The role of EP2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1

2020 ◽  
pp. bjophthalmol-2020-317762
Author(s):  
Jacques A Bertrand ◽  
David F Woodward ◽  
Joseph M Sherwood ◽  
Jenny W Wang ◽  
Darryl R Overby
Keyword(s):  
Intraocular Pressure ◽  
Ex Vivo ◽  
Hypotensive Activity ◽  
Long Term Effects ◽  
Gene Encoding ◽  
Knock Out ◽  
Pharmacological Mechanism ◽  
Knock Out Mice

BackgroundA single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP2 receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. The present studies were intended to determine EP2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP2 receptors.MethodsThe protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP2 receptor knock-out mice (B6.129-Ptger2tm1Brey/J; EP2KO). Both ocular normotensive and steroid-induced ocular hypertensive (SI-OHT) mice were studied. IOP was measured tonometrically under general anaesthesia. Aqueous humour outflow facility was measured ex vivo using iPerfusion in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days prior.ResultsBoth the initial 1-day and the protracted multiday effects of JV-GL1 in the SI-OHT model for glaucoma were abolished by deletion of the gene encoding the EP2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP2KO mice, but in littermate SI-OHT EP2WT control mice, JV-GL1 statistically significantly lowered IOP for 4–6 days.ConclusionsBoth the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP2 receptor dependent.

scholarly journals The relative role of PLCβ and PI3Kγ in platelet activation

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 110-117 ◽  
Author(s):  
Lurong Lian ◽  
Yanfeng Wang ◽  
Julia Draznin ◽  
Don Eslin ◽  
Joel S. Bennett ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Ex Vivo ◽  
Functional Explanation ◽  
Relative Role ◽  
Filamentous Actin ◽  
Knock Out ◽  
Essentially Normal ◽  
Platelet Signaling ◽  
Knock Out Mice

Stimulation of platelet G protein–coupled receptors results in the cleavage of phosphatidylinositol 4,5-trisphosphate (PIP2) into inositol 1,4,5-trisphosphate and 1,2-diacylglycerol by phospholipase C (PLCβ). It also results in the phosphorylation of PIP2 by the γ isoform of phosphatidylinositol 3-kinase (PI3Kγ) to synthesize phosphatidylinositol 3,4,5-trisphosphate. To understand the role of PIP2 in platelet signaling, we evaluated knock-out mice lacking 2 isoforms of PLCβ (PLCβ2 and PLCβ3) or lacking the Gβγ-activated isoform of PI3K (PI3Kγ). Both knock-out mice were unable to form stable thrombi in a carotid injury model. To provide a functional explanation, knock-out platelets were studied ex vivo. PLCβ2/β3–/– platelets failed to assemble filamentous actin, had defects in both secretion and mobilization of intracellular calcium, and were unable to form stable aggregates following low doses of agonists. Platelets lacking PI3Kγ disaggregated following low-dose adenosine diphosphate (ADP) and had a mildly impaired ability to mobilize intracellular calcium. Yet, they exhibited essentially normal actin assembly and secretion. Remarkably, both PLCβ2/β3–/– and PI3Kγ–/– platelets spread more slowly upon fibrinogen. These results suggest substantial redundancy in platelet signaling pathways. Nonetheless, the diminished ability of knock-out platelets to normally spread after adhesion and to form stable thrombi in vivo suggests that both PLCβ2/β3 and PI3Kγ play vital roles in platelet cytoskeletal dynamics.

scholarly journals Synuclein Deficiency Results in Age-Related Respiratory and Cardiovascular Dysfunctions in Mice

2020 ◽  
Vol 10 (9) ◽  
pp. 583
Author(s):  
Patrick S. Hosford ◽  
Natalia Ninkina ◽  
Vladimir L. Buchman ◽  
Jeffrey C. Smith ◽  
Nephtali Marina ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Physiological Role ◽  
Normal Function ◽  
Whole Body ◽  
Cardiovascular Reflexes ◽  
Long Term Effects ◽  
Gene Encoding ◽  
Age Related

Synuclein (α, β, and γ) proteins are highly expressed in presynaptic terminals, and significant data exist supporting their role in regulating neurotransmitter release. Targeting the gene encoding α-synuclein is the basis of many animal models of Parkinson’s disease (PD). However, the physiological role of this family of proteins in not well understood and could be especially relevant as interfering with accumulation of α-synuclein level has therapeutic potential in limiting PD progression. The long-term effects of their removal are unknown and given the complex pathophysiology of PD, could exacerbate other clinical features of the disease, for example dysautonomia. In the present study, we sought to characterize the autonomic phenotypes of mice lacking all synucleins (α, β, and γ; αβγ−/−) in order to better understand the role of synuclein-family proteins in autonomic function. We probed respiratory and cardiovascular reflexes in conscious and anesthetized, young (4 months) and aged (18–20 months) αβγ−/− male mice. Aged mice displayed impaired respiratory responses to both hypoxia and hypercapnia when breathing activities were recorded in conscious animals using whole-body plethysmography. These animals were also found to be hypertensive from conscious blood pressure recordings, to have reduced pressor baroreflex gain under anesthesia, and showed reduced termination of both pressor and depressor reflexes. The present data demonstrate the importance of synuclein in the normal function of respiratory and cardiovascular reflexes during aging.

Endothelial Tyrosine Kinase Tie1 Is Required for Normal Schlemm’s Canal Development

2022 ◽  
Author(s):  
Jing Du ◽  
Benjamin R. Thomson ◽  
Tuncer Onay ◽  
Susan E. Quaggin
Keyword(s):  
Intraocular Pressure ◽  
Quantitative Polymerase Chain Reaction ◽  
Schlemm’S Canal ◽  
Knock Out ◽  
Schlemm's Canal ◽  
Elevated Intraocular Pressure ◽  
Knock Out Mice ◽  
And Function ◽  
The Impact

Background: Schlemm’s canal (SC) is a large vessel residing in the iridocorneal angle and is required to regulate aqueous humor outflow. Normal SC structure and function is indispensable for maintaining normal intraocular pressure, and elevated intraocular pressure is a risk factor for development of glaucoma. Recent reports have identified a key role of the angiopoietin-Tie2 pathway for SC development and function; however, the role of the orphan receptor Tie1 has not been clarified. Methods: We used Tie1 knock out mice to study the function of Tie1 in SC development and function. Real-time quantitative polymerase chain reaction and Western blot analyses were used to verify Tie1 deletion. High-resolution microscopy of mouse SC whole mount and cross sections were used to study SC morphology. Measurement of intraocular pressure in live mice was used to study the impact of Tie1 on SC function. Results: Tie1 is highly expressed in both human and mouse SC. Tie1 knock out mice display hypomorphic SC and elevated intraocular pressure as a result of attenuated SC development. Conclusions: Tie1 is indispensable for SC development and function, supporting it as a novel target for future SC-targeted glaucoma therapies and a candidate gene for glaucoma in humans.

Are all granzymes cytotoxic in vivo?

2014 ◽  
Vol 395 (2) ◽  
pp. 181-202 ◽  
Author(s):  
Lars T. Joeckel ◽  
Phillip I. Bird
Keyword(s):  
Serine Proteases ◽  
Ex Vivo ◽  
Cytotoxic Lymphocytes ◽  
Cytotoxic Effects ◽  
Knock Out ◽  
Granzyme A ◽  
Knock Out Mice

Abstract Granzymes are serine proteases mainly found in cytotoxic lymphocytes. The most-studied member of this group is granzyme B, which is a potent cytotoxin that has set the paradigm that all granzymes are cyototoxic. In the last 5 years, this paradigm has become controversial. On one hand, there is a plethora of sometimes contradictory publications showing mainly caspase-independent cytotoxic effects of granzyme A and the so-called orphan granzymes in vitro. On the other hand, there are increasing numbers of reports of granzymes failing to induce cell death in vitro unless very high (potentially supra-physiological) concentrations are used. Furthermore, experiments with granzyme A or granzyme M knock-out mice reveal little or no deficit in their cytotoxic lymphocytes’ killing ability ex vivo, but indicate impairment in the inflammatory response. These findings of non-cytotoxic effects of granzymes challenge dogma, and thus require alternative or additional explanations to be developed of the role of granzymes in defeating pathogens. Here we review evidence for granzyme cytotoxicity, give an overview of their non-cytotoxic functions, and suggest technical improvements for future investigations.

Reshaping the Economic Structure in Argentina: The Role of External Debt during the Macri Administration (2015–2019)

2021 ◽  
pp. 048661342097642
Author(s):  
Juan E. Santarcángelo ◽  
Juan Manuel Padín
Keyword(s):  
External Debt ◽  
Economic Structure ◽  
The United States ◽  
Jel Classification ◽  
Financial Capital ◽  
Economic Policies ◽  
Right Wing ◽  
Long Term Effects

Argentina’s right-wing shift in the 2015 presidential election concluded twelve years of center-left rule. The elected president, Mauricio Macri, claimed that the economy would experience normalization of existing imbalances and recover its strength in a “new political era.” However, the new administration quickly restored the dominance of neoliberal economic policies through a comprehensive set of initiatives, which centrally included the return to international financial debt and equity markets and submission to the International Monetary Fund’s (IMF) rules. This article analyzes Argentina’s external-debt-growth process and discusses its objectives and long-term effects. This paper posits that the indebtedness process carried out by the Macri administration—and its modality—not only increased the relevance of financial capital in the Argentine economy but also structurally conditioned any future nonorthodox alternative path of development. This outcome cannot be understood without taking into account the deliberate role of the United States, the IMF, and the top companies that operate in Argentina, as well as the complicity of many political sectors. JEL Classification: H63, F34, F63

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

Mother, baby and Facebook makes three: does social media provide social support for new mothers?

2018 ◽  
Vol 168 (1) ◽  
pp. 122-139 ◽  
Author(s):  
Catherine Archer ◽  
Kai-Ti Kao
Keyword(s):  
Social Support ◽  
Social Media ◽  
Media Use ◽  
Long Term Effects ◽  
New Mothers ◽  
Social Media Use ◽  
Extreme Stress ◽  
Ability To Act

Many mothers can find themselves increasingly isolated and overwhelmed after giving birth to a new baby. This period can be a source of extreme stress, anxiety and depression, which can not only have an economic impact on national health services, but can also have long-term effects on the development of the child. At the same time, social media use among most new mothers has become ubiquitous. This research investigates the role of social media, potentially as a mechanism for social support, among Australian mothers of young children aged from birth to 4 years. The findings indicate that participants had mixed responses to their social media use. While social support was deemed a benefit, there were also some negative aspects to social media use identified. The findings highlight the need to critically interrogate social media’s ability to act as a source of social support for new mothers.

The long-term effects of stress: role of miRNAs in the development of vulnerable and resilient phenotype

2021 ◽  
Vol 131 ◽  
pp. 105496
Author(s):  
M. Mazzelli ◽  
N. Cattane ◽  
V. Begni ◽  
M. Papp ◽  
M.A. Riva ◽  
...  
Keyword(s):  
Long Term Effects ◽  
Effects Of Stress
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