scholarly journals The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

2017 ◽  
Author(s):  
Christina A. Peixoto ◽  
Ana K.S. Nunes ◽  
Catarina Rapôso
Keyword(s):  
Cgmp Signaling ◽  
Therapeutic Opportunity

scholarly journals HAUSP Stabilizes SOX2 through Deubiquitination to Maintain Self-renewal and Tumorigenic Potential of Glioma Stem Cells

2021 ◽  
Author(s):  
Zhi Huang ◽  
Kui Zhai ◽  
Qiulian Wu ◽  
Xiaoguang Fang ◽  
Qian Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioma Stem Cells ◽  
Posttranslational Regulation ◽  
Malignant Growth ◽  
Self Renewal ◽  
Animal Survival ◽  
Promising Target ◽  
Tumorigenic Potential ◽  
Therapeutic Opportunity

Glioblastoma (GBM) is the most lethal brain tumor containing glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance. The self-renewal and tumorigenic potential of GSCs are maintained by core stem cell transcription factors including SOX2. Defining the posttranslational regulation of SOX2 may offer new insights into GSC biology and potential therapeutic opportunity. Here, we discover that HAUSP stabilizes SOX2 through deubiquitination to maintain GSC self-renewal and tumorigenic potential. HAUSP is preferentially expressed in GSCs in perivascular niches in GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted SOX2 degradation, induced GSC differentiation, impaired GSC tumorigenic potential, and suppressed GBM tumor growth. Importantly, pharmacological inhibition of HAUSP synergized with radiation to inhibit GBM growth and extended animal survival, indicating that targeting HAUSP may overcome GSC-mediated radioresistance. Our findings reveal an unappreciated crucial role of HAUSP in the GSC maintenance and provide a promising target for developing effective anti-GSC therapeutics to improve GBM treatment.

C-type natriuretic peptide inhibits ANP secretion and atrial dynamics in perfused atria: NPR-B-cGMP signaling

2000 ◽  
Vol 278 (1) ◽  
pp. H208-H221 ◽  
Author(s):  
Sook Jeong Lee ◽  
Sung Zoo Kim ◽  
Xun Cui ◽  
Suhn Hee Kim ◽  
Kyung Sun Lee ◽  
...  
Keyword(s):  
Stroke Volume ◽  
Natriuretic Peptide ◽  
Rank Order ◽  
Extracellular Fluid ◽  
Atrial Pacing ◽  
Atrial Myocytes ◽  
Cgmp Production ◽  
Cgmp Signaling ◽  
Intracellular Ca

The purpose of the present experiments was to define the role of C-type natriuretic peptide (CNP) in the regulation of atrial secretion of atrial natriuretic peptide (ANP) and atrial stroke volume. Experiments were performed in perfused beating and nonbeating quiescent atria, single atrial myocytes, and atrial membranes. CNP suppressed in a dose-related fashion the increase in atrial stroke volume and ANP secretion induced by atrial pacing. CNP caused a right shift in the positive relationships between changes in the secretion of ANP and atrial stroke volume or translocation of the extracellular fluid (ECF), which indicates the suppression of atrial myocytic release of ANP into the paracellular space. The effects of CNP on the secretion and contraction were mimicked by 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). CNP increased cGMP production in the perfused atria, and the effects of CNP on the secretion of ANP and atrial dynamics were accentuated by pretreatment with an inhibitor of cGMP phosphodiesterase, zaprinast. An inhibitor of the biological natriuretic peptide receptor (NPR), HS-142-1, attenuated the effects of CNP. The suppression of ANP secretion by CNP and 8-BrcGMP was abolished by a depletion of extracellular Ca2+ in nonbeating atria. Natriuretic peptides increased cGMP production in atrial membranes with a rank order of potency of CNP > BNP > ANP, and the effect was inhibited by HS-142-1. CNP and 8-BrcGMP increased intracellular Ca2+ concentration transients in single atrial myocytes, and mRNAs for CNP and NPR-B were expressed in the rabbit atrium. From these results we conclude that atrial ANP release and stroke volume are controlled by CNP via NPR-B-cGMP mediated signaling, which may in turn act via regulation of intracellular Ca2+.

Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes

2014 ◽  
Vol 104 ◽  
pp. 60-73 ◽  
Author(s):  
Catarina Rapôso ◽  
Rayana Leal de Almeida Luna ◽  
Ana Karolina Santana Nunes ◽  
Rodolfo Thomé ◽  
Christina Alves Peixoto
Keyword(s):  
Cgmp Signaling

Identification of mutation biomarkers underpinning colon cancer sidedness and cetuximab sensitivity.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 629-629
Author(s):  
Timothy Joseph Yeatman ◽  
Mingli Yang ◽  
Michael J. Schell ◽  
Andrey Loboda ◽  
Michael Nebozhyn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Global Gene Expression ◽  
Ras Mutation ◽  
Mutation Status ◽  
Therapeutic Opportunity ◽  
Global Gene Expression Analysis ◽  
Msi Analysis ◽  
Mutant Genes ◽  
Ranking Analysis

629 Background: Currently, extended RAS testing ( KRAS/ NRAS) in colorectal cancer (CRC) patients identifies only non-responders to EGFR inhibitor (EGFRi) therapies, and accurate prediction of drug-sensitive subpopulations remains problematic in patients, even with wild-type RAS. Moreover, the molecular basis for the laterality of anti-EGFR sensitivity is poorly understood. Methods: 468 CRCs were analyzed by global gene expression analysis, DNA sequencing (1321 cancer related genes) and MSI analysis. Tumors were stratified by a validated gene expression cetuximab sensitivity (CTX-S) score, and then correlated with identified high frequency mutations, resulting in a ranking of CTX-S score-associated mutated genes (see Table). Results: Ranking analysis revealed MSI-H status and KRAS mutation as the most negatively-correlated among all patients and MSS patients, respectively. Conversely, APC and TP53 were the most highly positively-correlated mutant genes in both all patient- and MSS-cases. Deeper analysis revealed that the combination of mutant APC + TP53 ( A + P) was more common in left vs. right CRCs (52% vs 21%), and even more pronounced in MSS vs MSI cases (47% vs 2%). CTX-S scores were highest in mutant A + P patients with WT RAS, but surprisingly, were nearly as high in mutant A + P patients with mutant RAS. CRC PDX models validated these results with a favorable CR/PR/SD vs PD association. Conclusions: Here we report the discovery of a cooperative role of APC and TP53 mutations in identifying EGFRi-sensitive CRC subpopulations. Our data suggest that addition of the routine sequencing of APC and TP53 to extended RAS testing may expand the EGFRi therapeutic opportunity (by up to 25%), regardless of RAS mutation status. [Table: see text]

Abstract 348: Inhibition Of Phosphodiesterase 5 Attenuates Angiotensin II-dependent Hypertension And Renal Vascular Dysfunction In C57bl/6 Mice But Not In Enos-Ko Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Manuel Thieme ◽  
Sema Sivritas ◽  
Sebastian A Potthoff ◽  
Evanthia Mergia ◽  
Lars C Rump ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Tone ◽  
Vascular Dysfunction ◽  
Pivotal Role ◽  
Ang Ii ◽  
Cgmp Signaling ◽  
Renal Vascular ◽  
The Impact

The kidney plays an outstanding role in the blood pressure (BP) regulation. The renal vasoconstrictor response to angiotensin (Ang) II is balanced by the NO/cGMP-signalling cascade. Ang II causes hypertension and vascular dysfunction by reducing cGMP sensitivity. Ang II is able to increase cGMP degradation by activating phosphodiesterase (PDE)1 and PDE5. The aim of the present study was to identify the predominant PDE subunit regulating renal blood flow (RBF) and vascular tone during hypertension. Therefore, we tested in vivo effects of acute PDE1 (vinpocetine) and PDE5 (sildenafil) inhibition at baseline and during acute Ang II infusion (200ng/kg/min). Furthermore, we examined the impact of PDE-inhibition on Ang II dependent hypertension (500ng/kg/min; 14 days) and on renal vascular function in the isolated perfused kidney. Acute vinpocetine administration (0.8-800μg/kg BW) showed almost no effect on systemic BP and RBF at baseline and during acute Ang II infusion. In contrast, sildenafil (0.8-800μg/kg BW) significantly decreased BP under baseline conditions. During acute Ang II infusion, BP reduction and RBF increase induced by sildenafil was even more pronounced suggesting a pivotal role of the PDE5 in the regulation of renal vascular tone. Based on these results, we tested whether inhibition of the PDE5 protects from hypertension and vascular dysfunction. Indeed, chronic sildenafil treatment significantly attenuated Ang II dependent hypertension in C57BL/6 (vehicle vs. sil: 156±4 vs. 139±7; p<0.05). Moreover, Sildenafil treatment significantly improved NO-dependent vasorelaxation in kidneys of Ang II- treated C57BL/6. To confirm that PDE5 is activated by an increased NO/cGMP signaling, we used eNOS-KO mice, a model known for decreased NO dependent cGMP generation. In eNOS-KO mice, sildenafil failed to reduce Ang II dependent hypertension (172,4 ± 4,3 mmHg vs. 166,1 ± 3,8 mmHg, p=0,2753) and did not improve vascular dysfunction in Ang II treated kidneys. In summary, the PDE5 is the predominant PDE regulating RBF. Inhibition of PDE5 by sildenafil ameliorates chronic Ang II dependent hypertension and improves vascular dysfunction. This study reveals new evidence for the pivotal role of PDE5 in the pathogenesis of AngII-induced hypertension.

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