MicroRNAs (miRNAs) are small non-coding RNAs, 18–23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications.

https://gut.bmj.com/content/gutjnl/64/3/504.full.pdf

MicroRNAs: new players in IBD

Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies.

/pdf/the-emerging-role-of-mirnas-in-inflammatory-bowel-disease-a-2iqdphf1to.pdf

The emerging role of miRNAs in inflammatory bowel disease: a review

Acting as inflammatory mediators, tumor oncogenes or suppressors, microRNAs are involved in cell survival, death, epithelial–mesenchymal transition and metastasis, etc. Investigating the communication between microRNAs and tumorigenesis is critical to our understanding of the pathogenesis of multiple disease states. Currently, colorectal carcinoma (CRC), one of the most common malignancies worldwide, has a poor prognosis due to lack of an effective therapeutic option. Increasing evidence has identified altered profiles and regulatory potential of microRNAs in conditions related to environmentally-caused colorectal inflammation and colitis-associated cancer. Many studies have shed light on a more thorough understanding of the function and distribution of microRNAs in CRC initiation and emergence. However, the molecular mechanisms by which microRNAs modulate cellular processes still need to be further elucidated and may offer a foundation for evaluating microRNA-based therapeutic potential for CRC in both animal models and clinical trials. In this review, the roles and mechanisms of microRNAs involved in CRC from pathogenesis to therapy are summarized and discussed, which may provide more useful hints for CRC prevention and therapy.

/pdf/micrornas-in-colorectal-carcinoma-from-pathogenesis-to-3io4naca1n.pdf

MicroRNAs in colorectal carcinoma--from pathogenesis to therapy.

The last decade has seen tremendous success in identifying genetic loci associated with inherited susceptibility to Crohn's diesease (CD), with 140 loci identified in the most recent GWAS meta-analysis.1 However, these determinants collectively explain only an estimated 13.6%1 of disease variability, and the biological variation each confers is unclear. The importance of noninherited factors in pathogenesis has been highlighted by studies on the increasing incidence of CD, especially in children,2,3 and in the developing world,4,5 and by a greater understanding of the effects of gut microbiota and diet on risk.6,7 A critical objective for CD research is to characterize the interaction between genetic and environmental factors.

Epigenetic alteration has emerged as a potential mechanism through which these interactions may occur.8 Developments allowing rapid assaying of cytosine methylation at nearly 5 × 105 positions, and insights into confounding effects in study design9 have provided the impetus to build on promising pilot data from previous generation technology to allow epigenome-wide association studies (EWAS) to become a valuable complement to the more mature GWAS.10 Epigenome mapping has been used to identify DNA regulatory elements, explore cancer biology, and provide a growing body of findings in complex diseases, such as rheumatoid arthritis,11 multiple sclerosis,12 type 2 diabetes, and obesity.13,14

Although the relationship between methylation and gene expression and function is incompletely understood, relevant modifying influences include age, ethnicity, smoking, gut microbiota, and diet.15–18 DNA-binding factors can directly influence methylation, and in turn, altering methylation can directly influence expression.19,20 We hypothesized that identification of altered levels of methylation, which are significantly associated with disease state, whether predating or following disease, offers the potential for discovering new pathways integral to the disease process and for predicting disease status.

/pdf/two-stage-genome-wide-methylation-profiling-in-childhood-1157tpqttp.pdf

Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci.

Inflammatory bowel disease (IBD) is believed to develop via a complex interaction between genetic, environmental factors and the mucosal immune system. Crohn’s disease and ulcerative colitis are two major clinical forms of IBD. MicroRNAs (miRNAs) are a class of small, endogenous, noncoding RNA molecules, and evolutionary conserved in animals and plants. It controls protein production at the post-transcriptional level by targeting mRNAs for translational repression or degradation. MiRNAs are important in many biological processes, such as signal transduction, cellular proliferation, differentiation and apoptosis. Considerable attention has been paid on the key role of miRNAs in autoimmune and inflammatory disease, especially IBD. Recent studies have identified altered miRNA profiles in ulcerative colitis, Crohn’s disease and inflammatory bowel disease-associated colorectal cancer. In addition, emerging data have implicated that special miRNAs which suppress functional targets play a critical role in regulating key pathogenic mechanism in IBD. MiRNAs were found involving in regulation of nuclear transcription factor kappa B pathway (e.g., miR-146a, miR-146b, miR-122, miR-132, miR-126), intestinal epithelial barrier function (e.g., miR-21, miR-150, miR-200b) and the autophagic activity (e.g., miR-30c, miR-130a, miR-106b, miR-93, miR-196). This review aims at discussing recent advances in our understanding of miRNAs in IBD pathogenesis, their role as disease biomarkers, and perspective for future investigation and clinical application.

Implication of miRNAs for inflammatory bowel disease treatment: Systematic review.

miR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn's disease.

Staphylococcus aureus represents a notorious opportunistic pathogen causing various infections in biofilm nature, imposing remarkable therapeutic challenges worldwide. The catabolite control protein A (CcpA), a major regulator of carbon catabolite repression (CCR), has been recognized to modulate S. aureus biofilm formation, while the underlying mechanism remains to be fully elucidated. In this study, the reduced biofilm was firstly determined in the ccpA deletion mutant of S. aureus clinical isolate XN108 using both crystal violet staining and confocal laser scanning microscopy. RNA-seq analysis suggested that sak-encoding staphylokinase (Sak) was significantly upregulated in the mutant ∆ccpA, which was further confirmed by RT-qPCR. Consistently, the induced Sak production correlated the elevated promoter activity of sak and increased secretion in the supernatants, as demonstrated by Psak-lacZ reporter fusion expression and chromogenic detection, respectively. Notably, electrophoretic mobility shift assays showed that purified recombinant protein CcpA binds directly to the promoter region of sak, suggesting the direct negative control of sak expression by CcpA. Double isogenic deletion of ccpA and sak restored biofilm formation for mutant ∆ccpA, which could be diminished by trans-complemented sak. Furthermore, the exogenous addition of recombinant Sak inhibited biofilm formation for XN108 in a dose-dependent manner. Together, this study delineates a novel model of CcpA-controlled S. aureus biofilm through direct inhibition of sak expression, highlighting the multifaceted roles and multiple networks regulated by CcpA.

/pdf/ccpa-regulates-staphylococcus-aureus-biofilm-formation-cojyv0mx.pdf

CcpA Regulates Staphylococcus aureus Biofilm Formation through Direct Repression of Staphylokinase Expression

Background The association between the risk of heart disease and tobacco smoking has been studied in previous work, but there are arguments among various population. We aimed to investigate the association between heart disease incidence and smoking status among older adults. Methods A cross-sectional analysis was conducted with 10,891 older adults in the 2 most recent waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), 2011–2014 and 2014–2018. The data included individual weighting variables to ensure they were nationally representative. The parameters consisted of age, sex, body mass index (BMI), smoking status, and disease history was collected. Smoking measures included current/former/never status, pack-years and the time to first cigarette. Heart disease included coronary artery disease, arrhythmias, heart failure, valve diseases and other heart conditions. Respondents with missed values were excluded. Multivariable logistic regression analyses were performed. Results Among the 10,006 respondents included in the analyses, 4,501 (44.9%) were men. The median age was 88 years old [interquartile range (IQR), 78–96]. A total of 6,713 respondents (67.1%) were nonsmokers, 1,695 respondents (16.9%) were former smokers, and 1,598 respondents (16.0%) were current smokers. The incidence of heart disease was significantly higher in smokers compared with nonsmokers (14.5% vs. 12.8%, P=0.018). Female smokers and those over 80 years old had higher morbidity than male smokers. After adjusting for sex, age, BMI, hypertension, diabetes, area of residency, alcohol status, and exercise status, smokers still had an increased risk of heart disease [odds ratio (OR) 1.29, 95% confidential interval (CI): 1.10–1.50, P=0.001]. The incidence of heart disease also increased with higher intensity of smoking for each additional pack-year (OR 1.01, 95% CI: 1.00–1.02, P=0.011). Conclusions For elderly adults, current or former smoking was largely associated with heart disease incidence, especially in females and those over 80 years old. These variables could be considered for inclusion in future heart disease risk prediction models.

https://atm.amegroups.com/article/viewFile/108174/pdf

Association between tobacco smoking and heart disease in older adults: a cross-sectional study based on the Chinese Longitudinal Healthy Longevity Survey

Burkholderia pseudomallei is the causal agent of melioidosis, a deadly tropical infectious disease that lacks a vaccine. On the basis of the attenuated Staphylococcus aureus RN4220-Δagr (RN), we engineered the RN4220-Δagr/pdhB-hcp1 strain (RN-Hcp1) to generate B. pseudomallei hemolysin-coregulated protein 1 (Hcp1)-loaded membrane vesicles (hcp1MVs). The immunization of BALB/c mice with hcp1MVs mixed with adjuvant by a three-dose regimen increased the serum specific IgG production. The serum levels of inflammatory factors, including TNF-α and IL-6, in hcp1MV-vaccinated mice were comparable with those in PBS-challenged mice. The partial adjuvant effect of staphylococcal MVs was observed with the elevation of specific antibody titer in hcp1MV-vaccinated mice relative to those that received the recombinant Hcp1 protein (rHcp1) or MVs derived from RN strain (ΔagrMVs). The hcp1MVs/adjuvant vaccine protected 70% of mice from lethal B. pseudomallei challenge. Immunization with hcp1MVs only protected 60% of mice, whereas vaccination with rHcp1 or ΔagrMVs conferred no protection. Moreover, mice that received hcp1MVs/adjuvant and hcp1MVs immunization had low serum TNF-α and IL-6 levels and no inflammatory infiltration in comparison with other groups. In addition, all surviving mice in hcp1MVs/adjuvant and hcp1MVs groups exhibited no culturable bacteria in their lungs, livers, and spleens five days postinfection. Overall, our data highlighted a new strategy for developing B. pseudomallei vaccine and showed that Hcp1-incorporated staphylococcal MV is a promising candidate for the prevention of acute melioidosis.

/pdf/hcp1-loaded-staphylococcal-membrane-vesicle-vaccine-protects-2sl94yyg.pdf

Mingxia Zheng

Papers

miR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn's disease.

CcpA Regulates Staphylococcus aureus Biofilm Formation through Direct Repression of Staphylokinase Expression

Association between tobacco smoking and heart disease in older adults: a cross-sectional study based on the Chinese Longitudinal Healthy Longevity Survey

Hcp1-loaded staphylococcal membrane vesicle vaccine protects against acute melioidosis