scholarly journals Cold stress protein RBM3 responds to hypothermia and is associated with good stroke outcome

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Paulo Ávila-Gómez ◽  
Alba Vieites-Prado ◽  
Antonio Dopico-López ◽  
Saima Bashir ◽  
Héctor Fernández-Susavila ◽  
...  
Keyword(s):  
Body Temperature ◽  
Molecular Marker ◽  
Ischaemic Stroke ◽  
Rna Binding ◽  
Stress Protein ◽  
Brain Regions ◽  
Phase Iii ◽  
Binding Motif ◽  
Stroke Patients ◽  
Ischaemic Brain

Abstract RNA-binding motif protein 3 is a molecular marker of hypothermia that has proved neuroprotective in neurodegenerative disease models. However, its relationship to the well-recognized therapeutic effect of hypothermia in ischaemic stroke had not been studied. In this work, the expression of RNA-binding motif protein 3 was investigated in ischaemic animal models subjected to systemic and focal brain hypothermia, specifically the effects of RNA-binding motif protein 3 silencing and overexpression on ischaemic lesions. Moreover, the association of RNA-binding motif protein 3 levels with body temperature and clinical outcome was evaluated in two independent cohorts of acute ischaemic stroke patients (n = 215); these levels were also determined in a third cohort of 31 patients derived from the phase III EuroHYP-1 trial of therapeutic cooling in ischaemic stroke. The preclinical data confirmed the increase of brain RNA-binding motif protein 3 levels in ischaemic animals subjected to systemic and focal hypothermia; this increase was selectively higher in the cooled hemisphere of animals undergoing focal brain hypothermia, thus confirming the direct effect of hypothermia on RNA-binding motif protein 3 expression, while RNA-binding motif protein 3 up-regulation in ischaemic brain regions led to functional recovery. Clinically, patients with body temperature <37.5°C in the first two cohorts had higher RNA-binding motif protein 3 values at 24 h and good outcome at 3 months post-ischaemic stroke, while RNA-binding motif protein 3 levels in the cooled third cohort tended to exceed those in placebo-treated patients. These results make RNA-binding motif protein 3 a molecular marker associated with the effect of hypothermia in ischaemic stroke and suggest its potential application as a promising protective target.

The expression of the cold shock protein RNA binding motif protein 3 is transcriptionally responsive to organ temperature in mice

2020 ◽  
Vol 27 ◽  
Author(s):  
Ayako Ushio ◽  
Ko Eto
Keyword(s):  
Gene Expression ◽  
Body Temperature ◽  
Rna Binding ◽  
Mild Hypothermia ◽  
Reproductive Organs ◽  
The Body ◽  
Cold Shock Protein ◽  
Binding Motif ◽  
Liver And Kidney ◽  
The Brain

Background: Mild hypothermia, i.e. maintenance of organ temperature by up to 8°C lower than body temperature, is a critical strategy for exerting some functions of the cells and organs normally, and is an useful therapy for recovering properly from some diseases, including myocardial infarction, cardiac arrest, brain injury, and ischemic stroke. Nevertheless, there were no focusses so far on organ temperature and potential responses of gene expression to organ temperature in organs of homeothermic animals that survive under normal conditions. Objective: The present study aimed to assess organ temperature in homeothermic animals and evaluate the effect of their organ temperature on the expression of the cold shock protein RNA binding motif protein 3 (RBM3), and to gain insights into the organ temperature-mediated regulation of RBM3 gene transcription via Nuclear factor β-light-chain-enhancer of activated B cells (NF-κB) p65, which had been identified as a transcription factor that is activated by undergoing the Ser276 phosphorylation and promotes the RBM3 gene expression during mild hypothermia. Methods: We measured the temperature of several organs, where RBM3 expression was examined, in female and male mice. Next, in male mice, we tested NF-κB p65 expression and its Ser276 phosphorylation in organs that have their lower temperature than body temperature and compared them with those in organs that have their temperature near body temperature. Results: Organ temperature was around 32°C in the brain and reproductive organs, which is lower than the body temperature, and around 37°C in the heart, liver, and kidney, which is comparable to the body temperature. The expression of RBM3 was detected greatly in the brain and reproductive organs with their organ temperature of around 32°C, and poorly in the heart, liver, and kidney with their organ temperature of around 37°C. In accordance with the changes in the RBM3 expression, the NF-κB p65 Ser276 phosphorylation was detected more greatly in the testis and brain with their organ temperature of around 32°C, than in the heart, liver, and kidney with their organ temperature of around 37°C, although the NF-κB p65 expression was unchanged among all the organs tested. Discussion: Our data suggested that organ temperature lower than body temperature causes the expression of RBM3 in the brain and reproductive organs of mice, and that lower organ temperature causes the NF-κB p65 activation through the Ser276 phosphorylation, resulting in an increase in the RBM3 gene transcription, in the brain and reproductive organs of mice. Conclusion: The study may present the possibility that organ temperature-induced alterations in gene expression are organ specific in homeotherms and the possibility that organ temperature-induced alterations in gene expression are transcriptionally regulated in some organs of homeotherms.

scholarly journals Platelet-Reactive Antibodies in Patients after Ischaemic Stroke—An Epiphenomenon or a Natural Protective Mechanism

2020 ◽  
Vol 21 (21) ◽  
pp. 8398
Author(s):  
Young Eun Park ◽  
Rushi Penumarthy ◽  
Paul P. Sun ◽  
Caroline Y. Kang ◽  
Marie-Christine Morel-Kopp ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Thrombus Formation ◽  
National Institutes Of Health ◽  
Neurological Dysfunction ◽  
Protective Mechanism ◽  
Stroke Patients ◽  
Neuroprotective Effects ◽  
Platelet Antibodies ◽  
Ischaemic Brain ◽  
Ischaemic Brain Damage

Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations. Using a flow cytometry-based platelet immunofluorescence method, we detected platelet-reactive antibodies in 15 of 48 (31%) stroke patients and two of 50 (4%) controls (p < 0.001). Western blotting revealed heterogeneous reactivities with platelet proteins, some of which overlapped with brain proteins. Stroke patients who carried anti-platelet antibodies presented with larger infarcts and more severe neurological dysfunction, which manifested as higher scores on the National Institutes of Health Stroke Scale (NIHSS; p = 0.009), but they had a greater recovery in the NIHSS by the time of hospital discharge (day 7 ± 2) compared with antibody-negative patients (p = 0.043). Antibodies from stroke sera reacted more strongly with activated platelets (p = 0.031) and inhibited platelet aggregation by up to 30.1 ± 2.8% (p < 0.001), suggesting the potential to interfere with thrombus formation. In conclusion, platelet-reactive antibodies can be found in patients soon after ischaemic stroke and correlate with better short-term outcomes, suggesting a potential novel mechanism limiting thrombosis.

235: The RNA-Binding Protein IMP3: A Novel Molecular Marker Predicts Progression of Superficial (TA and T1) Urothelial Carcinomas of Bladder

2007 ◽  
Vol 177 (4S) ◽  
pp. 78-79
Author(s):  
Lioudmila Sitnikova ◽  
Gary Mendese ◽  
Qin Lui ◽  
Bruce A. Woda ◽  
Di Lu ◽  
...  
Keyword(s):  
Molecular Marker ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Urothelial Carcinomas

scholarly journals The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 883
Author(s):  
Anna Gaertner ◽  
Julia Bloebaum ◽  
Andreas Brodehl ◽  
Baerbel Klauke ◽  
Katharina Sielemann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Early Onset ◽  
Target Genes ◽  
Frameshift Mutation ◽  
Rna Binding ◽  
Splicing Factor ◽  
Binding Motif ◽  
Rich Domain ◽  
Generation Sequencing

A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20.

scholarly journals RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing

Oncogene ◽  
2021 ◽  
Author(s):  
Qiuxia Yan ◽  
Peng Zeng ◽  
Xiuqin Zhou ◽  
Xiaoying Zhao ◽  
Runqiang Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Aerobic Glycolysis ◽  
Histological Grade ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Hnrnp A1

AbstractThe prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

scholarly journals Mechanical thrombectomy in acute ischaemic stroke patients with pre-interventional intracranial haemorrhage following intravenous thrombolysis

2021 ◽  
pp. 197140092110091
Author(s):  
Hanna Styczen ◽  
Matthias Gawlitza ◽  
Nuran Abdullayev ◽  
Alex Brehm ◽  
Carmen Serna-Candel ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Ischaemic Stroke ◽  
Acute Ischaemic Stroke ◽  
Intracranial Haemorrhage ◽  
Mechanical Thrombectomy ◽  
Intravenous Thrombolysis ◽  
Modified Rankin Scale ◽  
Large Vessel Occlusion ◽  
Stroke Patients ◽  
Vessel Occlusion

Background Data on outcome of endovascular treatment in patients with acute ischaemic stroke due to large vessel occlusion suffering from intravenous thrombolysis-associated intracranial haemorrhage prior to mechanical thrombectomy remain scarce. Addressing this subject, we report our multicentre experience. Methods A retrospective analysis of consecutive acute ischaemic stroke patients treated with mechanical thrombectomy due to large vessel occlusion despite the pre-interventional occurrence of intravenous thrombolysis-associated intracranial haemorrhage was performed at five tertiary care centres between January 2010–September 2020. Baseline demographics, aetiology of stroke and intracranial haemorrhage, angiographic outcome assessed by the Thrombolysis in Cerebral Infarction score and clinical outcome evaluated by the modified Rankin Scale at 90 days were recorded. Results In total, six patients were included in the study. Five individuals demonstrated cerebral intraparenchymal haemorrhage on pre-interventional imaging; in one patient additional subdural haematoma was observed and one patient suffered from isolated subarachnoid haemorrhage. All patients except one were treated by the ‘drip-and-ship’ paradigm. Successful reperfusion was achieved in 4/6 (67%) individuals. In 5/6 (83%) patients, the pre-interventional intracranial haemorrhage had aggravated in post-interventional computed tomography with space-occupying effect. Overall, five patients had died during the hospital stay. The clinical outcome of the survivor was modified Rankin Scale=4 at 90 days follow-up. Conclusion Mechanical thrombectomy in patients with intravenous thrombolysis-associated intracranial haemorrhage is technically feasible. The clinical outcome of this subgroup of stroke patients, however, appears to be devastating with high mortality and only carefully selected patients might benefit from endovascular treatment.

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