the distinct aspects of somatic cell reprogramming are discussed. The molecular mechanisms of generation of induced pluripotent stem (iPS) cells from somatic cells via the introduction of transcription factors into adult somatic cells are considered. Particular attention is focused on the generation of iPS cells without genome modifications via the introduction of the mRNA of transcription factors or the use of small molecules. Furthermore, the strategy of direct reprogramming of somatic cells omitting the generation of iPS cells is considered. The data concerning the differences between ES and iPS cells and the problem of epigenetic memory are also discussed. In conclusion, the possibility of using iPS cells in regenerative medicine is considered. PMID:22708059

  6. Drug-induced status epilepticus.

    Science.gov (United States)

    Cock, Hannah R

    2015-08-01

    Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case ascertainment and establishing causation substantially weaken epidemiological estimates. Some antiepileptic drugs, particularly those with sodium channel or GABA(γ-aminobutyric acid)-ergic properties, frequently exacerbate seizures and may lead to SE if used inadvertently in generalized epilepsies or less frequently in other epilepsies. Tiagabine seems to have a particular propensity for triggering nonconvulsive SE sometimes in patients with no prior history of seizures. In therapeutic practice, SE is most commonly seen in association with antibiotics (cephalosporins, quinolones, and some others) and immunotherapies/chemotherapies, the latter often in the context of a reversible encephalopathy syndrome. Status epilepticus following accidental or intentional overdoses, particularly of antidepressants or other psychotropic medications, has also featured prominently in the literature: whilst there are sometimes fatal consequences, this is more commonly because of cardiorespiratory or metabolic complications than as a result of seizure activity. A high index of suspicion is required in identifying those at risk and in recognizing potential clues from the presentation, but even with a careful analysis of patient and drug factors, establishing causation can be difficult. In addition to eliminating the potential trigger, management should be as for SE in any other circumstances, with the exception that phenobarbitone is recommended as a second-line treatment for suspected toxicity-related SE where the risk of cardiovascular complications is higher anyways and may be exacerbated by phenytoin. There are also specific recommendations/antidotes in some situations. The outcome of drug-induced status epilepticus is mostly good when promptly identified and treated, though less so in the context of overdoses. This article is

  7. Induced gravity and gauge interactions revisited

    International Nuclear Information System (INIS)

    Broda, Boguslaw; Szanecki, Michal

    2009-01-01

    It has been shown that the primary, old-fashioned idea of Sakharov's induced gravity and gauge interactions, in the 'one-loop dominance' version, works astonishingly well yielding phenomenologically reasonable results. As a byproduct, the issue of the role of the UV cutoff in the context of the induced gravity has been reexamined (an idea of self-cutoff induced gravity). As an additional check, the black hole entropy has been used in the place of the action. Finally, it has been explicitly shown that the induced coupling constants of gauge interactions of the standard model assume qualitatively realistic values.

  8. Radiation-induced instability of human genome

    International Nuclear Information System (INIS)

    Ryabchenko, N.N.; Demina, Eh.A.

    2014-01-01

    A brief review is dedicated to the phenomenon of radiation-induced genomic instability where the increased level of genomic changes in the offspring of irradiated cells is characteristic. Particular attention is paid to the problems of genomic instability induced by the low-dose radiation, role of the bystander effect in formation of radiation-induced instability, and its relationship with individual radiosensitivity. We believe that in accordance with the paradigm of modern radiobiology the increased human individual radiosensitivity can be formed due to the genome instability onset and is a significant risk factor for radiation-induced cancer

  9. Quinine-induced tinnitus in rats.

    Science.gov (United States)

    Jastreboff, P J; Brennan, J F; Sasaki, C T

    1991-10-01

    Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

  10. An evaluation of a hubless inducer and a full flow hydraulic turbine driven inducer boost pump

    Science.gov (United States)

    Lindley, B. K.; Martinson, A. R.

    1971-01-01

    The purpose of the study was to compare the performance of several configurations of hubless inducers with a hydrodynamically similar conventional inducer and to demonstrate the performance of a full flow hydraulic turbine driven inducer boost pump using these inducers. A boost pump of this type consists of an inducer connected to a hydraulic turbine with a high speed rotor located in between. All the flow passes through the inducer, rotor, and hydraulic turbine, then into the main pump. The rotor, which is attached to the main pump shaft, provides the input power to drive the hydraulic turbine which, in turn, drives the inducer. The inducer, rotating at a lower speed, develops the necessary head to prevent rotor cavitation. The rotor speed is consistent with present main engine liquid hydrogen pump designs and the overall boost pump head rise is sufficient to provide adequate main pump suction head. This system would have the potential for operating at lower liquid hydrogen tank pressures.

  11. The transition time induced narrow linewidth of the electromagnetically induced transparency in caesium vapour

    International Nuclear Information System (INIS)

    Li Luming; Peng Xiang; Liu Cheng; Guo Hong; Chen Xuzong

    2004-01-01

    We observed a narrow linewidth (∼60 kHz) in a Doppler-broadened system showing electromagnetically induced transparency in caesium atomic vapour. The transition time induced reduction of the linewidth is illustrated both theoretically and experimentally

  12. Towards inducing superconductivity into graphene

    Science.gov (United States)

    Efetov, Dmitri K.

    Graphenes transport properties have been extensively studied in the 10 years since its discovery in 2004, with ground-breaking experimental observations such as Klein tunneling, fractional quantum Hall effect and Hofstadters butterfly. Though, so far, it turned out to be rather poor on complex correlated electronic ground states and phase transitions, despite various theoretical predictions. The purpose of this thesis is to help understanding the underlying theoretical and experimental reasons for the lack of strong electronic interactions in graphene, and, employing graphenes high tunability and versatility, to identify and alter experimental parameters that could help to induce stronger correlations. In particular graphene holds one last, not yet experimentally discovered prediction, namely exhibiting intrinsic superconductivity. With its vanishingly small Fermi surface at the Dirac point, graphene is a semi-metal with very weak electronic interactions. Though, if it is doped into the metallic regime, where the size of the Fermi surface becomes comparable to the size of the Brillouin zone, the density of states becomes sizeable and electronic interactions are predicted to be dramatically enhanced, resulting in competing correlated ground states such as superconductivity, magnetism and charge density wave formation. Following these predictions, this thesis first describes the creation of metallic graphene at high carrier doping via electrostatic doping techniques based on electrolytic gates. Due to graphenes surface only properties, we are able to induce carrier densities above n>1014 cm-2 (epsilonF>1eV) into the chemically inert graphene. While at these record high carrier densities we yet do not observe superconductivity, we do observe fundamentally altered transport properties as compared to semi-metallic graphene. Here, detailed measurements of the low temperature resistivity reveal that the electron-phonon interactions are governed by a reduced, density

  13. Vaccination with IL-6 analogues induces autoantibodies to IL-6 and influences experimentally induced inflammation

    DEFF Research Database (Denmark)

    Galle, Pia; Jensen, Lene; Andersson, Christina

    2007-01-01

    ; yet they appear healthy and do not exhibit overt clinical or laboratory abnormalities. We induced comparable levels of aAb-IL-6 in different mouse strains by vaccination with immunogenic IL-6 analogues. We observed that the induced aAb-IL-6 protected against collagen-induced arthritis and experimental...

  14. Protective immunity to UV radiation-induced skin tumours induced by skin grafts and epidermal cells

    International Nuclear Information System (INIS)

    Ronald Sluyter; Kylie S Yuen; Gary M Halliday

    2001-01-01

    There is little evidence that cutaneous dendritic cells (DC), including epidermal Langerhans cells (LC), can induce immunity to UV radiation (UVR)-induced skin tumours. Here, it is shown that cells within skin can induce protective antitumour immunity against a UVR-induced fibrosarcoma. Transplantation of the skin overlying subcutaneous tumours onto naive recipients could induce protective antitumour immunity, probably because the grafting stimulated the tumour Ag-loaded DC to migrate to local lymph nodes. This suggests that cutaneous APC can present tumour Ag to induce protective antitumour immunity. Previously, it has been shown that immunization of mice with MHC class II+ epidermal cells (EC) pulsed with tumour extracts could induce delayed-type hypersensitivity against tumour cells. Here, this same immunization protocol could induce protective immunity against a minimum tumorigenic dose of UVR-induced fibrosarcoma cells, but not higher doses. Epidermal cells obtained from semiallogeneic donors and pulsed with tumour extract could also induce protective immunity. However, presentation of BSA Ag from the culture medium was found to contribute to this result using semiallogeneic EC. The results suggest that LC overlying skin tumours may be able to induce protective immunity to UVR-induced tumours if stimulated to migrate from the skin. Copyright (2001) Australasian Society of Immunology Inc

  15. Psychiatric sequelae of induced abortion.

    Science.gov (United States)

    Gibbons, M

    1984-03-01

    An attempt is made to identify and document the problems of comparative evaluation of the more recent studies of psychiatric morbidity after abortion and to determine the current consensus so that when the results of the joint RCGP/RCOG study of the sequelae of induced abortion become available they can be viewed in a more informed context. The legalization of abortion has provided more opportunities for studies of subsequent morbidity. New laws have contributed to the changing attitudes of society, and the increasing acceptability of the operation has probably influenced the occurrence of psychiatric sequelae. The complexity of measuring psychiatric sequelae is evident from the many terms used to describe symptomatology and behavioral patterns and from the number of assessment techniques involved. Numerous techniques have been used to quantify psychiatric sequelae. Several authors conclude that few psychiatric problems follow an induced abortion, but many studies were deficient in methodology, material, or length of follow-up. A British study in 1975 reported a favorable outcome for a "representative sample" of 50 National Health Service patients: 68% of these patients had an absence of or only mild feelings of guilt, loss, or self reproach and considered abortion as the best solution to their problem. The 32% who had an adverse outcome reported moderate to severe feelings of guilt, regret, loss, and self reproach, and there was evidence of mental illness. In most of these cases the adverse outcome was related to the patient's environment since the abortion. A follow-up study of 126 women, which compared the overall reaction to therapeutic abortion between women with a history of previous mild psychiatric illness and those without reported that a significantly different emotional reaction could not be demonstrated between the 2 groups. In a survey among women seeking an abortion 271 who were referred for a psychiatric opinion regarding terminations of pregnancy

  16. Mechanistic review of drug-induced steatohepatitis

    International Nuclear Information System (INIS)

    Schumacher, Justin D.; Guo, Grace L.

    2015-01-01

    Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

  17. Distribution of induced activity in tungsten targets

    International Nuclear Information System (INIS)

    Donahue, R.J.; Nelson, W.R.

    1988-09-01

    Estimates are made of the induced activity created during high-energy electron showers in tungsten, using the EGS4 code. Photon track lengths, neutron yields and spatial profiles of the induced activity are presented. 8 refs., 9 figs., 1 tab

  18. On helicon wave induced radial plasma transport

    International Nuclear Information System (INIS)

    Petrzilka, V.

    1993-04-01

    Estimates of helicon wave induced radial plasma transport are presented. The wave induced transport grows or decreases in dependence on the sign of the azimuthal wave number; these changes in transport may play an important role in helicon wave plasma sources. (author) 5 figs., 18 refs

  19. Induced topological pressure for topological dynamical systems

    International Nuclear Information System (INIS)

    Xing, Zhitao; Chen, Ercai

    2015-01-01

    In this paper, inspired by the article [J. Jaerisch et al., Stochastics Dyn. 14, 1350016, pp. 1-30 (2014)], we introduce the induced topological pressure for a topological dynamical system. In particular, we prove a variational principle for the induced topological pressure

  20. Linking aboveground and belowground inducible plant resistance

    NARCIS (Netherlands)

    Bezemer, T.M.

    2009-01-01

    Induced resistance of plants against pests and diseases via plant defense responses is well documented and can occur aboveground, in the leaves, and belowground in the roots. A number of recent studies have shown that soil-borne pests can also induce plant resistance aboveground and vice versa.

  1. Studies of positron induced luminescence from polymers

    International Nuclear Information System (INIS)

    Xu, J.; Hulett, L.D. Jr.; Lewis, T.A.; Tolk, N.H.

    1994-01-01

    Light emission from polymers (anthracene dissolved in polystryrene) induced by low-energy positrons and electrons has been studied. Results indicate a clear difference between optical emissions under positron and electron bombardment. The positron-induced luminescence spectrum is believed to be generated by both collisional and annihilation processes

  2. Gravitational Zero Point Energy induces Physical Observables

    OpenAIRE

    Garattini, Remo

    2010-01-01

    We consider the contribution of Zero Point Energy on the induced Cosmological Constant and on the induced Electric/Magnetic charge in absence of matter fields. The method is applicable to every spherically symmetric background. Extensions to a generic $f(R) $ theory are also allowed. Only the graviton appears to be fundamental to the determination of Zero Point Energy.

  3. Laughter-induced left bundle branch block.

    Science.gov (United States)

    Chow, Grant V; Desai, Dipan; Spragg, David D; Zakaria, Sammy

    2012-10-01

    We present the case of a patient with ischemic heart disease and intermittent left bundle branch block, reproducibly induced by laughter. Following treatment of ischemia with successful deployment of a drug-eluting stent, no further episodes of inducible LBBB were seen. Transient ischemia, exacerbated by elevated intrathoracic pressure during laughter, may have contributed to onset of this phenomenon. © 2012 Wiley Periodicals, Inc.

  4. Inducible limb-shaking transitory ischemic attacks

    DEFF Research Database (Denmark)

    Rosenbaum, Sverre; Ovesen, Christian; Futrell, Nancy

    2016-01-01

    with exercise-induced weakness associated with tremor in his right arm. His left internal carotid artery was occluded at the bifurcation. Administration of statin and antiplatelet did not relieve his symptoms, and his stereotypic, exercise-induced "limb-shaking" episodes persisted. He underwent successful...

  5. Mechanistic review of drug-induced steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Schumacher, Justin D., E-mail: Justin.d.schumacher@rutgers.edu; Guo, Grace L.

    2015-11-15

    Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

  6. Proton induced X-ray emission analysis

    International Nuclear Information System (INIS)

    Khan, Rashiduzzman

    1976-09-01

    The developments in proton induced X-ray emission analysis are reviewed. Techniques for analyzing thick and thin samples of different origin are described. Discussions on the application of proton induced X-ray emission analysis in different fields, comparison of the sensitivity of this method with other analytical techniques, its limitations and possible improvements are presented

  7. Treatment of lithium induced tremor with atenolol.

    Science.gov (United States)

    Davé, M

    1989-03-01

    This is the first report on the successful treatment of one patient with lithium induced tremor with hydrophilic atenolol, which is a relatively selective beta 1 adrenergic receptor blocker. Atenolol's advantages over lipophilic beta blockers in the treatment of lithium induced tremor are discussed.

  8. Collagen-induced arthritis in mice

    NARCIS (Netherlands)

    Bevaart, Lisette; Vervoordeldonk, Margriet J.; Tak, Paul P.

    2010-01-01

    Collagen-induced arthritis (CIA) in mice is an animal model for rheumatoid arthritis (RA) and can be induced in DBA/1 and C57BL/6 mice using different protocols. The CIA model can be used to unravel mechanisms involved in the development of arthritis and is frequently used to study the effect of new

  9. Uridine prevents fenofibrate-induced fatty liver.

    Directory of Open Access Journals (Sweden)

    Thuc T Le

    Full Text Available Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD and acyl-CoA oxidase 1 (ACOX1, and induces excessive accumulation of long chain fatty acids (LCFA and very long chain fatty acids (VLCFA. Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.

  10. The origin of electromagnetically induced absorption

    International Nuclear Information System (INIS)

    Park, Jong Dae; Hwang, Sung Tae; Lee, Ho Seong; Park, Sung Jong; Cho, Hyuck; Choi, Won Sik

    2000-01-01

    Recently, there have been a lot of interests in the coherence superposition of atomic states which are formed by laser fields. Coherent population trapping(CTP), electromagnetically induced transparency(EIT), enhancement of the refractive index without absorption, lasing without inversion(LWI), and electromagnetically induced absorption(EIA) are the examples where coherence effects are important. Previously, the spontaneous transfer of the light-induced coherence from the excited level to the ground one was emphasized for the essential ingredient for electromagnetically induced absorption. In this paper, we have considered a case where linearly polarized coupling laser and probe laser are applied to the same degenerated ground and excited levels. We have solved the master equations for density matrix using time varying Hamiltonian and studied the absorption spectra at various conditions. We demonstrate that EIA can be observed without spontaneous transfer of the light-induced coherence in F g = 1 -> F e = 2 D2 transitions of Hydrogen atoms

  11. Thalidomide induces apoptosis in undifferentiated human induced pluripotent stem cells.

    Science.gov (United States)

    Tachikawa, Saoko; Nishimura, Toshinobu; Nakauchi, Hiromitsu; Ohnuma, Kiyoshi

    2017-10-01

    Thalidomide, which was formerly available commercially to control the symptoms of morning sickness, is a strong teratogen that causes fetal abnormalities. However, the mechanism of thalidomide teratogenicity is not fully understood; thalidomide toxicity is not apparent in rodents, and the use of human embryos is ethically and technically untenable. In this study, we designed an experimental system featuring human-induced pluripotent stem cells (hiPSCs) to investigate the effects of thalidomide. These cells exhibit the same characteristics as those of epiblasts originating from implanted fertilized ova, which give rise to the fetus. Therefore, theoretically, thalidomide exposure during hiPSC differentiation is equivalent to that in the human fetus. We examined the effects of thalidomide on undifferentiated hiPSCs and early-differentiated hiPSCs cultured in media containing bone morphogenetic protein-4, which correspond, respectively, to epiblast (future fetus) and trophoblast (future extra-embryonic tissue). We found that only the number of undifferentiated cells was reduced. In undifferentiated cells, application of thalidomide increased the number of apoptotic and dead cells at day 2 but not day 4. Application of thalidomide did not affect the cell cycle. Furthermore, immunostaining and flow cytometric analysis revealed that thalidomide exposure had no effect on the expression of specific markers of undifferentiated and early trophectodermal differentiated cells. These results suggest that the effect of thalidomide was successfully detected in our experimental system and that thalidomide eliminated a subpopulation of undifferentiated hiPSCs. This study may help to elucidate the mechanisms underlying thalidomide teratogenicity and reveal potential strategies for safely prescribing this drug to pregnant women.

  12. Diet-induced obesity attenuates endotoxin-induced cognitive deficits.

    Science.gov (United States)

    Setti, Sharay E; Littlefield, Alyssa M; Johnson, Samantha W; Kohman, Rachel A

    2015-03-15

    Activation of the immune system can impair cognitive function, particularly on hippocampus dependent tasks. Several factors such as normal aging and prenatal experiences can modify the severity of these cognitive deficits. One additional factor that may modulate the behavioral response to immune activation is obesity. Prior work has shown that obesity alters the activity of the immune system. Whether diet-induced obesity (DIO) influences the cognitive deficits associated with inflammation is currently unknown. The present study explored whether DIO alters the behavioral response to the bacterial endotoxin, lipopolysaccharide (LPS). Female C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for a total of five months. After consuming their respective diets for four months, mice received an LPS or saline injection and were assessed for alterations in spatial learning. One month later, mice received a second injection of LPS or saline and tissue samples were collected to assess the inflammatory response within the periphery and central nervous system. Results showed that LPS administration impaired spatial learning in the control diet mice, but had no effect in DIO mice. This lack of a cognitive deficit in the DIO female mice is likely due to a blunted inflammatory response within the brain. While cytokine production within the periphery (i.e., plasma, adipose, and spleen) was similar between the DIO and control mice, the DIO mice failed to show an increase in IL-6 and CD74 in the brain following LPS administration. Collectively, these data indicate that DIO can reduce aspects of the neuroinflammatory response as well as blunt the behavioral reaction to an immune challenge. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Saw palmetto-induced pancreatitis.

    Science.gov (United States)

    Jibrin, Ismaila; Erinle, Ayodele; Saidi, Abdulfattah; Aliyu, Zakari Y

    2006-06-01

    Saw palmetto is a frequently used botanical agent in benign prostatic enlargement (BPH). Although it has been reported to cause cholestatic hepatitis and many medical conditions, Saw palmetto has not been implicated in acute pancreatitis. We report a case of a probable Saw palmetto induced acute hepatitis and pancreatitis. A 55-year-old reformed alcoholic, sober for greater than 15 years, presented with severe non-radiating epigastric pain associated with nausea and vomiting. His only significant comorbidity is BPH for which he intermittently took Saw palmetto for about four years. Physical examination revealed normal vital signs, tender epigastrium without guarding or rebound tenderness. Cullen and Gray Turner signs were negative. Complete blood count and basic metabolic profile were normal. Additional laboratory values include a serum amylase: 2,152 mmol/L, lipase: 39,346 mmol/L, serum triglyceride: 38 mmol/L, AST: 1265, ALT: 1232 and alkaline phosphatase was 185. Abdominal ultrasound and magnetic resonance cholangiography revealed sludge without stones. A hepatic indole diacetic acid scan was negative. Patient responded clinically and biochemically to withdrawal of Saw palmetto. Two similar episodes of improvements followed by recurrence were noted with discontinuations and reinstitution of Saw Palmetto. Simultaneous and sustained response of hepatitis and pancreatitis to Saw palmetto abstinence with reoccurrence on reinstitution strongly favors drug effect. "Natural" medicinal preparations are therefore not necessarily safe and the importance of detailed medication history (including "supplements") cannot be over emphasized.

  14. Dipole-induced exchange bias.

    Science.gov (United States)

    Torres, Felipe; Morales, Rafael; Schuller, Ivan K; Kiwi, Miguel

    2017-11-09

    The discovery of dipole-induced exchange bias (EB), switching from negative to positive sign, is reported in systems where the antiferromagnet and the ferromagnet are separated by a paramagnetic spacer (AFM-PM-FM). The magnitude and sign of the EB is determined by the cooling field strength and the PM thickness. The same cooling field yields negative EB for thin spacers, and positive EB for thicker ones. The EB decay profile as a function of the spacer thickness, and the change of sign, are attributed to long-ranged dipole coupling. Our model, which accounts quantitatively for the experimental results, ignores the short range interfacial exchange interactions of the usual EB theories. Instead, it retains solely the long range dipole field that allows for the coupling of the FM and AFM across the PM spacer. The experiments allow for novel switching capabilities of long range EB systems, while the theory allows description of the structures where the FM and AFM are not in atomic contact. The results provide a new approach to design novel interacting heterostructures.

  15. Flow induced vibrations of piping

    International Nuclear Information System (INIS)

    Gibert, R.J.; Axisa, F.

    1977-01-01

    In order to design the supports of piping systems, estimations of the vibrations induced by the fluid conveyed through the pipes are generally needed. For that purpose it is necessary to calculate the model parameters of liquid containing pipes. In most computer codes, fluid effects are accounted for just by adding the fuid mass to the structure. This may lead to serious errors.- Inertial effects from the fluid are not correctly evaluated especially in the case of bended or of non-uniform section pipes. Fluid boundary conditions are simply ignored. - In many practical problems fluid compressibility cannot be negelcted, even in the low frequencies domain which corresponds to efficient excitation by turbulent sources of the flow. This paper presents a method to take into account these efects, by solving a coupled mechanical acoustical problem: the computer code TEDEL of the C.E.A./D.E.M.T. System, based on the finite-elements method, has been extended to calculate simultaneously the pressure fluctuations in the fluid and the vibrations of the pipe. (Auth.)

  16. Pairing induced superconductivity in holography

    Science.gov (United States)

    Bagrov, Andrey; Meszena, Balazs; Schalm, Koenraad

    2014-09-01

    We study pairing induced superconductivity in large N strongly coupled systems at finite density using holography. In the weakly coupled dual gravitational theory the mechanism is conventional BCS theory. An IR hard wall cut-off is included to ensure that we can controllably address the dynamics of a single confined Fermi surface. We address in detail the interplay between the scalar order parameter field and fermion pairing. Adding an explicitly dynamical scalar operator with the same quantum numbers as the fermion-pair, the theory experiences a BCS/BEC crossover controlled by the relative scaling dimensions. We find the novel result that this BCS/BEC crossover exposes resonances in the canonical expectation value of the scalar operator. This occurs not only when the scaling dimension is degenerate with the Cooper pair, but also with that of higher derivative paired operators. We speculate that a proper definition of the order parameter which takes mixing with these operators into account stays finite nevertheless.

  17. Mantle superplumes induce geomagnetic superchrons

    Directory of Open Access Journals (Sweden)

    Peter eOlson

    2015-07-01

    Full Text Available We use polarity reversal systematics from numerical dynamos to quantify the hypothesis that the modulation of geomagnetic reversal frequency, including geomagnetic superchrons, results from changes in core heat flux related to growth and collapse of lower mantle superplumes. We parameterize the reversal frequency sensitivity from numerical dynamos in terms of average core heat flux normalized by the difference between the present-day core heat flux and the core heat flux at geomagnetic superchron onset. A low-order polynomial fit to the 0-300 Ma Geomagnetic Polarity Time Scale (GPTS reveals that a decrease in core heat flux relative to present-day of approximately 30% can account for the Cretaceous Normal Polarity and Kiaman Reverse Polarity Superchrons, whereas the hyper-reversing periods in the Jurassic require a core heat flux equal to or higher than present-day. Possible links between GPTS transitions, large igneous provinces (LIPs, and the two lower mantle superplumes are explored. Lower mantle superplume growth and collapse induce GPTS transitions by increasing and decreasing core heat flux, respectively. Age clusters of major LIPs postdate transitions from hyper-reversing to superchron geodynamo states by 30-60 Myr, suggesting that superchron onset may be contemporaneous with LIP-forming instabilities produced during collapses of lower mantle superplumes.

  18. Chemotherapy-induced sclerosing cholangitis

    Energy Technology Data Exchange (ETDEWEB)

    Sandrasegaran, K.; Alazmi, W.M.; Tann, M.; Fogel, E.L.; McHenry, L.; Lehman, G.A

    2006-08-15

    Aim: To review the computed tomography (CT), magnetic resonance imaging (MRI) and cholangiographic findings of chemotherapy-induced sclerosing cholangitis (CISC). Methods: Between January 1995 and December 2004, 11 patients in the endoscopic retrograde cholangiography database were identified with CISC. Twelve CT, four MRI, 69 endoscopic and nine antegrade cholangiographic studies in these patients were reviewed. Serial change in appearance and response to endoscopic treatment were recorded. Results: CISC showed segmental irregular biliary dilatation with strictures of proximal extrahepatic bile ducts. The distal 5 cm of common bile duct was not affected in any patient. CT and MRI findings included altered vascular perfusion of one or more liver segments, liver metastases or peritoneal carcinomatosis. Biliary strictures needed repeated stenting in 10 patients (mean: every 4.7 months). Cirrhosis (n = 1) or confluent fibrosis (n = 0) were uncommon findings. Conclusion: CISC shares similar cholangiographic appearances to primary sclerosing cholangitis (PSC). Unlike PSC, biliary disease primarily involved ducts at the hepatic porta rather than intrahepatic ducts. Multiphasic contrast-enhanced CT or MRI may show evidence of perfusion abnormalities, cavitary liver lesions, or metastatic disease.

  19. Radiation induced sulfur dioxide removal

    International Nuclear Information System (INIS)

    Chmielewski, A.G.

    2000-01-01

    The biggest source of air pollution is the combustion of fossil fuels, were pollutants such as particulate, sulfur dioxide (SO 2 ), nitrogen oxides (NO x ), and volatile organic compounds (VOC) are emitted. Among these pollutants, sulfur dioxide plays the main role in acidification of the environment. The mechanism of sulfur dioxide transformation in the environment is partly photochemical. This is not direct photooxidation, however, but oxidation through formed radicals. Heterogenic reactions play an important role in this transformation as well; therefore, observations from environmental chemistry can be used in air pollution control engineering. One of the most promising technologies for desulfurization of the flue gases (and simultaneous denitrification) is radiation technology with an electron accelerator application. Contrary to the nitrogen oxides (NO x ) removal processes, which is based on pure radiation induced reactions, sulfur dioxide removal depends on two pathways: a thermochemical reaction in the presence of ammonia/water vapor and a radiation set of radiochemical reactions. The mechanism of these reactions and the consequent technological parameters of the process are discussed in this paper. The industrial application of this radiation technology is being implemented in an industrial pilot plant operated by INCT at EPS Kaweczyn. A full-scale industrial plant is currently in operation in China, and two others are under development in Japan and Poland. (author)

  20. Valproic Acid Induced Hyperammonaemic Encephalopathy

    International Nuclear Information System (INIS)

    Amanat, S.; Shahbaz, N.; Hassan, Y.

    2013-01-01

    Objective: To observe clinical and laboratory features of valproic acid-induced hyperammonaemic encephalopathy in patients taking valproic acid. Methods: Observational study was conducted at the Neurology Department, Dow University of Health Sciences, Civil Hospital, Karachi, from February 26, 2010 to March 20, 2011. Ten patients on valproic acid therapy of any age group with idiopathic or secondary epilepsy, who presented with encephalopathic symptoms, were registered and followed up during the study. Serum ammonia level, serum valproic acid level, liver function test, cerebrospinal fluid examination, electroencephalogram and brain imaging of all the patients were done. Other causes of encephalopathy were excluded after clinical and appropriate laboratory investigations. Microsoft Excel 2007 was used for statistical analysis. Results: Hyperammonaemia was found in all patients with encephalopathic symptoms. Rise in serum ammonia was independent of dose and serum level of valproic acid. Liver function was also found to be normal in 80% (n=8) of the patients. Valproic acid was withdrawn in all patients. Three (30%) patients improved only after the withdrawal of valproic acid. Six (60%) patients improved after L-Carnitine replacement, one (10%) after sodium benzoate. On followup, serum ammonia had reduced to normal in five (50%) patients and to more than half of the baseline level in two (20%) patients. Three (30%) patients were lost to followup after complete clinical improvement. Conclusion: Within therapeutic dose and serum levels, valproic acid can cause symptomatic hyperammonaemia resulting in encephalopathy. All patients taking valproic acid presenting with encephalopathic symptoms must be monitored for the condition. (author)