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• Research Paper Volume 13, Issue 19 pp 23233-23244

  Long non-coding RNA CRNDE as potential biomarkers facilitate inflammation and apoptosis in alcoholic liver disease

  Relevance score: 10.06485

  Yifeng Yan, Liang Ren, Yan Liu, Liang Liu

  Keywords: alcoholic liver disease, lncRNA CRNDE, IL-6, biomarker

  Published in Aging on October 11, 2021

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  Due to persistent inconsistencies in the expression data of alcoholic liver disease (ALD), it is necessary to turn to “pre-laboratory” comprehensive analysis in order to accelerate effective precision medicine and transformation research. We screened pseudogene-derived lncRNA associated with ALD by comparative analysis of 2 independent data sets from GEO. Three lncRNAs (CRNDE, RBMS3-AS3, and LINC01088) were demonstrated to be potentially useful diagnostic markers in ALD. Among them, the expression of CRNDE is up-regulated. Therefore, we focus on CRNDE. Kyoto Encyclopedia of Genes and Genomes pathways analysis revealed higher CRNDE can activate MAPK signaling pathway, apoptosis, wnt signaling pathway, and hematopoietic cell lineage. Next, we established ALD animal model and verified the success of the modeling. The result showed ALD tissues in mice had significantly higher CRNDE levels than normal tissues. Moreover, the increase of IL-6 in the serum of mice in the low-dose group is related to the activation of inflammatory factors after alcohol-induced liver injury. In addition, alcohol can induce apoptosis, and knockdown of CRNDE can reduce apoptosis. Our integrated expression profiling identified CRNDE independently associated with ALD. CRNDE can facilitate inflammation and apoptosis in ALD.

• Research Paper Volume 13, Issue 12 pp 16667-16683

  Correlation of IL-6 and JAK2/STAT3 signaling pathway with prognosis of nasopharyngeal carcinoma patients

  Relevance score: 8.838827

  Mengqi Zhuang, Xiaotong Ding, Wenli Song, Huimin Chen, Hui Guan, Yang Yu, Zicheng Zhang, Xinzhe Dong

  Keywords: IL-6, JAK2/STAT3 signaling pathway, clinicopathological features, prognosis, nasopharyngeal carcinoma

  Published in Aging on June 22, 2021

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  IL-6 is reported to be the main upstream activator, instead of the downstream target of JAK2/STAT3. This study is intended to explore the correlation of IL-6 and JAK2/STAT3 signaling pathway with clinicopathological features and prognosis in nasopharyngeal carcinoma (NPC). First, NPC tissues and normal nasopharyngeal epithelial tissues were obtained from 117 NPC patients. Next, we detected expression levels of IL-6 in serum and those of STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in tissues. A follow-up was conducted in all the patients and the survival was analyzed. To verify the correlation of IL-6 and JAK2/STAT3 pathway, CNE-1 and SUNE1 NPC cells were interpreted with IL-6 and JAK2/STAT3 signaling pathway inhibitor AG490 to detect cell viability, migration and invasion. We observed thatIL-6 increased in serum of NPC patients. The expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in NPC tissues were higher and correlated with TNM stage and lymph node metastasis (LNM). Survival rates were reduced in patients with positive expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1. LNM and positive expressions of IL-6 and p-STAT3 were risk factors for poor prognosis of NPC. Besides, recombinant human IL-6 promoted cell proliferation, invasion and migration while AG490 inhibited cell proliferation, invasion and migration in CNE-1 and SUNE1 NPC cells. The results demonstrated that increased IL-6 expression and the activated JAK2/STAT3 signaling pathway had effects on prognosis and reduced the survival time in NPC patients, which provide a potential target for the treatment of NPC.

• Research Paper Volume 13, Issue 10 pp 13615-13625

  The effect of IL-6/Piezo2 on the trigeminal neuropathic pain

  Relevance score: 9.219159

  MingXing Liu, Yan Li, Jun Zhong, Lei Xia, NingNing Dou

  Keywords: trigeminal neuropathic pain, Piezo2, IL-6, ectopic action potentials, inflammation

  Published in Aging on April 23, 2021

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  The nature of trigeminal neuropathic pain (TN) attacks is regarded as the ignition of ectopic action potentials from the trigeminal root following vascular compression, which seemed to be related to transmembrane proteins and inflammation factors. This study focused on the mechanosensitive channel Piezo2 and cytokine IL-6.

  The chronic constriction injury of infraorbital nerve in SD rats was used to establish the TN model. The trigeminal ganglion was then achieved to perform immunocytochemistry studies.

  A significant upregulation of Piezo2 and IL-6 was showed in the TN model rats. The Piezo2 positive accounted for 72.3±9.5% in those IL-6 positive neurons. The Piezo2 co-localized with CGRP, IB4 and NF-200 but not with GFAP, which implied that it was expressed in both the C-type and the A-type neurons. After administration of GsMTx4 or anti-rat IL-6 antibody in the TN model, the dynamic allodynia and pinprick hyperalgesia scores as well as the mechanical threshold changed significantly. In the sham-operation rates, with local administration of IL-6, an upregulation of Piezo2 was also exhibited.

  Our study demonstrated that the up-regulation of Piezo2 in the pain afferent neurons following trigeminal nerve injury may play a role in the development of the neuralgia. Meanwhile, the expression of Piezo2 may be modulated by inflammatory cytokines, such as IL-6.

• Research Paper Volume 13, Issue 4 pp 5150-5163

  Nampt promotes osteogenic differentiation and lipopolysaccharide-induced interleukin-6 secretion in osteoblastic MC3T3-E1 cells

  Relevance score: 10.087261

  Shan He, Hanxiang Zhang, Yang Lu, Zhaosi Zhang, Xiang Zhang, Nian Zhou, Zhenming Hu

  Keywords: Nampt, Sirt1, IL-6, NF-κB, inflammation

  Published in Aging on February 1, 2021

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  The Nicotinamide phosphoribosyltransferase (Nampt)-NAD-Sirt1 pathway modulates processes involved in the pathogenesis of multiple diseases by influencing inflammation. This study aimed to explore the effect of Nampt in osteogenic differentiation and inflammatory response of osteoblastic MC3T3-E1 cells. We developed an in vitro model of lipopolysaccharide (LPS)-induced inflammation and showed that Nampt and Sirt1 were significantly upregulated in LPS-treated MC3T3-E1 cells. LPS induced secretion of the proinflammatory cytokine interleukin-6 (IL-6) and attenuated osteogenic differentiation. Then we transfected cells with adenoviruses to knock down or over express Nampt. Nampt promoted the expression of IL-6, TAK1 and phospho-NF-κB p65 after LPS treatment. Overexpression of Nampt overrode the effect of LPS and rescued LPS-induced inhibition on osteogenic differentiation. FK866, a Nampt inhibitor, had the same inhibitory effect as Nampt knockdown. In addition, Sirt1 suppression by EX527 decreased IL-6 secretion and NF-κB activation without changing the level of Nampt. EX527 also decreased osteogenic differentiation. Incubation with NMN or SRT 1720 also counteract the inhibitory effect of LPS and rescued osteoblast differentiation. Therefore, we demonstrated that Nampt acted both in promoting osteoblast differentiation and in enhancing inflammatory response, mediated by Sirt1 in MC3T3-E1 cells.

• Research Paper Volume 13, Issue 2 pp 1571-1590

  Fighting the storm: could novel anti-TNFα and anti-IL-6 C. sativa cultivars tame cytokine storm in COVID-19?

  Relevance score: 8.134704

  Anna Kovalchuk, Bo Wang, Dongping Li, Rocio Rodriguez-Juarez, Slava Ilnytskyy, Igor Kovalchuk, Olga Kovalchuk

  Keywords: COVID-19, SARS-CoV2, cytokine storm, TNFα, IL-6, fibrosis, medical cannabis

  Published in Aging on January 19, 2021

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  The main aspects of severe COVID-19 disease pathogenesis include hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of all cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed, that can efficiently and swiftly downregulate TNFα, IL-6, and the inflammatory cytokine cascade, in order to curb inflammation and prevent fibrosis, and lead to disease remission.

  Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis.

  Initially, to analyze the anti-inflammatory effects of novel C. sativa cultivars, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis cultivars. We noted that out of seven studied extracts of novel C. sativa cultivars, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of COX2, TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. These data were further confirmed in the WI-38 lung fibroblast cell line model. Most importantly, one of the tested extracts had no effect at all, and one exerted effect that may be deleterious, signifying that careful cannabis cultivar selection must be based on thorough pre-clinical studies.

  The observed pronounced inhibition of TNFα and IL-6 is the most important finding, because these molecules are currently considered to be the main targets in COVID-19 cytokine storm and ARDS pathogenesis.

  Novel anti-TNFα and anti-IL-6 cannabis extracts can be useful additions to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ - the inflammatory underpinning of aging and frailty.

• Research Paper Volume 13, Issue 3 pp 3443-3458

  Hypoxia-inducible factor 2-alpha-dependent induction of IL-6 protects the heart from ischemia/reperfusion injury

  Relevance score: 10.06485

  Jia-Wei Wu, Hao Hu, Dan Li, Li-Kun Ma

  Keywords: myocardial ischemia-reperfusion injury, HIF2α, IL-6

  Published in Aging on January 10, 2021

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  Myocardial ischemia-reperfusion injury (MIRI) results in increased myocardial infarct size and leads to poor clinical outcomes. Hypoxia-inducible factor 2-alpha (HIF2α) exerts myocardial protective effects during MIRI through as yet unclear mechanisms. Here, we show that knockdown of HIF2α with cardiotropic recombinant adeno-associated virus serotype 9 (rAAV9) in mouse hearts significantly increased the infarct sizes during myocardial ischemia/reperfusion (MI/R). In addition, HIF2α transcriptionally regulated the expression of interleukin 6 (IL-6) in cardiomyocytes to elicit cardioprotection. Likewise, IL-6 deficiency aggravated MIRI, while treatment with recombinant IL-6 had cardioprotective effects and rescued the mice with HIF2α knockdown. Furthermore, IL-6 treatment significantly activated the PI3K/Akt and STAT3 signaling pathways in the myocardium during MI/R, and the specific inhibitors wortmannin (specific phosphoinositide 3-kinase inhibitor) and Stattic (specific STAT3 inhibitor) substantially abolished HIF2α/IL-6-induced cardioprotection. These studies suggest that HIF2α transcription regulates the expression of IL-6 in cardiomyocytes and plays a protective role during MI/R.

• Research Paper Volume 12, Issue 15 pp 15328-15333

  Interleukin-6 -174 G/C polymorphism is associated with the risk of basal cell carcinoma in a Chinese Han population

  Relevance score: 8.962446

  Jing Wang, Yi Chen

  Keywords: IL-6 -174 G/C polymorphism, basal cell carcinoma, case-control study

  Published in Aging on August 14, 2020

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  To explore the association between the IL-6 -174 G/C polymorphism and the risk of basal cell carcinoma (BCC) in a Chinese population, we performed a case-control study involving 265 BCC patients and 341 controls. Genotyping was performed using polymerase chain reaction with sequence-specific primers. The data showed that the GG+CG and GG genotypes were associated with an increased risk of BCC. The G allele increased the risk of BCC. Moreover, stratified analyses indicated the risk was higher in males, smokers, drinkers, and those aged ≥ 60 years. Cross-over analysis confirmed that the combined effects of the GG or CG genotype and environmental factors (smoking and alcohol consumption) contribute to an increased risk of BCC. In addition, the IL-6 -174 G/C polymorphism was related to larger tumors and multiple lesions. These findings indicate that the IL-6 -174 G/C polymorphism is associated with an increased risk of BCC in a Chinese population. This locus is thus a potential diagnostic marker for predicting susceptibility to BCC.

• Research Paper Volume 11, Issue 22 pp 10610-10625

  Ets2 suppresses inflammatory cytokines through MAPK/NF-κB signaling and directly binds to the IL-6 promoter in macrophages

  Relevance score: 9.192407

  Xianwei Ma, Zhengyu Jiang, Na Li, Wei Jiang, Peng Gao, Mingjin Yang, Xiya Yu, Guifang Wang, Yan Zhang

  Keywords: Ets2, Toll-like receptor, pro-inflammatory cytokine, macrophage, IL-6

  Published in Aging on November 27, 2019

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  Proper activation of Toll-like receptor (TLR)-mediated signaling and production of proinflammatory cytokines are critical for the initiation of innate immunity, while the specific mechanism maintaining inflammatory homeostasis remains mostly unknown. Here, we show that Ets2 is upregulated following LPS and VSV stimulation. Ets2 knockdown or knockout leads to increased IL-6, TNF-α, and IFN-β production in macrophages. Consistently, Ets2-deficient mice show exacerbated inflammatory cytokine production and are more susceptible to CLP-induced sepsis. Mechanistically, Ets2 inhibits the LPS- and VSV-induced activation of ERK1/2, JNK, p38, and p65. Ets2 also binds to the promoter of IL-6 to inhibit transcription. Collectively, the results of the present study show the negative regulatory role of Ets2 in LPS- and VSV-induced inflammation through the suppression of MAPK/NF-κB signaling, direct binding to the IL-6 promoter and inhibition of transcription.

  

  LPS and VSV promote Ets2 expression and nuclear translocation. (A, B) Ets2 mRNA expression in mouse primary peritoneal macrophages stimulated with 100 ng/ml LPS (A) or VSV at an MOI of 10 (B) for the indicated times, as detected by real-time PCR (n=3). (C) Immunoblot analysis and quantification of Ets2 expression in mouse primary peritoneal macrophages stimulated with 100 ng/ml LPS or VSV at an MOI of 10 for the indicated times. (D, E) Immunoblot analysis (D) and quantitative measurement (E) of nuclear/total lysate ratio of Ets2 of mouse primary peritoneal macrophages pretreated with SB203580, PD98059, or SP600125 (20 μM for 30 min) and then stimulated with or without 100 ng/ml LPS for 3 h. U6 was used as an internal reference for the nucleus. Data are shown as the mean ± s.d. Student’s t-test compared with the control group. *, P<0.05, and **, P<0.01.

  
  
  

  

  Ets2 inhibits LPS-induced IL-6 and TNF-α production in macrophages. (A) Immunoblot analysis of the expression of Ets2 in mouse primary peritoneal macrophages transfected with control siRNA (Ctrl) or Ets2-targeted siRNA (Ets2) with LPS stimulation for indicated time. (B,C) IL-6 (B) and TNF-α (C) mRNA expression of cells stimulated with 100 ng/ml LPS for the indicated times. (D, E) IL-6 (D) and TNF-α (E) mRNA expression in Ets2^fl/flLyz2cre⁻or Ets2^fl/flLyz2cre⁺ mouse primary peritoneal macrophages stimulated with 100 ng/ml LPS for the indicated times. (F, G) ELISA assay of IL-6 (F) and TNF-α (G) in the supernatant of the cells stimulated with 100 ng/ml LPS for the indicated times. Data are shown as the mean ± s.d. of three samples. Student’s t-test compared with the control or Ets2^fl/flLyz2cre^- group. *, P<0.05, and **, P<0.01.

  
  
  

  

  Ets2 inhibits VSV-induced IFN-β, IL-6, and TNF-α production in macrophages. (A–C) IFN-β (A), IL-6 (B) and TNF-α (C) mRNA expression of cells stimulated with VSV at an MOI of 10 for the indicated times. d-f: IFN-β (D), IL-6 (E), and TNF-α (F) mRNA expression in Ets2^fl/flLyz2cre⁻ or Ets2^fl/flLyz2cre⁺ mouse primary peritoneal macrophages stimulated with VSV at an MOI of 10 for the indicated times. (G–I) ELISA assay of IFN-β (G), IL-6 (H), and TNF-α (I) in the supernatants of cells stimulated with VSV at an MOI of 10 for the indicated times. (J–L) ELISA assay of IFN-β (J), IL-6 (K), and TNF-α (L) in the supernatants of the cells stimulated with VSV at an MOI of 10 for the indicated times in Ets2^fl/flLyz2cre⁻or Ets2^fl/flLyz2cre⁺ mouse primary peritoneal macrophages. Data are shown as the mean ± s.d. of three samples. Student’s t-test compared with the control or Ets2^fl/flLyz2cre^- group. *, P<0.05, and **, P<0.01.

  
  
  

  

  Ets2 inhibits LPS-induced IL-6 and TNF-α production and improves the survival of CLP-induced sepsis in vivo. (A, B) ELISA assay of IL-6 (A) and TNF-α (B) in the serum of Ets2^fl/flLyz2cre⁻ or Ets2^fl/flLyz2cre⁺ mice, intraperitoneally injected with LPS (1 μg/g body weight) for 5 h (n=3 per phenotype). (C, D) ELISA assay of IL-6 (C) and TNF-α (D) in the serum of Ets2^fl/flLyz2cre⁻ or Ets2^fl/flLyz2cre⁺ mice at 6 h after CLP surgery (n=4 per phenotype). (E–G) Continuous IL-6 (E) and TNF-α (F) at postoperative day 1, 3, 5, 7, and survival rate (G) of Ets2^fl/flLyz2cre⁻ or Ets2^fl/flLyz2cre⁺ mice given CLP or Sham surgery (n=10 per phenotype). Data are shown as the mean ± s.e.m. Student’s t-test compared with the Ets2^fl/flLyz2cre^- group for ELISA experiments. A log-rank test was used for survival data. *, P<0.05.

  
  
  

  

  Ets2 inhibits NF-κB and MAPK signaling. (A, B) Immunoblot analysis of phosphorylated and total ERK1/2, JNK, p38 and NF-κB p65 in mouse primary peritoneal macrophages transfected with control siRNA (Ctrl siRNA) or Ets2-targeted siRNA (Ets2 siRNA) (A) and primary peritoneal macrophages of Ets2^fl/flLyz2cre⁻ or Ets2^fl/flLyz2cre⁺ mice (B), stimulated with 100 ng/ml LPS for the indicated times. (C, D) Immunoblot analysis of phosphorylated and total ERK1/2, JNK, p38, and NF-κB p65 in primary peritoneal macrophages transfected with control siRNA (Ctrl siRNA) or Ets2-targeted siRNA (Ets2 siRNA) (C) and primary peritoneal macrophages of Ets2^fl/flLyz2cre⁻ or Ets2^fl/flLyz2cre⁺ mice (D) stimulated with VSV at an MOI of 10 for the indicated times.

  
  
  

  

  Ets2 inhibits IL-6 transcription by binding to the IL-6 promoter. (A) ChIP analysis of the IL-6 promoter using an Ets2 antibody in mouse primary peritoneal macrophages treated with LPS for the indicated times. (B) Luciferase assay of IL-6 reporter gene expression in HEK293 cells transfected with 50 ng of a MyD88-expressing plasmid, 90 ng of an IL-6 luciferase reporter plasmid, and 10 ng of a pTK-Renilla-luciferase reporter plasmid, together with 0, 10, 25 or 50 ng of an Ets2-expressing plasmid. Luciferase activity was measured and normalized to Renilla luciferase activity. Data are shown as the mean ± s.d. Student’s t-test compared with the control group. **, P<0.01.

  
  
  

  

  Ets2 inhibits NF-κB-dependent IL-6 transcription. (A) Schematic diagram of truncated IL-6 promoter-reporter plasmids constructed by deleting the regions at −1176/−1081, −1176/−801, −1176/−451, and −1176/−171. (B) Luciferase assay in HEK293 cells transfected with 50 ng of a MyD88-expressing plasmid, 90 ng of the truncated IL-6 promoter-luciferase reporter plasmids, and 10 ng of a pTK-Renilla-luciferase reporter plasmid, together with 0, 10, 25 or 50 ng of an Ets2-expressing plasmid. Luciferase activity was measured and normalized by Renilla luciferase activity. (C) IL-6 promoter sequence shown from position -80 to -21. (D) Luciferase assay in HEK293 cells transfected with 50 ng of a p65-expressing plasmid, 90 ng of the truncated IL-6 luciferase reporter plasmids, and 10 ng of a pTK-Renilla-luciferase reporter plasmid, together with 0, 10, 25 or 50 ng of an Ets2-expressing plasmid. Luciferase activity was measured and normalized to Renilla luciferase activity. Data are shown as the mean ± s.d. Student’s t-test compared with the control group. **, P<0.01.

  
  
  

• Research Paper Volume 11, Issue 13 pp 4463-4477

  Long non-coding RNA LINC00265 promotes inflammation via sponging miR-let-7a in abdominal aortic aneurysm

  Relevance score: 9.608866

  Yunshu Su, Jichang Hu, Hongwen Lan, Yongjie Chen, Xiang Wei

  Keywords: abdominal aortic aneurysms, LINC00265, IL-6, let-7a, biomarker

  Published in Aging on July 4, 2019

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  Due to persistent inconsistencies in the expression data of abdominal aortic aneurysms (AAA), it is necessary to turn to "pre-laboratory" comprehensive analysis in order to accelerate effective precision medicine and transformation research. We screened pseudogene-derived lncRNA associated with AAA by comparative analysis of four independent data sets from GEO. Three lncRNAs (LINC00265, RBMS3-AS3 and LINC01088) were demonstrated to be potentially useful diagnostic markers in AAA. Each of these lncRNAs could provide a high accuracy on AAA classification as estimated by ROC curve analysis, especially the LINC00265. AAA tissues and AAA induced by Ang- II in mice had significantly higher LINC00265 levels than paired adjacent normal tissues. Moreover, knockdown of abdominal aortic LINC00265 can reduce the formation of abdominal aortic aneurysm induced by Ang- II and its corresponding inflammatory response. Mechanistic analysis indicated that LINC00265 on the occurrence of abdominal aortic aneurysm is related to the inhibition of microRNA let-7a activity through ceRNA mechanism, which induces the up-regulation of interleukin-6 in abdominal aorta. Our integrated expression profiling identified LINC00265 independently associated with AAA. LncRNA LINC00265 in vascular smooth muscle of abdominal aorta can mediate the formation of abdominal aortic aneurysm by promoting inflammation of aortic wall.

  

  Three deregulated lncRNAs were identified by integrated analysis of AAA expression datasets. (A) The flowchart of the integrated analysis and functional validation. In silico bioinformatics data analysis pipeline consists of curation of four publically available datasets, data preprocessing, and integrated analysis, dataset validation, validation for diagnostic/prognostic values, KEGG pathway and target gene validation, and in vitro and in vivo functional validation. (B) Hierarchical clustering analysis of differentially expressed lncRNAs (fold change>1; P<0.05) in AAA and NAT in GSE7084a dataset. (C) Hierarchical clustering analysis of differentially expressed lncRNAs (fold change>1; P<0.05) in AAA and NAT in GSE7084b dataset. (D) Hierarchical clustering analysis of differentially expressed lncRNAs (fold change>1; P<0.05) in AAA and NAT in GSE47472 dataset. (E) Hierarchical clustering analysis of differentially expressed lncRNAs (fold change>1; P<0.05) in AAA and NAT in GSE57691 dataset. (F) Log FC heatmap of each expression microarray, the abscissa represent the GEO IDs, the ordinate represents the gene name, the red represents log FC > 0, the green represents log FC < 0 and the value in the box represents the log FC value.

  
  
  

  

  LINC00265 may serve as significant markers in AAA. (A) An ROC curve built on a univariate classification model based on independent dataset for predicting AAA. (B) Venn diagrams of predicted LINC00265 targets genes and differentially expressed genes. (C) A barplot of top ten KEGG pathways that are enriched for the LINC00265 targets. (D) A dotplot of top ten KEGG pathways that are enriched for the LINC00265 targets.

  
  
  

  

  Relative expression of LINC00265, let-7a and IL-6 in AAA andApoE^−/− AAA model mice. (A) qRT-PCR was performed to detect relative LINC00265 expression in AAA tissues and NAT. Each circle and block represents an individual subject. n=25 for each group. (B) Aortic full-length visualdiagram. (C) Male ApoE^−/− mice were infused with Ang II (1000 ng/kg/min) for 28 days to induce AAA. Relative LINC00265 expression was significantly upregulated in the abdominal aortas from Ang II treated mice at days 14 and 28 compared with mice that received an equal volume of NS. N = 5 for each time point. (D) IL-6 mRNA and protein levels are shown for the AAA tissues and NAT. Each circle and block represents an individual subject. n=25 for each group. (F) Scatter plots showing the inverse association between let-7a and IL-6 mRNA levels. Each circle represents an individual subject. AAA: abdominal aortic aneurysm; NAT: normal aortic tissue. *P < 0.05, **P < 0.01.

  
  
  

  

  MiRNA let-7a respectively binds to LINC00265 and IL-6 genes. (A) The identification of VMSC by α-smooth muscle actin. (B) The position of LINC00265 in VSMCs. (C) Construction of normal and mutant sequences of IL-6 gene and LINC00265. (B–D). Luciferase activity reflecting IL-6 transcriptional activity. Mimic NC+IL-6-WT: invalid let-7a overexpression+lL wild type sequence; Mimic-NC+IL-6 Mut: pseudo let-7a overexpression+IL-6 mutant sequence; let-7a mimic+IL-6-WT: let-7a overexpression+IL-6 wild type sequence; Mimic NC+lL-6-Mut: let-7a overexpression+lL mutant sequence; Mimic NC: invalid let-7a overexpression; Mimics let-7a: let-7a overexpression; LINC00265 wt: LINC00265 wild type sequence; LINC00265-mut: LINC00265 mutant sequences; IL-6-WT: IL-6 wild type sequence; IL-6-Mut: IL-6 mutant gene sequence; pcDNA3.1-LINC00265: the overexpression sequence of LINC00265; pcDNA3.1-NC: meaningless LINC00265 antisense carrier. VSMCs: vascular smooth muscle cells. *P < 0.05, **P < 0.01.

  
  
  

  

  Effects of overexpression or knockout of LINC00265 and let-7a analogues on IL-6 content in cultured smooth muscle cells in vitro. (A) Effects of overexpression of LINC00265 and let-7a analogues on IL-6 content in cultured smooth muscle cells in vitro, immunofluorescence of lL-6 in vascular smooth muscle cells of abdominal aorta (green fluorescence represented cytoplasm, blue fluorescence represented nucleus, Red fluorescence represents intracellular IL-6 protein). (B) Quantitative analysis of IL-6 in overexpression of LINC00265 and let-7a analogues in vascular smooth muscle cells of aorta. (C) Effects of knockout of LINC00265 and let-7a analogues on IL-6 content in cultured smooth muscle cells in vitro, immunofluorescence of lL-6 in vascular smooth muscle cells of abdominal aorta (green fluorescence represented cytoplasm, blue fluorescence represented nucleus, Red fluorescence represents intracellular IL-6 protein). (D) Quantitative analysis of IL-6 in knockout of LINC00265 and let-7a analogues in vascular smooth muscle cells of aorta. *P < 0.05, **P < 0.01.

  
  
  

  

  Silence of LINC00265 can slow down the formation of abdominal aortic aneurysm induced by Ang II and its corresponding inflammatory pathological changes in vivo. (A) Aortic full-length visualdiagram after silence of LINC00265. (B) The incidence ofabdominal aortic aneurysms. (C) External diameter of maximum abdominal aortic aneurysm. (D) Systolic blood pressure in mice. (E) Plasma IL-6 concentration. *P < 0.05, **P < 0.01.

  
  
  

• Research Paper Volume 4, Issue 2 pp 133-143

  Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

  Relevance score: 8.459147

  Angie M. Y. Shum, Theodore Mahendradatta, Ryland J. Taylor, Arran B. Painter, Melissa M. Moore, Maria Tsoli, Timothy C. Tan, Stephen J. Clarke, Graham R. Robertson, Patsie Polly

  Keywords: Cancer cachexia, IL-6, MEF2C, Myofibril loss, Mitochondria, Colon 26 (C26) carcinoma

  Published in Aging on February 21, 2012

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  Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia.

  

  Frozen sections of lower hindlimbs of (A) non-tumor-bearing (non-TB) control and (B) C26-bearing mice were immunohistochemically stained for MHC type I protein. Positive myofibers stained a relative dark brown compared to myofibers negative for the protein of interest. (C-D) The whole soleus muscle was subjected to myofiber cross-sectional area analysis to compare the proportion of myofiber type 1 (positively stained) and type 2 (negatively stained) in tumor-bearing mice versus non-TB controls. A more prominent reduction of bigger myofibers and a corresponding increase of smaller myofibers was seen in type 2 myofibers (n = 3).

  
  
  

  

  (A) Gene expression of Socs3, Il6ra, gp130, Tnfr1 and Tnfr2 were assessed as an indicator of inflammatory signaling (n = 4). Expression of all genes was increased at the endpoint in C26-bearing mice. (B) Longitudinal experiments demonstrated the rise of plasma IL-6 preceded the significant increase of Socs3 and Il-6ra at the transcript level. Data are presented as arithmetic means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared to non-TB controls (n = 4 expect the non-TB groups on day 8 (n = 3) and day 14 (n = 2)).

  
  
  

  

  (A) Representative electron micrograph of muscle from non-tumor-bearing (non-TB) control mice. Magnification: × 8000. (B) Representative electron micrographs of muscle from C26-bearing mice. Magnification: × 8000 (i & ii), × 10000 (iii). (C) A higher magnification of muscle from C26-bearing mice. Vesicle-like structures (arrow); apparent tearing of myofiber (asterisk). Magnification: × 25000 (i & ii), × 30000 (iii). (D) Representative electron micrographs of muscle highlighting the morphologies of mitochondria. Electron-lucent areas (arrow); swelling (triangle); vesicle-like structures (asterisk). Magnification: × 40000 (i, ii & iv), × 30000 (iii). (E) Percentage of mitochondria with different morphologies in C26-bearing and non-TB mice. Data are presented as arithmetic means ± SEM. *p < 0.05, **p < 0.01 (n = 3). A reduced proportion of normal mitochondria and increased percentage of abnormal mitochondria with various changes were seen in C26-bearing mice compared to non-TB animals.

  
  
  

  

  Expression of MEF2C at (A) gene (n = 4) and (B) protein levels (n = 3). Expression of MEF2C target genes which govern (C) muscle structural intergrity and (D) energy homeostasis. Data are presented as arithmetic means ± SEM. *p < 0.05, ***p < 0.001 compared to non-tumor-bearing (non-TB) controls (n = 4). Expression of MEF2C was downregulated at both mRNA and protein levels. Altered mRNA expression was also seen in myozenins (myoz), myokinase (Mk) and myoglobin (Mb) which indicated disrupted muscle structure integrity and energy homeostasis in skeletal muscle during cancer cachexia.

  
  
  

  

  The catalytic subunit of calcineurin was reduced at the protein level at endpoint cachexia. Data are presented as arithmetic means ± SEM. **p < 0.01 compared to non-tumor-bearing (non-TB) controls (n = 3).

  
  
  

  

  Expression and activity of MEF2C are regulated by calcineurin. Chronic activation of IL-6 signaling in skeletal muscle results in an upregulated expression of SOCS3. SOCS3 has been shown to delocalize calcineurin from its usual Z-line position to the periphery of a myofiber. This might affect its function and hence impact on the downstream targets like MEF2C. Since MEF2C is a key regulator of many myogenic and energy homeostatic molecules, any perturbation in its activity could greatly affect muscle performance and integrity. Such alterations may accelerate muscle breakdown and disintegration of the tissue contributing to fatigue and weakness during cancer cachexia.

  
  
  

• Commentary Volume 1, Issue 5 pp 438-441

  Keeping your senescent cells under control

  Relevance score: 8.473809

  Lars Zender, K. Lenhard Rudolph

  Keywords: Senescence associated secretory phenotype, SASP, stress signaling, Il-6, telomeres, oncogene induced senescence

  Published in Aging on May 6, 2009

  

  Different cellular stresses can induce senescence including telomere shortening, DNA damage, and oncogene activation. Senescence of tumor cells represents a cell intrinsic tumor suppressor mechanism. In contrast senescence of non-transformed cells in aging organs may lead to loss of proliferative competition and selection of malignant clones. The senescence associated secretory phenotype (SASP) could have different effects on aging and cancer: (i) it could contribute to the induction and maintenance of senescence via a feedback loop, (ii) it could activate immune response leading to improved clearance of senescent tumor cells, (iii) it could stimulate proliferation of neighbouring tumor cells, (iv) it could impair the function of non-transformed tissue stem cells.

  
  
  

• Research Paper Volume 1, Issue 4 pp 402-411

  MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8

  Relevance score: 9.219159

  Dipa Bhaumik, Gary K. Scott, Shiruyeh Schokrpur, Christopher K. Patil, Arturo V. Orjalo, Francis Rodier, Gordon J. Lithgow, Judith Campisi

  Keywords: miRNA, DNA damage, IL-1α, IL-6, IL-8, inflammation

  Published in Aging on April 21, 2009

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  Senescence is a cellular program that irreversibly arrests the proliferation of damaged cells and induces the secretion of the inflammatory mediators IL- 6 and IL-8 which are part of a larger senescence associated secretory phenotype (SASP). We screened quiescent and senescent human fibroblasts for differentially expressed microRNAS (miRNAs) and found that miRNAs 146a and 146b (miR-146a/b) were significantly elevated during senescence. We suggest that delayed miR-146a/b induction might be a compensatory response to restrain inflammation. Indeed, ectopic expression of miR-146a/b in primary human fibroblasts suppressed IL-6 and IL-8 secretion and downregulated IRAK1, a crucial component of the IL-1 receptor signal transduction pathway. Cells undergoing senescence without induction of a robust SASP did not express miR-146a/b. Further, IL-1α neutralizing antibodies abolished both miR-146a/b expression and IL-6 secretion. Our findings expand the biological contexts in which miRNA-146a/b modulates inflammatory responses. They suggest that IL-1 receptor signaling initiates both miR-146a/b upregulation and cytokine secretion, and that miR-146a/b is expressed in response to rising inflammatory cytokine levels as part of a negative feedback loop that restrains excessive SASP activity.

  

  (A) Northern blot analysis of total RNA prepared from proliferating (P), quiescent (Q), damage (bleomycin)-induced senescent (DS) and replicatively senescent (RS) HCA2 cells. We analyzed 10 μg of RNA from P, Q and DS cells, but 5 μg of RNA from RS cells. After separation and transfer to membranes, the blots were probed for miR-146a. Equal RNA loading was confirmed by probing for the small RNA species U6. Values for the percentage of cells incorporating bromodeoxyuridine (% BrdU) or expressing the sensecence-associated beta-galactosidase (% SA-β-gal) are indicated below each lane. (B) Northern blot analysis of RNA from DS cells. Cells were harvested for RNA at the days indicated after cells were induced to senesce by bleomycin. The blot was initially probed for miR-146a, then stripped and reprobed for miR-146b. The proliferation levels (% BrdU) and % cells that express the SA-β-gal are indicated. (C) Northern blot analysis of replicatively senescencing cells. Cells were harvested at the PD (population doubling level) indicated below the figure. The proliferation levels (% BrdU) and % cells that express the SA-β-gal are indicated. (D) Northern blot analysis of cells treated with H₂O₂ (0.1 mM for 2 h) or infected with the lentivirus expressing oncogenic RASV12. Cells were harvested for RNA at the indicated days after treatment. The proliferation levels (% BrdU) and % cells that express the SA-β-gal are indicated.

  
  
  

  

  (A) Northern blot analysis of total RNA prepared from control (insertless virus-infected) HCA2 cells (cntrl), cells infected with a miR-146a-expressing virus (146a) and cells infected with a miR-146b-expressing virus (146b). 8 μg of total RNA was loaded in each lane. (B) Western blot analysis of total protein lysates prepared from proliferating cells (cntrl, PD32), or cells overexpressing miR-146a or miR-146b, and analyzed for IRAK1 (top panel) and TRAF6 (bottom panel). Actin protein levels served as a loading control.

  
  
  

  

  (A) Western blot analyses of TCA-precipitated proteins prepared from CM collected over 24 h from cells infected with the lentivirus backbone (cntrl) or lentiviruses expressing miR-146a (146a) or miR-146b (146b). The blot was analyzed for IL-6, IL-8 and IGFBP3. Equal loading was based on cell number prior to collection of CM and IGFBP3 levels. Proliferating indicates cells described in Figure 2A. The same cells were treated with bleomycin and CM was harvested 11 days later (senescent). (B) IL-6 in CM from the cell populations described in Fig 3A was measured by ELISA. The data are reported as 10^-6 pg per cell per day. (C) RT-PCR analysis of transcript levels of IL-6 and IL-8 in miR-146a/b-overexpressing cells. RNA collected from proliferating cells was used as the control (cntrl).

  
  
  

  

  (A) & (B) Proliferating BJ (PD 36) and IMR90 (PD 38) cells were treated with bleomycin to induce senescence. CM and RNA were harvested 11 d later. (A) Western analysis for secreted IL-6. (B) Northern analysis for miR-146a. (C) Northern analysis for miR-146a levels in replicatively senescent BJ and IMR90 cells. The PD levels at which cells were harvested for analysis is given below each lane. BJ cells reach complete senescence after approximately 70 PDs, whereas IMR90 cells are nearly completely senescent by PD61. (D) & (E) Proliferating IMR90 cells (PD40) were either untreated (Pro), treated with bleomycin (DS) or infected with the lentivirus expressing oncogenic RAS (RAS). CM and RNA were collected 11 days after treatment or infection. (D) Western analysis for IL-6 in CM. (E) Northern analysis for miR-146a and U6 (control) levels.

  
  
  

  

  (A) Northern analysis for miR-146a levels in damage-induced senescent HCA2 cells treated with neutralizing antibodies against IL1-α and IL1-β. HCA2 cells (PD 35) were used and induced to senesce by treatment with bleomycin. Cells were harvested for RNA 11 days later. Details of the procedure are described in ‘Experimental Procedures. (B) Western analysis for IL-6 in damage-induced senescent HCA2 cells treated with neutralizing antibodies to IL-1α and IL-1β. CM were harvested 11 days after bleomycin treatment. (C) Model for the role of miR-146a/b in senescent cells: In response to a high SASP (right branch), IL-1α interacts with the IL-1α receptor (IL-1αR) and the signaling pathway that involves IRAK1 is fully activated. This activation leads to the well-documented activation of the transcription factor NFкB and production of IL-6, IL-8 and also miRNA-146a/b. miRNA-146a/b is a component of a negative feedback loop and acts to downregulate the levels of IRAK1, hence restraining the levels of IL-6 and IL8. However, in response to a low SASP (left branch), the signaling pathway is not sufficiently activated. Thus there is a low level of IL-6 and IL-8 secretion and miRNA-146a/b is not upregulated.

  
  
  

• Research Paper pp undefined-undefined

  Pentraxin 3 depletion (PTX3 KD) inhibited myocardial fibrosis in heart failure after myocardial infarction

  Relevance score: 8.813851

  Yufang Xu, Yiting Hu, Yanping Geng, Na Zhao, Caiyun Jia, Haojing Song, Wanjun Bai, Caihui Guo, Lili Wang, Yanhui Ni, Xiaoyong Qi

  Keywords: heart failure, myocardial infarction, myocardial fibrosis, pentraxin 3, IL-6/STAT3 pathway

  Published in Aging on Invalid Date

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  Background: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI.

  Methods: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings.

  Results: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment.

  Conclusions: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.

• Research Paper pp undefined-undefined

  Coumarin-chalcone hybrid LM-021 and indole derivative NC009-1 targeting inflammation and oxidative stress to protect BE(2)-M17 cells against α-synuclein toxicity

  Relevance score: 7.475896

  Pei-Ning Yang, Wan-Ling Chen, Jun-Wei Lee, Chih-Hsin Lin, Yi-Ru Chen, Chung-Yin Lin, Wenwei Lin, Ching-Fa Yao, Yih-Ru Wu, Kuo-Hsuan Chang, Chiung-Mei Chen, Guey-Jen Lee-Chen

  Keywords: Parkinson’s disease/α-synuclein, NLRP1/3, IL-1β/IL-6 signaling, GSH/GSSG, therapeutics

  Published in Aging on Invalid Date

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  Parkinson’s disease (PD) is featured mainly by the loss of dopaminergic neurons and the presence of α-synuclein-containing aggregates in the substantia nigra of brain. The α-synuclein fibrils and aggregates lead to increased oxidative stress and neural toxicity in PD. Chronic inflammation mediated by microglia is one of the hallmarks of PD pathophysiology. In this report, we showed that coumarin-chalcone hybrid LM-021 and indole derivative NC009-1 reduced the expression of major histocompatibility complex-II, NLR family pyrin domain containing (NLRP) 3, caspase-1, inducible nitric oxide synthase, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in α-synuclein-activated mouse BV-2 microglia. Release of pro-inflammatory mediators including nitric oxide, IL-1β, IL-6 and TNF-α were also mitigated. In BE(2)-M17 cells expressing A53T α-synuclein aggregates, LM-021 and NC009-1 reduced α-synuclein aggregation, neuroinflammation, oxidative stress and apoptosis, and promoted neurite outgrowth. These protective effects were mediated by downregulating NLRP1, IL-1β and IL-6, and their downstream pathways including nuclear factor (NF)-κB inhibitor alpha (IκBα)/NF-κB P65 subunit (P65), c-Jun N-terminal kinase (JNK)/proto-oncogene c-Jun (JUN), mitogen-activated protein kinase 14 (P38)/signal transducer and activator of transcription (STAT) 1, and Janus kinase 2 (JAK2)/STAT3. The study results indicate LM-021 and NC009-1 as potential new drug candidates for PD.

• Research Paper pp undefined-undefined

  Tissue immunoexpression of IL-6 and IL-18 in aging men with BPH and MetS and their relationship with lipid parameters and gut microbiota - derived short chain fatty acids

  Relevance score: 7.146034

  Weronika Ratajczak, Maria Laszczyńska, Aleksandra Rył, Barbara Dołęgowska, Olimpia Sipak, Ewa Stachowska, Marcin Słojewski, Anna Lubkowska

  Keywords: benign prostatic hyperplasia (BPH), metabolic syndrome (MetS), lipids, interleukin 6 (IL-6), interleukin 18 (IL-18), short-chain fatty acids

  Published in Aging on Invalid Date

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  Recent studies indicate that inflammation is one of the causes of the development of benign prostatic hyperplasia (BPH). Inflammation may result from past infections, metabolic disorders, but also from the state of functioning of the intestinal microbiota. The aim of the study was to assess whether the diagnostic lipid parameters for metabolic syndrome and short-chain fatty acids (SCFAs) are related to the immunoexpression of interleukins in prostate tissue with benign hyperplasia.

  The study involved 103 men with BPH, who were divided into two groups depending on the presence of MetS. We analysed tissue immunoexpression of two proinflammatory interleukins: IL-6, which is known to be involved in the development of BPH, and IL-18, which has not been analysed so far. The results of our study indicate that men with BPH + MetS in the stroma of the prostate have a significantly higher overall percentage of IL-6+ cells compared to men without MetS (p = 0.034). The analysis of IL-18 immunoexpression in prostate tissue indicated that in men with BPH + MetS, the glandular part of the prostate had a significantly higher percentage of cells with strong IL-18 expression (p = 0.040). We also noticed a relationship between tissue expression of IL-6 and IL-18 and lipid parameters (TG and HDL). We conclude that lipid disorders occurring in men with BPH increase inflammation in the prostate gland. Moreover, it has also been demonstrated for the first time that, indirectly, through SCFAs, the gut microbiota can act to prevent or create an inflammatory microenvironment in the prostate gland.