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Additional file 3: Table S2. miR-125b-5p predicted targets from miRWalk.

Additional file 4: Table S1. Primers used in the present study.

Additional file 1: Figure S1. Cell distribution of BALF of in PBS or Der f1-treated mice; Figure S2. Full length blot for Figure 5D.

Additional file 2: Table S1. miR-125b-5p predicted targets from ENCORI.

Additional file 4: Fig. S2. The LINC01003/CAV1 axis regulates glioma in vitro and in vivo.A transwell assay was employed to determine the migration ability of U87MG cells. The migrating glioma cells were counted.Western blot was used to detect the expression levels of p-FAK in U87MG cells.An xenograft tumor model was generated by U87MG cells. The tumor volume and weight in nude mice were measured. Data represent the mean ± SD; * P < 0.05, ** P < 0.01, and ***P < 0.001.

Additional file 4: Table S3. lncRNA target miR-125b-5p.

Additional file 6: Fig. S3. The relationship between m6A enzymes with LINC01003.m6A enzymes may perturb the expression of LINC01003.The correlation between m6A enzymes with LINC01003 in glioma tissues from the GEPIA2 database.

Additional file 3: Fig. S1. CAV1 is upregulated in glioma tissues and cells.The expression of CAV1 in GBM, LGG, and normal brain tissues from the Gene Expression Profiling Interactive Analysis 2database.The expression of CAV1 in World Health Organizationgrade II–IV tumors from the Chinese Glioma Genome Atlasdatabase. Kaplan–Meier curves from theGEPIA2 orCGGA database determined the relevance between CAV1 expression and overall survival in each subtype or each grade of glioma patients.RT-qPCR was used to detect the expression level of CAV1 in U87MG and U251 cells with LINC01003 knockdown. * P < 0.05, ** P < 0.01, and ***P < 0.001.

Phosphorylation of the eukaryotic translation initiation factor 2 α-subunit (eIF2ɑ)，which subsequently upregulates activating transcription factor 4 (ATF4), is the core event in the integrated stress response (ISR) pathway. Previous studies indicate phosphorylation of eIF2ɑ in atrial tissue in response to atrial fibrillation (AF). This study investigated the role of ISR pathway in experimental AF by using a small-molecule ISR inhibitor (ISRIB). Accordingly, rats were subjected to coronary artery occlusion to induce myocardial infarction (MI), or sham operation, and received either trans-ISRIB (2 mg/kg/day, i.p.) or vehicle for seven days. Thereafter, animals were subjected to the AF inducibility test by transesophageal rapid burst pacing followed by procurement of left atrium (LA) for assessment of atrial fibrosis, inflammatory indices, autophagy-related proteins, ISR activation, ion channel, and connexin43 expression. Results showed a significant increase in the AF vulnerability and the activation of ISR in LA as evidenced by enhanced eIF2α phosphorylation. ISRIB treatment suppressed upregulation of ATF4, fibrosis as indexed by determination of α-smooth muscle actin and collagen levels, inflammatory macrophage infiltration (i.e., CD68 and iNOS/CD68-positive macrophage) and autophagy as determined by expression of LC3. Further, ISRIB treatment reversed the expression of relevant ion channel (i.e., Nav1.5, Cav1.2, and Kv4.3) and Cx43 remodeling. Collectively, the results suggest that the ISR is a key pathway in pathogenesis of AF, post-MI, and represents a novel target for treatment of AF. Significance Statement Activation of integrated stress response (ISR) pathway as evidenced by enhanced eIF2α phosphorylation in left atrium plays a key role in atrial fibrillation (AF). A small-molecule ISR inhibitor (ISRIB) reduces AF and atrial arrhythmogenic substrate. The mechanism of ISRIB may be mediated by suppressing ISR pathway-related cardiac fibrosis, inflammatory macrophage infiltration, autophagy, and restoring the expression of ion channel and Cx43. This study suggests a key dysfunctional role for ISR in pathogenesis of AF with implications for novel treatment.

BackgroundCrohn’s disease (CD) is characterized by repetitive phases of remission and exacerbation, the quality of life of patients with CD is strongly influenced by disease activity, as patients in the active phase experience significantly worse symptoms. To investigate the underlying mechanism of how the course of CD is exacerbated based on the bi-directionality of the brain-gut axis (BGA), we conducted a multi-modality neuroimaging study that combined resting-state functional magnetic resonance imaging (rs-fMRI) with proton magnetic resonance spectroscopy (MRS) to detect abnormalities in the anterior cingulate cortex (ACC).Materials and MethodsClinical scales including Visual Analog Scale (VAS) and Hospital Anxiety and Depression Scale (HADS) were used to evaluate the degree of abdominal pain and mood state of participants. We made a comparison between CD patients in the active phase, the remission phase and healthy controls (HCs), not only employed the innovative wavelet-transform to analyze the amplitude of low frequency fluctuation (ALFF) but also compared the sensitivity of wavelet-transform and the traditional fast Fourier transform (FFT). Brain metabolites such as glutamate (Glu), myo-inositol (mIns) and gamma-aminobutyric acid (GABA) were also detected. Then correlation analysis was made to see whether changes in the ACC correlated with CD’s clinical symptoms.ResultsCD patients in the active phase showed higher VAS scores (p = 0.025), the scores of anxiety and depression were also higher (all p < 0.05). Wavelet-transform is slightly more sensitive in the current research. Patients in the active phase exhibited higher ALFF in the left ACC and the left superior frontal gyrus, medial (SFGmed). Patients in the active phase showed increased Glu levels in the ACC than patients in the remission phase or HCs (p = 0.039 and 0.034 respectively) and lower levels of mIns than HCs (p = 0.036). There was a positive correlation between mWavelet-ALFF values of the ACC and HADS-depression scores in CD patients (r = 0.462, p = 0.006). Besides, concentrations of Glu positively correlated with mWavelet-ALFF in the ACC in all participants (r = 0.367, p = 0.006).ConclusionAbnormal spontaneous activity and metabolic levels in the ACC were detected in CD patients in the active phase along with severer abdominal pain and worse mood state, these may contribute to the exacerbation of CD. Therefore, the ACC might be a potential neural alternative for managing the exacerbation of CD.