Enhancement of Autophagy in Macrophages via the p120-Catenin-Mediated mTOR Signaling Pathway.

Autophagy serves as a critical regulator of immune responses in sepsis. Macrophages are vital constituents of both innate and adaptive immunity. In this study, we delved into the intricate role of p120-catenin (p120) in orchestrating autophagy in macrophages in response to endotoxin stimulation. Depletion of p120 effectively suppressed LPS-induced autophagy in both J774A.1 macrophages and murine bone marrow-derived macrophages. LPS not only elevated the interaction between p120 and L chain 3 (LC3) I/II but also facilitated the association of p120 with mammalian target of rapamycin (mTOR). p120 depletion in macrophages by small interfering RNA reduced LPS-induced dissociation of mTOR and Unc-51-like kinase 1 (ULK1), leading to an increase in the phosphorylation of ULK1. p120 depletion also enhanced LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3, 7-aminoactinomycin D staining, and TUNEL assay. Notably, inhibiting autophagy reversed the decrease in apoptosis caused by LPS stimulation in macrophages overexpressing p120. Additionally, the ablation of p120 inhibited autophagy and accentuated apoptosis in alveolar macrophages in LPS-challenged mice. Collectively, our findings strongly suggest that p120 plays a pivotal role in fostering autophagy while concurrently hindering apoptosis in macrophages, achieved through modulation of the mTOR/ULK1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders.

Co-Treatment with the Herbal Medicine SIP3 and Donepezil Improves Memory and Depression in the Mouse Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a lethal, progressive neurodegenerative disorder that has been linked to a deficiency of the neurotransmitter acetylcholine. Currently, many acetylcholinesterase inhibitors, such as donepezil, are widely used for the treatment of AD. On the other hand, the efficacy of long-term donepezil use is limited. SIP3, a mixture of three herbal extracts from Santalum album, Illicium verum, and Polygala tenuifolia, is a new formula derived from traditional Korean herbal medicine. OBJECTIVE: We assessed the synergistic effect of SIP3 and donepezil co-treatment on symptoms of AD using APP/PS1 transgenic mice. METHODS: In this study, a Drosophila AD model and SH-SY5Y clles were used to assess the toxicity of SIP3, and APPswe/PS1dE9 (APP/PS1) transgenic mice were used to evaluate the cognitive-behavioral and depression-like behavior effect of SIP3 and donepezil co-treatment on symptoms of AD. The cerebral cortex or hippocampus transcriptomes were analyzed by RNA sequencing and miRNA to investigate the molecular and cellular mechanisms underlying the positive effects of SIP3 on AD. RESULTS: In the passive avoidance test (PAT) and Morris water maze (MWM) test, the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice in the mid-stage of AD compared to the group treated with donepezil only. In addition, co-administration of SIP3 and donepezil effectively reduced the depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of the cerebral cortex transcriptome and miRNA of the hippocampus showed that the gene expression profiles after a low dose SIP3 co-treatment were more similar to those of the normal phenotype mice than those obtained after the donepezil treatment alone. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, showed that differentially expressed genes were involved in the locomotor behavior and neuroactive ligand-receptor interactions. These results suggest that a co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice. CONCLUSION: Co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice.

Neoline Improves Memory Impairment and Reduces Amyloid-ß Level and Tau Phosphorylation Through AMPK Activation in the Mouse Alzheimer's Disease Model.

BACKGROUND: Alzheimer's disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated. OBJECTIVE: We offer the investigation of the effects of neoline in AD. METHODS: In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated. RESULTS: Neoline improved memory and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-ß in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-ß, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-ß levels in the brain of Tg-APPswe/PS1dE9 AD mice. CONCLUSION: Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD.

Association of C-Reactive Protein with Risk of Developing Type 2 Diabetes Mellitus, and Role of Obesity and Hypertension: A Large Population-Based Korean Cohort Study.

This study was undertaken to assess the associations of C-reactive protein (CRP) with incident type-2 diabetes mellitus (T2DM) and to determine the joint effect of obesity and hypertension on them in the large-scale population-based Korean cohort of the Korean Genome and Epidemiology study (KoGES). We included 22,946 men and women from 11 rural communities at baseline (2005-2011). Epidemiological data and blood samples were collected. Incident physician-diagnosed T2DM cases (130 men and 148 women) were self-reported or based on fasting glucose ≥126 mg/dL or HbA1c level ≥6.5% during a median follow-up of 3.0 years (58,916 person-years) between 2007 and 2014. After multivariate adjustment for T2DM risk factors, the hazard ratios for developing T2DM in the highest CRP tertile (T3), compared with the lowest (T1), was 2.80 (1.73-4.52; p for trend <0.0001) in women and 1.67 (1.00-2.45; p for trend 0.02) in men. The associations between CRP and incident T2DM were more prominent among the older group (≥50 years). And CRP and its combination with obesity and hypertension were associated with increased risk of T2DM. In conclusion, we found positive associations between CRP and incident T2DM in a large population-based Korean cohort.