scholarly journals Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

2008 ◽  
Vol 411 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Jaya P. Gnana-Prakasam ◽  
Pamela M. Martin ◽  
Barbara A. Mysona ◽  
Penny Roon ◽  
Sylvia B. Smith ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Müller Cells ◽  
Photoreceptor Cells ◽  
The Body ◽  
Mouse Retina ◽  
Muller Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Hepcidin Expression

Hepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells and the RPE (retinal pigment epithelium) within the retina. Since the retina is protected by the retinal–blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells and RPE cells, closely resembling the expression pattern of ferroportin. We also show that bacterial LPS (lipopolysaccharide) is a regulator of hepcidin expression in Müller cells and the RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the TLR4 (Toll-like receptor-4). The upregulation of hepcidin by LPS occurs independent of Hfe (human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent down-regulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

scholarly journals Reprogramming of endogenous Müller cells into photoreceptor-like cells induced by small-molecule compounds in mice

2021 ◽  
Author(s):  
Yuya Fujii ◽  
Mitsuru Arima ◽  
Yusuke Murakami ◽  
Koh-Hei Sonoda
Keyword(s):  
Intravitreal Injection ◽  
Small Molecule ◽  
Messenger Rna ◽  
Glycogen Synthase ◽  
Müller Cells ◽  
Photoreceptor Cells ◽  
Lineage Tracing ◽  
Muller Cells

Abstract Lifelong visual impairment occurs from retinal diseases due to the inability of photoreceptor cells to regenerate in mammals. We demonstrated that endogenous Müller cells (MCs) in mice differentiate into photoreceptor-like cells by intravitreal injection of four small-molecule compounds: tumor growth factor-β inhibitor, bone morphogenetic protein inhibitor, glycogen synthase kinase 3 inhibitor, and γ-secretase inhibitor. In vitro, the messenger RNA of rhodopsin (Rho) in MCs increased 30-fold, and 25% of cultured MCs expressed Rho protein 7 days after stimulation with these compounds. In vivo, Rho-positive cells were regenerated on day 7 after the intravitreal injection of four compounds, accompanied with recovery of Rho-derived scotopic function. Lineage tracing in mice treated with N-methyl-N-nitrosourea, a disease model of photoreceptor degeneration, showed that the regenerated Rho-positive cells were originated from endogenous MCs. Finally, the regeneration of Rho-positive cells was also induced in the retina of rd10 mice, a model with similar genetic mutation as humans. Notably, the intravitreal injection significantly reduced cone cell death in rd10 mice. This treatment could be a new strategy in retinal regenerative medicine where mammalian endogenous MCs are reprogrammed into photoreceptor cells independent of transplantation or gene transfer.

scholarly journals Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 599
Author(s):  
Víctor Farré-Alins ◽  
Alejandra Palomino-Antolín ◽  
Paloma Narros-Fernández ◽  
Ana Belen Lopez-Rodriguez ◽  
Céline Decouty-Perez ◽  
...  
Keyword(s):  
Injury Severity ◽  
White Blood Cells ◽  
Serum Amyloid ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Important Link ◽  
Tlr4 Mrna ◽  
Serum Amyloid A1

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

Lack of Toll-like receptor 4 decreases lipopolysaccharide-induced bone resorption in C3H/HeJ mice in vivo

2008 ◽  
Vol 23 (3) ◽  
pp. 190-195 ◽  
Author(s):  
H. Nakamura ◽  
Y. Fukusaki ◽  
A. Yoshimura ◽  
C. Shiraishi ◽  
M. Kishimoto ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3216
Author(s):  
Maryvonne Ardourel ◽  
Chloé Felgerolle ◽  
Arnaud Pâris ◽  
Niyazi Acar ◽  
Khaoula Ramchani Ben Othman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Müller Cells ◽  
Nutritional Supplement ◽  
Glutamine Metabolism ◽  
Muller Cells ◽  
Omega 3 ◽  
Glutamine Synthesis ◽  
The Impact

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

Functional significance and neural basis of larval lamprey startle behaviour

1987 ◽  
Vol 133 (1) ◽  
pp. 121-135 ◽  
Author(s):  
S. N. Currie ◽  
R. C. Carlsen
Keyword(s):  
Functional Significance ◽  
Action Potentials ◽  
Startle Response ◽  
Müller Cells ◽  
The Body ◽  
Simultaneous Action ◽  
Muller Cells ◽  
Neural Basis ◽  
Lateral Body ◽  
Motor Effects

1. The vibration-evoked startle response mediates rapid withdrawal in burrowed larval lampreys (ammocoetes). Ammocoetes withdraw in response to vibration by contracting pre-existing lateral bends in the trunk and tail, thus pulling their heads deeper into the burrow. 2. The motor effects of an ammocoete startle response are dependent on pre-existing posture. Areas of lateral body curvature contract more and exhibit larger electromyogram (EMG) amplitudes on their inner sides than on their outer sides. 3. Both of the anterior Mth and posterior Mth' (Mauthner) cells and both of the B1 and B2 (bulbar) Muller cells fired action potentials in response to vibration of the otic capsules. Both B3 and B4 Muller cells were inhibited by vibration, while M (mesencephalic) and I1 (isthmic) Muller cells were inhibited by ipsilateral vibration and excited by contralateral vibration. 4. Simultaneous action potentials in both of the anterior Mth cells were appropriate and sufficient for initiating the startle response EMG in a semi-intact preparation. 5. This study demonstrates a Mauthner-initiated startle response which activates musculature on both sides of the body to produce a rapid withdrawal movement and is thus adapted to the eel-like form and burrowed lifestyle of larval lampreys.

Hepcidin inhibition improves iron homeostasis in ferrous sulfate and LPS treatment model in mice

Drug Research ◽  
2021 ◽  
Author(s):  
Vishal Patel ◽  
Amit Joharapurkar ◽  
Samadhan Kshirsagar ◽  
Maulik Patel ◽  
Hiren Patel ◽  
...  
Keyword(s):  
Ferrous Sulfate ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
The Body ◽  
Rapid Screening ◽  
Iron Dextran ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Serum Hepcidin ◽  
Lps Treatment

Abstract Background Hepcidin, a liver-derived peptide, regulates the absorption, distribution, and circulation of iron in the body. Inflammation or iron overload stimulates hepcidin release, which causes the accumulation of iron in tissues. The inadequate levels of iron in circulation impair erythropoiesis. Inhibition of hepcidin may increase iron in circulation and improve efficient erythropoiesis. Activin-like kinase (ALK) inhibitors decrease hepcidin. Methods In this work, we have investigated an ALK inhibitor LDN193189 for its efficacy in iron homeostasis. The effect of LDN193189 treatment was assessed in C57BL6/J mice, in which hepcidin was induced by either ferrous sulfate or lipopolysaccharide (LPS) injection. Results After two hours of treatment, ferrous sulfate increased serum and liver iron, serum hepcidin, and liver hepcidin expression. On the other hand, LPS reduced serum iron in a dose-related manner after six hours of treatment. LDN193189 treatment increased serum iron, decreased spleen and liver iron, decreased serum hepcidin and liver hepcidin expression in ferrous sulfate-treated mice, and increased serum iron in LPS-induced hypoferremia. We observed that ferrous sulfate caused a significantly higher increase in liver iron, serum hepcidin, and liver hepcidin than turpentine oil or LPS in mice. Iron dextran (intraperitoneal or intravenous) increased serum iron, but LDN193189 did not show hyperferremia with iron dextran stimulus. Conclusion Ferrous sulfate-induced hyperferremia can be a valuable and rapid screening model for assessing the efficacy of hepcidin inhibitors.

scholarly journals A2AR Antagonists Upregulate Expression of GS and GLAST in Rat Hypoxia Model

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Jun Yu ◽  
Yan Yan ◽  
Yiye Chen ◽  
Yan Zheng ◽  
Xiaoyan Yu ◽  
...  
Keyword(s):  
Müller Cells ◽  
Muller Cells ◽  
Cell Viability Assay ◽  
Hypoxic Conditions ◽  
Viability Assay ◽  
Drug Concentrations ◽  
A Cell ◽  
Short Time

Background. The aim of this study was to research the effects of glutamine synthetase (GS) and glutamate aspartate transporter (GLAST) in rat Müller cells and the effects of an adenosine A2AR antagonist (SCH 442416) on GS and GLAST in hypoxia both in vivo and in vitro. Methods. This study used RT-PCR and Western blotting to quantify the expressions of GS and GLAST under different hypoxic conditions as well as the expressions of GS and GLAST at different drug concentrations. A cell viability assay was used to assess drug toxicity. Results. mRNA and protein expression of GS and GLAST in hypoxia Group 24 h was significantly increased. mRNA and protein expressions of GS and GLAST both increased in Group 1 μM SCH 442416 compared with other groups. One micromolar SCH 442416 could upregulate GS and GLAST’s activity in hypoxia both in vivo and in vitro. Conclusions. Hypoxia activates GS and GLAST in rat retinal Müller cells in a short time in vitro. (2) A2AR antagonists upregulate the activity of GS and GLAST in hypoxia both in vivo and in vitro.

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