scholarly journals EPH/EPHRIN SIGNALING CONTROLS PROGENITOR IDENTITIES IN THE VENTRAL SPINAL CORD

2016 ◽  
Author(s):  
Julien Laussu ◽  
Christophe Audouard ◽  
Anthony Kischel ◽  
Poincyane Assis-Nascimento ◽  
Nathalie Escalas ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Cell Communication ◽  
Dependent Manner ◽  
Eph Receptors ◽  
Loss Of Function ◽  
Summary Statement ◽  
Dose Dependent ◽  
Ventral Spinal Cord

SUMMARY STATEMENTThis article by Laussu et al. describes a role for Eph:ephrin signaling in controlling the identity of neural progenitors in the ventral spinal cord.Early specification of progenitors of the ventral spinal cord involves the morphogen Sonic Hedgehog which induces distinct progenitor identities in a dose-dependent manner. Following these initial patterning events, progenitor identities have to be maintained in order to generate appropriate numbers of progeny. Here we provide evidence that communication via Eph:ephrin signaling is required to maintain progenitor identities in the ventral spinal cord. We show that ephrinB2 and ephrinB3 are expressed in restricted progenitor domains in the ventral spinal cord while several Eph receptors are more broadly expressed. Further, we provide evidence that expression of Efnb3 and EphA4 is controlled by Shh. Genetic loss-of-function analyses indicate that expression of ephrinB2 and ephrinB3 is required to control progenitor identities and in vitro experiments reveal that activation of Eph forward signaling in spinal progenitors up-regulates the expression of the identity transcription factor Nkx2.2. Altogether our results indicate that cell-to-cell communication is necessary to control progenitor identity in the ventral spinal cord.

GFI1 Is a Tumor Suppressor in Myeloid Progenitors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2942-2942
Author(s):  
Aditya Chaubey ◽  
Shane Hormon ◽  
Chinavenmeni S. Velu ◽  
Tristan Bourdeau ◽  
Jinfang Zhu ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Myeloid Leukemia ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Increased Risk ◽  
Myeloid Leukemias ◽  
Dose Dependent ◽  
Anterior Posterior

Abstract In severe congenital neutropenia (SCN) patients and mice with Growth factor independent-1 (Gfi1) loss of function, arrested progenitors are suspended in a hyperproliferative state while terminal granulpoiesis is blocked. SCN patients are at increased risk for the development of acute myeloid leukemia. We demonstrate that Gfi1 directly targets HoxA9, Pbx1 and Meis1 during normal myelopoiesis. Gfi1−/− progenitors exhibit elevated levels of HoxA9, Pbx1 and Meis1, exaggerated HoxA9-Pbx1-Meis1 activity, and increased persistence in vivo and in vitro. Limiting HoxA9 alleles corrects, in a dose dependent manner, in vivo and in vitro phenotypes observed with loss of Gfi1. Moreover, in a manner conserved in Drosophila anterior/posterior patterning, we demonstrate that these factors can compete for occupancy of DNA sequences encoding composite Gfi1-HoxA9-Pbx1-Meis1 binding sites. Finally, the expression of Gfi1 and HoxA9 are inverse and stratify human myeloid leukemias, suggesting a role for HoxA9- Gfi1 antagonism in human AML. In agreement with this, a myeloproliferative disorder progresses into a rapid, lethal and transplantable myeloid leukemia in a Gfi1−/− setting. We conclude that the lifespan and oncogenic transformation of hematopoietic progenitor cells is regulated through a conserved competition between Gfi1 and HoxA9-Pbx1-Meis1.

scholarly journals Compound Phyllanthus urinaria L Inhibits HBV-Related HCC through HBx-SHH Pathway Axis Inactivation

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Yun Li ◽  
Mingjie Jiang ◽  
Mingshun Li ◽  
Yingjie Chen ◽  
Chunshan Wei ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Sonic Hedgehog ◽  
Dependent Manner ◽  
Shh Pathway ◽  
Phyllanthus Urinaria ◽  
Gli 1 ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Dose Dependent

Compound Phyllanthus urinaria L (CP) is a traditional formula widely used in clinical practice for hepatocellular carcinoma (HCC), especially HBV-related HCC. HBx, HBV X gene encoded X protein, has positive correlation with the abnormal SHH pathway in HBV-related HCC. So, we predicted that CP has the capability of anti-HBV-related HCC maybe via inactivating the HBx-Hedgehog pathway axis. HepG2-HBx cells, HBx overexpression, were treated with CP (70μg/ml and 35 μg/ml, respectively) for 48 hours and the mice which received the HepG2-HBx cells were treated with CP (625mg/kg and 300 mg/kg, respectively) for 17 days to evaluate the effect of CP on HBV-related HCC. HBx could accelerate HepG2 cells proliferation, clone formation, and migration in vitro and also could strengthen tumor growth in mice. However, CP could significantly decrease HepG2-HBx cells proliferation, clone formation, and migration in vitro and also could inhibit tumors growth in mice in a dose-dependent manner. Mechanism studies suggested that HBx upregulated the mRNA and proteins expression of Sonic hedgehog (SHH), transmembrane receptor patched (PTCH-1), smoothened (SMO), oncogene homolog transcription factors-1 (GLI-1), and oncogene homolog transcription factors-2 (GLI-2), which are compositions of the SHH pathway. CP could inhibit the mRNA and proteins expression of SHH, PTCH-1, GLI-1, and HBx. It may be one of the underlying mechanisms of CP to delay the HBV-related HCC development through the HBx-SHH pathway axis inactivation.

scholarly journals Gfi1 integrates progenitor versus granulocytic transcriptional programming

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5466-5475 ◽  
Author(s):  
Shane R. Horman ◽  
Chinavenmeni S. Velu ◽  
Aditya Chaubey ◽  
Tristan Bourdeau ◽  
Jinfang Zhu ◽  
...  
Keyword(s):  
Dependent Manner ◽  
Loss Of Function ◽  
Lineage Specification ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Dose Dependent ◽  
Transcription Program ◽  
Myeloid Progenitors

AbstractIn patients with severe congenital neutropenia (SCN) and mice with growth factor independent-1 (Gfi1) loss of function, arrested myeloid progenitors accumulate, whereas terminal granulopoiesis is blocked. One might assume that Gfi-null progenitors accumulate because they lack the ability to differentiate. Instead, our data indicate that Gfi1 loss of function deregulates 2 separable transcriptional programs, one of which controls the accumulation and lineage specification of myeloid progenitors, but not terminal granulopoiesis. We demonstrate that Gfi1 directly represses HoxA9, Pbx1, and Meis1 during normal myelopoiesis. Gfi1−/− progenitors exhibit elevated levels of HoxA9, Pbx1 and Meis1, exaggerated HoxA9-Pbx1-Meis1 activity, and progenitor transformation in collaboration with oncogenic K-Ras. Limiting HoxA9 alleles corrects, in a dose-dependent manner, in vivo and in vitro phenotypes observed with loss of Gfi1 in myeloid progenitor cells but did not rescue Gfi1−/− blocked granulopoiesis. Thus, Gfi1 integrates 2 events during normal myeloid differentiation; the suppression of a HoxA9-Pbx1-Meis1 progenitor program and the induction of a granulopoietic transcription program.

Oxygenation of 18-hydroxycorticosterone as the final reaction for aldosterone biosynthesis

1984 ◽  
Vol 107 (3) ◽  
pp. 395-400 ◽  
Author(s):  
Itaru Kojima ◽  
Etsuro Ogata ◽  
Hiroshi Inano ◽  
Bun-ichi Tamaoki
Keyword(s):  
Carbon Monoxide ◽  
Hydroxysteroid Dehydrogenase ◽  
Dependent Manner ◽  
In Vitro Production ◽  
Mitochondrial Preparation ◽  
Final Reaction ◽  
Vitro Production ◽  
Dose Dependent ◽  
Cytochrome P 450

Abstract. Incubation of 18-hydroxycorticosterone with the sonicated mitochondrial preparation of bovine adrenal glomerulosa tissue leads to the production of aldosterone, as measured by radioimmunoassay. The in vitro production of aldosterone from 18-hydroxycorticosterone requires both molecular oxygen and NADPH, and is inhibited by carbon monoxide. Cytochrome P-450 inhibitors such as metyrapone, SU 8000. SU 10603, SKF 525A, amphenone B and spironolactone decrease the biosynthesis of aldosterone from 18-hydroxycorticosterone. These results support the conclusion that the final reaction in aldosterone synthesis from 18-hydroxycorticosterone is catalyzed by an oxygenase, but not by 18-hydroxysteroid dehydrogenase. By the same preparation, the production of [3H]aldosterone but not [3H]18-hydroxycorticosterone from [1,2-3H ]corticosterone is decreased in a dose-dependent manner by addition of non-radioactive 18-hydroxycorticosterone.

Appraisal of Immunological Impacts of Melaleuca leucadendra Extract over Macrophage Performance in Vitro

2020 ◽  
Keyword(s):  
Nitric Oxide ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Reduced Pressure ◽  
Medical Plant ◽  
Dose Dependent ◽  
Level Production ◽  
Melaleuca Leucadendra ◽  
Phagocytic Killing

This trial research was performed to discuss the immune-influence of Melaleuca leucadendra ‘paper-bark tree’ dried leaves which is an important medical plant known in many regions in the world. The leaves were dissolved in a mixture of (ethanol + water) (3:1) mixture, then filtered, evaporated and dried under reduced pressure to obtain leaves extract. The macrophages of blood derived origin were provided from rats and mixed with three different leaves extracts doses in tissue culture plates and incubated then stained with fluorescent acridine orange and examined under fluorescent microscope to assess the phagocytic and killing potency. The wells contents were aspirated and assayed for nitric oxide and interleukin-2 levels. The results displayed an obvious increase in phagocytic, killing performance as well as nitric oxide and IL-2 level production than control in a dose dependent manner. The obtained results suggested the immune-stimulant impact of the paper-bark tree leaves.

Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro

2001 ◽  
Vol 91 (6) ◽  
pp. 2703-2712 ◽  
Author(s):  
Stephen M. Johnson ◽  
Julia E. R. Wilkerson ◽  
Daniel R. Henderson ◽  
Michael R. Wenninger ◽  
Gordon S. Mitchell
Keyword(s):  
Brain Stem ◽  
Respiratory Activity ◽  
Dependent Manner ◽  
Frequency Increase ◽  
Burst Frequency ◽  
Bath Application ◽  
Burst Amplitude ◽  
Dose Dependent ◽  
The Brain

Brain stem preparations from adult turtles were used to determine how bath-applied serotonin (5-HT) alters respiration-related hypoglossal activity in a mature vertebrate. 5-HT (5–20 μM) reversibly decreased integrated burst amplitude by ∼45% ( P < 0.05); burst frequency decreased in a dose-dependent manner with 20 μM abolishing bursts in 9 of 13 preparations ( P < 0.05). These 5-HT-dependent effects were mimicked by application of a 5-HT1A agonist, but not a 5-HT1B agonist, and were abolished by the broad-spectrum 5-HT antagonist, methiothepin. During 5-HT (20 μM) washout, frequency rebounded to levels above the original baseline for 40 min ( P < 0.05) and remained above baseline for 2 h. A 5-HT3 antagonist (tropesitron) blocked the post-5-HT rebound and persistent frequency increase. A 5-HT3 agonist (phenylbiguanide) increased frequency during and after bath application ( P < 0.05). When phenylbiguanide was applied to the brain stem of brain stem/spinal cord preparations, there was a persistent frequency increase ( P < 0.05), but neither spinal-expiratory nor -inspiratory burst amplitude were altered. The 5-HT3receptor-dependent persistent frequency increase represents a unique model of plasticity in vertebrate rhythm generation.

scholarly journals Antifungal activity of dendritic cell lysosomal proteins against Cryptococcus neoformans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Benjamin N. Nelson ◽  
Savannah G. Beakley ◽  
Sierra Posey ◽  
Brittney Conn ◽  
Emma Maritz ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Mammalian Cells ◽  
Cysteine Proteases ◽  
Dependent Manner ◽  
Life Threatening ◽  
Opportunistic Fungal Pathogen ◽  
Dose Dependent ◽  
Lysosomal Proteins

AbstractCryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans. Previous studies have shown that the fungus is phagocytosed by dendritic cells (DCs) and trafficked to the lysosome where it is killed by both oxidative and non-oxidative mechanisms. While certain molecules from the lysosome are known to kill or inhibit the growth of C. neoformans, the lysosome is an organelle containing many different proteins and enzymes that are designed to degrade phagocytosed material. We hypothesized that multiple lysosomal components, including cysteine proteases and antimicrobial peptides, could inhibit the growth of C. neoformans. Our study identified the contents of the DC lysosome and examined the anti-cryptococcal properties of different proteins found within the lysosome. Results showed several DC lysosomal proteins affected the growth of C. neoformans in vitro. The proteins that killed or inhibited the fungus did so in a dose-dependent manner. Furthermore, the concentration of protein needed for cryptococcal inhibition was found to be non-cytotoxic to mammalian cells. These data show that many DC lysosomal proteins have antifungal activity and have potential as immune-based therapeutics.

scholarly journals Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuxing Shen ◽  
Chao Wu ◽  
Meng Lei ◽  
Qing Yan ◽  
Haoyang Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Serum Enzyme ◽  
Herg Channels ◽  
Anti Tumor Activity ◽  
Dose Dependent

AbstractCarfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

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