Icariin ameliorates glycolytic dysfunction in Alzheimer's disease models by activating the Wnt/ß-catenin signaling pathway.

It was reported that the Wnt/ß-catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/ß-catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg-AD mice were treated with ICA. HT22 cells, the Aß25-35 peptide and Dickkopf-1 (DKK1) agent (a specific inhibitor of the Wnt/ß-catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti-AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg-AD mice back to wild-type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aß25-35. However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg-AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/ß-catenin pathway.

Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer's disease models.

Objective: To investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis. Methods: RIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of hnRNP A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of hnRNP A1 was used to observe the effect of overexpression of hnRNP A1 on glycolysis of Aß25-35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay. Results: The results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aß25-35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of hnRNP A1 binding to amyloid precursor protein (APP) RNA was found to increase Aß expression, while Aß25-35 also down-regulated hnRNP A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

Hydro-biogeochemical modeling of the early-stage outbreak of green tide (Ulva prolifera) driven by land-based nutrient loads in the Jiangsu coast.

The outbreak of a large-scale green tide (Ulva prolifera) will have a serious impact on marine environment, ecological functions, landscape, and coastal social economy. Eutrophication is generally considered to be the most important driving factor of this phenomenon. It is difficult to obtain the pressure-impact relationship between land-based loading and green tides by only surveying or monitoring, whereas modeling can perform this task easily. In this study, therefore, a hydro-biogeochemical model was established and verified by the measured hydrodynamic and water quality variables. In the initial outbreak area of Jiangsu coast, China, we studied the relationship between U. prolifera bloom and the driving factors of nutrient loads and structures by modeling different scenarios of land source inputs. It was found that the ratio of nitrogen to phosphorus could be affected significantly, which triggered the bloom of U. prolifera. When the land-based input doubled or halved, the dissolved inorganic nitrogen concentration increased 20.6% or decreased 9.5%, respectively, which might result in 14.5% increase or 46.3% decrease in the green tide, respectively. It was also found that the nutrient distribution and structure was affected by the land-based load, which caused the outbreak of U. prolifera. Moreover, the total nutrient load must be controlled to prevent the outbreak of green tide in the Jiangsu coast.

[Compound huangdai tablet as induction therapy for 193 patients with acute promyelocytic leukemia].

OBJECTIVE: To report the results of curative and adverse effects of compound huangdai tablet (CHDT) as induction therapy for 193 patients with acute promyelocytic leukemia (APL). METHODS: CHDT was administered 1.25 g orally three times a day after meal for three days, then the dosage was gradually increased to 7.5 g/d. RESULTS: One hundred and ninety-three patients achieved complete remission (CR), 78.8% of whom in 30 to 60 days with an average time of 44.3 d. No serious infection, bleeding or DIC occurred during the treatment course. The major adverse effects were gastrointestinal symptoms. There was no change in lanine transaminase, urea, creatinine or electrocardiographic QTc interval in 110 APL patients observed before and after the treatment. CONCLUSION: CHDT therapy is a modality of higher CR rate, good safety and tolerance without bone marrow suppression for APL patients.