Sphingomonas Paucimobilis-derived Extracellular Vesicles Reverse Aβ-induced Dysregulation of Neurotrophic Factors, Mitochondrial Function, and Inflammatory Factors through MeCP2-mediated Mechanism

Article

作者: Lee, Eun-Hwa ; Park, So-Young ; Hong, Jin-Hwan ; Kim, Yoon-Keun ; Han, Pyung-Lim ; Kwon, Hyejin ; Paeng, Jae-Won ; Park, Jin-Young

Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by Spa-EV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.

2024-04-01·Allergology International

Lactobacillus paracasei-derived extracellular vesicles alleviate neutrophilic asthma by inhibiting the JNK pathway in airway epithelium

Article

作者: Kim, Yoon-Keun ; Sim, Soyoon ; Choi, Youngwoo ; Park, Hyeon Ju ; Park, Hae-Sim

BACKGROUNDLactobacillus paracasei has been known to reduce airway resistance and inflammation in asthma. However, the therapeutic effect of its extracellular vesicles (EVs) in patients with asthma remains unclear.METHODSTo validate the clinical relevance of L. paracasei-derived EVs (LpEV) in asthma, the composition of gut microbial EVs was verified by metagenomics in LPS-induced C57BL/6 mice. The components of proteins and metabolites in LpEV were identified by peptide mass fingerprinting and metabolomic analysis. The serum levels of specific IgG1 or IgG4 antibodies to LpEV were compared by ELISA between patients with eosinophilic asthma (EA, n = 10) and those with neutrophilic asthma (NA, n = 10) as well as with healthy controls (HCs, n = 10). Finally, therapeutic effects of LpEV and their metabolites in asthma were validated in vivo/in vitro.RESULTSSignificantly lower proportions of EVs derived from Lactobacillus at the genus level were noted in mice with NA than in control mice. Moreover, the serum levels of LpEV-specific IgG4, but not IgG1, were lower in patients with NA than in those with EA or in HCs and positively correlated with FEV₁ (%) values. In addition, oral administration of LpEV reduced airway resistance and inflammation in mice with NA. Finally, LpEV and their 3 metabolites (dodecanoic acid, palmitoleic acid, and D-(-)-tagatose) significantly inhibited JNK phosphorylation/IL-8 production in airway epithelium in vitro.CONCLUSIONSThese findings suggest that LpEV may have a therapeutic potential targeting NA by suppressing the JNK pathway and proinflammatory cytokine production in airway epithelium.

2023-10-31·Experimental Neurobiology

Extracellular Vesicles Released by Lactobacillus paracasei Mitigate Stress-induced Transcriptional Changes and Depression-like Behavior in Mice

Article

作者: Kim, Yoon-Keun ; Lee, Eun-Hwa ; Kwon, Hyejin ; Park, Jin-Young ; Choi, Juli ; Han, Pyung-Lim

Various probiotic strains have been reported to affect emotional behavior. However, the underlying mechanisms by which specific probiotic strains change brain function are not clearly understood. Here, we report that extracellular vesicles derived from Lactobacillus paracasei (Lpc-EV) have an ability to produce genome-wide changes against glucocorticoid (GC)-induced transcriptional responses in HT22 hippocampal neuronal cells. Genome-wide analysis using microarray assay followed by Rank-Rank Hypergeometric Overlap (RRHO) method leads to identify the top 20%-ranked 1,754 genes up- or down-regulated following GC treatment and their altered expressions are reversed by Lpc-EV in HT22 cells. Serial k-means clustering combined with Gene Ontology enrichment analyses indicate that the identified genes can be grouped into multiple functional clusters that contain functional modules of "responses to stress or steroid hormones", "histone modification", and "regulating MAPK signaling pathways". While all the selected genes respond to GC and Lpc-EV at certain levels, the present study focuses on the clusters that contain Mkp-1, Fkbp5, and Mecp2, the genes characterized to respond to GC and Lpc-EV in opposite directions in HT22 cells. A translational study indicates that the expression levels of Mkp-1, Fkbp5, and Mecp2 are changed in the hippocampus of mice exposed to chronic stress in the same directions as those following GC treatment in HT22 cells, whereas Lpc-EV treatment restored stress-induced changes of those factors, and alleviated stress-induced depressive-like behavior. These results suggest that Lpc-EV cargo contains bioactive components that directly induce genome-wide transcriptional responses against GC-induced transcriptional and behavioral changes.

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2022-06-01

·Healthcare IT News

Thonburi Hospital signs latest partnership to pursue smart hospital transformation

Thai private healthcare provider Thonburi Hospital has signed a memorandum of understanding with Chunghwa Telecom Co., a Taiwan-based telecommunications company, for their continued collaboration in the hospital's digital transformation. Thonburi is a tertiary care provider with a network of 18 private hospitals in Thailand. According to a press statement, their latest agreement is for their continued partnership on using Chunghwa's smart ward point-of-care solutions. Powered by Taiwanese medical AI firm imedtac and medical device company MD Healthcare from Thailand, Chunghwa is able to deliver smart ward solutions to Thonburi Hospital, including a smart nursing station, an all-in-one vital sign kiosk, an automated dispensing cabinet, an e-paper bedside information display and a ToF fall management system. WHY IT MATTERS As healthcare players in Southeast Asia are now dealing with post-COVID-19 challenges, they now also require an infrastructure that will enable them to deliver services in a constantly changing environment, said Hsueh-Lan Wu, chairman of Chunghwa Telecom Thailand. So far, the smart hospital applications provided by Chunghwa have reduced the workload burden for the staff of Thonburi Hospital, enhanced the quality of medical services, and raised its operational performance. Thonburi Hospital CEO Dr Siripong Luengvarinkul said they believed that "better information collection, organisation, and distribution are vital to precision medicine, which ultimately enables doctors and paramedics to deliver better healthcare inside and beyond hospital grounds". THE LARGER TREND The Thai health system continues its digital transformation through tech integrations and ICT adoptions. Late last year saw the Siriraj Hospital of Mahidol University launch what could be the largest 5G smart hospital in Southeast Asia. The hospital was built with the support of the National Broadcasting and Telecommunications Commission and Huawei Thailand. Huawei is also collaborating with Thailand's Department of Medical Services to roll out 5G technologies to two public hospitals, the National Cancer Institute and Rajavithi Hospital . ON THE RECORD "We value the simplicity, friendliness, and comprehensive connectivity in our information technologies over complicated and novel systems that distract from the healthcare we bring to our patients," Thonburi's Dr Siripong further emphasised.

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