Alzheimer’s disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.

BackgroundBoth type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age-associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase-3β (GSK-3β) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients.MethodsThe cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK-3β activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses.FindingsWe recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan), and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM-nMCI) or with MCI (termed T2DM-MCI). There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE ε2, ApoE ε3, tGSK3β and pS9GSK3β between the two groups. Compared with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, ApoE ε4 allele, higher olfactory score and higher rGSK-3β (ratio of total GSK-3β to Ser9-phosphorylated GSK-3β) in the training set and the validation set. The OR values of age, ApoE ε4 gene, olfactory score and rGSK-3β were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE ε4 gene, olfactory score and rGSK-3β were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86%, diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively.InterpretationAging, activation of peripheral circulating GSK-3β, expression of ApoE ε4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.

The present study examined the potential function and underlying mechanisms of microRNA-125a (miR-125a) in thyroiditis. Mice were subcutaneously administered with 100 µg porcine thyroglobulin weekly for 2 weeks to establish the thyroiditis model. Results of the in vivo study demonstrated that miR-125a serum expression was upregulated in thyroiditis mice compared with the control group. In vitro studies were performed on a mouse macrophage cell line in which a model of thyroiditis was established using 10 ng/ml human interferon-γ. Upregulated miR-125a expression was achieved via mimic transfection. Increased miR-125a expression reduced autophagy and cell proliferation, increased the apoptotic rate and the expression of pro-inflammatory factors tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-18 via downregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. PI3K inhibition enhanced the ability of miR-125a to increase the inflammatory response in vitro via regulation of the PI3K/Akt/mTOR signaling pathway. These results suggest miR-125a inhibited autophagy in a model of thyroiditis through the PI3K/Akt/mTOR signaling pathway.

2021) Homeobox A5 activates p53 pathway to inhibit proliferation and promote apoptosis of adrenocortical carcinoma cells by inducing

In the present study, we evaluated the curative effect of dipeptidyl peptidase-IV (DPP-IV) inhibitor alogliptin combined with motor imagery under hyperbaric oxygen in diabetic nephropathy (DN) with silent cerebral infarction (SCI). Two-hundred newly diagnosed DN patients with and without SCI were included. The SCI patients were divided into two treatment groups: Alogliptin (A group, n=50) and alogliptin combined with motor imagery under hyperbaric oxygen (B group, n=50). The degrees of neurocognitive dysfunction were evaluated at baseline and after 6 months of treatment. Thromboelastograms (TEGs) mapping were conducted. Serum glycoprotein VI (GPVI) mRNA expression and urine 11-DH-TXB2 levels were determined. Compared to group A patients, the severity of neurofunctional defects, GPVI mRNA expression and 11-DH-TXB2 levels were significantly lower in group B (P<0.05), while comprehensive, MoCA scores were higher in group B. The MoCA subscores of visuospatial/executive function, attention and concentration were significantly higher compared to group A (P<0.05). The sub-scores of computation, abstract thinking, language competence, memory and orientation were also higher in group B but the differences were not significant (P>0.05). TEG indexes were improved in both groups after treatment as manifested by increased R and K values, but there was significant improvement in group B. Intra-group comparisons revealed a time-dependent effect of treatment. In conclusion, the treatment of alogliptin combined with motor imagery under hyperbaric oxygen can better promote thrombolysis absorption, restore brain damage and improve neurocognitive function in DN with silent cerebral infarction.