Lung cancer accounts for the large majority of cancer incidence and mortality worldwide for decades. The dysbiotic microbiome and its metabolite secretions in the gut have been regarded as the dominant biological factors in oncogenesis, development, and progression, adding probiotic components of which have come to be potential therapeutic regimes. However, there still exists little knowledge about whether probiotic microorganisms in lower airways inhibit lung cancer by lung microenvironment remodulation. In this study, we performed bioinformatics analysis from previous sequencing data and specific microbiome databases to identify the potent protective microbes in lower airways, followed by bacterial cultivation and morphological verifications in vitro. We found that Paenibacillus odorifer was correlated closely with the anti-tumorous by-product acetic acid in lower respiratory tract. Additionally, the enrichment of this microorganism in the health, rather than in lung neoplasms from public data sets, further confirmed its protective activity in preserving pulmonary homeostasis. Colony cultivation of this strain and targeted metabolite analysis indicated that Paenibacillus odorifer proliferation was weakened at 37°C but lasted longer than it did at the optimal temperature. And performing as a candidate origin of acetic acid, this strain was liable to inhibit the growth of lung cancer cells in time- and dose-dependent approaches which was validated by colony formation assays. These results suggested that Paenibacillus odorifer functions as a candidate probiotic in lower airways to restrict lung cancer cell growth by releasing protective molecules, indicating a potential preventive microbial strategy.IMPORTANCEVarious types of microorganisms in lower respiratory tracts protect local homeostasis against oncogenesis. Although extensive efforts engaged in gut microbiome-mediated pulmonary carcinogenesis, emerging evidence suggested the crucial role of microbial metabolites from respiratory tracts in modulating carcinogenesis-related host inflammation and DNA damage in lung cancer, which was still not fully understood in lower respiratory tract microbes and its metabolite-mediated microecological environment homeostasis in preventing or alleviating lung cancer. In this study, we analyzed the lower respiratory tract microbiome and SCFAs expression among different lung segments from the same participants, further identifying that Paenibacillus odorifer was correlated closely with anti-tumorous by-product, acetate acid in lower respiratory tract by multi-omics analysis. And previous experiments showed this strain could inhibit the growth of lung cancer cells in vitro. These findings indicated that Paenibacillus odorifer in lower respiratory tracts might perform as a candidate probiotic against lung carcinogenesis by releasing protective factor acetate, which further presented a promising diagnostic and interventional approach in clinical settings of lung cancer.

Abstract LncRNAs take extensive effects in immune cells to mediate various autoimmune diseases. However, its potential role in development of SLE remains uncertain. We screened out candidate lncRNA in exosomes from SLE patients and the healthy, and was further validated in mouse model by histological examinations in vivo. Additional morphological verification was exploited to validate its biological functions by construction of plasmids in vitro. H19 in serum exosomes of patients was escalated, and could also promote the proliferation and migration of macrophages. Additionally, H19 mainly recruited miR-145-5p and promotes the expression of downstream targeted protein PAI-1. It further promoted the release of SLE-associated proinflammatory factors via Jak2-STAT3 axis, and in turn facilitated the polarization of M1 macrophages. Our study uncovered a potential mechanism of lncRNA H19 in mediating macrophage polarization and leading to the release of proinflammatory factors, providing a new intervention target for treating SLE.

Objective To investigate the role of long non-coding RNA (lncRNA) RP11-288L9.1 in systemic lupus erythematosus (SLE) and its potential mechanism. Methods Transcriptome sequencing (RNA-seq) was used to screen the differentially expressed lncRNAs in peripheral blood mononuclear cells (PBMCs) of SLE patients, and the expression levels of these lncRNAs in 8 pairs of SLE patients and healthy controls were further verified by qRT-PCR. The knockdown as well as over-expression models of RP11-288L9.1 were constructed respectively by transfecting recombinant lentivirus into macrophages, and the transfection efficiency was determined subsequently. The subcellular distribution of RP11-288L9.1 was detected by fluorescence in situ hybridization (FISH) technique. Moreover, CCK-8 assay and Annexin V-FITC apoptosis detection kit were applied to examine the proliferation and apoptosis of macrophages in both models, and qRT-PCR was conducted to detect the expression of macrophage-related inflammatory cytokines, IL-1β, IL-6, IL-4, IL-10 and TGF-β1 after the transfection. Results Six differentially expressed lncRNAs were found (P < 0.05), in which RP11-288L9.1 was significantly up-regulated (P < 0.01), and mainly located in the cytoplasm of macrophages. The over-expression of RP11-288L9.1 promoted the apoptosis and inhibited the proliferation of macrophages (P < 0.05), increasing the levels of IL-1β and IL-6, and decreasing those of IL-4, IL-10 and TGF-β1 (P < 0.01). In contrast, the knockdown of RP11-288L9.1 significantly induced the proliferation of macrophages and inhibited the apoptosis (P < 0.05), with lowered levels of IL-1β and IL-6 and elevated IL-4, IL-10 and TGF-β1 (P < 0.01). Conclusion RP11-288L9.1 is highly expressed in the PBMCs of SLE patients, and regulates immune response in macrophages by affecting the synthesis of inflammatory cytokines, which may contribute to the occurrence of SLE.

Purpose:Systemic lupus erythematosus (SLE) is a serious autoimmune disease. Its molecular pathogenesis, especially the long non-coding RNA (lncRNA) function, remains unclear. We want to investigate the lncRNA dysregulation profile and their molecular mechanisms in SLE.Methods:In this study, we analyzed the transcriptome profiles (RNA-seq) of peripheral blood mononuclear cells (PBMCs) from SLE patients and two published transcriptome datasets to explore lncRNA profiles. The differentially expressed lncRNAs were confirmed by quantitative real-time PCR in another set of female patients. We constructed the lncRNA-mRNA regulatory networks by performing weighted gene co-expression network analysis (WGCNA). Dysregulated lncRNA AC007278.2 was repressed by short hairpin RNA (shRNA) in Jurkat cells. Dual-luciferase reporter gene assay was performed to investigate the regulatory mechanism of AC007278.2 on target gene CCR7.Results:We observed dominant up-regulation of transcripts, including mRNAs and lncRNAs, in SLE patients. By WGCNA method, we identified three modules that were highly related to SLE. We then focused on one lncRNA, AC007278.2, with a T-helper 1 lineage-specific expression pattern. We observed consistently higher AC007278.2 expression in SLE patients. Co-expression network revealed that AC007278.2 participated in the innate immune response and inflammatory bowel disease pathways. By knocking down AC007278.2 expression, we found that AC007278.2 could regulate the expression of inflammatory and cytokine stimulus response-related genes, including CCR7, AZU1, and TNIP3. AC007278.2 inhibits the functional CCR7 promoter to repress its transcription, thereby regulating autoimmunity and follicular T-helper cell differentiation.Conclusion:In summary, our study indicated the important regulatory role of lncRNAs in SLE. AC007278.2 may be treated as a novel biomarker for SLE diagnosis and treatment.

目的:使用生物信息学方法鉴定干燥综合征(SS)的关键差异表达基因(DEGs).方法:从基因数据库中下载GSE23117和GSE127952的基因表达谱,用GEO2R在线工具和Venn软件筛选出其中的DEGs.通过DAVID网站进行GO和KEGG分析.使用STRING工具建立蛋白质-蛋白质相互作用(PPI)网络,用Cytoscape软件进行模块分析.结果:在SS标本中总共检测到31个DEGs重叠区域.其中28个上调基因和3个下调基因主要在免疫炎症中起作用.KEGG分析显示DEGs与细胞因子-细胞因子受体相互作用、趋化因子信号通路、阿米巴病和白细胞跨内皮迁移有关.PPI和模块分析显示CXCL9、CXCL11、CXCL13、CCR1、CD69、PTPRC、GPR183、MMP9和IL-10基因显著富集.结论:CXCL9、CXCL11、CXCL13、CCR1、CD69、PTPRC、GPR183、MMP9和IL-10可能与SS的发生和进展有关.

49岁男性患者,胸背部皮损1年余.皮肤科情况:颈部、胸部、背部、双前臂可见片状红斑、瘀点、瘀斑,伴轻度糜烂.组织病理:真皮内可见团块状淀粉样物质沉积,部分围绕在毛囊及血管周围.刚果红染色阳性.骨髓穿刺:多发性骨髓瘤.诊断:原发性系统性淀粉样变病.