Friend virus induces in mice acute erythroleukemia characterized by two distinct stages, an initial polyclonal expansion of infected erythroid progenitor cells mediated by the viral glycoprotein gp55, followed by the acquisition of additional genetic alterations, including the mutation of p53 and retroviral insertion into the PU
Cataract is the leading cause of visual impairment, and posterior capsular opacification (PCO) is the most common long-term complication of modern cataract surgery, which can cause severe visual impairment after surgery. The proliferation, migration, and epithelial-mesenchymal transition (EMT) of residual lens epithelial cells (LECs) stimulated by growth factors and cytokines, are the key pathological mechanisms involved in the development of PCO. This study demonstrated that non-steroidal anti-inflammatory drug (NSAID), bromfenac, was capable of effectively inhibiting cell migration, overexpression of EMT markers, such as fibronectin (FN), matrix metalloproteinase 2 (MMP2), α-smooth muscle actin (α-SMA), and transcription factor Snail, and extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3β (GSK-3β) signaling induced by transforming growth factor-β2 (TGF-β2) in vitro . The inhibitory effect of bromfenac on TGF-β2-induced EMT was also verified on a primary lens epithelial cell model using human anterior capsules. Furthermore, based on ultrasonic spray technology, we developed a drug-eluting intraocular lens (IOL) using poly (lactic-co-glycolic acid) (PLGA) with sustained bromfenac release ability for the prevention of PCO development. In the rabbit models of cataract surgery, bromfenac-eluting IOL exhibited remarkable PCO prevention and inflammation suppression effects with excellent biocompatibility. In conclusion, bromfenac can inhibit TGF-β2-induced cell migration and the EMT of LECs via ERK/GSK-3β/Snail signaling. The present study offers a novel approach for preventing PCO through PLGA-based drug sustained-release IOLs.
Leukemogenesis requires two classes of mutations, one that promotes proliferation and one that blocks differentiation. The erythroleukemia induced by Friend virus is a multistage disease characterized by an early proliferative stage driven by the interaction of the viral glycoprotein, gp55, with Sf-Stk and the EpoR, and a late block to differentiation resulting from retroviral insertion in the Pu.1 locus. We demonstrate here that activation of Stat3 by Sf-Stk in the early stage of disease is essential for the progression of erythroleukemia in the presence of differentiation signals induced by the EpoR, but is dispensable in the late stages of the disease. Furthermore, we identify Pu.1 as a Stat3 target gene in the early stages of erythroleukemia development. Our results support a model whereby the activation of Stat3 in the early stage of disease plays a pivotal role in regulating differentiation through the upregulation of Pu.1, thus inhibiting differentiation and favoring the expansion of infected erythroblasts and enhancing the pool of progenitors available for the acquisition of additional mutations, including insertional activation of Pu.1, resulting in full leukemic transformation.
Receptor tyrosine kinases (RTKs) activate downstream signaling through cognate growth factor receptor-induced dimerization and autophosphorylation. Overexpression of RTKs can lead to constitutive activation due to increased dimerization in the absence of ligand, and downstream signals are presumed to be the same as the ligand-induced signals. We have shown that the murine Ron (mRon) receptor tyrosine kinase exhibits constitutive activation of the MAP kinase pathway that is independent of the two docking site tyrosines, whereas activation of this pathway in response to ligand (macrophage-stimulating protein) is abolished in the absence of these tyrosines. Furthermore, we identified three tyrosines (Tyr-1175, Tyr-1265, and Tyr-1294) within the kinase domain that play critical but overlapping roles in controlling constitutive Erk activation by mRon. Phenylalanine mutations at these three tyrosines results in a receptor that fails to constitutively activate the Erk pathway but retains the ability to induce Erk phosphorylation in response to ligand stimulation. The ability of mRon to activate the MAP kinase pathway is dependent on c-Src activity, and we have shown that c-Src co-immunoprecipitates with mRon. c-Src fails to interact with mRon when the three tyrosines required for MAP kinase activation are mutated, whereas the presence of any one of these tyrosines alone restores Erk phosphorylation and recruitment of c-Src. Thus, the ligand-dependent and -independent activity of mRon can be uncoupled through the alteration of selective sets of tyrosines.
Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia.
BackgroundCataract is the leading cause of blindness worldwide. Many observational studies assessed the relationship between postmenopausal hormone replacement therapy (HRT) and risk of cataract development, but the reported results were controversial. The aim of present meta-analysis was to evaluate the association of postmenopausal hormone replacement therapy with risk of cataract development.MethodsThe eligible observational studies, including cross-sectional, case–control and cohort studies, were identified by searching PubMed and Embase during March of 2013. Either a fixed- or a random-effects model was used to calculate the pooled odds ratio (OR) with its 95% confidence interval (95%CI). Subgroup analysis on cataract types was performed.ResultsA total of four cohort and five case-control or cross-sectional studies were finally included into this meta-analysis. Overall, a significant decreased risk of developing any type of cataract was found in ever HRT group as compared with non-HRT group among cohort studies (OR 0.83; 95%CI: 0.71,0.97) and case-control or cross-sectional studies (OR 0.74; 95%CI: 0.59,0.93). Subgroup analysis on cataract types determined that the significantly decreased risk of nuclear cataract in current HRT group (OR 0.72; 95%CI: 0.61,0.85) and also a critically reduced risk of nuclear cataract in ever HRT group (OR 0.80; 95% CI: 0.64,1.01) were found among case-control or cross-sectional studies, as compared with non-HRT group. No association of HRT with risk of cortical and posterior subcapsular cataract was observed.ConclusionsThe results of present meta-analysis indicate that postmenopausal hormone use may play a protective role in cataract development.
The evidence of acupressure is limited in the management of dysmenorrhea. To evaluate the efficacy of acupressure in the treatment of primary dysmenorrhea based on randomized controlled trials (RCTs), we searched MEDLINE, the Chinese Biomedical Database (CBM), and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception until March 2012. Two reviewers independently selected articles and extracted data. Statistical analysis was performed with RevMan 5.1 software. Eight RCTs were identified from the retrieved 224 relevant records. Acupressure improved pain measured with VAS (−1.41 cm 95% CI [−1.61, −1.21]), SF-MPQ at the 3-month followup (WMD −2.33, 95% CI [−4.11, −0.54]) and 6-month followup (WMD −4.67, 95% CI [−7.30, −2.04]), and MDQ at the 3-month followup (WMD −2.31, 95% CI [−3.74, −0.87]) and 6-month followup (WMD −4.67, 95% CI [−7.30, −2.04]). All trials did not report adverse events. These results were limited by the methodological flaws of trials.
Alternative splicing of signaling proteins can contribute to the complexity of signaling networks. We find that expression of mouse RON, but not human RON, results in constitutive receptor autophosphorylation, ligand-independent activation of the mitogen-activated protein kinase pathway, and association of the receptor with c-Src. Using chimeric receptors, we mapped the region for this difference in signaling capacity of mouse and human RON to the juxtamembrane domain. Expression of these receptors in primary erythroid progenitor cells also demonstrated a functional difference in the ability of mouse and human RON to support erythropoietin-independent colony formation that mapped to the juxtamembrane domain. Splicing of the mouse RON receptor tyrosine kinase transcript results in the constitutive deletion of an exon used by all other known RON orthologs that encodes part of the juxtamembrane domain of the receptor. Mutational analysis indicated that the two tyrosines present in this region in human RON, one of which has been previously shown to be a c-Cbl binding site, are not responsible for this difference. However, deletion of this region in the context of human RON enhanced receptor phosphorylation, activation of mitogen-activated protein kinase, and association of c-Src at levels comparable with those observed with mouse RON. These data provide direct evidence that the divergence of exon usage among different species can generate a protein with novel activity and subsequently add to the complexity of cellular signaling regulation.The modular nature of signaling proteins greatly facilitates the rapid evolution of a large number of molecules with various combinations of functional domains, increasing the possibility for combinatorial regulation. Furthermore, individual exons frequently correspond to basic folding and functional modules of a given protein (1). Expectedly, alternative splicing constitutes an important mechanism for protein evolution and diversification. By simply including or excluding certain exons, genes could reorganize their functional motifs to achieve novel activities without taking the risk of deleteriously mutating the coding sequence. Receptor tyrosine kinases (RTKs) 2 play a fundamental role in the regulation of animal development and pathogenesis. Intramolecular interactions, receptor dephosphorylation, and degradation form multiple layers of defense against uncontrolled kinase activity. The binding of growth factors enhances the enzymatic activity of the kinase domain by relieving structural constraints (2), resulting in tyrosine phosphorylation of the receptor that serves as an assembly platform for downstream signaling molecules (3). Alternative splicing, resulting in similar relief of these constraints, is one mechanism by which RTKs could become constitutively activated in tumor cells. Recent studies have identified several transforming transcripts of the human RON receptor tyrosine kinase, generated by alternative splicing of exons 5, 6, and 11 in the extracellular domain in pa...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.