scholarly journals RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

2020 ◽  
Author(s):  
Yang Jiao ◽  
Jianjian Wang ◽  
Huixue Zhang ◽  
Yuze Cao ◽  
Yang Qu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Experimental Stroke ◽  
Inflammasome Activation ◽  
Cerebral Ischemic

Abstract Background Microglia are rapidly activated after ischemic stroke and participate in the occurrence of neuroinflammation, which exacerbates the injury of ischemic stroke. Receptor Interacting Serine Threonine Kinase 1 (RIPK1) is thought to be involved in the development of inflammatory responses, but its role in ischemic microglia remains unclear. Here, we applied recombinant human thioredoxin-1 (rhTrx-1), a potential neuroprotective agent, to explore the role of rhTrx-1 in inhibiting RIPK1-mediated neuroinflammatory responses in microglia. Method Middle cerebral artery occlusion (MCAO) and Oxygen and glucose deprivation (OGD) were conducted for in vivo and in vitro experimental stroke models. The expression of RIPK1 in microglia after ischemia was examined. The inflammatory response of microglia was analyzed after treatment with rhTrx-1 and Necrostatin-1 (Nec-1, inhibitors of RIPK1), and the mechanisms were explored. In addition, the effects of rhTrx-1 on neurobehavioral deficits and cerebral infarct volume were examined. Results RIPK1 expression was detected in microglia after ischemia. Molecular docking results showed that rhTrx-1 could directly bind to RIPK1. In vitro experiments found that rhTrx-1 reduced necroptosis, mitochondrial membrane potential damage, Reactive oxygen species (ROS) accumulation and NLR Family, pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting RIPK-1 expression, and regulated microglial M1/M2 phenotypic changes, thereby reducing the release of inflammatory factors. Consistently, in vivo experiments found that rhTrx-1 treatment attenuated cerebral ischemic injury by inhibiting the inflammatory response. Conclusion Our study demonstrates the role of RIPK1 in microglia-arranged neuroinflammation after cerebral ischemia. Administration of rhTrx-1 provides neuroprotection in ischemic stroke-induced microglial neuroinflammation by inhibiting RIPK1 expression.

scholarly journals Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Tang ◽  
Mengchun Zhou ◽  
Rongrong Huang ◽  
Ling Shen ◽  
Li Yang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Astrocyte Activation ◽  
Hect Domain ◽  
P38 Inhibitor ◽  
Ubiquitin Protein Ligase ◽  
Primary Mouse ◽  
Lps Treatment

Abstract Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.

scholarly journals The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma

2021 ◽  
Vol 20 ◽  
pp. 153303382199528
Author(s):  
Qing Lv ◽  
Qinghua Xia ◽  
Anshu Li ◽  
Zhiyong Wang
Keyword(s):  
Tumor Microenvironment ◽  
Interleukin 1 ◽  
Mrna Level ◽  
Inflammatory Factors ◽  
Stomach Carcinoma ◽  
Downstream Target ◽  
Volume Weight

This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-κB signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-κB, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.

scholarly journals The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4370
Author(s):  
Cássia de Fáveri ◽  
Paula M. Poeta Fermino ◽  
Anna P. Piovezan ◽  
Lia K. Volpato
Keyword(s):  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Integrative Review ◽  
Inflammatory Factors ◽  
Resolvin D1 ◽  
Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

scholarly journals Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shinjini Chakraborty ◽  
Veronika Eva Winkelmann ◽  
Sonja Braumüller ◽  
Annette Palmer ◽  
Anke Schultze ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Inflammatory Responses ◽  
Experimental Models ◽  
Lung Damage ◽  
C5a Receptor ◽  
Cytokine Levels ◽  
Vitro Model

AbstractSingular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.

Abstract WMP31: Dedifferentiation of Smooth Muscle Cells and its Potential Contribution to Pathogenesis of Intracranial Aneurysms

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Mieko Oka ◽  
Nobuhiko Ohno ◽  
Takakazu Kawamata ◽  
Tomohiro Aoki
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Inflammatory Responses ◽  
Muscle Cells ◽  
Inflammatory Factors ◽  
Potential Contribution ◽  
Electron Microscopic

Introduction: Intracranial aneurysm (IA) affects 1 to 5 % in general public and becomes the primary cause of subarachnoid hemorrhage, the most severe form of stroke. However, currently, no drug therapy is available for IAs to prevent progression and rupture of lesions. Elucidation of mechanisms underlying the disease is thus mandatory. Considering the important role of vascular smooth muscle cells (SMCs) in the maintenance of stiffness of arterial walls and also in the pathogenesis of atherosclerosis via mediating inflammatory responses, we in the present study analyzed morphological or phenotypical changes of SMCs during the disease development in the lesions. Methods: We subjected rats to an IA model in which lesions are induced by increase of hemodynamic force loading on intracranial arterial bifurcations and performed histopathological analyses of induced lesions including the electron microscopic examination. We then immunostained specimens from induced lesions to explore factors responsible for dedifferentiation or migration of SMCs. In vitro study was also done to examine effect of some candidate factors on dedifferentiation or migration of cultured SMCs. Results: We first found the accumulation of SMCs underneath the endothelial cell layer mainly at the neck portion of the lesion. These cells was positive for the embryonic form of myosin heavy chain, a marker for the dedifferentiated SMCs, and the expression of pro-inflammatory factors like TNF-α. In immunostaining to explore the potential factor regulating the dedifferentiation of SMCs, we found that Platelet-derived growth factor-BB (PDGF-BB) was expressed in endothelial cells at the neck portion of IA walls. Consistently, recombinant PDGF-BB could promote the dedifferentiate of SMCs and chemo-attracted them in in vitro. Finally, in the stenosis model of the carotid artery, PDGF-BB expression was induced in endothelial cells in which high wall shear stress was loaded and the dedifferentiation of SMCs occurred there. Conclusions: The findings from the present study imply the role of dedifferentiated SMCs partially recruited by PDGF-BB from endothelial cells in the formation of inflammatory microenvironment at the neck portion of IA walls, leading to the progression of the disease.

scholarly journals MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xudong Wang ◽  
Yali Wang ◽  
Mingjian Kong ◽  
Jianping Yang
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

scholarly journals A Comparative Transcriptome Analysis of Human and Porcine Choroid Plexus Cells in Response to Streptococcus suis Serotype 2 Infection Points to a Role of Hypoxia

2021 ◽  
Vol 11 ◽  
Author(s):  
Alexa N. Lauer ◽  
Rene Scholtysik ◽  
Andreas Beineke ◽  
Christoph Georg Baums ◽  
Kristin Klose ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Choroid Plexus ◽  
Cellular Proliferation ◽  
Inflammatory Responses ◽  
Streptococcus Suis ◽  
Gene Set Enrichment Analysis ◽  
Rna Seq

Streptococcus suis (S. suis) is an important opportunistic pathogen, which can cause septicemia and meningitis in pigs and humans. Previous in vivo observations in S. suis-infected pigs revealed lesions at the choroid plexus (CP). In vitro experiments with primary porcine CP epithelial cells (PCPEC) and human CP epithelial papilloma (HIBCPP) cells demonstrated that S. suis can invade and traverse the CP epithelium, and that the CP contributes to the inflammatory response via cytokine expression. Here, next generation sequencing (RNA-seq) was used to compare global transcriptome profiles of PCPEC and HIBCPP cells challenged with S. suis serotype (ST) 2 infected in vitro, and of pigs infected in vivo. Identified differentially expressed genes (DEGs) were, amongst others, involved in inflammatory responses and hypoxia. The RNA-seq data were validated via quantitative PCR of selected DEGs. Employing Gene Set Enrichment Analysis (GSEA), 18, 28, and 21 enriched hallmark gene sets (GSs) were identified for infected HIBCPP cells, PCPEC, and in the CP of pigs suffering from S. suis ST2 meningitis, respectively, of which eight GSs overlapped between the three different sample sets. The majority of these GSs are involved in cellular signaling and pathways, immune response, and development, including inflammatory response and hypoxia. In contrast, suppressed GSs observed during in vitro and in vivo S. suis ST2 infections included those, which were involved in cellular proliferation and metabolic processes. This study suggests that similar cellular processes occur in infected human and porcine CP epithelial cells, especially in terms of inflammatory response.

scholarly journals HIF-1α is a key mediator of the lung inflammatory potential of lithium-ion battery particles

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Violaine Sironval ◽  
Mihaly Palmai-Pallag ◽  
Rita Vanbever ◽  
François Huaux ◽  
Jorge Mejia ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Hypoxia Inducible Factor ◽  
Lithium Ion ◽  
In Vitro Assays ◽  
Inhalation Toxicity ◽  
Cobalt Nickel ◽  
Occupational Settings

Abstract Background Li-ion batteries (LIB) are increasingly used worldwide. They are made of low solubility micrometric particles, implying a potential for inhalation toxicity in occupational settings and possibly for consumers. LiCoO2 (LCO), one of the most used cathode material, induces inflammatory and fibrotic lung responses in mice. LCO also stabilizes hypoxia-inducible factor (HIF) -1α, a factor implicated in inflammation, fibrosis and carcinogenicity. Here, we investigated the role of cobalt, nickel and HIF-1α as determinants of toxicity, and evaluated their predictive value for the lung toxicity of LIB particles in in vitro assays. Results By testing a set of 5 selected LIB particles (LCO, LiNiMnCoO2, LiNiCoAlO2) with different cobalt and nickel contents, we found a positive correlation between their in vivo lung inflammatory activity, and (i) Co and Ni particle content and their bioaccessibility and (ii) the stabilization of HIF-1α in the lung. Inhibition of HIF-1α with chetomin or PX-478 blunted the lung inflammatory response to LCO in mice. In IL-1β deficient mice, HIF-1α was the upstream signal of the inflammatory lung response to LCO. In vitro, the level of HIF-1α stabilization induced by LIB particles in BEAS-2B cells correlated with the intensity of lung inflammation induced by the same particles in vivo. Conclusions We conclude that HIF-1α, stabilized in lung cells by released Co and Ni ions, is a mechanism-based biomarker of lung inflammatory responses induced by LIB particles containing Co/Ni. Documenting the Co/Ni content of LIB particles, their bioaccessibility and their capacity to stabilize HIF-1α in vitro can be used to predict the lung inflammatory potential of LIB particles.

scholarly journals LncRNA NEAT1/microRNA-129-5p/SOCS2 axis regulates liver fibrosis in alcoholic steatohepatitis

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Junfeng Ye ◽  
Yuanqiang Lin ◽  
Ying Yu ◽  
Di Sun
Keyword(s):  
Liver Fibrosis ◽  
Liver Function ◽  
Inflammatory Factors ◽  
Cytokine Signaling ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Inflammation Reaction

Abstract Background Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to play an essential role in non-alcoholic fatty liver disease. However, the role of NEAT1 in regulation of alcoholic steatohepatitis (ASH) remains largely unknown. This study aims to explore the role of NEAT1 in ASH by mediating microRNA-129-5p (miR-129-5p) targeting suppressor of cytokine signaling 2 (SOCS2). Methods NEAT1, miR-129-5p and SOCS2 expression in serum of ASH patients were assessed. In the in vitro cellular experiment, we transfected siRNAs, oligonucleotides or plasmids into ethanol-induced AML-12 mouse hepatocytes to alter NEAT1 and miR-129-5p expression, and inflammatory factors and lipid content were determined. In the in vivo animal experiment, we injected lentiviruses carrying siRNAs, oligonucleotides or plasmids onto ASH mice (ASH induced by feeding mice a Lieber-DeCarli ethanol diet) to alter NEAT1 and miR-129-5p expression through the tail vein. Serum liver function, blood lipids and inflammatory factors were detected; liver histopathology, liver cell apoptosis, and fibrosis were observed. The relationship between NEAT1 and miR-129-5p, or between miR-129-5p and SOCS2 was verified. Results MiR-129-5p was reduced while NEAT1 and SOCS2 were elevated in ASH. Inhibited NEAT1 or elevated miR-129-5p suppressed the elevated lipid metabolism and restrained inflammation reaction in ethanol-stimulated AML-12 cells. The promoted miR-129-5p and inhibited NEAT1 could improve the liver function and repress blood lipid, inflammation reaction, hepatocyte apoptosis and liver fibrosis in ethanol-induced ASH mice. Furthermore, NEAT1 could negatively regulate miR-129-5p to target SOCS2. Conclusion We have found that the inhibited NEAT1 could suppress liver fibrosis in ASH mice by promoting miR-129-5p and restraining SOCS2, thereby decelerating the development of ASH.

scholarly journals The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 501-515 ◽  
Author(s):  
Kunpeng Wu ◽  
Yan Yuan ◽  
Huihui Yu ◽  
Xin Dai ◽  
Shu Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Macrophage Polarization ◽  
Short Chain Fatty Acids ◽  
Inflammasome Activation ◽  
Microbial Metabolites ◽  
M1 Macrophage ◽  
The Impact

Abstract The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1β, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow–derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage’s response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.

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