Hyperhomocysteinemia (Hhcy) may induce memory deficits with β‐amyloid (Aβ) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma ...homocysteine level and attenuated tau hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer‐like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2‐week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy‐induced memory deficits, enhance long‐term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up‐regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy‐induced tau hyperphosphorylation at multiple AD‐related sites through activation protein phosphatase‐2A (PP2A) with decreased inhibitory demethylated PP2AC at Leu309 and phosphorylated PP2AC at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin‐1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy‐induced AD‐like pathological changes and memory deficits.
We have found that betaine can attenuate Hcy‐induced spatial memory deficits with possible mechanisms that may involve in the expresions or/and activations of several memory‐related proteins, and increase the dendritic branches and spine density in hippocampal CA1 region. It also attenuated AD‐like tau hyperphosphorylation by activation PP2A, and inhibited Aβ aggregation by decreasing PS‐1.
Protein phosphatase-2A (PP2A), an important phosphatase in dephosphorylating tau and preserving synapse, is significantly suppressed in Alzheimer's disease (AD), but the mechanism is not well ...understood. Here, we studied whether phosphotyrosyl phosphatase activator (PTPA) could activate PP2A by reducing its inhibitory phosphorylation at tyrosine 307 (P-PP2AC). We found that overexpression of PTPA activated PP2A by decreasing the level of P-PP2AC with reduced phosphorylation of tau, while knockdown of PTPA inhibited PP2A by increasing the level of P-PP2AC with enhanced tau phosphorylation. We also observed that expression of PTPA could upregulate the protein and mRNA levels of protein tyrosine phosphatase 1B (PTP1B) and simultaneous downregulation of PTP1B eliminated PTPA-induced PP2A activation. Importantly, we also found that the protein level of PTPA is downregulated in the brains of AD patients, and the AD transgenic mouse models with expression of mutant human amyloid precursor protein (hAPP) or the longest human tau (htau), respectively. Our data indicate that PTPA may activate PP2A through activating PTP1B and thus reducing the level of P-PP2AC, therefore upregulation of PTPA may represent a potential strategy in rescuing PP2A and arresting tau pathology in AD.
► PTPA activated PP2A by decreasing P-PP2AC level with reduced tau phosphorylation. ► PTPA modulates the phosphorylation of PP2AC by PTP1B. ► PTPA level decreases in the brains of AD patients and transgenic mice models.
The intracellular accumulation of hyperphosphorylated tau plays a crucial role in neurodegeneration of Alzheimer's disease (AD), but the mechanism is not fully understood. From the observation that ...tau hyperphosphorylation renders cells more resistant to chemically-induced cell apoptosis, we have proposed that tau-involved apoptotic abortion may be the trigger of neurodegeneration. Here, we further studied whether this phenomenon is also applicable for the cell death induced by constitutively expressed factors, such as death-associated protein kinase 1 (DAPK1). We found that DAPK1 was upregulated and accumulated in the brain of human tau transgenic mice. Overexpression of DAPK1 in HEK293 and N2a cells decreased cell viability with activation of caspase-3, whereas simultaneous expression of tau antagonized DAPK1-induced apoptotic cell death. Expression of DAPK1 induced tau hyperphosphorylation at Thr231, Ser262, and Ser396 with no effects on protein phosphatase 2A, glycogen synthase kinase-3β, protein kinase A, calcium/calmodulin dependent protein kinase II, cell division cycle 2, or cyclin dependent protein kinase 5. The phosphorylation level of microtubule affinity-regulating kinase 2 (MARK2) was increased by expression of DAPK1, but simultaneous downregulation of MARK2 did not affect the DAPK1-induced tau hyperphosphorylation. DAPK1 was co-immunoprecipitated with tau proteins both in vivo and in vitro, and expression of the kinase domain-truncated DAPK1 did not induce tau hyperphosphorylation. These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by intelligence decline, behavioral disorders and cognitive disability. The purpose of this study was to ...investigate gene expression in AD, based on published microarray data on Tg2576 mice. Hierarchical Cluster Analysis and Gene Ontology were employed to group genes together on the basis of their product characteristics and annotation data. Genes with prominent alterations were clustered into apoptosis and axon guidance pathways. Based on our findings and those of previous studies, we propose that the mitochondria-mediated apoptotic pathway plays a crucial role in the neuronal loss and synaptic dysfunction associated with AD. Furthermore, based on the findings of Positional Gene Enrichment analysis and Gene Set Enrichment analysis, we propose that the regulation of transcription of AD genes may be an important pathogenic factor in this neurodegenerative disease. Our results highlight the importance of genes that could subsequently be examined for their potential as prognostic markers for AD.
GSK-3β (glycogen synthase kinase-3β), a crucial tau kinase, negatively regulates PP2A (protein phosphatase 2A), the most active tau phosphatase that is suppressed in the brain in AD (Alzheimer's ...disease). However, the molecular mechanism is not understood. In the present study we found that activation of GSK-3β stimulates the inhibitory phosphorylation of PP2A at Tyr307 (pY307-PP2A), whereas inhibition of GSK-3β decreased the level of pY307-PP2A both in vitro and in vivo. GSK-3β is a serine/threonine kinase that can not phosphorylate tyrosine directly, therefore we measured PTP1B (protein tyrosine phosphatase 1B) and Src (a tyrosine kinase) activities. We found that GSK-3β can modulate both PTP1B and Src protein levels, but it only inhibits PTP1B activity, with no effect on Src. Furthermore, only knockdown of PTP1B but not Src by siRNA (small interfering RNA) eliminates the effects of GSK-3β on PP2A. GSK-3β phosphorylates PTP1B at serine residues, and activation of GSK-3β reduces the mRNA level of PTP1B. Additionally, we also observed that GSK-3 negatively regulates the protein and mRNA levels of PP2A, and knockdown of CREB (cAMP-response-element-binding protein) abolishes the increase in PP2A induced by GSK-3 inhibition. The results of the present study suggest that GSK-3β inhibits PP2A by increasing the inhibitory Tyr307 phosphorylation and decreasing the expression of PP2A, and the mechanism involves inhibition of PTP1B and CREB.
•Three types of lubrication injection and distribution characteristics are introduced.•The effect of misalignment reduces the reduction in the frictional coefficient to 71%.•The occasional gravel ...leads the misleading reduction of 60%.•The excessive volumes of lubricant with high viscosity lead the reductions greater than 88%.•The effects have greater influences on the lubrication performance than the injection type.
Pipejacking technologies has been extensively chosen by many mega cities worldwide to construct their sewer pipelines. Lubrication has been deemed to be the key factor in manipulating the performance of pipejacking works. Inadequate lubrication during pipejacking can lead exaggerated jacking force causing damages to the jacked pipe string and adjoining properties. Due to limited studies, a consensus has not yet reached. This study gives an access of evaluating the lubrication performance via the reduction in the frictional coefficient μ and investigates the impacts of injection type, soil and lubrication natures, and misalignment on the lubrication performance for a pipejacking project in alluvial soil deposits. The effect of misalignment, while ramming through the 8–21 m section of gravel at Drive C, gears up the frictional stress τld to 12.5 kPa (compared to 0.4 kPa of the 2–8 m section of the same gravel) and reduces the reduction to 71%. While traversing through the 24–31 m section of clayey gravel at Drive D, the occasional gravel not being long enough to develop lower face resistance leads the misleading reduction of 60%. These factors have greater influences on the lubrication performance than the injection type. The presented results would be helpful in managing the lubrication performance while pipe ramming for upcoming pipejacking project.
The repair and reconstruction of maxillary and mandibular extensive defects have put huge challenges to surgeons. The fibular free flap (FFF) is one of the standard treatment choices for ...reconstruction. The conventional FFF has deficiencies, such as forming poor oral mucosa, limited flap tissue, and perforator vessel variation. To improve the use of FFF, we add the flexor hallucis longus (FHL) in the flap (FHL-FFF). In this paper, we described the advantage and indication of FHL-FFF and conducted a retrospective study to compare FHL-FFF and FFF without FHL.
Fifty-four patients who underwent FFF were enrolled and divided into two groups: nFHL group (using FFF without FHL, 38 patients) and FHL group (using FHL-FFF, 16 patients). The perioperative clinical data of patients was collected and analyzed.
The flaps all survived in two groups. We mainly used FHL to fill dead space, and the donor-site morbidity was slight. In FHL group, flap harvesting time was shorter (118.63 ± 11.76 vs 125.74 ± 11.33 min, P = 0.042), the size of flap's skin paddle was smaller (16.5 (0-96) vs 21.0(10-104) cm
, P = 0.027) than nFHL group. There were no significant differences (P > 0.05) in hospital days, hospitalization expense, rate of perioperative complications, etc. between the two groups. Compared with FFF without FHL, FHL-FFF will neither affect the use of flap nor bring more problems.
The FHL-FFF simplifies the flap harvesting operation. The FHL can form good mucosa and make FFF rely less on skin paddle. It can be used for adding flap tissue and dealing with perforator vessel variation in reconstruction of maxillary and mandibular extensive defects.
Four new 2-arylbenzofuran derivatives, cathafurans A (1), B (2), C (3), and D (4), were isolated from the stem bark of Morus cathayana. Their structures were determined by spectroscopic methods. ...Compounds 2 and 3 exhibited moderate activities against five human cancer cell lines, with IC50 values ranging from 6.17 to 9.60 μg/mL.
The low accuracy limits the use of fibular free flap (FFF). We apply digital navigation and 3D printing model technology in mandibular reconstruction to improve FFF’s accuracy.
34 patients who ...underwent with FFF to repair mandibular defects were divided into Navigation Group (13 cases, using digital navigation and 3D printing model) and Control Group (21 cases, only 3D printing model). We retrospectively reviewed patients’ hospitalization information and evaluated patients by subjective and objective items, such as UW-Qol scale, CT data.
The operation time of Navigation Group was higher significantly than Control Group (10.36 ± 1.87vs9.00 ± 1.34 h).There were no significant differences in early postoperative complications. The Qol score of appearance, motion, anxiety were higher significantly in Navigation Group. The CT results showed that mandibular angle deviation and chin deflection of Navigation Group were better significantly than Control Group (1.72 ± 1.29° vs 3.69 ± 1.67°, 2.45 ± 1.39 vs 5.19 ± 2.13 mm).
The digital navigation can improve FFF’s accuracy in mandibular reconstruction. It doesn’t significantly increase complications. The digital navigation’s installation and operation methods should be simplified to shorter operation time and expand its application.
We propose a two‐dimensional (2D)/ three‐dimensional (3D) mixed display system based on polarization division multiplexing. The polarization division multiplexing device is composed of a polarization ...switching layer, a polarization‐dependent liquid crystal micro‐lens array (LCMLA) and a scattering polarizer. According to the polarization state of incident light switched by the polarization switching layer, the combined action of polarization‐dependent LCMLA and scattering polarizer can form both point light source array for 3D display and scattered light source for 2D display. The 2D/3D mixed images can be reconstructed through the precise control of the polarization direction of each pixel. The advantage of the proposed system is that a point light source array and a surface light source are formed only by adjusting the state of the polarization switching layer. What's more, our proposed system has low driving voltage and relatively compact system volume.
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