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Original citation: J Clin Invest. 2022;132(8):e149160. https://doi.org/10.1172/JCI149160. https://doi.org/10.1172/JCI168441 The left panel of Figure 5G originally showed a histogram that was inadvertently duplicated from Figure 5E. The correct figure panel is [...]

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146VKI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis., Introduction Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders and is characterized by progressive memory impairment and cognitive deficits, often manifested pathologically by the deposition of [...]

Deguelin, a natural component derived from leguminous plants, has been used as pesticide in some regions. Accumulating evidence show that deguelin has promising chemopreventive and therapeutic activities against cancer cells. This study shows that low concentrations of deguelin can lead to significant delay in zebrafish embryonic development through growth inhibition and induction of apoptosis. Furthermore, we identified fibroblast growth factor receptor 4 ( FGFR4) as the putative target of deguelin. The candidate was initially identified by a microarray approach and then validated through in vitro experiments using hormone-responsive ( MCF-7) and nonresponsive ( MDA- MB-231) human breast cancer cell lines. The results show that deguelin suppressed cell proliferation and induced apoptosis in both cancer cell lines, but not in Hs 578Bst cells, by blocking PI3K/ AKT and mitogen-activated protein kinases ( MAPK) signaling. The FGFR4 mRNA and protein level also diminished in a dose-dependent manner. Interestingly, we found that forced FGFR4 overexpression attenuated deguelin-induced proliferative suppression and apoptotic cell death in both zebrafish and MCF-7 cell lines, p- AKT and p- ERK levels were restored upon FGFR4 overexpression. Taken together, our results strongly suggest that deguelin inhibition of PI3K/ AKT and MAPK signaling in zebrafish and breast cancer cell lines is partially mediated through down-regulation of FGFR4 activity. [ABSTRACT FROM AUTHOR]

In this paper, we study the infinity behavior of the bounded subharmonic functions on a Ricci non-negative Riemannian manifold M. We first show that limr→∞ [This equation cannot be converted in ascii text] &intB(r) Δ hdv = 0 if h is a bounded subharmonic function. If we further assume that the Laplacian decays pointwisely faster than quadratically we show that h approaches its supremun pointwisely at infinity, under certain auxiliary conditions on the volume growth of M. In particular, our result applies to the case when the Riemannian manifold has maximum volume growth. We also derive a representation formula in our paper, from which one can easily derive Yau's Liouville theorem on bounded harmonic functions. [ABSTRACT FROM AUTHOR]

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis. [ABSTRACT FROM AUTHOR]

The task of quality of service (QoS) routing is to find a route in the network that satisfies a set of constraints while maintaining high utilization of network resources. It is well-known that this problem is NP-complete. In this paper, a new method of integer linear program model for QoS routing problem was proposed. The idea is to include complicating constraints in the objective function with the "penalty" term, and then obtain the Lagrangian relaxation integer linear problem. For the constraint matrix is totally uniinodular, the relaxation can be solved rapidly from a linear program. Updating of Lagrangian multipliers are calculated easily by penalty function method. Numerical computational results indicate that the proposed method is effect. [ABSTRACT FROM AUTHOR]

Objective: To observe the effects of deguelin on the proliferation of breast cancer MCF-7 cells and lung cancer H1299 cells in vitro and the expression of minichromosome maintenance protein 3 (MCM3) and CDC45 in the cells., Methods: MTT assay was used to evaluate the proliferation of MCF-7 and H1299 cells exposed to different concentrations of deguelin for 48, 72 or 96 h. The growth of the cells was observed microscopically and the changes of MCM3 and CDC45 expressions in MCF-7 and H1299 cells following deguelin treatment were detected with fluorescence quantitative PCR., Results: The proliferation of MCF-7 cells was significantly inhibited by exposure to 0.25, 0.5, 1, 5, 10, 30, and 50 µmol/L deguelin for 48, 72, and 96 h in a concentration- and time-dependent manner. In MCF-7 cells, the IC 50 of deguelin at 48, 72, and 96 h was 9, 3, and 2 µmol/L, respectively. Deguelin treatments of H1299 cells at 0.5, 1, 5, 10, 30, 50, and 100 µmol/L also resulted in a concentration- and time-dependent inhibition of the cell growth with an IC 50 at 96 h of 2 µmol/L. Optical microscopy of the cells revealed a decreased number of viable cells with obvious cell shrinkage following deguelin treatments. The expression of MCM3 and CDC45 were significantly reduced in the cells after deguelin treatments., Conclusion: Deguelin can inhibit the proliferation of MCF-7 and H1299 cells in vitro and down-regulate the expression of MCM3 and CDC45 in the cells.

Objective: To investigate performance of a biotinylated imaging probe 3a for targeted imaging of breast cancer cells., Methods: Ultraviolet absorption spectrum and fluorescence spectrum were employed to analyze the spectral characteristics of 3a. The fluorescence spectrums of 3a treated with different concentrations of glutathione (GSH) were obtained to determine the sensibility of 3a to GSH. Flow cytometry was used to determine the cellular uptake of 3a by MCF-7 cells, MDA-MB-231 cells and Hs 578Bst cells in the presence or absence of biotin, and the imaging performance of 3a in the 3 cell lines was assessed under an inverted fluorescent microscope. The toxicity of 3a to the cells was evaluated using MTT method., Results: 3a showed the strongest absorption peak at 510 nm, and its fluorescence emission signal was the strongest at 544 nm. As the concentration of GSH increased (0-6 mmol/L), 3a exhibited an increasing fluorescence signal at 544 nm. The cellular uptake of 3a was markedly higher in MDA-MB-231 cells and MCF-7 cells than in Hs 578Bst cells. The imaging studies showed that 3a had a good breast cancer cell-targeting property and produced clear images under fluorescent microscope. MTT assay demonstrated no obvious toxicity of 3a in Hs 578Bst cells even at the concentration of 20 µmol/L, but MCF-7 cells and MDA-MB-231 cells exposed to 2-20 µmol/L 3a showed a lowered cell viability., Conclusion: 3a is capable of targeted imaging of breast cancer cells mediated by biotin. 3a at the concentration of 2-20 µmol/L has minimal cytotoxicity to normal breast cells but can lower the viability of breast cancer cells.

The effect and mechanism of mulberry leaves extracts (MLE) on glucose uptake of insulin-resistant HepG2 cells in vitro was explored. The insulin resistant models of HepG2 were induced by high concentration of insulin for 24 h. The models were incubated in a buffer containing mulberry leaves extracts. The glucose consumption was detected by glucose assay kits and the AMP-activated protein kinase (AMPK), Akt activation was examined by Western blotting. Mulberry leaves polysaccharides, mulberry leaves flavonoids and mulberry leaves extracts advanced glucose uptake of insulin-resistant HepG2 cells; Mulberry leaves extracts enhance phosphorylation of AMPK. Mulberry leaves extracts do not change the phosphorylation status of Akt. The glucose consumptions of insulin resistant model of HepG2 were promoted by mulberry leaves extracts. MLE stimulates HepG2 cell AMPK activity acutely without changing the Akt activity.

Objective: To investigate the process of separating and purifying total flavonoids from Smilax glabra., Methods: With the contents of total flavonoids, astilbin and engelitin as indices, the optimum process of separating and purifying flavonoids from Smilax glabra was screened by static and dynamic adsorption tests., Results: The static saturated adsorption capacity of polyamide resin to flavonoids of Smilax glabra was 144 mg/g (saturated in 2 h). The dynamic adsorption capacity was 128.125 mg/g, the optimum conditions of elution were as follows: the adsorbed resin was washed by 20BV water firstly, then by 20BV 95% ethanol. The content of obtained total flavonoids reached 71.84%, as the content of astilbin was 14.32%, and the content of engelitin was 1. 08%., Conclusions: The total flavonoids of Smilax glabra is able to be easily separated and purified by polyamide resin under the optimum conditions above.

Aim: To study a new way to prepare high-dosage paclitaxel entrapped magnetic targeted nanoparticles and evaluate its quality., Methods: Fe3O4 nanoparticles are prepared by co-depositing, at the same time ultrasonic is used to decrease soft agglomerate of nanoparticles and increase disperse level of it. The property of nanoparticles surface is improved to make the integrating of liposome and nanoparticle to be tighter. At last, paclitaxel entrapped magnetic solid liposome nanoparticles have been prepared by microemulsion-curing under low-temperature. The loading efficiency and encapsulating rate were determined by reverse-phase high-perfomance chromatography., Results: The nanoparticles have spherical shape. Diameter of nanoparticle ranged from 150 nm to 170 nm. 98.29% of the drug is entrapped in the particle., Conclusion: Magnetic susceptibility of nanoparticles is high, and the nanoparticles meet with the demand of targeted delivery system.