scholarly journals Characterization and Validation of Arg286 Residue of IL-1RAcP as a Potential Drug Target for Osteoarthritis

2021 ◽  
Vol 8 ◽  
Author(s):  
Angela Dailing ◽  
Kelsey Mitchell ◽  
Ngoc Vuong ◽  
Kyung Hyeon Lee ◽  
Reva Joshi ◽  
...  
Keyword(s):  
Complex Formation ◽  
Cell Model ◽  
Interaction Network ◽  
Inflammatory Cells ◽  
High Energy ◽  
Downstream Signaling ◽  
Chronic Disability ◽  
Native Sequence ◽  
A Cell ◽  
Complex Architecture

Osteoarthritis (OA) is the most common form of arthritis and the fastest growing cause of chronic disability in the world. Formation of the ternary IL-1β /IL-1R1/IL-1RAcP protein complex and its downstream signaling has been implicated in osteoarthritis pathology. Current OA therapeutic approaches target either the cytokine IL-1β or the primary receptor IL-1RI but do not exploit the potential of the secondary receptor IL-1RAcP. Our previous work implicated the Arg286 residue of IL-1RAcP as a key mediator of complex formation. Molecular modeling confirmed Arg286 as a high-energy mediator of the ternary IL-1β complex architecture and interaction network. Anti-IL-1RAcP monoclonal antibodies (mAb) targeting the Arg286 residue were created and were shown to effectively reduce the influx of inflammatory cells to damaged joints in a mouse model of osteoarthritis. Inhibitory peptides based on the native sequence of IL-1RAcP were prepared and examined for efficacy at disrupting the complex formation. The most potent peptide inhibitor had an IC50 value of 304 pM in a pull-down model of complex formation, and reduced IL-1β signaling in a cell model by 90% at 2 μM. Overall, therapies that target the Arg286 region surface of IL-1RAcP, and disrupt subsequent interactions with subunits, have the potential to serve as next generation treatments for osteoarthritis.

INVERSE UNCERTAINTY QUANTIFICATION OF A CELL MODEL USING A GAUSSIAN PROCESS METAMODEL

2020 ◽  
Vol 10 (4) ◽  
pp. 333-349
Author(s):  
Kevin de Vries ◽  
Anna Nikishova ◽  
Benjamin Czaja ◽  
Gábor Závodszky ◽  
Alfons G. Hoekstra
Keyword(s):  
Gaussian Process ◽  
Uncertainty Quantification ◽  
Cell Model ◽  
A Cell

Preincubation with Sn-complexes causes intensive intracellular retention of 99mTc in thyroid cells in vitro

2012 ◽  
Vol 51 (05) ◽  
pp. 179-185 ◽  
Author(s):  
M. Wendisch ◽  
D. Aurich ◽  
R. Runge ◽  
R. Freudenberg ◽  
J. Kotzerke ◽  
...  
Keyword(s):  
Cell Model ◽  
Low Energy ◽  
Thyroid Cells ◽  
Low Energy Electrons ◽  
A Cell ◽  
Vitro Model ◽  
Uptake Studies ◽  
Radiobiological Effects ◽  
Radioactivity Retention

SummaryTechnetium radiopharmaceuticals are well established in nuclear medicine. Besides its well-known gamma radiation, 99mTc emits an average of five Auger and internal conversion electrons per decay. The biological toxicity of these low-energy, high-LET (linear energy transfer) emissions is a controversial subject. One aim of this study was to estimate in a cell model how much 99mTc can be present in exposed cells and which radiobiological effects could be estimated in 99mTc-overloaded cells. Methods: Sodium iodine symporter (NIS)- positive thyroid cells were used. 99mTc-uptake studies were performed after preincubation with a non-radioactive (cold) stannous pyro - phosphate kit solution or as a standard 99mTc pyrophosphate kit preparation or with pure pertechnetate solution. Survival curves were analyzed from colony-forming assays. Results: Preincubation with stannous complexes causes irreversible intracellular radioactivity retention of 99mTc and is followed by further pertechnetate influx to an unexpectedly high 99mTc level. The uptake of 99mTc pertechnetate in NIS-positive cells can be modified using stannous pyrophosphate from 3–5% to >80%. The maximum possible cellular uptake of 99mTc was 90 Bq/cell. Compared with nearly pure extracellular irradiation from routine 99mTc complexes, cell survival was reduced by 3–4 orders of magnitude after preincubation with stannous pyrophosphate. Conclusions: Intra cellular 99mTc retention is related to reduced survival, which is most likely mediated by the emission of low-energy electrons. Our findings show that the described experiments constitute a simple and useful in vitro model for radiobiological investigations in a cell model.

scholarly journals Gambogic acid protects LPS-induced apoptosis and inflammation in a cell model of neonatal pneumonia through the regulation of TrkA/Akt signaling pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xu Gao ◽  
Jingya Dai ◽  
Guifang Li ◽  
Xinya Dai
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Cell Model ◽  
Akt Signaling ◽  
Gambogic Acid ◽  
Akt Signaling Pathway ◽  
Western Blot Assay ◽  
A Cell ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Abstract Objective In this work, we investigated the effects of gambogic acid (GA) on lipopolysaccharide (LPS)-induced apoptosis and inflammation in a cell model of neonatal pneumonia. Method Human WI-38 cells were maintained in vitro and incubated with various concentrations of GA to examine WI-38 survival. GA-preincubated WI-38 cells were then treated with LPS to investigate the protective effects of GA on LPS-induced death, apoptosis and inflammation. Western blot assay was utilized to analyze the effect of GA on tropomyosin receptor kinase A (TrkA) signaling pathway in LPS-treated WI-38 cells. In addition, human AKT serine/threonine kinase 1 (Akt) gene was knocked down in WI-38 cells to further investigate the associated genetic mechanisms of GA in protecting LPS-induced inflammation and apoptosis. Results Pre-incubating WI-38 cells with low and medium concentrations GA protected LPS-induced cell death, apoptosis and inflammatory protein productions of IL-6 and MCP-1. Using western blot assay, it was demonstrated that GA promoted TrkA phosphorylation and Akt activation in LPS-treated WI-38 cells. Knocking down Akt gene in WI-38 cells showed that GA-associated protections against LPS-induced apoptosis and inflammation were significantly reduced. Conclusions GA protected LPS-induced apoptosis and inflammation, possibly through the activations of TrkA and Akt signaling pathway. This work may broaden our understanding on the molecular mechanisms of human neonatal pneumonia.

Glycans in scaffold design in tissue reconstruction

2021 ◽  
pp. 088391152199784
Author(s):  
Nipun Jain ◽  
Shashi Singh
Keyword(s):  
Cell Attachment ◽  
Low Cost ◽  
Growth Conditions ◽  
Downstream Signaling ◽  
Cell Carrier ◽  
Wide Range ◽  
Proliferation And Differentiation ◽  
Different Types ◽  
Tissue Reconstruction ◽  
A Cell

Development of an artificial tissue by tissue engineering is witnessed to be one of the long lasting clarified solutions for the damaged tissue function restoration. To accomplish this, a scaffold is designed as a cell carrier in which the extracellular matrix (ECM) performs a prominent task of controlling the inoculated cell’s destiny. ECM composition, topography and mechanical properties lead to different types of interactions between cells and ECM components that trigger an assortment of cellular reactions via diverse sensing mechanisms and downstream signaling pathways. The polysaccharides in the form of proteoglycans and glycoproteins yield better outcomes when included in the designed matrices. Glycosaminoglycan (GAG) chains present on proteoglycans show a wide range of operations such as sequestering of critical effector morphogens which encourage proficient nutrient contribution toward the growing stem cells for their development and endurance. In this review we discuss how the glycosylation aspects are of considerable importance in everyday housekeeping functions of a cell especially when placed in a controlled environment under ideal growth conditions. Hydrogels made from these GAG chains have been used extensively as a resorbable material that mimics the natural ECM functions for an efficient control over cell attachment, permeability, viability, proliferation, and differentiation processes. Also the incorporation of non-mammalian polysaccharides can elicit specific receptor responses which authorize the creation of numerous vigorous frameworks while prolonging the low cost and immunogenicity of the substance.

scholarly journals Positively Charged Lipid as Potential Tool to Influence the Fate of Ethosomes

2021 ◽  
Vol 11 (15) ◽  
pp. 7060
Author(s):  
Antonia Mancuso ◽  
Maria Chiara Cristiano ◽  
Massimo Fresta ◽  
Daniele Torella ◽  
Donatella Paolino
Keyword(s):  
Cell Model ◽  
Human Keratinocytes ◽  
Skin Delivery ◽  
Physico Chemical ◽  
Cell Mortality ◽  
Mean Size ◽  
A Cell ◽  
Negative Surface ◽  
Cytotoxic Studies

Ethosomes® are one of the main deformable vesicles proposed to overcome the stratum corneum. They are composed of lecithin, ethanol and water, resulting in round vesicles characterized by a narrow size distribution and a negative surface charge. Taking into account their efficiency to deliver drugs into deeper skin layers, the current study was designed to evaluate the influence of different lipids on the physico-chemical features of traditional ethosomes in the attempt to influence their fate. Three lipids (DOPE, DSPE and DOTAP) were used for the study, but only DOTAP conferred a net positive charge to ethosomes, maintaining a narrow mean size lower than 300 nm and a good polydispersity index. Stability and in vitro cytotoxic studies have been performed using Turbiscan Lab analysis and MTT dye exclusion assay, respectively. Data recorded demonstrated the good stability of modified ethosomes and a reasonable absence of cell mortality when applied to human keratinocytes, NCTC 2544, which are used as a cell model. Finally, the best formulations were selected to evaluate their ability to encapsulate drugs, through the use of model compounds. Cationic ethosomes encapsulated oil red o and rhodamine b in amounts comparable to those recorded from conventional ethosomes (over 50%). Results recorded from this study are encouraging as cationic ethosomes may open new opportunities for skin delivery.

scholarly journals PapRIV, a BV-2 microglial cell activating quorum sensing peptide

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yorick Janssens ◽  
Nathan Debunne ◽  
Anton De Spiegeleer ◽  
Evelien Wynendaele ◽  
Marta Planas ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Cell Model ◽  
Dependent Manner ◽  
Communication Signals ◽  
Gram Positive Bacteria ◽  
A Cell ◽  
Gastro Intestinal Tract

AbstractQuorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced by Bacillus cereus species. PapRIV showed in vitro activating properties of BV-2 microglia cells and was able to cross the in vitro Caco-2 cell model and reach the brain. In vivo peptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNFα and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-κB dependent manner. Different metabolites were identified in serum, of which the main metabolite still remained active. PapRIV is thus able to cross the gastro-intestinal tract and the blood–brain barrier and shows in vitro activating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.

Periodontal ligament fibroblasts as a cell model to study osteogenesis and osteoclastogenesis in fibrodysplasia ossificans progressiva

Bone ◽  
2018 ◽  
Vol 109 ◽  
pp. 168-177 ◽  
Author(s):  
Teun J. de Vries ◽  
Ton Schoenmaker ◽  
Dimitra Micha ◽  
Jolanda Hogervorst ◽  
Siham Bouskla ◽  
...  
Keyword(s):  
Periodontal Ligament ◽  
Cell Model ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Periodontal Ligament Fibroblasts ◽  
A Cell
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