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α-synuclein (α-syn) is a highly conserved and thermostable protein that is widely distributed in human brain. An intracellular aggregation of α-syn in dopaminergic neurons is the hallmark of a group of neurodegenerative diseases including Parkinson's disease. Interestingly, α-syn is also highly expressed in red blood cells and is considered as one of the most abundant proteins in red blood cells. Moreover, α-syn is thought to play a regulatory role during normal erythropoiesis. However, whether α-syn participates in the pathogenesis of erythroid diseases has not been reported. In this review, we discuss the protein structure of α-syn and the importance of α-syn in erythropoiesis. [ABSTRACT FROM AUTHOR]

The presumed involvement of paired box gene 5 (PAX5) in B-lymphomagenesis is based largely on the discovery of Pax5-specific translocations and somatic hypermutations in non-Hodgkin lymphomas. Yet mechanistically, the contribution of Pax5 to neoplastic growth remains undeciphered. Here we used 2 Myc-induced mouse B lymphoma cell lines, Myc5-M5 and Myc5-M12, which spontaneously silence Pax5. Reconstitution of these cells with Pax5-tamoxifen receptor fusion protein (Pax5ER(TAM)) increased neoplastic growth in a hormone-dependent manner. Conversely, expression of dominant-negative Pax5 in murine lymphomas and Pax5 knockdown in human lymphomas negatively affected cell expansion. Expression profiling revealed that Pax5 was required to maintain mRNA levels of several crucial components of B cell receptor (BCR) signaling, including CD79a, a protein with the immunoreceptor tyrosine-based activation motif (ITAM). In contrast, expression of 2 known ITAM antagonists, CD22 and PIR-B, was suppressed. The key role of BCR/ITAM signaling in Pax5-dependent lymphomagenesis was corroborated in Syk, an ITAM-associated tyrosine kinase. Moreover, we observed consistent expression of phosphorylated BLNK, an activated BCR adaptor protein, in human B cell lymphomas. Thus, stimulation of neoplastic growth by Pax5 occurs through BCR and is sensitive to genetic and pharmacological inhibitors of this pathway. [ABSTRACT FROM AUTHOR]

Abstract: In mice, zygotic or pro-B-cell-specific knock-out of the Pax5 gene allows differentiation of pro-B-cells into all hematopoietic lineages. We previously generated and characterized a murine B-cell lymphoma, dubbed Myc5, whose cells spontaneously lose Pax5 expression when cultured in vitro, but regain it when re-injected into syngeneic mice. In cultured Myc5 cells, the loss of Pax5 correlates with the acquisition of myeloid markers, such as CD11b and F4/80. Here, we sought to determine whether these cells are truly B-macrophage-restricted or, like Pax5-null progenitors, can give rise to additional hematopoietic lineages. In vitro differentiation assays with various cytokines showed that Myc5 cells do not differentiate into NK cells, dendritic cells, neutrophils, or osteoclasts. At the same time, in the presence of macrophage colony-stimulating factor (M-CSF), they readily phagocytose latex beads and provide T-cell help. Both phenomena are indicative of the bona fide macrophage phenotype. Conversely, enforced Pax5 re-expression in macrophage-like Myc5 cells led to down-regulation of the M-CSF receptor and re-acquisition of some B-cell surface markers (e.g., CD79a) and lineage-specific transcription factors (e.g., IRF4 and Blimp). Retrovirally encoded Pax5 also restored expression of several master B-cell differentiation proteins, such as the IL-7 receptor and transcription factor E2A. In contrast, levels of EBF were unaffected by Pax5 suggesting that EBF acts exclusively upstream of Pax5 and might contribute to Pax5 expression. Indeed, transduction with an EBF-encoding retrovirus partly reactivated endogenous Pax5. Our data reveal the complex relationship between B-cell-specific transcription factors and suggest the existence of numerous feedback mechanisms. [Copyright &y& Elsevier]

High diversity and differential evolution profiles have been observed for DD34E/ Tc1 transposons; several families originating from these groups, such as DD34E/ ZB , DD34E/ SB , DD35E/ TR , DD36E/ IC, and DD38E/ IT , have been well defined. Even though Frisky , Tiang , Tsessebe, and Topi transposons have been identified in Anopheles gambiae , their taxonomic distribution and phylogenetic relationship in nature remain largely unknown. The evolutionary profiles of Frisky , Tiang , Tsessebe , and Topi homology transposons were investigated in the current study. In total, 254 homology transposons of Frisky , Tiang , Hob , Tsessebe, and Topi were obtained in 200 species by data mining. The phylogenetic tree revealed that these transposons were classified into five main clades (Frisky , Tiang , Hob , Tsessebe , and Topi) forming a monophyletic clade with 98% bootstrap support, belonging to the DD34E/ Tc1 group, and named as Skipper (SK). SK transposons show a wide distribution in animals; however, differential taxonomic distribution patterns were observed for the subfamilies of Frisky , Tiang , Hob , Tsessebe, and Topi ; extensive invasion of Frisky in animals was found, whereas Tiang , Hob , Tsessebe, and Topi were mainly detected in Diptera. SK elements share a similar structural organization and display high sequence identities across subfamilies. Evolutionary dynamics and structural analysis revealed that SK s in some species, such as Bombyx mori , Lordiphosa magnipectinata , Carassius gibelio , Triplophysa dalaica , and Silurus glanis , have recently evolved and present as intact copies, indicating that SK s in these genomes may be active. Together, these observations improve our understanding of the diversity of DD34E/ Tc1 transposons and their impacts on genome evolution in animals. [ABSTRACT FROM AUTHOR]

AIM: To investigate the role of Ywhab in the growth of mouse B-cell lymphoma, and to explore the potential underlying mechanisms. METHODS : The correlation between Ywhab and human diffuse large B-cell lymphoma (DLBCL) was investigated by bioinformatics analysis. Infection with retroviral vector was performed to establish stable mouse B-cell lymphoma 38B9 cell line with overexpression of Ywhab gene, which was verified by RT-qPCR and Western blot. The impact of Ywhab overexpression on 38B9 cell growth both in vitro and in vivo was detected by cell counting, CCK-8 assay, and subcutaneous tumor loading experiments. The expression of apoptosis-related proteins was detected by RT-qPCR and Western blot. Co-immunoprecipitation combined with mass spectrometry (CoIP-MS) was employed to search for proteins specifically binding to Ywhab gene product 14-3-3β, which was confirmed by Western blot and molecular docking analysis. RESULTS: The Ywhab gene exhibited low expression in DLBCL, which was correlated with poor clinical prognosis of DLBCL patients. Compared with normal mouse bone marrow B cells, Ywhab expression was low in 38B9 cells. Overexpression of Ywhab induced apoptosis of 38B9 cells both in vitro and in vivo, promoted the expression of pro-apoptotic proteins Puma, Noxa and Bax at both mRNA and protein levels, and inhibited the mRNA and protein expression of anti-apoptotic protein Bcl2 (P<0. 05). The 14-3-3β protein specifically bound to Hsp90aa1 and reduced Hsp90aa1 protein levels, thereby suppressing the growth of 38B9 cells. CONCLUSION: Ywhab promotes the apoptosis of B-cell lymphoma cells by binding to Hsp90aa1 and thereby inhibiting the function of Hsp90aa1. [ABSTRACT FROM AUTHOR]

Myc is a pivotal protooncogenic transcription factor that contributes to the development of almost all Burkitt's lymphomas and about one-third of diffuse large B-cell lymphomas. How B-cells sustain their uncontrolled proliferation due to high Myc is not yet well defined. Here, we found that Myc trans-represses the expression of murine LAPTM5, a gene coding a lysosome-associated protein, by binding to two E-boxes in the LAPTM5 promoter. While the product of intact mRNA (CDS+3′UTR) of LAPTM5 failed to suppress the growth of B-lymphomas, either the protein coded by coding sequence (CDS) itself or the non-coding 3′-untranslated region (3′UTR) mRNA was able to inhibit the growth of B-lymphomas. Moreover, Myc trans-activated miR-17-3p, which promoted tumor growth. Strikingly, LAPTM5 3′UTR contains 11 miR-17-3p-binding sites through which the LAPTM5 protein synthesis was inhibited. The functional interplay between low LAPTM5 mRNA and high miR-17-3p due to high Myc in B-lymphomas leads to further dampening of tumor-suppressive LAPTM5 protein, which promotes tumor progression. Our results indicate that Myc inhibits LAPTM5 expression in B-lymphoma cells by transcriptional and post-transcriptional modifications. [ABSTRACT FROM AUTHOR]

miR-144/451 and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulate two antioxidative systems that have been identified to maintain redox homeostasis in erythroid cells by removing excess reactive oxygen species (ROS). Whether these two genes coordinate to affect ROS scavenging and the anemic phenotype, or which gene is more important for recovery from acute anemia, has not been explored. To address these questions, we crossed miR-144/451 knockout (KO) and Nrf2 KO mice and examined the phenotype change in the animals as well as the ROS levels in erythroid cells either at baseline or under stress condition. Several discoveries were made in this study. First, Nrf2/miR-144/451 double-KO mice unexpectedly exhibit similar anemic phenotypes as miR-144/451 single-KO mice during stable erythropoiesis, although compound mutations of miR-144/451 and Nrf2 lead to higher ROS levels in erythrocytes than single gene mutations. Second, Nrf2/miR-144/451 double-mutant mice exhibit more dramatic reticulocytosis than miR-144/451 or Nrf2 single-KO mice during days 3 to 7 after inducing acute hemolytic anemia using phenylhydrazine (PHZ), indicating a synergistic effect of miR-144/451 and Nrf2 on PHZ-induced stress erythropoiesis. However, the coordination does not persist during the whole recovery stage of PHZ-induced anemia; instead, Nrf2/miR-144/451 double-KO mice follow a recovery pattern similar to miR-144/451 single-KO mice during the remaining period of erythropoiesis. Third, the complete recovery from PHZ-induced acute anemia in miR-144/451 KO mice takes longer than in Nrf2 KO mice. Our findings demonstrate that complicated crosstalk between miR-144/451 and Nrf2 does exist and the crosstalk of these two antioxidant systems is development-stage-dependent. Our findings also demonstrate that miRNA deficiency could result in a more profound defect of erythropoiesis than dysfunctional transcription factors. [ABSTRACT FROM AUTHOR]

The bicistronic microRNA (miRNA) locus miR-144/451 is highly expressed during erythrocyte development, although its physiological roles are poorly understood. We show that miR-144/451 ablation in mice causes mild erythrocyte instability and increased susceptibility to damage after exposure to oxidant drugs. This phenotype is deeply conserved, as miR-451 depletion synergizes with oxidant stress to cause profound anemia in zebrafish embryos. At least some protective activities of miR-451 stem from its ability to directly suppress production of 14-3-3ζ phospho-serine/threonine-binding protein that inhibits nuclear accumulation of transcription factor FoxO3, a positive regulator of erythroid anti-oxidant genes. Thus, in miR-144/451^/^ erythroblasts, 14-3-3ζ accumulates, causing partial relocalization of FoxO3 from nucleus to cytoplasm with dampening of its transcriptional program, including anti-oxidant-encoding genes Cat and Gpx1. Supporting this mechanism, overexpression of 14-3-3ζ in erythroid cells and fibroblasts inhibits nuclear localization and activity of FoxO3. Moreover, shRNA suppression of 14-3-3ζ protects miR-144/451^/^ erythrocytes against peroxide-induced destruction, and restores catalase activity. Our findings define a novel miRNA-regulated pathway that protects erythrocytes against oxidant stress, and, more generally, illustrate how a miRNA can influence gene expression by altering the activity of a key transcription factor. [ABSTRACT FROM AUTHOR]

Oxidative stress and abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) influence atherosclerosis formation and development. Oxidative stress significantly influences the abnormal proliferation and migration of VSMCs, and nuclear factor erythroid 2-related factor 2 (Nrf2) is a major antioxidant factor. However, the precise function of Nrf2 in the regulation of abnormal proliferation and migration of VSMCs and atherosclerosis is unclear. We investigated the proliferation and migration of VSMCs in atherosclerosis in male Apoe −/− and Apoe −/− Nrf2 −/− mice fed a high-fat diet for 12 weeks. In cultured mouse VSMCs, we studied the effect of Nrf2 on ox-LDL-stimulated proliferation and migration by using siRNA treatment to silence Nrf2. We then performed dual luciferase reporter and immunoprecipitation assays to study the interaction between Nrf2 and the promoter sequence of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Our results demonstrate that Nrf2 expression levels were increased in the aorta and VSMCs of mice in the atherosclerosis model group compared with the control group. We also provide evidence that Nrf2 deficiency attenuated atherosclerotic plaque burden, diminished proliferation, and migration of VSMCs but enhanced VSMC-specific marker gene expression in vitro and in vivo. This is related to Nrf2 binding to the promoter sequence of LOX-1. Furthermore, Nrf2 downregulation contributes to restrain both transcriptional and translational activities of LOX-1. Together, our data indicate that Nrf2 insufficiency is linked to attenuation of atherosclerosis, and could diminish the pathological process by blunting LOX-1-mediated proliferation and migration of VSMCs. [Display omitted] • Nrf2 drives atherosclerotic plaque formation. • Ox-LDL augments the expression of Nrf2 in mouse vascular smooth muscle cells (VSMCs). • Nrf2 induces proliferation and migration of VSMCs in Apoe −/− mice and in vitro. • Nrf2 deficiency diminishes LOX-1 activity and the oxidative stress level of VSMCs in vitro and in vivo. • Nrf2 binds LOX-1 promoter and increases its expression. [ABSTRACT FROM AUTHOR]

The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor crucial in cellular defense against oxidative and electrophilic stresses. Recent research has highlighted the significance of NRF2 in normal erythropoiesis and anemia. NRF2 regulates genes involved in vital aspects of erythroid development, including hemoglobin catabolism, inflammation, and iron homeostasis in erythrocytes. Disrupted NRF2 activity has been implicated in various pathologies involving abnormal erythropoiesis. In this review, we summarize the progress made in understanding the mechanisms of NRF2 activation in erythropoiesis and explore the roles of NRF2 in various types of anemia. This review also discusses the potential of targeting NRF2 as a new therapeutic approach to treat anemia. [Display omitted] • NRF2 is essential for erythroid homeostasis. • NRF2 protein stability is regulated by interactions with KEAP1 and other factors. • The expression of NRF2 during erythroid development is dynamic. • Targeting NRF2 offers potential therapeutic benefits for anemia treatment. [ABSTRACT FROM AUTHOR]

PAX5, a B cell-specific transcription factor, is overexpressed through chromosomal translocations in a subset of B cell lymphomas. Previously, we had shown that activation of immunoreceptor tyrosine-based activation motif (ITAM) proteins and B cell receptor (BCR) signaling by PAX5 contributes to B-lymphomagenesis. However, the effect of PAX5 on other oncogenic transcription factor-controlled pathways is unknown. Using a MYC-induced murine lymphoma model as well as MYC-transformed human B cell lines, we found that PAX5 controls c-MYC protein stability and steady-state levels. This promoter-independent, posttranslational mechanism of c-MYC regulation was independent of ITAM/BCR activity. Instead it was controlled by another PAX5 target, CD19, through the PI3K-AKT-GSK3β axis. Consequently, MYC levels in B cells from CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19 in murine lymphomas with spontaneous silencing of PAX5 boosted MYC levels, expression of its key target genes, cell proliferation in vitro, and overall tumor growth in vivo. In human B-lymphomas, CD19 mRNA levels were found to correlate with those of MYC-activated genes. They also negatively correlated with the overall survival of patients with lymphoma in the same way that MYC levels do. Thus, CD19 is a major BCR-independent regulator of MYC-driven neoplastic growth in B cell neoplasms. [ABSTRACT FROM AUTHOR]

Human adenocarcinomas commonly harbor mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. All three genetic lesions are potentially pro-angiogenic, as they sustain production of vascular endothelial growth factor (VEGF). Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth. In addition, VEGF levels were unaffected by Myc, but enhanced neovascularization correlated with downregulation of anti-angiogenic thrombospondin-1 (Tsp1) and related proteins, such as connective tissue growth factor (CTGF). Both Tsp1 and CTGF are predicted targets for repression by the miR-17-92 microRNA cluster, which was upregulated in colonocytes coexpressing K-Ras and c-Myc. Indeed, miR-17-92 knockdown with antisense 2′-O-methyl oligoribonucleotides partly restored Tsp1 and CTGF expression; in addition, transduction of Ras-only cells with a miR-17-92–encoding retrovirus reduced Tsp1 and CTGF levels. Notably, miR-17-92–transduced cells formed larger, better-perfused tumors. These findings establish a role for microRNAs in non–cell-autonomous Myc-induced tumor phenotypes. [ABSTRACT FROM AUTHOR]

Ablation of miR‐144/451 disrupts homeostasis of erythropoiesis. Myc, a protooncogenic protein, is essential for erythroblast proliferation but commits rapid downregulation during erythroid maturation. How erythroblasts orchestrate maturation processes through coding and non‐coding genes is largely unknown. In this study, we use miR‐144/451 knockout mice as in vivo model, G1E, MEL erythroblast lines and erythroblasts from fresh mouse fetal livers as in vitro systems to demonstrate that targeted depletion of miR‐144/451 blocks erythroid nuclear condensation and enucleation. This is due, at least in part, to the continued high expression of Myc in erythroblasts when miR‐144/451 is absent. Specifically, miR‐144/451 directly inhibits Myc in erythroblasts. Loss of miR‐144/451 locus derepresses, and thus, increases the expression of Myc. Sustained high levels of Myc in miR‐144/451‐depleted erythroblasts blocks erythroid differentiation. Moreover, Myc reversely regulates the expression of miR‐144/451, forming a positive miR‐144/451‐Myc feedback to ensure the complete shutoff of Myc during erythropoiesis. Given that erythroid‐specific transcription factor GATA1 activates miR‐144/451 and inactivates Myc, our findings indicate that GATA1‐miR‐144/451‐Myc network safeguards normal erythroid differentiation. Our findings also demonstrate that disruption of the miR‐144/451‐Myc crosstalk causes anemia, suggesting that miR‐144/451 might be a potential therapeutic target in red cell diseases. [ABSTRACT FROM AUTHOR]

Abstract Aneuploidy refers to aberrancies in cellular chromosome count, which is prevalent in most human cancers. Chemotherapy is an effective cancer treatment; however, the development of drug resistance is a major concern of conventional chemotherapy. The chemotherapy agent hydroxyurea (HU) targets proliferating cells and has long been applied to treat various human cancers. It remains elusive whether aneuploidy affects the drug sensitivity of hydroxyurea. By generating an inducible aneuploidy model, we found that aneuploid colon cancer cells were resistant to HU treatment compared to euploid controls. Surprisingly, further analyses showed that the HU resistance was dependent on the expression of wild type p53. Activation of the p53 pathway in aneuploidy cells reduced cell proliferation but generated resistance of tumor cells to HU treatment. HU resistance was abrogated in aneuploid cells if p53 was absent but re-gained when inducing proliferation repression in cells by serum deprivation. Our results demonstrate that the HU resistance developed in aneuploid colon cancer cells is mediated by wild type p53 and indicates the prognostic value of combining karyotypic and p53 status in clinical cancer treatment. Graphical abstract fx1 Highlights • Aneuploid colon cancer cells show chemoresistance to hydroxyurea. • Wildtype p53 mediates hydroxyurea resistance in aneuploid colon cancer cells. • Aneuploidy represses cell proliferation via the p53 pathway. • Suppressing cell proliferation by serum starvation generates hydroxyurea resistance. • Karyotype-based stratifying responses to hydroxyurea should be evaluated in clinic. [ABSTRACT FROM AUTHOR]

Highlights • Mice with remote fear memory are sensitive to original and novel reconditioning. • Reconditioning in an original fearful context causes remote fear memory resistance. • Reconditioning in a novel context produces more fear reactions in mice with remote fear memory. • Stress sensitivity of remote fear may be induced by fear memory system consolidation over time. Abstract Exposure of some individuals to recurring traumatic events from the same perpetrator or situation, such as during child abuse or domestic violence, is quite prevalent. Studies have shown that the number of traumatic events experienced is positively related to the severity of post-traumatic stress disorder and other mental disorders. Using a contextual fear conditioning (Cond1) and reconditioning (Cond2) paradigm, which were separated by either 1 or 35 days, we examined fear responses to immediate extinction and retrieval-extinction procedures after repeated fear conditioning stress. Based on the time interval between Cond1 and Cond2, the animals were divided into recent and remote fear memory groups. We observed that when Cond2 was performed in the original conditioning context in which Cond1 was performed, the reconditioned remote fear memory was resistant to the disruptive effect of immediate extinction and retrieval-extinction paradigms. Furthermore, the resistance to disruptive effects could be induced by very low shock intensities, which cannot even induce any fear response in naive animals. When Cond2 was performed in a novel context, animals with remote fear memory acquired a significantly higher fear response to the novel context. Our findings suggest that remote fear memory may be more sensitive to reconditioning and resistant to post-reconditioning disruption. [ABSTRACT FROM AUTHOR]

The cell migration capability of A549 and SK-MES-1 cells was determined using a cell scratch test. (C) Representative images and (D) statistical analysis are presented. [Corrigedum] miR-185 inhibits non-small cell lung cancer cell proliferation and invasion through targeting of SOX9 and regulation of Wnt signaling A549 and SK-MES-1 cells were transfected with miR-185 mimics or miR-185 inhibitor to achieve ectopic miR-185 expression or miR-185 inhibition. [Extracted from the article]

To investigate the effects of Lycium barbarum polysaccharide (LBP) on pathological symptoms and behavioral deficits in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. The therapeutic effects of LBP were monitored with an Open field test, a Rotarod test and a Morris water maze test. We also investigated the mechanisms with qRT-PCR and Western blotting analyses. After a relatively short-term LBP treatment, the total distance and walking time of PD mice significantly increased. The staying duration on the rod of PD mice increased in the Rotarod test. LBP can up-regulate levels of SOD2, CAT and GPX1 and inhibit the abnormal aggregation of α-synuclein induced by MPTP. LBP treatment can also up-regulate the phosphorylation of AKT and mTOR, and may play its protective role by activating the PTEN/AKT/mTOR signaling axis. These results suggest that LBP can effectively alleviate the degeneration in the nigrostriatal system induced by MPTP treatment. It may be a potential candidate for the treatment of Parkinson’s disease. [ABSTRACT FROM AUTHOR]

SRY-box 9 (SOX9) is an important transcription factor required for development, which has additionally been reported to be an independent prognostic indicator for the survival of patients with non-small cell lung cancer (NSCLC). Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs/miRs) may contribute to the initiation and progression of cancer. SOX9 may be regulated by a number of miRNAs in different types of cancer, including in NSCLC. The present study sought to identify novel candidate miRNAs associated with SOX9 in NSCLC using online tools, and investigated the detailed functions of miR-185, which suppressed SOX9 mRNA expression most strongly out of the candidate miRNAs. It was observed that ectopic miR-185 expression significantly suppressed NSCLC cell proliferation, invasion and migration. Using luciferase reporter gene and RNA immunoprecipitation assays, SOX9 was confirmed to be a direct target of miR-185. In addition, the downstream Wnt signaling-associated factors β-catenin and c-Myc proto-oncogene protein (Myc) were demonstrated to be inhibited by miR-185 overexpression. SOX9, β-catenin and c-Myc mRNA expression was significantly upregulated in NSCLC tissues, and was inversely correlated with miR-185 expression. The results of the present study demonstrated that rescuing miR-185 expression in NSCLC, thereby inhibiting SOX9 expression and the downstream Wnt signaling, and leading to the suppression of NSCLC cell proliferation, invasion and migration, may be a promising strategy for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Post-stroke cognitive impairment (PSCI), commonly seen in the clinical practice, is a major factor impeding patient rehabilitation. Enriched environment (EE) intervention is a simple and effective way to improve cognitive impairment, partially due to the rebalancing of the basal forebrain-hippocampus cholinergic signaling pathway. Epigenetic changes have been identified in many cognitive disorders. However, studies on the effects of EE on epigenetic regulation of cholinergic circuits in PSCI animal models have not yet been reported. In this study, we established a photothrombotic mouse PSCI model and showed that after EE intervention, mice with PSCI had significantly improved water maze performance, better induction of hippocampal long-term potentiation (LTP), enhanced function of the basal forebrain-hippocampus cholinergic circuits of contralateral side of stroke and relatively balanced acetylation homeostasis compared to those of PSCI mice in standard environments (SE). In addition, PSCI mice in EE expressed much higher levels of p-CREB and CBP than in SE, and the chromatins bound to M-type promoter of ChAT gene were more acetylated. These results demonstrate that EE plays an important role in the improvement of PSCI and the underlying mechanism may involve in the acetylation of histones bound to the ChAT gene promoter in cholinergic circuits. [ABSTRACT FROM AUTHOR]

Modification of the bone marrow microenvironment is considered as a promising strategy to control leukemic cell proliferation, diseases progression and relapse after treatment. However, due to the diversity and complexity of the cellular and molecular compartments in the leukemic microenvironment, it is extremely difficult to dissect the role of each individual molecule or cell type in vivo. Here we established an in vitro system to dissect the role of lipopolysaccharide (LPS), stromal cells and endothelial cells in the growth of mouse myeloid tumor cells and B-lymphoma cells. We found that either LPS or bone marrow stromal cells as a feeder layer in culture is required for the proliferation of myeloid tumor cells. Surprisingly, the growth of myeloid leukemic cells on stromal cells is strongly inhibited when coupled with LPS in culture. This opposing effect of LPS, a complete switch from pro-proliferation to antitumor growth is due, at least in part, to the rapidly increased production of interleukin 12, Fas ligand and tissue inhibitor of metalloproteinases-2 from stromal cells stimulated by LPS. These results demonstrate that LPS can either facilitate or attenuate tumor cell proliferation, thus changing the disease course of myeloid leukemias through its direct effect or modulation of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (Lnc RNAs) are longer than 200 nucleotide noncoding RNAs without apparent functional coding capacity that function as regulators of cell growth and development. In recent years, increasing evidence implicates the involvement of Lnc RNAs in erythropoiesis. shlnc- EC6 is a Lnc RNA associated with erythroid differentiation but the mechanism remains undefined. In this study, we found that knockdown of shlnc- EC6 in purified mouse fetal liver erythroid progenitor and hematopoietic stem cells ( FLEPHSCs) significantly blocked erythroid enucleation. We also showed that Rac1 was negatively regulated by shlnc- EC6 at the posttranscriptional level via specific binding to sites within the 3′ UTR of Rac1 m RNA. Moreover, we found that knockdown of shlnc- EC6 led to upregulation of Rac1, followed by the activation of the downstream protein PIP5K, and subsequently resulted in the inhibition of enucleation in cultured mouse fetal erythroblasts. Thus, our findings suggest that shlnc- EC6 acts as a novel modulator to regulate mouse erythropoiesis via Rac1/ PIP5K signaling pathway. [ABSTRACT FROM AUTHOR]

Summary: The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1-induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA-binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus nondifferentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1-bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that polycomb repressive complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1-repressed genes. These data provide insights into GATA-1-mediated gene regulation in vivo. [Copyright &y& Elsevier]

Autophagy is a lysosome-dependent degradative pathway frequently activated in tumor cells treated with chemotherapy or radiation. Whether autophagy observed in treated cancer cells represents a mechanism that allows tumor cells to survive therapy or a mechanism for initiating a nonapoptotic form of programmed cell death remains controversial. To address this issue, the role of autophagy in a Myc-induced model of lymphoma generated from cells derived from p53ER(TAM)/p53ER(TAM) mice (with ER denoting estrogen receptor) was examined. Such tumors are resistant to apoptosis due to a lack of nuclear p53. Systemic administration of tamoxifen led to p53 activation and tumor regression followed by tumor recurrence. Activation of p53 was associated with the rapid appearance of apoptotic cells and the induction of autophagy in surviving cells. Inhibition of autophagy with either chloroquine or ATG5 short hairpin RNA (shRNA) enhanced the ability of either p53 activation or alkylating drug therapy to induce tumor cell death. These studies provide evidence that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators and a rationale for the use of autophagy inhibitors such as chloroquine in combination with therapies designed to induce apoptosis in human cancers. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha (TNF-α)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-α family of death receptor ligands and holds great therapeutic potential as a tumor cell-specific cytotoxic agent. Using a panel of established tumor cell lines and normal cells, we found a significant difference between the number of TRAIL-sensitive cells expressing high levels of c-myc and TRAIL-resistant cells expressing low levels of c-myc (P < 0.05, n = 19). We also found a direct linear correlation between c-myc levels and TRAIL sensitivity in TRAIL-sensitive cell lines (r = 0.94, n = 6). Overexpression of c-myc or activation of a myc-estrogen receptor (ER) fusion sensitized TRAIL-resistant cells to TRAIL. Conversely, small interfering RNA (siRNA)-mediated knockdown of c-myc significantly reduced both c-myc expression and TRAIL-induced apoptosis. The gene encoding the inhibitor of caspase activation, FLICE inhibitory protein (FLIP), appears to be a direct target of c-myc-mediated transcriptional repression. Overexpression of c-myc or activation of myc-estrogen receptor (ER) decreased FLIP levels both in cell culture and in mouse models of c-myc-induced tumorigenesis, while knocking down c-myc using siRNA increased FLIP expression. Chromatin immunoprecipitation and luciferase reporter analyses showed that c-myc binds and represses the human FLIP promoter. c-myc expression enhanced TRAIL-induced caspase 8 cleavage and FLIP cleavage at the death-inducing signaling complex. Combined siRNA-mediated knockdown of FLIP and c-myc resensitized cells to TRAIL. Therefore, c-myc down-regulation of FLIP expression provides a universal mechanism to explain the ability of c-myc to sensitize cells to death receptor stimuli. In addition, identification of c-myc as a major determinant of TRAIL sensitivity provides a potentially important screening tool for identification of TRAIL-sensitive tumors. [ABSTRACT FROM AUTHOR]

Tectochrysin, a flavonoid compound, can be isolated from propolis, Alpinia oxyphylla Miq , and Lychnophora markgravii. This study evaluated the efficacy of tectochrysin in the treatment of shrimp tropomyosin (ST)-induced mouse asthma. Mice were sensitized with intraperitoneal (i.p.) injection of ST together with aluminum hydroxide as an adjuvant to establish a mouse model of asthma. Mice were i.p.-treated daily with tectochrysin. IgE levels in plasma, Th2 cytokines from both bronchoalveolar lavage (BAL) fluid and splenocytes, and CD200R on basophils in peripheral blood were measured. Histological analyses of lung tissues and accumulation of leukocytes in BAL fluid were performed. Lung eosinophil peroxidase, catalase and glutathione peroxidase activities were examined. ST was found to markedly increase eosinophilic inflammation and Th2 response in mice. Tectochrysin treatment reduced the level of IgE in plasma, the percentage of eosinophils in total white blood cells in peripheral blood, the total number of cells in BAL fluid, and eosinophil peroxidase activity in lung tissues. Tectochrysin attenuated ST-induced infiltration of eosinophils and epithelial mucus secretion in lung tissues and suppressed the overproduction of Th2 cytokines (IL-4 and IL-5) in BAL fluid. Tectochrysin also attenuated Th2 cytokine (IL-4 and IL-5) production from antigen-stimulated murine splenocytes in vitro , decreased the expression of CD200R on basophils in peripheral blood of asthmatic mice and inhibited IL-4 secretion from IgE-sensitized RBL-2H3 cells. In addition, tectochrysin enhanced catalase and glutathione peroxidase activities in lung tissues. Our findings demonstrate that TEC ameliorates allergic airway inflammation by suppressing Th2 response and oxidative stress. [ABSTRACT FROM AUTHOR]

• Shrimp tropomyosin (ST) induces more intense immunological and histopathological changes than ovalbumin in mice. • ST-induced allergy without adjuvants exhibits several hallmarks of mouse asthma. • ST-induce model in mice is a suitable model of allergic asthma that offers significant advantages over OVA-induced model due to the availability of inexpensive, reliable, and easy-to-establish method. Allergic asthma remains an important worldwide health issue. Animal models are valuable for understanding the pathophysiological mechanisms of asthma and the development of effective therapeutics. This study aims to develop an alternative murine model induced by shrimp tropomyosin (ST) instead of ovalbumin (OVA). To investigate responses to short-term exposure to antigens, mice were sensitized with intraperitoneal injections of ST or ST plus aluminum adjuvant on days 0, 7, 14 followed by an intranasal challenge with ST for seven consecutive days. We reveal that sensitization with ST alone or ST plus aluminum induces significant levels of serum total IgE and ST-specific IgE in mice. Challenge results show that ST causes severe eosinophilic airway inflammation. Histology analysis of the lung tissues demonstrates airway inflammation and mucus hypersecretion within the bronchi in mice exposed to ST. Analysis of the cell composition in bronchoalveolar lavage fluid (BALF) shows a significant increase in eosinophil count in ST alone and ST plus aluminum groups. We also detect increased CD4+ T lymphocytes in lung tissues and production of helper T cell type 2-associated cytokines (IL-4 and IL-5) in BALF. In addition, airway hyperresponsiveness to methacholine in ST alone and ST plus aluminum groups is much higher than that in control groups. For the chronic model, mice were sensitized by ST or ST plus aluminum adjuvant for 3 weeks and challenged with ST for 6 weeks. We find severe structural changes in animals upon prolonged exposure to ST, including goblet cell hyperplasia, collagen deposition, and smooth muscle thickening. In conclusion, ST-induced asthma is a simple murine model for studying pathogenesis of asthma and evaluating new therapeutic drugs. [ABSTRACT FROM AUTHOR]