Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aß and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aß plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD.

PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling.

Background: P21-activated kinase 4 (PAK4) involves in cell proliferation in cancer and mutually regulates with p53, a molecule is demonstrated to control cell autophagy by mammalian target of rapamycin (mTOR)/protein kinase B (AKT) signaling. Since the signaling exhibits an association with PAK family members in cell autophagy, it implies that PAK4-relevant proliferation may be impacted by autophagy via p53 with a lack of evidence in cancer cells. Methods: In this research, transient and stable PAK4-knockdown human hepatocarcinoma cell lines (HepG2) were constructed by transfection of PAK4-RNA interference (RNAi) plasmid and lentivirus containing PAK4-RNAi plasmid, respectively. We investigated cell proliferation using methyl thiazolyl tetrazolium (MTT) and Cell Counting Kit 8 (CCK8) assays, cell cycle by flow cytometry (FCM) and cell autophagy by monodansylcadaverine (MDC) staining and autophagic biomarker's expression, and detected the expressions of p53, mTOR, phosphorylated-AKT (p-AKT) and AKT by immunofluorescence and western blot to explore the mechanism. Results: We successfully constructed transient and stable PAK4-knockdown HepG2 cell lines, and detected dysfunction of the cells' proliferation. An increased expression of p53, as a molecule of cell-cycle-surveillance on G1/S phase, was demonstrated in the cells although the cell cycle blocked at G2/M. And then, we detected increased autophagosome and autophagic biomarker LC3-II, and decreased expressions in p-AKT and mTOR. Conclusions: The proliferation is reduced in PAK4-knockdown HepG2 cells, which is relative to not only cell cycle arrest but also cell autophagy, and p53/mTOR/p-AKT signaling involves in the cell progress. The findings provide a new mechanism on PAK4 block in cancer therapy.

[Experimental study on the treatment of low level radioactive waste water by inorganic nanofiltration membrane].

Soluble sodium poly(acrylic) acid (NaPAA) with molecular weight of 2000-5000 was selected as an assistant reagent of inorganic nanofiltration membrane which was used to treat low level radioactive waste water mainly containing radionuclides 90Sr, 137Cs and 60Co. The effect of non-active simulated wastewater pH and NaPAA concentration on the retention efficiency of non-active nuclides strontium, cesium and cobalt ions and membrane permeation flux were explored, and the effect mechanism was also preliminarily discussed. The optimum process parameters were decided: pH 7-8, NaPAA volume concentration no lower than 0.1%. Real radioactive waste water was treated under optimum experiment condition. The results show that the decontamination efficiency of total beta and gamma emitters of low-level radioactive wastewater were both up to about 95% by inorganic nanofiltration assisted by NaPAA, and the permeation flux was also satisfying.

Comparison of di-n-methyl phthalate biodegradation by free and immobilized microbial cells.

OBJECTIVE: To compare the biodegradation of di-n-methyl pathalate by free and immobilized microbial cells. METHODS: The enrichment and isolation technique was used to isolate the microorganism. The PAV-entrapment method was utilized to immobilize the microorganisms. The scanning electron microscophy (SEM) was used to observe the growth and distribution of microbial cells immobilized inside the PVA bead gels. The GC/MS method was used to identify the main intermediates of DMP degradation. RESULTS: The microbial cells could grow quite well in PVA gel. The metabolic pathway did not change before and after immobilization of the microbial cells. The degradation rate of immobilized cells was higher than that of free cells. CONCLUSION: The immobilized microbial cells possess advantages than free cells when applied to the biodegradation of toxic organic pollutants.