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Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by impairments in social interactions and communication, restricted interests and repetitive behaviors. Several studies report a high prevalence of gastrointestinal (GI) symptoms in autistic individuals. Cumulative evidence reveals that the gut microbiota and its metabolites (especially short-chain fatty acids, SCFAs) play an important role in GI disorders and the pathogenesis of ASD. However, the composition of the gut microbiota and its association with fecal SCFAs and GI symptoms of autistic children remain largely unknown. In the present study, we sequenced the bacterial 16S rRNA gene, detected fecal SCFAs, assessed GI symptoms and analyzed the relationship between the gut microbiome and fecal SCFAs in autistic and neurotypical individuals. The results showed that the compositions of the gut microbiota and SCFAs were altered in ASD individuals. We found lower levels of fecal acetic acid and butyrate and a higher level of fecal valeric acid in ASD subjects. We identified decreased abundances of key butyrate-producing taxa ( Ruminococcaceae, Eubacterium, Lachnospiraceae and Erysipelotrichaceae ) and an increased abundance of valeric acid associated bacteria ( Acidobacteria ) among autistic individuals. Constipation was the only GI disorder in ASD children in the present study. We also found enriched Fusobacterium , Barnesiella, Coprobacter and valeric acid-associated bacteria ( Actinomycetaceae ) and reduced butyrate-producing taxa in constipated autistic subjects. It is suggested that the gut microbiota contributes to fecal SCFAs and constipation in autism. Modulating the gut microbiota, especially butyrate-producing bacteria, could be a promising strategy in the search for alternatives for the treatment of autism spectrum disorder.

The 2020 Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for the development of the Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease9 (CRISPR/Cas9) gene editing technology that provided new tools for precise gene editing. It is possible to target any genomic locus virtually using only a complex nuclease protein with short RNA as a site-specific endonuclease. Since cancer is caused by genomic changes in tumor cells, CRISPR/Cas9 can be used in the field of cancer research to edit genomes for exploration of the mechanisms of tumorigenesis and development. In recent years, the CRISPR/Cas9 system has been increasingly used in cancer research and treatment and remarkable results have been achieved. In this review, we introduced the mechanism and development of the CRISPR/Cas9-based gene editing system. Furthermore, we summarized current applications of this technique for basic research, diagnosis and therapy of cancer. Moreover, the potential applications of CRISPR/Cas9 in new emerging hotspots of oncology research were discussed, and the challenges and future directions were highlighted.

House dust mites (HDM) are one of the important factors of airway allergic diseases, HDM allergens can be detected in the human gut mucosa, which induces local inflammation and increases intestinal epithelial permeability. This study tests a hypothesis that HDM contribute to the development of OVA (ovalbumin)-induced intestinal allergy. The serum levels of IgE against HDM in patients with food allergy were detected with UniCAP100 (Pharmacia, Uppsala, Sweden); a mouse model of food allergy was developed with OVA and HDM as the specific antigens. Compared to healthy controls, patients with food allergy have higher levels of serum HDM-specific IgE. Compared to food allergy alone groups, the levels of HDM-specific IgE in patients with food allergy and asthma or allergic rhinitis were significantly higher. In mouse models, we found that HDM/OVA induced allergy-like symptoms, lower body temperature, and lower body weight. The levels of IgE, IgG1, mMCP-1 (mouse mast cell protease-1), IL-4 and IL-5 in the HDM and HDM + CT (cholera toxin) groups were higher than the control groups, and the levels of IgE, IgG1, IL-4 and IL-5 in the HDM, OVA and HDM + OVA groups were higher than the control groups. The pathological changes of intestinal tissues in the HDM and HDM + CT/the HDM, OVA and HDM + OVA groups were more severe, more eosinophil infiltration than the control groups. Moreover, exposure to HDM induced intestinal barrier dysfunction, and facilitated the development of intestinal allergy in mice. In conclusion, HDM exposure enhances immune responses to OVA-induced food allergy.

The deregulation of immune responses is what causes food allergy (FA) to occur. FA’s cause is still unknown. The goal of this study is to investigate the mechanism how the impaired production of IL-10 occurs in peripheral naive B cells of patients with FA. Samples from patients with FA and healthy controls (HC) were used to isolate CD19 + CD45R + naive B cells from peripheral blood mononuclear cells (PBMC). Lipopolysaccharide (LPS) exposure was used to assess the expression of interleukin-10 (IL-10) in B cells. Although the FA and HC groups had similar total B cell counts, the FA patients had fewer IL-10 + B cell counts than the HC group. In peripheral B cells, the concentrations of IL-10 were inversely related to the concentrations of specific IgE, Th2 and Th1 cytokines in the serum. In patients with FA, peripheral B cells experienced impaired immune-suppressive functions. Galectin-9 could restore the defective induction of IL-10 expression in naive B cells of FA patients. In conclusion, FA patients with naive B cells experience impaired IL-10 induction. The induction of IL-10 in naive B cells of FA patients can be restored by galectin-9 treatment, which triggers B cells to differentiate into immune regulatory B cells.

Non-alcoholic fatty liver disease (NAFLD) has become a common liver disease in recent decades. No effective treatment is currently available. Probiotics and natural functional food may be promising therapeutic approaches to this disease. The present study aims to investigate the efficiency of the anthraquinone from Cassia obtusifolia L. (AC) together with cholesterol-lowering probiotics (P) to improve high-fat diet (HFD)-induced NAFLD in rat models and elucidate the underlying mechanism. Cholesterol-lowering probiotics were screened out by MRS-cholesterol broth with ammonium ferric sulfate method. Male Sprague-Dawley rats were fed with HFD and subsequently administered with AC and/or P. Lipid metabolism parameters and fat synthesis related genes in rat liver, as well as the diversity of gut microbiota were evaluated. The results demonstrated that, compared with the NAFLD rat, the serum lipid levels of treated rats were reduced effectively. Besides, cholesterol 7α-hydroxylase (CYP7A1), low density lipoprotein receptor (LDL-R) and farnesoid X receptor (FXR) were up-regulated while the expression of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR) was reduced. The expression of peroxisome proliferator activated receptor (PPAR)-α protein was significantly increased while the expression of PPAR-γ and sterol regulatory element binding protein-1c (SREBP-1c) was down-regulated. In addition, compared with HFD group, in AC, P and AC+P group, the expression of intestinal tight-junction protein occludin and zonula occluden-1 (ZO-1) were up-regulated. Furthermore, altered gut microbiota diversity after the treatment of probiotics and AC were analysed. The combination of cholesterol-lowering probiotics and AC possesses a therapeutic effect on NAFLD in rats by up-regulating CYP7A1, LDL-R, FXR mRNA and PPAR-α protein produced in the process of fat metabolism while down-regulating the expression of HMGCR, PPAR-γ and SREBP-1c, and through normalizing the intestinal dysbiosis and improving the intestinal mucosal barrier function.

Environmental pollutants are known to aggravate allergic diseases, but the molecular mechanisms by which polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) potentiate allergic airway inflammation remain poorly understood. We investigated how BaP co-exposure modifies house dust mite (HDM)-driven allergic airway responses, focusing on the role of the NLRP3 inflammasome in dendritic cells (DCs). Mice were sensitized and challenged intranasally with HDM with or without BaP. Airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL) cell counts, lung histopathology, and serum HDM-specific IgE were assessed. Cytokine production and epithelial alarmins were measured by ELISA. The role of NLRP3 was evaluated using Nlrp3 / mice, bone marrow-derived DC (BMDC) cultures, and adoptive transfer of lung DCs. T helper cell polarization was analyzed in OT-II co-culture assays. Co-exposure to BaP and HDM markedly exacerbated airway inflammation, with enhanced AHR, increased eosinophil and neutrophil infiltration, severe goblet cell hyperplasia, and elevated HDM-specific IgE. Cytokine analysis revealed synergistic induction of Th2 (IL-4, IL-5, IL-13) and Th17 (IL-17A) responses, alongside increased epithelial alarmins (TSLP, IL-33). This exacerbated phenotype was abolished in Nlrp3 / mice, which failed to produce IL-1β/IL-18 and exhibited attenuated inflammation. , BaP synergized with HDM to activate NLRP3 in BMDCs, leading to caspase-1 cleavage, IL-1β release, and enhanced CD80/CD86 expression. Adoptive transfer of BaP/HDM-exposed WT lung DCs, but not Nlrp3 / DCs, was sufficient to drive allergic airway inflammation in naïve recipients. Finally, BaP-conditioned WT DCs skewed naïve CD4 T cells toward Th2 and Th17 lineages, an effect absent in Nlrp3 / DCs. BaP amplifies allergic airway disease by activating the NLRP3 inflammasome in DCs, thereby enhancing DC maturation, cytokine release, and pathogenic Th2/Th17 polarization. These findings identify a critical mechanism linking environmental pollutants to exacerbated allergic asthma and highlight the NLRP3 inflammasome as a potential therapeutic target.

Background Nearly half of patients with recurrent pregnancy loss (RPL) link to disrupted maternal immune tolerance. IL-10-production regulatory B cells (Bregs) are functionally impaired in RPL, but the underlying mechanisms remain unclear. This study aimed to identify these mechanisms and test suberoylanilide hydroxamic acid (SAHA) as a potential therapy. Methods Peripheral Bregs were isolated from 30 RPL patients and 30 healthy controls (HCs). Epigenetic assays (chromatin immunoprecipitation for DNMT1 occupancy, methylation profiling of the IL10 promoter), ubiquitination analyses (focusing on K48-linked polyubiquitin chains), and functional co-cultures with CD3/CD28-activated effector T cells (Teffs) were performed. SAHA (0.5–5 μM) was tested after validating non-toxicity via cell viability assays. Results Compared to HCs, RPL Bregs showed significantly elevated IL10 promoter methylation (HC: 22 ± 5% vs. RPL: 48 ± 8%; p <  0.0001) and overexpression of DNA methyltransferase 1 (DNMT1), which correlated with reduced IL-10 secretion (HC: 325 ± 45 pg/mL vs. RPL: 180 ± 30 pg/mL; p <  0.001) and impaired Teff suppression (suppressive index: HC: 0.52 ± 0.08 vs. RPL: 0.21 ± 0.06; p <  0.001). DNMT1 accumulation in RPL Bregs was driven by reduced binding to the E3 ubiquitin ligase TRIM28, leading to diminished K48-linked polyubiquitination (a signal for proteasomal degradation). Treatment with SAHA restored TRIM28 expression, enhanced DNMT1 ubiquitination and degradation, reversed IL10 promoter hypermethylation, and rescued IL-10 secretion and Breg-mediated Teff suppression. These effects were abolished by TRIM28 siRNA, confirming TRIM28 dependence. Conclusion TRIM28 deficiency disrupts DNMT1 degradation, leading to DNMT1-mediated IL10 silencing and Breg dysfunction in RPL. SAHA targets the TRIM28-DNMT1-IL10 axis to restore immune tolerance, representing a precision therapy for immune-mediated RPL.

Th2 polarization is essential for the pathogenesis of allergic rhinitis (AR). Th2 polarization's mechanism requires further understanding. IL-4 is the primary cytokine involved in Th2 response. Fibroblasts play a role in immune regulation. This study aims to elucidate the role of nasal mucosal fibroblast-derived IL-4 in the induction of Th2 responses. Nasal mucosal tissues were obtained from surgically removed samples from patients with nasal polyps, whether with or without AR. Fibroblasts were isolated from the tissues by flow cytometry cell sorting, and analyzed by RNA sequencing (RNAseq). The data from RNAseq showed that nasal fibroblasts expressed genes of GATA3, CD80, CD83, CD86, STAT6, IL2, IL4, IL5, IL6, IL13 and costimulatory factor. The data were verified by RT-qPCR. The level of gene activity was positively correlated with those of AR-related cytokines present in nasal secretions. Nasal fibroblasts release IL-4 upon activation. Nasal fibroblasts had the ability to transform naive CD4+ T cells into Th2 cells, which can be eliminated by inhibiting IL-4 receptor or CD28 in CD4+ T cells. To sum up, nasal mucosal fibroblasts produce IL-4, which can induce Th2 cell development. The data implicate that nasal fibroblasts are involved in the pathogenesis of nasal allergy.

Allergic airway inflammation, characterized by Th2 cytokine production and eosinophilic infiltration, is a hallmark of asthma. The airway epithelium plays a pivotal role in orchestrating allergic responses by releasing cytokines such as oncostatin M (OSM). This study investigates the role of OSM in dust mite extract (DME)-induced allergic airway inflammation and identifies a novel mechanism by which OSM drives Th2-polarized inflammation. A murine model of DME-induced airway inflammation was established. Mice were treated with CelEd, a nanoparticle carrying fibroblast-targeting device and ATF4 siRNA. We observed that DME exposure significantly upregulates OSM expression in airway epithelial cells, both at the mRNA and protein levels. This finding was corroborated in human bronchial epithelial cell lines, where DME exposure induced dose-dependent OSM secretion. Intranasal administration of OSM in naïve mice phenocopied the hallmark features of allergic inflammation, including eosinophilic infiltration and elevated Th2 cytokines, highlighting OSM's sufficiency to drive allergic responses. Mechanistically, we discovered that OSM promotes IL-4 production through fibroblast reprogramming, involving endoplasmic reticulum stress (ERS) activation. OSM signaling in fibroblasts led to ERS and subsequent activation of the PERK-eIF2α-ATF4 pathway, which drives IL-4 transcription via the ATF4/Mef2d/GATA3 axis. Importantly, targeting this pathway through fibroblast-specific ATF4 knockdown significantly alleviated allergic pathology, including airway eosinophilia, Th2 cytokine production, and airway hyperresponsiveness. These findings underscore the critical role of OSM in allergic airway inflammation and identify the OSM-ERS-IL-4 axis as a potential therapeutic target for asthma and other allergic diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.