scholarly journals MicroRNA-92a negatively regulates neurofibromin 2 and inhibits its tumor suppressive function

2018 ◽  
Author(s):  
Krizelle Mae M. Alcantara ◽  
Reynaldo L. Garcia
Keyword(s):  
Neurofibromatosis Type ◽  
Apoptosis Resistance ◽  
Lung Cancers ◽  
Actin Organization ◽  
Protein Levels ◽  
Evolutionarily Conserved ◽  
Tumor Suppressive Function ◽  
Hct116 Cells

ABSTRACTInactivation of the tumor suppressor Merlin leads to the development of benign nervous system tumors of neurofibromatosis type 2. Merlin deficiency is also observed in human malignancies including colorectal and lung cancers. Causes of Merlin inactivation include deleterious mutations in the encoding neurofibromin 2 gene (NF2) and aberrant Merlin proteasomal degradation. Here, we show that NF2 is also regulated by microRNAs (miRNAs) through interaction with evolutionarily conserved miRNA response elements (MREs) within its 3’-untranslated region (3‘UTR). Dual luciferase assays in HCT116 and A549 show downregulation of wild type NF2 by miR-92a via its 3’UTR but not NF2-3’UTR with mutated MRE. HCT116 cells transfected with miR-92a show significant downregulation of endogenous NF2 mRNA and protein levels, which were rescued by co-transfection of a target protector oligonucelotide specific for the miR-92a binding site within NF2-3’UTR. MiR-92a overexpression in HCT116 and A549 resulted in increased migration and proliferation, apoptosis resistance, and altered F-actin organization compared to controls. This study provides functional proof of the unappreciated role of miRNAs in NF2 regulation and tumor progression.

scholarly journals EXPRESS: Pulmonary Hypertension Associated With Neurofibromatosis Type 2

2021 ◽  
pp. 204589402110295
Author(s):  
Hirohisa Taniguchi ◽  
Tomoya Takashima ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Asuka Furukawa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neurofibromatosis Type ◽  
Pulmonary Vascular Remodeling ◽  
Life Threatening ◽  
History Of ◽  
Pulmonary Arterial ◽  
First Time

Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from IPAH patients compared to control lungs, suggesting a potential role of NF2 in PAH development. To our knowledge, this is the first time that precapillary PH has been described in a patient with NF2. The altered endothelial NF2 expression pattern in PAH lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodeling associated to these severe life-threatening conditions.

Neurofibromatosis type 2: growth stimulation of mixed acoustic schwannoma by concurrent adjacent meningioma: possible role of growth factors

1998 ◽  
Vol 89 (1) ◽  
pp. 149-154 ◽  
Author(s):  
Roberto Pallini ◽  
Angelo Tancredi ◽  
Patrizia Casalbore ◽  
Delio Mercanti ◽  
Luigi M. Larocca ◽  
...  
Keyword(s):  
Neurofibromatosis Type ◽  
Growth Stimulation ◽  
Neurofibromatosis Type 2 ◽  
Annual Growth Rate ◽  
Content Type ◽  
Acoustic Schwannoma ◽  
Epidermal Growth ◽  
The One

✓ The authors report the case of a young man suffering from neurofibromatosis type 2 (NF2) who harbored bilateral acoustic schwannomas and a parasellar meningioma. Neuroimaging studies performed during a 4-year follow-up period showed that the bilateral schwannomas had grown very little and at similar rates. However, after the meningioma had infiltrated the tentorium and approached the ipsilateral schwannoma at the incisura, both Schwann cell tumors started to grow rapidly, particularly the one adjacent to the meningioma, of which the percentage of annual growth rate increased by approximately a factor of 102. At the same time, magnetic resonance imaging showed that this tumor also changed its features. During surgery, the acoustic schwannoma was firmly adherent to both meningioma and tentorium. Histological examination revealed meningotheliomatous cells in the schwannoma adjacent to the meningioma. Antiphosphotyrosine immunoblotting of PC12 cells was compatible with the presence of an epidermal growth factor (EGF)—like molecule in the cerebrospinal fluid (CSF) of the patient. This factor was not detected in the CSF of five other NF2 patients, two of whom bore associated bilateral acoustic schwannomas and meningioma in remote locations. It is hypothesized that the meningotheliomatous cells infiltrating the schwannoma triggered an autocrine/paracrine growth—stimulatory mechanism that involved an EGF-like factor.

scholarly journals The Plasmatic Aldosterone and C-Reactive Protein Levels, and the Severity of Covid-19: The Dyhor-19 Study

2020 ◽  
Vol 9 (7) ◽  
pp. 2315 ◽  
Author(s):  
Orianne Villard ◽  
David Morquin ◽  
Nicolas Molinari ◽  
Isabelle Raingeard ◽  
Nicolas Nagot ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Clinical Course ◽  
Clinical Status ◽  
Plasma Renin ◽  
Ordinal Scale ◽  
C Reactive Protein ◽  
Protein Levels ◽  
Reactive Protein

Background. The new coronavirus SARS-CoV-2, responsible for the Covid-19 pandemic, uses the angiotensin converting enzyme type 2 (ACE2), a physiological inhibitor of the renin angiotensin aldosterone system (RAAS), as a cellular receptor to infect cells. Since the RAAS can induce and modulate pro-inflammatory responses, it could play a key role in the pathophysiology of Covid-19. Thus, we aimed to determine the levels of plasma renin and aldosterone as indicators of RAAS activation in a series of consecutively admitted patients for Covid-19 in our clinic. Methods. Plasma renin and aldosterone levels were measured, among the miscellaneous investigations needed for Covid-19 management, early after admission in our clinic. Disease severity was assessed using a seven-category ordinal scale. Primary outcome of interest was the severity of patients’ clinical courses. Results. Forty-four patients were included. At inclusion, 12 patients had mild clinical status, 25 moderate clinical status and 7 severe clinical status. In univariate analyses, aldosterone and C-reactive protein (CRP) levels at inclusion were significantly higher in patients with severe clinical course as compared to those with mild or moderate course (p < 0.01 and p = 0.03, respectively). In multivariate analyses, only aldosterone and CRP levels remained positively associated with severity. We also observed a positive significant correlation between aldosterone and CRP levels among patients with an aldosterone level greater than 102.5 pmol/L. Conclusions. Both plasmatic aldosterone and CRP levels at inclusion are associated with the clinical course of Covid-19. Our findings may open new perspectives in the understanding of the possible role of RAAS for Covid-19 outcome.

Cortisol-mediated potentiation of uterine artery contractility: effect of pregnancy

2002 ◽  
Vol 283 (1) ◽  
pp. H238-H246 ◽  
Author(s):  
Daliao Xiao ◽  
Xiaohui Huang ◽  
Soochan Bae ◽  
Charles A. Ducsay ◽  
Lubo Zhang
Keyword(s):  
Uterine Artery ◽  
Vascular Reactivity ◽  
Maternal Plasma ◽  
Apparent Dissociation Constant ◽  
Protein Levels ◽  
No Release ◽  
Endothelial Nitric Oxide

During pregnancy, maternal plasma cortisol concentrations approximately double. Given that cortisol plays an important role in the regulation of vascular reactivity, the present study investigated the potential role of cortisol in potentiation of uterine artery (UA) contractility and tested the hypothesis that pregnancy downregulated the cortisol-mediated potentiation. In vitro cortisol treatment (3, 10, or 30 ng/ml for 24 h) produced a dose-dependent increase in norepinephrine (NE)-induced contractions in both nonpregnant and pregnant (138–143 days gestation) sheep UA. However, this cortisol-mediated response was significantly attenuated by ∼50% in pregnant UA. The 11β-hydroxysteroid dehydrogenase (11-βHSD) inhibitor carbenoxolone did not change the effect of cortisol in nonpregnant UA but abolished its effect in pregnant UA by increasing the NE pD2 in control tissues from 6.20 ± 0.05 to 6.59 ± 0.11. The apparent dissociation constant value of NE α1-adrenoceptors was not changed by cortisol in pregnant UA but was decreased in nonpregnant UA. There was no difference in glucocorticoid receptor density between nonpregnant and pregnant UA. Cortisol significantly decreased endothelial nitric oxide (NO) synthase protein levels and NO release in both nonpregnant and pregnant UA, but the effect of cortisol was attenuated in pregnant UA by ∼50%. Carbenoxolone alone had no effects on NO release in nonpregnant UA but was decreased in pregnant UA. These results suggest that cortisol potentiates NE-mediated contractions by decreasing NO release and increasing NE-binding affinity to α1-adrenoceptors in nonpregnant UA. Pregnancy attenuates UA sensitivity to cortisol, which may be mediated by increasing type-2 11-βHSD activity in UA.

scholarly journals Focus on the Role of NLRP3 Inflammasome in Diseases

2020 ◽  
Vol 21 (12) ◽  
pp. 4223 ◽  
Author(s):  
Roberta Fusco ◽  
Rosalba Siracusa ◽  
Tiziana Genovese ◽  
Salvatore Cuzzocrea ◽  
Rosanna Di Paola
Keyword(s):  
Immune System ◽  
Nlrp3 Inflammasome ◽  
Neurologic Disorders ◽  
Evolutionarily Conserved ◽  
The Family ◽  
Bowel Diseases ◽  
Protective Reaction ◽  
Inflammatory Bowel

Inflammation is a protective reaction activated in response to detrimental stimuli, such as dead cells, irritants or pathogens, by the evolutionarily conserved immune system and is regulated by the host. The inflammasomes are recognized as innate immune system sensors and receptors that manage the activation of caspase-1 and stimulate inflammation response. They have been associated with several inflammatory disorders. The NLRP3 inflammasome is the most well characterized. It is so called because NLRP3 belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent evidence has greatly improved our understanding of the mechanisms by which the NLRP3 inflammasome is activated. Additionally, increasing data in animal models, supported by human studies, strongly implicate the involvement of the inflammasome in the initiation or progression of disorders with a high impact on public health, such as metabolic pathologies (obesity, type 2 diabetes, atherosclerosis), cardiovascular diseases (ischemic and non-ischemic heart disease), inflammatory issues (liver diseases, inflammatory bowel diseases, gut microbiome, rheumatoid arthritis) and neurologic disorders (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurological disorders), compared to other molecular platforms. This review will provide a focus on the available knowledge about the NLRP3 inflammasome role in these pathologies and describe the balance between the activation of the harmful and beneficial inflammasome so that new therapies can be created for patients with these diseases.

Reduced expression of renal Na+ transporters in rats with PTH-induced hypercalcemia

2004 ◽  
Vol 286 (3) ◽  
pp. F534-F545 ◽  
Author(s):  
Weidong Wang ◽  
Chunling Li ◽  
Tae-Hwan Kwon ◽  
R. Tyler Miller ◽  
Mark A. Knepper ◽  
...  
Keyword(s):  
Fractional Excretion ◽  
Urinary Concentration ◽  
High Dose ◽  
Thick Ascending Limb ◽  
Urinary Osmolality ◽  
Protein Levels ◽  
Severe Hypercalcemia ◽  
Type 3

The purpose of this study was to evaluate whether the natriuresis and polyuria seen in parathyroid hormone (PTH)-induced hypercalcemia are associated with dysregulation of renal Na transporters. Rats were infused with three different doses of human PTH [PTH ( 1 - 34 ); 7.5, 10, and 15 μg·kg-1·day-1 sc] or vehicle for 48 h using osmotic minipumps. The rats treated with PTH developed significant hypercalcemia (plasma total calcium levels: 2.71 ± 0.03, 2.77 ± 0.02, and 3.42 ± 0.06 mmol/l, respectively, P < 0.05 compared with corresponding controls). The rats with severe hypercalcemia induced by high-dose PTH developed a decreased glomerular filtration rate (GFR), increased urine output, reduced urinary osmolality, increased urinary Na excretion, and fractional excretion of Na. This was associated with downregulation (calculated as a fraction of control levels) of whole kidney expression of type 2 Na-Pi cotransporter (NaPi-2; 16 ± 6%), type 3 Na/H exchanger (NHE3; 42 ± 7%), Na-K-ATPase (55 ± 2%), and bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1; 25 ± 4%). In contrast, an upregulation of the Ca2+-sensing receptor (CaR) was observed. Rats treated with moderate-dose PTH exhibited unchanged GFR but decreased urinary concentration. The whole kidney expression of NHE3 (52 ± 8%) and NaPi-2 (26 ± 5%) was persistently decreased, whereas BSC-1 and Na-K-ATPase protein levels were not altered. CaR expression was also increased. Moreover, rats treated with low-dose PTH showed very mild hypercalcemia but unchanged GFR, normal urinary concentration, and unchanged expression of Na transporters and CaR. In conclusion, the reduced expression of major renal Na transporters is likely to play a role in the increased urinary Na excretion and decreased urinary concentration in rats with PTH-induced hypercalcemia. Moreover, the increase in the CaR in the thick ascending limb (TAL) may indicate a potential role of the CaR in inhibiting Na transport in the TAL.

scholarly journals PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ji-Eun Kim ◽  
Duk-Shin Lee ◽  
Tae-Hyun Kim ◽  
Hana Park ◽  
Min-Ju Kim ◽  
...  
Keyword(s):  
Neurofibromatosis Type ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Dependent Manner ◽  
Filamentous Actin ◽  
Murine Double Minute ◽  
Underlying Mechanisms ◽  
Activity Dependent

AbstractNeurofibromin 2 (NF2, also known as merlin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. NF2 is also an actin-binding protein that functions in an intrinsic signaling network critical for actin dynamics. Although protein kinase A (PKA)-mediated NF2-serin (S) 10 phosphorylation stabilizes filamentous actin (F-actin), the underlying mechanisms of NF2-S10 dephosphorylation and the role of NF2 in seizures have been elusive. Here, we demonstrate that pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) dephosphorylated NF2-S10 site as well as cofilin-S3 site. In addition, NF2-S10 dephosphorylation reversely regulated murine double minute-2 (Mdm2) and postsynaptic density 95 (PSD95) degradations in an activity-dependent manner, which increased seizure intensity and its progression in response to kainic acid (KA). In addition, NF2 knockdown facilitated seizure intensity and its progress through F-actin instability independent of cofilin-mediated actin dynamics. Therefore, we suggest that PLPP/CIN may be a potential therapeutic target for epileptogenesis and NF2-associated diseases.

scholarly journals MOLECULAR CYTOGENETIC STUDY OF THE NF2 GENE DELETION IN MENINGIOMA IN SUDANESE PATIENTS

2013 ◽  
Vol 16 (2) ◽  
pp. 29-32 ◽  
Author(s):  
Y. AbdElmontalab Farah ◽  
I. Fadl Elmula ◽  
Hm. Abushama ◽  
K. Kreskowski ◽  
T. Liehr
Keyword(s):  
Cytogenetic Study ◽  
Chromosomal Rearrangements ◽  
Neurofibromatosis Type ◽  
Suppressor Gene ◽  
Central Nervous System Tumor ◽  
Nf2 Gene ◽  
System Tumor

ABSTRACT Meningioma is the second most common adult central nervous system tumor. Mutations and/or deletions within the tumor suppressor gene neurofibromatosis type 2 (NF2) are associated with meningioma development and progression. We studied 29 meningioma samples by cytogenetic analysis and interphase fluorescence in situ hybridization (I-FISH) using a locus-specific probe for the NF2 gene region. We detected loss of the NF2 gene in all samples except for one. In 10 of the 29 samples, karyotypic analyses confirmed the I-FISH results and revealed additional numerical and/or structural rearrangements in nine of them. Our study confirmed: i) the limited role of banding cytogenetics in assessing chromosomal rearrangements in meningioma, as this tumor is hard to be grown in cell culture; ii) we could show that two-color I-FISH is well-suited for NF2-deletion screening. Our results were in accordance with those of comparable studies, even though the frequency of 97.0% of meningiomas with NF2 deletions is exceptionally high in the studied Sudanese patients

scholarly journals Generally applicable transcriptome-wide analysis of translation using anota2seq

2019 ◽  
Vol 47 (12) ◽  
pp. e70-e70 ◽  
Author(s):  
Christian Oertlin ◽  
Julie Lorent ◽  
Carl Murie ◽  
Luc Furic ◽  
Ivan Topisirovic ◽  
...  
Keyword(s):  
Translational Control ◽  
Gene Expression Regulation ◽  
Neurological Diseases ◽  
Mrna Translation ◽  
Protein Levels ◽  
Pathological Conditions ◽  
Evolutionarily Conserved ◽  
Statistical Identification ◽  
Advance Knowledge

Abstract mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated contributes to various disorders including metabolic and neurological diseases and cancer. Notwithstanding that optimal and universally applicable methods are critical for understanding the complex role of translational control under physiological and pathological conditions, approaches to analyze translatomes are largely underdeveloped. To address this, we developed the anota2seq algorithm which outperforms current methods for statistical identification of changes in translation. Notably, in contrast to available analytical methods, anota2seq also allows specific identification of an underappreciated mode of gene expression regulation whereby translation acts as a buffering mechanism which maintains protein levels despite fluctuations in corresponding mRNA abundance (‘translational buffering’). Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes which is anticipated to advance knowledge regarding the role of translation in homeostasis and disease.

scholarly journals Neurofibromatosis type 2: growth stimulation of mixed acoustic schwannoma by concurrent adjacent meningioma: possible role of growth factors

1998 ◽  
Vol 4 (4) ◽  
pp. E11
Author(s):  
Roberto Pallini ◽  
Angelo Tancredi ◽  
Patrizia Casalbore ◽  
Delio Mercanti ◽  
Luigi M. Larocca ◽  
...  
Keyword(s):  
Neurofibromatosis Type ◽  
Growth Stimulation ◽  
Neurofibromatosis Type 2 ◽  
Annual Growth Rate ◽  
Acoustic Schwannoma ◽  
Epidermal Growth ◽  
The One

The authors report the case of a young man suffering from neurofibromatosis type 2 (NF2) who harbored bilateral acoustic schwannomas and a parasellar meningioma. Neuroimaging studies performed during a 4-year follow-up period showed that the bilateral schwannomas had grown very little and at similar rates. However, after the meningioma had infiltrated the tentorium and approached the ipsilateral schwannoma at the incisura, both Schwann cell tumors started to grow rapidly, particularly the one adjacent to the meningioma, of which the percentage of annual growth rate increased by approximately a factor of 102. At the same time, magnetic resonance imaging showed that this tumor also changed its features. During surgery, the acoustic schwannoma was firmly adherent to both meningioma and tentorium. Histological examination revealed meningotheliomatous cells in the schwannoma adjacent to the meningioma. Antiphosphotyrosine immunoblotting of PC12 cells was compatible with the presence of an epidermal growth factor (EGF)-like molecule in the cerebrospinal fluid (CSF) of the patient. This factor was not detected in the CSF of five other NF2 patients, two of whom bore associated bilateral acoustic schwannomas and meningioma in remote locations. It is hypothesized that the meningotheliomatous cells infiltrating the schwannoma triggered an autocrine/paracrine growth-stimulatory mechanism that involved an EGF-like factor.

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