NF1 mutation drives neuronal activity-dependent initiation of optic glioma.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth.

Pediatric low-grade gliomas (LGGs) frequently do not engraft in immunocompromised mice, limiting their use as an experimental platform. In contrast, murine Neurofibromatosis-1 (Nf1) optic LGG stem cells (o-GSCs) form glioma-like lesions in wild-type, but not athymic, mice following transplantation. Here, we show that the inability of athymic mice to support o-GSC engraftment results from impaired microglia/macrophage function, including reduced expression of Ccr2 and Ccl5, both of which are required for o-GSC engraftment and Nf1 optic glioma growth. Impaired Ccr2 and Ccl5 expression in athymic microglia/macrophages was restored by T-cell exposure, establishing T-cell-microglia/macrophage interactions as critical stromal determinants that support NF1 LGG growth.

Knockdown of LAP2α inhibits adipogenesis of human adipose-derived stem cells and ameliorates high-fat diet-induced obesity.

Adipogenesis, a pivotal cellular process involving the differentiation of mesenchymal stem cells (MSCs) to mature adipocytes, plays a significant role in various physiological functions. Dysregulation of adipogenesis is implicated in conditions such as obesity. However, the complete molecular understanding of adipogenesis remains elusive. This study aimed to uncover the novel role of lamina-associated polypeptide 2 alpha (LAP2α) in human adipose-derived stem cells (hASCs) adipogenesis and its impact on high-fat diet (HFD)-induced obesity and associated metabolic disturbances. LAP2α expression was assessed during the adipogenic differentiation of hASCs using RT-qPCR and western blotting. The functional role of LAP2α in adipogenesis was explored both in vitro and in vivo through loss- and gain-of-function studies. Moreover, mice with HFD-induced obesity received lentivirus injection to assess the effect of LAP2α knockdown on fat accumulation. Molecular mechanisms underlying LAP2α in adipogenic differentiation were investigated using RT-qPCR, Western blotting, immunofluorescence staining, and Oil Red O staining. LAP2α expression was upregulated during hASCs adipogenic differentiation. LAP2α knockdown hindered adipogenesis, while LAP2α overexpression promoted adipogenic differentiation. Notably, LAP2α deficiency resisted HFD-induced obesity, improved glucose intolerance, mitigated insulin resistance, and prevented fatty liver development. Mechanistically, LAP2α knockdown attenuated signal transducer and activator of transcription 3 (STAT3) activation by reducing the protein level of phosphorylated STAT3. A STAT3 activator (Colivelin) counteracted the negative impact of LAP2α deficiency on hASCs adipogenic differentiation. Taken together, our current study established LAP2α as a crucial regulator of hASCs adipogenic differentiation, unveiling a new therapeutic target for obesity prevention.

The power of the few.

Converging evidence from numerous laboratories has revealed that malignant brain cancers are complex ecological systems composed of distinct cellular and acellular elements that collectively dictate glioblastoma biology. Our understanding of the individual contributions of each of these components is vital to the design of effective therapies against these cancers. In this issue of Genes & Development, Zanca and colleagues (pp. 1212-1227) demonstrate that one subpopulation of glioblastoma cells expressing a mutant epidermal growth factor receptor (EGFRvIII) is responsible for the survival of non-EGFRvIII-expressing tumor cells as well as for evading molecularly targeted therapy.

Atomic-Level Regulation of Cu-Based Electrocatalyst for Enhancing Oxygen Reduction Reaction: From Single Atoms to Polymetallic Active Sites.

The slow kinetics of cathodic oxygen reduction reactions (ORR) in fuel cells and the high cost of commercial Pt-based catalysts limit their large-scale application. Cu-based single-atom catalysts (SACs) have received increasing attention as a promising ORR catalyst due to their high atom utilization, high thermodynamic activity, adjustable electronic structure, and low cost. Herein, the recent research progress of Cu-based catalysts is reviewed from single atom to polymetallic active sites for ORR. First, the design and synthesis method of Cu-based SACs are summarized. Then the atomic-level structure regulation strategy of Cu-based catalyst is proposed to improve the ORR performance. The different ORR catalytic mechanism based on the different Cu active sites is further revealed. Finally, the design principle of high-performance Cu-based SACs is proposed for ORR and the opportunities and challenges are further prospected.

High-Performance Photoinduced Tunneling Self-Driven Photodetector for Polarized Imaging and Polarization-Coded Optical Communication based on Broken-Gap ReSe2 /SnSe2 van der Waals Heterojunction.

Novel 2D materials with low-symmetry structures exhibit great potential applications in developing monolithic polarization-sensitive photodetectors with small volume. However, owing to the fact that at least half of them presented a small anisotropic factor of ≈2, comprehensive performance of present polarization-sensitive photodetectors based on 2D materials is still lower than the practical application requirements. Herein, a self-driven photodetector with high polarization sensitivity using a broken-gap ReSe2 /SnSe2 van der Waals heterojunction (vdWH) is demonstrated. Anisotropic ratio of the photocurrent (Imax /Imin ) could reach 12.26 (635 nm, 179 mW cm-2 ). Furthermore, after a facile combination of the ReSe2 /SnSe2 device with multilayer graphene (MLG), Imax /Imin of the MLG/ReSe2 /SnSe2 can be further increased up to13.27, which is 4 times more than that of pristine ReSe2 photodetector (3.1) and other 2D material photodetectors even at a bias voltage. Additionally, benefitting from the synergistic effect of unilateral depletion and photoinduced tunneling mechanism, the MLG/ReSe2 /SnSe2 device exhibits a fast response speed (752/928 µs) and an ultrahigh light on/off ratio (105 ). More importantly, MLG/ReSe2 /SnSe2 device exhibits excellent potential applications in polarized imaging and polarization-coded optical communication with quaternary logic state without any power supply. This work provides a novel feasible avenue for constructing next-generation smart polarization-sensitive photodetector with low energy consumption.

The RIG-I-NRF2 axis regulates the mesenchymal stromal niche for bone marrow transplantation.

Bone marrow-derived mesenchymal stem cells (BMSCs) support bone formation and constitute the stromal niche in regulating hematopoietic stem cells (HSCs). Stromal niche dysfunction affects HSC engraftment during transplantation; however, the underlying mechanisms remain elusive. In the present study, we found that all-trans retinoic acid (ATRA) and inflammation stress upregulated retinoic acid-inducible gene I (RIG-I) in BMSCs. Excess RIG-I expression damaged the clonogenicity, bone-forming ability of BMSCs and particularly their stromal niche function that supports HSC expansion in vitro and engraftment in vivo. Mechanistically, RIG-I elevation promoted the degradation of NRF2, a checkpoint for antioxidant cellular response, by altering the RIG-I-Trim25-Keap1-NRF2 complex, leading to reactive oxygen species (ROS) accumulation and BMSC damage. Genetic inhibition of RIG-I sustained NRF2 protein levels and reduced ROS levels in ATRA-treated BMSCs, thus preserving their clonogenicity, bone-forming ability, and stromal niche function in supporting HSC engraftment in mice. More importantly, RIG-I inhibition recovered the ATRA-treated stromal niche function to enhance HSC engraftment and emergency myelopoiesis for innate immunity against the bacterium Listeria monocytogenes during transplantation. Overall, we identified a noncanonical role of RIG-I in the regulation of the stromal niche for HSC transplantation.

Development and first-in-human study of PSMA-targeted PET tracers with improved pharmacokinetic properties.

PURPOSE: A series of new 68Ga-labeled tracers based on [68Ga]Ga-PSMA-617 were developed to augment the tumor-to-kidney ratio and reduce the activity accumulation in bladder, ultimately minimize radiation toxicity to the urinary system. METHODS: We introduced quinoline group, phenylalanine and decanoic acid into different tracers to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Their binding affinity onto LNCaP cells was determined through in vitro saturation assays and competition binding assays. In vivo metabolic study, PET imaging and biodistribution experiment were performed in LNCaP tumor-bearing B-NSG male mice. The most promising tracer was selected for first-in-human study. RESULTS: Four radiotracers were synthesized with radiochemical purity (RCP) > 95% and molar activity in a range of 20.0-25.5 GBq/µmol. The binding affinities (Ki) of TWS01, TWS02 to PSMA were in the low nanomolar range (< 10 nM), while TWS03 and TWS04 exhibited binding affinities with Ki > 20 nM (59.42 nM for TWS03 and 37.14 nM for TWS04). All radiotracers exhibited high stability in vivo except [68Ga]Ga-TWS03. Micro PET/CT imaging and biodistribution analysis revealed that [68Ga]Ga-TWS02 enabled clear tumor visualization in PET images at 1.5 h post-injection, with higher tumor-to-kidney ratio (T/K, 0.93) and tumor-to-muscle ratio (T/M, 107.62) compared with [68Ga]Ga-PSMA-617 (T/K: 0.39, T/M: 15.01) and [68Ga]Ga-PSMA-11 (T/K: 0.15, T/M: 24.00). In first-in-human study, [68Ga]Ga-TWS02 effectively detected PCa-associated lesions including primary and metastatic lesions, with lower accumulation in urinary system, suggesting that [68Ga]Ga-TWS02 might be applied in the detection of bladder invasion, with minimized radiation toxicity to the urinary system. CONCLUSION: Introduction of quinoline group, phenylalanine and decanoic acid into different tracers can modulate the binding affinity and pharmacokinetics of PSMA in vivo. [68Ga]Ga-TWS02 showed high binding affinity to PSMA, excellent pharmacokinetic properties and clear imaging of PCa-associated lesions, making it a promising radiotracer for the clinical diagnosis of PCa. Moreover, TWS02 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for PCa treatment without significant side effects. TRIAL REGISTRATION: The clinical evaluation of this study was registered On October 30, 2021 at https://www.chictr.org.cn/ (No: ChiCTR2100052545).

Deciphering the Roles of Extracellular Polymeric Substances (EPS) in Shaping Disinfection Kinetics through Permanent Removal via Genetic Disruption.

Extracellular polymeric substances (EPS) ubiquitously encapsulate microbes and play crucial roles in various environmental processes. However, understanding their complex interactions with dynamic bacterial behaviors, especially during the disinfection process, remains very limited. In this work, we investigated the impact of EPS on bacterial disinfection kinetics by developing a permanent EPS removal strategy. We genetically disrupted the synthesis of exopolysaccharides, the structural components of EPS, in Pseudomonas aeruginosa, a well-known EPS-producing opportunistic pathogen found in diverse environments, creating an EPS-deficient strain. This method ensured a lasting absence of EPS while maintaining bacterial integrity and viability, allowing for real-time in situ investigations of the roles of EPS in disinfection. Our findings indicate that removing EPS from bacteria substantially lowered their susceptibility threshold to disinfectants such as ozone, chloramine B, and free chlorine. This removal also substantially accelerated disinfection kinetics, shortened the resistance time, and increased disinfection efficiency, thereby enhancing the overall bactericidal effect. The absence of EPS was found to enhance bacterial motility and increase bacterial cell vulnerability to disinfectants, resulting in greater membrane damage and intensified reactive oxygen species (ROS) production upon exposure to disinfectants. These insights highlight the central role of EPS in bacterial defenses and offer promising implications for developing more effective disinfection strategies.

Machine Learning-Assisted Optimization of Mixed Carbon Source Compositions for High-Performance Denitrification.

Appropriate mixed carbon sources have great potential to enhance denitrification efficiency and reduce operational costs in municipal wastewater treatment plants (WWTPs). However, traditional methods struggle to efficiently select the optimal mixture due to the variety of compositions. Herein, we developed a machine learning-assisted high-throughput method enabling WWTPs to rapidly identify and optimize mixed carbon sources. Taking a local WWTP as an example, a mixed carbon source denitrification data set was established via a high-throughput method and employed to train a machine learning model. The composition of carbon sources and the types of inoculated sludge served as input variables. The XGBoost algorithm was employed to predict the total nitrogen removal rate and microbial growth, thereby aiding in the assessment of the denitrification potential. The predicted carbon sources exhibited an enhanced denitrification potential over single carbon sources in both kinetic experiments and long-term reactor operations. Model feature analysis shows that the cumulative effect and interaction among individual carbon sources in a mixture significantly enhance the overall denitrification potential. Metagenomic analysis reveals that the mixed carbon sources increased the diversity and complexity of denitrifying bacterial ecological networks in WWTPs. This work offers an efficient method for WWTPs to optimize mixed carbon source compositions and provides new insights into the mechanism behind enhanced denitrification under a supply of multiple carbon sources.

[Ubiquitin-specific protease 42 regulates osteogenic differentiation of human adipose-derived stem cells].

OBJECTIVE: To explore the effect of ubiquitin-specific protease 42 (USP42) on osteogenic differentiation of human adipose-derived stem cells (hASCs) in vivo and in vitro. METHODS: A combination of experiments was carried out with genetic depletion of USP42 using a lentiviral strategy. Alkaline phosphatase (ALP) staining and quantification, alizarin red S (ARS) staining and quantification were used to determine the osteogenic differentiation ability of hASCs under osteogenic induction between the experimental group (knockdown group and overexpression group) and the control group. Quantitative reverse transcription PCR (qRT-PCR) was used to detect the expression levels of osteogenesis related genes in the experimental group and control group, and Western blotting was used to detect the expression levels of osteogenesis related proteins in the experimental group and control group. Nude mice ectopic implantation experiment was used to evaluate the effect of USP42 on the osteogenic differentiation of hASCs in vivo. RESULTS: The mRNA and protein expressions of USP42 in knockdown group were significantly lower than those in control group, and those in overexpression group were significantly higher than those in control group. After 7 days of osteogenic induction, the ALP activity in the knockdown group was significantly higher than that in the control group, and ALP activity in overexpression group was significantly lower than that in control group. After 14 days of osteogenic induction, ARS staining was significantly deeper in the knockdown group than in the control group, and significantly lighter in overexpression group than in the control group. The results of qRT-PCR showed that the mRNA expression levels of ALP, osterix (OSX) and collagen type Ⅰ (COLⅠ) in the knockdown group were significantly higher than those in the control group after 14 days of osteogenic induction, and those in overexpression group were significantly lower than those in control group. The results of Western blotting showed that the expression levels of runt-related transcription factor 2 (RUNX2), OSX and COLⅠ in the knockout group were significantly higher than those in the control group at 14 days after osteogenic induction, while the expression levels of RUNX2, OSX and COLⅠ in the overexpression group were significantly lower than those in the control group. Hematoxylin-eosin staining of subcutaneous grafts in nude mice showed that the percentage of osteoid area in the knockdown group was significantly higher than that in the control group. CONCLUSION: Knockdown of USP42 can significantly promote the osteogenic differentiation of hASCs in vitro and in vivo, and overexpression of USP42 significantly inhibits in vivo osteogenic differentiation of hASCs, and USP42 can provide a potential therapeutic target for bone tissue engineering.

Cooperative Rh-O5/Ni(Fe) Site for Efficient Biomass Upgrading Coupled with H2 Production.

Designing efficient and durable bifunctional catalysts for 5-hydroxymethylfurfural (HMF) oxidation reaction (HMFOR) and hydrogen evolution reaction (HER) is desirable for the co-production of biomass-upgraded chemicals and sustainable hydrogen, which is limited by the competitive adsorption of hydroxyl species (OHads) and HMF molecules. Here, we report a class of Rh-O5/Ni(Fe) atomic site on nanoporous mesh-type layered double hydroxides with atomic-scale cooperative adsorption centers for highly active and stable alkaline HMFOR and HER catalysis. A low cell voltage of 1.48 V is required to achieve 100 mA cm-2 in an integrated electrolysis system along with excellent stability (>100 h). Operando infrared and X-ray absorption spectroscopic probes unveil that HMF molecules are selectively adsorbed and activated over the single-atom Rh sites and oxidized by in situ-formed electrophilic OHads species on neighboring Ni sites. Theoretical studies further demonstrate that the strong d-d orbital coupling interactions between atomic-level Rh and surrounding Ni atoms in the special Rh-O5/Ni(Fe) structure can greatly facilitate surface electronic exchange-and-transfer capabilities with the adsorbates (OHads and HMF molecules) and intermediates for efficient HMFOR and HER. We also reveal that the Fe sites in Rh-O5/Ni(Fe) structure can promote the electrocatalytic stability of the catalyst. Our findings provide new insights into catalyst design for complex reactions involving competitive adsorptions of multiple intermediates.

Single-Atom Catalysts for Hydrogen Activation.

Selective hydrogenation is one of the most important reactions in fine chemical industry, and the activation of H2 is the key step for hydrogenation. Catalysts play a critical role in selective hydrogenation, and some single-atom catalysts (SACs) are highly capable of activating H2 in selective hydrogenation by virtue of the maximized atom utilization and the highly uniform active sites. Therefore, more research efforts are needed for the rational design of SACs with superior H2 -activating capabilities. Herein, the research progress on H2 activation in typical hydrogenation systems (such as alkyne hydrogenation, hydroformylation, hydrodechlorination, hydrodeoxygenation, nitroaromatics hydrogenation, and polycyclic aromatics hydrogenation) is reviewed, the mechanisms of SACs for H2 activation are summarized, and the structural regulation strategies for SACs are proposed to promote H2 activation and provide schemes for the design of high-selectivity hydrogenation catalysts from the atomic scale. At the end of this review, an outlook on the opportunities and challenges for SACs to be developed for selective hydrogenation is presented.

Ionic Liquid-Assisted Ink for Inkjet-Printed Indium Tin Oxide Transparent and Conductive Thin Films.

Drop-on-demand inkjet printing is used to deposit indium tin oxide (ITO) transparent and conductive thin films. ITO printable ink is prepared by dissolving indium hydroxide and tin (IV) chloride into ethanol with the assistance of acetic acid/tert-butylamine ionic liquid. Ionic liquid-assisted ITO ink exhibits a complete wetting behavior on the glass substrate and a tunable viscosity, which makes it particularly suitable for the inkjet printing fabrication of ITO thin films. After annealing at 500 °C in forming gas, ITO thin films with a sheet resistance of 99 Ω/□, a resistivity of 2.28 × 10-3 Ω·cm, and a transmittance of 95.2% in the range of 400-1000 nm can be obtained. The effects of annealing temperature on the resistivity, mobility, carrier concentration, transmittance, and optical band gap are investigated systematically. Compared with commercial ITO thin films made by conventional vacuum-based deposition approaches, these printable ITO thin films have a higher material utilization.

Genome-wide cross-cancer analysis illustrates the critical role of bimodal miRNA in patient survival and drug responses to PI3K inhibitors.

Heterogeneity of cancer means many tumorigenic genes are only aberrantly expressed in a subset of patients and thus follow a bimodal distribution, having two modes of expression within a single population. Traditional statistical techniques that compare sample means between cancer patients and healthy controls fail to detect bimodally expressed genes. We utilize a mixture modeling approach to identify bimodal microRNA (miRNA) across cancers, find consistent sources of heterogeneity, and identify potential oncogenic miRNA that may be used to guide personalized therapies. Pathway analysis was conducted using target genes of the bimodal miRNA to identify potential functional implications in cancer. In vivo overexpression experiments were conducted to elucidate the clinical importance of bimodal miRNA in chemotherapy treatments. In nine types of cancer, tumors consistently displayed greater bimodality than normal tissue. Specifically, in liver and lung cancers, high expression of miR-105 and miR-767 was indicative of poor prognosis. Functional pathway analysis identified target genes of miR-105 and miR-767 enriched in the phosphoinositide-3-kinase (PI3K) pathway, and analysis of over 200 cancer drugs in vitro showed that drugs targeting the same pathway had greater efficacy in cell lines with high miR-105 and miR-767 levels. Overexpression of the two miRNA facilitated response to PI3K inhibitor treatment. We demonstrate that while cancer is marked by considerable genetic heterogeneity, there is between-cancer concordance regarding the particular miRNA that are more variable. Bimodal miRNA are ideal biomarkers that can be used to stratify patients for prognosis and drug response in certain types of cancer.

Synthesis of 4-Aryl-1,3,4-benzotriazepinones from Isatoic Anhydrides and Hydrazonyl Chlorides.

An efficient synthesis of 4-aryl-1,3,4-benzotriazepinones from readily available isatoic anhydrides and hydrazonyl chlorides was developed. In this facile protocol, a series of functionalized 1,3,4-benzotriazepinones were conveniently obtained with broad substrate scope and excellent functional group tolerance.

Integrating genome-wide association studies with selective sweep reveals genetic loci associated with tolerance to low phosphate availability in Brassica napus.

Oilseed rape (Brassica napus L.; B. napus) is an important oil crop worldwide. However, the genetic mechanisms of B. napus adaptations to low phosphate (P) stress are largely unknown. In this study, a genome-wide association study (GWAS) identified 68 SNPs significantly associated with seed yield (SY) under low P (LP) availability, and 7 SNPs significantly associated with phosphorus efficiency coefficient (PEC) in two trials. Among these SNPs, two, chrC07__39807169 and chrC09__14194798, were co-detected in two trials, and BnaC07.ARF9 and BnaC09.PHT1;2 were identified as candidate genes of them, respectively, by combining GWAS with quantitative reverse-transcription PCR (qRT-PCR). There were significant differences in the gene expression level of BnaC07.ARF9 and BnaC09.PHT1;2 between P-efficient and -inefficiency varieties at LP. SY_LP had a significant positive correlation with the gene expression level of both BnaC07.ARF9 and BnaC09.PHT1;2. BnaC07.ARF9 and BnaA01.PHR1 could directly bind the promoters of BnaA01.PHR1 and BnaC09.PHT1;2, respectively. Selective sweep analysis was conducted between ancient and derived B. napus, and detected 1280 putative selective signals. Within the selected region, a large number of genes related to P uptake, transport, and utilization were detected, such as purple acid phosphatase (PAP) family genes and phosphate transporter (PHT) family genes. These findings provide novel insights into the molecular targets for breeding P efficiency varieties in B. napus. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01399-9.

The therapeutic effect of phellopterin on colitis-associated cancer and its effects on TLR4/NF-κB pathway and macrophage M2 polarization.

This study was conducted to investigate the effect and mechanism of phellopterin on colitis-associated cancer (CAC). For this purpose, CAC mouse model was established by AOM/DSS method, and the therapeutic effects of phellopterin in different doses were compared. The levels of interleukin-6 (IL-6), IL-1ß, IL-10, and tumor necrosis factor-α (TNF-α) in peripheral blood were detected by ELISA. The changes in T lymphocyte subsets and the expressions of CD163, CD206, Arg-1, and Ym-1 in colonic macrophages were detected. The expression of TLR4 and NF-κB p65 in the colon was tested by Western blot. Results showed that as against the Model group, the body weight and survival rate of mice treated with phellopterin were increased, the disease activity index, hematochezia rate, and tumor formation rate were decreased, the colon length was increased, and the number of tumors and spleen index were decreased (P<0.05). As against the Model group, the proportion of CD4+ and CD8+ in the peripheral blood of phellopterin intervention mice increased, the content of IL-6, IL-1ß, and TNF-α decreased, and the content of IL-10 increased. The expression of CD163, CD206, Arg-1, and Ym-1 in colonic macrophages was decreased. The protein expressions of TLR4 and NF-κB p65 in colon tissue were decreased (P<0.05). The effect of phellopterin intervention on CAC was dose-dependent. In conclusion, phellopterin can improve the symptoms and inflammatory response of CAC and inhibit the occurrence of colon cancer (CC) by inhibiting M2 polarization of macrophages and activation of the TLR4/NF-κB pathway.

SNHG14 facilitates cell proliferation in colorectal cancer through targeting KRAS via Hippo-YAP signaling.

Accumulating evidence indicates the significant role of lncRNAs in multiple biological processes and cancer progression. However, most lncRNAs in CRC remain to be excavated. In this study, we investigated SNHG14 in CRC. SNHG14 which was generally under-expressed in normal colon specimens revealed by UCSC was uncovered as markedly highly expressed in CRC cell lines. Besides, SNHG14 was a contributor to CRC cell proliferation. Additionally, we demonstrated that SNHG14 facilitated CRC cell proliferation in a KRAS-dependent manner. Moreover, the mechanistic investigations indicated that SNHG14 interacted with YAP and therefore inactivated the Hippo pathway, so as to enhance YAP-targeted KRAS expression in CRC. Furthermore, SNHG14 was explained as transcriptionally activated by FOS, a previously identified common effector molecule of KRAS and YAP. All in all, our findings elucidated a feedback loop of SNHG14/YAP/KRAS/FOS in facilitating CRC tumorigenesis, which may help develop novel effective targets for CRC patients.

Insights into inactivation and response mechanisms of sublethal Listeria monocytogenes treated by cold plasma with joint transcriptomics and metabolomics.

AIM: The aim of the current study is to elucidate the inactivation and molecular response pattern of sublethal Listeria monocytogenes to cold plasma-mediated two-pronged oxidative microenvironments from a high-throughput multi-omics perspective. METHODS AND RESULTS: First joint transcriptomics and metabolomics analyses revealed that significantly expressed genes and metabolites were mainly involved in enhanced transmembrane transport and Fe2+/Cu+ efflux, amino acid limitation, cytoplasmic pH homeostasis, reconfiguration of central carbon metabolism flux, and energy conservation strategy, which triggered the surge of intracellular endogenous oxidative stress and finally mediated bacterial ferroptosis and pathogenicity attenuation. Typical antioxidant systems such as the TrxR-Trx system and common antioxidant genes (e.g. sodA, katA, ahpC, trxA, spxA) were inhibited, and the more prominent antioxidant pathways include methionine metabolism, the pentose phosphate pathway, and glutathione metabolism, as well as the DNA repair systems. CONCLUSIONS: Therefore, our work confirmed from the transcriptional and metabolic as well as physiological levels that cold plasma-mediated intracellular oxidative stress induced big perturbations in pathways as a driving force for the inactivation and pathogenicity attenuation of L. monocytogenes. SIGNIFICANCE AND IMPACT OF STUDY: This study provided new insights for the construction of multi-dimensional mechanisms of bacterial inactivation and pathogenicity attenuation for the precise control and inactivation of microorganisms in plasma non-thermal processing.