Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways.

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.

Macrophages, rather than DCs, are responsible for inflammasome activity in the GM-CSF BMDC model.

Inflammasomes are one of the most important mechanisms for innate immune defense against microbial infection but are also known to drive various inflammatory disorders via processing and release of the cytokine IL-1ß. As research into the regulation and effects of inflammasomes in disease has rapidly expanded, a variety of cell types, including dendritic cells (DCs), have been suggested to be inflammasome competent. Here we describe a major fault in the widely used DC-inflammasome model of bone marrow-derived dendritic cells (BMDCs) generated with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We found that among GM-CSF bone marrow-derived cell populations, monocyte-derived macrophages, rather than BMDCs, were responsible for inflammasome activation and IL-1ß secretion. Therefore, GM-CSF bone marrow-derived cells should not be used to draw conclusions about DC-dependent inflammasome biology, although they remain a useful tool for analysis of inflammasome responses in monocytes-macrophages.

The m6A reader SlYTH2 negatively regulates tomato fruit aroma by impeding the translation process.

N6-methyladenosine (m6A) is a fundamentally important RNA modification for gene regulation, whose function is achieved through m6A readers. However, whether and how m6A readers play regulatory roles during fruit ripening and quality formation remains unclear. Here, we characterized SlYTH2 as a tomato m6A reader protein and profiled the binding sites of SlYTH2 at the transcriptome-wide level. SlYTH2 undergoes liquid-liquid phase separation and promotes RNA-protein condensate formation. The target mRNAs of SlYTH2, namely m6A-modified SlHPL and SlCCD1B associated with volatile synthesis, are enriched in SlYTH2-induced condensates. Through polysome profiling assays and proteomic analysis, we demonstrate that knockout of SlYTH2 expedites the translation process of SlHPL and SlCCD1B, resulting in augmented production of aroma-associated volatiles. This aroma enrichment significantly increased consumer preferences for CRISPR-edited fruit over wild type. These findings shed light on the underlying mechanisms of m6A in plant RNA metabolism and provided a promising strategy to generate fruits that are more attractive to consumers.

The plastid-localized lipoamide dehydrogenase 1 is crucial for redox homeostasis, tolerance to arsenic stress and fatty acid biosynthesis in rice.

Soil contamination with arsenic (As) can cause phytotoxicity and reduce crop yield. The mechanisms of As toxicity and tolerance are not fully understood. In this study, we used a forward genetics approach to isolate a rice mutant, ahs1, that exhibits hypersensitivity to both arsenate and arsenite. Through genomic resequencing and complementation tests, we identified OsLPD1 as the causal gene, which encodes a putative lipoamide dehydrogenase. OsLPD1 was expressed in the outer cell layer of roots, root meristem cells, and in the mesophyll and vascular tissues of leaves. Subcellular localization and immunoblot analysis demonstrated that OsLPD1 is localized in the stroma of plastids. In vitro assays showed that OsLPD1 exhibited lipoamide dehydrogenase (LPD) activity, which was strongly inhibited by arsenite, but not by arsenate. The ahs1 and OsLPD1 knockout mutants exhibited significantly reduced NADH/NAD+ and GSH/GSSG ratios, along with increased levels of reactive oxygen species and greater oxidative stress in the roots compared with wild-type (WT) plants under As treatment. Additionally, loss-of-function of OsLPD1 also resulted in decreased fatty acid concentrations in rice grain. Taken together, our finding reveals that OsLPD1 plays an important role for maintaining redox homeostasis, conferring tolerance to arsenic stress, and regulating fatty acid biosynthesis in rice.

SNHG16/miR-205/HDAC5 is involved in the progression of renal fibrosis.

Renal interstitial fibrosis (RIF) represents an irreversible and progressive pathological manifestation of chronic renal disease, which ultimately leads to end-stage renal disease. Long noncoding RNAs (lncRNAs) have been suggested to be involved in the progression of RIF. Small nucleolar RNA host gene 16 (SNHG16), a member of lncRNAs, has been found to be involved in the progression of pulmonary fibrosis. This paper first researched the effect of SNHG16 on renal fibrosis. We established a unilateral ureteral obstruction (UUO)-induced mouse RIF model by ligation of the left ureter to evaluate the biological function of SNHG16 in RIF. As a result, SNHG16 was upregulated in UUO-induced renal fibrotic tissues. Knockdown of SNHG16 inhibited RIF and reduced alpha-smooth muscle actin (α-SMA), fibronectin, and college IV expression. miR-205 was a target of SNHG16, and downregulated in UUO-induced renal fibrotic tissues. Inhibition of miR-205 promoted RIF and increased the expression of α-SMA, college IV, and fibronectin. Overexpression of SNHG16 promoted the UUO-induced RIF, but miR-205 abrogated this effect of SNHG16. Histone deacetylase 5 (HDAC5) showed high expression in UUO-induced renal fibrotic tissues. Knockdown of HDAC5 significantly reduced α-SMA, fibronectin, and college IV expression in renal tissues of UUO-induced mice. Inhibition of miR-205 promoted HDAC5 expression, but knockdown of SNHG16 inhibited HDAC5 expression in renal tissues of UUO-induced mice. In conclusion, SHNG16 is highly expressed in renal fibrotic tissues of UUO-induced mice. Knockdown of SHNG16 may prevent UUO-induced RIF by indirectly upregulating HDAC5 via targeting miR-205. SHNG16 may be novel target for treating renal fibrosis.

Cancer progression and tumor hypercoagulability: a platelet perspective.

Venous thromboembolism, which is common in cancer patients and accompanies or even precedes malignant tumors, is known as cancer-related thrombosis and is an important cause of cancer- associated death. At present, the exact etiology of the elevated incidence of venous thrombosis in cancer patients remains elusive. Platelets play a crucial role in blood coagulation, which is intimately linked to the development of arterial thrombosis. Additionally, platelets contribute to tumor progression and facilitate immune evasion by tumors. Tumor cells can interact with the coagulation system through various mechanisms, such as producing hemostatic proteins, activating platelets, and directly adhering to normal cells. The relationship between platelets and malignant tumors is also significant. In this review article, we will explore these connections.

Construction and efficacy testing of DNA vaccines containing HLA-A*02:01-restricted SARS-CoV-2 T-cell epitopes predicted by immunoinformatics.

Vaccines play essential roles in the fight against the COVID-19 pandemic. The development and assessment of COVID-19 vaccines have generally focused on the induction and boosting of neutralizing antibodies targeting the SARS-CoV-2 spike (S) protein. Due to rapid and continuous variation in the S protein, such vaccines need to be regularly updated to match newly emerged dominant variants. T-cell vaccines that target MHC I- or II-restricted epitopes in both structural and non-structural viral proteins have the potential to induce broadly cross-protective and long-lasting responses. In this work, the entire proteome encoded by SARS-CoV-2 (Wuhan-hu-1) is subjected to immunoinformatics-based prediction of HLA-A*02:01-restricted epitopes. The immunogenicity of the predicted epitopes is evaluated using peripheral blood mononuclear cells from convalescent Wuhan-hu-1-infected patients. Furthermore, predicted epitopes that are conserved across major SARS-CoV-2 lineages and variants are used to construct DNA vaccines expressing multi-epitope polypeptides. Most importantly, two DNA vaccine constructs induce epitope-specific CD8 + T-cell responses in a mouse model of HLA-A*02:01 restriction and protect immunized mice from challenge with Wuhan-hu-1 virus after hACE2 transduction. These data provide candidate T-cell epitopes useful for the development of T-cell vaccines against SARS-CoV-2 and demonstrate a strategy for quick T-cell vaccine candidate development applicable to other emerging pathogens.

Astragaloside IV ameliorates peritoneal fibrosis by promoting PGC-1α to reduce apoptosis in vitro and in vivo.

Prolonged exposure of the peritoneum to high glucose dialysate leads to the development of peritoneal fibrosis (PF), and apoptosis of peritoneal mesothelial cells (PMCs) is a major cause of PF. The aim of this study is to investigate whether Astragaloside IV could protect PMCs from apoptosis and alleviate PF. PMCs and rats PF models were induced by high glucose peritoneal fluid. We examined the pathology of rat peritoneal tissue by HE staining, the thickness of rat peritoneal tissue by Masson's staining, the number of mitochondria and oxidative stress levels in peritoneal tissue by JC-1 and DHE fluorescence staining, and mitochondria-related proteins and apoptosis-related proteins such as PGC-1α, NRF1, TFAM, Caspase3, Bcl2 smad2 were measured. We used hoechst staining and flow cytometry to assess the apoptotic rate of PMCs in the PF model, and further validated the observed changes in the expressions of PGC-1α, NRF1, TFAM, Caspase3, Bcl2 smad2 in PMCs. We further incubated PMCs with MG-132 (proteasome inhibitor) and Cyclohexylamine (protein synthesis inhibitor). The results demonstrated that Astragaloside IV increased the expression of PGC-1α by reducing the ubiquitination of PGC-1α. It was further found that the protective effects of Astragaloside IV on PMCs were blocked when PGC-1α was inhibited. In conclusion, Astragaloside IV effectively alleviated PF both in vitro and in vivo, possibly by promoting PGC-1α to enhance mitochondrial synthesis to reduce apoptotic effects.

Targeting NF-κB pathway by dietary lignans in inflammation: expanding roles of gut microbiota and metabolites.

Inflammation is a major factor affecting human health. Nuclear factor-kappa B (NF-κB) plays a vital role in the development of inflammation, and the promoters of most inflammatory cytokine genes have NF-κB-binding sites. Targeting NF-κB could be an exciting route for the prevention and treatment of inflammatory diseases. As important constituents of natural plants, lignans are proved to have numerous biological functions. There are growing pieces of evidence demonstrate that lignans have the potential anti-inflammatory activities. In this work, the type, structure and source of lignans and the influence on mitigating the inflammation are systematically summarized. This review focuses on the targeting NF-κB signaling pathway in the inflammatory response by different lignans and their molecular mechanisms. Lignans also regulate gut microflora and change gut microbial metabolites, which exert novel pathway to prevent NF-κB activation. Taken together, lignans target NF-κB with various mechanisms to inhibit inflammatory cytokine expressions in the inflammatory response. It will provide a scientific theoretical basis for further research on the anti-inflammatory effects of lignans and the development of functional foods.

Surface Engineering of TiO2 Nanosheets to Boost Photocatalytic Methanol Dehydrogenation for Hydrogen Evolution.

Low-cost high-efficiency H2 evolution is indispensable for its large-scale applications in the future. In the research, we expect to build high active photocatalysts for sunlight-driven H2 production by surface engineering to adjust the work function of photocatalyst surfaces, adsorption/desorption ability of substrates and products, and reaction activation energy barrier. Single-atom Pt-doped TiO2-x nanosheets (NSs), mainly including two facets of (001) and (101), with loading of Pt nanoparticles (NPs) at their edges (Pt/TiO2-x-SAP) are successfully prepared by an oxygen vacancy-engaged synthetic strategy. According to the theoretical simulation, the implanted single-atom Pt can change the surface work function of TiO2, which benefits electron transfer, and electrons tend to gather at Pt NPs adsorbed at (101) facet-related edges of TiO2 NSs for H2 evolution. Pt/TiO2-x-SAP exhibits ultrahigh photocatalytic performance of hydrogen evolution from dry methanol with a quantum yield of 90.8% that is ∼1385 times higher than pure TiO2-x NSs upon 365 nm light irradiation. The high H2 generation rate (607 mmol gcata-1 h-1) of Pt/TiO2-x-SAP is the basis for its potential applications in the transportation field with irradiation of UV-visible light (100 mW cm-2). Finally, lower adsorption energy for HCHO on Ti sites originated from TiO2 (001) doping single-atom Pt is responsible for high selective dehydrogenation of methanol to HCHO, and H tends to favorably gather at Pt NPs on the TiO2 (101) surface to produce H2.

Exosome-sheathed ROS-responsive nanogel to improve targeted therapy in perimenopausal depression.

The development of natural membranes as coatings for nanoparticles to traverse the blood-brain barrier (BBB) presents an effective approach for treating central nervous system (CNS) disorders. In this study, we have designed a nanogel loaded with PACAP and estrogen (E2), sheathed with exosomes and responsive to reactive oxygen species (ROS), denoted as HA NGs@exosomes. The objective of this novel design is to serve as a potent drug carrier for the targeted treatment of perimenopausal depression. The efficient cellular uptake and BBB penetration of HA NGs@exosomes has been demonstrated in vitro and in vivo. Following intranasal intervention with HA NGs@exosomes, ovariectomized mice under chronic unpredictable mild stress (CUMS) have shown improved behavioral performance, indicating that HA NGs@exosomes produced a rapid-onset antidepressant effect. Moreover, HA NGs@exosomes exhibit notable antioxidant and anti-inflammatory properties and may regulate the expression of pivotal proteins in the PACAP/PAC1 pathway to promote synaptic plasticity. Our results serve as a proof-of-concept for the utility of exosome-sheathed ROS-responsive nanogel as a promising drug carrier for the treatment of perimenopausal depression.

Molecular mechanisms underlying the toxicity and detoxification of trace metals and metalloids in plants.

Plants take up a wide range of trace metals/metalloids (hereinafter referred to as trace metals) from the soil, some of which are essential but become toxic at high concentrations (e.g., Cu, Zn, Ni, Co), while others are non-essential and toxic even at relatively low concentrations (e.g., As, Cd, Cr, Pb, and Hg). Soil contamination of trace metals is an increasing problem worldwide due to intensifying human activities. Trace metal contamination can cause toxicity and growth inhibition in plants, as well as accumulation in the edible parts to levels that threatens food safety and human health. Understanding the mechanisms of trace metal toxicity and how plants respond to trace metal stress is important for improving plant growth and food safety in contaminated soils. The accumulation of excess trace metals in plants can cause oxidative stress, genotoxicity, programmed cell death, and disturbance in multiple physiological processes. Plants have evolved various strategies to detoxify trace metals through cell-wall binding, complexation, vacuolar sequestration, efflux, and translocation. Multiple signal transduction pathways and regulatory responses are involved in plants challenged with trace metal stresses. In this review, we discuss the recent progress in understanding the molecular mechanisms involved in trace metal toxicity, detoxification, and regulation, as well as strategies to enhance plant resistance to trace metal stresses and reduce toxic metal accumulation in food crops.

[Research status of Bovis Calculus and relevant Chinese patent medicines based on bibliometric analysis].

With scarce resources, natural Bovis Calculus is expensive and hard to meet clinical demand. At the moment, four kinds of Bovis Calculus are available on the market: the natural product, in vitro cultured product, synthesized product, and the product formed in cow after manual intervention. In this study, papers on the four kinds of Bovis Calculus products and relevant Chinese patent medicines were searched from Web of Science, PubMed, and China National Knowledge Infrastructure(CNKI). CiteSpace, citexs AI, and CNKI were employed for bibliometric analysis and knowledge map analysis. On this basis, the status, trend, and focuses of research on Bovis Calculus and relevant Chinese patent medicines were summarized. The results suggested overall slow development in the research on Bovis Calculus and relevant Chinese patent medicines with three typical growth stages. It is consistent with the development of Bovis Calculus substitutes and the national policy for the development of traditional Chinese medicine. At the moment, the research on Bovis Calculus and relevant Chinese patent medicines has been on the rise. In recent years, there has been an explosion of research on them, particularly the quality control of Bovis Calculus and the Chinese patent medicines, the pharmacological efficacy of Chinese patent medicines, such as Angong Niuhuang Pills, and the comparison of the quality of various Bovis Calculus products. However, there is a paucity of research on the pharmacological efficacy and the mechanism of Bovis Calculus. This medicinal and the relevant Chinese patent medicines have been studied from diverse perspectives and China becomes outstanding in this research field. However, it is still necessary to reveal the chemical composition, pharmacological efficacy, and mechanism through multi-dimensional deep research.

The role and interaction between transcription factor NAC-NOR and DNA demethylase SlDML2 in the biosynthesis of tomato fruit flavor volatiles.

Flavor-imparting volatile chemicals accumulate as fruits ripen, making major contributions to taste. The NAC transcription factor nonripening (NAC-NOR) and DNA demethylase 2 (SlDML2) are essential for tomato fruit ripening, but details of the potential roles and the relationship between these two regulators in the synthesis of volatiles are lacking. Here, we show substantial reductions in fatty acid and carotenoid-derived volatiles in tomato slnor and sldml2 mutants. An unexpected finding is the redundancy and divergence in volatile profiles, biosynthetic gene expression, and DNA methylation in slnor and sldml2 mutants relative to wild-type tomato fruit. Reduced transcript levels are accompanied by hypermethylation of promoters, including the NAC-NOR target gene lipoxygenase (SlLOXC) that is involved in fatty acid-derived volatile synthesis. Interestingly, NAC-NOR activates SlDML2 expression by directly binding to its promoter both in vitro and in vivo. Meanwhile, reduced NAC-NOR expression in the sldml2 mutant is accompanied by hypermethylation of its promoter. These results reveal a relationship between SlDML2-mediated DNA demethylation and NAC-NOR during tomato fruit ripening. In addition to providing new insights into the metabolic modulation of flavor volatiles, the outcome of our study contributes to understanding the genetics and control of fruit ripening and quality attributes in tomato.

Low-Level Cefepime Exposure Induces High-Level Resistance in Environmental Bacteria: Molecular Mechanism and Evolutionary Dynamics.

Antibiotics exert selective pressures on clinically relevant antibiotic resistance. It is critical to understand how antibiotic resistance evolves in environmental microbes exposed to subinhibitory concentrations of antibiotics and whether evolutionary dynamics and emergence of resistance are predictable. In this study, Comamonas testosteroni isolated from wastewater activated sludge were subcultured in a medium containing 10 ng/mL cefepime for 40 days (∼300 generations). Stepwise mutations were accumulated, leading to an ultimate 200-fold increase in the minimum inhibitory concentration (MIC) of cefepime. Early stage mutation in DNA polymerase-encoding gene dnaE2 played an important role in antibiotic resistance evolution. Diverse resistance mechanisms were employed and validated experimentally, including increased efflux, biofilm formation, reduced antibiotic uptake, and drug inactivation. The cefepime minimal selective concentrations (MSCs) and relative fitness of susceptible, intermediate, and resistant mutants were determined. Agent-based modeling of the modified Moran process enabled simulations of resistance evolution and predictions of the emergence time and frequency of resistant mutants. The unraveled cefepime resistance mechanisms could be employed by broader bacteria, and the newly developed model is applicable to the predictions of general resistance evolution. The improved knowledge facilitates the assessment, prediction, and mitigation of antibiotic resistance progression in antibiotic-polluted environments.

A Recognition Method of Aggressive Driving Behavior Based on Ensemble Learning.

Aggressive driving behavior (ADB) is one of the main causes of traffic accidents. The accurate recognition of ADB is the premise to timely and effectively conduct warning or intervention to the driver. There are some disadvantages, such as high miss rate and low accuracy, in the previous data-driven recognition methods of ADB, which are caused by the problems such as the improper processing of the dataset with imbalanced class distribution and one single classifier utilized. Aiming to deal with these disadvantages, an ensemble learning-based recognition method of ADB is proposed in this paper. First, the majority class in the dataset is grouped employing the self-organizing map (SOM) and then are combined with the minority class to construct multiple class balance datasets. Second, three deep learning methods, including convolutional neural networks (CNN), long short-term memory (LSTM), and gated recurrent unit (GRU), are employed to build the base classifiers for the class balance datasets. Finally, the ensemble classifiers are combined by the base classifiers according to 10 different rules, and then trained and verified using a multi-source naturalistic driving dataset acquired by the integrated experiment vehicle. The results suggest that in terms of the recognition of ADB, the ensemble learning method proposed in this research achieves better performance in accuracy, recall, and F1-score than the aforementioned typical deep learning methods. Among the ensemble classifiers, the one based on the LSTM and the Product Rule has the optimal performance, and the other one based on the LSTM and the Sum Rule has the suboptimal performance.

A gene expression signature that correlates with CD8+T cell expansion in acute Epstein-Barr virus infection.

Acute infectious mononucleosis (AIM) is associated with Epstein-Barr virus (EBV) infection. We explored molecular mechanisms regarding the expression of CD8+T cells in convalescence stage (CONV). Differentially expressed genes (DEGs) were identified by analyzing GEO expression profiles. Subsequently, Gene Set Enrichment Analysis (GSEA), Protein-Protein Interactions (PPI) network, and gene-micro RNAs networks were used to identify hub genes and associated pathways. GSEA provided evidence that the top 3 gene sets in GSEA were all related to integrins. We identified ten hub genes in the PPI network and DGIdb was applied to predict potential targets that might reverse the expression of hub genes. Our study enhances a mechanistic understanding of the CD8+T cells expansion in acute EBV infection and provides potential treatment targets for further research. Keywords: acute infectious mononucleosis; bioinformatics; CD8+T cells; differentially expressed genes; EBV.

Cadmium Inhibits Lateral Root Emergence in Rice by Disrupting OsPIN-Mediated Auxin Distribution and the Protective Effect of OsHMA3.

Cadmium (Cd) strongly inhibits root growth, especially the formation of lateral roots (LRs). The mechanism of Cd inhibition on LR formation in rice (Oryza sativa) remains unclear. In this study, we found that LR emergence in rice was inhibited significantly by 1 �M Cd and almost completely arrested by 5 �M Cd. Cd suppressed both the formation and subsequent development of the lateral root primordium (LRP). By using transgenic rice expressing the auxin response reporters DR5::GUS and DR5rev::VENUS, we found that Cd markedly reduced the auxin levels in the stele and LRP. Cd rapidly downregulated the expression of the auxin efflux transporter genes OsPIN1b, OsPIN1c and OsPIN9 in the stele and LRP. The emergence of LRs in a rice cultivar with a null allele of OsHMA3 (Heavy Metal ATPase 3) was more sensitive to Cd than cultivars with functional alleles. Overexpression of functional OsHMA3 in rice greatly alleviated the inhibitory effect of Cd, but the protective effect of OsHMA3 was abolished by the auxin polar transport inhibitor 1-N-naphthylphthalamic acid. The results suggest that Cd inhibits LR development in rice by disrupting OsPIN-mediated auxin distribution to LRP and OsHMA3 protects against Cd toxicity by sequestering Cd into the vacuoles.

Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis.

BACKGROUND: The NLRP3-mediated pyroptosis, which could be regulated by miRNA-27a, is a key player in the development of depression. Isoliquiritin is a phenolic flavonoid compound that has been demonstrated to suppress NLRP3-mediated pyroptosis. However, it is still unknown whether isoliquiritin could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by stimulating miRNA-27a. Thus, in the current study, we explored the antidepressant activity of isoliquiritin and its underlying mechanism. METHODS: Expression of miRNA-27a in depressed patients or mice was measured using qRT-PCR. Luciferase reporter assay was performed to illustrate the link between miRNA-27a and SYK. Lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) depression models were established to investigate the antidepressant actions of isoliquiritin. Changes in miRNA-27a/SYK/NF-κB axis and NLRP3-mediated pyroptosis were also examined. The role of miRNA-27a in isoliquiritin-related antidepressant effect was further investigated by using miRNA-27a inhibitors and mimics of miRNA-27a. RESULTS: Our results showed the miRNA-27a expression was downregulated in the serum of depressed patients, and decreased serum and hippocampus expression of miRNA-27a were observed in rodent models of depression. SYK gene expression was significantly reduced by miRNA-27a mimic incubation. Isoliquiritin profoundly attenuated LPS or CSDS-induced depressive symptoms, as well as CSDS-induced anxiety behavior. In the hippocampus, LPS and CSDS decreased miRNA-27a mRNA expression; increased the protein levels of SYK, p-NF-κB, and NLRP3: cleaved Caspase-1, IL-1ß, and GSDMD-N: and elevated the concentration of IL-1ß, IL-6, and TNF-α, which were all restored by isoliquiritin administration. Meanwhile, isoliquiritin upregulated the hippocampal NeuN protein level, improved the survival and morphology of neurons, and decreased pyroptosis-related neuronal cell death. Moreover, isoliquiritin protected primary microglia against LPS and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation in vitro, evidenced by declined protein levels of p-NF-κB, NLRP3; cleaved Caspase-1, IL-1ß, and GSDMD-N; upregulated miRNA-27a mRNA expression; and decreased the mRNA and protein levels of SYK. Nevertheless, miRNA-27a inhibitors significantly reversed isoliquiritin-generated therapeutic efficacy in CSDS mice and in vitro. Furthermore, the cytoprotective effect of isoliquiritin was similar to that of miRNA-27a mimics in LPS and ATP-treated primary microglia. Taken together, these findings suggest that isoliquiritin possesses potent antidepressant property, which requires miRNA-27a/SYK/NF-κB axis controlled decrease of pyroptosis via NLRP3 cascade.

A comparative investigation on the role and interaction of EsxA and EsxB in host immune response.

Staphylococcus aureus (S. aureus) is a frequent and major cause of bovine mastitis; it poses a tremendous economic burden to dairy industries of numerous countries. Early-secretion antigen-6 secretion system (ESS) has been viewed as an essential virulence and pathogenic factor of S. aureus. EsxA and EsxB are small acidic proteins secreted by ESS and identified as potential T-cell antigens of S. aureus. Unlike those of Mycobacterium tuberculosis (M. tuberculosis), the EsxA and EsxB of S. aureus do not form a dimer. Instead, EsxA dimerizes with itself or EsaC. Therefore, the interaction of EsxA and EsxB remains incompletely understood. In this study, to explore their interactions, EsxA and EsxB were expressed and used for immunization, alone or in combination, of murine infection models. Both components can interact with each other. Through the analysis of the immune response by immunological method, EsxB could significantly enhance the EsxA-specific IgG2a antibody level and increase the proliferation proportion of CD8+ T cells. These results indicate that when vaccinated with EsxA, EsxB can play a critical role in stimulating T helper 1 immunity by activating IgG2a and CD8+ T cells. We further show that vaccination with the combination of EsxA and EsxB resulted in enhanced stimulation of TLR-4 and improved protection against S. aureus. The findings may help us better understand the role of EsxB in the virulence and pathogenesis of S. aureus.