HSCs-derived exosomes regulate the levels of inflammatory cytokines in HIBECs through miR-122-5p mediated p38 MAPK signaling pathway.

PBC is an autoimmune-mediated liver disease, and intrahepatic biliary epithelial cells (IBECs) are the target cells of early damage. Previous studies found that miRNAs and inflammation is closely related to PBC. In this study, we extracted exosomes from serum and human IBECs supernatant, and RNA-sequence analyzed the expression profiles of miRNAs. Elisa measured the levels of inflammatory cytokines. RT- qPCR and western blot detected the levels of miR-122-5p, p38 and p-p38. The results showed that 263 differentially expressed (DE) miRNAs were identified in serum exosomes of PBC patients. The levels of IL-1ß, IL-6, IL-12, IL-17 A, IFN-γ, TNF-α and TGF-ß1 in peripheral blood of PBC patients were higher than those of normal controls. According to the validation results and previous literature, exosomal miR-122-5p was finally selected as the study object, and correlated with inflammatory factors. In vitro experiments further found that exosomal miR-122-5p may derive from hepatic stellate cells (HSCs), and can be HIBECs intake, and influence HIBECs inflammatory factor levels though p38 MAPK signaling pathways. This may provide a new strategy for the treatment of PBC.

SLAMF8 can predict prognosis of pan-cancer and the immunotherapy response effectivity of gastric cancer.

SLAMF8, the eighth member of the Signaling Lymphocytic Activation Molecule Family (SLAMF), functions in the regulation of the development and activity of diverse immune cells as a costimulatory receptor within the SLAMF family. Studies had revealed that SLAMF8 is expressed higher in several autoimmune inflammation diseases and tumors. Nevertheless, the connection between SLAMF8 and pan-cancer remains undisclosed. The research investigated the correlation between SLAMF8 and various factors including the immune microenvironment, microsatellite instability, immune novel antigen, gene mutation, immune regulatory factors, immune blockade TMB, and immune or molecular subtypes of SLAMF8 in verse cancer types. Immunohistochemistry was ultimately employed to validate the presence of the SLAMF8 gene in various tumor types including hepatocellular carcinoma, prostate adenocarcinoma, and kidney renal clear cell carcinoma. Furthermore, the relationship between SLAMF8 expression and the therapeutic efficacy of the PD1 blockade agent, Sintilimab, treatment in gastric cancer was validated. The result of differential analysis suggested that SLAMF8 was over-expressed in pan-cancer compared with paracancerous tissues. The analysis of survival indicated a connection between SLAMF8 and the overall prognosis in different types of cancers, where higher levels of SLAMF8 were found to be significantly linked to unfavorable outcomes in patients but favorable outcome of immunotherapy in gastric cancer. Significant correlations were observed between SLAMF8 levels and pan-cancer tumorigenesis, tumor metabolism, and immunity. As a result, SLAMF8 may become an important prognostic biomarker in the majority of tumors and a hopeful gene target for immunotherapy against gastric cancer.

Role of increased IGFBP2 in trophoblast cell proliferation and recurrent spontaneous abortion development: A pilot study.

Recurrent spontaneous abortion (RSA) is a serious condition that adversely affects women's health. Differentially expressed proteins (DEPs) in plasma of patients experiencing RSA is helpful to find new therapeutic targets and identified with mass spectrometry. In 57 DEPs, 21 were upregulated and 36 were downregulated in RSA. Gene ontology analyses indicated that identified DEPs were associated with cell proliferation, including significantly downregulated insulin-like growth factor binding protein 2 (IGFBP2). Immunohistochemical result using clinical decidual tissues also showed that IGFBP2 expression was significantly decreased in RSA trophoblasts. Cell proliferation assay indicated that IGFBP2 treatment increased the proliferation and mRNA expressions of PCNA and Ki67 in trophoblast cells. Transcriptome sequencing experiments and Kyoto Encyclopedia of Genes and Genomes analyses revealed that gene expression for components in PI3K-Akt pathway in trophoblasts was significantly upregulated following IGFBP2 treatment. To confirm bioinformatics findings, we did cell-based experiments and found that treatment of inhibitors for insulin-like growth factor (IGF)-1 receptor-PI3K-Akt pathway significantly reduced IGFBP2-induced trophoblast cell proliferation and mRNA expressions of PCNA and Ki67. Our findings suggest that IGFBP2 may increase trophoblast proliferation through the PI3K-Akt signaling pathway to affect pregnancy outcomes and that IGFBP2 may be a new target for future research and treatment of RSA.

Bone Marrow Mesenchymal Stem Cells Release miR-378a-5p-Carried Extracellular Vesicles to Alleviate Rheumatoid Arthritis.

This study investigates whether bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) can affect rheumatoid arthritis (RA) by delivering microRNA (miR)-378a-5p to regulate the interferon regulatory factor 1/signal transducer and transcription 1 (IRF1/STAT1) axis. We identified RA-associated miRNAs using the GEO microarray dataset GSE121894. We found the most important miRNAs in RA synovial tissues using RT-qPCR. BMSC-derived EVs were ultracentrifuged and cocultured with human synovial microvascular endothelial cells (HSMECs) in vitro. Dual-luciferase and RNA immunoprecipitation studies examined miR-378a-5p's specific binding to IRF1. We also measured angiogenesis, migration, and proliferation using CCK-8, Transwell, and tube formation assays. Collagen-induced arthritis (CIA) mice models were created by inducing arthritis and scoring it. RA synovial tissues had low miR-378a-5p expression, whereas BMSC-derived EVs had high levels. The transfer of miR-378a-5p by BMSC-derived EVs to HSMECs boosted proliferation, migration, and angiogenesis. miR-378a-5p inhibited IRF1. MiR-378a-5p-containing BMSC-derived EVs decreased STAT1 phosphorylation and HSMEC IRF1 expression. EVs with miR-378a-5p mimic promoted HSMEC proliferation, migration, and angiogenesis, whereas dexmedetomidine inhibited STAT1 phosphorylation. In CIA mice, BMSC-derived EVs containing miR-378a-5p enhanced synovial vascular remodeling and histopathology. Thus, miR-378a-5p from BMSC-derived EVs promotes HSMEC proliferation, migration, and angiogenesis, inactivating the IRF1/STAT1 axis and preventing RA.

MicroRNA-221-3p Targets THBS1 to Promote Wound Healing in Diabetes.

Introduction: Diabetes foot ulcer (DFU) is a serious complication of diabetes characterized with chronic foot ulceration, poor wound healing (WH), and persistent inflammation. MiR-221-3p, as microRNA, has been shown to accelerate WH in previous study, but the underlying mechanisms are poorly understood. Methods: In this study, we aimed to determine how miR-221-3p influences WH by targeting THBS1. The effect of miRNA-221-3p on wound healing of diabetes by epidermal injection of miRNA-221-3p agomir. In vitro generated human immortalized keratinocytes (HaCaT cells) were transfected with miR-mimics and negative control with high glucose treatment. The effects of miRNA-221-3p on cell apoptosis and angiogenesis using cell apoptosis assay and the tube formation assay, respectively. Direct target interaction of miR-221-3p and predicted target sites in 3'UTR of THBS1 were examined by luciferase reporter gene assay. Breeding miRNA-221 knockout mice for experimental verification. Results: We found that miRNA-221-3p overexpression at the wound edge of normal mice and diabetes mice can promote WH. As contrast, WH of miR-221 knockout mice delayed with increased epithelial apoptosis and reduced angiogenesis in the dermis. miR-221-3p was found to inhibit apoptosis in HaCaT cells, and enhanced angiogenesis in human umbilical vein endothelial cells (HUVECs) that were co-cultured. Bioinformatics analysis as well as the dual-luciferase reporter assay revealed miR-221-3p to target 3' untranslated region of THBS1. Conclusion: Our findings suggested miR-221-3p might exert an essential impact on diabetes WH via inhibition of THBS1 and lack of miR-221-3p possibly results in impaired healing in chronic wounds of type 2 diabetes. Therefore, developing medicine such as chemically modified analogs of miR-221-3p in future could benefit patients with DFU.

Roles of Non-Coding RNAs in Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune-mediated chronic cholestatic liver disease, fatigue, and skin itching are the most common clinical symptoms. Its main pathological feature is the progressive damage and destruction of bile duct epithelial cells. Non-coding RNA (NcRNA, mainly including microRNA, long non-coding RNA and circular RNA) plays a role in the pathological and biological processes of various diseases, especially autoimmune diseases. Many validated ncRNAs are expected to be biomarkers for the diagnosis or treatment of PBC. This review will elucidate the pathogenesis of PBC and help to identify potential ncRNA biomarkers for PBC.