Nuclear receptors, including Esrrb, Dax1, and Nr5a2, have been shown to be involved in pluripotency maintenance. Yet, the role of their coactivators in mouse embryonic stem cells remains unexplored. ...Here, we demonstrated that the nuclear receptor coactivator 3 (Ncoa3) is essential for pluripotency maintenance. Knockdown of Ncoa3 not only compromises the expression of pluripotency markers but also impairs in vitro and in vivo differentiation potential of mouse ESCs. Ncoa3 binds to the Nanog promoter and recruits the histone acetyltransferase CREB binding protein (CBP) and the histone arginine methyltransferase CARM1 to activate Nanog expression. Moreover, glycogen synthase kinase 3 GSK3 signaling down-regulates the Ncoa3 protein level to suppress Nanog expression. Thus, Ncoa3 not only contributes to self-renewal by activating Nanog but also facilitates ESC differentiation as a break point to disrupt the core transcriptional circuitry of pluripotency.
Background: Transcriptional regulation plays an important role in pluripotency maintenance.
Results: Knockdown of the nuclear receptor coactivator 3 (Ncoa3) compromises the pluripotency of mouse embryonic stem cells.
Conclusion: Ncoa3 binds to and activates the Nanog promoter, thus promoting self-renewal of mouse embryonic stem cells.
Significance: Uncovering the novel role and mechanism of Ncoa3 in pluripotency maintenance.
Nonsense-mediated mRNA decay (NMD) is a highly conserved pathway that selectively degrades aberrant RNA transcripts. In this study, we proved that NMD regulates the epithelial–mesenchymal transition ...(EMT) of lung adenocarcinoma (ADC). Moreover, we found that NMD core factor UP-frameshift 1 tends to be expressed at lower levels in human ADC tissues than in normal lung tissues, thereby raising the possibility that NMD may be downregulated to permit ADC oncogenesis. Our experiments in human ADC cell lines showed that downregulating NMD can promote EMT. Moreover, EMT can be inhibited by upregulating NMD. We tested the role of TGF-ß signaling and found that NMD influences EMT by targeting the TGF-ß signaling pathway. Our findings reveal that NMD is a potential tumor regulatory mechanism and may be a potential therapeutic target for ADC.
•Nonsense mediated RNA decay (NMD) is an mRNA surveillance process. UPF1 is a key player among NMD process.•UPF1 is significantly downregulation in lung ADC tissues, showing that NMD is downregulated to permit ADC oncogenesis.•Downregulating NMD can promote EMT in ADC cell lines. And upregulating NMD can obvious inhibit the process of EMT.•NMD through targeting the TGF-ß signaling pathway to regulate the process of EMT.
Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This ...study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients.
Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs.
A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 10
/L).
Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis.
Molecular imprinting is a useful method to make enzyme mimics for protein recognition. Classic protein imprinting involves entrapping proteins within polysiloxane or polyacrylamide, but due to the ...rigidity of the recognition sites and the limited interaction between proteins and small molecule monomers, they often have unsatisfactory capacity, poor reproducibility and low specificity. In this report, “soft” and flexible recognition sites that can allow “induced fit” of the target proteins were created by a novel surface imprinting technique. When about 25% of the template proteins were removed, the unremoved proteins created “soft” and flexible loops that can lock into place upon protein rebinding, which provides additional favorable interactions between the rebind proteins and the imprinted sites. The adsorption capacity of the surface imprinted silica is 24.8×10−7mol/g. The “soft” recognition sites can distinguish target hemoglobin from other proteins such as bovine serum albumin, Cytochrome C and RNase A.
► Soft and flexible recognition sites were created by a novel surface imprinting technique. ► The recognition sites can allow “induced fit” of the target proteins. ► It provides additional favorable interactions between the rebind proteins and the imprinted sites. ► The “soft” recognition sites can distinguish target hemoglobin from other proteins.
Despite the development of various treatments, metastasis remains a significant problem with lung adenocarcinoma (ADC). The role and mechanism of epithelial splicing regulatory protein 1 (ESRP1), an ...epithelial-specific RNA binding protein, on promoting the invasion and metastasis of lung ADC remain to be fully elucidated. Immunohistochemical analysis in 125 human lung ADC tissue samples demonstrated that ESRP1 overexpression was inversely related to the presence of metastases, tumor size, and clinical stage of lung ADC. Impaired ESRP1 expression was also found to stimulate the invasion capacity of lung ADC cells both in vitro and in vivo. Functionally, overexpression of the ZEB1 gene decreased ESRP1 expression, and knockdown of the ZEB1 gene caused increased ESRP1 expression. On the basis of a gene array analysis, the expression of ESRP1 was associated with the regulation of the extracellular matrix. The expression of CD44 and fibroblast growth factor receptor, representatives that interact with the extracellular matrix, was studied. The CD44 subtypes promoted lung ADC cell invasion by regulating matrix metalloproteinase 2 expression. In conclusion, ESRP1 inhibits the invasion and metastasis of lung ADC and plays a role in regulating proteins involved in epithelial-to-mesenchymal transition.
Abstract
Background
Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Our previous study showed that hippocampal peroxisome ...proliferator-activated receptor δ (PPARδ) overexpression displays antidepressive effect and enhances hippocampal neurogenesis during chronic stress. Herein, we further extended our curiosity to investigate whether downregulating PPARδ could cause depressive-like behaviors through downregulation of neurogenesis.
Methods
Stereotaxic injection of lentiviral vector, expressing short hairpin RNA complementary to the coding exon of PPARδ, was done into the bilateral dentate gyri of the hippocampus, and the depression-like behaviors were observed in mice. Additionally, hippocampal neurogenesis, brain-derived neurotrophic factor and cAMP response element-binding protein were measured both in vivo and in vitro.
Results
Hippocampal PPARδ knockdown caused depressive-like behaviors and significantly decreased neurogenesis, neuronal differentiation, levels of mature brain-derived neurotrophic factor and phosphorylated cAMP response element-binding protein in the hippocampus. In vitro study further confirmed that PPARδ knockdown could inhibit proliferation and differentiation of neural stem cells. Furthermore, these effects were mimicked by repeated systemic administration of a PPARδ antagonist, GSK0660 (1 or 3 mg/kg i.p. for 21 d).
Conclusions
These findings suggest that downregulation of hippocampal PPARδ is associated with depressive behaviors in mice through an inhibitory effect on cAMP response element-binding protein/brain-derived neurotrophic factor-mediated adult neurogenesis in the hippocampus, providing new insights into the pathogenesis of depression.
Angiogenesis is a process of new blood vessel formation from pre-existing vessels. It is a normal and vital process in growth and development, as well as in wound healing and in the formation of ...granulation tissue. Total flavones of
(TFA) are the major constituents of the traditional Chinese herb
L. Medic. The aim of this study is to investigate the effect of TFA on angiogenic ability using human umbilical vein endothelial cells (HUVECs)
and chick chorioallantoic membrane (CAM)
. HUVECs were treated with TFA at different concentrations. Cell viability, cell cycle progression, cell apoptosis, cell migration and tubular formation were investigated. The expression of vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR, VEGFR-2) was examined by immunohistochemistry to identify mechanism of action of TFA. CAM model was used to evaluate the effect of TFA on angiogenesis
. Our results showed that TFA promoted HUVECs proliferation in a dose- and time-dependent manner. It increased HUVECs migratory ability and the number of tubular structure, promoted vessel formation in HUVECs culture and CAM model. Furthermore, TFA treatment resulted in a decrease in cell apoptosis and enhanced the expression of VEGF and KDR. Taken together, TFA, as the major active component isolated from the traditional Chinese herb
L. Medic, could enhance angiogenic ability of HUVECs
and CAM
. TFA may be used in the treatment of wound healing and ischemic/reperfusion injuries.
We use transport, inelastic neutron scattering, and angle-resolved photoemission experiments to demonstrate that the stoichiometric LiFeAs is an intrinsically electron-overdoped superconductor ...similar to those of the electron-overdoped NaFe sub(1-x)T sub(x)As and BaFe sub(2-x)T sub(x)As sub(2) (T = Co, Ni). Furthermore, we show that although transport properties of the stoichiometric superconducting LiFeAs and Li-deficient nonsuperconducting Li sub(1-x)FeAs are different, their electronic and magnetic properties are rather similar. Therefore, the nonsuperconducting Li sub(1-x)FeAs is also in the electron overdoped regime, where small Li deficiencies near the FeAs octahedra can dramatically suppress superconductivity through the impurity scattering effect.
Extragonadal primary yolk sac tumor of the intestinal tract origin is exceedingly rare. Through a multiple disciplinary team, the diagnosis and treatment of primary intestinal yolk sac tumor were ...further defined. We report 2 such cases with detailed histologic and immunohistochemical analysis. The two patients were a 7-year-old girl and a 29-year-old woman. Both of them preoperatively had an elevated serum alpha fetoprotein (AFP) level (≥ 1,210 ng/mL). The tumors are located in the intestine and imaging examination indicated the rectum as the primary site. Grossly the mass was grey-white and crisp texture. Microscopic examination featured reticular, microcystic, macrocystic, papillary, solid, and some glandular patterns. Immunohistochemically, tumor cells of both cases were positive for SALL4, AFP, pan-cytokeratin (AE1/AE3), and glypican-3. Simultaneously, a stain for EMA, OCT4, CD30, HCG, vimentin and CK20 were negative in all 2 neoplasms. The features of morphology, immunohistochemistry, laboratory examinations and imaging studies consist of the diagnosis of primary yolk sac tumor of the intestine.
Dear Editor Histone deacetylase 6 （Hdac6） is a mostly cytoplasmic class II HDAC. Many proteins have been identified as substrates of Hdac6. Among them, the most well characterized sub- strate of ...Hdac6 is a-tubulin. Through deacetylating acety- lated lysine 40 in a-tubulin, Hdac6 modulates the acetylation of microtubules （Hubbert et al., 2002）.
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