scholarly journals Nrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers

2013 ◽  
Vol 34 (5) ◽  
pp. 900-913 ◽  
Author(s):  
Keiko Taguchi ◽  
Ikuo Hirano ◽  
Tohru Itoh ◽  
Minoru Tanaka ◽  
Atsushi Miyajima ◽  
...  
Keyword(s):  
Double Mutant ◽  
Target Genes ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Double Deletion ◽  
Polycystic Liver ◽  
Long Term Observation ◽  
The Impact ◽  
Abnormal Expansion

Keap1-Nrf2 system plays a central role in the stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 activity is abrogated in response to oxidative or electrophilic stresses, leading to Nrf2 stabilization and coordinated activation of cytoprotective genes. We recently found that nuclear accumulation of Nrf2 is significantly increased by simultaneous deletion of Pten and Keap1, resulting in the stronger activation of Nrf2 target genes. To clarify the impact of the cross talk between the Keap1-Nrf2 and Pten–phosphatidylinositide 3-kinase–Akt pathways on the liver pathophysiology, in this study we have conducted closer analysis of liver-specificPten::Keap1double-mutant mice (Pten::Keap1-Alb mice). The Pten::Keap1-Alb mice were lethal by 1 month after birth and displayed severe hepatomegaly with abnormal expansion of ductal structures comprising cholangiocytes in a Nrf2-dependent manner. Long-term observation of Pten::Keap1-Alb::Nrf2+/−mice revealed that the Nrf2-heterozygous mice survived beyond 1 month but developed polycystic liver fibrosis by 6 months. Gsk3 directing the Keap1-independent degradation of Nrf2 was heavily phosphorylated and consequently inactivated by the double deletion ofPtenandKeap1genes. Thus, liver-specific disruption ofKeap1andPtenaugments Nrf2 activity through inactivation of Keap1-dependent and -independent degradation of Nrf2 and establishes the Nrf2-dependent molecular network promoting the hepatomegaly and cholangiocyte expansion.

scholarly journals Phenotype of the Aging-Dependent Spontaneous Onset of Hearing Loss in DBA/2 Mice

2021 ◽  
Vol 8 (3) ◽  
pp. 49
Author(s):  
Min-Soo Seo ◽  
Byeonghyeon Lee ◽  
Kyung-Ku Kang ◽  
Soo-Eun Sung ◽  
Joo-Hee Choi ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Early Stage ◽  
Auditory Brainstem ◽  
Dependent Manner ◽  
Intrinsic Properties ◽  
Hearing Ability ◽  
Brainstem Response ◽  
Long Term Observation ◽  
Spontaneous Onset

DBA/2 mice are a well-known animal model for hearing loss developed due to intrinsic properties of these animals. However, results on the phenotype of hearing loss in DBA/2 mice have been mainly reported at an early stage in mice aged ≤7 weeks. Instead, the present study evaluated the hearing ability at 5, 13, and 34 weeks of age using DBA/2korl mice. Auditory brainstem response test was performed at 8–32 KHz at 5, 13, and 34 weeks of age, and hearing loss was confirmed to be induced in a time-dependent manner. In addition, histopathological evaluation at the same age confirmed the morphological damage of the cochlea. The findings presented herein are the results of the long-term observation of the phenotype of hearing loss in DBA/2 mice and can be useful in studies related to aging-dependent hearing loss.

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

scholarly journals The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor

2019 ◽  
Vol 105 (3) ◽  
pp. 716-734 ◽  
Author(s):  
Benjamin Small ◽  
Charles E F Millard ◽  
Edwina P Kisanga ◽  
Andreanna Burman ◽  
Anika Anam ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Uterine Fibroid ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
The Body ◽  
Dependent Manner ◽  
Ulipristal Acetate

Abstract Context The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. Objective To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. Design Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. Results Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. Conclusions These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.

scholarly journals Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-β receptor I to inhibit TGF-β signaling

2015 ◽  
Vol 112 (23) ◽  
pp. E3000-E3009 ◽  
Author(s):  
Premalatha Shathasivam ◽  
Alexandra Kollara ◽  
Maurice J. Ringuette ◽  
Carl Virtanen ◽  
Jeffrey L. Wrana ◽  
...  
Keyword(s):  
Target Genes ◽  
Tissue Growth ◽  
Nuclear Accumulation ◽  
Ovarian Cancer Cells ◽  
Hippo Signaling ◽  
Ph Domain ◽  
Mouse Development ◽  
Transcriptional Responses ◽  
Β Receptor ◽  
The Impact

Drosophila melted encodes a pleckstrin homology (PH) domain-containing protein that enables normal tissue growth, metabolism, and photoreceptor differentiation by modulating Forkhead box O (FOXO), target of rapamycin, and Hippo signaling pathways. Ventricular zone expressed PH domain-containing 1 (VEPH1) is the mammalian ortholog of melted, and although it exhibits tissue-restricted expression during mouse development and is potentially amplified in several human cancers, little is known of its function. Here we explore the impact of VEPH1 expression in ovarian cancer cells by gene-expression profiling. In cells with elevated VEPH1 expression, transcriptional programs associated with metabolism and FOXO and Hippo signaling were affected, analogous to what has been reported for Melted. We also observed altered regulation of multiple transforming growth factor-β (TGF-β) target genes. Global profiling revealed that elevated VEPH1 expression suppressed TGF-β–induced transcriptional responses. This inhibitory effect was verified on selected TGF-β target genes and by reporter gene assays in multiple cell lines. We further demonstrated that VEPH1 interacts with TGF-β receptor I (TβRI) and inhibits nuclear accumulation of activated Sma- and Mad-related protein 2 (SMAD2). We identified two TβRI-interacting regions (TIRs) with opposing effects on TGF-β signaling. TIR1, located at the N terminus, inhibits canonical TGF-β signaling and promotes SMAD2 retention at TβRI, similar to full-length VEPH1. In contrast, TIR2, located at the C-terminal region encompassing the PH domain, decreases SMAD2 retention at TβRI and enhances TGF-β signaling. Our studies indicate that VEPH1 inhibits TGF-β signaling by impeding the release of activated SMAD2 from TβRI and may modulate TGF-β signaling during development and cancer initiation or progression.

scholarly journals Current assessment results of the efficacy and safety of scleroplasty in progressive myopia

2021 ◽  
Vol 14 (1) ◽  
pp. 96-103
Author(s):  
E. N. Iomdina ◽  
E. P. Tarutta ◽  
G. A. Markosian ◽  
J. I. Gavrilova
Keyword(s):  
Plastic Material ◽  
Biologically Active ◽  
Efficacy And Safety ◽  
Short Term ◽  
Current Assessment ◽  
Progressive Myopia ◽  
Long Term Observation ◽  
The Impact ◽  
Observation Results

The purpose of the review is to analyze the data of recent studies (performed in the last two decades) of the efficacy and safety of sclera reinforcement surgeries for progressive myopia in children and adults. Short-term and long-term observation results are presented, indicating the impact of the initial degree of myopia, the patient's age, surgical technique and the choice of plastic material on the outcome of the intervention and the further course of the myopic process. The advantages of a biologically active synthetic graft are described, which makes it possible to deposit drugs that stimulate scleral crosslinking and have a biomechanical, trophic and hemodynamic effect. Crosslinking of scleral collagen is a promising approach to the treatment of myopia.

Assessment of exposure loads of chemicals in workers of the main professions of aluminum production in Eastern Siberia

2019 ◽  
Vol 1 (7) ◽  
pp. 406-411 ◽  
Author(s):  
Nina M. Meshchakova ◽  
Alexey V. Merinov ◽  
Salim F. Shayakhmetov ◽  
Lyudmila G. Lisetskaya
Keyword(s):  
Aluminum Electrolysis ◽  
Aluminum Production ◽  
Electrolysis Cell ◽  
Chemical Factor ◽  
Professional Groups ◽  
Harmful Substances ◽  
The Aluminum Industry ◽  
Long Term Observation ◽  
The Impact

Introduction. In the production of aluminum, one of the main adverse factors is the air pollution of the working area with f uorine-containing compounds and dust-gas-aerosol mixture, the impact of which can lead to health problems in workers. When establishing the connection of morbidity with the profession, it is important to assess the exposure loads of harmful substances. T is aspect of research in the aluminum industry is not suf iiently covered in the literature. T e aim of the study is to quantify the exposure loads of priority toxicants in workers of the main professions of aluminum production, depending on the applied technologies of aluminum electrolysis. Materials and methods. Exposure loads (EL) of chemicals at workers of aluminum production were calculated taking into account the data of a long-term assessment of the working area air for the content of the main harmful substances in workshops with technology of self-baking anode (TSA) and modernized using technology of prebaked anode (TPA). Results. It has been established that with the use of the traditional electrolysis technology (TSA), the average annual EL indicators in the professions of the electrolysis cell, anodechik and crane operators f uctuated noticeably in the dynamics of long-term observation, exceeding the indicators of the control EL. It is shown that the modernized electrolysis technology (TPA) allows to reduce the EL indicators of chemicals, with the exception of hydrof uoride — one of the priority components of the chemical factor. T e actual EL indicators of this substance in the professional groups did not depend on the applied electrolysis technology and, as before, exceeded the EL control indicators. Conclusions: Calculations of EL by harmful substances in the production of aluminum have shown that when using TSA, electrolysis cells and anodetes experience the greatest EL, exceeding control indicators, and the lowest  — crane operators. T e transition to a modernized TPA leads to a decrease in the EL indicators, with the exception of the hydrof uoride, a priority component of the chemical factor.

scholarly journals RUNX1 contributes to the mesenchymal subtype of glioblastoma in a TGFβ pathway-dependent manner

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Kai Zhao ◽  
Xiaoteng Cui ◽  
Qixue Wang ◽  
Chuan Fang ◽  
Yanli Tan ◽  
...  
Keyword(s):  
Target Genes ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Functional Studies ◽  
The Impact ◽  
Tgfβ Pathway ◽  
Genome Atlas

AbstractRunt-Related Transcription Factor 1 (RUNX1) is highly expressed in the Mesenchymal (Mes) subtype of glioblastoma (GBM). However, the specific molecular mechanism of RUNX1 in Mes GBM remains largely elusive. In this study, cell and tumor tissue typing were performed by RNA-sequencing. Co-immunoprecipitation (co-IP) and immunofluorescence (IF) were employed to identify members of the RUNX1 transcriptional protein complex. Bioinformatics analysis, chromatin immunoprecipitation (ChIP), and luciferase reporter experiments were utilized to verify target genes. Analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) verified the expression levels and prognoses associated with RUNX1/p-SMAD3/SUV39H1 target genes. In vivo patient-derived xenograft (PDX) studies and in vitro functional studies verified the impact of RUNX1 on the occurrence and development of GBM. The results showed that RUNX1 was upregulated in Mes GBM cell lines, tissues and patients and promoted proliferation and invasion in GBM in a TGFβ pathway-dependent manner in vivo and in vitro. We found and verified that BCL3 and MGP are transcriptionally activated by p-SMAD3 /RUNX1, while MXI1 is transcriptionally suppressed by the RUNX1/SUV39H1-H3K9me3 axis. This finding offers a theoretical rationale for using molecular markers and choosing therapeutic targets for the Mes type of GBM.

Analysis of Long-Term Observation of Highway Arch Bridge Oparno

2016 ◽  
Vol 249 ◽  
pp. 209-214
Author(s):  
Vojtěch Kolínský ◽  
Jan L. Vítek
Keyword(s):  
Rheological Properties ◽  
Detailed Comparison ◽  
Bridge Construction ◽  
Final State ◽  
Arch Bridge ◽  
Arch Bridges ◽  
Long Term Observation ◽  
Long Term Behavior ◽  
The Impact

The paper deals with evaluation of experimental data collected during the Oparno arch bridge construction and with subsequent analysis of the construction process and long-term behavior with regard to rheological properties of concrete. The Oparno valley bridge is composed of two separate concrete arch structures with spans of 135 metres (this is currently the second longest span of concrete arch bridge in the Czech Republic). It was built using cantilever casting technology with temporary cable-stays and auxiliary pylons. The data recorded for this study include detailed geodetic measurement of the bridge structure during construction, along with measured strains and temperatures in the arches. Most of the data was measured during the bridge construction in 2008 and 2009. Data significant for long term behavior of structure are still being collected. Verification of different concrete material models and their suitability for design of arch bridges built by free cantilevering will be a main result of the analysis. On the basis of a detailed comparison of numerical results and measured deflections, strains and temperatures, it is possible to quantify the impact of rheological properties of the material (or their individual input parameters) on the resulting structural behavior. Unlike previous research, the examined structure is made of reinforced concrete (not prestressed) and consists of compact solid section and in the final state it is mainly in compression.

scholarly journals AB0233 REASONS AND RISK FACTOR FOR DISCONTINUATION OF BIOLOGIC AGENTS FOR RHEUMATOID ARTHRITIS PATIENTS IN LONG-TERM OBSERVATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1142.3-1143
Author(s):  
K. Terabe ◽  
N. Takahashi ◽  
S. Asai ◽  
Y. Hirano ◽  
Y. Kanayama ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Adverse Events ◽  
Retention Rate ◽  
University Hospital ◽  
Biologic Agent ◽  
Long Term Observation ◽  
The Impact ◽  
Agent Treatment

Background:Rheumatoid arthritis (RA) patients who failed a first biologic agent due to any reasons have the option of switching to a second one along with the strategy of biologic agent treatment. Patients go over switching to the next one at failing their biologic agent. On the other hand, there are some patients who discontinue any biologic agent treatment due to various reasons such as tolerability concern, complications, economic issue, remission and so on1 2. The impact of this concern has been less studied.Objectives:The objective of this study was to investigate the reasons and the risk factors for discontinuation any biologic agent in RA patients.Methods:To Include patients who are observed long-term, patients who underwent biologic agent treatment between 2003 and 2007 at Nagoya University Hospital and 12 other institutes (Tsurumai Biologics Communication Study Group) were enrolled. 570 patients who were confirmed continuation or discontinuation of biologic agent treatment were enrolled. The last observation was September 2017. We analyzed the retention rate of biologic agent treatment and the reasons for discontinuation. To identify the risks for discontinuation, baseline demographics were compared between the continuing group and the disc continuing group using cox hazard regression analysis.Results:In total 570 patients, the average duration of treatment with biologics was 6.6±3.3 (years) and total patient-year was 3739 in this study. 458 patients were administered biologics continuously, 112 patients were withdrawn. Table 1 showed the demographic data in total patients. The retention rate was 96.0% (discontinuation n=23) at least 1 year from starting biologics treatment, 92.6% (n=42) at 3 years, 88.2% (n=67) at 5 years, 84.4% (n=89) at 7 years, 81.1% (n=108) at 10 years. In 112 patients who discontinued, the reasons were adverse events in 74 patients, lack of effectiveness in 11 patients, others in 27 patients. Comparison of incidence for discontinuation using cumulative hazard function, the reason of adverse events was significantly higher than others reasons (Figure 1). To identify the risks of discontinuation, we analyzed by multivariable Cox proportional hazard modeling in patients who discontinued treatment due to adverse events, the risk factors (hazard ratio: HR, confidence interval: CI) were over 3 of Steinblocker class (HR 1.85 [1.02-2.04]), age (HR:1.07 [1.04-1.10]) and Non-concomitant with methotrexate (HR 1.90 [1.08-3.33]) (Figure 2).Table 1.Age (years)56.1 ± 13.4Gender n (% male)110 (19%) n (% female)460 (81%)Disease duration (years)11.1 ± 9.8stage 1,2104 (19%) 3,4455 (81%)class 1,2336 (60%) 3,4225 (40%)Methotrexate use, no (%)400 (70%)Glucocorticoid use, no (%)262 (47%)Rheumatoid Factor, no (%)287 (65%)anti CCP antibody, no (%)137 (87%)Conclusion:The most common reason for discontinuation was adverse events in long term observation. The risk factors for discontinuation were class, age, and non-concomitant MTX. These results suggested that comorbidity has a significant impact on continuation rates because there are some reasons of non-concomitant MTX in addition to relate with age and the activities of daily living.References:[1]Marussa B, et al. j.clin thera. 2011; 33(7): 901-913[2]Alejandro S, et al. Rheumatol. 2016; 55(3): 523-34Disclosure of Interests:KENYA TERABE: None declared, Nobunori Takahashi Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Ono, Pfizer, Takeda, and UCB Japan, Shuji Asai Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Takeda, and UCB Japan, Yuji Hirano Speakers bureau: Tanabe-Mitsubishi, Pfizer, Eisai, Abbie, Chugai, Bristol-Meyers, Jansen, Astellas, UCB, Eli-Lilly, Asahikasei, Daiichi-Sankyo, Amgen, Yasuhide Kanayama: None declared, Toshihisa Kojima Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Janssen, Mitsubishi Tanabe, Pfizer, and Takeda, Consultant of: AbbVie, Grant/research support from: Chugai, Eli Lilly, Astellas, Abbvie, and Novartis

scholarly journals Eritrea’s Chosen Trauma and the Legacy of the Martyrs: The Impact of Postmemory on Political Identity Formation of Second-Generation Diaspora Eritreans

2021 ◽  
Vol 56 (1) ◽  
pp. 19-38
Author(s):  
Nicole Hirt
Keyword(s):  
Identity Formation ◽  
Second Generation ◽  
Political Identity ◽  
Media Analysis ◽  
Social Media Analysis ◽  
Long Distance ◽  
Post Conflict ◽  
Long Term Observation ◽  
The Impact

In the collective memory of Eritreans, the liberation struggle against Ethiopia symbolises the heroic fight of their fallen martyrs against oppression. After independence, the Eritrean People’s Liberation Front created an autocratic regime, which is adored by many second-generation diaspora Eritreans living in democracies. I engage with bodies of literature exploring the political importance of collective trauma in post-conflict societies and apply two theoretical notions, “postmemory” and “chosen trauma,” to explain how the government’s narrative of Eritrean history produced a culture of nationalism through the glorification of the martyrs. This narrative and the trauma experienced by their parents created experiences of postmemory among the second-generation diaspora that have influenced their worldview. I demonstrate how Eritrean pro-government activists utilise US-born artists who recently discovered their Eritreanness, such as Tiffany Haddish, to instil long-distance nationalism. The article is based on a social media analysis, long-term observation of Eritrean diaspora communities, and recent fieldwork.

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