Diet Control and Swimming Exercise Ameliorate HFD-Induced Cognitive Impairment Related to the SIRT1-NF-κB/PGC-1α Pathways in ApoE-/- Mice.

High-fat diet- (HFD-) induced neuroinflammation may ultimately lead to an increased risk of cognitive impairment. Here, we evaluate the effects of diet control and swimming or both on the prevention of cognitive impairment by enhancing SIRT1 activity. Twenty-week-old ApoE-/- mice were fed a HFD for 8 weeks and then were treated with diet control and/or swimming for 8 weeks. Cognitive function was assessed using the novel object recognition test (NORT) and Y-maze test. The expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), brain-derived neurotrophic factor (BDNF), nuclear factor kappa B p65 (NF-κB p65), interleukin-1ß (IL-1ß), and tumour necrosis factor-α (TNF-α) in the hippocampus was measured by western blotting. The levels of fractional anisotropy (FA), N-acetylaspartate (NAA)/creatine (Cr) ratio, choline (Cho)/Cr ratio, and myo-inositol (MI)/Cr ratio in the hippocampus were evaluated by diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) using 7.0-T magnetic resonance imaging (MRI). Our results showed that cognitive dysfunction and hippocampal neuroinflammation appeared to be remarkably observed in apolipoprotein E (ApoE)-/- mice fed with HFD. Diet control plus swimming significantly reversed HFD-induced cognitive decline, reduced the time spent exploring the novel object, and ameliorated spontaneous alternation in the Y-maze test. Compared with the HFD group, ApoE-/- mice fed diet control and/or subjected to swimming had an increase in FA, NAA/Cr, and Cho/Cr; a drop in MI/Cr; elevated expression levels of SIRT1, PGC-1α, and BDNF; and inhibited production of proinflammatory cytokines, including NF-κB p65, IL-1ß, and TNF-α. SIRT1, an NAD+-dependent class III histone enzyme, deacetylases and regulates the activity of PGC-1α and NF-κB. These data indicated that diet control and/or swimming ameliorate cognitive deficits through the inhibitory effect of neuroinflammation via SIRT1-mediated pathways, strongly suggesting that swimming and/or diet control could be potentially effective nonpharmacological treatments for cognitive impairment.

Comprehensive utilization of palm kernel cake for producing mannose and manno-oligosaccharide mixture and yeast culture.

Palm kernel cake (PKC) is an agricultural waste derived from palm kernel oil manufacturing, and its production is increasing year by year. It is very urgent to process this agricultural waste in an environmentally friendly way. Here, PKC was used to produce mannose and manno-oligosaccharides mixture (MMOM) and yeast culture (YC) through enzymolysis and solid-state fermentation (SSF). In enzymolysis, five factors were optimized separately and a response surface methodology analysis was performed. Then, enzymolysis of PKC was carried out at the optimal condition, and the extraction efficiency of mannose and manno-oligosaccharides reached 68.90% with mannose concentration achieving 60.27 g/L. After enzymolysis, the enzymatic hydrolysate was dried by spray drying, and the contents of MMOM reached 42.9%. In SSF, the enzymolysis residues were utilized with inoculating Saccharomyces cerevisiae for yielding YC. After optimization, the cells number of S. cerevisiae reached 2.08 × 109 cells/g and the crude protein content was increased to 27.31%. Therefore, a novel approach to produce feed additives, including MMOM and YC, with high value by comprehensive utilization of PKC was proposed, which has good application prospects in the breeding industry. KEY POINTS: • New idea for the comprehensive utilization of PKC is proposed. • PKC was used to produce mannose and mannan-oligosaccharides mixture (MMOM) by enzymolysis and spray drying. • The enzymolysis residues were reused via SSF for producing yeast culture (YC).

Channel capacity of orbital-angular-momentum-based wireless communication systems with partially coherent elegant Laguerre-Gaussian beams in oceanic turbulence.

For practical wireless communication links, one of the critical challenges is the random fluctuation of turbulence that will impair link performance. Here a transmission model of partially coherent elegant Laguerre-Gaussian (ELG) beams in oceanic turbulence is established. An analytical formula for channel capacity of a partially coherent ELG beam propagating through a turbulent ocean is derived. The effects of oceanic turbulence on the evolution of channel capacity performance are studied quantitatively in a series of numerical simulations. Research results show that decreasing the rate of dissipation of mean-square temperature and ratio of temperature to salinity, as well as increasing the dissipation rate of turbulent kinetic energy per unit mass of fluid of a turbulent ocean can significantly improve communication channel capacity. Furthermore, choosing optimum beam source parameters is favorable to mitigate the influence of oceanic turbulence. Results also show that in the underwater turbulence, the partially coherent ELG beams are more affected by turbulence as compared to the fully coherent ELG beams. These study results may provide potential help in designing the free-space optical vortex communication systems.

Full-Waveform LiDAR Point Clouds Classification Based on Wavelet Support Vector Machine and Ensemble Learning.

Light Detection and Ranging (LiDAR) produces 3D point clouds that describe ground objects, and has been used to make object interpretation in many cases. However, traditional LiDAR only records discrete echo signals and provides limited feature parameters of point clouds, while full-waveform LiDAR (FWL) records the backscattered echo in the form of a waveform, which provides more echo information. With the development of machine learning, support vector machine (SVM) is one of the commonly used classifiers to deal with high dimensional data via small amount of samples. Ensemble learning, which combines a set of base classifiers to determine the output result, is presented and SVM ensemble is used to improve the discrimination ability, owing to small differences in features between different types of data. In addition, previous kernel functions of SVM usually cause under-fitting or over-fitting that decreases the generalization performance. Hence, a series of kernel functions based on wavelet analysis are used to construct different wavelet SVMs (WSVMs) that improve the heterogeneity of ensemble system. Meanwhile, the parameters of SVM have a significant influence on the classification result. Therefore, in this paper, FWL point clouds are classified by WSVM ensemble and particle swarm optimization is used to find the optimal parameters of WSVM. Experimental results illustrate that the proposed method is robust and effective, and it is applicable to some practical work.

Propagation and dynamical characteristics of a Bessel-Gaussian beam in a chiral medium.

Based on the ABCD transfer matrix and Collins formula, the analytical expressions of the complex amplitude of the Bessel-Gaussian beam in a chiral medium are derived. By introducing vector potential in the Lorentz gauge, the electromagnetic field components of the Bessel-Gaussian beam are determined under the paraxial approximation. Through numerical calculations, the propagation of the Bessel-Gaussian beam in a chiral medium is examined. Results show that Bessel-Gaussian beams split into the left circularly polarized beam and the right circularly polarized beam with different propagation trajectories. The propagation trajectory of the Bessel-Gaussian beam can be controlled by varying half-cone angles of the Bessel-Gaussian beam and the chiral parameter of the medium. The dynamical characteristics, including energy, momentum, spin, and orbital angular momentum, of Bessel-Gaussian beams in a chiral medium are also simulated and discussed in detail. The results will be helpful to understand the interaction mechanism between structured light beams and a chiral medium.

Alisol A Exerts Neuroprotective Effects Against HFD-Induced Pathological Brain Aging via the SIRT3-NF-κB/MAPK Pathway.

Chronic consumption of a high-fat diet (HFD) has profound effects on brain aging, which is mainly characterized by cognitive decline, inflammatory responses, and neurovascular damage. Alisol A (AA) is a triterpenoid with therapeutic potential for metabolic diseases, but whether it has a neuroprotective effect against brain aging caused by a HFD has not been investigated. Six-month-old male C57BL6/J mice were exposed to a HFD with or without AA treatment for 12 weeks. Behavioral tasks were used to assess the cognitive abilities of the mice. Neuroinflammation and changes in neurovascular structure in the brains were examined. We further assessed the mechanism by which AA exerts neuroprotective effects against HFD-induced pathological brain aging in vitro and in vivo. Behavioral tests showed that cognitive function was improved in AA-treated animals. AA treatment reduced microglia activation and inflammatory cytokine release induced by a HFD. Furthermore, AA treatment increased the number of hippocampal neurons, the density of dendritic spines, and the expression of tight junction proteins. We also demonstrated that AA attenuated microglial activation by targeting the SIRT3-NF-κB/MAPK pathway and ameliorated microglial activation-induced tight junction degeneration in endothelial cells and apoptosis in hippocampal neurons. The results of this study show that AA may be a promising agent for the treatment of HFD-induced brain aging.

Swimming Training Mitigates Neurological Impairment of Intracerebral Haemorrhage in Mice via the Serine-Threonine Kinase/Glycogen Synthase Kinase 3ß Signalling Pathway.

Swimming training (ST) can mitigate functional disorders in neurological diseases, but the effect and mechanism of ST in improving the neurological function of intracerebral haemorrhage (ICH) have not been reported. Our study aimed to explore the protective effect of early ST on ICH mice and its relationship with the serine-threonine kinase (Akt)/glycogen synthase kinase 3ß (GSK3ß) pathway. Our findings showed that the ICH model mice had poor behavioural manifestations in the Y maze test and open field test compared to the ST group and sham group. The modified neurological severity score was increased in the ICH mice, and 7 days of ST intervention significantly attenuated the neurological deficits. The ratios of myo-inositol/creatine, lactate/creatine and glutamate/creatine were decreased, and the ratios of N-acetylaspartate/creatine and choline/creatine were increased in the ICH mice with ST intervention. ST intervention decreased the expression of Iba1 and GFAP. Seven days of ST significantly increased the expression of p-Akt/Akt compared to that in the ICH mice. Furthermore, the Akt kinase inhibitor GSK690693 exacerbated neurological impairment, increased the expression of Iba1, GFAP and Bax/Bcl-2, and reversed the anti-apoptotic effects and anti-glia activation of ST, which was associated with the inhibition of p-Akt/Akt and p-GSK3ß/GSK3ß expression. These results indicated that the protective role of ST in ICH was mediated via the Akt/GSK3ß pathway. In conclusion, ST displayed neuroprotection by inhibiting apoptosis and glial activation in ICH mice by activating the Akt/GSK3ß signalling pathway.

TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance.

Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes. SIGNIFICANCE: The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.

A novel kinase inhibitor, LZT-106, downregulates Mcl-1 and sensitizes colorectal cancer cells to BH3 mimetic ABT-199 by targeting CDK9 and GSK-3ß signaling.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and is associated with poor prognosis and high mortality. Despite advances in treatment with chemotherapy, CRC remains a major cause of drug resistance-related cancer deaths. One of the main reasons for such resistance is dysregulation of Mcl-1 expression. In this study, we identified LZT-106 as a novel kinase inhibitor that was able to bind to CDK9 with potent inhibitory ability, and indirectly regulate the expression of Mcl-1. However, different regulatory profiles were observed between LZT-106 and the well-studied CDK9 inhibitor flavopiridol with regards to Mcl-1 inhibition. Via Western blotting, real-time PCR and immunoprecipitation, we confirmed that LZT-106 was also able to target GSK-3ß signaling and facilitate the degradation of Mcl-1. And LZT-106 was shown to synergize with ABT-199 to induce apoptosis even in the RKO cell line that overexpressed Mcl-1. Finally, LZT-106 significantly inhibited tumor growth in a xenograft mouse model with minimal toxicity. Overall, our findings suggest that LZT-106 is a promising candidate drug for the treatment of patients with CRC.

CRMP2 is a therapeutic target that suppresses the aggressiveness of breast cancer cells by stabilizing RECK.

Metastatic breast cancer is characterized by high mortality and limited therapeutic target. During tumor metastasis, cytoskeletal reorganization is one of the key steps in the migration and invasion of breast cancer cells. Collapsin response mediator protein 2 (CRMP2) is a cytosolic phosphoprotein that plays an important role in regulating cytoskeletal dynamics. Previous researches have reported that altered CRMP2 expression is associated with breast cancer progression, but the underlying mechanism remains poorly understood. Here, we show that CRMP2 expression is reduced in various subtypes of breast cancers and negatively correlated with lymphatic metastasis. Overexpression of CRMP2 significantly inhibits invasion and stemness in breast cancer cells, while downregulation of CRMP2 promotes cell invasion, which is not required for tubulin polymerization. Mechanistic studies demonstrate that CRMP2 interacts with RECK, prevents RECK degradation, which, in turn, blocks NF-κB and Wnt signaling pathways. Furthermore, we find that phosphorylation of CRMP2 at T514 and S522 remarkably abolishes its functions to bind with RECK and to inhibit cell invasion. Pharmacologic rescue of CRMP2 expression suppressed breast cancer metastasis in vitro and in vivo and stimulated a synergetic effect with FN-1501 that induces CRMP2 dephosphorylation. Collectively, this study highlights the potential of CRMP2 as a therapeutic target in breast cancer metastasis and reveals a distinct mechanism of CRMP2.