G-quadruplex-enhanced circular single-stranded DNA (G4-CSSD) adsorption of miRNA to inhibit colon cancer progression.

BACKGROUND: Chromosomal heterogeneity leads to the abnormal expression and mutation of tumor-specific genes. Drugs targeting oncogenes have been extensively developed. However, given the random mutation of tumor suppressor genes, the development of its targeted drugs is difficult. METHODS: Our early research revealed that artificial circular single-stranded DNA (CSSD) can restore multiple tumor suppressor genes to inhibit tumor malignant progression by adsorbing miRNA. Here, we improved CSSD to a fully closed single-stranded DNA with G quadruplex DNA secondary structure (G4-CSSD), which made G4-CSSD with higher acquisition rate and decreased degradation. The Cancer Genome Atlas (TCGA) and Human Protein Atlas database were used to predict tumour suppressor genes in colon cancer. Cellular and animal experiments were performed to validate the role of G4-CSSD in cancer cell progression. RESULTS: In colon cancer, we observed the simultaneous low expressions of chloride channel accessory 1 (CLCA1), UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and UDP glucuronosyltransferase family 2 member A3 (UGT2A3), which indicated an favourable prognosis. After repressing miR-590-3p with G4-CSSD590, the upregulation of CLCA1, B3GNT6 and UGT2A3 inhibited the proliferation and metastasis of colon cancer cells. CONCLUSIONS: This study may provide basis for new treatment methods for colon cancer by restoration of tumor suppressor genes.

Hydrogen regulates mitochondrial quality to protect glial cells and alleviates sepsis-associated encephalopathy by Nrf2/YY1 complex promoting HO-1 expression.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a complication of the central nervous system in patients with sepsis. Currently, no effective treatment for sepsis is available. Hydrogen plays a protective role in different diseases; however, the detailed mechanism of hydrogen-treated disease remains unclear. The purpose of this study was to investigate the effect of hydrogen on SAE in vitro and in vivo and the mechanism of hydrogen in mitochondrial dynamics and its function in astrocytes and microglia stimulated by lipopolysaccharides (LPSs). METHODS: Animal models of SAE were generated by cecal ligation and puncture, and the SAE model was established by in vitro LPS stimulation. MTT, lactate dehydrogenase (LDH), reactive oxygen species (ROS), heme oxygenase-1 (HO-1) activity, mitochondrial membrane potential (MMP), and cell apoptosis assays were used to determine the effect of hydrogen on astrocytes and microglia stimulated by LPSs. The relationships between nuclear factor erythroid 2-related factor 2 (Nrf2), YY1, and HO-1 were examined by chromatin immunoprecipitation and co-immunoprecipitation. Mitochondrial homeostasis-related proteins in LPS-stimulated glial cells and brain tissues of SAE mice were detected by western blotting. The effects of hydrogen treatment in the SAE mouse model were investigated using Morris water maze and Y-maze analyses. RESULTS: After performing experiments with different concentrations of LPSs in vitro, we selected 1000 ng/ml for subsequent experiments. Hydrogen attenuated the increase in ROS, LDH, and apoptosis and promoted decreases in cell activity and MMP, further promoting an increase in HO-1 expression induced by LPSs in astrocytes and microglia. Moreover, hydrogen further promoted the expression of Nrf2, HO-1, PGC-1α, TFAM, PARKIN, and PINK1, inhibited LPS-induced OPA1 and MFN2 expression in astrocytes and microglia, and downregulated the expression of DRP1 after LPS induction. Intriguingly, hydrogen treatment enhanced the binding between Nrf2 and YY1. However, silencing Nrf2 or YY1 abolished the protective effects of hydrogen on cell activity, LDH, ROS, and MMP; apoptosis; and regulation of Nrf2, HO-1, PGC-1α, TFAM, OPA1, DRP1, MFN2, PARKIN, and PINK1 in microglia. Finally, hydrogen treatment improved the results of behavioral detection, apoptosis, Nrf2, HO-1, PGC-1α, TFAM, OPA1, DRP1, MFN2, PARKIN, PINK1, and cytokines in SAE in vivo. CONCLUSIONS: Hydrogen improved cell injury and mitochondrial quality, which were associated with HO-1 expression promoted by the Nrf2/YY1 complex in vitro. Thus, hydrogen treatment may represent a novel therapeutic method for treating SAE.

Biomimetic Immunosuppressive Exosomes that Inhibit Cytokine Storms Contribute to the Alleviation of Sepsis.

Sepsis is a disease characterized by multiple organ failure caused by immune hyperactivation and cytokine storms. Studies have shown that the incidence of sepsis in melanoma patients is substantially lower compared to the general population. It is also observed that experimental tumor-bearing animals have high survival rates after sepsis induction, suggesting that tumors may suppress sepsis-associated immune overactivation, thereby alleviating sepsis. Based on the above-described findings, this work assesses whether tumor cells play an antisepsis role in mice through the secretion of exosomes. Analysis of exosome activity reveals that the induced exosomes (iExo) secreted by tumor cells following lipopolysaccharide (LPS) treatment improve sepsis to a greater extent than normal secretory exosomes. Further analysis reveals that iExo exert their protective effects mainly through seven key miRNAs. In vitro bionic simulation of exosomes is carried out using exosome mimics generated by loading the aforementioned microRNAs into hyaluronic acid-polyethylenimine nanoparticles. Exosome mimics at specific miRNA ratios alleviate sepsis in mice and cynomolgus monkeys, indicating that biomimetic simulation of tumor-suppressive exosomes may represent a promising therapeutic method for the treatment of sepsis and cytokine-storm-related conditions.

Corrigendum: CircAFF1 aggravates vascular endothelial cell dysfunction mediated by miR-516b/SAV1/YAP1 axis.

[This corrects the article DOI: 10.3389/fphys.2020.00899.].

Downregulation of circFASTKD1 ameliorates myocardial infarction by promoting angiogenesis.

Circular RNAs (circRNAs), a novel class of endogenous long non-coding RNAs, have attracted considerable attention due to their closed continuous loop structure and potential clinical value. In this study, we investigated the function of circFASTKD1 in vascular endothelial cells. CircFASTKD1 bound directly to miR-106a and relieved its inhibition of Large Tumor Suppressor Kinases 1 and 2, thereby suppressing the Yes-Associated Protein signaling pathway. Under both normal and hypoxic conditions, the ectopic expression of circFASTKD1 reduced the viability, migration, mobility and tube formation of vascular endothelial cells, whereas the downregulation of circFASTKD1 induced angiogenesis by promoting these processes. Moreover, downregulation of circFASTKD1 in mice improved cardiac function and repair after myocardial infarction. These findings indicate that circFASTKD1 is a potent inhibitor of angiogenesis after myocardial infarction and that silencing circFASTKD1 exerts therapeutic effects during hypoxia by stimulating angiogenesis in vitro and in vivo.

circAFF1 Aggravates Vascular Endothelial Cell Dysfunction Mediated by miR-516b/SAV1/YAP1 Axis.

Pathological vascular endothelial damage caused by hypoxia is the basis of many vascular-related diseases. However, the role of circular RNA in hypoxic vascular injury is still poorly understood. Here, we found that hypoxia induced AFF1 circular RNA (circAFF1) can activate the SAV1/YAP1 and lead to the dysfunction of vascular endothelial cells. In HUV-EC-C and HBEC-5i cells, circAFF1 was upregulated under CoCl2 induced hypoxic conditions. The abnormal expression of circAFF1 inhibited the proliferation, tube formation, migration of vascular endothelial cells. The effect of circAFF1 is achieved by the adsorption of miR-516b to release SAV1, which in turn causes the phosphorylation of YAP1. Moreover, we found that the upregulation of circAFF1 in 235 Patients with subarachnoid hemorrhage. Taken together, we clarify the role of circAFF1/miR-516b/SAV1/YAP1 axis in vascular endothelial dysfunction and its potential early diagnostic value of disease caused by hypoxia injury in blood vessels.