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  • We previously found that GLP and exendin

    2019-07-24

    We previously found that GLP-1 and exendin-4 exerted protective effects against high glucose-induced toxicity in PC12 Relebactam [4,14]. However, the mechanisms of action of GLP-1RA on metabolic memory-induced neurotoxicity are largely unknown. Our in vitro experiments indicated that incubation of cells with GLP-1 or exendin-4 protected against neuronal cell injury induced by high glucose treatment followed by withdrawal. Detailed investigations of the underlying molecular mechanisms were also performed to evaluate the beneficial effects of GLP-1 and exendin-4 on neuronal cells as a suitable in vitro model for metabolic memory. The FoxO family of transcription factors plays key roles in diabetic complications and diabetes-induced oxidative stress [44], which is related to metabolic memory. Several modifications of FoxO, including phosphorylation and deacetylation, affect its activation [[27], [28], [29]]. In vitro results demonstrated that FoxO activity, especially FoxO1, played a crucial role, and Sirt1-dependent FoxO1 deacetylation and Akt-dependent FoxO1 phosphorylation were involved in the effects of GLP-1. The in vivo experiments also confirmed that the GLP-1R/FoxO1 axis played an important role in the attenuating effect of exendin-4/lixisenatide in high glucose-induced metabolic memory in neuronal cells. The regulatory trend of p-Akt was consistent with p-FoxO1. The role of Sirt1 was much more complicated. Previous studies suggested that Sirt1 exerted dual effects on FoxO1 [27,29]. Therefore, we confirmed the roles of Sirt1/FoxO1 in metabolic memory and GLP-1 analogue effects in vivo, and further examined Sirt1/FoxO1 roles using a Sirt1 inhibitor and FoxO1 siRNA in vitro. In conclusion, the present study demonstrated that GLP-1 and its analogues exerted beneficial effects on neuronal cell damage produced by high glucose treatment followed by withdrawal and learning and memory in db/db mice with normalized blood glucose levels. The most likely mechanisms of these beneficial effects involved Sirt1-dependent deacetylation and Akt-dependent phosphorylation of FoxO1. This study provides evidence for the beneficial effects of GLP-1RA on metabolic memory in neurons and the GLP-1 analogue and metformin combination therapy efficiency on dementia.
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    Introduction Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder, affecting 1:20,000 to 1:40,000 individuals, mostly foetuses and infants [1] and is a common cause of perinatal death [2]. It manifests as extreme bilateral enlargement of cystic kidneys in utero, associated with hepatic ductal plate abnormalities and pulmonary hypoplasia [3,4]. In those patients who survive the perinatal period, the majority will require renal replacement therapy (dialysis/transplantation) within the first decade [5]. Recently, however, ARPKD patients have been diagnosed in their 30s with relatively mild renal insufficiency [6]. Besides the typical renal manifestations associated with ARPKD, a significant percentage of ARPKD patients manifest extra-renal phenotypes, such as liver fibrosis and dilated bile ducts (Caroli's syndrome) [7], suggesting a previously unrecognised, wide spectrum of disease severity. ARPKD is caused by mutations in PKHD1, the gene encoding Fibrocystin. Fibrocystin is a membrane-associated receptor-like protein of 447 kDa, composed of a large, modular extracellular N-terminal domain, a single transmembrane domain and a short intracellular C-terminal region [8]. Many different mutations in PKHD1 have been reported throughout the whole gene and the combination of mutations determines the phenotype of ARPKD patients. Patients with two truncating mutations have a lethal phenotype, whereas the presence of at least one missense change can be compatible with life, indicating that many missense mutations are hypomorphic alleles that generate partially functional protein [9]. Modifier genes are also believed to play a role in the range of disease severity observed in ARPKD [4,[10], [11], [12]].