Depending on its expression level, RUNX1 can act as a tumor promoter or suppressor in hematological malignancies. The clinical impact of RUNX1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown, however. We evaluated the prognostic significance of RUNX1 expression using several public microarray datasets. In the testing group (n = 157), high RUNX1 expression (RUNX1high) was associated with poorer overall survival (OS; P = 0.0025) and event-free survival (EFS; P = 0.0025) than low RUNX1 expression (RUNX1low). In addition, the prognostic significance of RUNX1 was confirmed using European Leukemia Net (ELN) genetic categories and multivariable analysis, which was further validated using a second independent CN-AML cohort (n = 162, OS; P = 0.03953). To better understand the mechanisms of RUNX1, we investigated genome-wide gene/microRNAs expression signatures and cell signaling pathways associated with RUNX1 expression status. Several known oncogenes/oncogenic microRNAs and cell signaling pathways were all up-regulated, while some anti-oncogenes and molecules of immune activation were down-regulated in RUNX1high CN-AML patients. These findings suggest RUNX1high is a prognostic biomarker of unfavorable outcome in CN-AML, which is supported by the distinctive gene/microRNA signatures and cell signaling pathways.

Probucol, an agent characterized by lipid-lowering and antioxidant property, retards atherosclerosis effectively. To test the hypothesis that probucol might act its antiatherosclerotic role by suppressing immune maturation of dendritic cells (DCs), 7-week-old LDLR mice were rendered diabetic with streptozotocin (STZ) and then fed either a high-fat diet only or added with 0.5% (wt/wt) probucol for 4 months, and human monocyte-derived dendritic cells were preincubated with or without probucol and stimulated by oxidized low-density lipoprotein. In STZ-induced diabetic LDLR mice, probucol treatment significantly lowered plasma total cholesterol and high-density lipoprotein-cholesterol levels; regressed aortic atherosclerotic lesions; reduced splenic CD40, CD80, CD86, MHC-II expression, and plasma IL-12p70 production; and decreased the expression of CD11c DCs within atherosclerotic lesions. In vitro, oxidized low-density lipoprotein promoted human monocyte-derived dendritic cells maturation; stimulated CD40, CD86, CD1a, HLA-DR expression; increased tumor necrosis factor-α production; and decreased IL-4 production. However, these effects were obviously inhibited by probucol pretreatment. In conclusion, our study indicated that probucol effectively retarded atherosclerosis at least partly through lipid-lowering and inhibiting immune maturation of CD11c DCs in STZ-induced diabetic LDLR mice.

In this study, we examined the expression of lncRNA ENST00000413528 in glioma and determined its role in glioma development.

All cells obtain 2'-deoxyribonucleotides for DNA synthesis through the activity of a ribonucleotide reductase (RNR). The class I RNRs found in humans and pathogenic bacteria differ in (i) use of Fe(II), Mn(II), or both for activation of the dinuclear-metallocofactor subunit, β; (ii) reaction of the reduced dimetal center with dioxygen or superoxide for this activation; (iii) requirement (or lack thereof) for a flavoprotein activase, NrdI, to provide the superoxide from O2; and (iv) use of either a stable tyrosyl radical or a high-valent dimetal cluster to initiate each turnover by oxidizing a cysteine residue in the α subunit to a radical (Cys•). The use of manganese by bacterial class I, subclass b-d RNRs, which contrasts with the exclusive use of iron by the eukaryotic Ia enzymes, appears to be a countermeasure of certain pathogens against iron deprivation imposed by their hosts. Here, we report a metal-free type of class I RNR (subclass e) from two human pathogens. The Cys• in its α subunit is generated by a stable, tyrosine-derived dihydroxyphenylalanine radical (DOPA•) in β. The three-electron oxidation producing DOPA• occurs in Escherichia coli only if the β is coexpressed with the NrdI activase encoded adjacently in the pathogen genome. The independence of this new RNR from transition metals, or the requirement for a single metal ion only transiently for activation, may afford the pathogens an even more potent countermeasure against transition metal-directed innate immunity.

The imbalance between the GABA-mediated inhibition and the glutamate-mediated excitation is the primary pathological mechanism of epilepsy. GABAergic and glutamatergic neurotransmission have become the most important targets for controlling epilepsy. Ginsenoside compound K (GCK) is a main metabolic production of the ginsenoside Rb1, Rb2, and Rc in the intestinal microbiota. Previous studies show that GCK promoted the release of GABA from the hippocampal neurons and enhanced the activity of GABAA receptors. GCK is shown to reduce the expression of NMDAR and to attenuate the function of the NMDA receptors in the brain. The anti-seizure effects of GCK have not been reported so far. Therefore, this study aimed to investigate the effects of GCK on epilepsy and its potential mechanism. The rat model of seizure or status epilepticus (SE) was established with either Pentylenetetrazole or Lithium chloride-pilocarpine. The Racine's scale was used to evaluate seizure activity. The levels of the amino acid neurotransmitters were detected in the pilocarpine-induced epileptic rats. The expression levels of GABAARα1, NMDAR1, KCC2, and NKCC1 protein in the hippocampus were determined via western blot or immunohistochemistry after SE. We found that GCK had deceased seizure intensity and prolonged the latency of seizures. GCK increased the contents of GABA, while the contents of glutamate remained unchanged. GCK enhanced the expression of GABAARα1 in the brain and exhibited a tendency to decrease the expression of NMDAR1 protein in the hippocampus. The expression of KCC2 protein was elevated by the treatment of GCK after SE, while the expression of NKCC1 protein was reversely down-regulated. These findings suggested that GCK exerted anti-epileptic effects by promoting the hippocampal GABA release and enhancing the GABAAR-mediated inhibitory synaptic transmission.

Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in gastric cancer (GC) are poorly characterized. Here, we investigated the role of AR in GC cell migration, invasion and metastatic potential. Our data showed that AR expression was positively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by activation of AKT and upregulation of matrix metalloproteinase 9 (MMP9). AR overexpression induced increases in GC cell migration, invasion and proliferation in vitro and in vivo. These effects were attenuated by inhibition of AKT, AR and MMP9. AR overexpression upregulated MMP9 protein levels, whereas this effect was counteracted by AR siRNA. Inhibition of AKT by siRNA or an inhibitor (MK-2206 2HC) decreased AR protein expression in both stably transfected and parental SGC-7901 cells. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that AR bound to the AR-binding sites of the MMP9 promoter. In summary, AR overexpression induced by AKT phosphorylation upregulated MMP9 by binding to its promoter region to promote gastric carcinogenesis. The AKT/AR/MMP9 pathway plays an important role in GC metastasis and may be a novel therapeutic target for GC treatment.

Elevated MELK expression is featured in multiple tumors and correlated with tumorigenesis and tumor development. This study is aimed to investigate the mechanisms of MELK-mediated development of gastric cancer.

Several studies suggest that mesenchymal stem cells (MSCs) possess antitumor properties; however, the exact mechanisms remain unclear. Recently, microvesicles (MVs) are considered as a novel avenue intercellular communication, which may be a mediator in MSCs-related antitumor effect. In the present study, we evaluated whether MVs derived from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) may inhibit bladder tumor T24 cells growth using cell culture and the BALB/c nu/nu mice xenograft model. CCK-8 assay and Ki-67 immunostaining were performed to estimate cell proliferation in vitro and in vivo. Flow cytometry and TUNEL assay were used to assess cell cycle and apoptosis. To study the conceivable mechanism by which hWJMSC-MVs attenuate bladder tumor T24 cells, we estimated the expression of Akt/p-Akt, p-p53, p21 and cleaved Caspase 3 by Western blot technique after exposing T24 cells to hWJMSC-MVs for 24, 48 and 72h. Our data indicated that hWJMSC-MVs can inhibit T24 cells proliferative viability via cell cycle arrest and induce apoptosis in T24 cells in vitro and in vivo. This study showed that hWJMSC-MVs down-regulated phosphorylation of Akt protein kinase and up-regulated cleaved Caspase 3 during the process of anti-proliferation and pro-apoptosis in T24 cells. These results demonstrate that hWJMSC-MVs play a vital role in hWJMSC-induced antitumor effect and may be a novel tool for cancer therapy as a new mechanism of cell-to-cell communication.

The association between the glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and gynecological cancer susceptibility has been evaluated in many studies. However, the results remain controversial. Thus, this meta-analysis, based on 10 published case-control studies, was designed to clarify the association of the GSTP1 Ile105Val polymorphism with gynecological cancer risk. Our results suggested that there was no significant association between the GSTP1 Ile105Val polymorphism and the risk of gynecological cancer in all genetic models (GG vs. AA: odds ratio [OR] = 1.41, 95% confidence interval [CI] = 0.75-2.26; AG vs. AA: OR = 1.13, 95% CI = 0.74-1.73; AG/GG vs. AA: OR = 1.17, 95% CI = 0.75-1.81; GG vs.

Microvesicles (MVs) derived from human Wharton's jelly mesenchymal stem cells (MSC-MVs) were demonstrated to ameliorate acute lung injury (ALI). We have previously found that MSC-MV-transferred hepatocyte growth factor was partly involved in their therapeutic effects. Since MSC-MVs also contained a substantial quantity of miR-100, which plays an important role in lung cancer and injury, we speculated that miR-100 might similarly account for a part of the therapeutic effects of MSC-MVs.

Increased autophagy of prostate cancer (PC) cells contributes to their resistance to chemotherapy. Recently, we reported that a long non-coding RNA (lncRNA)-breast-cancer anti-estrogen resistance 4 (BCAR4)-is highly expressed in PC and contributes to castration resistance through activation of GLI2 signaling. However, the role of BCAR4 in the regulation of PC cell autophagy is unknown and is the subject of the current study.

Bleomycin is a common antitumor agent used to treat many different types of malignancies; however, its main side effect is pulmonary fibrosis. The mechanism of bleomycin-induced pulmonary fibrosis (BIPF) has not been fully elucidated. Therefore, to further explore the molecular mechanisms of BIPF, we screened for microRNA (miRNA) and mRNA expression obtained from BIPF samples from the Gene Expression Omnibus database. Subsequently, we identified the differentially expressed miRNAs and genes that overlapped with the differentially expressed miRNAs target genes, predicted by using the miRWalk database selected as a candidate. The candidate genes were visualized based on Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses. A protein-protein interaction network was constructed. Hub differentially expressed genes were selected and corresponding miRNAs to construct a miRNA-mRNA regulation network. Then, we chose three key miRNAs to study their regulatory relationship in bleomycin-induced pulmonary fibrosis. Finally, mouse lung epithelial cells TC-1 and MLE-12 were treated with bleomycin with qPCR to validate the results of three important hub genes and all key miRNAs. And dual-luciferase report experiment was carried out to verify the interaction of mmu-miR-1946a and serpina3n. The results revealed that the imbalance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a pivotal role in the occurrence and development of BIPF. In addition, Serpina3n and mmu-miR-1946a were proved interaction and may be involved in the regulation of the balance between MMP-9 and TIMP-1. The experimental results also verify the analysis. Our findings provide new insights into the key mediators and pathways related to the molecular mechanisms of BIPF.

The Nocardia rubra cell wall skeleton (Nr-CWS) is an immunomodulator used clinically for its ability to modulate the body's immune function. Macrophages are an important hub of the immune response during wound healing. In this study, we hypothesized that a Nr-CWS could modulate macrophage physiological activities, polarize macrophages toward M2, and promote wound healing. Through in vivo experiments, we made two full-thickness excisional wounds on the backs of mice; one was treated with a Nr-CWS, and the other was treated with saline. We photographed and recorded the wound change every other day. We observed the histopathological examination and collagen deposition using H&E and Masson staining, then analyzed the macrophage surface markers using immunofluorescence. Through in vitro experiments, we studied the effect of the Nr-CWS on RAW264.7 cells through CCK8, transwell, flow cytometry, western blot, immunofluorescence, and ELISA. We found that the Nr-CWS can enhance the proliferation, migration, and phagocytosis of macrophages. In addition, it can promote the recruitment of macrophages on the wound surface, polarize macrophages to M2, and increase the expression of pro-healing cytokines. Ultimately, the Nr-CWS accelerated wound healing.

Ketone body oxidation yields more ATP per mole of consumed oxygen than glucose. However, whether an increased ketone body supply in hypoxic cardiomyocytes and ischemic hearts is protective or not remains elusive. The goal of this study is to determine the effect of β-hydroxybutyrate (β-OHB), the main constituent of ketone bodies, on cardiomyocytes under hypoxic conditions and the effects of ketogenic diet (KD) on cardiac function in a myocardial infarction (MI) mouse model.

Hydrogen sulfide (H2S) has been identified as an important gasotransmitter. H2S donor can release H2S sustained and is used as wound dressing. Endothelial progenitor cells (EPCs), given their regenerative ability, have also been reported to enhance wound healing. However, effective drug carriers are missing for the clinical application of H2S and EPCs. In this study, we investigated a novel drug carrier nanofibrous membrane, which was prepared by blending the recombinant spider silk protein (rMaSp) and sodium hydrogen sulfide (NaHS) by electrospun. Our results show that the rMaSp/NaHS nanofibrous membrane is associated with high hemocompatibility and cytocompatibility and is capable of stably releasing H2S for a long period of time. We also tested the rMaSp/NaHS membrane loaded with EPCs in an in vivo cutaneous wound model. We showed that the rMaSp/NaHS/EPC system significantly enhances wound regeneration efficiency as compared to rMaSp membrane and rMaSp/NaHS membrane. This study provides key evidence supporting the clinical application of nanofibrous membrane in the field of skin tissue regeneration.

The complete mitogenome of Nasimyia megacephala Yang & Yang, 2010 (Stratiomyidae: Pachygastrinae) successfully sequenced. The mitogenome of N. megacephala is a circular DNA molecule of 16,069 bp in length with 72% AT content, consisting of 13 PCGs, two rRNAs, 22 tRNAs, and a large control region. The gene order is consistent with other dipteran mitogenomes. The phylogenetic tree was reconstructed using maximum likelihood analysis, and the topology revealed that Pachygastrinae is not a monophyletic group.

Exosome complex (EXOSC) genes, which encode a multi-protein intracellular complex, mediate the degradation of various types of RNA molecules. EXOSCs, also known as polymyositis/scleroderma complexes, exist in eukaryotic cells and archaea, and primarily mediate 3' to 5'mRNA degradation. However, how EXOSC genes are implicated in processes of B-cell immune-associated pathways and B-cell tumorigenesis remains unclear. The present bioinformatics study indicated that 6 of 10 EXOSC genes, particularly the EXO.index, were able to predict the survival of patients with mantle cell lymphoma (MCL), by analyzing gene expression profiles of 123 patients with MCL from the Gene Expression Omnibus database. The results suggested that EXOSC gene expression may be a molecular marker for MCL. Compared with the whole transcript profile, patients with MCL with a high EXO.index exhibited poorer survival and decreased RNA levels, which was also verified in a second dataset. The EXOSC genes may be associated with DNA repair and B-cell activation pathways, which may be the cause of poorer survival of patients with MCL.

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

Renal cancer is a common malignancy of the urinary system, and renal clear cell carcinoma (RCCC) is the most common pathological type. Transmembrane channel-like (TMC) protein is an evolutionarily conserved gene family containing 8 members, however there is still a lack of comprehensive analysis about TMC family members in RCCC. In this study, we analyzed the expression of TMC family members in RCCC from TCGA and investigated the prognosis values and immune infiltration of TMC family members in RCCC. We found that TMC2, TMC3, TMC5, TMC7 and TMC8 were significantly related with overall survival (OS) of RCCC patients. TMC3, TMC6, and TMC8 was positively correlated with the degree of immune infiltration in RCCC. TMC2, TMC6, TMC7, and TMC8 were positively correlated with immune checkpoint genes, whereas TMC4 was negative. According to KEGG and GO analysis, almost all TMCs except TMC4 were involved in the immune response. Thus, we may regard the TMC family members as novel biomarkers to predict potential prognosis and immunotherapeutic response in RCCC patients.

Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.