Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Tim-3 regulates the immunosuppressive function of decidual MDSCs via the Fyn-STAT3-C/EBPß pathway during Toxoplasma gondii infection.

Myeloid-derived suppressor cells (MDSCs) play a key role in maintaining maternal-fetal tolerance for a successful pregnancy, but the role of MDSCs in abnormal pregnancy caused by Toxoplasma gondii infection is unknown. Herein, we revealed a distinct mechanism by which T-cell immunoglobulin domain and mucin domain containing protein-3 (Tim-3), an immune checkpoint receptor that balances maternal-fetal tolerance during pregnancy, contributes to the immunosuppressive function of MDSCs during T. gondii infection. The expression of Tim-3 in decidual MDSCs was significantly downregulated following T. gondii infection. The proportion of monocytic MDSCs population, the inhibitory effect of MDSCs on T-cell proliferation, the levels of STAT3 phosphorylation, and the expression of functional molecules (Arg-1 and IL-10) in MDSCs were all decreased in T. gondii-infected pregnant Tim-3 gene knockout (Tim-3KO) mice compared with infected pregnant WT mice. After treatment with Tim-3-neutralizing Ab in vitro, the expression levels of Arg-1, IL-10, C/EBPß, and p-STAT3 were decreased, the interaction between Fyn and Tim-3 or between Fyn and STAT3 was weakened, and the binding ability of C/EBPß to the promoters of ARG1 and IL10 was decreased in human decidual MDSCs with T. gondii infection, while opposite results were observed following treatment with galectin-9 (a ligand for Tim-3). Inhibitors of Fyn and STAT3 also downregulated the expression of Arg-1 and IL-10 in decidual MDSCs and exacerbated adverse pregnancy outcomes caused by T. gondii infection in mice. Therefore, our studies discovered that the decrease of Tim-3 after T. gondii infection could downregulate the functional molecules of Arg-1 and IL-10 expression in decidual MDSCs through the Fyn-STAT3-C/EBPß signaling pathway and weaken their immunosuppressive function, which eventually contribute to the development of adverse pregnancy outcomes.

Phylogenetic distance-decay patterns are not explained by local community assembly processes in freshwater lake microbial communities.

While water and sediment microbial communities exhibit pronounced spatio-temporal patterns in freshwater lakes, the underlying drivers are yet poorly understood. Here, we evaluated the importance of spatial and temporal variation in abiotic environmental factors for bacterial and microeukaryotic community assembly and distance-decay relationships in water and sediment niches in Hongze Lake. By sampling across the whole lake during both Autumn and Spring sampling time points, we show that only bacterial sediment communities were governed by deterministic community assembly processes due to abiotic environmental drivers. Nevertheless, consistent distance-decay relationships were found with both bacterial and microeukaryotic communities, which were relatively stable with both sampling time points. Our results suggest that spatio-temporal variation in environmental factors was important in explaining mainly bacterial community assembly in the sediment, possibly due lesser disturbance. However, clear distance-decay patterns emerged also when the community assembly was stochastic. Together, these results suggest that abiotic environmental factors do not clearly drive the spatial structuring of lake microbial communities, highlighting the need to understand the role of other potential drivers, such as spatial heterogeneity and biotic species interactions.

Long non­coding RNA SNHG5 promotes osteogenic differentiation of human periodontal ligament stem cells via mediating miR­23b­3p/Runx2 axis.

The treatment of bone loss due to periodontitis has posed a great challenge for physicians for decades. Therefore, it is of extraordinary significance to identify an effective regeneration scheme for alveolar bone. This study aimed to investigate long non-coding RNA (lncRNA) small nucleolar RNA host gene 5 (SNHG5) whether sponges microRNA-23b-3p (miR-23b-3p) to achieve the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). Results revealed that the expression of SNHG5 was upregulated whereas that of miR-23b-3p was downregulated in osteogenic hPDLSCs. Alizarin red staining assays and qRT-PCR demonstrated that SNHG5 silencing or miR-23b-3p overexpression inhibits hPDLSCs osteogenic differentiation and vice versa. In addition, miR-23b-3p partially abolished the promotive effect of SNHG5 on osteogenic differentiation of hPDLSCs. Dual luciferase report and RNA pulldown assay verified that miR-23b-3p is a regulatory target of SNHG5 and that Runx2 is a gene target of miR-23b-3p. In brief, the results demonstrate that SNHG5 promotes the osteogenic differentiation of hPDLSCs by regulating the miR-23b-3p/Runx2 axis. Our study provides novel mechanistic insights into the critical role of lncRNA SNHG5 as a miR-23b-3p sponge to regulate Runx2 expression in hPDLSCs and may serve as a potential therapeutics target for periodontitis.

MeDAS: a Metazoan Developmental Alternative Splicing database.

Alternative splicing is widespread throughout eukaryotic genomes and greatly increases transcriptomic diversity. Many alternative isoforms have functional roles in developmental processes and are precisely temporally regulated. To facilitate the study of alternative splicing in a developmental context, we created MeDAS, a Metazoan Developmental Alternative Splicing database. MeDAS is an added-value resource that re-analyses publicly archived RNA-seq libraries to provide quantitative data on alternative splicing events as they vary across the time course of development. It has broad temporal and taxonomic scope and is intended to assist the user in identifying trends in alternative splicing throughout development. To create MeDAS, we re-analysed a curated set of 2232 Illumina polyA+ RNA-seq libraries that chart detailed time courses of embryonic and post-natal development across 18 species with a taxonomic range spanning the major metazoan lineages from Caenorhabditis elegans to human. MeDAS is freely available at https://das.chenlulab.com both as raw data tables and as an interactive browser allowing searches by species, tissue, or genomic feature (gene, transcript or exon ID and sequence). Results will provide details on alternative splicing events identified for the queried feature and can be visualised at the gene-, transcript- and exon-level as time courses of expression and inclusion levels, respectively.

Dynamic 3D radiomics analysis using artificial intelligence to assess the stage of COVID-19 on CT images.

OBJECTIVE: To develop a dynamic 3D radiomics analysis method using artificial intelligence technique for automatically assessing four disease stages (i.e., early, progressive, peak, and absorption stages) of COVID-19 patients on CT images. METHODS: The dynamic 3D radiomics analysis method was composed of three AI algorithms (the lung segmentation, lesion segmentation, and stage-assessing AI algorithms) that were trained and tested on 313,767 CT images from 520 COVID-19 patients. This proposed method used 3D lung lesion that was segmented by the lung and lesion segmentation algorithms to extract radiomics features, and then combined with clinical metadata to assess the possible stage of COVID-19 patients using stage-assessing algorithm. Area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were used to evaluate diagnostic performance. RESULTS: Of 520 patients, 66 patients (mean age, 57 years ± 15 [standard deviation]; 35 women), including 203 CT scans, were tested. The dynamic 3D radiomics analysis method used 30 features, including 27 radiomics features and 3 clinical features to assess the possible disease stage of COVID-19 with an accuracy of 90%. For the prediction of each stage, the AUC of stage 1 was 0.965 (95% CI: 0.934, 0.997), AUC of stage 2 was 0.958 (95% CI: 0.931, 0.984), AUC of stage 3 was 0.998 (95% CI: 0.994, 1.000), and AUC of stage 4 was 0.975 (95% CI: 0.956, 0.994). CONCLUSION: With high diagnostic performance, the dynamic 3D radiomics analysis using artificial intelligence could represent a potential tool for helping hospitals make appropriate resource allocations and follow-up of treatment response. KEY POINTS: • The AI segmentation algorithms were able to accurately segment the lung and lesion of COVID-19 patients of different stages. • The dynamic 3D radiomics analysis method successfully extracted the radiomics features from the 3D lung lesion. • The stage-assessing AI algorithm combining with clinical metadata was able to assess the four stages with an accuracy of 90%, a macro-average AUC of 0.975.

miR-23b mediates TNF-α-Inhibited Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Targeting Runx2.

Periodontitis is the most prevalent oral infection disease, which causes the destruction of periodontal supporting tissues and eventual tooth loss. This study aimed to investigate the molecular mechanism of miRNA-23b (miR-23b) in regulating the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in an inflammatory environment. Results revealed that tumor necrosis factor-α (TNF-α), a notoriously inflammatory cytokine, remarkably attenuated the osteogenic differentiation of hPDLSCs, which were partially rescued by SKL2001 (Wnt/ß-catenin agonist). We further explored the underlying roles of miRNAs involved in TNF-α-inhibited osteogenesis of hPDLSCs. The miR-23b significantly increased with TNF-α stimulation, which was abolished by SKL2001. Similar to the effect of TNF-α, miR-23b agonist (agomir-23b) dramatically reduced the expression of runt-related transcription factor 2 (Runx2) and suppressed the osteogenic differentiation of hPDLSCs. The inhibition of miR-23b significantly increased Runx2, which is the major transcription factor during osteogenesis, thereby indicating that miR-23b was an endogenous regulator of Runx2 in hPDLSCs. Bioinformatic analysis and dual luciferase reporter assays confirmed that Runx2 was a target gene of miR-23b. Furthermore, the gain function assay of Runx2 revealed that the Runx2 overexpression efficiently reversed the suppression of the osteogenic differentiation of hPDLSCs with miR-23b agonist, suggesting that the suppressing effect of miR-23b on osteogenesis was mediated by Runx2 inhibition. Our study clarified that miR-23b mediated the TNF-α-inhibited osteogenic differentiation of hPDLSCs by targeting Runx2. Therefore, the expanded function of miR-23b in the osteogenesis of hPDLSCs under inflammatory conditions. This study might provide new insights and a novel therapeutic target for periodontitis.

SCOAT-Net: A novel network for segmenting COVID-19 lung opacification from CT images.

Automatic segmentation of lung opacification from computed tomography (CT) images shows excellent potential for quickly and accurately quantifying the infection of Coronavirus disease 2019 (COVID-19) and judging the disease development and treatment response. However, some challenges still exist, including the complexity and variability features of the opacity regions, the small difference between the infected and healthy tissues, and the noise of CT images. Due to limited medical resources, it is impractical to obtain a large amount of data in a short time, which further hinders the training of deep learning models. To answer these challenges, we proposed a novel spatial- and channel-wise coarse-to-fine attention network (SCOAT-Net), inspired by the biological vision mechanism, for the segmentation of COVID-19 lung opacification from CT images. With the UNet++ as basic structure, our SCOAT-Net introduces the specially designed spatial-wise and channel-wise attention modules, which serve to collaboratively boost the attention learning of the network and extract the efficient features of the infected opacification regions at the pixel and channel levels. Experiments show that our proposed SCOAT-Net achieves better results compared to several state-of-the-art image segmentation networks and has acceptable generalization ability.

A deep-learning-based framework for severity assessment of COVID-19 with CT images.

Millions of positive COVID-19 patients are suffering from the pandemic around the world, a critical step in the management and treatment is severity assessment, which is quite challenging with the limited medical resources. Currently, several artificial intelligence systems have been developed for the severity assessment. However, imprecise severity assessment and insufficient data are still obstacles. To address these issues, we proposed a novel deep-learning-based framework for the fine-grained severity assessment using 3D CT scans, by jointly performing lung segmentation and lesion segmentation. The main innovations in the proposed framework include: 1) decomposing 3D CT scan into multi-view slices for reducing the complexity of 3D model, 2) integrating prior knowledge (dual-Siamese channels and clinical metadata) into our model for improving the model performance. We evaluated the proposed method on 1301 CT scans of 449 COVID-19 cases collected by us, our method achieved an accuracy of 86.7% for four-way classification, with the sensitivities of 92%, 78%, 95%, 89% for four stages. Moreover, ablation study demonstrated the effectiveness of the major components in our model. This indicates that our method may contribute a potential solution to severity assessment of COVID-19 patients using CT images and clinical metadata.

TGF-ß1 improving abnormal pregnancy outcomes induced by Toxoplasma gondii infection: Regulating NKG2D/DAP10 and killer subset of decidual NK cells.

Our current aim was to investigate whether injection of TGF-ß1 played an important role in improving abnormal pregnancy outcomes with T. gondii infection and how the TGF-ß1 regulated. Results showed that TGF-ß1 exhibited improved pregnancy outcomes induced by T. gondii infection. dNK cytotoxicity was increased with T. gondii infection while decreased with TGF-ß1 treatment. dNK cytotoxicity related NKG2D/DAP10 expression, perforin, granzyme, IFN-γ and killer subsets were all increased with T. gondii infection while decreased after TGF-ß1 treatment. In addition, anti-TGF-ß1 antibodies could aggregate the cytotoxicity of dNK cells and the levels of molecules above. These results indicated that TGF-ß1 treatment could improve the abnormal pregnancy outcomes with T. gondii infection by decreasing the cytotoxicity of dNK cells mediated by NKG2D/DAP10 pathway and killer subset. These results suggested that TGF-ß1 might be a potential immunoprotective method for the treatment of abnormal pregnancy outcomes following T. gondii infection.

Variations in several morphological characteristics and Cd/Pb accumulation capacities among different ecotypes of torpedograss responding to Cd-Pb stresses.

Torpedograss (Panicum repens) has been recognized as an useful plant species for phytoremediation of water-level-fluctuation zones, which is a worldwide challenge. In this study, 10 ecotypes collected from tropical zone and flooded habitats (Group A) and subtropical zone and drought habitats (Group B) were used to clarify their responses to Cd-Pb stresses and effects of long-term adaptation on their morphological features and Cd-Pb accumulation capacities. Branch capacity, shoot and root biomasses of Group A under control were smaller than those of Group B, while the opposite results were observed under Cd-Pb stresses. The average plant shoot Cd concentrations of Group A under L-Cd-Pb and H-Cd-Pb were 24.84 and 52.38 mg kg-1, respectively, significantly lower than those of Group B (36.81 and 67.60 mg kg-1), while the variation among each group was insignificant, suggesting that habitat isolation and long-term adaptation may have led to differentiation in morphological features and metal uptake capacity. Torpedograss possesses high tolerance to Cd-Pb toxicities, and those ecotypes with larger biomass had higher Cd-Pb accumulation capacities. Torpedograss is a potential plant species for Cd phytoremediation and approximately 16 years would be required to clean soil contained by Cd as high as 10 mg kg-1 using the selected torpedograss ecotypes.

IL-10 regulate decidual Tregs apoptosis contributing to the abnormal pregnancy with Toxoplasma gondii infection.

This study aims to investigate whether IL-10 regulate decidual Treg cells apoptosis to reverse the abnormal pregnancy outcomes with Toxoplasma gondii (T. gondii) infection. Recombinant mouse IL-10 (rIL-10) treatment and IL-10 deficiency (IL-10(-/-)) abnormal pregnancy animal models with T. gondii infection were established. Apoptosis related molecules cleaved Caspase-3 and Caspase-8 in decidual Treg cells were examined using flow cytometry. The levels of cleaved Caspase-3 and Caspase-8 in decidual Treg cells were up-regulated with T. gondii infection. Compared to infected group, the expressions of cleaved Caspase-3 and Caspase-8 in decidual Treg cells were down-regulated in rIL-10-treated group, while up-regulated in infected IL-10(-/-) group. In addition, pregnant outcomes were improved in rIL-10-treated group, while worse in IL-10(-/-) group compared to infected group. These findings revealed that IL-10 reduced the decidual Treg cells apoptosis contributing to improving adverse pregnant outcomes following T. gondii infection.

Expression of transferrin receptor/TFRC protein in bladder cancer cell T24 and its role in inducing iron death in bladder cancer.

Bladder cancer (BC) is a very common malignant tumor in the urinary system. However, the incidence rate, recurrence rate, progression rate and metastasis rate of bladder cancer are still very high, leading to poor long-term prognosis of patients. This study was to investigate the expression of transferrin receptor/TFRC protein in bladder cancer tissue and its role in inducing iron death of T24 human bladder cancer cells. Based on the intersection of 259 FerrDb genes in the iron death database with GSE13507 and GSE13167 data sets, 54 genes related to iron death in bladder cancer were obtained. Analyzing 54 genes, KEGG enrichment analysis showed that the pathways involved were mainly focused on iron death, autophagy, and tumor center carbon metabolism. GO analysis found that the molecular functions mainly gather in ubiquitin like protein ligase binding, ubiquitin protein ligase binding, and antioxidant activity. In the cellular components, it is mainly distributed in pigment granules, melanosomes, and the basal lateral plasma membrane. In biological processes, it is enriched in nutrient level responses, responses to extracellular stimuli, and cellular redox homeostasis. Screen out the top 10 core genes. The 10 core genes are SLC2A1, TFRC, EGFR, KRAS, CAV1, HSPA5, NFE2L2, VEGFA, PIK3CA, and HRAS. Finally, TFRC was selected as the research object. TCGA analysis showed that the expression level in bladder cancer tissue was higher than that in normal tissue, and the difference was statistically significant (P < 0.001). Conclusion (1) TFRC is highly expressed in many kinds of tumors, and it is more highly expressed in bladder cancer than in normal bladder tissue. (2) TFRC has certain diagnostic and prognostic value in bladder cancer. (3) Erastin, an iron death inducer, induced the iron death of T24 human bladder cancer cells, knocked down the expression of TFRC in T24 human bladder cancer cells, and preliminarily verified that silencing TFRC could inhibit the iron death of T24 human bladder cancer cells.

The effect of Toxoplasma gondii infection on galectin-9 expression in decidual macrophages contributing to dysfunction of decidual NK cells during pregnancy.

BACKGROUND: Toxoplasma gondii infection causes adverse pregnancy outcomes by affecting the expression of immunotolerant molecules in decidual immune cells. Galectin-9 (Gal-9) is widely expressed in decidual macrophages (dMφ) and is crucial for maintaining normal pregnancy by interacting with the immunomodulatory protein T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3). However, the effects of T. gondii infection on Gal-9 expression in dMφ, and the impact of altered Gal-9 expression levels on the maternal-fetal tolerance function of decidual natural killer (dNK) cells, are still unknown. METHODS: Pregnancy outcomes of T. gondii-infected C57BL/6 and Lgals9-/- pregnant mice models were recorded. Expression of Gal-9, c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), and Forkhead box protein O1 (FOXO1) was detected by western blotting, flow cytometry or immunofluorescence. The binding of FOXO1 to the promoter of Lgals9 was determined by chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR). The expression of extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), cAMP-response element binding protein (CREB), phosphorylated CREB (p-CREB), T-box expressed in T cells (T-bet), interleukin 10 (IL-10), and interferon gamma (IFN-γ) in dNK cells was assayed by western blotting. RESULTS: Toxoplasma gondii infection increased the expression of p-JNK and FOXO1 in dMφ, resulting in a reduction in Gal-9 due to the elevated binding of FOXO1 with Lgals9 promoter. Downregulation of Gal-9 enhanced the phosphorylation of ERK, inhibited the expression of p-CREB and IL-10, and promoted the expression of T-bet and IFN-γ in dNK cells. In the mice model, knockout of Lgals9 aggravated adverse pregnancy outcomes caused by T. gondii infection during pregnancy. CONCLUSIONS: Toxoplasma gondii infection suppressed Gal-9 expression in dMφ by activating the JNK/FOXO1 signaling pathway, and reduction of Gal-9 contributed to dysfunction of dNK via Gal-9/Tim-3 interaction. This study provides new insights for the molecular mechanisms of the adverse pregnancy outcomes caused by T. gondii.

Single-cell transcriptomic analysis of decidual immune cell landscape in the occurrence of adverse pregnancy outcomes induced by Toxoplasma gondii infection.

BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite that can lead to adverse pregnancy outcomes, particularly in early pregnancy. Previous studies have illustrated the landscape of decidual immune cells. However, the landscape of decidual immune cells in the maternal-fetal microenvironment during T. gondii infection remains unknown. METHODS: In this study, we employed single-cell RNA sequencing to analyze the changes in human decidual immune cells following T. gondii infection. The results of scRNA-seq were further validated with flow cytometry, reverse transcription-polymerase chain reaction, western blot, and immunofluorescence staining. RESULTS: Our results showed that the proportion of 17 decidual immune cell clusters and the expression levels of 21 genes were changed after T. gondii infection. Differential gene analysis demonstrated that T. gondii infection induced the differential expression of 279, 312, and 380 genes in decidual NK cells (dNK), decidual macrophages (dMφ), and decidual T cells (dT), respectively. Our results revealed for the first time that several previously unknown molecules in decidual immune cells changed following infection. This result revealed that the function of maternal-fetal immune tolerance declined, whereas the killing ability of decidual immune cells enhanced, eventually contributing to the occurrence of adverse pregnancy outcomes. CONCLUSIONS: This study provides valuable resource for uncovering several novel molecules that play an important role in the occurrence of abnormal pregnancy outcomes induced by T. gondii infection.

A novel electrochemical biosensor for B-type natriuretic peptide detection based on CRISPR/Cas13a and chain substitution reaction.

B-type natriuretic peptide (BNP) is a biomarker for heart failure, a serious and prevalent disease that requires rapid and accurate diagnosis. In this study, we developed a novel electrochemical biosensor for BNP detection based on CRISPR/Cas13a and chain substitution reaction. The biosensor consists of a DNA aptamer that specifically binds to BNP, a T7 RNA polymerase that amplifies the signal, a CRISPR/Cas13a system that cleaves the target RNA, and a two-dimensional DNA nanoprobe that generates an electrochemical signal. The biosensor exhibits high sensitivity, specificity, and stability, with a detection limit of 0.74 aM. The biosensor can also detect BNP in human serum samples with negligible interference, demonstrating its potential for clinical and point-of-care applications. This study presents a novel strategy for integrating CRISPR/Cas13a and chain substitution reaction into biosensor design, offering a versatile and effective platform for biomolecule detection.

Decidual natural killer cells dysfunction is caused by IDO downregulation in dMDSCs with Toxoplasma gondii infection.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in maintaining maternal-fetal tolerance by expressing some immune-suppressive molecules, such as indoleamine 2,3-dioxygenase (IDO). Toxoplasma gondii (T. gondii) infection can break the immune microenvironment of maternal-fetal interface, resulting in adverse pregnancy outcomes. However, whether T. gondii affects IDO expression in dMDSCs and the molecular mechanism of its effect are still unclear. Here we show, the mRNA level of IDO is increased but the protein level decreased in infected dMDSCs. Mechanistically, the upregulation of transcriptional levels of IDO in dMDSCs is regulated through STAT3/p52-RelB pathway and the decrease of IDO expression is due to its degradation caused by increased SOCS3 after T. gondii infection. In vivo, the adverse pregnancy outcomes of IDO-/- infected mice are more severe than those of wide-type infected mice and obviously improved after exogenous kynurenine treatment. Also, the reduction of IDO in dMDSCs induced by T. gondii infection results in the downregulation of TGF-ß and IL-10 expression in dNK cells regulated through Kyn/AhR/SP1 signal pathway, eventually leading to the dysfunction of dNK cells and contributing the occurrence of adverse pregnancy outcomes. This study reveals a novel molecular mechanism in adverse pregnancy outcome induced by T. gondii infection.

DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice.

The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. Dor ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and Dor conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including Prr18, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in Dor-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging.

Excretory/Secretory Products from Schistosoma japonicum Eggs Alleviate Ovalbumin-Induced Allergic Airway Inflammation.

INTRODUCTION: Excretory/secretory products (ESPs) derived from helminths have been reported to effectively control allergic inflammation, which have better therapeutic prospects than live parasite infections. However, it remains unknown whether ESPs from schistosome eggs can protect against allergies, despite reports alleging that schistosome infection could alleviate disordered allergic inflammation. METHOD: In the present study, we investigated the protective effects of ESPs from Schistosoma japonicum eggs (ESP-SJE) on asthmatic inflammation. Firstly, we successfully established an allergic airway inflammation model in mice by alum-adjuvanted ovalbumin (OVA) sensitization and challenge. ESP-SJE were administered intraperitoneally on days -1 and 13 (before sensitization), on day 20 (before challenge), and on days 21-24 (challenge phase). RESULTS: The results showed that ESP-SJE treatment significantly reduced the infiltration of inflammatory cells, especially eosinophils into the lung tissue, inhibited the production of the total and OVA-specific IgE during OVA-sensitized and -challenged phases, respectively, and suppressed the secretion of Th2-type inflammatory cytokines (IL-4). Additionally, ESP-SJE treatment significantly upregulated the regulatory T cells (Tregs) in the lung tissue during OVA challenge. Furthermore, using liquid chromatography-mass spectrometry analysis and Treg induction experiments in vitro, we might identify nine potential therapeutic proteins against allergic inflammation in ESP-SJE. The targets of these candidate proteins included glutathione S-transferase, egg protein CP422 precursor, tubulin alpha-2/alpha-4 chain, actin-2, T-complex protein 1 subunit beta, histone H4, whey acidic protein core region, and molecular chaperone HtpG. CONCLUSION: Taken together, the results discussed herein demonstrated that ESP-SJE could significantly alleviate OVA-induced asthmatic inflammation in a murine model, which might be mediated by the upregulation of Treg in lung tissues that may be induced by the potential modulatory proteins. Therefore, potential proteins in ESP-SJE might be the best candidates to be tested for therapeutic application of asthma, thus pointing out to a possible new therapy for allergic airway inflammation.

LILRB4 regulates the function of decidual MDSCs via the SHP-2/STAT6 pathway during Toxoplasma gondii infection.

BACKGROUND: Toxoplasma gondii infection can cause adverse pregnancy outcomes, such as recurrent abortion, fetal growth restriction and infants with malformations, among others. Decidual myeloid-derived suppressor cells (dMDSCs) are a novel immunosuppressive cell type at the fetal-maternal interface which play an important role in sustaining normal pregnancy that is related to their high expression of the inhibitory molecule leukocyte immunoglobulin-like receptor B4 (LILRB4). It has been reported that the expression of LILRB4 is downregulated on decidual macrophages after T. gondii infection, but it remains unknown whether T. gondii infection can induce dMDSC dysfunction resulting from the change in LILRB4 expression. METHODS: LILRB4-deficient (LILRB4-/-) pregnant mice infected with T. gondii with associated adverse pregnancy outcomes, and anti-LILRB4 neutralized antibodies-treated infected human dMDSCs were used in vivo and in vitro experiments, respectively. The aim was to investigate the effect of LILRB4 expression on dMDSC dysfunction induced by T. gondii infection. RESULTS: Toxoplasma gondii infection was observed to reduce STAT3 phosphorylation, resulting in decreased LILRB4 expression on dMDSCs. The levels of the main functional molecules (arginase-1 [Arg-1], interleukin-10 [IL-10]) and main signaling molecules (phosphorylated Src-homology 2 domain-containing protein tyrosine phosphatase [p-SHP2], phosphorylated signal transducer and activator of transcription 6 [p-STAT6]) in dMDSCs were all significantly reduced in human and mouse dMDSCs due to the decrease of LILRB4 expression induced by T. gondii infection. SHP-2 was found to directly bind to STAT6 and STAT6 to bind to the promoter of the Arg-1 and IL-10 genes during T. gondii infection. CONCLUSIONS: The downregulation of LILRB4 expression on dMDSCs induced by T. gondii infection could regulate the expression of Arg-1 and IL-10 via the SHP-2/STAT6 pathway, resulting in the dysfunction of dMDSCs, which might contribute to adverse outcomes during pregnancy by T. gondii infection.