scholarly journals Epigallocatechin-3-Gallate Modulates Postoperative Pain by Regulating Biochemical and Molecular Pathways

2021 ◽  
Vol 22 (13) ◽  
pp. 6879
Author(s):  
Rosalba Siracusa ◽  
Francesco Monaco ◽  
Ramona D’Amico ◽  
Tiziana Genovese ◽  
Marika Cordaro ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Thermal Hyperalgesia ◽  
Camp Response Element Binding ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Lumbar Spinal Cord ◽  
Receptor Subtype ◽  
Time Points ◽  
Rich Domain ◽  
Chronic Post Surgical Pain

Treating postoperative (PO) pain is a clinical challenge. Inadequate PO pain management can lead to worse outcomes, for example chronic post-surgical pain. Therefore, acquiring new information on the PO pain mechanism would increase the therapeutic options available. In this paper, we evaluated the role of a natural substance, epigallocatechin-3-gallate (EGCG), on pain and neuroinflammation induced by a surgical procedure in an animal model of PO pain. We performed an incision of the hind paw and EGCG was administered for five days. Mechanical allodynia, thermal hyperalgesia, and motor dysfunction were assessed 24 h, and three and five days after surgery. At the same time points, animals were sacrificed, and sera and lumbar spinal cord tissues were harvested for molecular analysis. EGCG administration significantly alleviated hyperalgesia and allodynia, and reduced motor disfunction. From the molecular point of view, EGCG reduced the activation of the WNT pathway, reducing WNT3a, cysteine-rich domain frizzled (FZ)1 and FZ8 expressions, and both cytosolic and nuclear β-catenin expression, and the noncanonical β-catenin–independent signaling pathways, reducing the activation of the NMDA receptor subtype NR2B (pNR2B), pPKC and cAMP response element-binding protein (pCREB) expressions at all time points. Additionally, EGCG reduced spinal astrocytes and microglia activation, cytokines overexpression and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathway, downregulating inducible nitric oxide synthase (iNOS) activation, cyclooxygenase 2 (COX-2) expression, and prostaglandin E2 (PGE2) levels. Thus, EGCG administration managing the WNT/β-catenin signaling pathways modulates PO pain related neurochemical and inflammatory alterations.

DMSP – Database for Modeling Signaling Pathways

2008 ◽  
Vol 47 (02) ◽  
pp. 104-148
Author(s):  
M. Breit ◽  
B. Pfeifer ◽  
C. Baumgartner ◽  
R. Modre-Osprian ◽  
B. Tilg ◽  
...  
Keyword(s):  
Knowledge Base ◽  
Signaling Pathways ◽  
Protein Interaction ◽  
Initial Step ◽  
Point Of View ◽  
Biological Knowledge ◽  
Literature Study ◽  
Online Databases ◽  
Qualitative Level ◽  
Pathway Models

Summary Objectives: Presently, the protein interaction information concerning different signaling pathways is available in a qualitative manner in different online protein interaction databases. The challenge here is to derive a quantitative way of modeling signaling pathways from qualitative way of modeling signaling pathways from a qualitative level. To address this issue we developed a database that includes mathematical modeling knowledge and biological knowledge about different signaling pathways. Methods: The database is part of an integrative environment that includes environments for pathway design, visualization, simulation and a knowledge base that combines biological and modeling information concerning pathways. The system is designed as a client-server architecture. It contains a pathway designing environment and a simulation environment as upper layers with a relational knowledge base as the underlying layer. Results: DMSP – Database for Modeling Signaling Pathways incorporates biological datasets from online databases like BIND, DIP, PIP, and SPiD. The modeling knowledge that has been incorporated is based on a literature study. Pathway models can be designed, visualized and simulated based on the knowledge stored in the DMSP. The user can download the whole dataset and build pathway models using the knowledge stored in our database. As an example, the TNF? pathway model was implemented and tested using this approach. Conclusion: DMSP is an initial step towards the aim of combining modeling and biological knowledge concerning signaling pathways. It helps in understanding pathways in a qualitative manner from a qualitative level. Simulation results enable the interpretation of a biological system from a quantitative and systemtheoretic point of view.

On the Power of the Object

2017 ◽  
Author(s):  
Liubov Vetoshkina ◽  
Yrjö Engeström ◽  
Annalisa Sannino
Keyword(s):  
Point Of View ◽  
The Political ◽  
Material Objects ◽  
Human Beings ◽  
Work Activities ◽  
Skilled Performance ◽  
Rich Domain ◽  
Boat Building ◽  
Building Activity ◽  
History Of

By skillfully shaping and producing objects human beings externalize and make real their future-oriented imaginaries and visions. Material objects created by skilled performance make human lifeworlds durable. From the point of view of history making, wooden boat building is a particularly rich domain of skilled performance. This chapter is based on two research sites, one in Finland and the other in Russia. The analysis is divided into four layers or threads of history making, namely personal history, the history of the wooden boat community, the political history of the nations and their relations, and the history of the boats themselves as objects of boat-building activity. The chapter ends by discussing our findings and their implications for the understanding of skilled performance and history making in work activities and organizations.

scholarly journals Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

scholarly journals Long Term Effects of Neonatal Hypoglycemia on Muscarinic Receptor Function in the Cerebellum

2017 ◽  
Vol 2 (1) ◽  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Muscarinic Receptor ◽  
Receptor Subtype ◽  
Receptor Function ◽  
Long Term Effects ◽  
Neonatal Hypoglycemia ◽  
Neonatal Stress ◽  
Old Rats

Neonatal stress conditions like hypoglycemia cause brain damage by affecting various signaling pathways thereby causing long term effects on brain functions. A proper understanding of the signaling pathways affected by this stress will help to devise better neonatal care. The focus of the current study was to evaluate the effect of neonatal hypoglycemic insult on cerebellar metabotropic cholinergic receptor function in one month old rats. The receptor analysis of cholinergic muscarinic receptors were done by radioreceptor assays and gene expression was analysed using Real Time PCR. Neonatal hypoglycemia significantly reduced (p<0.001) the cerebellar muscarinic receptor density with a down regulation (p<0.001) of muscarinic M3 receptor subtype gene expression in one month old rats. Both muscarinic M1 and M2 receptor subtype expression were not significantly altered. The catabolic enzyme in acetyl choline metabolism- acetylcholine esterase – showed a significant (p<0.001) up regulation with no siginificant change in the anabolic enzyme – choline acetyl transferase, signifying a change in the turnover ratio. Targeting these pathways at different levels can be exploited to devise better treatment for neonatal stress management and also for diseases with impaired insulin secretion such as diabetes.

scholarly journals A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3400
Author(s):  
Barbara Bellei ◽  
Emilia Migliano ◽  
Mauro Picardo
Keyword(s):  
Signaling Pathways ◽  
Tumor Stroma ◽  
Malignant Cell ◽  
Point Of View ◽  
Cell Populations ◽  
Oncogenic Signaling ◽  
Stromal Microenvironment ◽  
Extracellular Matrix Components ◽  
Promising Avenue ◽  
Melanoma Therapy

The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. Thus, melanomagenesis is not only driven by malignant melanocytes, but also by the altered communication between melanocytes and non-malignant cell populations, including fibroblasts, endothelial and immune cells. In particular, cancer-associated fibroblasts (CAFs), also referred as melanoma-associated fibroblasts (MAFs) in the case of melanoma, are the most abundant stromal cells and play a significant contextual role in melanoma initiation, progression and metastasis. As a result of dynamic intercellular molecular dialogue between tumor and the stroma, non-neoplastic cells gain specific phenotypes and functions that are pro-tumorigenic. Targeting MAFs is thus considered a promising avenue to improve melanoma therapy. Growing evidence demonstrates that aberrant regulation of oncogenic signaling is not restricted to transformed cells but also occurs in MAFs. However, in some cases, signaling pathways present opposite regulation in melanoma and surrounding area, suggesting that therapeutic strategies need to carefully consider the tumor–stroma equilibrium. In this novel review, we analyze four major signaling pathways implicated in melanomagenesis, TGF-β, MAPK, Wnt/β-catenin and Hyppo signaling, from the complementary point of view of tumor cells and the microenvironment.

scholarly journals Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Natalia Malek ◽  
Mateusz Kucharczyk ◽  
Katarzyna Starowicz
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mrna Level ◽  
Inhibitory Effect ◽  
Lumbar Spinal Cord ◽  
Local Synthesis ◽  
Time Points ◽  
Pain Pathways ◽  
Lumbar Spinal ◽  
Synthesis And Degradation

Endocannabinoids (EC), particularly anandamide (AEA), released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs) and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI). All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development.

Tel-PDGFβR Specifically Induces Interferon-Stimulated Genes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1213-1213
Author(s):  
Hani Kim ◽  
Dwayne L. Barber
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Bone Marrow ◽  
Fusion Protein ◽  
Signaling Pathways ◽  
Bone Marrow Cells ◽  
Chromosomal Translocations ◽  
Time Points ◽  
Interferon Stimulated Genes ◽  
Marrow Cells

Abstract Chromosomal translocations involving tyrosine kinases play a significant role in human leukemia. Chronic myeloid leukemia (CML) is associated with the recurrent chromosomal translocation, BCR-ABL (t(9;22)(q34;q11)). Chronic myelomonocytic leukemia (CMML) is linked to TEL-PDGF-β Receptor (PDGFβR) (t(5;12)(q33;p13)) fusion. Another TEL fusion, TEL-JAK2 (t(9;12)(p24;p13) has been observed in CMML and Acute Lymphoid Leukemia. All three fusion proteins induce leukemia-like diseases in animal models, and this is attributed to the constitutive tyrosine kinase activity, which leads to dysregulation of their respective downstream signaling pathways. The downstream targets include STAT transcription factors, MAP kinases, and PI3 kinase. On the other hand, little is known about the gene transcription regulated by these fusions. The objective of our study is to determine whether BCR-ABL, TEL-PDGFβR and TEL-JAK2 induce distinct gene expression patterns when expressed in cell lines and retrovirally transduced bone marrow cells. Each fusion was expressed in an IL3-dependent murine myeloid cell line, Ba/F3. The specific inhibitor, Imatinib mesylate, was utilized to control the activation/inhibition of BCR-ABL and TEL-PDGFβR, and an inducible system was utilized for TEL-JAK2. Upon activation of the fusion protein, cells were collected at various time-points for cell cycle and microarray analysis (Affymetrix MOE430A). We utilized 8 hr, 12 hr, 24 hr and 1 wk time points. Our rationale was to monitor gene expression changes through the first cell cycle and then to examine the fingerprint at a steady state point. Analysis of the 1 wk data reveals that a subset of genes are co-regulated (2-fold, p&lt;0.05) by BCR-ABL, TEL-PDGFβR and TEL-JAK2 (Pim1, Id1b, Podxl, Cxcr4, Gp49b and Scin). Interestingly, analysis of the TEL-PDGFβR induced genes (10-fold, p&lt;0.05) revealed a significant overlap with Interferon-Stimulated Gene (ISG) dataset including Cxcl-10, Gbp1, Gbp2, Isg20, Ccl-5, Stat1, Irf7, Serpine-1 and Mx1. Genes identified in this microarray study have been confirmed by Q-PCR in Ba/F3 cells and confirmatory experiments in primary bone marrow cells transduced with each fusion protein are underway. In addition, we will determine whether the transcription of these targets is dependent on STAT1 by utilizing bone marrow cells from STAT1−/− mice. In conclusion, our data reveals that oncogenic chromosomal translocations activate both distinct and co-regulated gene expression and reveal a novel and specific role of Interferon-Stimulated Genes in signaling pathways downstream of TEL-PDGFβR.

Analysis of Changes in Endothelial Cell Protein Expression and Phosphorylation Induced by Cleaved High Molecular Weight Kininogen

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5195-5195
Author(s):  
Venkaiah Betapudi ◽  
Keith R. McCrae
Keyword(s):  
Molecular Weight ◽  
Endothelial Cells ◽  
Protein Expression ◽  
Signaling Pathways ◽  
High Molecular Weight ◽  
Tissue Remodeling ◽  
High Molecular Weight Kininogen ◽  
Time Points ◽  
Rapid Changes ◽  
In Cells

Abstract Abstract 5195 Background and objective: High molecular weight kininogen (HK) is an abundant plasma protein that functions as a critical cofactor in the kallikrein-kinin system. HK normally circulates in the single chain form, but is cleaved by plasma kallikrein to release the nonapeptide bradykinin and form cleaved high molecular weight kininogen (HKa) that consists of a heavy and light chain linked by a single disulfide bond. Conformational changes occurring in cleaved kininogen result in increased exposure of histidine and glycine-rich regions within kininogen domain 5 that impart HKa with unique properties, including the ability to inhibit angiogenesis by causing selective apoptosis of proliferating endothelial cells. However, neither the receptors that mediate the antiangiogenic activity of HKa nor the signaling pathways that lead to apoptosis have been rigorously defined. In this study we attempted to define specific signaling pathways activated following exposure of proliferating endothelial cells to HKa using a high-throughput, unbiased, microarray approach (Kinexus, Vancouver BC). Results: Endothelial cells were cultured at low density and stimulated to proliferate using 20 ng/ml bFGF in the absence or presence of HKa (15 nM). At various time points (20, 60 and 300 minutes) total cell extracts were prepared and analyzed using the Kinexus antibody microarray that includes 530 pan-specific and 270 phospho-site specific antibodies. In cells exposed to HKa, the analysis revealed increased expression of 109, 141 and 162 proteins, and decreased expression of 117, 68 and 59 proteins at the 20 min, 60 min, and 300 minute time points, respectively. In cells exposed to HKa, the number of newly-phosphorylated proteins increased from 30 at 20 minutes to 61 at 300 minutes after HKa treatment. Segregation of proteins whose expression level and/or phosphorylation state changed following exposure of cells to HKa into families demonstrated that HKa primarily targets protein kinases (61–70% of all proteins affected at the various time points), transcription factors (8–11%), and phosphatases (4–5%). Increased expression of several proteins involved in apoptosis, such as caspases 4, 6 and 7 and DNA fragmentation factors 35 and 45, and increased phosphorylation of stress regulated activating transcription factor 2 (ATF2) and apoptosis signal regulating protein kinase1 (ASK1) were evident within 20 minutes of exposure of cells to HKa. Metacore and Ingenuity pathway analysis of proteins that exhibited rapid changes in expression or phosphorylation revealed activation of several major signaling pathways including apoptosis, DNA damage response, angiogenesis, inflammation, and tissue remodeling and wound repair. Conclusion: Exposure of proliferating endothelial cells to HKa led to rapid changes in protein expression and phosphorylation. Most remarkable was the increased expression of several caspases within 20 minutes of addition of HKa to cells. Patterns of protein expression were consistent with activation of several pathways related to apoptosis, inflammation and tissue remodeling. These findings support suspected physiological functions of HK/HKa in vivo, and suggest specific proteins that may be targeted to further dissect effects of HKa on discrete cellular functions. Disclosures: No relevant conflicts of interest to declare.

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