Acute lung injury (ALI) is a severe clinical disease marked by dysregulated inflammation response and has a high rate of morbidity and mortality. Macrophages, which play diverse roles in the inflammatory response, are becoming therapeutic targets in ALI. In this study we investigated the effects of dehydrocostus lactone (DHL), a natural sesquiterpene, on macrophage activation and LPS-induced ALI. The macrophage cell line RAW264.7 and primary lung macrophages were incubated with DHL (0, 3, 5, 10 and 30 μmol/L) for 0.5 h and then challenged with LPS (100 ng/mL) for up to 8 hours. C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) to induce acute lung injury (ALI) and then treated with a range of DHL doses intraperitoneally (5 to 20 mg/kg). The results showed that DHL inhibited LPS-induced production of proinflammatory mediators such as iNOS, NO, and cytokines including TNF-α, IL-6, IL-1β, and IL-12 p35 by suppressing the activity of NF-κB via p38 MAPK/MK2 and Akt signaling pathway in macrophages. The in vivo results revealed that DHL significantly attenuated LPS-induced pathological injury and reduced cytokines expression in the lung. NF-κB, p38 MAPK/MK2 and Akt signaling molecules were also involved in the anti-inflammatory effect. Collectively, our findings suggested that DHL is a promising agent for alleviating LPS-induced ALI.
Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 (PRRT2) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2‐negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A‐positive and PRRT2‐positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A‐related PKD. © 2021 International Parkinson and Movement Disorder Society
Short-chain fatty acids (SCFAs) are important metabolites derived from the gut microbiota through fermentation of dietary fiber. SCFAs participate a number of physiological and pathological processes in the human body, such as host metabolism, immune regulation, appetite regulation. Recent studies on gut-brain interaction have shown that SCFAs are important mediators of gut-brain interactions and are involved in the occurrence and development of many neurodegenerative diseases, including Alzheimer's disease. This review summarizes the current research on the potential roles and mechanisms of SCFAs in AD. First, we introduce the metabolic distribution, specific receptors and signaling pathways of SCFAs in human body. The concentration levels of SCFAs in AD patient/animal models are then summarized. In addition, we illustrate the effects and mechanisms of SCFAs on the cognitive level, pathological features (Aβ and tau) and neuroinflammation in AD. Finally, we analyze the translational value of SCFAs as potential therapeutic targets for the treatment of AD.
Alzheimer’s disease (AD) is a devastating disease in the elderly with no known effective treatment. It is characterized by progressive deterioration of memory and cognition. Many new potential targets are being investigated to develop effective therapeutic strategies for AD. Neuropeptide S (NPS) is an endogenous peptide in the central nervous system, which has been shown to play a beneficial role in learning and memory. However, whether NPS can ameliorate cognitive deficits in AD remains unclear. In this study, we examined the effects of NPS treatment on the cognitive behaviors and pathological hallmarks in 8-month-old APPswe/PS1dE9 (APP/PS1) AD mice. We found that the APP/PS1 mice exhibited lower levels of NPS receptors (NPSRs) in the hippocampal area, and NPS administration increased c-Fos expression in the hippocampus and cortex, which suggests the NPS/NPSR system may contribute to the pathogenesis of AD. After an intracerebroventricular injection of NPS (1 nmol) for 2 weeks, we found NPS treatment ameliorated spatial memory deficits and promoted dendrite ramification and spine generation in hippocampal CA1 neurons, which was accompanied by the upregulation of postsynaptic density protein 95 (PSD95) and synapsin1. We also demonstrated that the injection of NPS decreased Aβ plaque deposits by decreasing the γ-secretase activity and the phosphorylation of APP at Thr668. Furthermore, application of NPS reversed the deficits in hippocampal late-phase long-term potentiation (LTP). These findings suggest NPS attenuated cognitive deficits by reducing pathological features in APP/PS1 mice, and NPS might be a potential therapeutic agent for AD.
There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer's disease.
Occipital cortical malformation (OCCM) is a disease caused by malformations of cortical development characterized by polymicrogyria and pachygyria of the occipital lobes and childhood-onset seizures. The recessive or complex heterozygous variants of the LAMC3 gene are identified as the cause of OCCM. In the present study, we identified novel complex heterozygous variants (c.470G > A and c.4030 + 1G > A) of the LAMC3 gene in a Chinese female with childhood-onset seizures. Cranial magnetic resonance imaging was normal. Functional experiments confirmed that both variant sites caused premature truncation of the laminin γ3 chain. Bioinformatics analysis predicted 10 genes interacted with LAMC3 with an interaction score of 0.4 (P value = 1.0e–16). The proteins encoded by these genes were mainly located in the basement membrane and extracellular matrix component. Furthermore, the biological processes and molecular functions from gene ontology analysis indicated that laminin γ3 chain and related proteins played an important role in structural support and cellular processes through protein-containing complex binding and signaling receptor binding. KEGG pathway enrichment predicted that the LAMC3 gene variant was most likely to participate in the occurrence and development of OCCM through extracellular matrix receptor interaction and PI3K-Akt signaling pathway.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.