Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway.

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3ß binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aß plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

Dietary Xylitol Supplement Ameliorated AD-related Neuronal Injury by Regulating Glucose Metabolism Relevant Amino Acids in Mice.

BACKGROUND: Alzheimer's disease (AD) is one of the most common irreversible degenerative diseases of the central nervous system. Recent studies have found that patients with AD generally experience abnormal glucose metabolism. Xylitol is a functional sugar alcohol, which has been reported to regulate glucose metabolism. OBJECTIVE: The present study was designed to determine whether xylitol can alleviate cognitive impairment in AD mice. METHODS: In the current research, 5% xylitol was supplemented in the diet to treat APP/PS1 transgenic AD mice for 2 months. Cognitive ability was measured by the Morris water maze, and anxiety-like behaviors were examined by open-field experiment. Hippocampal cellular apoptosis and mitochondria pathway related apoptotic proteins were tested by TUNEL staining and immunoblotting, respectively. By LC-MS, plasma levels of glucose metabolism intermediates and related amino acids were evaluated. RESULTS: Results showed that xylitol could significantly ameliorate anxiety-like activity in AD mice by partially regulating expression levels of mitochondrial pathway-related apoptotic proteins. Xylitolregulated glucose metabolism may play an important role in the process. CONCLUSION: The current study suggests that xylitol may be a potential candidate for improving neuropsychiatric behavior in AD by regulating the levels of TCA cycle intermediates and related amino acids in glucose metabolism.

Analysis of the efficacy and related factors of ventriculoperitoneal shunt for AIDS with cryptococcal meningitis.

Background: Cryptococcus neoformans is an opportunistic pathogen, which is more common in patients with AIDS. Increased intracranial pressure (ICP) is an important complication of cryptococcal meningitis (CM) and affects the therapeutic effect of CM. Objective: To evaluate the effect and treatment for the management of ventriculoperitoneal shunt (VPS) in the treatment of AIDS complicated with CM and to analyze the factors associated with VPS and the indices affecting the outcome of CM patients. Methods: A retrospective case study was conducted on patients with CM treated in the First Affiliated Hospital of Zhejiang University School of Medicine from 2011 to 2019. The Chi-square test was used for categorical variables and the Student's t-test was used for continuous variables. Multivariable analysis of baseline factors related to VPS placement was performed with stepwise logistic regression analysis, factors associated with the outcome of these patients were studied by Cox regression analysis, and Kaplan-Meier survival curves were constructed to assess the outcome of patients. Results: There were 96 patients with AIDS complicated with CM. VPS had a great effect on the patients, especially those with ICP > 350 mmH2O. The outcome, including the mortality rate and modified Rankin scale (MRS) score of these patients, significantly improved after the placement of VPS. The karnofsky performance status (KPS) scores of patients whose ICP > 350 mmH2O improved from 39.3 ± 21.3 at baseline to 88.7 ± 26.9 at 3 months after VPS, better than those without VPS. Multivariable analysis showed that visual impairment (OR, 0.026; 95% CI, 0.001, 0.567; P = 0.021) and ICP > 350 mmH2O (OR, 0.026; 95% CI, 0.002, 0.293; P = 0.003) were related elements with the placement of shunt, and KPS score (HR, 0.968; 95% CI, 0.943, 0.993; P = 0.013) and ICP > 350 mmH2O (HR, 2.801; 95% CI, 1.035, 7.580; P = 0.043) were indices of the outcome of AIDS patients with CM. For patients with ICP > 350 mmHg, Kaplan-Meier analysis showed that the 3-year outcome of patients with VPS was better than that of patients without VPS (P = 0.0067). Conclusion: VPS was associated with better 3-year survival rates, and postshunt placement complications like infections were rare. The identification of factors related to VPS in the initial diagnosis of CM can contribute to more active management and improve the outcome.

S-adenosylmethionine decarboxylase 1 and its related spermidine synthesis mediate PM2.5 exposure-induced neuronal apoptosis.

PM2.5 exposure is considered harmful to central nerve system, while the specific biochemical mechanism underlying is still unrevealed. Neuronal apoptosis is believed the crucial event in pathogenesis of neurodegenerative diseases, but evidence supporting neuronal apoptosis as the mechanism for PM2.5 exposure induced neuronal injury is insufficient. S-adenosylmethionine decarboxylase 1 (AMD1) and its related spermidine synthesis have been shown to associate with cellular apoptosis, but its role in PM2.5 exposure induced neuronal apoptosis was rarely reported. The current study was aimed to better understand contribution of AMD1 activity and spermidine in PM2.5 exposure induced neuronal apoptosis. Sixteen C57BL/6 male mice were randomly divided and kept into ambient PM2.5 chamber or filtered air chamber for 6 months to establish the mouse model of whole-body ambient PM2.5 chronic exposure. In parallel, PC12 cells and primary hippocampal neurons were applied for various concentrations of PM2.5 treatment (0, 25, 50, 100, 200, and 400 µg/mL) to explore the possible cellular and molecular mechanism which may be critically involved in the process. Results showed that PM2.5 exposure triggered neuronal apoptosis with increased expression of Bax/Bcl-2 and cleaved caspase-3. PM2.5 exposure reduced AMD1 expression and spermidine synthesis. AMD1 inhibition could mimic PM2.5 exposure induced neuronal apoptosis. Spermidine supplementation rescued against neurotoxicity and inhibited PM2.5 induced apoptosis via impaired depolarization of mitochondrial membrane potential and reduced mitochondrial apoptosis related proteins. In summary, our work demonstrated that exposure to PM2.5 led to neuronal apoptosis, which may be the key event in the process of air pollution induced neurodegenerative diseases. AMD1 and spermidine associated with neuronal apoptosis induced by PM2.5 exposure, which was at least partially dependent on mitochondria mediated pathway.

The Application of Brain Organoids: From Neuronal Development to Neurological Diseases.

Brain organoids are derived from induced pluripotent stem cells and embryonic stem cells under three-dimensional culture condition. The generation of an organoid requires the self-assembly of stem cells, progenitor cells, and multiple types of differentiated cells. Organoids display structures that resemble defined brain regions and simulate specific changes of neurological disorders; thus, organoids have become an excellent model for investigating brain development and neurological diseases. In the present review, we have summarized recent advances of the methods of culturing brain organoids and the applications of brain organoids in investigating neurodevelopmental and neurodegenerative diseases.

Ambient PM2.5 chronic exposure leads to cognitive decline in mice: From pulmonary to neuronal inflammation.

Fine particulate matter 2.5 (PM2.5), one of the main components of air pollutants, seriously threatens human health. Possible neuronal dysfunction induced by PM2.5 has received extensive attention. However, there is little evidence for the specific biochemical mechanism of neuronal injury induced by PM2.5. Moreover, the pathway for PM2.5 transport from peripheral circulation to the central nervous system (CNS) is still unclear. In the current work, C57BL/6 mice were chronically exposed to ambient PM2.5 for 3, 6, 9, and 12 months. Exposure to ambient PM2.5 resulted in a significant reduction of cognitive ability in mice by Morris water maze test. PM2.5 exposure induced a neuroinflammatory reaction after cognitive impairment, while inflammation in the hypothalamus and olfactory bulb tissue occurred earlier. The expression levels of integrity tight junction proteins in the blood-brain barrier (BBB) were reduced by PM2.5 exposure. Pulmonary inflammation occurred much earlier and diminished at later stage of PM2.5 exposure. The results indicated that chronic exposure to ambient PM2.5 led to cognitive decline in mice; CNS dysfunction may be due to neuroinflammatory reactions; the reduced integrity of the BBB allowed the influence of pulmonary inflammation to neuronal alterations. The work may provide promising therapeutic or preventive targets for air pollution-induced neurodegenerative disease.

Recent advances in understanding the mechanisms of PM2.5-mediated neurodegenerative diseases.

PM2.5 particles are widely believed to be associated with respiratory and cardiovascular diseases. However, recent studies have reported that PM2.5 may be associated with neurodegenerative diseases. The exact mechanism by which PM2.5 mediates neurotoxicity and cognitive dysfunction is still unclear. In the current work, we collected evidence supporting the association between PM2.5 exposure and development of neurodegenerative disorders. Evidence from epidemiological investigations, animal experiments, and ex vivo cell experiments showed that PM2.5 exposure may lead to neuroinflammation, oxidative stress, mitochondrial dysfunction, neuronal apoptosis, synaptic damage and ultimately neurodegenerative diseases.

Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice.

N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

A review of the possible associations between ambient PM2.5 exposures and the development of Alzheimer's disease.

PM2.5 particles in air pollution have been widely considered associated with respiratory and cardiovascular diseases. Recent studies have shown that PM2.5 can also cause central nervous system (CNS) diseases, including a variety of neurodegenerative diseases, such as Alzheimer's disease (AD). Activation of microglia in the central nervous system can lead to inflammatory and neurological damage. PM2.5 will reduce the methylation level of DNA and affect epigenetics. PM2.5 enters the human body through a variety of pathways to have pathological effects on CNS. For example, PM2.5 can destroy the integrity of the blood-brain barrier (BBB), so peripheral systemic inflammation easily crosses BBB and reaches CNS. The olfactory nerve is another way for PM2.5 particles to enter the brain. Surprisingly, PM2.5 can also enter the gastrointestinal tract, causing imbalances in the intestinal microecology to affect central nervous system diseases. The current work collected and discuss the mechanisms of PM2.5-induced CNS damage and PM2.5-induced neurodegenerative diseases.

The relationship between cholesterol level and Alzheimer's disease-associated APP proteolysis/Aß metabolism.

Globally, Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly population, the hallmark of which is amyloid ß (Aß) peptide. Energy metabolism and AD pathogenesis are believed to influence one another. Different cholesterol levels are thought to influence various steps in neurotoxic Aß generation, including amyloid precursor protein (APP) proteolysis and the corresponding activities of α-, ß-, and γ-secretases. In addition, cholesterol has been proved to mediate Aß metabolism, such as its fibrillation, transportation, degradation, and clearance processes. The current review discusses in detail the intimate interaction between the cholesterol level and the various aspects of APP proteolysis and Aß metabolism.

Stability of vitamin B12 with the protection of whey proteins and their effects on the gut microbiome.

Cobalamin degrades in the presence of light and heat, which causes spectral changes and loss of coenzyme activity. In the presence of beta-lactoglobulin or alpha-lactalbumin, the thermal- and photostabilities of adenosylcobalamin (ADCBL) and cyanocobalamin (CNCBL) are increased by 10-30%. Similarly, the stabilities of ADCBL and CNCBL are increased in the presence of whey proteins by 19.7% and 2.2%, respectively, when tested in gastric juice for 2 h. Due to the limited absorption of cobalamin during digestion, excess cobalamin can enter the colon and modulate the gut microbiome. In a colonic model in vitro, supplementation with cobalamin and whey enhanced the proportions of Firmicutes and Bacteroidetes spp. and reduced those of Proteobacteria spp., which includes pathogens such as Escherichia and Shigella spp., and Pseudomonas spp. Thus, while complex formation could improve the stability and bioavailability of cobalamin, these complexes might also mediate gut microecology to influence human nutrition and health.

(+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFκB signaling.

BACKGROUND: Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear. RESULTS: In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1ß-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling. CONCLUSIONS: Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.