scholarly journals Epac1 and Glycyrrhizin Both Inhibit HMGB1 Levels to Reduce Diabetes-Induced Neuronal and Vascular Damage in the Mouse Retina

2019 ◽  
Vol 8 (6) ◽  
pp. 772 ◽  
Author(s):  
Li Liu ◽  
Youde Jiang ◽  
Jena J. Steinle
Keyword(s):  
Inflammatory Mediators ◽  
Knockout Mice ◽  
Interleukin 1 ◽  
High Mobility ◽  
Sirtuin 1 ◽  
Mouse Retina ◽  
Necrosis Factor Alpha ◽  
Diabetic Retina ◽  
Factor Alpha

The role of high mobility group box 1 (HMGB1) in acute diabetic retinal damage has been demonstrated. We recently reported that glycyrrhizin, a HMGB1 inhibitor, protected the diabetic retina against neuronal, vascular, and permeability changes. In this study, we wanted to investigate the role of exchange protein for cAMP 1 (Epac1) on HMGB1 and the actions of glycyrrhizin. Using endothelial cell specific knockout mice for Epac1, we made some mice diabetic using streptozotocin, and treated some with glycyrrhizin for up to 6 months. We measured permeability, neuronal, and vascular changes in the Epac1 floxed and knockout mice. We also investigated whether Epac1 and glycyrrhizin work synergistically to reduce the retinal inflammatory mediators, tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL1β), as well as sirtuin 1 (SIRT1) levels. Epac1 and glycyrrhizin reduced inflammatory mediators with synergistic actions. Glycyrrhizin also increased SIRT1 levels in the Epac1 mice. Overall, these studies demonstrate that glycyrrhizin and Epac1 can work together to protect the retina. Finally, glycyrrhizin may regulate HMGB1 through increased SIRT1 actions.

scholarly journals Glycyrrhizin Protects the Diabetic Retina against Permeability, Neuronal, and Vascular Damage through Anti-Inflammatory Mechanisms

2019 ◽  
Vol 8 (7) ◽  
pp. 957 ◽  
Author(s):  
Li Liu ◽  
Youde Jiang ◽  
Jena J. Steinle
Keyword(s):  
Interleukin 1 ◽  
High Mobility ◽  
Necrosis Factor Alpha ◽  
Histological Changes ◽  
Diabetic Retina ◽  
Molecular Pattern ◽  
Retinal Capillary ◽  
Factor Alpha ◽  
Retinal Inflammation ◽  
Anti Inflammatory

Damage associated molecular pattern (DAMPs), such as high mobility group box 1 (HMGB1), may be involved in retinal inflammation in response to high glucose. To test whether HMGB1 inhibition could protect the diabetic retina, C57BL/6J mice were made diabetic and treated with glycyrrhizin, a HMGB1 inhibitor, for up to six months. Measurements of permeability, neuronal, and vascular changes were done, as well as assessments of HMGB1, tumor necrosis factor alpha (TNFα), and interleukin-1-beta (IL1β) levels. Retinal endothelial cells (REC) treated with glycyrrhizin had reduced IL1β and cleaved caspase 3 levels. Data also demonstrate that glycyrrhizin effectively reduced HMGB1 levels throughout the retina, as well as maintained normal retinal permeability and retinal capillary coverage. Glycyrrhizin maintained normal cell numbers in the ganglion cell layer and prevented thinning of the retina at two months. These histological changes were associated with reduced reactive oxygen species, as well as reduced HMGB1, TNFα, and IL1β levels. The data strongly imply that HMGB1 inhibition prevented diabetic retinal changes through anti-inflammatory pathways.

scholarly journals Monocyte Function in the Fetus and the Preterm Neonate: Immaturity Combined with Functional Impairment

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Zoe Iliodromiti ◽  
Anastasis Anastasiadis ◽  
Michail Varras ◽  
Kalliopi I. Pappa ◽  
Charalambos Siristatidis ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Interleukin 1 ◽  
Oxidative Capacity ◽  
Premature Neonate ◽  
Preterm Neonates ◽  
Necrosis Factor Alpha ◽  
Adhesion Ability ◽  
Monocyte Function ◽  
Monocytes And Macrophages ◽  
Factor Alpha

It is well known that the innate immunity system, involving the contribution of monocytes and macrophages, may dysfunction in fetuses and preterm neonates. Monocytes are capable of differentiating into dendritic cells (DCs) or into mucosal macrophages during certain infections and of producing inflammatory mediators such as TNF-α(tumor necrosis factor-alpha), nitric oxide, and reactive oxygen species. Fetuses as well as neonates are prone to infections as a result of a defective mechanism within the above mononuclear system. Monocyte function in fetuses and preterm neonates depends on the phagocytic and oxidative capacity of macrophages and their antigen-adhesion ability. Functional rather than anatomical impairment is probably the underlying cause, while a defective production of cytokines, such as TNF-α, IL-6 (Interleukin 6), IL-1β(Interleukin 1 beta), and G-CSF (Granulocyte Colony-Stimulating Factor), has also been involved. The insufficient production of the above inflammatory mediators and the phenomenon of endotoxin intolerance, which latter occurs during entry of any antigen into the premature neonate, place preterm neonates at higher risk for infections. Existing research data are herein presented which, however, are deficient and fragmental, this accounting for the fact that the precise pathophysiology of these disturbances is not yet fully clarified.

scholarly journals Modulators of crescentic glomerulonephritis.

1996 ◽  
Vol 7 (11) ◽  
pp. 2271-2278 ◽  
Author(s):  
R C Atkins ◽  
D J Nikolic-Paterson ◽  
Q Song ◽  
H Y Lan
Keyword(s):  
Poor Prognosis ◽  
Tumor Necrosis ◽  
Crescentic Glomerulonephritis ◽  
Interleukin 1 ◽  
Prominent Feature ◽  
Crescent Formation ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

Glomerular crescent formation is a prominent feature of aggressive forms of glomerulonephritis and is associated with a poor prognosis. An understanding of the mechanisms involved in crescent formation is crucial for the development of new therapies for this disease. This article reviews current ideas on the pathogenesis of glomerular crescent formation and describes methods for modulation of this process. Emphasis is given to the role of the proinflammatory cytokines interleukin-1 and tumor necrosis factor-alpha in crescent development and its modulation by cytokine blockade.

IL-6 enhances TNF-alpha- and IL-1-induced increase of Mn superoxide dismutase mRNA and O2 tolerance

1992 ◽  
Vol 263 (1) ◽  
pp. L22-L26 ◽  
Author(s):  
M. F. Tsan ◽  
J. E. White ◽  
P. J. Del Vecchio ◽  
J. B. Shaffer
Keyword(s):  
Superoxide Dismutase ◽  
Endothelial Cell ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Sod Activity ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Tracheal Insufflation

Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1), and interleukin-6 (IL-6) are multifunctional cytokines produced by a number of cells in response to endotoxin. We have previously demonstrated (M.-F. Tsan, J. E. White, T. A. Santana, and C. Y. Lee. J. Appl. Physiol. 68: 1211–1219, 1990, and M.-F. Tsan, C. Y. Lee, and J. E. White. J. Appl. Physiol. 71: 688–697, 1991) that tracheal insufflation of 5 micrograms of TNF-alpha or 1 microgram of IL-1 markedly protects rats against O2 toxicity and enhances pulmonary Mn superoxide dismutase (Mn SOD) activity. We now report that TNF-alpha and IL-1 at subprotective doses, e.g., 1 and 0.2 micrograms, respectively, act synergistically in protecting rats against O2 toxicity. Likewise, TNF-alpha and IL-1 at 0.005 microgram/ml each act synergistically in enhancing endothelial cell Mn SOD, but not Cu,Zn SOD mRNA levels. IL-6 at 5 or 10 micrograms provides no protective effect in rats against O2 toxicity and at up to 0.5 microgram/ml has no apparent effect on endothelial cell Mn or Cu,Zn SOD mRNA levels. However, IL-6 markedly enhances TNF-alpha- and IL-1-induced increases in Mn SOD mRNA levels and O2 tolerance. These results support an important role of Mn SOD in the protection against O2 toxicity.

scholarly journals Campylobacter jejuni-Induced Activation of Dendritic Cells Involves Cooperative Signaling through Toll-Like Receptor 4 (TLR4)-MyD88 and TLR4-TRIF Axes

2009 ◽  
Vol 77 (6) ◽  
pp. 2499-2507 ◽  
Author(s):  
Vijay A. K. Rathinam ◽  
Daniel M. Appledorn ◽  
Kathleen A. Hoag ◽  
Andrea Amalfitano ◽  
Linda S. Mansfield
Keyword(s):  
Dendritic Cells ◽  
Campylobacter Jejuni ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Myeloid Differentiation Factor ◽  
Cooperative Signaling

ABSTRACT Campylobacter jejuni is an important cause of human enteritis and has been linked to the development of autoimmune diseases. Recently we showed that infection of murine dendritic cells (DCs) with C. jejuni resulted in DC activation and induction of Campylobacter-specific Th1-effector responses. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) and/or Toll-interleukin 1 (IL-1) receptor domain-containing adaptor-inducing beta interferon (IFN-β) (TRIF) is critical in inducing immunity against pathogens. In this study, we investigated the role of TLR2, TLR4, MyD88, and TRIF signaling in C. jejuni-induced inflammatory activation of DCs. DC upregulation of major histocompatibility complex class II and costimulatory molecules after C. jejuni challenge was profoundly impaired by TLR2, TLR4, MyD88, and TRIF deficiencies. Similarly, C. jejuni-induced secretion of IL-12, IL-6, and tumor necrosis factor alpha was significantly inhibited in TLR2−/−, TLR4−/−, MyD88−/−, and TRIF−/− DCs compared to that in wild-type DCs; however, the magnitude of inhibition was greater in MyD88−/−, TRIF−/−, and TLR4−/− DCs than in TLR2−/− DCs. Furthermore, C. jejuni induced interferon regulatory factor 3 phosphorylation and IFN-β secretion by DCs in a TLR4-TRIF-dependent fashion, further demonstrating activation of this pathway by C. jejuni. Importantly, TLR2, TLR4, MyD88, and TRIF deficiencies all markedly impaired the Th1-priming ability of C. jejuni-infected DCs. Thus, our results show that cooperative signaling through the TLR4-MyD88 and TLR4-TRIF axes represents a novel mechanism mediating C. jejuni-induced inflammatory responses of DCs. To our knowledge, such a mechanism has not been demonstrated previously for an intact bacterium.

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