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The failure of breast cancer treatment is largely due to the development of estrogen independence. Current data illustrate that Hedgehog (Hh) signaling may play an important role in breast cancer development. Here, we show that th...
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The failure of breast cancer treatment is largely due to the development of estrogen independence. Current data illustrate that Hedgehog (Hh) signaling may play an important role in breast cancer development. Here, we show that the expression of the Hh effector protein, Gli1 was significantly higher in estrogen-independent breast cancer cells than in estrogen-dependent cells. Our data showed for the first time that stable expression of Gli1 in ER positive breast cancer cell lines MCF-7 and T47D can induce estrogen-independent proliferation and promote G1/S phase transition, which associated with cyclin-Rb axi. Gli1 can also attenuate the response of proliferation to estrogenic stimulation, which was correlated with down-regulation of expression of ERalpha and PR, as well as down-regulation of transactivation of ERalpha. Our results suggest that up-regulation of Gli1 in breast cancer cells may be one of the mechanisms responsible for developing estrogen independence and this process may be regulated through down-regulation of expression and transactivation of ERalpha.
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The present study sought to investigate mechanisms by which p53 induction contributes to excitotoxic neuronal injury. Rats were intrastriatally administered the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid (QA), th...
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The present study sought to investigate mechanisms by which p53 induction contributes to excitotoxic neuronal injury. Rats were intrastriatally administered the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid (QA), the changes in the expression of p53 and its target genes involved in apoptosis and autophagy, including p53-upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, damage-regulated autophagy modulator (DRAM) and other autophagic proteins including microtubule-associated protein 1 light chain 3 (LC3) and beclin 1 were assessed. The contribution of p53-mediated autophagy activation to apoptotic death of striatal neurons was assessed with co-administration of the nuclear factor-kappaB (NF-kappaB) inhibitor SN50, the p53 inhibitor Pifithrin-alpha (PFT-alpha) or the autophagy inhibitor 3-methyladenine (3-MA). The increased formation of autophagosomes and secondary lysosomes were observed with transmission electron microscope after excitotoxin exposure. QA induced increases in the expression of p53, PUMA, Bax and a decrease in Bcl-2. These changes were significantly attenuated by pre-treatment with SN50, PFT-alpha or 3-MA. SN50, PFT-alpha or 3-MA also reversed QA-induced upregulation of DRAM, the ratio of LC3-II/LC3-I and beclin 1 protein levels in the striatum. QA-induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by SN50, PFT-alpha or 3-MA. These results suggest that overstimulation of NMDA receptors can induce NF-kappaB-dependent expression of p53. p53 participates in excitotoxic neuronal death probably through both apoptotic and autophagic mechanisms.
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The hypoxia-inducible factors have recently been identified as critical regulators of angiogenic-osteogenic coupling. Mice overexpressing HIFalpha subunits in osteoblasts produce abundant VEGF and develop extremely dense, highly v...
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The hypoxia-inducible factors have recently been identified as critical regulators of angiogenic-osteogenic coupling. Mice overexpressing HIFalpha subunits in osteoblasts produce abundant VEGF and develop extremely dense, highly vascularized long bones. In this study, we investigated the individual contributions of Hif-1alpha and Hif-2alpha in angiogenesis and osteogenesis by individually disrupting each Hifalpha gene in osteoblasts using the Cre-loxP method. Mice lacking Hif-1alpha demonstrated markedly decreased trabecular bone volume, reduced bone formation rate, and altered cortical bone architecture. By contrast, mice lacking Hif-2alpha had only a modest decrease in trabecular bone volume. Interestingly, long bone blood vessel development measured by angiography was decreased by a similar degree in both DeltaHif-1alpha and DeltaHif-2alpha mice suggesting a common role for these Hifalpha subunits in skeletal angiogenesis. In agreement with this idea, osteoblasts lacking either Hif-1alpha or Hif-2alpha had profound reductions in VEGF mRNA expression but only the loss of Hif-1alpha impaired osteoblast proliferation. These findings indicate that expression of both Hif-1alpha and Hif-2alpha by osteoblasts is required for long bone development. We propose that both Hif-1alpha and Hif-2alpha function through cell non-autonomous modes to promote vascularization of bone and that Hif-1alpha also promotes bone formation by exerting direct actions on the osteoblast.
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BACKGROUND: We tested the hypothesis that in newborn rats, sevoflurane may cause seizures, neurotoxicity, and impairment in synaptic plasticity-effects that may be diminished by the Na-K-2Cl cotransporter 1 inhibitor, bumetanide. ...
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BACKGROUND: We tested the hypothesis that in newborn rats, sevoflurane may cause seizures, neurotoxicity, and impairment in synaptic plasticity-effects that may be diminished by the Na-K-2Cl cotransporter 1 inhibitor, bumetanide. METHODS: Electroencephalography, activated caspase-3, and hippocampal long-term potentiation were measured in rats exposed to 2.1% sevoflurane for 0.5-6 h at postnatal days 4-17 (P4-P17). RESULTS: Arterial blood gas samples drawn at a sevoflurane concentration of 2.1% showed no evidence of either hypoxia or hypoventilation in spontaneously breathing rats. Higher doses of sevoflurane (e.g., 2.9%) caused respiratory depression. During anesthesia maintenance, the electroencephalography exhibited distinctive episodes of epileptic seizures in 40% of P4-P8 rats. Such seizure-like activity was not detected during anesthesia maintenance in P10-P17 rats. Emergence from 3 h of anesthesia with sevoflurane resulted in tonic/clonic seizures in some P10-P17 rats but not in P4-P8 rats. Bumetanide (5 micromol/kg, intraperitoneally) significantly decreased seizures in P4-P9 rats but did not affect the emergence seizures in P10-P17 rats. Anesthesia of P4 rats with sevoflurane for 6 h caused a significant increase in activated caspase-3 and impairment of long-term potentiation induction measured at 1 and 14-17 days after exposure to sevoflurane, respectively. Pretreatment of P4 rats with bumetanide nearly abolished the increase in activated caspase-3 but did not alleviate impairment of long-term potentiation. CONCLUSION: These results support the possibility that excitatory output of sevoflurane-potentiated gamma-aminobutyric acid type A/glycine systems may contribute to epileptogenic and neurotoxic effects in early postnatal rats.
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FSH regulates follicular growth in a stage-development fashion. Although preantral follicle stage is gonadotropin responsive, FSH is not required for preantral follicular growth. With the antrum, the follicles continue growing und...
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FSH regulates follicular growth in a stage-development fashion. Although preantral follicle stage is gonadotropin responsive, FSH is not required for preantral follicular growth. With the antrum, the follicles continue growing under the influence of FSH and become gonadotropin dependent. Although thyroid hormone is important for normal female reproductive function, its role and interaction with FSH in the regulation of preantral ovarian follicular growth is yet to be defined. In the present study, we have examined the action and interaction of FSH and T(3) in the regulation of the growth of preantral follicles, especially in their transition from preantral to early antral stage, using an established follicle culture system and evaluated the involvement of growth differentiation factor-9 (GDF-9) in this process in vitro. We have demonstrated that although T(3) alone had no effect on follicular development, it markedly enhanced FSH-induced preantral follicular growth. Although FSH alone significantly down-regulated FSH receptor (FSHR) mRNA abundance in the preantral follicles and T(3) alone was ineffective, expression of the message was significantly increased in the presence of both hormones. In addition, intra-oocyte injection of GDF-9 antisense oligonucleotides (GDF-9 morpholino) induced follicular cell apoptosis and suppressed follicular growth induced by FSH and T(3). These responses were attenuated by exogenous GDF-9. Our findings support the concept that thyroid hormone regulates ovarian follicular development through its direct action on the ovary and that promotes FSH-induced preantral follicular growth through up-regulation of FSHR, a mechanism dependent on the expression and action of oocyte-derived GDF-9.
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FOXO1A and FOXO3A are two members of the FoxO family. FOXO3A has recently been linked to human longevity in Japanese, German and Italian populations. Here we tested the genetic contribution of FOXO1A and FOXO3A to the longevity ph...
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FOXO1A and FOXO3A are two members of the FoxO family. FOXO3A has recently been linked to human longevity in Japanese, German and Italian populations. Here we tested the genetic contribution of FOXO1A and FOXO3A to the longevity phenotype in Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were selected and genotyped in 1817 centenarians and younger individuals. Two SNPs of FOXO1A were found to be associated with longevity in women (P = 0.01-0.005), whereas all three SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). One SNP from FOXO1A was found not to be associated with longevity. In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 (0.58-0.90) and 1.38 (1.08-1.76), P = 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (0.51-0.86), P = 0.0014; CGT: OR (95% CI) = 1.48 (1.12-1.94), P = 0.0035] and in women [GTC: OR (95% CI) = 0.75 (0.60-0.94), P = 0.0094; CGT: OR (95% CI) = 1.47 (1.16-1.86), P = 0.0009]. The haplotype association tests were validated by permutation analysis. The association of FOXO1A with female longevity was replicated in 700 centenarians and younger individuals that were sampled geographically different from the original population. Thus, we demonstrate that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by genders.
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This study presents a green post-grafting method to prepare functional mesoporous silica
materials. In the functionalisation stage, potassium iodide was applied as catalyst, and
ecofriendly ethanol was used as solvent. The optimal...
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This study presents a green post-grafting method to prepare functional mesoporous silica
materials. In the functionalisation stage, potassium iodide was applied as catalyst, and
ecofriendly ethanol was used as solvent. The optimal molecular ratio of the reagent was n
(potassium iodide)/n (3-chloropropyltriethoxysilane)/n (2-mercaptobenzothiazole)51?5 : 1 : 1?5.
The reaction could be completed after reflux for 12 h at 90uC. The resulting materials were
characterised by scanning electron microscopy, X-ray diffraction, nitrogen adsorption–desorption,
Fourier transform infrared spectroscopy and elemental analysis. The results indicate that
the large pore (the maximal size isy8?62 nm) functional mesoporous silica could be prepared by
our improved graft method, which has a high efficiency of 50?63%. The functional mesoporous
silica was applied to adsorb trace amount of heavy metal ions [Hg(II), Pb(II) and Cd(II)]. The
materials exhibit large adsorption capacity and excellent regeneration ability.
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Neodymium doped yttrium carbonate precursors were synthesised via a normal strike
coprecipitation route, employing NH4HCO3 as precipitant and (NH4)2SO4 as surfactant.
Nd:Y2O3 powders were obtained through calcining the precursors ...
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Neodymium doped yttrium carbonate precursors were synthesised via a normal strike
coprecipitation route, employing NH4HCO3 as precipitant and (NH4)2SO4 as surfactant.
Nd:Y2O3 powders were obtained through calcining the precursors at 1100uC for 3 h. The
precursors, Nd:Y2O3 powders and ceramics samples were characterised by means of several
analytic techniques, such as differential thermal and thermogravimetric analysis, Fourier
transform infrared, X-ray powder diffraction, TEM and SEM. The as synthesised precursors were
amorphous, which gradually changed from agglomeration to needle-like shape along with the
increase in (NH4)2SO4. The Nd:Y2O3 powders derived from needle shaped precursors exhibited
good dispersion with mean particle sizes at ,50 nm. The well dispersed Nd:Y2O3 powders also
showed good sinterability, and the corresponding sintered ceramics samples were highly
transparent.
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Our earlier studies have shown the in vitro and in vivo targeting of a generation 5 (G5) dendrimer-based multifunctional conjugate that contained folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeuti...
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Our earlier studies have shown the in vitro and in vivo targeting of a generation 5 (G5) dendrimer-based multifunctional conjugate that contained folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeutic drug. To clinically apply the synthesized G5-FA-MTX nanotherapeutic, it is important that the anticancer conjugate elicits cytotoxicity specifically and consistently. Toward this objective, we evaluated the large-scale synthesis of a G5-FA-MTX conjugate (Lot # 123-34) for its cytotoxic potential and specificity in vitro and in vivo. The cytotoxicity and specificity were tested by using a coculture assay in which FA receptor-expressing and nonexpressing cells (KB and SK-BR-3 cells, respectively) were cultured together and preferential killing was examined. The in-vitro data were compared with the in-vivo data obtained from a heterogeneous xenograft tumor model. The animal model of the artificial heterogeneous xenograft tumor showed that the nanotherapeutic was preferentially cytotoxic to KB cells.
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OBJECTIVES: To: 1) characterize diet in Inuvialuit; 2) determine the foods and nutrients to be targeted for a nutritional intervention program; and 3) develop a Quantitative Food Frequency Questionnaire (QFFQ) to evaluate the prog...
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OBJECTIVES: To: 1) characterize diet in Inuvialuit; 2) determine the foods and nutrients to be targeted for a nutritional intervention program; and 3) develop a Quantitative Food Frequency Questionnaire (QFFQ) to evaluate the program and monitor nutrition transition for Inuvialuit in the Northwest Territories (NWT), Canada. METHODS: Twenty-four-hour dietary recalls were collected among 101 Inuvialuit aged 19 years and over in two communities in the NWT. All foods reported in the recall were tabulated for inclusion in the QFFQ. RESULTS: Forty-eight men and 53 women (mean age 49 and 45 yrs, respectively) completed the recalls. Mean energy intake was 2,352 kcal and 1,739 kcal for men and women, respectively. Mean daily intakes of many nutrients including dietary fibre, calcium, and vitamins A, C and E, and total folate were much lower than recommended. The most frequently reported foods were non-nutrient-dense store-bought foods. Most traditional foods (TF) were reported one time by one person. The top two contributors to energy intake, 'sugar added to tea and coffee' and 'sweetened juices and drinks', were targeted by the intervention program. A 145-item QFFQ was developed including 41 TF and 8 categories of consumption frequency. CONCLUSIONS: This study has provided dietary intake data previously unavailable for Inuvialuit and highlighted nutrients and foods to be targeted for the intervention program. The QFFQ is up-to-date, culturally appropriate, and currently being used to evaluate the intervention program, Healthy Foods North, which aims to reduce dietary- and lifestyle-related risk factors for chronic disease in Inuvialuit.
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