Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), due to their inner functional substances, have shown great value in treating acute myocardial infarction (AMI). However, their clinical application is limited by a low yield. In the present study, we cultured EVs using a hollow fiber bioreactor-based three-dimensional (3D) system, and assessed their therapeutic effectiveness on AMI. The MSCs separated from fresh human umbilical cord were planted into the flasks of two systems: two-dimensional (2D) culture and hollow-fiber-bioreactor based 3D culture. EVs were extracted from the culture supernatants. Characteristics and yields of EVs from two culture systems, namely 2D-EVs and 3D-EVs, were compared. A rat model of AMI was built up to assess their therapeutic efficacy on AMI. The yield of 3D-EVs was higher, with biofunctions similar to those of 2D-EVs. 3D-EVs repressed the apoptosis of cardiomyocytes, facilitated angiogenesis, and regulated the transition of macrophage subpopulations after myocardial infarction, and eventually improved cardiac function in the AMI rats. The hollow fiber 3D culture system can increase the yield of MSCs-derived EVs to render a strong cardioprotective effect in AMI rats.

Collagen type X alpha 1 (COL10A1) is a member of the collagen family and the main matrix component. However, COL10A1 expression and prognosis relationship remains unclear in gastric cancer (GC). Through the analysis of database of Oncomine, the Cancer Genome Atlas (TCGA) as well as the Gene Expression Omnibus (GEO), in contrast to the tissue of normal gastric, COL10A1 in gastric cancer, had been upregulated. The high expression of COL10A1 was obviously related to T stage (P = 0.025) and lymph node metastasis (P = 0.025). It has been illustrated by the analysis of logistic regression that COL10A1’s heightened expression in gastric cancer had been essentially linked with pathological stage, tumor differentiation, and T classification. The Kaplan–Meier curve in the Kaplan-Meier plotter database (P = 0.0371) and GSE84437 (P = 0.002) indicate that patients with high COL10A1 expression possess poor prognosis, specifically GC patients with lymph node metastasis have it. TCGA’s Multivariate analysis (P = 0.025) and GSE84437 dataset (P = 0.034) show that high expression COL10A1 is a key independent predictor of poor overall survival. Searching KEGG pathway enrichment by GSEA, the results suggested that 29 pathways were enriched. qRT-PCR technique was used for verification of the COL10A1’s high expression in gastric cancer in contrast to the normal gastric tissues. In conclusion, COL10A1 is of great importance in predicting the survival rate of GC patients. Graphical abstract

Background: Characterized by the presence of inflammation, fibrosis, and bile duct proliferation, cholestatic liver disease (CLD) affects people of all age groups. Takeda G-protein-coupled receptor (TGR5) has been implicated in the suppression of inflammation via toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB). Kupffer cells and their M1 polarization play important roles in inflammation and cholestatic liver injury via production of pro-inflammatory cytokines. Nevertheless, the function of TGR5 signaling in CLD is largely unknown. Methods: We conducted liver tissue experiments, animal experiments, serum marker testing, liver histology analysis, Kupffer cell experiments, RNA extraction and Real-time PCR, western blotting, evaluation of ROS production by flow cytometry and statistical differences were analyzed by student t-test using GraphPad Prism. Results: We found that serum bile acid (BA) and TGR5 levels were elevated in patients with cholestasis cirrhosis. Knockout of TGR5 in animals significantly increased bile duct ligation (BDL)-caused liver injury through increasing oxidative stress, promoting M1-predominant polarization of Kupffer cells, and elevating the serum levels of inflammatory cytokines. In contrast, TGR5 activation inhibited ROS production, secretion of pro-inflammatory cytokines, and M1-predominant polarization of Kupffer cells. Moreover, results showed that TGR5 exerted its effects via suppressing NF-κB signaling and activating nuclear factor 2 (Nrf2)/HO-1 signaling. Finally, the effect of TGR5 on cholestatic liver damage was also confirmed in vivo. Conclusions: TGR5 activation protected against BDL-induced CLD by both suppressing inflammation via inhibiting the NF-κB pathway and reducing ROS production via activation of Nrf2/HO-1 signaling. These findings show the importance of TGR5 in CLD and provide new insight into therapeutic strategies for CLD.

Background: The roles of circRNA and N6‐methyladenosine (m⁶A) methylation in Crohn's disease (CD) have drawn much attention. Therefore, this investigation aimed to discover how the m⁶A modification of circRNAs contributes to CD progression.Methods: The study performed circRNA sequencing on colon samples from four CD patients and four normal controls (NCs) to screen for dysregulated circRNAs. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was performed to validate the candidate circRNA expression and determine its correlation to CD‐associated inflammatory indicators. In vivo and in vitro investigations were conducted to examine the functions and pathways of circPRKAR1B in CD, besides investigating the m⁶A modification role in circRNA expression modulation.Results: The RNA‐seq revealed that hsa_circ_0008039 (circPRKAR1B) was the most significant upregulated circRNA and was identified as the candidate circRNA for further examinations. Relative circPRKAR1B expression was significantly upregulated in CD colon tissues and closely related to CD‐associated inflammatory indices. The circPRKAR1B expression and function were regulated by methyltransferase‐like 3 (METTL3)‐mediated m⁶A methylation. In vitro studies indicated that circPRKAR1B promoted pyroptosis mediated by NLRP3 inflammasome (NLRP3; nucleotide‐binding oligomerization domain, leucine‐rich repeat and pyrin domain‐containing 3) and impaired autophagy by interacting with the RNA‐binding protein (RBP) SPTBN1, (SPTBN1; spectrin beta, non‐erythrocytic 1). The in vivo investigations revealed the treatment effects of si‐circPRKAR1B and si‐METTL3 in colitis models of IL‐10‐deficient mice.Conclusion: Our study reveals that METTL3‐mediated m⁶A modification of circPRKAR1B promotes Crohn's colitis by aggravating NLRP3 inflammasome‐mediated pyroptosis via autophagy impairment in colonic epithelial cells.

Colorectal cancer (CRC) is one of the most mortal cancers in the world. Multiple factors and bio-processes are associated with in tumorigenesis and metastasis of CRC, including cellular senescence and immune evasion. This study aims to identify prognostic and immune-meditating effects of INHBA in CRC. Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database to screen the differentially expressed genes (DEGs) in senescent cells and CRC tissues from the Cancer Genome Atlas (TCGA). Key factor was settled from the alternative DEGs set. Enrichment analyses and functional networks prediction were determined from online databases. Correlation analyses were performed to reveal the association among key factor, immune infiltration, T cell biomarkers and immune checkpoints. Moreover, expressions of key factors and immune checkpoints of tissue and blood samples from CRC patients as well as human CRC cell lines were measured. Results showed that Inhibin beta A (INHBA) was sorted out as a senescence-related factor and a prognostic predictor in CRC. What's more, INHBA was found highly co-expressed with T-cell biomarkers and immune checkpoints. In conclusion, INHBA was considered as a senescence-related regulator and a prognostic predictor in CRC, which also mediating immune evasion.