scholarly journals Regulation of telomere homeostasis and genomic stability in cancer by N6-adenosine methylation (m6A)

2021 ◽  
Vol 7 (31) ◽  
pp. eabg7073
Author(s):  
Ji Hoon Lee ◽  
Juyeong Hong ◽  
Zhao Zhang ◽  
Bárbara de la Peña Avalos ◽  
Cecilia J. Proietti ◽  
...  
Keyword(s):  
Genomic Stability ◽  
Cancer Genome ◽  
Mrna Levels ◽  
Telomere Dysfunction ◽  
Rna Methylation ◽  
P53 Signaling ◽  
Per Se ◽  
Telomere Homeostasis ◽  
Underlying Mechanisms

The role of RNA methylation on N6-adenosine (m6A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m6A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m6A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m6A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.

scholarly journals Interfering with pak4 Protein Expression Affects Osteosarcoma Cell Proliferation and Migration

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yuxin Fu ◽  
Lun Fang ◽  
Qipu Yin ◽  
Qi Wu ◽  
Wei Sui ◽  
...  
Keyword(s):  
Protein Expression ◽  
Osteosarcoma Cell ◽  
Mrna Levels ◽  
Osteosarcoma Cells ◽  
Migration Ability ◽  
M Phase ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Proliferation And Migration

Purpose. A number of studies have discovered various roles of PAK4 in human tumors, including osteosarcoma. However, the exact role of PAK4 in osteosarcoma and its mechanism have yet to be determined. Therefore, this study focused on interrogating the PAK4 effect on the proliferation and migration ability of osteosarcoma and its underlying mechanisms. Materials and Methods. Western blot and QRT-PCR were utilized to quantify the PAK4 relative protein and mRNA levels. To measure cellular viability and mobility, the MTT and wound-healing assays were preferred. Results. With the adenovirus-mediated overexpression of PAK4, the proliferation and migration of U2-OS and MG-63 osteosarcoma cells were stimulated. Furthermore, a liposome-mediated knockout of PAK4 will inhibit osteosarcoma cells from proliferating. In terms of mechanism, we observed the positive correlation of PAK4 expression with expression of P21, CyclinD1, CyclinE1, CDK2, and CDK6, which drives G0/G1 to the G2/M phase transition. PAK4 can also activate Erk expression in OS cells and induce EMT. Conclusion. Interfering with PAK4 protein expression has been shown to affect osteosarcoma proliferation and migration.

scholarly journals Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuanrui Ma ◽  
Jiaqing Xiang ◽  
Guixiao Huang ◽  
Yaxi Zhao ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Cholestatic Liver Disease ◽  
P53 Signaling ◽  
Promising Target ◽  
Underlying Mechanisms ◽  
Cholestatic Liver Injury ◽  
P53 Signaling Pathway

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

scholarly journals Systematic Analyses of the Role of the Reader Protein of N6-Methyladenosine RNA Methylation, YTH Domain Family 2, in Liver Hepatocellular Carcinoma

2020 ◽  
Vol 7 ◽  
Author(s):  
Xiang-yang Shao ◽  
Jin Dong ◽  
Han Zhang ◽  
Ying-song Wu ◽  
Lei Zheng
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Immune Cells ◽  
Cancer Genome ◽  
Gene Set Enrichment Analysis ◽  
Domain Family ◽  
Rna Methylation ◽  
Yth Domain ◽  
Liver Hepatocellular Carcinoma

BackgroundYTH domain family (YTHDF) 2 acts as a “reader” protein for RNA methylation, which is important in tumor regulation. However, the effect of YTHDF2 in liver hepatocellular carcinoma (LIHC) has yet to be elucidated.MethodsWe explored the role of YTHDF2 in LIHC based on publicly available datasets [The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO)]. A bioinformatics approach was employed to analyze YTHDF2. Logistic regression analyses were applied to analyze the correlation between YTHDF2 expression and clinical characteristics. To evaluate the effect of YTHDF2 on the prognosis of LIHC patients, we used Kaplan–Meier (K–M) curves. Gene set enrichment analysis (GSEA) was undertaken using TCGA dataset. Univariate and multivariate Cox analyses were used to ascertain the correlations between YTHDF2 expression and clinicopathologic characteristics with survival. Genes co-expressed with YTHDF2 were identified and detected using publicly available datasets [LinkedOmics, University of California, Santa Cruz (UCSC), Gene Expression Profiling Interactive Analysis (GEPIA), and GEO]. Correlations between YTHDF2 and infiltration of immune cells were investigated by Tumor Immune Estimation Resource (TIMER) and GEPIA.ResultsmRNA and protein expression of YTHDF2 was significantly higher in LIHC tissues than in non-cancerous tissues. High YTHDF2 expression in LIHC was associated with poor prognostic clinical factors (high stage, grade, and T classification). K–M analyses indicated that high YTHDF2 expression was correlated with an unfavorable prognosis. Univariate and multivariate Cox analyses revealed that YTHDF2 was an independent factor for a poor prognosis in LIHC patients. GSEA revealed that the high-expression phenotype of YTHDF2 was consistent with the molecular pathways implicated in LIHC carcinogenesis. Analyses of receiver operating characteristic curves showed that YTHDF2 might have a diagnostic value in LIHC patients. YTHDF2 expression was associated positively with SF3A3 expression, which implied that they may cooperate in LIHC progression. YTHDF2 expression was associated with infiltration of immune cells and their marker genes. YTHDF2 had the potential to regulate polarization of tumor-associated macrophages, induce T-cell exhaustion, and activate T-regulatory cells.ConclusionYTHDF2 may be a promising biomarker for the diagnosis and prognosis of LIHC and may provide new directions and strategies for LIHC treatment.

scholarly journals Upregulation of Gastric Norepinephrine With β-Adrenoceptors and Gastric Dysmotility in a Rat Model of Functional Dyspepsia

2020 ◽  
pp. 135-143
Author(s):  
J. SONG ◽  
T. WANG ◽  
X. ZHANG ◽  
B. LI ◽  
C. ZHU ◽  
...  
Keyword(s):  
Rat Model ◽  
Gastric Motility ◽  
Delayed Gastric Emptying ◽  
Organ Bath ◽  
Mrna Levels ◽  
Protein Levels ◽  
Gastric Smooth Muscle ◽  
Gastric Corpus ◽  
Underlying Mechanisms

Disordered motility is one of the most important pathogenic characteristics of unctional dyspepsia (FD), although the underlying mechanisms remain unclear. Since the sympathetic system is important to the regulation of gastrointestinal motility, the present study aimed to investigate the role of norepinephrine (NE) and adrenoceptors in disordered gastric motility in a rat model with FD. The effect of exogenous NE on gastric motility in control and FD rats was measured through an organ bath study. The expression and distribution of β-adrenoceptors were examined by real-time PCR, Western blotting and immunofluorescence. The results showed that endogenous gastric NE was elevated in FD rats, and hyperreactivity of gastric smooth muscle to NE and delayed gastric emptying were observed in the rat model of FD. The mRNA levels of β1-adrenoceptor and norepinephrine transporter (NET) and the protein levels of β2-adrenoceptor and NET were increased significantly in the gastric corpus of FD rats. All three subtypes of β-adrenoceptors were abundantly distributed in the gastric corpus of rats. In conclusion, the enhanced NE and β-adrenoceptors and NETs may be contributed to the disordered gastric motility in FD rats.

scholarly journals Key role of piRNAs in telomeric chromatin maintenance and telomere nuclear positioning in Drosophila germline

2017 ◽  
Author(s):  
Elizaveta Radion ◽  
Valeriya Morgunova ◽  
Sergei Ryazansky ◽  
Natalia Akulenko ◽  
Sergey Lavrov ◽  
...  
Keyword(s):  
Small Rnas ◽  
Telomere Dysfunction ◽  
Specific Mechanism ◽  
Telomere Elongation ◽  
Histone 3 ◽  
Telomere Function ◽  
Telomere Homeostasis ◽  
End Capping ◽  
Pirna Pathway

AbstractTelomeric small RNAs related to PIWI-interacting RNAs (piRNAs) were discovered in different species, however, their role in germline-specific telomere function remains poorly understood. Using a Drosophila model, we show that the piRNA pathway provides a strong germline-specific mechanism of telomere homeostasis. We show that telomeric retrotransposon arrays belong to a unique class of dual-strand piRNA clusters whose transcripts, required for telomere elongation, serve simultaneously as piRNA precursors and their only targets. However, the ability to produce piRNAs and bind Rhino – a germline-specific homolog of heterochromatic protein 1 (HP1) – varies along telomeres. Most likely, this heterogeneity is determined by the peculiarities of telomeric retrotransposons themselves. piRNAs play a pivotal role in the establishment and maintenance of telomeric and subtelomeric chromatin in the germline facilitating loading of HP1 and histone 3 lysine 9 trimethylation mark – highly conservative telomere components – at different telomeric regions. piRNA pathway disruption results in telomere dysfunction characterized by a loss of heterochromatic components and translocation of telomeres from the periphery to the nuclear interior but does not affect the telomere end capping.

Response Interference as a Mechanism Underlying Implicit Measures

2008 ◽  
Vol 24 (4) ◽  
pp. 218-225 ◽  
Author(s):  
Bertram Gawronski ◽  
Roland Deutsch ◽  
Etienne P. LeBel ◽  
Kurt R. Peters
Keyword(s):  
Task Performance ◽  
Psychological Research ◽  
Implicit Measures ◽  
Mediation Model ◽  
Response Interference ◽  
Relevant Evidence ◽  
Moderated Mediation Model ◽  
Stimulus Features ◽  
Underlying Mechanisms

Over the last decade, implicit measures of mental associations (e.g., Implicit Association Test, sequential priming) have become increasingly popular in many areas of psychological research. Even though successful applications provide preliminary support for the validity of these measures, their underlying mechanisms are still controversial. The present article addresses the role of a particular mechanism that is hypothesized to mediate the influence of activated associations on task performance in many implicit measures: response interference (RI). Based on a review of relevant evidence, we argue that RI effects in implicit measures depend on participants’ attention to association-relevant stimulus features, which in turn can influence the reliability and the construct validity of these measures. Drawing on a moderated-mediation model (MMM) of task performance in RI paradigms, we provide several suggestions on how to address these problems in research using implicit measures.

The More You Say, the Less They Hear

2015 ◽  
Vol 27 (4) ◽  
pp. 159-169 ◽  
Author(s):  
Elsbeth D. Asbeek Brusse ◽  
Marieke L. Fransen ◽  
Edith G. Smit
Keyword(s):  
Hearing Protection ◽  
Entertainment Education ◽  
Mediating Role ◽  
Attitude Measures ◽  
Underlying Mechanisms

Abstract. This study examined the effects of disclosure messages in entertainment-education (E-E) on attitudes toward hearing protection and attitude toward the source. In addition, the (mediating) role of the underlying mechanisms (i.e., transportation, identification, and counterarguing) was studied. In an experiment (N = 336), three different disclosure messages were compared with a no-disclosure condition. The results show that more explicit disclosure messages negatively affect transportation and identification and stimulate the generation of counterarguments. In addition, the more explicit disclosure messages affect both attitude measures via two of these processes (i.e., transportation and counterarguing). Less explicit disclosure messages do not have this effect. Implications of the findings are discussed.

Parliament as the Foreign Policy Actor: the Resources of the Parliamentary Diplomacy

2018 ◽  
Vol 42 ◽  
pp. 316-321
Author(s):  
Boris I. Ananyev ◽  
Daniil A. Parenkov
Keyword(s):  
Foreign Policy ◽  
International Security ◽  
New Technologies ◽  
Conservative Approach ◽  
National Interests ◽  
Policy Actor ◽  
Security Challenges ◽  
Essential Idea ◽  
Per Se

The aim of the article is to show the role of parliament in the foreign policy within the framework of the conservative school of thought. The authors examine both Russian and Western traditions of conservatism and come to the conclusion that the essential idea of “the rule of the best” has turned to be one of the basic elements of the modern legislative body per se. What’s more, parliament, according to the conservative approach, tends to be the institution that represents the real spirit of the nation and national interests. Therefore the interaction of parliaments on the international arena appears to be the form of the organic communication between nations. Parliamentary diplomacy today is the tool that has the potential to address to the number of issues that are difficult to deal with within the framework of the traditional forms of IR: international security, challenges posed by new technologies, international sanctions and other.

Gedanken zu Genesis 46,8–27

2019 ◽  
Vol 63 (1) ◽  
pp. 93-104
Author(s):  
Wilfried Warning
Keyword(s):  
Close Reading ◽  
Per Se ◽  
Distinct Distribution

Abstract In general, commentators consider Gen 46:8–27 as a secondary addition. Close reading brings to light the structuring role of verses 18 and 25 („these were the sons of Zilpah / Bilhah … and these she bore to Jacob, sixteen souls / seven souls”). In a ten-part outline based on the personal name (PN) „Jacob” v. 18 takes the fourth and v.25 the fourth from last positions. In Genesis 37–50 the noun נפש „soul” occurs thirteen times – now v. 18 takes the sixth and v. 25 the sixth-from-last positions. The thirteen-part table based on the PN „Ruben” stands out for two reasons: Firstly, in Genesis the term „Ruben the first born of Jacob” shows up only twice, namely in the first (34,23) and last (46,8) texts. Secondly, as regards content 37,22 and 42,22 are correlated. In the 13-part outline they take the sixth and sixth-from-last positions respectively. The distinct distribution of these terms indicates that the passage per se is well structured and, what is more, at the same time it has been skillfully integrated in Gen 37–50 and in the Jacob-Joseph cycle.

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

Sign in / Sign up

Export Citation Format

Share Document