Alzheimer’s disease (AD) is a complex neurodegenerative disease in the elderly and the most common cause of human dementia. AD is characterized by accumulation of abnormal protein aggregates ...including amyloid plaques (composed of beta-amyloid (Aβ) peptides) and neurofibrillary tangles (formed by hyper-phosphorylated tau protein). Synaptic plasticity, neuroinflammation, calcium signaling etc. also show dysfunction in AD patients. Autophagy is an evolutionarily conserved lysosome-dependent cellular event in eukaryotes. It is closely linked to modulation of protein metabolism, through which damaged organelles and mis-folded proteins are degraded and then recycled to maintain protein homeostasis. Accumulating evidence has shown that impaired autophagy also contributes to AD pathogenesis. In the present review, we highlight the role of autophagy, including bulk and selective autophagy, in regulating metabolic circuits in AD pathogenesis. We also discuss the potential and future perspectives of autophagy-inducing strategies in AD therapeutics.
•The current knowledge about autophagy and the regulation of autophagic pathway.•The role of autophagy in regulating metabolic circuits during AD pathogenesis.•The potential of autophagy-inducing strategy in AD therapeutics.
Strontium ranelate is a newly approved drug that can reduce the risk of vertebral fracture, which is attributed to its dual function in increasing the bone formation and decreasing the bone ...resorption. Strontium‐containing hydroxyapatite was also demonstrated to stimulate the osteoblast activity and inhibit the osteoclast activity. However, the molecular mechanisms of strontium underlying such beneficial effects were still not fully understood. In this study, we investigated the effects of strontium on the osteogenic differentiation of human mesenchymal stem cells (MSCs) and its related mechanism; its osteogenic potential was also evaluated using a calvarial defect model in rats. We found that strontium could enhance the osteogenic differentiation of the MSCs, with upregulated extracellular matrix (ECM) gene expression and activated Wnt/β‐catenin pathway. After transplanting the collagen‐strontium‐substituted hydroxyapatite scaffold into the bone defect region, histology and computed tomography scanning revealed that in vivo bone formation was significantly enhanced; the quantity of mature and remodeled bone substantially increased and ECM accumulated. Interestingly, strontium induced an increase of β‐catenin expression in newly formed bone area. In this study, we showed for the first time that strontium could stimulate the β‐catenin expression in vitro and in vivo, which might contribute to the enhanced osteogenic differentiation of MSCs and in vivo bone formation. STEM CELLS 2011;29:981–991
Chronic exposure to stressors can disrupt normal brain function and induce anxiety-like behavior and neurobiological alterations in the basolateral amygdala (BLA). Here, we showed that unpredictable ...chronic mild stress (UCMS) induced anxiety-like behavior, lowered glutamatergic neuronal activity and reactive astrocytes in the BLA. Using optogenetic tools, we found that activation of BLA glutamatergic neurons did not rescue anxiety-like behavior in stressed mice. In contrast, however, optogenetic activation of the BLA astrocytes relieved stress-induced anxiety, and, interestingly, chronic optogenetic manipulation fully restored the UCMS-induced behavioral and neurobiological dysfunctions, including anxiety-like behavior, lower c-Fos expression in the BLA, S100 overexpression in the BLA, and higher serum corticosterone concentration. Thus, our findings suggest that chronic manipulation of BLA astrocytes is a potential therapeutic intervention target for pathological anxiety.
•Chronic stress decreased BLA excitatory neurons’ activities in a novel anxiogenic environment.•Optogenetic activation of BLA glutamatergic neurons did not rescue anxiety-like behavior in stressed mice.•Acute light stimulation of BLA astrocytes partially reversed anxiety-like behavior after exposure to chronic stressors.•Chronic light stimulation of BLA astrocytes rescued anxiety-like behavior in stressed mice.
The mechanical properties of graphite in the forms of single graphene layer and graphite flakes (containing several graphene layers) were investigated using molecular dynamics (MD) simulation. The ...in-plane properties, Young’s modulus, Poisson’s ratio, and shear modulus, were measured, respectively, by applying axial tensile stress and in-plane shear stress on the simulation box through the modified NPT ensemble. In order to validate the results, the conventional NVT ensemble with the applied uniform strain filed in the simulation box was adopted in the MD simulation. Results indicated that the modified NPT ensemble is capable of characterizing the material properties of atomistic structures with accuracy. In addition, it was found the graphene layers exhibit higher moduli than the graphite flakes; thus, it was suggested that the graphite flakes have to be expanded and exfoliated into numbers of single graphene layers in order to provide better reinforcement effect in nanocomposites.
The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs). Here, we show that PV activity within the ...nucleus accumbens shell (sNAc) is required for producing anxiety-like avoidance when mice are under anxiogenic situations. Firing rates of sNAc
neurons were negatively correlated to exploration time in open arms (threatening environment). In addition, sNAc
neurons exhibited high excitability in a chronic stress mouse model, which generated excessive maladaptive avoidance behavior in an anxiogenic context. We also discovered a novel GABAergic pathway from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAc
neurons. Optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNST
→ sNAc
synapses, which in turn explains the hyperexcitability of sNAc PV neurons on stressed models. Therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to an anxious state. Finally, we identified that the majority GABAergic input neurons, which innervate sNAc
cells, were expressing somatostatin (SOM), and also revealed that coordination between SOM- and PV- cells functioning in the BNST → NAc circuit has an inhibitory influence on anxiety-like responses. Our findings provide a potentially neurobiological basis for therapeutic interventions in pathological anxiety.
To achieve cheap and highly efficient separation of oil/water mixtures, a superhydrophobic ployvinylidene fluoride (PVDF) and microcrystalline cellulose (MCC) composite membrane was prepared by a ...two-step method, in which MCC and PVDF were directly mixed to form the membrane at 25 °C, then lauric acid was induced on surface of the membrane using grafting method. Then membranes were characterized using field emission scanning electron microscope (SEM) Attenuated total reflection infrared spectra (FTIR-ATR). Thermogravimetric analysis (TGA), water contact angle (WCA). The water contact angle of the superhydrophobic membrane in air is 153° ± 2° and the separation efficiency for different immiscible oil/water mixtures is above 99%. The superhydrophobic membrane (119.6 mg/g loading amount of lauric acid) has a high flux of 8800 L m−2 h−1 for n-hexane-water mixture and stable separation performance to kerosene-water mixture, which can be reused 20 times without decreasing the separation efficiency. Meanwhile, surfactant-stabilized emulsions can be effectively separated using the superhydrophobic membrane under gravity. Besides, the superhydrophobic film can be degraded in soil.
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•The superhydrophobic PML membrane was fabricated by grafting lauric acid onto microcrystalline cellulose (MCC).•The separation efficiency of PML film for oil-water mixtures is above 99% and stable.•PML membranes were prepared by simply blending PVDF and MCC without dissolving MCC.•Water-in-oil emulsions stabilized with surfactant can be separated by PML films under gravity.•The PML film can be degraded in soil.
Neural firing patterns are critical for specific information coding and transmission, and abnormal firing is implicated in a series of neural pathologies. Recent studies have indicated that enhanced ...burst firing mediated by T-type voltage-gated calcium channels (T-VGCCs) in specific neuronal subtypes is involved in several mental or neurological disorders such as depression and epilepsy, while suppression of T-VGCCs relieve related symptoms. Burst firing consists of groups of relatively high-frequency spikes separated by quiescence. Neurons in a variety of brain areas, including the thalamus, hypothalamus, cortex, and hippocampus, display burst firing, but the ionic mechanisms that generating burst firing and the related physiological functions vary among regions. In this review, we summarize recent findings on the mechanisms underlying burst firing in various brain areas, as well as the roles of burst firing in several mental and neurological disorders. We also discuss the ion channels and receptors that may regulate burst firing directly or indirectly, with these molecules highlighted as potential intervention targets for the treatment of mental and neurological disorders.
Mood disorders have multiple phenotypes and complex underlying biological mechanisms and, as such, there are no effective therapeutic strategies. A review of recent work on the role of astrocytes in ...mood disorders is thus warranted, which we embark on here. We argue that there is tremendous potential for novel strategies for therapeutic interventions based on the role of astrocytes. Astrocytes are traditionally considered to have supporting roles within the brain, yet emerging evidence has shown that astrocytes have more direct roles in influencing brain function. Notably, evidence from postmortem human brain tissues has highlighted changes in glial cell morphology, density and astrocyte-related biomarkers and genes following mood disorders, indicating astrocyte involvement in mood disorders. Findings from animal models strongly imply that astrocytes not only change astrocyte morphology and physiological characteristics but also influence neural circuits via synapse structure and formation. This review pays particular attention to interactions between astrocytes and neurons and argues that astrocyte dysfunction affects the monoaminergic system, excitatory-inhibitory balance and neurotrophic states of local networks. Together, these studies provide a foundation of knowledge about the exact role of astrocytes in mood disorders. Importantly, we then change the focus from neurons to glial cells and the interactions between the two, so that we can understand newly proposed mechanisms underlying mood disorders, and to identify more diagnostic indicators or effective targets for treatment of these diseases.
•First application of Fomitopsis pinicola in the solid fermentation of wheat bran.•Alkylresorcinols content were significantly improved, and the bran had a special flavor.•The textural and functional ...properties of the bread were significantly improved.
Wheat bran was solid state fermented by Fomitopsis pinicola. The results showed that the processing properties were increased by fermentation and the content of total phenol and alkylresorcinols was 5.91 and 1.55 times of the unfermented bran respectively by the 6th day. The total antioxidant capacity was 5.73 times of the unfermented sample by the 4th day. Electronic nose analysis showed that the fermented wheat bran had a special flavor. GC–MS analysis found that 4-ethyl-2-methoxy-phenol was the main flavor substance, which was sharply increased during the fermentation. Furthermore, the textural properties of the dough and bread containing fermented bran were significantly improved. The content of phytic acid in the bread was significantly decreased, while the protein, total phenol and alkylresorcinols contents were significantly increased. Results suggest that solid state fermentation by Fomitopsis pinicola is a promising way to improve wheat bran to a nutritious and flavorful cereal food ingredient.
Atherosclerosis involves a slow process of plaque formation on the walls of arteries, and comprises a leading cause of cardiovascular disease. Long non-coding RNAs (lncRNAs) have been implicated in ...the pathogenesis of atherosclerosis. In this study, we aim to explore the possible involvement of lncRNA 'cyclin-dependent kinase inhibitor 2B antisense noncoding RNA' (CDKN2B-AS1) and CDKN2B in the progression of atherosclerosis.
Initially, we quantified the expression of CDKN2B-AS1 in atherosclerotic plaque tissues and, in THP-1 macrophage-derived, and human primary macrophage (HPM)-derived foam cells. Next, we established a mouse model of atherosclerosis using apolipoprotein E knockout (ApoE
) mice, where lipid uptake, lipid accumulation, and macrophage reverse cholesterol transport (mRCT) were assessed, in order to explore the contributory role of CDKN2B-AS1 to the progression of atherosclerosis. RIP and ChIP assays were used to identify interactions between CDKN2B-AS1, CCCTC-binding factor (CTCF), enhancer of zeste homologue 2 (EZH2), and CDKN2B. Triplex formation was determined by RNA-DNA pull-down and capture assay as well as EMSA experiment.
CDKN2B-AS1 showed high expression levels in atherosclerosis, whereas CDKN2B showed low expression levels. CDKN2B-AS1 accelerated lipid uptake and intracellular lipid accumulation whilst attenuating mRCT in THP-1 macrophage-derived foam cells, HPM-derived foam cells, and in the mouse model. EZH2 and CTCF were found to bind to the CDKN2B promoter region. An RNA-DNA triplex formed by CDKN2B-AS1 and CDKN2B promoter was found to recruit EZH2 and CTCF in the CDKN2B promoter region and consequently inhibit CDKN2B transcription by accelerating histone methylation.
The results demonstrated that CDKN2B-AS1 promotes atherosclerotic plaque formation and inhibits mRCT in atherosclerosis by regulating CDKN2B promoter, and thereby could be a potential therapeutic target for atherosclerosis.
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