Abstract WP143: Identification of Socially-Regulated Circulating Microrna Signatures in Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Juneyoung Lee ◽  
Venugopal R Venna ◽  
Louise D McCullough
Keyword(s):  
Mirna Expression ◽  
Protein A ◽  
Fold Increase ◽  
Artery Occlusion ◽  
Mirna Biogenesis ◽  
Circulating Microrna ◽  
Key Enzyme ◽  
Socially Isolated ◽  
Underlying Mechanisms ◽  
Potential Biomarkers

Introduction: Epidemiological and clinical studies strongly support that social isolation (SI) is associated with higher mortality after stroke. SI has been identified as a risk factor in a wide variety of diseases, including stroke. However, few studies have attempted to identify the underlying mechanisms contributing to the detrimental effect of SI. To better understand systemic and global regulation networks governed by social factors, and in an attempt to identify viable biomarkers, we profiled changes in circulating microRNA (miRNA) expression in aged stroke mice after SI. Methods: Aged C57BL/6 mice (18-20 months) of both sexes were pair-housed (PH) or socially isolated (SI) for two weeks prior to sham or a 60-minute middle cerebral artery occlusion surgery. Mice were sacrificed two weeks after surgery and blood samples were obtained for profiling of plasma miRNAs. Using whole miRNAome analysis, differentially expressed miRNAs by isolation, stroke and sex differences were comprehensively identified and compared using bioinformatics. We further used mimic and antagomiR treatments to confirm a potential role of the identified miRNAs. Results: Stroke significantly changed 8 miRNAs including miR-467d-3p ( P =0.0014), miR-376b-3p ( P =0.013) and miR-297c-5p ( P =0.016) in PH groups (sham vs. stroke). In a comparison between PH vs. SI in stroke mice, stroke SI mice showed a differential miRNA profile (11 miRNAs) including let-7 family potentially targeting Dicer protein, a key enzyme for miRNA biogenesis. Interestingly, compared to sham SI mice, stroke SI mice had a 2-fold increase in the number of altered miRNAs (21 miRNAs) including miR-129-1-3p ( P =0.0075), miR-28a-3p ( P =0.0091) and miR-204-5p ( P =0.016). Finally, we found a strong sex difference in miRNA expression in response to SI. Conclusions: We identified several key miRNAs as potential biomarkers for 1) stroke, 2) SI and 3) SI/stroke. These miRNA signatures are highly unique and create a complex gene-regulatory network that depends on the social environment. Our data provide potential biomarkers and identify several miRNAs that could lead to significant improvements in diagnosis of elderly patients at elevated risk for the detrimental effects of loneliness.

scholarly journals MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

2021 ◽  
Vol 7 (3) ◽  
pp. 38
Author(s):  
Alexandra Korotaeva ◽  
Danzan Mansorunov ◽  
Natalya Apanovich ◽  
Anna Kuzevanova ◽  
Alexander Karpukhin
Keyword(s):  
Mirna Expression ◽  
Malignant Tumors ◽  
Neuroendocrine Neoplasms ◽  
Specific Expression ◽  
Clinical Biomarkers ◽  
Different Types ◽  
Functional Features ◽  
First Time ◽  
Potential Biomarkers

Neuroendocrine neoplasms (NEN) are infrequent malignant tumors of a neuroendocrine nature that arise in various organs. They occur most frequently in the lungs, intestines, stomach and pancreas. Molecular diagnostics and prognosis of NEN development are highly relevant. The role of clinical biomarkers can be played by microRNAs (miRNAs). This work is devoted to the analysis of data on miRNA expression in NENs. For the first time, a search for specificity or a community of their functional characteristics in different types of NEN was carried out. Their properties as biomarkers were also analyzed. To date, more than 100 miRNAs have been characterized as differentially expressed and significant for the development of NEN tumors. Only about 10% of the studied miRNAs are expressed in several types of NEN; differential expression of the remaining 90% was found only in tumors of specific localizations. A significant number of miRNAs have been identified as potential biomarkers. However, only a few miRNAs have values that characterized their quality as markers. The analysis demonstrates the predominant specific expression of miRNA in each studied type of NEN. This indicates that miRNA’s functional features are predominantly influenced by the tissue in which they are formed.

Abstract W MP87: PDGF Contributes to BMSC Treatment Induced Neurogenesis and White Matter and Axonal Remodeling in T2DM Stroke Rats

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alex Zacharek ◽  
Tao Yan ◽  
Michael Chopp` ◽  
Poornima Venkat ◽  
Ruizhou Ning ◽  
...  
Keyword(s):  
Cell Migration ◽  
White Matter ◽  
Artery Occlusion ◽  
Border Zone ◽  
Axonal Outgrowth ◽  
Ischemic Brain ◽  
Neuroblast Migration ◽  
Gene And Protein Expression ◽  
Underlying Mechanisms

Objective: Our previous studies have found that bone-marrow-stromal cell (BMSC) treatment of stroke in Type two DM (T2DM) rats, initiated at 3 days after stroke, improved functional recovery. Neurogenesis and white matter (WM) remodeling play an important role in neurorestorative effects after stroke. In this study, we tested whether BMSCs regulate neurogenesis and WM remodeling and the underlying mechanisms of BMSC induced neurorestorative effects in T2DM stroke rats. Methods: T2DM was induced with streptozotocin injection in addition to a high fat diet. T2DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo), then treated with human BMSCs (5X106) or vehicle control (n=8/group) initiated at 3 days after MCAo and rats were monitored for 28 days. Neuroblast migration, WM changes, and gene and protein expression were measured in the ischemic brain. Subventricular zone (SVZ) explant cell migration and primary cortical neuron (PCN) axonal outgrowth measurements were performed in vitro. Results: BMSC treatment in T2DM rats significantly improves functional outcome and increases WM remodeling identified by increased myelin and axonal density. BMSCs also increase the neuroblast migration protein doublecortin (DCX, 25.0±4.3% vs control: 4.5±1.1%), platelet-derived growth factor (PDGF)-AA, and bFGF expression in the ischemic border zone. Angiogenic ELISA array data are consistent with the immunostaining data, showing that BMSC treatment increases PDGF-AA (2.1 fold), PDGF-BB (2.5 fold) and bFGF (1.8 fold) in the ischemic brain. Using an in vitro cell culture model, we found that BMSCs secrete high levels of PDGF. PDGF treatment significantly increases SVZ explant cell migration (1.7 fold) and PCN axonal outgrowth (1.9 fold) compared to non-treatment control. Inhibition of PDGF with neutralized anti-PDGF antibody significantly attenuates BMSC conditioned medium induced SVZ cell migration and PCN axon outgrowth. Conclusion: BMSC treatment of stroke in T2DM increases WM remodeling and neurogenesis as well as increases PDGF expression. PDGF not only promotes neuronal migration, but also increases axonal outgrowth. Therefore, increasing PDGF likely contributes to BMSC induced neurogenesis and WM remodeling in T2DM stroke rats.

Cilioretinal artery occlusion associated with cisplatin

2018 ◽  
Vol 25 (4) ◽  
pp. 969-971 ◽  
Author(s):  
Ali Alkan ◽  
Serap Talaz
Keyword(s):  
Risk Factor ◽  
Rare Complication ◽  
Fold Increase ◽  
Visual Disturbance ◽  
Artery Occlusion ◽  
Important Risk Factor ◽  
Treatment Modalities ◽  
Thromboembolic Events ◽  
Cilioretinal Artery Occlusion ◽  
Cilioretinal Artery

Introduction Cancer is an important risk factor for venous and arterial thromboembolic events. Treatment with chemotherapy was associated with a 6.5-fold increase in the risk of thromboembolic events. Here, we present a patient with cilioretinal artery emboli during cisplatin-based therapy. Case report A 54-year-old male patient with a diagnosis of metastatic small cell carcinoma was under cisplatin-based regimen. He presented with visual disturbance. Retinal fluorescein angiography showed multiple plaques located in cilioretinal artery and cilioretinal artery occlusion. After excluding other potential etiological factors, patient was diagnosed with cilioretinal artery occlusion associated with cisplatin. Discussion In oncology practice, patients are prone to thromboembolic events due to primary disease, underlying comorbidities and treatment modalities. In addition to numerous toxicities, cisplatin is an important risk factor for thromboembolic events. Clinicians caring patients with a diagnosis of cancer should be aware of this rare complication of cisplatin-based therapies.

scholarly journals Saccharomyces cerevisiae ubiquitin-like protein Rub1 conjugates to cullin proteins Rtt101 and Cul3 in vivo

2004 ◽  
Vol 377 (2) ◽  
pp. 459-467 ◽  
Author(s):  
Jose M. LAPLAZA ◽  
Magnolia BOSTICK ◽  
Derek T. SCHOLES ◽  
M. Joan CURCIO ◽  
Judy CALLIS
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein A ◽  
Fold Increase ◽  
Lysine Residue ◽  
Reading Frame ◽  
E3 Ligases ◽  
C Terminus ◽  
Dependent Modification ◽  
F Box Protein

In Saccharomyces cerevisiae, the ubiquitin-like protein Rub1p (related to ubiquitin 1 protein) covalently attaches to the cullin protein Cdc53p (cell division cycle 53 protein), a subunit of a class of ubiquitin E3 ligases named SCF (Skp1–Cdc53–F-box protein) complex. We identified Rtt101p (regulator of Ty transposition 101 protein, where Ty stands for transposon of yeast), initially found during a screen for proteins to confer retrotransposition suppression, and Cul3p (cullin 3 protein), a protein encoded by the previously uncharacterized open reading frame YGR003w, as two new in vivo targets for Rub1p conjugation. These proteins show significant identity with Cdc53p and, therefore, are cullin proteins. Modification of Cul3p is eliminated by deletion of the Rub1p pathway through disruption of either RUB1 or its activating enzyme ENR2/ULA1. The same disruptions in the Rub pathway decreased the percentage of total Rtt101p that is modified from approx. 60 to 30%. This suggests that Rtt101p has an additional RUB1- and ENR2-independent modification. All modified forms of Rtt101p and Cul3p were lost when a single lysine residue in a conserved region near the C-terminus was replaced by an arginine residue. These results suggest that this lysine residue is the site of Rub1p-dependent and -independent modifications in Rtt101p and of Rub1p-dependent modification in Cul3p. An rtt101Δ strain was hypersensitive to thiabendazole, isopropyl (N-3-chlorophenyl) carbamate and methyl methanesulphonate, but rub1Δ strains were not. Whereas rtt101Δ strains exhibited a 14-fold increase in Ty1 transposition, isogenic rub1Δ strains did not show statistically significant increases. Rtt101K791Rp, which cannot be modified, complemented for Rtt101p function in a transposition assay. Altogether, these results suggest that neither the RUB1-dependent nor the RUB1-independent form of Rtt101p is required for Rtt101p function. The identification of additional Rub1p targets in S. cerevisiae suggests an expanded role for Rub in this organism.

scholarly journals GnasR201C Induces Murine Pancreatic Cystic Neoplasms through Suppression of YAP1 Signaling and Transcriptional Reprogramming

2018 ◽  
Author(s):  
Noboru Ideno ◽  
Hiroshi Yamaguchi ◽  
Bidyut Ghosh ◽  
Sonal Gupta ◽  
Takashi Okumura ◽  
...  
Keyword(s):  
Protein A ◽  
Ductal Adenocarcinoma ◽  
Cystic Neoplasms ◽  
Transcriptional Reprogramming ◽  
Kaplan Meier ◽  
Stimulatory G Protein ◽  
Kinase Cascade ◽  
Well Differentiated ◽  
Underlying Mechanisms ◽  
Pancreatic Neoplasia

ABSTRACTBackground & AimsSomatic “hotspot” mutations of GNAS, which encodes for the alpha subunit of stimulatory G-protein, are present in ~60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. There are currently no cognate animal models that recapitulate the biology of mutant Gnas-induced IPMNs, and the underlying mechanisms that lead to the cystic pathway of neoplasia in the pancreas remain unknown.MethodsWe generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras; Gnas mice) where pancreas-specific GnasR201C expression was induced by doxycycline administration. In this model, mutant Kras is constitutively expressed, and control mice were produced through absence of doxycycline. Separate cohorts of mice were utilized for timed necropsies and for Kaplan-Meier survival analysis. Isogenic cell lines (with doxycycline inducible mutant Gnas expression) were propagated from the resulting pancreatic ductal adenocarcinoma (PDAC).ResultsCo-expression of KrasG12D and GnasR201C resulted in the development of pancreatic cystic lesions resembling human IPMNs in 100% of mice, with higher grades of epithelial dysplasia observed over time. Approximately one-third of Kras; Gnas mice developed PDAC at a median of 38 weeks post doxycycline induction. GnasR201C did not accelerate oncogenic transformation with KrasG12D, but rather, reprogrammed Ras-induced neoplasms towards a well-differentiated phenotype. GnasR201C induction led to activation of the inhibitory Hippo kinase cascade and cytoplasmic sequestration of phosphorylated YAP1 protein, a phenomenon that was also observed in human IPMN with GNAS mutations.ConclusionsGNASR201C functions not as a traditional oncogene, but rather as an “oncomodulator” of KRAS-mediated pancreatic neoplasia, through suppression of YAP1 and transcriptional reprogramming towards a differentiated (large ductal) phenotype.

scholarly journals The lectin level and the effect of abscisic acid on hemagglutinating activity during rye germination

2014 ◽  
Vol 58 (3) ◽  
pp. 343-350 ◽  
Author(s):  
Mirosława Ferens-Sieczkowska ◽  
Joanna Karczewska ◽  
Bronisława Morawiecka
Keyword(s):  
Abscisic Acid ◽  
Trace Amount ◽  
Protein A ◽  
Fold Increase ◽  
Hemagglutinating Activity ◽  
Lectin Activity ◽  
Immunological Properties ◽  
Early Germination ◽  
Molecular Masses

As we have previously found, the embryo is the only source of lectin in the mature, dry rye seed. During early germination the lectin activity decreased and most of it was found in the coleoptile. Leaves were found to contain only a trace amount of this protein. A 5-7 fold increase in the amount of lectin was found in grains which had imbibed for 6­12 hours in the presence of 10<sup>-5</sup>M and 10<sup>-4</sup>M ABA. At an ABA concentration of 10<sup>-4</sup>M, about 6 µg of lectin per germ was found even in grains which had been germinating for 5 days. The immunological properties and molecular masses of both RGA and RGA­like lectin accumulated in the presence of ABA were found to be identical.

Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Becca Ward ◽  
Mohammed Abdelsaid ◽  
Tianzheng Yu ◽  
Yisang Yoon ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Proton Channel ◽  
Ros Generation ◽  
Vascular Integrity ◽  
Voltage Gated ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

Expression, phosphorylation and nuclear localization of the human P1 protein, a homologue of the yeast Mcm 3 replication protein

1995 ◽  
Vol 108 (4) ◽  
pp. 1381-1389 ◽  
Author(s):  
D. Schulte ◽  
R. Burkhart ◽  
C. Musahl ◽  
B. Hu ◽  
C. Schlatterer ◽  
...  
Keyword(s):  
Sequence Similarity ◽  
Protein A ◽  
Fold Increase ◽  
S Phase ◽  
Human Protein ◽  
Replication Protein ◽  
High Sequence Similarity ◽  
Central Regions ◽  
Mcm Proteins ◽  
Carboxy Terminal

The human protein P1 belongs to a newly discovered class of mammalian nuclear proteins with high sequence homology to yeast replication proteins. We present the entire amino acid sequence of the human protein P1 as predicted from the cDNA sequence, and show that P1 shares three central regions of high sequence similarity (about 75%) and a highly hydrophilic carboxy-terminal region with the yeast Mcm3 replication protein. The human genome most probably contains one P1 gene which is activated when HeLa cells progress to S phase, as shown by a several-fold increase in P1-specific mRNA. However, the amounts of P1 protein do not detectably change during this period, but P1 protein becomes phosphorylated at the beginning of S phase. In contrast to the yeast Mcm proteins, which disappear from nuclei after initiation of DNA replication, protein P1 remains in the nucleus during and after S phase. P1 is dispersed in mitotic cells and may be excluded from binding to chromosomes.

scholarly journals 2712. Safety and Immunogenicity of two Doses of ExPEC4V Vaccine Against Extraintestinal Pathogenic Escherichia coli Disease in Healthy Adult Participants

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S954-S954
Author(s):  
William B Smith ◽  
Darren Abbanat ◽  
Bart Spiessens ◽  
Oscar Go ◽  
Wouter Haazen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Geometric Mean ◽  
Protein A ◽  
Fold Increase ◽  
Vaccine Safety ◽  
Double Blind Study ◽  
Double Blind ◽  
Grade 3 ◽  
O Antigens

Abstract Background The ExPEC4V vaccine contains 4 Escherichia coli O-antigens (O1A, O2, O6A, O25B) conjugated to exotoxin protein A and is being studied for prevention of Invasive Extraintestinal pathogenic E. coli (ExPEC) Disease (IED). This phase-2 double-blind study assessed safety and immunogenicity of ExPEC4V Clinical Trial Material (CTM), manufactured via a redesigned process (optimized O1A strain). Methods Participants (≥18 years) in stable health were randomized (3:1) to receive ExPEC4V dose 4:4:4:8 μg PS/serotype or placebo on Day 1 and second vaccination on Day 181 (6 months after first vaccination). Participants will be followed for safety until end of study at Day 360. Reactogenicity and immunogenicity (by ELISA, opsonophagocytic killing [OPA] assays) were evaluated pre-vaccination, and 15 days after first and second vaccinations (Day 195). Results Of 100 participants randomized (mean age 56, 48% males) and vaccinated (ExPEC4V, n = 75; placebo, n = 25), 97 completed Day 30. Solicited local AEs were higher for ExPEC4V (38.7%) than placebo (20%); most frequent was pain/tenderness (38.7% vs 20%). Solicited systemic AEs were higher in ExPEC4V (49.3%) than placebo (20%); most frequent was fatigue (32% vs. 12%). No serious or grade 3 solicited local AEs were reported. One participant in ExPEC4V experienced a grade 3 solicited systemic fatigue considered vaccine-related by investigator. ExPEC4V demonstrated immune responses against all serotypes at Day 15. Geometric mean titer effective concentration rank by serotypes was O2 > O1A > O6 > O25B (Figures 1 and 2). At Day 15, ≥ 82% of participants in ExPEC4V and none in placebo had ≥2-fold increase from baseline of ELISA titer for all serotypes. In ExPEC4V, ≥47% had ≥2-fold increase from baseline of OPA titer for all serotypes, while 8% in placebo had ≥2-fold increase only for O6A. Good correlation was observed between ELISA and OPA across serotypes (r ≥ 0.76). Conclusion ExPEC4V elicited robust and functional immune responses across all serotypes and was well tolerated with no vaccine safety findings. This study supports the development of future multivalent ExPEC vaccine to prevent IED. Disclosures All authors: No reported disclosures.

scholarly journals Regulatory Mechanism of MicroRNA Expression in Cancer

2020 ◽  
Vol 21 (5) ◽  
pp. 1723 ◽  
Author(s):  
Zainab Ali Syeda ◽  
Siu Semar Saratu’ Langden ◽  
Choijamts Munkhzul ◽  
Mihye Lee ◽  
Su Jung Song
Keyword(s):  
Molecular Mechanism ◽  
Mirna Expression ◽  
Messenger Rna ◽  
Target Genes ◽  
Regulatory Mechanism ◽  
Physiological Role ◽  
Mirna Biogenesis ◽  
Transcriptional Level ◽  
Detailed Knowledge ◽  
Cancer Pathogenesis

Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3′ UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.

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