RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation.

A timely inflammatory response is crucial for early viral defense, but uncontrolled inflammation harms the host. Retinoic acid-inducible gene I (RIG-I) has a pivotal role in detecting RNA viruses, yet the regulatory mechanisms governing its sensitivity remain elusive. Here we identify PTENα, an N-terminally extended form of PTEN, as an RNA-binding protein with a preference for the CAUC(G/U)UCAU motif. Using both in vivo and in vitro viral infection assays, we demonstrated that PTENα restricted the host innate immune response, relying on its RNA-binding capacity and phosphatase activity. Mechanistically, PTENα directly bound to viral RNA and enzymatically converted its 5'-triphosphate to 5'-monophosphate, thereby reducing RIG-I sensitivity. Physiologically, brain-intrinsic PTENα exerted protective effects against viral inflammation, while peripheral PTENα restricted host antiviral immunity and, to some extent, promoted viral replication. Collectively, our findings underscore the significance of PTENα in modulating viral RNA- and RIG-I-mediated immune recognition, offering potential therapeutic implications for infectious diseases.

Graphene oxide suppresses the growth and malignancy of glioblastoma stem cell-like spheroids via epigenetic mechanisms.

BACKGROUND: Glioblastoma stem-like cells (GSCs) are hypothesized to contribute to self-renewal and therapeutic resistance in glioblastoma multiforme (GBM) tumors. Constituting only a small percentage of cancer cells, GSCs possess "stem-like", tumor-initiating properties and display resistance to irradiation and chemotherapy. Thus, novel approaches that can be used to suppress GSCs are urgently needed. A new carbon material-graphene oxide (GO), has been reported to show potential for use in tumor therapy. However, the exact effect of GO on GSCs and the inherent mechanism underlying its action are not clear. In this study, we aimed to investigate the usefulness of GO to inhibit the growth and promote the differentiation of GSCs, so as to suppress the malignancy of GBM. METHODS: In vitro effects of GO on sphere-forming ability, cell proliferation and differentiation were evaluated in U87, U251 GSCs and primary GSCs. The changes in cell cycle and the level of epigenetic modification H3K27me3 were examined. GO was also tested in vivo against U87 GSCs in mouse subcutaneous xenograft models by evaluating tumor growth and histological features. RESULTS: We cultured GSCs to explore the effect of GO and the underlying mechanism of its action. We found, for the first time, that GO triggers the inhibition of cell proliferation and induces apoptotic cell death in GSCs. Moreover, GO could promote the differentiation of GSCs by decreasing the expression of stem cell markers (SOX2 and CD133) and increasing the expression of differentiation-related markers (GFAP and ß-III tubulin). Mechanistically, we found that GO had a striking effect on GSCs by inducing cell cycle arrest and epigenetic regulation. GO decreased H3K27me3 levels, which are regulated by EZH2 and associated with transcriptional silencing, in the promoters of the differentiation-related genes GFAP and ß-III tubulin, thereby enhancing GSC differentiation. In addition, compared with untreated GSCs, GO-treated GSCs that were injected into nude mice exhibited decreased tumor growth in vivo. CONCLUSION: These results suggested that GO could promote differentiation and reduce malignancy in GSCs via an unanticipated epigenetic mechanism, which further demonstrated that GO is a potent anti-GBM agent that could be useful for future clinical applications.

Antitumor Activity and Mechanism of Robustic Acid from Dalbergia benthami Prain via Computational Target Fishing.

Dalbergia benthami Prain (D.benthami) is an important legume species of the Dalbergia family, due to the use of its trunk and root heart in traditional Chinese medicine (TCM). In the present study, we reported the isolation, characterization and pharmacological activities of robustic acid (RA) from the ethyl acetate extract of D. benthami Prain. The SwissADME prediction showed that the RA satisfied the Lipinski's rule of five (molecule weight (MW): 380.39 g/mol, lipid-water partition coefficient (log P): 3.72, hydrogen bond donors (Hdon): 1, hydrogen bond acceptors (Hacc): 6, rotatable bonds (Rbon): 3. Other chemical and pharmacological properties of this RA were also evaluated, including topological polar surface area (TPSA) = 78.13 Šand solubility (Log S) = -4.8. The probability values of the antineoplastic, anti-free radical activities and topoisomerase I (TopoⅠ) inhibitory activity were found to be 0.784, 0.644 and 0.379, respectively. The molecular docking experiment using the Surflex-Dock showed that the Total Score and C Score of RNA binding with the human DNA-Topo I complex were 7.80 and 4. The MTS assay experiment showed that the inhibitory rates of RA on HL-60, MT4, Hela, HepG2, SK-OV-3 and MCF-7 cells were 37.37%, 97.41%, 81.22%, 34.4%, 32.68% and 51.4%, respectively. In addition, RA exhibited an inhibitory effect on the angiogenesis of zebrafish embryo, a good TopoⅠ inhibitory activity at a 10 mM concentration and in a dose-dependent manner, excellent radical scavenging in the DPPH and ABTS assays, and the free radical scavenging rate was close to the positive control (BHT) at different concentrations (0.5-2.0 mg/mL). Furthermore, 18 potential targets were found for this RA by PharmMapper, including ANXA3, SRC, FGFR2, GSK3B, CSNK2B, YARS, LCK, EPHA2, MAPK14, RORA, CRABP2, PPP1CC, METAP2, MME, TTR, MET and KDR. The GO and KEGG pathway analysis revealed that the "protein tyrosine kinase activity", "rap1 signaling pathway" and "PI3K-Akt signaling pathway" were significantly enriched by the RA target genes. Our results will provide new insights into the pharmaceutical use of this species. More importantly, our data will expand our understanding of the molecular mechanisms of RA functions.

Chryseobacterium zhengzhouense sp. nov., isolated from groundwater of the well in a vegetable field, and emended description of the genus Chryseobacterium.

A Gram-negative, strictly aerobic, non-motile, asporogenous rod-shaped bacterium, designated M05W1-39A1(T), was isolated from a Chinese cabbage farmland located in Zhengzhou. China, and subjected to a taxonomic study. Strain M05W1-39A1(T) was found to grow optimally at 25-30 °C, at pH 6.0-7.0 and in the presence of 0.5-2.0 % (w/v) NaCl. According to phylogenetic analysis using 16S rRNA gene sequences, strain M05W1-39A1(T) belongs to the genus Chryseobacterium and is closely related to Chryseobacterium arachidis LMG 27813(T) (98.8 %) and Chryseobacterium geocarposphaera LMG 27811(T) (98.1 %). The DNA G + C content was determined to be 35.3 mol%. The respiratory quinone was identified as MK-6 and the predominant cellular fatty acids as iso-C15:0, Summed feature 3 (C16:1 ω7c/C16:1 ω6c), iso-C17:0 3-OH and Summed feature 9 (iso-C17:1 ω9c). Based on the genotypic, chemotaxonomic and phenotypic data, strain M05W1-39A1(T) is concluded to represent a novel species of the genus Chryseobacterium, for which the name Chryseobacterium zhengzhouense sp. nov. is proposed. The type strain is M05W1-39A1(T) (=HNMC11208(T) = CGMCC 1.15067(T) = JCM 30863(T)).

Methylopila henanense sp. nov., a novel methylotrophic bacterium isolated from tribenuron methyl-contaminated wheat soil.

A bacterial strain, designated LYBFD3-16A2(T), was isolated from tribenuron methyl contaminated wheat soil. Cells were observed to be Gram-negative short rods with a single flagellum. The strain was found to utilize methanol, glucose, maltose and mannitol as carbon and energy sources, and utilized glutamate, leucine, phenylalanine as organic nitrogen sources. Strain LYBFD3-16A2(T) was found to be aerobic, to form urease, produce hydrogen sulfide and reduce nitrate to nitrite. The indole test in tryptone broth was observed to be positive. The major cellular fatty acids were identified as C18:1ω7c (81.3 %), 11-methylC18:1ω7c (7.9 %), C18:0 (3.0 %) and C16:0 (3.0 %). The major phospholipids were identified as phosphatidylcholine, phosphatidylethanolamine, phosphatidyglycerol and diphosphatidylglycerol. The main ubiquinone was identified as Q-10. The DNA G+C content was determined to be between 70.2 and 70.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated the affiliation of strain LYBFD3-16A2 to members of the genus Methylopila. The DNA-DNA hybridization values of the novel strain with the type strains of the most closely related species Methylopila musalis MUSA(T) and Methylopila jiangsuensis JZL-4(T) were 35.4 % and 31.4 % respectively. The genotypic and phenotypic characterization, along with chemotaxonomic properties of strain LYBFD3-16A2(T), showed that the strain represents a novel species of the genus Methylopila for which the name Methylopila henanense sp. nov. is proposed. The type strain is LYBFD3-16A2(T) (=CGMCC1.10703(T) = LMG 25959(T)).

TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Digital Spatial Profiling Reveals Functional Shift of Enterochromaffin Cell in Patients With Ulcerative Colitis.

As a major component of the enteroendocrine system, enterochromaffin (EC) cells play a key role in ulcerative colitis (UC). However, the scarcity of EC cells has limited the investigation of their function. In this study, we applied digital spatial profiling to acquire transcriptomic data for EC cells and other epithelial cells from colonoscopic biopsy samples from eight patients with UC and seven healthy controls. Differential expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were performed to identify differentially expressed genes and pathways and coexpression networks. Results were validated using an online dataset obtained by single-cell RNA sequencing, along with immunofluorescence staining and quantitative real-time PCR. In healthy participants, 10 genes were significantly enriched in EC cells, functionally concentrated in protein and bioamine synthesis. A coexpression network containing 17 hub genes, including TPH1, CHGA, and GCLC, was identified in EC cells. In patients with UC, EC cells gained increased capacity for protein synthesis, along with novel immunological functions such as antigen processing and presentation, whereas chemical sensation was downregulated. The specific expression of CHGB and RGS2 in EC cells was confirmed by immunofluorescence staining. Our results illuminate the transcriptional signatures of EC cells in the human colon. EC cells' newly observed functional shift from sensation to secretion and immunity indicates their pivotal role in UC.

Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling.

RIG-I/DDX58 plays a key role in host innate immunity. However, its therapeutic potential for inflammation-related cancers remains to be explored. Here we identify frameshift germline mutations of RIG-I occurring in patients with colon cancer. Accordingly, Rig-ifs/fs mice bearing a frameshift mutant Rig-i exhibit increased susceptibility to colitis-related colon cancer as well as enhanced inflammatory response to chemical, virus or bacteria. In addition to interruption of Rig-i mRNA translation, the Rig-i mutation changes the secondary structure of Rig-i pre-mRNA and impairs its association with DHX9, consequently inducing a circular RNA generation from Rig-i transcript, thereby, designated as circRIG-I. CircRIG-I is frequently upregulated in colon cancers and its upregulation predicts poor outcome of colon cancer. Mechanistically, circRIG-I interacts with DDX3X, which in turn stimulates MAVS/TRAF5/TBK1 signaling cascade, eventually activating IRF3-mediated type I IFN transcription and aggravating inflammatory damage. Reciprocally, all-trans retinoic acid acts as a DHX9 agonist, ameliorates immunopathology through suppression of circRIG-I biogenesis. Collectively, our results provide insight into mutant RIG-I action and propose a potential strategy for the treatment of colon cancer.

MicroRNA-204 plays a role as a tumor suppressor in Newcastle disease virus-induced oncolysis in lung cancer A549 cells.

Tumor development and progression are closely associated with various microRNAs (miRNAs/miRs). We have previously shown that Newcastle disease virus (NDV) strain 7793 induces oncolysis in lung cancer. However, how NDV exerts its oncolytic effect on lung cancer remains to be investigated. The present study assessed the role of miR-204 in the NDV-induced oncolysis of lung cancer A549 cells by oncolysis induction in vitro. miR-204 was significantly upregulated in NDV-treated A549 cells. Overexpression or inhibition of miR-204 was significantly associated with NDV-induced oncolysis in A549 cells. Caspase-3 and Bax, major regulators of the apoptosis pathway, were regulated by miR-204, and the association between caspase-3-related apoptosis and miR-204 was identified in NDV-mediated oncolysis. These data demonstrated that miR-204 as a tumor suppressor played a role in NDV-induced oncolysis in lung cancer cells. The present study demonstrates the potential of strategies using miRs to improve oncolytic NDV potency, and highlights miR-204 as a tumor suppressor in NDV-induced oncolysis of lung cancer cells.

[Preparation of anatase-type TiO2 nanoparticals from Ti(SO4)2 solution under hydrothermal conditions and its photocatalytic performance].

Anatase-type TiO2 fine powders were synthesized under hydrothermal condition. The precursor was obtained via precipitation route using Ti(SO4)2. The characterization of the as-prepared sample was confirmed by TEM, XRD, UV-Vis and low temperature N2 adsorption measurements (BET). The photocatalytic activity was also investigated by the degradation of methyl orange solutions. The particles of the as-synthesized sample with narrow size distribution had an average diameter of about 24 nm. The specific BET surface area of the as-synthesized sample was about 56 m2 x g(-1), which is similar to the commercial TiO2 (P25). The prepared materials showed the similar photocatalytic activity when compared with the performance of commercial TiO2 (P25).

[Fabrication and photocatalytic activity of Pt-inserted titania nanotubes].

Titania nanotubes (TNTs) were synthesized by hydrothermal treatment of rutile-phase TiO2 nanoparticals in NaOH solution at 110 degrees C for 24 hours. After drying in aceton for 36 h, the TNTs were under vacuum drying for 24 h at room temperature. The Pt-inserted titania nanotubes (Pt/TNTs) were obtained by filling H2 PtCl6 ethanol solution into the TNTs after vacuum drying. The characterizations of the as-synthesized samples were confirmed by TEM, XRD, and UV-Vis. The photocatalytic activity of the Pt/TNTs was investigated by photo-induced decomposition of methyl orange(MO)under the main 365 nm UV-light. In order to comparison, the photocatalytic activity of both the rutile-phase TiO2 nanoparticles and pure TNTs were also investigated at the same time under the same experimental conditions. The TEM images show that the TNTs are hollow, a few hundred nanometers long, and the inner/outer diameter is about 6/10 nm. The crystal structure of TNTs is H2Ti2O5 x H2O with a little Na. Both the shape and the crystalline of the TNTs are not changed after the modification. The oval or round Pt0 nanoparticals, about 3 nm in diameter, are found only in the nanotubes. Pt/TNTs exhibit enhanced absorption at the visible range in the UV-Vis spectra and its start absorption band edge(lambda0 approximately 457 nm)is obviously redshifted compared to the rutile-phase TiO2 nanoparticals and pure TNTs. The Pt nanoparticles are found to significantly enhance the photocatalytic activity of TNTs. Pt/TNTs are demonstrated to be highly efficient for the UV-light induced photocatalytic decomposition of MO compared to both the rutile-phase TiO2 nanoparticals and pure TNTs. After irradiation for 60 min, the photocatalysis decomposition rate of MO in rutile-phase TiO2 nanoparticals, TNTs and Pt/TNTs are 46.8%, 57.2% and 84.6% respectively.

SOX19b regulates the premature neuronal differentiation of neural stem cells through EZH2-mediated histone methylation in neural tube development of zebrafish.

OBJECTIVE: Neural tube defects (NTDs) are the most serious and common birth defects in the clinic. The SRY-related HMG box B1 (SoxB1) gene family has been implicated in different processes of early embryogenesis. Sox19b is a maternally expressed gene in the SoxB1 family that is found in the region of the presumptive central nervous system (CNS), but its role and mechanism in embryonic neural stem cells (NSCs) during neural tube development have not yet been explored. Considering that Sox19b is specific to bony fish, we intended to investigate the role and mechanism of Sox19b in neural tube development in zebrafish embryos. MATERIAL AND METHODS: Morpholino (MO) antisense oligonucleotides were used to construct a Sox19b loss-of-function zebrafish model. The phenotype and the expression of related genes were analysed by in situ hybridization and immunolabelling. Epigenetic modifications were detected by western blot and chromatin immunoprecipitation. RESULTS: In this study, we found that zebrafish embryos exhibited a reduced or even deleted forebrain phenotype after the expression of the Sox19b gene was inhibited. Moreover, we found for the first time that knockdown of Sox19b reduced the proliferation of NSCs; increased the transcription levels of Ngn1, Ascl1, HuC, Islet1, and cyclin-dependent kinase (CDK) inhibitors; and led to premature differentiation of NSCs. Finally, we found that knockdown of Sox19b decreased the levels of EZH2/H3K27me3 and decreased the level of H3K27me3 at the promoters of Ngn1 and ascl1a. CONCLUSION: Together, our data demonstrate that Sox19b plays an essential role in early NSC proliferation and differentiation through EZH2-mediated histone methylation in neural tube development. This study established the role of transcription factor Sox19b and epigenetic factor EZH2 regulatory network on NSC development, which provides new clues and theoretical guidance for the clinical treatment of neural tube defects.

TIGAR promotes neural stem cell differentiation through acetyl-CoA-mediated histone acetylation.

Cellular metabolism plays a crucial role in controlling the proliferation, differentiation, and quiescence of neural stem cells (NSCs). The metabolic transition from aerobic glycolysis to oxidative phosphorylation has been regarded as a hallmark of neuronal differentiation. Understanding what triggers metabolism reprogramming and how glucose metabolism directs NSC differentiation may provide new insight into the regenerative potential of the brain. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is an endogenous inhibitor of glycolysis and is highly expressed in mature neurons. However, its function in embryonic NSCs has not yet been explored. In this study, we aimed to investigate the precise roles of TIGAR in NSCs and the possible involvement of metabolic reprogramming in the TIGAR regulatory network. We observed that TIGAR is significantly increased during brain development as neural differentiation proceeds, especially at the peak of NSC differentiation (E14.5-E16.5). In cultured NSCs, knockdown of TIGAR reduced the expression of microtubule-associated protein 2 (MAP2), neuron-specific class III beta-tubulin (Tuj1), glial fibrillary acidic protein (GFAP), Ngn1, and NeuroD1, and enhanced the expression of REST, suggesting that TIGAR is an important regulator of NSC differentiation. Furthermore, TIGAR enhanced the expression of lactate dehydrogenase B (LDHB) and the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) markers, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α), nuclear respiratory factor (NRF1), and MitoNEET during NSC differentiation. TIGAR can decrease lactate production and accelerate oxygen consumption and ATP generation to maintain a high rate of OXPHOS in differentiated NSCs. Interestingly, knockdown of TIGAR decreased the level of acetyl-CoA and H3K9 acetylation at the promoters of Ngn1, Neurod1, and Gfap. Acetate, a precursor of acetyl-CoA, increased the level of H3K9 acetylation and rescued the effect of TIGAR deficiency on NSC differentiation. Together, our data demonstrated that TIGAR promotes metabolic reprogramming and regulates NSC differentiation through an epigenetic mechanism.

Redox properties of humic substances under different environmental conditions.

Humic substances (HS) are one of the most important parts of dissolved organic matter which are ubiquitous in environments playing an important role in many (bio)geochemical processes. In order to define the effects of environmental conditions on the biological transformation of compounds in the presence of HS, microbial reduction rates of ferrihydrite under different HS concentrations, environmental temperature, and pH values were determined. The results showed that increasing the concentration of standard humic substances (Pahokee peat standard humic acids (PPHA) or Pahokee peat standard fulvic acids (PPFA)) purchased from the International Humic Substances Society could compensate for the certain gap of reduction rates between low temperature (10 °C) and high temperature (35 °C). Furthermore, PPHA showed a greater stimulation of Fe(III) reduction than PPFA in common groundwater temperature (10-25 °C). The reduction rates decreased significantly when pH values were greater than 7.7 with total organic carbon (TOC) contents above 5 mg C/L, and protein-like fluorophore was detected here. When pH values were lower than 7.7, the PPHA fluorescence characteristic primarily showed humic-like fluorophore composed of quinone-like fluorophore, which corresponds to a high microbial reduction rate. The finding of this study is that fluorophore characteristics of HS linked to the microbial reduction rate under different environment conditions are able to provide a potential development for in-suit remediation process prediction.