scholarly journals Progressive Control of Streptococcus agalactiae-Induced Innate Inflammatory Response Is Associated with Time Course Expression of MicroRNA-223 by Neutrophils

2020 ◽  
Vol 88 (12) ◽  
Author(s):  
Maud Deny ◽  
Marta Romano ◽  
Olivier Denis ◽  
Georges Casimir ◽  
Mustapha Chamekh
Keyword(s):  
Inflammatory Response ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Group B Streptococcus ◽  
Early Time ◽  
Potential Contribution ◽  
Microbial Infection ◽  
Human Pathogenic Bacterium ◽  
Cytokines And Chemokines

ABSTRACT Group B streptococcus (GBS) is a human-pathogenic bacterium inducing a strong inflammatory response that may be detrimental for host tissues if not finely regulated. The inflammatory response can be modulated by different molecular mechanisms, among which growing evidence points toward the crucial role of microRNAs (miRNAs). Regarding innate inflammatory response, studies have reported that miR-223 is essential for the control of granulocyte proliferation and activation. Moreover, a number of investigations on miRNA expression profiling performed in various inflammatory settings have revealed that miR-223 is among the top differentially expressed miRNAs. Yet the dynamic pattern of expression of miR-223 in vivo with respect to the evolution of the inflammatory process, especially in microbial infection, remains elusive. In this study, we analyzed the kinetic expression of miR-223 in an inflammatory model of GBS-induced murine pneumonia and looked for correlates with inflammatory markers, including innate cell infiltrates. We found that miR-223 expression is rapidly induced at very early time points (3 to 6 h postinfection [p.i.]) mainly by lung-infiltrating neutrophils. Interestingly, the level of miR-223 accumulating in the lungs remains higher at later stages of infection (24 h and 48 h p.i.), and this correlates with reduced expression of primary inflammatory cytokines and chemokines and with a shift in infiltrating monocyte and macrophage subtypes toward a regulatory phenotype. Transient inhibition of miR-223 by an antagomir resulted in significant increase of CXCL2 expression and partial enhancement of infiltrating neutrophils in GBS-infected lung tissues. This suggests the potential contribution of miR-223 to the resolution phase of GBS-induced acute inflammation.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

scholarly journals ER Stress, UPR Activation and the Inflammatory Response to Viral Infection

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 798
Author(s):  
Mara Cirone
Keyword(s):  
Inflammatory Response ◽  
Viral Infection ◽  
Viral Infections ◽  
Protective Role ◽  
Microbial Infection ◽  
Unfolded Protein ◽  
Cytokines And Chemokines ◽  
Complex Process ◽  
Protein Response ◽  
Recognition Receptor

The response to invading pathogens such as viruses is orchestrated by pattern recognition receptor (PRR) and unfolded protein response (UPR) signaling, which intersects and converges in the activation of proinflammatory pathways and the release of cytokines and chemokines that harness the immune system in the attempt to clear microbial infection. Despite this protective intent, the inflammatory response, particularly during viral infection, may be too intense or last for too long, whereby it becomes the cause of organ or systemic diseases itself. This suggests that a better understanding of the mechanisms that regulate this complex process is needed in order to achieve better control of the side effects that inflammation may cause while potentiating its protective role. The use of specific inhibitors of the UPR sensors or PRRs or the downstream pathways activated by their signaling could offer the opportunity to reach this goal and improve the outcome of inflammation-based diseases associated with viral infections.

F-actin serves as a template for cytokeratin organization in cell free extracts

2002 ◽  
Vol 115 (7) ◽  
pp. 1373-1382 ◽  
Author(s):  
Kari L. Weber ◽  
William M. Bement
Keyword(s):  
Time Course ◽  
Early Time ◽  
Dynamic Imaging ◽  
Actin Network ◽  
Intact Cells ◽  
Time Points ◽  
Egg Extracts ◽  
Actin Cables

The microtubule, F-actin, and intermediate filament systems are often studied as isolated systems, yet the three display mutual interdependence in living cells. To overcome limitations inherent in analysis of polymer-polymer interactions in intact cells, associations between these systems were assessed in Xenopus egg extracts. In both fixed and unfixed extract preparations, cytokeratin associated with F-actin cables that spontaneously assembled in the extracts. Time-course experiments revealed that at early time points cytokeratin cables were invariably associated with F-actin cables,while at later time points they could be found without associated F-actin. In extract samples where F-actin assembly was prevented, cytokeratin formed unorganized aggregates rather than cables. Dynamic imaging revealed transport of cytokeratin by moving F-actin as well as examples of cytokeratin release from F-actin. Experimental alteration of F-actin network organization by addition of α-actinin resulted in a corresponding change in the organization of the cytokeratin network. Finally, pharmacological disruption of the F-actin network in intact, activated eggs disrupted the normal pattern of cytokeratin assembly. These results provide direct evidence for an association between F-actin and cytokeratin in vitro and in vivo, and indicate that this interaction is necessary for proper cytokeratin assembly after transition into the first mitotic interphase of Xenopus.

scholarly journals Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrew P. Sawaya ◽  
Rivka C. Stone ◽  
Stephen R. Brooks ◽  
Irena Pastar ◽  
Ivan Jozic ◽  
...  
Keyword(s):  
Wound Healing ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Diabetic Mouse ◽  
Transcriptional Networks ◽  
Life Threatening ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Abstract Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of “ideal” adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.

scholarly journals Aloin Preconditioning Attenuates Hepatic Ischemia/Reperfusion Injury via Inhibiting TLR4/MyD88/NF-κB Signal Pathway In Vivo and In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yichao Du ◽  
Baolin Qian ◽  
Lin Gao ◽  
Peng Tan ◽  
Hao Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Liver Tissue ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Primary Hepatocytes ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Background. Aloin exerts considerable protective effects in various disease models, and its effect on hepatic ischemia-reperfusion (HIR) injury remains unknown. This research is aimed at conducting an in-depth investigation of the antioxidant, anti-inflammatory, and antiapoptosis effects of aloin in HIR injury and explain the underlying molecular mechanisms. Methods. In vivo, different concentrations of aloin were intraperitoneally injected 1 h before the establishment of the HIR model in male mice. The hepatic function, pathological status, oxidative stress, and inflammatory and apoptosis markers were measured. In vitro, aloin (AL, C21H22O9) or lipopolysaccharide (LPS) was added to a culture of mouse primary hepatocytes before it underwent hypoxia/reoxygenation (H/R), and the apoptosis in the mouse primary hepatocytes was analyzed. Results. We found that 20 mg/kg was the optimum concentration of aloin for mitigating I/R-induced liver tissue damage, characterized by decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Aloin pretreatment substantially suppressed the generation of hepatic malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), and IL-6 and enhanced the hepatic superoxide dismutase (SOD) activities as well as glutathione (GSH) and IL-10 levels in the liver tissue of I/R mice; this indicated that aloin ameliorated I/R-induced liver damage by reducing the oxidative stress and inflammatory response. Moreover, aloin inhibited hepatocyte apoptosis and inflammatory response that was caused by the upregulated expression of Bcl-2, the downregulated expression of cleaved caspase3(C-caspase3), Bax, Toll-like receptor 4 (TLR4), FADD, MyD88, TRAF6, phosphorylated IKKα/β (p-IKKα/β), and phosphorylated nuclear factor κB p65 (p-NF-κB p65).

scholarly journals Therapeutic Effects of Curcumin—From Traditional Past to Present and Future Clinical Applications

2019 ◽  
Vol 20 (15) ◽  
pp. 3757 ◽  
Author(s):  
Beatrice Bachmeier ◽  
Dieter Melchart
Keyword(s):  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Scientific Evidence ◽  
Treatment Strategies ◽  
Therapeutic Effects ◽  
Microbial Infection ◽  
Therapeutic Benefits ◽  
Novel Treatment Strategies

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, is matter of public interest. An internet search of the term “Curcumin” displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a “miracle cure”. This circumstance makes it very difficult for researchers, who work in a scientifically sound and evidence-based manner on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin’s way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin’s molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future—either as monotherapy or in combination with other drugs or therapeutic applications.

scholarly journals Real-Time Analysis of Endogenous Wnt Signalling in 3D Mesenchymal Stromal Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Fatima Saleh ◽  
Alice Carstairs ◽  
S. Leah Etheridge ◽  
Paul Genever
Keyword(s):  
Time Course ◽  
Molecular Mechanisms ◽  
Adipogenic Differentiation ◽  
Wnt Signalling ◽  
Egfp Expression ◽  
Culture Techniques ◽  
Real Time Analysis ◽  
Pathway Activation

Wnt signalling has been implicated in the regulation of stem cell self-renewal and differentiation; however, the majority of in vitro studies are carried out using monolayer 2D culture techniques. Here, we used mesenchymal stromal cell (MSC) EGFP reporter lines responsive to Wnt pathway activation in a 3D spheroid culture system to mimic better the in vivo environment. Endogenous Wnt signalling was then investigated under basal conditions and when MSCs were induced to undergo osteogenic and adipogenic differentiation. Interestingly, endogenous Wnt signalling was only active during 3D differentiation whereas 2D cultures showed no EGFP expression throughout an extended differentiation time-course. Furthermore, exogenous Wnt signalling in 3D adipogenic conditions inhibited differentiation compared to unstimulated controls. In addition, suppressing Wnt signalling by Dkk-1 restored and facilitated adipogenic differentiation in MSC spheroids. Our findings indicate that endogenous Wnt signalling is active and can be tracked in 3D MSC cultures where it may act as a molecular switch in adipogenesis. The identification of the signalling pathways that regulate MSCs in a 3D in vivo-like environment will advance our understanding of the molecular mechanisms that control MSC fate.

scholarly journals GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-κB Pathway

2019 ◽  
Vol 30 (9) ◽  
pp. 1573-1586 ◽  
Author(s):  
Sonia Zambrano ◽  
Katja Möller-Hackbarth ◽  
Xidan Li ◽  
Patricia Q. Rodriguez ◽  
Emmanuelle Charrin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Knockout Mice ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Data Sets ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Inflammatory Processes

BackgroundInflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood.MethodsWe performed large-scale gene expression profiling of glomerulus-associated G protein–coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies. The expression of Gprc5b in disease was analyzed using quantitative PCR and immunofluorescence, and by analyzing published microarray data sets. In vivo studies were carried out in a podocyte-specific Gprc5b knockout mouse line. Mechanistic studies were performed in cultured human podocytes.ResultsWe identified an orphan GPCR, Gprc5b, as a novel gene highly enriched in podocytes that was significantly upregulated in common human glomerulopathies, including diabetic nephropathy, IgA nephropathy, and lupus nephritis. Similar upregulation of Gprc5b was detected in LPS-induced nephropathy in mice. Studies in podocyte-specific Gprc5b knockout mice showed that Gprc5b was not essential for normal development of the glomerular filtration barrier. However, knockout mice were partially protected from LPS-induced proteinuria and recruitment of inflammatory cells. Mechanistically, RNA sequencing in Gprc5b knockouts mice and experiments in cultured human podocytes showed that Gpr5cb regulated inflammatory response in podocytes via NF-κB signaling.ConclusionsGPRC5b is a novel podocyte-specific receptor that regulates inflammatory response in the glomerulus by modulating the NF-κB signaling pathway. Upregulation of Gprc5b in human glomerulopathies suggests that it may play a role in their pathogenesis.

scholarly journals Effects of acute and chronic inflammation on proteins involved in duodenal iron absorption in mice: a time-course study

2012 ◽  
Vol 108 (11) ◽  
pp. 1994-2001 ◽  
Author(s):  
Abitha Sukumaran ◽  
Joe Varghese ◽  
Jesintha Tamilselvan ◽  
Visalakshi Jeyaseelan ◽  
Thenmozhi Mani ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Early Time ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Expression Levels ◽  
Hepcidin Expression ◽  
Time Course Study ◽  
Acute And Chronic Inflammation

In order to understand better the molecular mechanisms involved in the pathogenesis of anaemia of inflammation, we carried out a time-course study on the effects of turpentine-induced acute and chronic inflammation on duodenal proteins involved in Fe absorption in mice. Expression levels of these proteins and hepatic hepcidin and serum Fe levels were determined in inflamed mice. In acutely inflamed mice, significantly increased expression of ferritin was the earliest change observed, followed by decreased divalent metal transporter 1 expression in the duodenum and increased hepcidin expression in the liver. Ferroportin expression increased subsequently, despite high levels of hepcidin. Hypoferraemia, which developed at early time periods studied, was followed by increased serum Fe levels at later points. The present results thus show that acute inflammation induced several changes in the expression of proteins involved in duodenal Fe absorption, contributing to the development of hypoferraemia. Resolution of inflammation caused attenuation of many of these effects. Effects in chronically inflamed mice were less consistent. The present results also suggest that inflammation-induced increases in ferritin appeared to override the effects of hepcidin on the expression levels of ferroportin in enterocytes.

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