scholarly journals Red Blood Cells-Coupled tPA Prevents Impairment of Cerebral Vasodilatory Responses and Tissue Injury in Pediatric Cerebral Hypoxia/Ischemia through Inhibition of ERK MAPK Activation

2009 ◽  
Vol 29 (8) ◽  
pp. 1463-1474 ◽  
Author(s):  
William M Armstead ◽  
Kumkum Ganguly ◽  
John W Kiessling ◽  
Xiao-Han Chen ◽  
Douglas H Smith ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Neuronal Degeneration ◽  
Tissue Injury ◽  
Mapk Pathway ◽  
Fibrinolytic Therapy ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Type ◽  
Erk Mapk ◽  
Novel Approach

Babies experience hypoxia (H) and ischemia (I) from stroke. The only approved treatment for stroke is fibrinolytic therapy with tissue-type plasminogen activator (tPA). However, tPA potentiates H/I-induced impairment of responses to cerebrovasodilators such as hypercapnia and hypotension, and blockade of tPA-mediated vasoactivity prevents this deleterious effect. Coupling of tPA to red blood cells (RBCs) reduces its central nervous system (CNS) toxicity through spatially confining the drug to the vasculature. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, is upregulated after H/I. In this study we determined whether RBC-tPA given before or after cerebral H/I would preserve responses to cerebrovasodilators and prevent neuronal injury mediated through the extracellular signal-related kinase (ERK) MAPK pathway. Animals given RBC-tPA maintained responses to cerebrovasodilators at levels equivalent to pre-H/I values. cerebrospinal fluid and brain parenchymal ERK MAPK was elevated by H/I and this upregulation was potentiated by tPA, but blunted by RBC-tPA. U0126, an ERK MAPK antagonist, also maintained cerebrovasodilation post H/I. Neuronal degeneration in CA1 hippocampus after H/I was not improved by tPA, but was ameliorated by RBC-tPA and U0126. These data suggest that coupling of tPA to RBCs offers a novel approach toward increasing the benefit/risk ratio of thrombolytic therapy for CNS disorders associated with H/I.

scholarly journals The p38/MK2 Axis in Monocytes of Fibromyalgia Syndrome Patients: An Explorative Study

Medicina ◽  
2021 ◽  
Vol 57 (4) ◽  
pp. 396
Author(s):  
Boya Nugraha ◽  
Renate Scheibe ◽  
Christoph Korallus ◽  
Matthias Gaestel ◽  
Christoph Gutenbrunner
Keyword(s):  
Pain Management ◽  
P38 Mapk ◽  
Fibromyalgia Syndrome ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Pain Syndromes ◽  
Novel Approach ◽  
Mitogen Activated Protein ◽  
The Mean ◽  
Direct Target

Background and Objectives: The aetiology and pathomechanism of fibromyalgia syndrome 12 (FMS) as one of chronic pain syndromes still need to be further elucidated. Mitogen-activated protein kinase (MAPK) pathway has been proposed as a novel approach in pain management. Since the major symptom of fibromyalgia syndrome (FMS) patients is pain, it became of interest whether MAPK pathways, such as the stress-activated p38 MAPK/MK2 axis, are activated in FMS patients. Therefore, this study aimed at determining p38 MAPK/MK2 in FMS patients. Materials and Methods: Phosphorylation of MAPK-activated protein kinases 2 (MK2), a direct target of p38 MAPK, was measured in monocytes of FMS and healthy controls (HCs) to monitor the activity of this pathway. Results: The mean level of phosphorylated MK2 was fivefold higher in FMS patients as compared to HCs (p < 0.001). Subgroup analysis revealed that antidepressants did not influence the activity of MK2 in FMS patients. Conclusions: This result indicates that the p38/MK2 pathway could be involved in the pathomechanism of FMS, could act as a clinical marker for FMS, and could be a possible target for pain management in FMS patients.

Abstract 2579: tPA Contributes To Aggravation of Endothelin and Thromboxane Induced Cerebrovasoconstriction After Hypoxia/Ischemia Through Upregulation of ERK MAPK

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
William Armstead ◽  
Heather Kaczynski ◽  
John Riley ◽  
Douglas Cines ◽  
Abd Al-Roof Higazi
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Tissue Type ◽  
Cranial Window ◽  
Pial Artery ◽  
Erk Mapk ◽  
Cerebral Vasoconstriction ◽  
Type Plasminogen Activator ◽  
Hypoxia Ischemia ◽  
Mitogen Activated Protein ◽  
Global Increase

Introduction: The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after hypoxia/ischemia (H/I) in pigs. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to vasodilator impairment. Impairment of stimulus induced vasodilation may result from tonic withdrawal and/or impairment of a vasodilator influence or upregulation of a vasoconstrictor. This study examined the effect of H/I on the vascular response to two important spasmogens released during CNS ischemic disorders, endothelin-1 (ET-1) and thromboxane, and the influence of tPA and ERK MAPK in such responses. Methods: Cerebral ischemia (20 min) was induced via global increase in intracranial pressure via saline infusion into a hollow bolt placed in the cranium (dura intact) while hypoxia (10 min, pO2 35 mm Hg) was produced by decreasing the inspired O2 via inhalation of N2. Vascular responses to topical ET-1 (10-10, 10-8 M) and U 46619 (1, 10 ng/ml) were obtained at 1h post insult. Phosphorylated and total ERK MAPK were measured by ELISA in the CSF of piglets equipped with a closed cranial window. Data (n=5) were analyzed by ANOVA, with significance at p less than 0.05. Results: H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimic U 46619, which was blocked by EEIIMD, an inhibitor of PAI-1’s vascular activity and signaling of tPA, but not its fibrinolytic action, but unchanged by its inactive analogue EEIIMR. CSF ERK MAPK was increased by H/I and potentiated by tPA. The ERK MAPK antagonist U 0126 blocked H/I induced aggravation of ET-1 and U 46619 vasoconstriction. Discussion: These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction through upregulation of tPA and ERK MAPK. These data suggest that thrombolytic therapy for treatment of CNS ischemic disorders can dysregulate cerebrohemodynamics by augmenting vasoconstriction induced by spasmogens co-released during CNS pathology.

scholarly journals Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder

2021 ◽  
Author(s):  
Shinsuke Oda ◽  
Masayoshi Fujisawa ◽  
Li Chunning ◽  
Toshihiro Ito ◽  
Takahiro Yamaguchi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Cancer Progression ◽  
Mapk Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Ki67 Index ◽  
Erk Activation ◽  
Non Invasive ◽  
Erk Mapk

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 negatively regulates cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

scholarly journals Centrifugation-free washing: A novel approach for removing immunoglobulin A from stored red blood cells

2018 ◽  
Vol 93 (4) ◽  
pp. 518-526 ◽  
Author(s):  
Eszter Vörös ◽  
Nathaniel Z. Piety ◽  
Briony C. Strachan ◽  
Madeleine Lu ◽  
Sergey S. Shevkoplyas
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Immunoglobulin A ◽  
Novel Approach

scholarly journals miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells

2020 ◽  
Vol 29 ◽  
pp. 096368972096246
Author(s):  
Chuhai Xie ◽  
Shengyao Liu ◽  
Boyi Wu ◽  
Yu Zhao ◽  
Binwei Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mapk Pathway ◽  
Biological Effects ◽  
Rapid Development ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Erk Mapk

Osteosarcoma is an aggressive malignancy with rapid development and poor prognosis. microRNA-19 (miR-19) plays an important role in several biological processes. Sprouty-related EVH1 domain protein 2 (SPRED2) is a suppressor of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling to inhibit tumor development and progression by promoting autophagy. In this study, we investigated the roles of miR-19, SPRED2, and autophagy in osteosarcoma. We detected the expression of miR-19, SPRED2, epithelial–mesenchymal transition (EMT) markers, and autophagy-related proteins via quantitative real-time polymerase chain reaction or western blot. To evaluate the function of miR-19 and SPRED2, we used MTT and colony formation assays to detect cell proliferation, Transwell, and wound-healing assays to detect cell invasion and migration. Targetscan and luciferase reporter assays confirmed the relationship between SPRED2 and miR-19. The expression of miR-19 was significantly upregulated in osteosarcoma, while SPRED2 was downregulated. miR-19 inhibitor reduced cell proliferation, invasion, migration, and EMT, while its cell biological effects were partially reversed by addition of autophagy inhibitor 3-methyladenine (3-MA) or SPRED2 siRNA in osteosarcoma. SPRED2, a suppressor of ERK/MAPK pathway that is known to trigger autophagy, was identified as a direct target of miR-19. SPRED2 overexpression increased cell proliferation, invasion, migration, and EMT by promoting autophagy, and the effects could be inhibited by 3-MA. Collectively, these findings reveal an underlying mechanism for development of osteosarcoma. miR-19 was upregulated in osteosarcoma cells, and negatively regulated SPRED2, thus promoting the malignant transformation of osteosarcoma cells via inhibiting SPRED2-induced autophagy. Therefore, miR-19/SPRED2 may be a potential target for the treatment of osteosarcoma.

scholarly journals Selective Hole Filling of Red Blood Cells for Improved Marker-Controlled Watershed Segmentation

Scanning ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Fatih Veysel Nurçin ◽  
Elbrus Imanov
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Human Error ◽  
Local Minimum ◽  
Machine Learning Algorithms ◽  
Watershed Segmentation ◽  
Hole Filling ◽  
Novel Approach ◽  
Manual Counting ◽  
Background Segmentation

Manual counting and evaluation of red blood cells with the presence of malaria parasites is a tiresome, time-consuming process that can be altered by environmental conditions and human error. Many algorithms were presented to segment red blood cells for subsequent parasitemia evaluation by machine learning algorithms. However, the segmentation of overlapping red blood cells always has been a challenge. Marker-controlled watershed segmentation is one of the methods that was implemented to separate overlapping red blood cells. However, a high number of overlapped red blood cells were still an issue. We propose a novel approach to improve the segmentation efficiency of marker-controlled watershed segmentation. Local minimum histogram background segmentation with a selective hole filling algorithm was introduced to improve segmentation efficiency of marker-controlled watershed segmentation on a high number of overlapping red blood cells. The local minimum was selected on the smoothed histogram for background segmentation. The combination of selective filling, convex hull, and Hough circle detection algorithms was utilized for the intact segmentation of red blood cells. The markers were computed from the resulted mask, and finally, marker-controlled watershed segmentation was applied to separate overlapping red blood cells. As a result, the proposed algorithm achieved higher background segmentation accuracy compared to popular background segmentation algorithms, and the inclusion of corner details improved watershed segmentation efficiency.

Investigation of the Role of Heme Oxygenase 1 During Erythroid Differentiation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1997-1997
Author(s):  
Daniel Garcia dos Santos ◽  
Jesse Eisenberg ◽  
Matthias Schranzhofer ◽  
Jose Artur Bogo Chies ◽  
Prem Ponka
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Conflicts Of Interest ◽  
Tissue Injury ◽  
Physiological Mechanism ◽  
Erythroid Differentiation ◽  
The Body ◽  
Erythroid Cell ◽  
Heme Oxygenase 1 ◽  
Erythroid Cells

Abstract Abstract 1997 Poster Board I-1019 Heme is a complex of iron with protoporphyrin IX that is essential for the function of all aerobic cells. However, if left unguarded, non-protein-bound heme promotes free radical formation, resulting in cell damage and tissue injury. The highest amounts of organismal heme (75-80%) are present in circulating red blood cells (RBC) whose precursors synthesize heme with rates that are at least 1 order of magnitude higher than those in the liver (on the per cell basis), which is the second most active heme producer in the body. The only physiological mechanism of heme degradation is by heme oxygenases (HO1 and HO2) that catalyze the rate-limiting step in the oxidative degradation of heme and are, therefore, involved in the control of cellular heme levels. Red blood cells contain the majority of heme destined for catabolism; this process takes place in splenic and hepatic macrophages following erythrophagocytosis of senescent RBC. Although the heme-inducible HO isoform, HO1, has been extensively studied in hepatocytes and many other non-erythroid cells, virtually nothing is known about the expression of HO1 in developing RBC. Similarly, it is unknown whether HO1 plays any role in erythroid cell development under physiological or pathophysiological conditions. In this study we have shown that HO1 protein is expressed in uninduced murine erythroleukemic (MEL) cells and that its levels, somewhat surprisingly, do not decrease during DMSO-induced erythroid differentiation. Moreover, we demonstrated that heme significantly induces HO1 in both uninduced and induced MEL cells. Additionally, we investigated the effect of sodium arsenite (NaAsO2), HO1 inducer, on heme and iron metabolism in MEL cells induced to erythroid differentiation. MEL cells treated with NaAsO2 displayed a significant reduction in globin expression and increased ferritin levels. Moreover, NaAsO2treatment decreased levels of transferrin receptor in cell membranes. These effects triggered by NaAsO2 could be prevented by the addiction of tin-protophorphyrin (SnPP), HO1 activity inhibitor. Using a siRNA specifically targeting HO1, we observed an increase in globin expression together with a small decrease in the expressin of ferritin in DMSO-induced MEL cells. These results suggest that an as yet unknown mechanism exists to protect heme against endogenous HO1 action during erythroid differentiation. In summary, our results showing that NaAsO2-induced HO1 in erythroid cells cause a defect in erythroid differentiation suggest that HO1 could play a role in some pathophysiological conditions such as thalassemias. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document