Pediococcus pentosaceus ZZ61 enhances growth performance and pathogenic resistance of silkworm Bombyx mori by regulating gut microbiota and metabolites.

Probiotics have attracted considerable attention in animal husbandry due to their positive effect on animal growth and health. This study aimed to screen candidate probiotic strain promoting the growth and health of silkworm and reveal the potential mechanisms. A novel probiotic Pediococcus pentosaceus strain (ZZ61) substantially promoted body weight gain, feed efficiency, and silk yield. These effects were likely mediated by changes in the intestinal digestive enzyme activity and nutrient provisioning (e.g., B vitamins) of the host, improving nutrient digestion and assimilation. Additionally, P. pentosaceus produced antimicrobial compounds and increased the antioxidant capacity to protect the host against pathogenic infection. Furthermore, P. pentosaceus affected the gut microbiome and altered the levels of gut metabolites (e.g., glycine and glycerophospholipids), which in turn promotes host nutrition and health. This study contributes to an improved understanding of the interactions between probiotic and host and promotes probiotic utilization in sericulture.

A new phenolic compound from Persicaria capitata.

Persicaria capitata was a frequently used Hmong medicinal flora in China. In this study, one new phenolic compound, capitaone A (1) together with 20 known ones, were isolated from the whole herb of P. capitata. Among them, 7 components (4, 9-11, 15-16, 20-21) were discovered from P. capitata for the first time. Their chemical structures were elucidated on the basis of extensive NMR and MS spectrum. Furthermore, three compounds (15, 20, 21) displayed remarkable cytotoxic activities against two human cancer cell lines (A549 and HepG2).

tiRNA-Val-CAC-2 interacts with FUBP1 to promote pancreatic cancer metastasis by activating c­MYC transcription.

Cumulative studies have established the significance of transfer RNA-derived small RNA (tsRNA) in tumorigenesis and progression. Nevertheless, its function and mechanism in pancreatic cancer metastasis remain largely unclear. Here, we screened and identified tiRNA-Val-CAC-2 as highly expressed in pancreatic cancer metastasis samples by tsRNA sequencing. We also observed elevated levels of tiRNA-Val-CAC-2 in the serum of pancreatic cancer patients who developed metastasis, and patients with high levels of tiRNA-Val-CAC-2 exhibited a worse prognosis. Additionally, knockdown of tiRNA-Val-CAC-2 inhibited the metastasis of pancreatic cancer in vivo and in vitro, while overexpression of tiRNA-Val-CAC-2 promoted the metastasis of pancreatic cancer. Mechanically, we discovered that tiRNA-Val-CAC-2 interacts with FUBP1, leading to enhanced stability of FUBP1 protein and increased FUBP1 enrichment in the c-MYC promoter region, thereby boosting the transcription of c-MYC. Of note, rescue experiments confirmed that tiRNA-Val-CAC-2 could influence pancreatic cancer metastasis via FUBP1-mediated c-MYC transcription. These findings highlight a potential novel mechanism underlying pancreatic cancer metastasis, and suggest that both tiRNA-Val-CAC-2 and FUBP1 could serve as promising prognostic biomarkers and potential therapeutic targets for pancreatic cancer.

The m6A modification-mediated positive feedback between glycolytic lncRNA SLC2A1-DT and c-Myc promotes tumorigenesis of hepatocellular carcinoma.

Glycolysis exerts a key role in the metabolic reprogramming of cancer. Specific long non-coding RNAs (lncRNAs) have been identified to exhibit oncogenic glycolysis regulation. Nevertheless, the precise mechanisms by which glycolysis-related lncRNAs control hepatocellular carcinoma (HCC) are still unknown. We profiled and analyzed glycolysis-associated lncRNA signatures using HCC specimens from The Cancer Genome Atlas (TCGA) dataset. Considerable upregulation of the glycolysis-related lncRNA SLC2A1-DT was noted in HCC tissues; this upregulation was strongly linked with advanced tumor stage and poor prognosis. Cell culture and animal-related studies indicated that knockdown or overexpression of SLC2A1-DT obviously restrained or promoted glycolysis, propagation, and metastasis in HCC cells. Mechanistically, SLC2A1-DT enhanced the interaction of protein between ß-catenin and YWHAZ, suppressing the binding between ß-catenin and ß-TrCP, an E3 ubiquitin ligase. Thereby, SLC2A1-DT impeded the ß-TrCP-dependent ubiquitination and ß-catenin degradation. The upregulated ß-catenin activated the transcription of c-Myc, which then increased the transcription of glycolytic genes including SLC2A1, LDHA, and HK2. Additionally, we revealed that c-Myc transcriptionally induced the expression of methyltransferase 3 (METTL3), which increased N6-methyladenosine (m6A) modification and stability of SLC2A1-DT in a YTHDF1 dependent manner. Collectively, we show that the lncRNA SLC2A1-DT promotes glycolysis and HCC tumorigenesis by a m6A modification-mediated positive feedback mechanism with glycolytic regulator c-Myc and suggested as an innovative treatment option and indicator for HCC.

[The Three-dimensional Environment of Type â Collagen Gels With Varying Stiffness Modulates the Immunological Functions of NK Cells]. / 不同刚度â 型胶原凝胶三维环境调控NKç»†èƒžå ç–«åŠŸèƒ½.

Objective: To construct type Ⅰ collagen gels with different stiffness and to investigate the effects of three-dimensional (3D) culture environments of the gels on the morphology, free migration ability, and cell killing function of natural killer (NK) cells. Methods: Type Ⅰ collagen was isolated from the tails of Sprague Dawley (SD) rats and collagen gels with different levels of stiffnesses were prepared accordingly. The microstructure of the collagen gels was observed by laser confocal microscopy. The stiffness of the collagen gels was assessed by measuring the plateau modulus with a rheometer. NK-92MI cells were cultured in collagen gels with different levels of stiffness. The morphology of NK-92MI cells was observed by inverted microscope. High content imaging system was used to record the free migration process of NK-92MI cells and analyze the migration speed and distance. NK-92MI cells were cultured with type Ⅰ collagen gels with different levels of stiffness for 24 h and 48 h and, then, co-cultured with human colorectal DLD-1, a human adenocarcinoma epithelial cell line. CCK8 assay was performed to determine the proliferation rate of DLD-1 cells and analyze the cell killing ability of NK-92MI cells. Results: Low-stiffness type Ⅰ collagen gel and high-stiffness type Ⅰ collagen gel with the respective stiffness of (10.970±2.10) Pa and (114.50±3.40) Pa were successfully prepared. Compared with those cultured with the low-stiffness type Ⅰ collagen gel, the NK-92MI cells in the high-stiffness type Ⅰ collagen gel showed a more elongated shape (P<0.05), the mean area of the cells was reduced ([69.88±26.97] µm2 vs. [46.59±21.62] µm2, P<0.05), the roundness of the cells decreased (0.82±0.12 vs. 0.78±0.18, P<0.05), cell migration speed decreased ([2.50±0.91] µm/min vs. [1.70±0.72] µm/min, P<0.001) and the migration distance was shortened ([147.10±53.74] µm vs. [98.03± 40.95] µm, P<0.0001), with all the differences being statistically significant. Compared with those cultured with the low-stiffness type Ⅰ collagen gel, NK-92MI cells cultured with high-stiffness type Ⅰ collagen gel for 24 h could promote DLD-1 cell proliferation, with the proliferation rate being (46.39±12.79)% vs. (65.87±4.45)% (P<0.05) and reduce the cell killing ability. Comparison of the cells cultured for 48 h led to similar results, with the proliferation rates being (31.36±2.88)% vs. (74.57±2.16)% (P<0.05), and the differences were all statistically significant. Conclusion: The 3D culture environment of type Ⅰ collagen gels with different levels of stiffness alters the morphology, migration ability, and killing function of NK-92MI cells. This study provides the research basis for exploring and understanding the mechanisms by which the biomechanical microenvironment affects the immune response of NK cells, as well as laying the theoretical foundation for optimizing immunotherapy protocols.

New Insights into the Role of Humic Acid in Permanganate Oxidation of Diclofenac: A Novel Electron Transfer Mechanism.

Humic acid (HA) ubiquitously existing in aquatic environments has been reported to significantly impact permanganate (KMnO4) decontamination processes. However, the underlying mechanism of the KMnO4/HA system remained elusive. In this study, an enhancing effect of HA on the KMnO4 oxidation of diclofenac (DCF) was observed over a wide solution pH range of 5-9. Surprisingly, the mechanism of HA-induced enhancement varied with solution pH. Quenching and chemical probing experiments revealed that manganese intermediates (Mn(III)-HA and MnO2) were responsible for the enhancement under acidic conditions but not under neutral and alkaline conditions. By combining KMnO4 decomposition, galvanic oxidation process experiments, electrochemical tests, and FTIR and XPS analysis, it was interestingly found that HA could effectively mediate the electron transfer from DCF to KMnO4 in neutral and alkaline solutions, which was reported for the first time. The formation of an organic-catalyst complex (i.e., HA-DCF) with lower reduction potential than the parent DCF was proposed to be responsible for the accelerated electron transfer from DCF to KMnO4. This electron transfer likely occurred within the complex molecule formed through the interaction between HA-DCF and KMnO4 (i.e., HA-DCF-KMnO4). These results will help us gain a more comprehensive understanding of the role of HA in the KMnO4 oxidation processes.

IL-8 from CD248-expressing cancer-associated fibroblasts generates cisplatin resistance in non-small cell lung cancer.

Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.

Identification of Hub Genes and Prediction of Targeted Drugs for Rheumatoid Arthritis and Idiopathic Pulmonary Fibrosis.

There is a potential link between rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). The aim of this study is to investigate the molecular processes that underlie the development of these two conditions by bioinformatics methods. The gene expression samples for RA (GSE77298) and IPF (GSE24206) were retrieved from the Gene Expression Omnibus (GEO) database. After identifying the overlapping differentially expressed genes (DEGs) for RA and IPF, we conducted functional annotation, protein-protein interaction (PPI) network analysis, and hub gene identification. Finally, we used the hub genes to predict potential medications for the treatment of both disorders. We identified 74 common DEGs for further analysis. Functional analysis demonstrated that cellular components, biological processes, and molecular functions all played a role in the emergence and progression of RA and IPF. Using the cytoHubba plugin, we identified 7 important hub genes, namely COL3A1, SDC1, CCL5, CXCL13, MMP1, THY1, and BDNF. As diagnostic indicators for RA, SDC1, CCL5, CXCL13, MMP1, and THY1 showed favorable values. For IPF, COL3A1, SDC1, CCL5, CXCL13, THY1, and BDNF were favorable diagnostic markers. Furthermore, we predicted 61 Chinese and 69 Western medications using the hub genes. Our research findings demonstrate a shared pathophysiology between RA and IPF, which may provide new insights for more mechanistic research and more effective treatments. These common pathways and hub genes identified in our study offer potential opportunities for developing more targeted therapies that can address both disorders.

Aberrant R-loop-mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis.

Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality of aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an R-loop scoring model to characterize the R-loop state according to the identified R-loop regulators related to EGFR mutations, tissue origins, and TNM stage. We then evaluated the relationships of the R-loop score with the tumor microenvironment (TME) and treatment response. Furthermore, the potential roles of FANCI-mediated R-loops in LUAD were explored using a series of in vitro experiments. Results showed that malignant cells with low R-loop scores displayed glycolysis and epithelial-mesenchymal transition pathway activation and immune escape promotion, thereby hampering the antitumor therapeutic effects. Cell communication analysis suggested that low R-loop scores contributed to T cell exhaustion. We subsequently validated the prognostic value of R-loop scores by using bulk transcriptome datasets across 33 tumor types. The R-loop scoring model well predicted patients' therapeutic response to targeted therapy, chemotherapy, or immunotherapy in 32 independent cohorts. Remarkably, changes in R-loop distribution mediated by FANCI deficiency blocked the activity of Ras signaling pathway, suppressing tumor-cell proliferation and dissemination. In conclusion, this study reveals the underlying molecular mechanism of metabolic reprogramming and T cell exhaustion under R-loop score patterns, and the changes in R-loops mediated by R-loop regulators resulting in tumor progression. Therefore, incorporating anticancer methods based on R-loop or R-loop regulators into the treatment schemes of precision medicine may be beneficial.

[Research progress of interaction between CAFs and M2 macrophages to promote tumor progression].

Cancer associated fibroblasts (CAFs) are one of the main components of tumor microenvironment (TME). In TME, the interaction between tumor cells and non-tumor cells or among non tumor cells can promote the occurrence and development of tumors. CAFs can interact with a variety of immune cells and promote the occurrence and development of tumors by inhibiting the function of adaptive immune cells and reshaping the immune microenvironment in TME. The interaction between CAFs and macrophages and the induction of macrophage polarization towards M2 type play an important role in promoting tumor occurrence and development. This article reviews the research progress of CAF in promoting the polarization of M2 macrophages.

Comparative study of Fe(II)/sulfite, Fe(II)/PDS and Fe(II)/PMS for p-arsanilic acid treatment: Efficient organic arsenic degradation and contrasting total arsenic removal.

As a widely used feed additives, p-arsanilic acid (p-AsA) frequently detected in the environment poses serious threats to aquatic ecology and water security due to its potential in releasing more toxic inorganic arsenic. In this work, the efficiency of Fe(II)/sulfite, Fe(II)/PDS and Fe(II)/PMS systems in p-AsA degradation and simultaneous arsenic removal was comparatively investigated for the first time. Efficient p-AsA abatement was achieved in theses Fe-based systems, while notable discrepancy in total arsenic removal was observed under identical acidic condition. By using chemical probing method, quenching experiments, isotopically labeled water experiments, p-AsA degradation was ascribed to the combined contribution of high-valent Fe(IV) and SO4•-in these Fe(II)-based system. In particular, the relative contribution of Fe(IV) and SO4•- in the Fe(II)/sulfite system was highly dependent on the molar ratio of [Fe(II)] and [sulfite]. Negligible arsenic removal was observed in the Fe(II)/sulfite and Fe(II)/PDS systems, while ∼80% arsenic was removed in the Fe(II)/PMS system under identical acidic condition. This interesting phenomenon was due to that ferric precipitation only occurred in the Fe(II)/PMS system. As(V) was further removed via adsorption onto the iron precipitate or the formation of ferric arsenate-sulfate compounds, which was confirmed by particle diameter measurements, fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Through tuning solution pH, complete removal of total arsenic could achieve in all three systems. Among these three Fe-based technologies, the hybrid oxidation-coagulation Fe(II)/PMS system demonstrated potential superiority for arsenic immobilization by not requiring pH adjustment for coagulation and facilitating the in-situ generation of ferric arsenate-sulfate compounds with comparably low solubility levels like scorodite. These findings would deepen the understanding of these three Fe-based Fenton-like technologies for decontamination in water treatment.

Clinical impact of metagenomic next-generation sequencing of peripheral blood for the diagnosis of invasive mucormycosis: a single-center retrospective study.

IMPORTANCE: Given the high fatality rates, prompt and accurate identification of the fungal culprit is crucial, emphasizing the need for invasive mucormycosis. Unfortunately, mucormycosis lacks definitive biomarkers, depending primarily on smears, cultures, or pathology, all necessitating invasive specimen collection from the infection site. However, obtaining valid specimens early in critically ill patients poses substantial risks and challenges. Whether peripheral blood metagenomic next-generation sequencing (mNGS) can enhance early mucormycosis diagnosis, especially when direct specimen collection from the infection site is challenging, is warranted. This is a large-scale clinical study conducted to evaluate the utility and clinical impact of mNGS of peripheral blood for the diagnosis of invasive mucormycosis. We believe our study provided both novelty in translational medicine and a great value for the medical community to understand the strengths and limitations of mNGS of peripheral blood as a new diagnostic tool for the diagnosis and management of invasive mucormycosis.

The application of nanopore targeted sequencing for pathogen diagnosis in bronchoalveolar lavage fluid of patients with pneumonia: a prospective multicenter study.

OBJECTIVE: To evaluate the value of nanopore targeted sequencing in diagnosing pneumonia pathogens. METHODS: This large-scale multicentre prospective study performed in 8 hospitals across China from April to October 2022. Hospitalised patients with a diagnosis of pneumonia at admission were included. Complete clinical data were collected, and bronchoalveolar lavage fluid were obtained from each patient. These samples underwent simultaneous testing using conventional microbial testing, metagenomic next-generation sequencing, and nanopore targeted sequencing. RESULTS: A total of 218 patients were included. Among the 168 cases of pulmonary infection, 246 strains of pathogens were confirmed. Nanopore targeted sequencing outperformed conventional microbial testing, identifying more pathogens with a sensitivity increase of 47.9% (77.2% vs. 29.3%). Metagenomic next-generation sequencing had a sensitivity of 82.9%. Total of 70.1% patients had consistent results in both metagenomic next-generation sequencing and nanopore targeted sequencing. Nanopore targeted sequencing exhibited significantly higher sensitivity in detecting Pneumocystis jiroveci, cytomegalovirus, Mycobacterium tuberculosis, Nontuberculous mycobacteria, Streptococcus pneumoniae, and Mycoplasma pneumoniae compared to conventional microbial testing. However, metagenomic next-generation sequencing demonstrated higher sensitivity than nanopore targeted sequencing for Aspergillus (88.5% vs. 53.8%). Regarding the detection of co-infections, nanopore targeted sequencing displayed significantly higher sensitivity than conventional microbial testing (76.7% vs. 28.7%) and was on par with metagenomic next-generation sequencing (76.7% vs. 82.9%). CONCLUSION: Nanopore targeted sequencing performs equally well as metagenomic next-generation sequencing in bronchoalveolar lavage fluid for pathogen diagnosis in pneumonia, both methods showing higher sensitivity than conventional microbial testing. Nanopore targeted sequencing can be considered a reliable method for diagnosing pathogens in pneumonia.

Oxidation of amine-based pharmaceuticals with unactivated peroxymonosulfate: Kinetics, mechanisms, and elimination efficiency of NDMA formation.

Amine-based pharmaceuticals are a significant class of N-nitrosodimethylamine (NDMA) precursors. This study investigated the use of unactivated peroxymonosulfate (PMS) to control amine-based pharmaceuticals and their NDMA formation potential. Kinetic analysis and product identification revealed that sumatriptan and doxylamine primarily underwent reactions at their tertiary amine group, while ranitidine and nizatidine had both tertiary amine and thioether group as reaction sites. The NDMA formation from sumatriptan and doxylamine during post-chloramination was significantly reduced with the abatement of the parent contaminants, while the formation of NDMA remained high even if full abatement of ranitidine and nizatidine was achieved. Product formation kinetics and reference standard tests revealed the great contribution of transformation products to NDMA formation. Ranitidine could be oxidized to sulfoxide-type product ranitidine-SO and N-oxide type product ranitidine-NO. Ranitidine-SO exhibited a high NDMA yield comparable to that of ranitidine (>90%), while ranitidine-NO showed a low NDMA yield (2%). With further oxidation of ranitidine-SO at the tertiary amine group, NDMA formation was reduced by more than 90%. The underlying mechanism for the importance of the tertiary amine group in NDMA formation was demonstrated by quantum chemical calculation. These findings underscore the potential of PMS pre-oxidation on NDMA control.

Computational Insight into the Nature and Strength of the π-Hole Type Chalcogen∙∙∙Chalcogen Interactions in the XO2∙∙∙CH3YCH3 Complexes (X = S, Se, Te; Y = O, S, Se, Te).

In recent years, the non-covalent interactions between chalcogen centers have aroused substantial research interest because of their potential applications in organocatalysis, materials science, drug design, biological systems, crystal engineering, and molecular recognition. However, studies on π-hole-type chalcogen∙∙∙chalcogen interactions are scarcely reported in the literature. Herein, the π-hole-type intermolecular chalcogen∙∙∙chalcogen interactions in the model complexes formed between XO2 (X = S, Se, Te) and CH3YCH3 (Y = O, S, Se, Te) were systematically studied by using quantum chemical computations. The model complexes are stabilized via one primary X∙∙∙Y chalcogen bond (ChB) and the secondary C-H∙∙∙O hydrogen bonds. The binding energies of the studied complexes are in the range of -21.6~-60.4 kJ/mol. The X∙∙∙Y distances are significantly smaller than the sum of the van der Waals radii of the corresponding two atoms. The X∙∙∙Y ChBs in all the studied complexes except for the SO2∙∙∙CH3OCH3 complex are strong in strength and display a partial covalent character revealed by conducting the quantum theory of atoms in molecules (QTAIM), a non-covalent interaction plot (NCIplot), and natural bond orbital (NBO) analyses. The symmetry-adapted perturbation theory (SAPT) analysis discloses that the X∙∙∙Y ChBs are primarily dominated by the electrostatic component.

LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2.

BACKGROUND: Long non-coding RNAs (LncRNAs) have been extensively studied to play essential roles in tumor progression. However, more in-depth studies are waiting to be solved on how lncRNAs regulate the progression of hepatocellular carcinoma (HCC). METHODS: Different expression levels of lncRNAs in HCC cells were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The effects of lncRNA FTO Intronic Transcript 1 (FTO-IT1) on HCC cells were assessed by gain- and loss-of-function experiments. Colony formation assay, Edu assay, glucose uptake and lactic acid production assay were performed to evaluate the regulation of proliferation and glycolysis of HCC cells by FTO-IT1. The binding between protein interleukin enhancer binding factor 2/3 (ILF2/ILF3) and FTO-IT1 was determined by RNA pull-down, mass spectroscopy and RNA immunoprecipitation experiments. RNA stability assay, quantitative reverse transcription PCR and Western blot were employed to determine the regulatory mechanisms of FTO-IT1 on fat mass and obesity-associated (FTO). Methylated RNA immunoprecipitation assay was used to assessed the regulation of key enzymes of glycolysis by FTO. The role of FTO-IT1/FTO in vivo was confirmed via xenograft tumor model. RESULTS: LncRNA FTO-IT1, an intronic region transcript of FTO gene, was highly expressed in HCC and associated with poor prognosis of patients with HCC. FTO-IT1 was related to proliferation and glycolysis of HCC cells, and contributed to the malignant progression of HCC by promoting glycolysis. Mechanistically, FTO-IT1 induced stabilization of FTO mRNA by recruiting ILF2/ILF3 protein complex to 3'UTR of FTO mRNA. As a demethylase for N6-methyladenosine (m6A), FTO decreased m6A modification on mRNAs of glycolysis associated genes including GLUT1, PKM2, and c-Myc which alleviated the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated mRNA degradation. Therefore, the upregulated expression of FTO-IT1 leaded to overexpression of GLUT1, PKM2, and c-Myc by which enhanced glycolysis of HCC. Meanwhile, it was found that c-Myc transcriptional regulated expression of FTO-IT1 by binding to its promoter area under hypo-glucose condition, forming a reciprocal loop between c-Myc and FTO-IT1. CONCLUSIONS: This study identified an important role of the FTO-IT1/FTO axis mediated m6A modification of glycolytic genes contributed to glycolysis and tumorigenesis of HCC, and FTO-IT1 might be served as a new therapeutic target for HCC.

Knocking out Selenium Binding Protein 1 Induces Depressive-Like Behavior in Mice.

Selenium binding protein 1 (SELENBP1) is involved in neurologic disorders, such as multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and schizophrenia. However, the role of SELENBP1 in the neurogenesis of depression, which is a neurologic disorder, and the underlying mechanisms of oxidative stress and inflammation in depression remain unknown. In this study, we evaluated the changes in the expression levels of SELENBP1 in the hippocampus of a mouse model of depression and in the serum of human patients with depression using the Gene Expression Omnibus database. These changes were validated using blood samples from human patients with depression and mouse models with chronic unpredictable mild stress (CUMS)-induced depressive-like behavior. We also investigated the effects of SELENBP1 knockout (KO) on inflammation, oxidative stress, and hippocampal neurogenesis in mice with CUMS-induced depression. Our results revealed that SELENBP1 levels was decreased in the blood of human patients with depression and in the hippocampus of mice with CUMS-induced depression. SELENBP1 KO increased CUMS-induced depressive behavior in mice and caused dysregulation of inflammatory cytokines and oxidative stress. This led to a decrease in the numbers of doublecortin- and Ki67-positive cells, which might aggravate CUMS-induced depressive symptoms. These findings suggest that SELENBP1 might be involved in the regulation of neurogenesis in mice with depression and could be served as a potential target for diagnosing and treating depression.

Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming.

Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs' immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (Treg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Ameliorative Effects of Lactobacillus paracasei L14 on Oxidative Stress and Gut Microbiota in Type 2 Diabetes Mellitus Rats.

Bioprospecting of more novel probiotic strains has attained continuous interest. This study aimed to investigate the beneficial effects of Lactobacillus paracasei strain L14, an isolate from a traditional Chinese dairy product, on type 2 diabetes mellitus (T2DM) rats. Preventive supplementation of strain L14 showed excellent anti-diabetic effects on high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM rats. It significantly reduced hyperglycemia, protected pancreatic ß-cell and liver function, and ameliorated oxidative stress while considerably improving dyslipidemia and inflammation. Furthermore, the strain modulated the gut microbiota to alleviate gut dysbiosis. Interestingly, most of these biochemical parameters could even restore to normal levels by the intervention of strain L14. The whole-genome sequencing of L14 was performed to provide a critical molecular basis for its probiotic activities. Genes related to antioxidant systems and other beneficial microbial metabolites like exopolysaccharides (EPS) biosynthesis were found. This study demonstrates that probiotic L. paracasei L14 has good potential for applications in functional food and pharmaceutical industries.

An electrochemical biosensor based on network-like DNA nanoprobes for detection of mesenchymal circulating tumor cells.

The identification and detection of mesenchymal circulating tumor cells （mCTCs） is important for early warning of tumor metastasis. The majority of conventional detection methods for CTCs rely on the recognition of epithelial biomarkers, which is technically challenging for detecting CTCs with epithelial-mesenchymal transition (EMT)-induced phenotypic alteration. In this work, we have constructed a label-free biosensor for sensitive electrochemical assay of mCTCs. In our design, the capture probe can recognize the vimentin overexpressed on the surface of mCTCs with high specificity. Meantime, the network-like DNA nanoprobes with multiple G-quadruplex/hemin complexes and multiple cholesterol molecules can be grafted to the cell surface based on the high affinity between cholesterol molecules and cell membrane. Owing to the mimic horseradish peroxidase of G-quadruplex/hemin complexes, strong electrochemical responses will be obtained for sensitive quantification of mCTCs with a detection limit of 8 cell mL-1. Moreover, the biosensor can effectively overcome the interference of vimentin negative cells or secretory vimentin, and realize the recovery tests in whole blood with high accuracy, thereby may further promoting the diagnosis and personalized treatment of cancer in clinic.