Protective effects of EphB2 on Aβ1–42 oligomer-induced neurotoxicity and synaptic NMDA receptor signaling in hippocampal neurons

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized pathologically by the abnormal deposition of extracellular amyloid-β (Aβ) oligomers. However, the nature and precise mechanism of the toxicity of Aβ oligomers are not clearly understood. Aβ oligomers have been previously shown to cause a major loss of EphB2, a member of the EphB family of receptor tyrosine kinases. To determine the effect of EphB2 on Aβ oligomer-induced neurotoxicity and the underlying molecular mechanisms, we examined the EphB2 gene in cultured hippocampal neurons. Using a cellular model of AD, Aβ_1–42 oligomers were confirmed to induce neurotoxicity in a time-dependent manner and result in a major decrease of EphB2. EphB2 overexpression could prevent the neurotoxicity of hippocampal neurons from exposure to Aβ_1–42 oligomers for 1 h. Further analysis revealed that EphB2 overexpression increased synaptic NR1 and NR2B expression in Aβ_1–42 oligomer-treated neurons. Moreover, EphB2 overexpression prevented Aβ_1–42 oligomer-induced downregulation of dephosphorylated p38 MAPK and phosphorylated CREB. Together, these results suggest that EphB2 is a factor which protects hippocampal neurons against the toxicity of Aβ_1–42 oligomers, and we infer that the protection of EphB2 is achieved by increasing the synaptic NMDA receptor level and downstream p38 MAPK and CREB signaling in hippocampal neurons. This study provides new molecular insights into the neuroprotective effect of EphB2 and highlights its potential therapeutic role in the management of AD.     

Antagonistic and synergistic effects of bone morphogenetic protein 2/7 and all‐trans retinoic acid on the osteogenic differentiation of rat bone marrow stromal cells

The osteogenesis of bone marrow stromal cells (BMSCs) is of paramount importance for the repair of large‐size bone defects, which may be compromised by the dietary‐accumulated all‐trans retinoic acid (ATRA). We have shown that heterodimeric bone morphogenetic protein 2/7 (BMP2/7) could induce bone regeneration in a significantly higher dose‐efficiency in comparison with homodimeric BMPs. In this study, we evaluated the effects of ATRA and BMP2/7 on the proliferation, differentiation, mineralization and osteogenic genes. ATRA and BMP2/7 exhibited both antagonistic and synergistic effects on the osteogenesis of BMSCs. ATRA significantly inhibited proliferation and expression of osteocalcin but enhanced the activity of alkaline phosphatase of BMSCs. On day 21, 50 ng/mL BMP2/7 could antagonize the inhibitive effects of ATRA and significantly enhance osteogenesis of BMSCs. These findings suggested a promising application potential of heterodimeric BMP2/7 in clinic to promote bone regeneration for the cases with dietary accumulated ATRA.     

Increased ��-tocotrienol content in seeds of transgenic rice overexpressing Arabidopsis ��-tocopherol methyltransferase

Vitamin E comprises a group of eight lipid soluble antioxidant compounds that are an essential part of the human diet. The ??-isomers of both tocopherol and tocotrienol are generally considered to have the highest antioxidant activities. ??-tocopherol methyltransferase (??-TMT) catalyzes the final step in vitamin E biosynthesis, the methylation of ??- and ??-isomers to ??- and ??-isomers. In present study, the Arabidopsis ??-TMT (AtTMT) cDNA was overexpressed constitutively or in the endosperm of the elite japonica rice cultivar Wuyujing 3 (WY3) by Agrobacterium-mediated transformation. HPLC analysis showed that, in brown rice of the wild type or transgenic controls with empty vector, the ??-/??-tocotrienol ratio was only 0.7, much lower than that for tocopherol (~19.0). In transgenic rice overexpressing AtTMT driven by the constitutive Ubi promoter, most of the ??-isomers were converted to ??-isomers, especially the ??- and ??-tocotrienol levels were dramatically decreased. As a result, the ??-tocotrienol content was greatly increased in the transgenic seeds. Similarly, over-expression of AtTMT in the endosperm also resulted in an increase in the ??-tocotrienol content. The results showed that the ??-/??-tocopherol ratio also increased in the transgenic seeds, but there was no significant effect on ??-tocopherol level, which may reflect the fact that ??-tocopherol is present in very small amounts in wild type rice seeds. AtTMT overexpression had no effect on the absolute total content of either tocopherols or tocotrienols. Taken together, these results are the first demonstration that the overexpression of a foreign ??-TMT significantly shift the tocotrienol synthesis in rice, which is one of the world??s most important food crops.     

CPEB1, a histone-modified hypomethylated gene,is regulated by miR-101 and involved in cell senescence in glioma

Epigenetic mechanisms have important roles in carcinogenesis. We certified that the mRNA translation-related gene cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is hypomethylated and overexpressed in glioma cells and tissues. The knockdown of CPEB1 reduced cell senescence by regulating the expression or distribution of p53 in glioma cells. CPEB1 is also regulated directly by the tumor suppressor miR-101, a potential marker of glioma. It is known that the histone methyltransferase enhancer of zeste homolog 2 (EZH2) and embryonic ectoderm development (EED) are direct targets of miR-101. We demonstrated that miR-101 downregulated the expression of CPEB1 through reversing the methylation status of the CPEB1 promoter by regulating the presence on the promoter of the methylation-related histones H3K4me2, H3K27me3, H3K9me3 and H4K20me3. The epigenetic regulation of H3K27me3 on CPEB1 promoter is mediated by EZH2 and EED. EZH2 has a role in the regulation of H3K4me2. Furthermore, the downregulation of CPEB1 induced senescence in a p53-dependent manner.     

Effects of dietary L-carnitine and coenzyme Q10 supplementation on performance and ascites mortality of broilers

The study was conducted to determine the effects of dietary L-carnitine and coenzyme Q₁₀ (CoQ₁₀) supplementation on growth performance and ascites mortality of broilers. A 3 × 3 factorial arrangement was employed with three levels (0, 75 and 150 mg/kg) of L-carnitine and three levels of CoQ₁₀ (0, 20 and 40 mg/kg) supplementation during the experiment. Five hundred and forty one-day-old Arbor Acre male broiler chicks were randomly allocated into nine groups with six replicates each. All birds were fed with the basal diets from day 1 to 7 and changed to the experimental diets from day 8. During day 15 to 21 all the birds were exposed to low ambient temperature (15 - 18°C) to induce ascites. The results showed that under this condition, growth performance of broilers were not significantly affected by CoQ₁₀ or L-carnitine + CoQ₁₀ supplementation during week 0 - 3 and 0 - 6, but body weight gain (BWG) of broilers was significantly reduced by 150 mg/kg L-carnitine during week 0 - 6. Packed cell volume (PCV) of broilers was significantly decreased by L-carnitine and L-carnitine + CoQ₁₀ supplementation (P < 0.05). Erythrocyte osmotic fragility (EOF), ascites heart index (AHI) and ascites mortality of broilers were significantly decreased by L-carnitine, CoQ₁₀ and L-carnitine + CoQ₁₀ supplementation. Though no significant changes were observed in total antioxidative capability (T-AOC), total superoxide dismutase (T-SOD) was increased by L-carnitine, CoQ₁₀ and L-carnitine + CoQ₁₀ supplementation (P < 0.05). Malonaldehyde (MDA) content was significantly decreased by CoQ₁₀ and L-carnitine + CoQ₁₀ supplementation. The results indicate that dietary L-carnitine and CoQ₁₀ supplementation reduce ascites mortality of broilers; the reason may be partially associated with their antioxidative effects.     

Stress-Derived Corticotropin Releasing Factor Breaches Epithelial Endotoxin Tolerance

Background and aims

Loss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance.

Methods

Epithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine.

Results

The established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2.

Conclusions

Psychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa.     

Actions of Hydrogen Sulfide and ATP-Sensitive Potassium Channels on Colonic Hypermotility in a Rat Model of Chronic Stress

Objective

To investigate the potential role of hydrogen sulphide (H₂S) and ATP-sensitive potassium (K_ATP) channels in chronic stress-induced colonic hypermotility.

Methods

Male Wistar rats were submitted daily to 1 h of water avoidance stress (WAS) or sham WAS (SWAS) for 10 consecutive days. Organ bath recordings, H₂S production, immunohistochemistry and western blotting were performed on rat colonic samples to investigate the role of endogenous H₂S in repeated WAS-induced hypermotility. Organ bath recordings and western blotting were used to detect the role of K_ATP channels in repeated WAS.

Results

Repeated WAS increased the number of fecal pellets per hour and the area under the curve of the spontaneous contractions of colonic strips, and decreased the endogenous production of H₂S and the expression of H₂S-producing enzymes in the colon devoid of mucosa and submucosa. Inhibitors of H₂S-producing enzymes increased the contractile activity of colonic strips in the SWAS rats. NaHS concentration-dependently inhibited the spontaneous contractions of the strips and the NaHS IC₅₀ for the WAS rats was significantly lower than that for the SWAS rats. The inhibitory effect of NaHS was significantly reduced by glybenclamide. Repeated WAS treatment resulted in up-regulation of Kir6.1 and SUR2B of K_ATP channels in the colon devoid of mucosa and submucosa.

Conclusion

The colonic hypermotility induced by repeated WAS may be associated with the decreased production of endogenous H₂S. The increased expression of the subunits of K_ATP channels in colonic smooth muscle cells may be a defensive response to repeated WAS. H₂S donor may have potential clinical utility in treating chronic stress- induced colonic hypermotility.     

Looking Time Predicts Choice but Not Aesthetic Value

Although visual fixations are commonly used to index stimulus-driven or internally-determined preference, recent evidence suggests that visual fixations can also be a source of decisional bias that moves selection toward the fixated object. These contrasting results raise the question of whether visual fixations always index comparative processes during choice-based tasks, or whether they might better reflect internal preferences when the decision does not carry any economic or corporeal consequences. In two experiments, participants chose which of two objects were more aesthetically pleasing (Exp.1) or appeared more organic (Exp.2), and provided independent aesthetic ratings of the stimuli. Our results demonstrated that fixation parameters were a better index of choice in both decisional domains than of aesthetic preference. The data support models in which visual fixations are specifically related to the evolution of decision processes even when the decision has no tangible consequences.     

从国家自然科学基金项目资助看植物科学态势

通过对2010-2015年度国家自然科学基金委员会生命科学部植物学学科资助的各类项目进行统计分析,总结了植物学学科资助的整体概况,详细分析了各类科学基金项目的资助特点、在不同分支学科和领域中的分布以及获资助排名前列的依托单位,并展望了我国未来植物学学科的发展趋势。