scholarly journals The Adenosinergic System in Diabetic Retinopathy

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
J. Vindeirinho ◽  
A. R. Santiago ◽  
C. Cavadas ◽  
A. F. Ambrósio ◽  
P. F. Santos
Keyword(s):  
Diabetic Retinopathy ◽  
Inflammatory Response ◽  
Adenosine Receptors ◽  
Therapeutic Targets ◽  
Experimental Results ◽  
Early Stages ◽  
The Impact

The neurodegenerative and inflammatory environment that is prevalent in the diabetic eye is a key player in the development and progression of diabetic retinopathy. The adenosinergic system is widely regarded as a significant modulator of neurotransmission and the inflammatory response, through the actions of the four types of adenosine receptors (A1R, A2AR, A2BR, and A3R), and thus could be revealed as a potential player in the events unfolding in the early stages of diabetic retinopathy. Herein, we review the studies that explore the impact of diabetic conditions on the retinal adenosinergic system, as well as the role of the said system in ameliorating or exacerbating those conditions. The experimental results described suggest that this system is heavily affected by diabetic conditions and that the modulation of its components could reveal potential therapeutic targets for the treatment of diabetic retinopathy, particularly in the early stages of the disease.

scholarly journals Quantitative Proteome Analysis of Atg5-Deficient Mouse Embryonic Fibroblasts Reveals the Range of the Autophagy-Modulated Basal Cellular Proteome

mSystems ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Kiran Bala Sharma ◽  
Manish Sharma ◽  
Suruchi Aggarwal ◽  
Amit Kumar Yadav ◽  
Shinjini Bhatnagar ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Proteome Analysis ◽  
Interferon Response ◽  
Type I ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
The Impact

ABSTRACT Basal autophagy is crucial for maintenance of cellular homeostasis. ATG5 is an essential protein for autophagosome formation, and its depletion has been extensively used as a tool to disrupt autophagy. Here, we characterize the impact of Atg5 deficiency on the cellular proteome of mouse embryonic fibroblasts (MEFs). Using a tandem mass tagging (TMT)-based quantitative proteomics analysis, we observe that 14% of identified proteins show dysregulated levels in atg5−/− MEFs. These proteins were distributed across diverse biological processes, such as cell adhesion, development, differentiation, transport, metabolism, and immune responses. Several of the upregulated proteins were receptors involved in transforming growth factor β (TGF-β) signaling, JAK-STAT signaling, junction adhesion, and interferon/cytokine-receptor interactions and were validated as autophagy substrates. Nearly equal numbers of proteins, including several lysosomal proteins and enzymes, were downregulated, suggesting a complex role of autophagy/ATG5 in regulating their levels. The atg5−/− MEFs had lower levels of key immune sensors and effectors, including Toll-like receptor 2 (TLR2), interferon regulatory factor 3 (IRF3), IRF7, MLKL, and STAT1/3/5/6, which were restored by reexpression of ATG5. While these cells could efficiently mount a type I interferon response to the double-stranded RNA (dsRNA) mimic poly(I·C), they were compromised in their inflammatory response to the bacterial pathogen-associated molecular patterns (PAMPs) lipopolysaccharide (LPS) and Pam3CSK4. Transcriptional activation and secretion of interleukin-6 (IL-6) in these cells could be recovered by ATG5 expression, supporting the role of autophagy in the TLR2-induced inflammatory response. This study provides a key resource for understanding the effect of autophagy/ATG5 deficiency on the fibroblast proteome. IMPORTANCE Autophagy performs housekeeping functions for cells and maintains a functional mode by degrading damaged proteins and organelles and providing energy under starvation conditions. The process is tightly regulated by the evolutionarily conserved Atg genes, of which Atg5 is one such crucial mediator. Here, we have done a comprehensive quantitative proteome analysis of mouse embryonic fibroblasts that lack a functional autophagy pathway (Atg5 knockout). We observe that 14% of the identified cellular proteome is remodeled, and several proteins distributed across diverse cellular processes with functions in signaling, cell adhesion, development, and immunity show either higher or lower levels under autophagy-deficient conditions. These cells have lower levels of crucial immune proteins that are required to mount a protective inflammatory response. This study will serve as a valuable resource to determine the role of autophagy in modulating specific protein levels in cells.

Role of A1 adenosine receptors in regulation of vascular tone

2005 ◽  
Vol 288 (3) ◽  
pp. H1411-H1416 ◽  
Author(s):  
Huda E. Tawfik ◽  
J. Schnermann ◽  
Peter J. Oldenburg ◽  
S. Jamal Mustafa
Keyword(s):  
Adenosine Receptors ◽  
Vascular Tone ◽  
Receptor Subtypes ◽  
Vascular Relaxation ◽  
Response Curves ◽  
Cgs 21680 ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Regulation Of Vascular Tone

The vascular response to adenosine and its analogs is mediated by four adenosine receptors (ARs), namely, A1, A2A, A2B, and A3. A2AARs and/or A2BARs are involved in adenosine-mediated vascular relaxation of coronary and aortic beds. However, the role of A1ARs in the regulation of vascular tone is less well substantiated. The aim of this study was to determine the role of A1ARs in adenosine-mediated regulation of vascular tone. A1AR-knockout [A1AR(−/−)] mice and available pharmacological tools were used to elucidate the function of A1ARs and the impact of these receptors on the regulation of vascular tone. Isolated aortic rings from A1AR(−/−) and wild-type [A1AR(+/+)] mice were precontracted with phenylephrine, and concentration-response curves for adenosine and its analogs, 5′- N-ethyl-carboxamidoadenosine (NECA, nonselective), 2-chloro- N6-cyclopentyladenosine (CCPA, A1AR selective), 2-(2-carboxyethyl)phenethyl amino-5′- N-ethylcarboxamido-adenosine (CGS-21680, A2A selective), and 2-chloro- N6-3-iodobenzyladenosine-5′- N-methyluronamide (Cl-IBMECA, A3 selective) were obtained to determine relaxation. Adenosine and NECA (0.1 μM) caused small contractions of 13.9 ± 3.0 and 16.4 ± 6.4%, respectively, and CCPA at 0.1 and 1.0 μM caused contractions of 30.8 ± 4.3 and 28.1 ± 3.9%, respectively, in A1AR(+/+) rings. NECA- and CCPA-induced contractions were eliminated by 100 nM of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, selective A1AR antagonist). Adenosine, NECA, and CGS-21680 produced an increase in maximal relaxation in A1AR(−/−) compared with A1AR(+/+) rings, whereas Cl-IBMECA did not produce contraction in either A1AR(+/+) or A1AR(−/−) rings. CCPA-induced contraction at 1.0 μM was eliminated by the PLC inhibitor U-73122. These data suggest that activation of A1ARs causes contraction of vascular smooth muscle through PLC pathways and negatively modulates the vascular relaxation mediated by other adenosine receptor subtypes.

‘Distant Lands’: The Management of Absentee Estates in Woodland High Suffolk, 1660–1800

Rural History ◽  
2001 ◽  
Vol 12 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Jonathan Theobald
Keyword(s):  
Early Stages ◽  
Methods And Techniques ◽  
Estate Management ◽  
The Impact

AbstractThe seventeenth and eighteenth centuries were a time when many of the landed classes chose to be absent from their estates. However, this same period also saw the early stages of a so-called ‘revolution’ in agricultural methods and techniques. This article, therefore, evaluates the impact of non-residency on estate management structures and agricultural progress. Specific issues examined here include the role of the steward, leasing policy, the promotion of new farming techniques and estate investment by the landlord. In this context, comparisons will be made between absentee, semi-resident and resident estates for the region of Woodland High Suffolk.

A novel mechanism of renal blood flow autoregulation and the autoregulatory role of A1 adenosine receptors in mice

2007 ◽  
Vol 293 (5) ◽  
pp. F1489-F1500 ◽  
Author(s):  
Armin Just ◽  
William J. Arendshorst
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Adenosine Receptors ◽  
Time Course ◽  
Tubuloglomerular Feedback ◽  
The Third ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Renal Blood Flow Autoregulation

Autoregulation of renal blood flow (RBF) is mediated by a fast myogenic response (MR; ∼5 s), a slower tubuloglomerular feedback (TGF; ∼25 s), and potentially additional mechanisms. A1 adenosine receptors (A1AR) mediate TGF in superficial nephrons and contribute to overall autoregulation, but the impact on the other autoregulatory mechanisms is unknown. We studied dynamic autoregulatory responses of RBF to rapid step increases of renal artery pressure in mice. MR was estimated from autoregulation within the first 5 s, TGF from that at 5–25 s, and a third mechanism from 25–100 s. Genetic deficiency of A1AR (A1AR−/−) reduced autoregulation at 5–25 s by 50%, indicating a residual fourth mechanism resembling TGF kinetics but independent of A1AR. MR and third mechanism were unaltered in A1AR−/−. Autoregulation in A1AR−/− was faster at 5–25 than at 25–100 s suggesting two separate mechanisms. Furosemide in wild-type mice (WT) eliminated the third mechanism and enhanced MR, indicating TGF-MR interaction. In A1AR−/−, furosemide did not further impair autoregulation at 5–25 s, but eliminated the third mechanism and enhanced MR. The resulting time course was the same as during furosemide in WT, indicating that A1AR do not affect autoregulation during furosemide inhibition of TGF. We conclude that at least one novel mechanism complements MR and TGF in RBF autoregulation, that is slower than MR and TGF and sensitive to furosemide, but not mediated by A1AR. A fourth mechanism with kinetics similar to TGF but independent of A1AR and furosemide might also contribute. A1AR mediate classical TGF but not TGF-MR interaction.

scholarly journals Single-Cell RNA Sequencing With Combined Use of Bulk RNA Sequencing to Reveal Cell Heterogeneity and Molecular Changes at Acute Stage of Ischemic Stroke in Mouse Cortex Penumbra Area

2021 ◽  
Vol 9 ◽  
Author(s):  
Kang Guo ◽  
Jianing Luo ◽  
Dayun Feng ◽  
Lin Wu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Single Cell ◽  
Rna Sequencing ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Acute Stage ◽  
Gene Markers ◽  
Molecular Changes ◽  
Early Stages ◽  
The Impact

Stroke has been the leading cause of adult morbidity and mortality over the past several years. After an ischemic stroke attack, many dormant or reversibly injured brain cells exist in the penumbra area. However, the pathological processes and unique cell information in the penumbra area of an acute ischemic stroke remain elusive. We applied unbiased single cell sequencing in combination with bulk RNA-seq analysis to investigate the heterogeneity of each cell type in the early stages of ischemic stroke and to detect early possible therapeutic targets to help cell survival. We used these analyses to study the mouse brain penumbra during this phase. Our results reveal the impact of ischemic stroke on specific genes and pathways of different cell types and the alterations of cell differentiation trajectories, suggesting potential pathological mechanisms and therapeutic targets. In addition to classical gene markers, single-cell genomics demonstrates unique information on subclusters of several cell types and metabolism changes in an ischemic stroke. These findings suggest that Gadd45b in microglia, Cyr61 in astrocytes, and Sgk3 in oligodendrocytes may play a subcluster-specific role in cell death or survival in the early stages of ischemic stroke. Moreover, RNA-scope multiplex in situ hybridization and immunofluorescence staining were applied to selected target gene markers to validate and confirm the existence of these cell subtypes and molecular changes during acute stage of ischemic stroke.

scholarly journals The Possible Role Of Toll-Like Receptor 4 In The Pathology Of Stroke

2017 ◽  
pp. 8
Author(s):  
Mohammad Allahtavakoli ◽  
Ali Shamsizadeh ◽  
Ali Roohbakhsh ◽  
Amir Moghadam-Ahmadi ◽  
Mohammad Reza Rahmani ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Inflammatory Response ◽  
System Response ◽  
Toll Like Receptor ◽  
Key Factors ◽  
Toll Like Receptor 4 ◽  
Brain Functions ◽  
Essential Components ◽  
The Impact

Stroke is a prevalent and dangerous health problem, which triggers an intense inflammatory response to Toll-like receptors (TLRs) activation. TLRs are the essential components of innate immunity system response, and therefore, they are one of the key factors involved in recognizing pathogens and internal ligands. Among TLRs, TLR4 significantly participates in the induction of inflammation and brain functions, hence, it has been hypothesized that this molecule is associated with several brain immune-related diseases such as stroke. It has also been proved that animals with TLR4 deficiency have higher protection against ischemia and the absence of TLR4 reduces the neuroinflammation and injuries associated with brain trauma. TLR4 deficiency may play a neuroprotective role in the occurrence of stroke. This article will review recent information regarding the impact of TLR4 in the pathogenicity of stroke.

scholarly journals Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-23 ◽  
Author(s):  
Stéphane Mandard ◽  
David Patsouris
Keyword(s):  
Inflammatory Response ◽  
Protective Role ◽  
Peroxisome Proliferator ◽  
Nuclear Control ◽  
Inflammatory Bowel ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands ◽  
The Impact

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARαand PPARβ/δagainst the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits.

scholarly journals THE IMPACT OF ENDOTHELIAL DYSFUNCTION IN THE DEVELOPMENT OF DIABETIC RETINOPATHY: ROLE OF INFLAMMATION

2015 ◽  
Vol 65 (10) ◽  
pp. A2079
Author(s):  
Gerasimos Siasos ◽  
Nikolaos Gouliopoulos ◽  
Marilita Moschos ◽  
Evangelos Oikonomou ◽  
Christina Kollia ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Endothelial Dysfunction ◽  
The Impact

The Basque-Cantabrian Basin: a natural laboratory to study the reactivation of a hyperextended system

2020 ◽  
Author(s):  
Jordi Miro Padrisa ◽  
Patricia Cadenas ◽  
Rodolphe Lescoutre ◽  
Josep Anton Muñoz ◽  
Gianreto Manatschal
Keyword(s):  
Cross Sections ◽  
Late Triassic ◽  
Entire Area ◽  
Early Stages ◽  
3D Geometry ◽  
Present Part ◽  
The Impact ◽  
Basque Cantabrian Basin ◽  
Natural Laboratory

<p>The Basque – Cantabrian Basin (BCB) corresponds to a Mesozoic hyperextended rift basin that was subsequently reactivated from Late Cretaceous to Cenozoic and is at present part of the Pyrenean orogen. Numerous studies have addressed the role of rift inheritance on the formation of orogens, but little consideration has been given to the rift segmentation and the along strike variability. In the BCB, most studies focused on a section at the central part of the basin, despite the amount of geological and geophysical data available on the entire area, which make it a perfect natural laboratory to study the reactivation of a hyperextended basin.</p><p>The aim of this study is threefold: (I) reveal the 3D geometry and the along strike variability of the BCB by doing three N-S transversal cross sections from east to west; (II) define the rift domains and their limits; and (III) study the impact of rift inheritance during the compressional reactivation mainly focusing on the former distal rift domains.</p><p>Our preliminary results show that the BCB is affected by a multistage and polyphase rift evolution including a first, widespread Permo – Triassic rift phase including Late Triassic salt, a Late Jurassic to Barremian extensional phase and a more prominent Aptian to Middle Cenomanian hyperextension phase.  This complex rift template had a major impact on the subsequent reactivation and can explain some of the along strike variabilities observed within the three regional cross sections. To the east, the BCB was completely reactivated and transported to the south over the Late Triassic salt, which acted as a decoupling level. On the contrary, the westernmost section preserves the rift-related structures only weakly reactivated, providing direct insights on the early stages of reactivation. Our observations show that underthrusting/subduction initiates within the exhumed mantle domain, while during initial collision, the necking domains acted as a buttress. Decollement levels during early stages are located in the former rift distal domains and use serpentinized mantle rocks, while during collision they migrate to more external parts and use intra-basement decoupling levels such as the ductile middle crust and/or salt horizons.</p><p>Key words: Rift inheritance, Pyrenees, Basque – Cantabrian Basin, hyperextension.</p>

scholarly journals Capitalising on chaos – exploring the impact and future of social media influencer engagement during the early stages of a global pandemic

2020 ◽  
pp. 1329878X2095815
Author(s):  
Catherine Archer ◽  
Katharina Wolf ◽  
Joseph Nalloor
Keyword(s):  
Public Health ◽  
Social Media ◽  
Luxury Goods ◽  
Early Stages ◽  
Global Pandemic ◽  
Starting Point ◽  
Public Health Information ◽  
Disaster Capitalism ◽  
The Impact

This article examines the role of influencers during the early stages of the COVID-19 pandemic, as well as the impact of the global pandemic on Social Media Influencers’ (SMIs) lifestyle and business model, using the concept of Disaster Capitalism as a springboard for discussion. Worldwide it first appeared that the global pandemic would severely impact SMI sole traders, as income from travel, luxury goods and other ‘lifestyle’ brands dried up. However, we suggest that brands and influencers themselves have pivoted to meet the COVID challenge, with some brands exploiting the opaque influence of these micro-celebrities. We further suggest that while a handful of governments and health organisations have recognised the reach and social capital of SMIs, their potential in health communication has been underutilised. We write this essay as a starting point, raising questions and calling for further research to be conducted to inform the understanding of SMIs’ role and potential as conveyors of public health information.

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