scholarly journals Biology of Intracranial Aneurysms: Role of Inflammation

2012 ◽  
Vol 32 (9) ◽  
pp. 1659-1676 ◽  
Author(s):  
Nohra Chalouhi ◽  
Muhammad S Ali ◽  
Pascal M Jabbour ◽  
Stavropoula I Tjoumakaris ◽  
L Fernando Gonzalez ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Intracranial Aneurysms ◽  
Clinical Problem ◽  
Vascular Wall ◽  
Expression Of Genes ◽  
Aneurysmal Dilation ◽  
Inflammatory Phenotype ◽  
Aneurysm Development ◽  
Precise Role

Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

scholarly journals Il6/Sil6R Regulates Tnfα-Inflammatory Response In Synovial Fibroblasts Through Modulation of Transcriptional and Post-Transcriptional Mechanisms

2020 ◽  
Author(s):  
Alvaro Valin ◽  
Manuel J. Del Rey ◽  
Cristina Municio ◽  
Alicia Usategui ◽  
Marina Romero ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
De Novo ◽  
Inflammatory Cells ◽  
Synovial Fibroblasts ◽  
Matrix Metalloproteases ◽  
P Value ◽  
Polymorphonuclear Cells ◽  
Expression Of Genes

Abstract Introduction: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα or IL6 and sIL6R for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cicloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assesed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results IL6/sIL6R stimulation of TNFα treated SF cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

Discovery of Side- and Shear-Dependent miRNAs and mRNAs in Human Aortic Valvular Endothelial Cells

2011 ◽  
Author(s):  
Casey J. Holliday ◽  
Randall F. Ankeny ◽  
Hanjoong Jo ◽  
Robert M. Nerem
Keyword(s):  
Endothelial Cells ◽  
Aortic Valve ◽  
Oscillatory Flow ◽  
Expression Profiles ◽  
Flow Conditions ◽  
Expression Of Genes ◽  
Inflammatory Phenotype ◽  
Cardiovascular Pathologies ◽  
Laminar Shear

Aortic valve (AV) disease is diagnosed by severe symptoms, such as calcification, and typically treated by AV replacement and repair surgeries. The mechanism by which AV disease occurs, specifically the role of the endothelium remains relatively unknown. It is known that disease preferentially occurs on the fibrosa, or aortic side, where it is exposed to disturbed, oscillatory flow, whereas the ventricularis, or side facing the left ventricle, experiences pulsatile, laminar shear and remains non-calcified [1, 2]. Research shows that regulation of miRNAs, short nucleotide segments targeting mRNAs, coincides with cardiovascular pathologies [3] though expression profiles of miRNAs and the mRNAs they modulate in human AV endothelial cells (HAVECs) have not been reported. We hypothesize that disturbed flow conditions present on the fibrosa stimulate ECs to modify expression of genes and miRNAs to induce a pro-inflammatory phenotype.

scholarly journals The PAF1 complex cell-autonomously promotes oogenesis in Caenorhabditis elegans

2021 ◽  
Author(s):  
Yukihiko Kubota ◽  
Natsumi Ota ◽  
Hisashi Takatsuka ◽  
Takuma Unno ◽  
Shuichi Onami ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Rna Polymerase Ii ◽  
Oocyte Maturation ◽  
Germ Line ◽  
Biological Processes ◽  
Wild Type ◽  
Expression Of Genes ◽  
A Cell ◽  
Precise Role

The RNA polymerase II-associated factor 1 complex (PAF1C) is a protein complex that consists of LEO1, RTF1, PAF1, CDC73, and CTR9, and has been shown to be involved in Pol II-mediated transcriptional and chromatin regulation. Although it has been shown to regulate a variety of biological processes, the precise role of the PAF1C during germ line development has not been clarified. In this study, we found that reduction in the function of the PAF1C components, LEO-1, RTFO-1, PAFO-1, CDC-73, and CTR-9, in Caenorhabditis elegans affects cell volume expansion of oocytes. Defects in oogenesis were also confirmed using an oocyte maturation marker, OMA-1::GFP. While four to five OMA-1::GFP-positive oocytes were observed in wild-type animals, their numbers were significantly decreased in pafo-1 mutantand leo-1(RNAi), cdc-73(RNAi), and pafo-1(RNAi) animals. Expression of a functional PAFO-1::mCherry transgene in the germline significantly rescued the oogenesis-defective phenotype of the pafo-1 mutants, suggesting that expression of the PAF1C in germ cells is required for oogenesis. Notably, overexpression of OMA-1::GFP partially rescued the oogenesis defect in the pafo-1 mutants. Based on our findings, we propose that the PAF1C promotes oogenesis in a cell-autonomous manner by positively regulating the expression of genes involved in oocyte maturation.

scholarly journals Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Luo ◽  
Faxi Wang ◽  
Fei Sun ◽  
Tiantian Yue ◽  
Qing Zhou ◽  
...  
Keyword(s):  
Septic Shock ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Endotoxic Shock ◽  
Sirna Delivery ◽  
Clinical Problem ◽  
Targeted Inhibition ◽  
Major Clinical Problem

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto-siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.

scholarly journals IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Alvaro Valin ◽  
Manuel J. Del Rey ◽  
Cristina Municio ◽  
Alicia Usategui ◽  
Marina Romero ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
De Novo ◽  
Inflammatory Cells ◽  
Synovial Fibroblasts ◽  
Matrix Metalloproteases ◽  
Polymorphonuclear Cells ◽  
Expression Of Genes ◽  
Two Factors

Abstract Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

scholarly journals IL6/sIL6R REGULATES TNFα-INFLAMMATORY RESPONSE IN SYNOVIAL FIBROBLASTS THROUGH MODULATION OF TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL MECHANISMS

2020 ◽  
Author(s):  
Alvaro Valin ◽  
Manuel J. Del Rey ◽  
Cristina Municio ◽  
Alicia Usategui ◽  
Marina Romero ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
De Novo ◽  
Inflammatory Cells ◽  
Synovial Fibroblasts ◽  
Matrix Metalloproteases ◽  
P Value ◽  
Polymorphonuclear Cells ◽  
Expression Of Genes

Abstract Introduction: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods: SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value <0.05 was considered statistically significant. Results: The stimulation of SF with IL6/sIL6R and TNFa, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions: These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

scholarly journals IL6/sIL6R Regulates Tnfa-Inflammatory Response in Synovial Fibroblasts Through Modulation of Transcriptional and Post-Transcriptional Mechanisms

2020 ◽  
Author(s):  
Alvaro Valin ◽  
Manuel J. Del Rey ◽  
Cristina Municio ◽  
Alicia Usategui ◽  
Marina Romero ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
De Novo ◽  
Inflammatory Cells ◽  
Synovial Fibroblasts ◽  
Matrix Metalloproteases ◽  
P Value ◽  
Polymorphonuclear Cells ◽  
Expression Of Genes

Abstract Introduction: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF.Methods: SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value <0.05 was considered statistically significant.Results: The stimulation of SF with IL6/sIL6R and TNFa, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions: These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

scholarly journals Role of matrix metalloproteinases in the pathogenesis of intracranial aneurysms

2019 ◽  
Vol 47 (1) ◽  
pp. E4 ◽  
Author(s):  
Xiaoran Zhang ◽  
William J. Ares ◽  
Philipp Taussky ◽  
Andrew F. Ducruet ◽  
Ramesh Grandhi
Keyword(s):  
Blood Flow ◽  
Matrix Metalloproteinases ◽  
Vascular Remodeling ◽  
Intracranial Aneurysms ◽  
Normal Function ◽  
Mechanical Forces ◽  
Significant Morbidity ◽  
Complex Interactions ◽  
Aneurysm Development

Intracranial aneurysms (IAs) are a result of complex interactions between biochemical and mechanical forces and can lead to significant morbidity if they rupture and cause subarachnoid hemorrhage. This review explores the role of matrix metalloproteinases (MMPs) in the pathogenesis and progression of IAs. In addition to providing a review of the normal function of MMPs, it is intended to explore the interaction between inflammation and abnormal blood flow and the resultant pathological vascular remodeling processes seen in the development and rupture of IAs. Also reviewed is the potential for the use of MMPs as a diagnostic tool for assessment of aneurysm development and progression.

Cerebral Vasospasm after Subarachnoid Hemorrhage: Putative Role of Inflammation

Neurosurgery ◽  
2003 ◽  
Vol 53 (1) ◽  
pp. 123-135 ◽  
Author(s):  
Aaron S. Dumont ◽  
Randall J. Dumont ◽  
Michael M. Chow ◽  
Chi-lung Lin ◽  
Tarkan Calisaneller ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Inflammatory Response ◽  
Cerebral Vasospasm ◽  
Molecular Basis ◽  
Common Pathway ◽  
Future Studies ◽  
Therapeutic Measures ◽  
Precise Role ◽  
Convincing Data

Abstract CEREBRAL VASOSPASM IS a common, formidable, and potentially devastating complication in patients who have sustained subarachnoid hemorrhage (SAH). Despite intensive research efforts, cerebral vasospasm remains incompletely understood from both the pathogenic and therapeutic perspectives. At present, no consistently efficacious and ubiquitously applied preventive and therapeutic measures are available in clinical practice. Recently, convincing data have implicated a role of inflammation in the development and maintenance of cerebral vasospasm. A burgeoning (although incomplete) body of evidence suggests that various constituents of the inflammatory response, including adhesion molecules, cytokines, leukocytes, immunoglobulins, and complement, may be critical in the pathogenesis of cerebral vasospasm. Recent studies attempting to dissect the cellular and molecular basis of the inflammatory response accompanying SAH and cerebral vasospasm have provided a promising groundwork for future studies. It is plausible that the inflammatory response may indeed represent a critical common pathway in the pathogenesis of cerebral vasospasm pursuant to SAH. Investigations into the nature of the inflammatory response accompanying SAH are needed to elucidate the precise role(s) of inflammatory events in SAH-induced pathologies.

scholarly journals Histone Acetyltransferase Mof Affects the Progression of DSS-Induced Colitis

2018 ◽  
Vol 47 (5) ◽  
pp. 2159-2169 ◽  
Author(s):  
Yang Yang ◽  
Jingyun Guan ◽  
Abdul Sami Shaikh ◽  
Yiran Liang ◽  
Lichao Sun ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Histone Acetyltransferase ◽  
Experimental Colitis ◽  
Conditional Knockout ◽  
Rna Seq ◽  
Histone H4 ◽  
Expression Of Genes ◽  
Differential Expression Of Genes

Background/Aims: Histone acetylation has been demonstrated to be associated with inflammation response. Histone acetyltransferase (HAT) Mof, specifically acetylating lysine 16 of histone H4 (H4K16), has been reported to regulate T cell differentiation. In addition, it has been suggested that acetylation of H4K16 is associated with the inflammatory response. We evaluated the role and potential mechanism of Mof in the development of experimental colitis. Methods: We used Mof conditional knockout mice to study the role of Mof in dextran sulfate sodium (DSS)-induced colitis and detected the differential expression of genes due to Mof deficiency involved in the inflammatory response, particularly the Th17 signaling pathway, by western blotting, quantitative PCR and RNA sequencing (RNA-seq). Results: A significant elevation of Mof was observed in colonic tissues of mice with DSS-induced colitis. Mof deficiency alleviated the severity of DSS- induced colitis in mice. We found that Th17 signaling pathway associated genes, including Il17a, Il22, RORγt, RORα, Stat3, TGF-β 1, and Il6, were downregulated in colon tissues with Mof deficiency. RNA-seq data analysis suggested that 68 genes were related to inflammatory response processing and 47 genes were downregulated in Mof defective colon tissues. Conclusion: Our study demonstrated that HAT Mof is involved in the development of colitis, and the lack of Mof ameliorates DSS-induced colitis in mice.

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