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Alzheimer's disease is characterized by amyloid-ß (Aβ) peptide accumulation in the brain. CALHM1, a cell-surface Ca²+ channel expressed in brain neurons, has anti-amyloidogenic properties in cell cultures. Here, we show that CALHM1 controls Aβ levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of Aβ clearance. Using pharmacological and genetic approaches in cell lines, we found that CALHM1 ion permeability and extracellular Ca²+ were required for the Aβ-lowering effect of CALHM1. Aβ level reduction by CALHM1 could be explained by an increase in extracellular Aβ degradation by insulin-degrading enzyme (IDE), extracellular secretion of which was strongly potentiated by CALHM1 activation. Importantly, Calhml knockout in mice reduced IDE enzymatic activity in the brain, and increased endogenous Aβ concentrations by up to ~50% in both the whole brain and primary neurons. Thus, CALHM1 controls Aβ levels in cell lines and in vivo by facilitating neuronal and Ca²+-dependent degradation of extracellular Aβ by IDE. This work identifies CALHM1 ion channel as a potential target for promoting amyloid clearance in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • Functional plant polysaccharides have good therapeutic effect on MetS. • Functional plant polysaccharides can improve Mets through a variety of mechanisms. • Functional plant polysaccharides are safe and effective. Metabolic syndrome (MetS) has become a worldwide public health problem with increasing global morbidity. Existing surgical and pharmaceutical treatments have certain side effects. Consequently, the search for anti-MetS active ingredients with long-lasting stable therapeutic effects and less toxic side effects has become a focal point of contemporary research. Functional polysaccharides with safe and excellent physiological activities have attracted more and more attention in the regulation of MetS, but a comprehensive understanding is still lacking. In this review, the effects and mechanisms of plant polysaccharides in the prevention and improvement of MetS by regulating intestinal flora, improving glucose and lipid metabolism disorders, maintaining the balance of islet internal environment and reducing systemic inflammation are summarized. Plant polysaccharides can be used to reduce the risk of metabolic diseases in a safe and dependable manner. [ABSTRACT FROM AUTHOR]

High-energy diets and lipid metabolism can lead to high levels of total cholesterol, a decrease in antioxidant, enzyme activity, and an increase in oxidative stress and dyslipidemia biomarker. In this study, the in vivo antihyperlipidemic and antioxidant effects of 1, 3-dioleoyl-2-palmitoyl triglyceride (OPO) using a high fat-diet model were investigated. The mice were divided into groups including high-fat model group (HF), auxiliary group (AG), positive Control group (PC), low OPO dose group (LO), medium OPO dose group (MO) and high OPO. OPO was administrated to 60 hyperlipidemia induced male Kunming mice at the dosage of 200, 400 and 800 mg/kg•d body weight, for 35 days. The results showed that the administration of OPO decreased the body weight from 43.92 g in HF to 37.74 g in HO group, liver index from 3.94% in HF to 3.43 in HO group and kidney index from 1.38 in HF % to 1.17% in HO group. The administration of OPO significantly decreased hyperlipidemia mice's serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels at P < 0.05. High-density lipoprotein cholesterol levels were increased with reductions of visceral hypertrophy and fat accumulation in model mice. Furthermore, in the HO group, superoxide dismutase, catalase and glutathione peroxidase levels increased significantly by 27.39, 38.33 and 22.90% at (P < 0.05), respectively. OPO also significantly reduced the enzyme activity of aspartate aminotransferase and alanine aminotransferase in serum at P < 0.05. These findings suggested that OPO has potential use in hyperlipidemia treatment and other health-related complications. [Display omitted] • The serum TC, TG, LDL-C levels were significantly decreased by OPO. • OPO also enhanced antioxidant enzyme activities in vivo. • OPO had hepatoprotective functions in the livers of studied mice. • OPO was effective in auxiliary regulation of hyperlipidemia. [ABSTRACT FROM AUTHOR]

CALHM1 is a plasma membrane voltage-gated Ca2+-permeable ion channel that controls amyloid-β (Aβ) metabolism and is potentially involved in the onset of Alzheimer's disease (AD). Recently, Rubio-Moscardo et al. (PLoS One (2013) 8: e74203) reported the identification of two CALHM1 variants, G330D and R154H, in early-onset AD (EOAD) patients. The authors provided evidence that these two human variants were rare and resulted in a complete loss of CALHM1 function. Recent publicly available large-scale exome sequencing data confirmed that R154H is a rare CALHM1 variant (minor allele frequency (MAF)  = 0.015%), but that G330D is not (MAF  = 3.5% in an African American cohort). Here, we show that both CALHM1 variants exhibited gating and permeation properties indistinguishable from wild-type CALHM1 when expressed in Xenopus oocytes. While there was also no effect of the G330D mutation on Ca2+ uptake by CALHM1 in transfected mammalian cells, the R154H mutation was associated with defects in the control by CALHM1 of both Ca2+ uptake and Aβ levels in this cell system. Together, our data show that the frequent CALHM1 G330D variant has no obvious functional consequences and is therefore unlikely to contribute to EOAD. Our data also demonstrate that the rare R154H variant interferes with CALHM1 control of cytosolic Ca2+ and Aβ accumulation. While these results strengthen the notion that CALHM1 influences Aβ metabolism, further investigation will be required to determine whether CALHM1 R154H, or other natural variants in CALHM1, is/are associated with EOAD. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a metabolic sensor involved in intracellular energy metabolism through the control of several homeostatic mechanisms, which include autophagy and protein degradation. Recently, we reported that AMPK activation by resveratrol promotes autophagy-dependent degradation of the amyloid-ß (Aß) peptides, the core components of the cerebral senile plaques in Alzheimer's disease. To identify more potent enhancers of Aß degradation, we screened a library of synthetic small molecules selected for their structural similarities with resveratrol. Here, we report the identification of a series of structurally related molecules, the RSVA series, which inhibited Aß accumulation in cell lines nearly 40 times more potently than did resveratrol. Two of these molecules, RSVA314 and RSVA405, were further characterized and were found to facilitate CaMKKß-dependent activation of AMPK, to inhibit mTOR (mammalian target of rapamycin), and to promote autophagy to increase Aß degradation by the lysosomal system (apparent EC50 ~1 µM). This work identifies the RSVA compounds as promising lead molecules for the development of a new class of AMPK activating drugs controlling mTOR signaling, autophagy, and Aß clearance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Transparent Zn 2 GeO 4 :Mn2+ films with excellent green photoluminescence and persistent luminescence properties were prepared by RF magnetron sputtering. • The films showed maximum luminescence intensity when annealing temperature reached 900 °C. • Essential and profound luminescence mechanism were deeply explored. At the same time, we put forward the essential method and idea of improving the luminescence performance. In this work, the effects of annealing temperatures on various properties (i.e., optical properties, surface morphologies and microstructures) of Mn doped Zn-Ge-O films that deposited on the quartz substrate by radio frequency (RF) magnetron sputtering were uncovered. The film without annealing is amorphous and presents a smooth surface as well as good transmittance over 95% in the visible region. Surprisingly, the amorphous Zn-Ge-O gradually transform into Zn 2 GeO 4 crystal with the uprising of annealing temperatures, endowing the annealed films with an intense green fluorescence (534 nm) under 310 nm ultraviolet light excitation and excellent persistent luminescence properties after the excitation. In addition, the nature of the films' luminescence mechanism was explored. Analysis suggests that higher annealing temperature will increase the crystallinity and grain size of Zn 2 GeO 4 , which can effectively affect the formation and increase the number of effective luminescence units, further improving the luminescence intensity. This research provides a crucial admission for improving the luminescence properties of Mn doped Zn 2 GeO 4 films. [ABSTRACT FROM AUTHOR]