scholarly journals Differential Response of Müller Cells and Microglia in a Mouse Retinal Detachment Model and Its Implications in Detached and Non-Detached Regions

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1972
Author(s):  
Seung-Hee Lee ◽  
Yong-Soo Park ◽  
Sun-Sook Paik ◽  
In-Beom Kim
Keyword(s):  
Retinal Detachment ◽  
Outer Nuclear Layer ◽  
Microglial Cells ◽  
Dependent Manner ◽  
Border Regions ◽  
Retinal Glial Cell ◽  
Threatening Condition ◽  
Gfap Immunoreactivity ◽  
Retinal Region ◽  
Hematoxylin And Eosin

Retinal detachment (RD) is a sight-threatening condition, leading to photoreceptor cell death; however, only a few studies provide insight into its effects on the entire retinal region. We examined the spatiotemporal changes in glial responses in a mouse RD model. In electroretinography, a- and b-waves were reduced in a time-dependent manner. Hematoxylin and eosin staining revealed a gradual decrease in the outer nuclear layer throughout the retinal region. Terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay showed that TUNEL-positive photoreceptors increased 5 days after RD and decreased by 14 days. Glial response was evaluated by immunohistochemistry using antibodies against glial fibrillary acidic protein (GFAP, Müller glial marker) and Iba-1 (microglial marker) and osteopontin (OPN, activated microglial marker). GFAP immunoreactivity increased after 7 days in complete RD, and was retained for 14 days. OPN expression increased in microglial cells 3–7 days after RD, and decreased by 14 days in the detached and border regions. Although OPN was not expressed in the intact region, morphologically activated microglial cells were observed. These retinal glial cell responses and photoreceptor degeneration in the border and intact regions suggest that the effects of RD in the border and intact retinal regions need to be understood further.

scholarly journals Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1652
Author(s):  
Chinmaya Panda ◽  
Clara Voelz ◽  
Pardes Habib ◽  
Christian Mevissen ◽  
Thomas Pufe ◽  
...  
Keyword(s):  
Tau Protein ◽  
Nlrp3 Inflammasome ◽  
Time Dependent ◽  
Microglial Cells ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Progressive Dementia ◽  
Microglial Polarization ◽  
Protein Levels ◽  
Pyrin Domain

Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1β (IL1β) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.

scholarly journals Anti-Inflammatory Activities of Compounds Isolated from the Rhizome of Anemarrhena asphodeloides

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2631 ◽  
Author(s):  
Zeyuan Wang ◽  
Jianfeng Cai ◽  
Qing Fu ◽  
Lingping Cheng ◽  
Lehao Wu ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Microglial Cells ◽  
No Production ◽  
Dependent Manner ◽  
Platycodin D ◽  
Protein Levels ◽  
Chemical Structures ◽  
Ic50 Values ◽  
Anti Inflammatory ◽  
Anemarrhena Asphodeloides

Fifteen unreported compounds in Anemarrhena asphodeloides, iriflophene (3), hostaplantagineoside C (7), tuberoside G (8), spicatoside B (9), platycodin D (14), platycoside A (15), platycodin D2 (16), polygalacin D2 (17), platycodin D3 (18), isovitexin (20), vitexin (21), 3,4-dihydroxyallylbenzene-3-O-α-l-rhamnopyranosyl(1→6)-β-d-glucopyranoside (22), iryptophan (24), adenosine (25), α-d-Glucose monoallyl ether (26), together with eleven known compounds (1, 2, 4–6, 10–13, 19 and 23), were isolated from the rhizomes of Anemarrhena asphodeloides. The chemical structures of these compounds were characterized using HRMS and NMR. The anti-inflammatory activities of the compounds were evaluated by investigating their ability to inhibit LPS-induced NO production in N9 microglial cells. Timosaponin BIII (TBIII) and trans-hinokiresinol (t-HL) exhibited significant inhibitory effects on the NO production in a dose-dependent manner with IC50 values of 11.91 and 39.08 μM, respectively. Immunoblotting demonstrated that TBIII and t-HL suppressed NO production by inhibiting the expressions of iNOS in LPS-stimulated N9 microglial cells. Further results revealed that pretreatment of N9 microglial cells with TBIII and t-HL attenuated the LPS-induced expression tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at mRNAs and protein levels. Moreover, the activation of nuclear factor-κB (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were inhibited by TBIII and t-HL, respectively. Our findings indicate that the therapeutic implication of TBIII and t-HL for neurogenerative disease associated with neuroinflammation.

scholarly journals Japanese Encephalitis Virus Infected Microglial Cells Secrete Exosomes Containing let-7a/b that Facilitate Neuronal Damage via Caspase Activation

2018 ◽  
Author(s):  
Sriparna Mukherjee ◽  
Irshad Akbar ◽  
Bharti Kumari ◽  
Sudhanshu Vrati ◽  
Anirban Basu ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Neuronal Damage ◽  
Cell Communication ◽  
Notch Signaling Pathway ◽  
Encephalitis Virus ◽  
Microglial Cells ◽  
Dependent Manner ◽  
Caspase Activation ◽  
Hek 293

AbstractExtracellular microRNAs (miRNAs) are essential for the cell to cell communication in the healthy and diseased brain. MicroRNAs released from the activated microglia upon neurotropic virus infection may exacerbate CNS damage. Here, we identified let-7a and let-7b (let-7a/b) as the overexpressed miRNAs in Japanese Encephalitis virus (JEV) infected microglia and assessed their role in JEV pathogenesis. We measured the let-7a/b expressions in JEV infected post-mortem human brains, mice brains and in mouse microglial N9 cells by the qRT-PCR and in situ hybridization assay. The interaction between let-7a/b and NOTCH signaling pathway further examined in Toll-like receptor 7 knockdown (TLR7 KD) mice to assess the functions. Exosomes released from JEV infected or let-7a/b mimic transfected N9, and HEK-293 cells were isolated and evaluated their function. We observed an upregulation of let-7a/b in the infected brains as well as in microglia. Knockdown of TLR7 or Inhibition of let-7a/b suppressed the JEV induced NOTCH activation possibly via NF-κB dependent manner and subsequently, attenuated JEV induced TNFα production in microglial cells. Further, exosomes secreted from JEV-infected microglial cells specifically contained let-7a/b. Exosomes overexpressed with let-7a/b were injected into BALB/c mice as well as co-incubated with mouse neuronal (Neuro2a) cells, or primary cortical neuron resulted in caspase activation leading to neuronal damage in the brain. Thus, our results provide evidence for the multifaceted role of let-7a/b miRNAs and unravel the exosomes mediated mechanism for JEV induced pathogenesis.

scholarly journals Regulation of the Fructose Transporter Gene Slc2a5 Expression by Glucose in Cultured Microglial Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 12668
Author(s):  
Tooru M. Mizuno ◽  
Pei San Lew ◽  
Gursagar Jhanji
Keyword(s):  
Cell Activation ◽  
Glucose Transporter ◽  
Early Gene ◽  
Microglial Cells ◽  
Dependent Manner ◽  
Nutritional Regulation ◽  
High Concentration ◽  
Activation Markers ◽  
Microglial Cell Line ◽  
Regulation Of Metabolism

Microglia play a role in the regulation of metabolism and pathogenesis of obesity. Microglial activity is altered in response to changes in diet and the body’s metabolic state. Solute carrier family 2 member 5 (Slc2a5) that encodes glucose transporter 5 (GLUT5) is a fructose transporter primarily expressed in microglia within the central nervous system. However, little is known about the nutritional regulation of Slc2a5 expression in microglia and its role in the regulation of metabolism. The present study aimed to address the hypothesis that nutrients affect microglial activity by altering the expression of glucose transporter genes. Murine microglial cell line SIM-A9 cells and primary microglia from mouse brain were exposed to different concentrations of glucose and levels of microglial activation markers and glucose transporter genes were measured. High concentration of glucose increased levels of the immediate-early gene product c-Fos, a marker of cell activation, Slc2a5 mRNA, and pro-inflammatory cytokine genes in microglial cells in a time-dependent manner, while fructose failed to cause these changes. Glucose-induced changes in pro-inflammatory gene expression were partially attenuated in SIM-A9 cells treated with the GLUT5 inhibitor. These findings suggest that an increase in local glucose availability leads to the activation of microglia by controlling their carbohydrate sensing mechanism through both GLUT5-dependent and –independent mechanisms.

Rhegmatogenous retinal detachment in Royal Naval personnel: A retrospective study

1992 ◽  
Vol 78 (3) ◽  
pp. 151-158
Author(s):  
C. D. T. Low ◽  
M. N. Jeffrey
Keyword(s):  
Primary Care ◽  
Retrospective Study ◽  
Retinal Detachment ◽  
Rhegmatogenous Retinal Detachment ◽  
Considerable Time ◽  
Poor Outcome ◽  
Operative Complications ◽  
Threatening Condition ◽  
Time Away ◽  
Post Operative Complications

AbstractA retrospective study was conducted to assess the various factors thought to influence the outcome of retinal detachment in RN personnel. A description of retinal detachment and its management, aimed at non-specialists, is given in the introduction.In the study period eight Servicemen had rhegmatogenous retinal detachments. All underwent conventional detachment surgery, but two required two further operations including vitrectomy. Important features of each patient’s detachment are discussed, as is post-operative progress. All patients spent a considerable time away from duty and three were discharged from the Service on medical grounds.Poor outcome could be related to myopia, trauma, delay in presentation to primary care, the number of operations performed and to post-operative complications.Advice is given regarding assessment and management of suspected cases by non-specialists. It is hoped that reporting this study will increase awareness within the RN of retinal detachment as a sight-threatening condition.

scholarly journals Expression of the Endoplasmic Reticulum Stress Marker GRP78 in the Normal Retina and Retinal Degeneration Induced by Blue LED Stimuli in Mice

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 995
Author(s):  
Yong Soo Park ◽  
Hong-Lim Kim ◽  
Seung Hee Lee ◽  
Yan Zhang ◽  
In-Beom Kim
Keyword(s):  
Endoplasmic Reticulum ◽  
Retinal Degeneration ◽  
Glial Cells ◽  
Cell Activation ◽  
Outer Nuclear Layer ◽  
Photoreceptor Cells ◽  
Dependent Manner ◽  
Normal Retina ◽  
Perinuclear Space ◽  
The Unfolded Protein Response

Retinal degeneration is a leading cause of blindness. The unfolded protein response (UPR) is an endoplasmic reticulum (ER) stress response that affects cell survival and death and GRP78 forms a representative protective response. We aimed to determine the exact localization of GRP78 in an animal model of light-induced retinal degeneration. Dark-adapted mice were exposed to blue light-emitting diodes and retinas were obtained at 24 h and 72 h after exposure. In the normal retina, we found that GRP78 was rarely detected in the photoreceptor cells while it was expressed in the perinuclear space of the cell bodies in the inner nuclear and ganglion cell layers. After injury, the expression of GRP78 in the outer nuclear and inner plexiform layers increased in a time-dependent manner. However, an increased GRP78 expression was not observed in damaged photoreceptor cells in the outer nuclear layer. GRP78 was located in the perinuclear space and ER lumen of glial cells and the ER developed in glial cells during retinal degeneration. These findings suggest that GRP78 and the ER response are important for glial cell activation in the retina during photoreceptor degeneration.

scholarly journals Walnut Oil and Blueberry Treatments Have Beneficial Individual but Not Synergistic Effects on Neuroinflammation In Vitro

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 904-904
Author(s):  
Derek Fisher ◽  
Danielle Cahoon ◽  
Barbara Shukitt-Hale
Keyword(s):  
Treatment Time ◽  
Synergistic Effects ◽  
Microglial Cells ◽  
Individual Treatment ◽  
Dependent Manner ◽  
Walnut Oil ◽  
Beneficial Effects ◽  
Nitrite Production ◽  
Freeze Dried

Abstract Objectives Neuroinflammation has been associated with cognitive decline and neurodegenerative disease. Walnuts and blueberries (BB) each provide neuroprotective anti-inflammatory components. However, it is unknown whether they act synergistically to enhance the effects seen with individual supplementation. This study aimed to examine the individual and potentially synergistic beneficial effects of walnut oil (WO) and BB on lipopolysaccharide (LPS)-induced neuroinflammation in rat microglial cells. The effects of pre-treatment time and concentration were also explored. Methods Rat microglial cells were pre-treated for 48 hours, 1, 2 or 4 weeks with control media or freeze-dried BB extract, WO or WO/BB diluted in media at 0.05, 0.1, 0.2, 0.5 and 1.0 mg/mL. At the end of each treatment time point, cells were stressed with LPS (100 ng/mL) overnight. Standard immunochemical techniques were used to measure biomarkers of inflammation: nitrite, inducible nitrous oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Data were analyzed using three-way ANOVAs with treatment, concentration, and time as experimental factors, and Tukey's post-hoc test to determine differences among groups. Results Results showed that BB, WO, and WO/BB reduced LPS-induced nitrite, COX2 and iNOS relative to control (P < 0.05). BB had a stronger effect on reducing nitrite production than WO/BB, and both BB and WO/BB were more effective than WO (P < 0.05). However, there were no significant differences between treatments for COX2 and iNOS expression. All three treatments attenuated LPS-induced nitrite, COX2, and iNOS in a concentration- and time-dependent manner (P < 0.05), with higher doses and longer treatment durations being most beneficial. Conclusions Although BB, WO and WO/BB reduced LPS-induced neuroinflammation, WO/BB was not more effective than either individual treatment. This result suggests that BB and WO do not act synergistically to attenuate inflammation in microglia. Additionally, the intermediate effect of WO/BB relative to BB and WO on nitrite suggests that BB is primarily responsible for the beneficial effects of WO/BB. Overall, the reduction in neuroinflammation following all treatments shows that the addition of blueberries and/or walnuts to the diet may attenuate the neurodegenerative effects of inflammation. Funding Sources Supported by USDA intramural funding.

scholarly journals The Protective Effects of α-Mangostin Attenuate Sodium Iodate-Induced Cytotoxicity and Oxidative Injury via Mediating SIRT-3 Inactivation via the PI3K/AKT/PGC-1α Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1870
Author(s):  
Chen-Ju Chuang ◽  
Meilin Wang ◽  
Jui-Hsuan Yeh ◽  
Tzu-Chun Chen ◽  
Shang-Chun Tsou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Cell Damage ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Protective Effects ◽  
Age Related

It is well known that age-related macular degeneration (AMD) is an irreversible neurodegenerative disease that can cause blindness in the elderly. Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a part of the pathogenesis of AMD. In this study, we evaluated the protective effect and mechanisms of alpha-mangostin (α-mangostin, α-MG) against NaIO3-induced reactive oxygen species (ROS)-dependent toxicity, which activates apoptosis in vivo and in vitro. MTT assay and flow cytometry demonstrated that the pretreatment of ARPE-19 cells with α-MG (0, 3.75, 7.5, and 15 μM) significantly increased cell viability and reduced apoptosis from NaIO3-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cleaved PARP-1, cleaved caspase-3 protein expression, and enhancement of Bcl-2 protein. Furthermore, pre-incubation of ARPE-19 cells with α-MG markedly inhibited the intracellular ROS and extracellular H2O2 generation via blocking of the abnormal enzyme activities of superoxide dismutase (SOD), the downregulated levels of catalase (CAT), and the endogenous antioxidant, glutathione (GSH), which were regulated by decreasing PI3K-AKT-PGC-1α-STRT-3 signaling in ARPE-19 cells. In addition, our in vivo results indicated that α-MG improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer by inhibiting the expression of cleaved caspase-3 protein. Taken together, our results suggest that α-MG effectively protects human ARPE-19 cells from NaIO3-induced oxidative damage via antiapoptotic and antioxidant effects.

scholarly journals Erythropoietin Abrogates Post-Ischemic Activation of the NLRP3, NLRC4, and AIM2 Inflammasomes in Microglia/Macrophages in a TAK1-Dependent Manner

2021 ◽  
Author(s):  
Ole Heinisch ◽  
Thomas Zeyen ◽  
Tobias Goldmann ◽  
Marco Prinz ◽  
Michael Huber ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Clinical Outcomes ◽  
Brain Damage ◽  
Nlrp3 Inflammasome ◽  
Microglial Cells ◽  
Disease Models ◽  
Dependent Manner ◽  
Pharmacological Inhibition ◽  
Protein Levels

AbstractInflammasomes are known to contribute to brain damage after acute ischemic stroke (AIS). TAK1 is predominantly expressed in microglial cells and can regulate the NLRP3 inflammasome, but its impact on other inflammasomes including NLRC4 and AIM2 after AIS remains elusive. EPO has been shown to reduce NLRP3 protein levels in different disease models. Whether EPO-mediated neuroprotection after AIS is conveyed via an EPO/TAK1/inflammasome axis in microglia remains to be clarified. Subjecting mice deficient for TAK1 in microglia/macrophages (Mi/MΦ) to AIS revealed a significant reduction in infarct sizes and neurological impairments compared to the corresponding controls. Post-ischemic increased activation of TAK1, NLRP3, NLRC4, and AIM2 inflammasomes including their associated downstream cascades were markedly reduced upon deletion of Mi/MΦ TAK1. EPO administration improved clinical outcomes and dampened stroke-induced activation of TAK1 and inflammasome cascades, which was not evident after the deletion of Mi/MΦ TAK1. Pharmacological inhibition of NLRP3 in microglial BV-2 cells did not influence post-OGD IL-1β levels, but increased NLRC4 and AIM2 protein levels, suggesting compensatory activities among inflammasomes. Overall, we provide evidence that Mi/MΦ TAK1 regulates the expression and activation of the NLRP3, NLRC4, AIM2 inflammasomes. Furthermore, EPO mitigated stroke-induced activation of TAK1 and inflammasomes, indicating that EPO conveyed neuroprotection might be mediated via an EPO/TAK1/inflammasome axis. Graphical Abstract

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